Contraceptive eligibility for women at high risk of HIV: guidance statement: recommendations on contraceptive methods used by women at high risk of HIV

Contraceptive eligibility for women at high risk of HIV Guidance statement Recommendations on contraceptive methods used by women at high risk of HIV

Contraceptive eligibility for women at high risk of HIV Guidance statement Recommendations on contraceptive methods used by women at high risk of HIV Contraceptive eligibility for women at high risk of HIV. Guidance statement: recommendations on contraceptive methods used by women at high risk of HIV ISBN 978-92-4-155057-4 © World Health Organization 2019 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. Contraceptive eligibility for women at high risk of HIV. Guidance statement: recommendations on contraceptive methods used by women at high risk of HIV. Geneva: World Health Organization; 2019. Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris. Sales, rights and licensing. To purchase WHO publications, see http://apps.who.int/bookorders. To submit requests for commercial use and queries on rights and licensing, see http://www.who.int/about/licensing. Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. The views expressed in this publication are those alone of the named authors and of the collective views of an international group of experts and do not necessarily represent the decisions or the policies of WHO. Printed in Switzerland Contraceptive eligibility for women at high risk of HIV: guidance statement | iii 1 2 3 4 5 ACKNOWLEDGEMENTS V ABBREVIATIONS VI EXECUTIVE SUMMARY VII BACKGROUND 1 METHODS OF GUIDELINE REVIEW AND DEVELOPMENT 2 2.1 Guideline Development Group 2 2.2 Guideline development process 2 2.3 Evidence Retrieval 3 2.4 Evidence Synthesis 4 2.5 Formulation of recommendations 4 SUMMARY OF THE EVIDENCE 4 3.1 Progestogen-only injectables 5 3.2 Progestogen-only implants 5 3.3 Progestogen-only pills 5 3.4 Intrauterine devices 5 3.5 Combined hormonal contraceptives 5 3.6 Additional evidence considered by the GDG 5 3.6.1 Biological data 5 3.6.2 Values and preferences of contraceptive users 6 RECOMMENDATIONS 6 4.1 Recommendations for contraceptive use among women at high risk of HIV infection 6 4.2 Rationale 7 IMPLICATIONS FOR POLICY-MAKERS, PROGRAMME MANAGERS AND HEALTH-CARE PROVIDERS 8 5.1 A woman’s risk of HIV should not restrict her contraceptive choice 8 5.2 Efforts to expand access to contraceptive options must continue 8 5.3 A renewed emphasis on HIV and STI prevention services is urgently needed 9 CONTENTS | Contraceptive eligibility for women at high risk of HIV: guidance statementiv CONTENTS (continued) KNOWLEDGE GAPS AND AREAS FOR RESEARCH 9 6.1 Contraceptive methods and HIV acquisition 9 6.2 HIV prevention 9 6.3 Community involvement 10 6.4 Increased funding for high-quality, policy-relevant research 10 DISSEMINATION OF THIS GUIDANCE STATEMENT 10 REFERENCES 11 ANNEX 1. GUIDELINE DEVELOPMENT GROUP AND EVIDENCE SECRETARIAT 13 ANNEX 2. DECLARATIONS OF CONFLICTS OF INTEREST 15 ANNEX 3. GRADE EVIDENCE PROFILES 17 ANNEX 4. EVIDENCE-TO-DECISION TABLE FOR HORMONAL CONTRACEPTIVE METHODS AND INTRAUTERINE DEVICES (IUDS) 21 ANNEX 5: SYSTEMATIC REVIEWS 23 6 7 Contraceptive eligibility for women at high risk of HIV: guidance statement | v ACKNOWLEDGEMENTS The World Health Organization (WHO) would like to thank the members of the Guideline Development Group and the Evidence Secretariat (Annex 1) for their contributions throughout the development of these important recommendations for women at high risk of HIV. WHO is very grateful for the suggestions provided by colleagues who peer reviewed the draft statement as members of the External Review Group. The development of this technical statement was financially supported by the Bill & Melinda Gates Foundation, the Netherlands Ministry of Foreign Affairs, the United States Agency for International Development, and the United States National Institutes of Health. | Contraceptive eligibility for women at high risk of HIV: guidance statementvi ABBREVIATIONS CIC combined injectable contraceptive COC combined oral contraceptive CRE WHO Office of Compliance, Risk Management and Ethics Cu-IUD copper-bearing intrauterine device DMPA depot medroxyprogesterone acetate DMPA-IM intramuscular depot medroxyprogesterone acetate DMPA-SC subcutaneous depot medroxyprogesterone acetate ECHO Evidence for Contraceptive Options and HIV Outcomes (Study) ETG etonogestrel FDA United States Food and Drug Administration GDG Guideline Development Group GRADE Grading of Recommendations Assessment, Development and Evaluation HR hazard ratio IRR incidence rate ratio IUD intrauterine device LNG levonorgestrel LNG-IUD levonorgestrel-releasing intrauterine device MEC Medical eligibility criteria for contraceptive use NET-EN norethisterone enanthate OTC over the counter POP progestogen-only pill PrEP pre-exposure prophylaxis (for HIV) RCT randomized controlled trial STI sexually transmitted infection WHO World Health Organization Contraceptive eligibility for women at high risk of HIV: guidance statement | vii EXECUTIVE SUMMARY The World Health Organization (WHO) convened a Guideline Development Group (GDG) meeting from 29 to 31 July 2019 to review global guidance on contraceptive eligibility for women at high risk of HIV acquisition to and determine whether revisions to the fifth edition of the Medical eligibility criteria for contraceptive use (MEC) were needed. The issue was deemed critical, particularly for sub-Saharan Africa, given the high lifetime risk of acquiring HIV alongside the importance of hormonal contraception in offering women and adolescent girls’ choice and in reducing their risk of unintended pregnancy, a common threat to the health, well-being and lives of women and adolescent girls. The GDG consisted of 28 participants from 19 countries, including experts in family planning and HIV, representatives from affected populations, clinicians, epidemiologists, researchers, programme managers, policy-makers and guideline methodologists. The GDG considered the following factors when formulating recommendations for each contraceptive method: ■ quality of the evidence (i.e. GRADE profile)1 ■ values and preferences of contraceptive users ■ balance of benefits and harms ■ priority of the problem ■ equity and human rights ■ feasibility. In formulating these recommendations, the GDG kept at the centre of their deliberations the individuals most affected by the recommendations – that is, those women wanting to prevent pregnancy who are at a high risk of HIV acquisition. Through consensus, the GDG agreed to the following new recommendations. These revisions mean that women at a high risk of HIV can use all methods of contraception without restriction. ■ Women at a high risk of HIV infection are eligible to use all progestogen-only contraceptive methods without restriction (MEC Category 1), including progestogen-only pill (POPs), intramuscular and subcutaneous depot medroxyprogesterone acetate (DMPA-IM and DMPA-SC), norethisterone enanthate (NET-EN), levonorgestrel (LNG) implants and etonogestrel (ETG) implants. ■ Women at a high risk of HIV infection are eligible to use copper-bearing intrauterine devices (Cu-IUDs) and LNG- IUDs without restriction (MEC Category 1). In considering the 1 GRADE = Grading of Recommendations Assessment, Development and Evaluation (for further information, see: http://www.gradeworkinggroup.org). use of IUDs, many women at a high risk of HIV are also at risk of other sexually transmitted infections (STIs); for these women, providers should refer to the MEC recommendation on women at an increased risk of STIs, and the Selected practice recommendations for contraceptive use: third edition on STI screening before IUD insertion. ■ Women at a high risk of HIV infection are eligible to use all combined hormonal contraceptive methods without restriction (MEC Category 1), including combined oral contraceptives (COCs), combined injectable contraceptives (CICs), combined contraceptive patches and combined vaginal rings. These recommendations were strongly informed by new epidemiological evidence, particularly from one high-quality randomized controlled trial (the ECHO trial), which did not demonstrate a statistically significant difference in HIV acquisition among women using the three contraceptive methods studied: DMPA-IM, Cu-IUDs and LNG implants. This high-quality evidence superseded the previously available observational evidence of low and low-to-moderate quality. For COCs and NET-EN injectables, evidence of low and low-to- moderate quality from observational studies indicated no increased risk of HIV infection. While no direct evidence was available for DMPA-SC, LNG-IUDs or ETG implants, there was no biological or clinical reason to believe that a lower hormonal dose, different delivery mechanism or different progestogen would modify HIV risk. A consideration of women’s values, preferences, views and concerns regarding contraceptive methods provided support for optimizing informed contraceptive choice and the availability of a wide range of contraceptive options. There are several key messages from this guidance for policy- makers, programme managers and health-care providers. ■ A woman’s risk of HIV does not restrict her contraceptive choice. ■ Efforts to expand contraceptive method options and ensure full and equitable access to family planning services must continue. ■ A renewed emphasis on HIV/STI testing and prevention services is urgently needed, including the integration of family planning and HIV/STI services as appropriate, along with sexual and reproductive health packages. | Contraceptive eligibility for women at high risk of HIV: guidance statementviii PROGESTOGEN-ONLY CONTRACEPTIVES Progestogen-only contraceptives (POCs) do not protect against sexually transmitted infections (STIs), including HIV. If there is a risk of STI/HIV, the correct and consistent use of condoms is recommended. When used correctly and consistently, condoms offer one of the most effective methods of protection against STIs, including HIV. Female condoms are effective and safe, but are not used as widely as male condoms by national programmes. Condition MEC category Clarification/evidence POP DMPA/ NET-EN LNG/ ETG High risk of HIV 1 1 1 EVIDENCE: High-quality evidence from one randomized controlled trial observed no statistically significant differences in HIV acquisition between: DMPA-IM versus Cu-IUD, DMPA-IM versus LNG implant, and Cu-IUD versus LNG implant. Of the low-to-moderate-quality evidence from 14 observational studies, some studies sug- gested a possible increased risk of HIV with progestogen-only injectable use, which was most likely due to unmeasured confounding. Low-quality evidence from 3 obser- vational studies did not suggest an increased HIV risk for implant users. No studies of sufficient quality were identified for POPs. Cu-IUD: copper-bearing intrauterine device; DMPA: depot medroxyprogesterone acetate (injectable); IM: intramuscular; LNG/ETG: levonorgestrel and etonogestrel (implants); MEC: Medical eligibility criteria for contraceptive use; NET-EN: norethisterone enanthate (injectable); POP: progestogen-only pill INTRAUTERINE DEVICES Intrauterine devices (IUDs) do not protect against sexually transmitted infections (STIs), including HIV. If there is a risk of STI/HIV, the correct and consistent use of condoms is recommended. When used correctly and consistently, condoms offer one of the most effective methods of protec- tion against STIs, including HIV. Female condoms are effective and safe, but are not used as widely as male condoms by national programmes. Condition MEC category Clarification/evidence Cu-IUD LNG-IUD (20 μg/24 hours) High risk of HIV Initiation Continuation Initiation Continuation CLARIFICATION: Many women at a high risk of HIV are also at risk of other STIs. For these women, refer to the recommendation in the Medical eligibility criteria for contra- ceptive use on women at an increased risk of STIs, and the Selected practice recommendations for contraceptive use on STI screening before IUD insertion. EVIDENCE: High-quality evidence from one randomized controlled trial, along with low-quality evidence from two observational studies, suggested no increased risk of HIV acquisition with Cu-IUD use. No studies were identified for LNG-IUDs. 1 1 1 1 Cu-IUD: copper-bearing intrauterine device; LNG-IUD: levonorgestrel-releasing IUD; MEC: Medical eligibility criteria for contraceptive use COMBINED HORMONAL CONTRACEPTIVES Combined hormonal contraceptives (CHCs) do not protect against sexually transmitted infections (STIs), including HIV. If there is a risk of STI/ HIV, the correct and consistent use of condoms is recommended. When used correctly and consistently, condoms offer one of the most effective methods of protection against STIs, including HIV. Female condoms are effective and safe, but are not used as widely as male condoms by national programmes. Condition MEC category Clarification/evidence COC P CVR CIC High risk of HIV 1 1 1 1 EVIDENCE: Low-to-moderate-quality evidence from 11 observational studies suggested no association between COC use (it was assumed that studies that did not specify oral contraceptive type examined mostly, if not exclusively, COC use) and HIV acquisition. No studies of P, CVR or CIC were identified. COC: combined oral contraceptive; CIC: combined injectable contraceptive; CVR: combined contraceptive vaginal ring; MEC: Medical eligibility criteria for contraceptive use; P: combined contraceptive patch Contraceptive eligibility for women at high risk of HIV: guidance statement | 1 Access to sexual and reproductive health services and information, including a comprehensive range of contraceptive methods, is fundamental to the rights and well-being of women and adolescent girls (1–4). There is a wide range of hormonal and non-hormonal modern contraceptive methods providing substantial individual and public health benefits. A core part of the work of the World Health Organization (WHO) is the development and maintenance of up-to-date, evidence-based guidance on contraceptive safety for individuals with particular medical conditions or medically relevant characteristics (5). The Medical eligibility criteria for contraceptive use (the MEC), fifth edition, offers national policy-makers and family planning programmes a comprehensive set of recommendations on the medical safety of contraceptive methods, allowing for the informed development of national policies, protocols and programmes (5). Global guidance about medical safety and eligibility facilitates the removal of unnecessary medical barriers to contraception. For over 20 years, the MEC has been used by countries to maximize safety and improve the quality of contraceptive care offered. Guidance about safety is kept up to date through continuous monitoring and reviews of published literature. In 2015, WHO released the fifth edition of the MEC (5). This edition contains more than 2000 recommendations for 25 different contraceptive methods, within the context of more than 80 medical conditions or medically relevant personal characteristics. Depending on the individual, more than one condition may need to be considered when making an informed contraceptive choice (5). The recommendations in the MEC are based on several considerations, including whether the use of a contraceptive method worsens the medical condition or creates additional health risks, and whether the condition makes the contraceptive method less effective (5). The MEC is part of a set of tools aiming to improve contraceptive coverage and care throughout the world. The MEC informs decisions about who might use a particular contraceptive method, through information and guidance about the safety and appropriateness of contraceptive care. The Selected practice recommendations for contraceptive use (the SPR) provides guidance on how to safely and effectively use various contraceptive methods (6). WHO produces a range of tools to support the use and implementation of contraceptive guidance, such as the MEC wheel and the Global handbook for providers (7, 8). Since 1996, the MEC has applied a four-category scale to indicate medical eligibility for particular contraceptive methods in the presence of particular conditions or individual characteristics (e.g. at high risk of HIV). For each condition or characteristic, contraceptive methods are placed into one of four numbered categories: 1. A condition for which there is no restriction for the use of contraceptive method. 2. A condition where the advantages of using the method generally outweigh the theoretical or proven risks. 3. A condition where the theoretical or proven risks usually outweigh the advantages of using the method. 4. A condition which represents an unacceptable health risk if the contraceptive method is used. The interpretation and application of the categories in practice are shown in Table 1. In the past, there has been mixed evidence about whether hormonal contraceptive methods – particularly depot medroxyprogesterone acetate (DMPA) – are associated with an increased risk of HIV acquisition. The available evidence consisted of theoretical biological data and observational studies with important limitations. In 2016, the independent TABLE 1. INTERPRETATION AND APPLICATION OF THE MEDICAL ELIGIBILITY CRITERIA (MEC) CATEGORIES Category With good resources for clinical judgement With limited resources for clinical judgement 1 Use the method in any circumstances Yes, use the method 2 Generally use the method 3 Use of the method not usually recommended unless more appropriate methods are not available or not acceptable No, do not use the method 4 Method not to be used BACKGROUND1 | Contraceptive eligibility for women at high risk of HIV: guidance statement2 2.1 Guideline Development Group The development of this guidance statement was undertaken by the independent Guideline Development Group (GDG) and an additional panel of external reviewers. The GDG consisted of 28 participants from 19 countries, including experts in family planning and HIV, representatives from affected populations, clinicians, epidemiologists, researchers, programme managers, policy- makers and guideline methodologists (see Annex 1). Following WHO guidance, months prior to the July 2019 meeting of the GDG, the name and brief biography of each proposed GDG member was published at the WHO website (https://www.who. int/reproductivehealth/publications/contraceptives-methods-hiv). The public was able to view and provide input on any perceived or real conflicts of interest of the proposed members. WHO responded to all comments and accordingly adjusted the final composition of the GDG. Prior to the GDG meeting, the WHO Secretariat and the GDG reviewed the members’ declarations of interests (Annex 2) and found no conflicts of interest sufficient to preclude anyone from participating in the deliberations or the development of the recommendations. The members of the GDG were also asked to declare any new conflicts of interest at the start of the meeting. None were declared. 2 For further information, see: http://www.gradeworkinggroup.org 2.2 Guideline development process This guidance statement was prepared according to the standards and requirements specified in the WHO handbook for guideline development (11). This process is used to ensure that WHO guidelines are of the highest quality and follow a transparent, systematic process. Key steps of the guideline process include determining the critical questions and outcomes, retrieving the evidence, synthesizing and grading the evidence, presenting it using a structured approach, and formulating recommendations. WHO’s Family Planning Guideline Steering Group determined the critical questions and outcomes to be considered by the GDG. Distinct types of evidence were identified as essential to review. These included the health evidence (randomized trials and observational epidemiological data), the evidence on biological plausibility and the data on the values and preferences of contraceptive users. Applying the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach,2 multiple factors are considered when formulating recommendations (12). These include the quality of the epidemiological evidence (found in the GRADE evidence profiles, which are prepared based on up-to-date Guideline Development Group (GDG) for the MEC reviewed the accumulating evidence regarding women at high risk of acquiring HIV (9). The GDG concluded that there remained uncertainty about whether the increased risk of HIV acquisition seen in some observational studies was a real effect of the contraceptive method used or whether it was a statistical artefact resulting from key limitations of observational studies (residual confounding in particular) (9). There also continued to be uncertainty about the clinical relevance of the biological data. In addition, there was concern that previous attempts to inform women of the uncertainty about both the epidemiological and biological data (through the use of a MEC clarification, indicated by an asterisk [*]) had not been effective. Given these concerns, the GDG concluded that MEC guidance should be changed. Thus, in 2017, the recommendation for progestogen- only injectable use among women at high risk of HIV infection was changed from MEC Category 1* (no restrictions to use, with a clarification) to MEC Category 2 (the benefits of use outweigh the risks), with an accompanying clarification (9). This new classification indicated that progestogen-only injectables could be used by women at high risk of HIV, because the advantages of these methods generally outweighed the possible disadvantages, and it highlighted that, when choosing these methods, there might need to be extra consideration of possible HIV acquisition, and counselling. As part of the 2017 revision, WHO reaffirmed its commitment to monitoring and assessing any new evidence relevant to contraceptive safety. New information, including results from a large, multinational randomized controlled trial (RCT) (10), led WHO to convene another GDG meeting in July 2019 to review all the available evidence and assess whether the MEC guidance needed revision. METHODS OF GUIDELINE REVIEW AND DEVELOPMENT2 Contraceptive eligibility for women at high risk of HIV: guidance statement | 3 systematic reviews); the values and preferences of contraceptive users; the balance of benefit and harms; the priority of the problem; equity and human rights; acceptability; and feasibility. The human rights principles and standards described in WHO’s guidance, Ensuring human rights in the provision of contraceptive information and services, were incorporated into deliberations (1). Owing to the focus on contraceptive safety, opportunity costs were not formally assessed during the formulation of the recommendations, since costs may vary widely throughout different regions (13). The GRADE evidence-to-decision framework (a tool encompassing quality of evidence, balance of benefits versus harms, values and preferences, priority of the problem, equity and human rights, feasibility) was used to ensure that recommendations were based on the consideration of all standards (11). 2.3 Evidence Retrieval Existing WHO recommendations on the use of specific contraceptive methods by women at high risk of HIV were reviewed in accordance with procedures outlined by the WHO Guidelines Review Committee and the GRADE approach to evidence review (11, 12). Three systematic reviews were conducted in preparation for the GDG meeting: two reviews pertained to the epidemiological evidence and the third review synthesized qualitative or quantitative studies on users’ values, preferences, views and concerns regarding contraceptive methods. The two systematic reviews of epidemiological evidence conducted for the GDG meeting were: 1. An updated systematic review on hormonal contraception and risk of HIV acquisition was conducted to include new studies published since 2016, when the last systematic review was undertaken (14). The review question was: ■ Among women at risk of HIV, does use of a hormonal contraceptive method compared with non-use of a hormonal contraceptive method (or use of another specific hormonal contraceptive method) increase risk of HIV acquisition? 2. A systematic review on copper-bearing intrauterine device (Cu-IUD) use and risk of HIV acquisition was also conducted. The review questions were: ■ Among women at risk of HIV, does use of a Cu-IUD compared with use of another non-hormonal contraceptive method or no contraceptive method increase risk of HIV acquisition? ■ Among women at risk of HIV, does use of a Cu-IUD compared with use of a specific hormonal contraceptive method increase risk of HIV acquisition? The selection criteria for the systematic reviews are listed in Table 2. The same study designs, population, comparators and outcomes were considered for all the contraceptive methods reviewed. TABLE 2. SELECTION CRITERIA FOR THE SYSTEMATIC REVIEWS Study design Longitudinal studies (randomized controlled trials and observational studies or meta-analyses containing data not captured in bibliographic database searches) Population Women of reproductive age at risk of HIV infection (women who were not living with HIV at baseline) Intervention Use of a specific contraceptive method: ■ hormonal contraception (injectables, oral contraceptives, implants, patches, rings or levonorgestrel-releasing intrauterine devices) ■ copper-bearing intrauterine devices (Cu-IUDs) Comparator One of two comparison groups: 1. non-use of a hormonal contraceptive method (either no contraceptive use or use of a non-hormonal method such as condoms or other barrier method, withdrawal, Cu-IUD or tubal ligation/vasectomy) 2. use of another specific method of hormonal contraception Outcome Incident, laboratory-confirmed HIV infection in women The two systematic reviews were conducted according to the preferred reporting items for systematic reviews and meta- analyses (PRISMA) (15). The PubMed and Embase databases were searched for studies published in any language in the peer-reviewed literature up to 26 June 2019. For individual studies, the risk of bias was assessed using a quality framework described in the previous review (14). Studies were classified into three levels: 1. “Unlikely to inform the primary question”: studies that had (a) no adjustment for any measure of condom use or (b) unclear measurement of exposure to contraception. 2. “Informative but with important limitations”: studies that had none of the flaws described above, but that still had the potential for unmeasured or residual confounding. 3. “Informative with few limitations”: studies that had none of the above flaws – likely to be a randomized controlled trial (RCT) that was assessed as having a low risk of bias on standard criteria for evaluating RCTs. The focus of the systematic reviews was on information from studies that were considered “informative but with important limitations” or “informative with few limitations.” to fall into levels 2 and 3. The values and preferences of contraceptive users were incorporated in multiple ways. First, an updated systematic review of qualitative or quantitative studies on users’ values, preferences, views and concerns regarding the contraceptive methods considered under the Medical eligibility criteria for contraceptive use (MEC) guidelines was conducted (16). This review covered studies from any country published in the peer-reviewed literature between January 2005 and December 2017. Just prior to the GDG meeting in July 2019, this review was informally updated for studies in either the peer-reviewed or grey literature that specifically looked at the values and preferences of contraceptive users relating to the issue of hormonal contraception and HIV acquisition. Second, because | Contraceptive eligibility for women at high risk of HIV: guidance statement4 the updated systematic review did not identify any information specific to key populations at risk of HIV, consultative engagements were conducted in May through July of 2019, including a global online survey of sex workers and participatory focus group discussions with female sex workers in Zimbabwe (through the Sisters with a Voice programme). Third, stakeholders representing specific affected populations, including women living with HIV, and young women, contributed their perspectives through a presentation and discussion of critical perspectives at the GDG meeting. An update about the biological data on the theoretical effect that contraception may have on HIV acquisition was prepared, reviewed and discussed at the GDG meeting, including consideration of the theoretical plausibility of individual methods of hormonal contraception having an influence on HIV acquisition. 2.4 Evidence Synthesis Epidemiological data were synthesized and evaluated according to the GRADE approach to evidence review (12). Based on this, randomized trials begin with a grade for strength of evidence of “high”, and observational studies start with a grade of “low”. The risk of bias was assessed for the summarized data using standard GRADE methods (17). Factors that could lower the evidence grade were limitations in the evidence (bias), inconsistency between studies, imprecision of estimates, indirectness of evidence, and publication bias (17–22). Randomized trials were assessed for bias by systematically evaluating for inadequate randomization/ allocation concealment; inadequate blinding of treatments; attrition and failure to use intention-to-treat analyses; selective outcome reporting; and crossover/contamination (17). Observational studies were assessed for bias by examining whether there was failure to develop and apply appropriate eligibility criteria, flawed measurement of exposures or outcomes, failure to adequately address confounding, or incomplete follow-up (17). Factors that could increase the evidence grade of observational studies included the presence of a dose-response relationship, a large magnitude of observed associations, and adjustment for plausible confounders affecting observed associations (22). 2.5 Formulation of recommendations Findings from the systematic reviews and associated GRADE evidence profiles (Annex 3) were presented at the GDG meeting. A presentation on the biological plausibility of hormonal contraception modifying the risk of HIV acquisition, and several presentations on contraceptive users’ values and preferences, were also given. These inputs were used to develop an evidence-to-decision framework (Annex 4), which served as the basis for the GDG’s deliberations during the meeting (12). All recommendations were arrived at by consensus. After the GDG’s recommendations were made, a small writing group prepared a draft guidance statement summarizing the decision and associated rationale. The draft was reviewed by the entire GDG and the external review group (see Annex 1). Comments received from the GDG and the external review group were considered and addressed by the writing group. The final version of this guidance statement was approved by the WHO Guidelines Review Committee on 22 August 2019. SUMMARY OF THE EVIDENCE3 The Evidence for Contraceptive Options and HIV Outcomes (ECHO) Study3 was the primary source of new evidence since the WHO last reviewed recommendations on contraception for women at high risk of HIV (9). The ECHO Study was a large randomized controlled trial (RCT) conducted in Eswatini, Kenya, South Africa and Zambia specifically designed to compare HIV incidence among users of three contraceptive methods: intramuscular depot medroxyprogesterone acetate (DMPA-IM), levonorgestrel (LNG) implants and copper-bearing intrauterine 3 For further information, see: http://echo-consortium.com devices (Cu-IUDs) (10). The trial randomized 7829 HIV- seronegative women, aged between 16 and 35 years, who desired effective contraception and consented to be randomized to one of the three contraceptive methods. There was no group of non-users of contraception in the ECHO trial because all of the women enrolled desired effective contraception. Women returned every three months for HIV testing, contraceptive counselling, safety monitoring, behavioural assessment and a comprehensive package of HIV Contraceptive eligibility for women at high risk of HIV: guidance statement | 5 prevention services; for up to 18 months. The main (primary) comparisons used a modified intention-to-treat analysis. In addition, pre-planned (secondary) analyses were conducted, restricted to continuous use of the assigned contraceptive method and adjusted for a number of important confounders, including vaginal sex without a condom, a new sexual partner in the previous three months, and more than one sexual partner. Statistical significance in the ECHO trial was taken to be a P-value less than 0.04 for the primary comparisons. No statistically significant associations were found for any of the primary comparisons between the three contraceptive methods (Annex 3). The quality of the evidence from this RCT was rated as high, due to its large size, strong randomization and allocation procedures, high follow-up rates, high continuation of the allocated contraceptive method, objective measurement of HIV incidence and comprehensive analysis of the results. Other evidence on hormonal contraception and HIV acquisition published since the 2016 review (14) was included in the evaluation of the body of evidence, along with a systematic review on Cu-IUDs and risk of HIV acquisition (Annex 3). For hormonal contraception, one new observational study and updated estimates from a previously included study were identified (23, 24). Adding this evidence to the previous 14 observational studies (14) did not change the conclusions of the previous review. Thus, the body of observational evidence suggested some concern about an increased risk of HIV acquisition with DMPA-IM use, but was generally reassuring for other methods of hormonal contraception. For intrauterine devices (IUDs), two observational studies did not suggest an increased risk of HIV acquisition with Cu-IUD use (23, 25). The quality of evidence from these observational studies was rated as low and low-to-moderate. 3.1 Progestogen-only injectables One RCT (the ECHO trial) observed no statistically significant differences in HIV acquisition when comparing DMPA-IM versus Cu-IUD, and DMPA-IM versus LNG implant (10). The quality of the evidence from this RCT was rated as high. Evidence from 14 observational studies of DMPA-IM, norethisterone enanthate (NET-EN) or unspecified progestogen- only injectables considered to be “informative but with important limitations” was assessed (14, 23, 24). Additional data from one new observational study and updated estimates from a previously included study did not change the conclusions of the previous review of observational evidence (14). The quality of the evidence from the observational studies was rated as low and low-to-moderate due to limitations that included unmeasured confounding. 3.2 Progestogen-only implants Three observational studies considered to be “informative but with important limitations” assessed implants. One had been included in the previous review (26), one provided an updated point estimate to that used for the previous review (24) and one provided an entirely new estimate of risk (23). Two of the studies assessed LNG implants (24, 26) and the third assessed women using either LNG or etonogestrel implants (23). None of the three studies suggested an increased risk of HIV acquisition with implant use, consistent with the conclusion of the previous review (14). The quality of the evidence from these studies was rated as low. 3.3 Progestogen-only pills No studies considered “informative but with important limitations” or “informative with few limitations” were identified for progestogen-only pills. 3.4 Intrauterine devices One RCT (the ECHO trial) observed no statistically significant differences in HIV acquisition between DMPA-IM and Cu-IUD, or Cu-IUD and LNG implants (10). The quality of the evidence from this RCT was rated as high. Two observational studies considered “informative but with important limitations” did not observe an association with HIV acquisition when comparing Cu-IUD use with tubal ligation or no contraceptive method use, DMPA-IM, NET-EN or implants (23, 25). The quality of this observational evidence was rated as low. No evidence was identified for LNG-IUDs. 3.5 Combined hormonal contraceptives Eleven observational studies deemed “informative but with important limitations” assessed the use of combined oral contraceptives (COC). (It was assumed that studies that did not specify the oral contraceptive type examined mostly, if not exclusively, examined COC use.) All of these studies were included in the previous review, while an updated estimate came from one newly available study (14, 24). Overall, these studies suggested no association between COC use and HIV acquisition. The quality of the evidence was rated as low-to-moderate. No evidence was identified for the combined contraceptive patch, ring or injectable. 3.6 Additional evidence considered by the GDG 3.6.1 BIOLOGICAL DATA Biological data pertaining to the plausibility of an effect of individual methods of hormonal contraception on HIV acquisition were reviewed. Several biological mechanisms by which individual methods of hormonal contraception could theoretically modify the risk of HIV acquisition have been postulated, but | Contraceptive eligibility for women at high risk of HIV: guidance statement6 sparse and contradictory data make it unclear which, if any, of these biological mechanisms are clinically relevant. Potential mechanisms include alteration of the systemic and local immune response and changes in the genital tract environment. It was noted that different forms of hormonal contraception may change these factors in different ways. Combined contraceptives containing both ethinylestradiol and a progestogen may have a different effect than progestogen-only methods. Additionally, various progestogen-only methods, such as DMPA and NET-EN injectables, may change immune function variably. It remains uncertain to what extent data from animal and laboratory studies, including in relation to progestogen type and dosing, can be applied to clinical outcomes in humans. 3.6.2 VALUES AND PREFERENCES OF CONTRACEPTIVE USERS The systematic review identified 375 studies from all regions of the world (27). Across studies, women’s values and preferences centred on themes of choice and available options, ease of use, side-effect profiles and contraceptive efficacy. Contextual factors, such as the contraceptive methods available, counselling from providers, and the opinions of social networks, influenced decision-making. From the grey literature, two additional studies were identified that were relevant to hormonal contraception and HIV specifically (28, 29). Both found that messages from the 4 “Free” means the freedom and ability to make a voluntary decision about contraceptive use without barriers or coercion; informed means complete, correct and clear information has been given about all the options, plus details about the chosen method 2017 WHO guidance were difficult for providers to explain fully and may not be completely understood by clients. The online survey of sex workers from multiple global regions found that individual preferences around contraception varied widely and could change over time; ongoing partnership and dialogue with sex workers is essential to understanding evolving priorities. In participatory focus groups, Zimbabwean sex workers said their contraceptive choices were shaped by a wide range of factors, including cost, accessibility, the way sex workers are treated at clinics, the influence of male partners, and contraceptive side-effects. Sex without a condom was common, and there was a need to strengthen access to HIV/STI prevention and contraceptive services. The community stakeholder presentation emphasized that, for some women, any level of increased HIV risk would be too high. It also highlighted that the ECHO trial was not set up to assess the difference in the risk of HIV acquisition between contraceptive users and non-users. Community stakeholders also emphasized that there was a lack of true contraceptive choice for many women and girls, saying the guidance should emphasize full, free and informed contraceptive choice,4 the procurement of a range of contraceptive methods, and investment in integrated contraception and HIV services. RECOMMENDATIONS4 4.1 Recommendations for contraceptive use among women at high risk of HIV infection All hormonal contraceptive methods and intrauterine devices (IUDs) now fall into Category 1 of the Medical eligibility criteria for contraceptive use (MEC) (5) for women at high risk of HIV. Thus, women at high risk of HIV can use all methods of contraception without restriction. ■ Women at high a risk of HIV infection are eligible to use all progestogen-only contraceptive methods without restriction (MEC Category 1), including progestogen-only pills (POPs), intramuscular depot medroxyprogesterone acetate (DMPA-IM), subcutaneous DMPA (DMPA-SC), norethisterone enanthate (NET-EN) injectables, levonorgestrel (LNG) implants, and etonogestrel implants. ■ Women at a high risk of HIV infection are eligible to use copper-bearing IUDs (Cu-IUDs) and LNG implants without restriction (MEC Category 1). In considering the use of IUDs, many women at a high risk of HIV are also at risk of other sexually transmitted infections (STIs); for these women, providers should refer to the MEC recommendation on women at increased risk of STIs and the Selected practice recommendations for contraceptive use on STI screening before IUD insertion (5, 6). ■ Women at a high risk of HIV infection are eligible to use all combined hormonal contraceptive methods without restriction (MEC Category 1), including combined oral Contraceptive eligibility for women at high risk of HIV: guidance statement | 7 contraceptives (COCs), combined injectable contraceptives (CICs), combined contraceptive patches (P) and combined vaginal rings (CVR). 4.2 Rationale The Guideline Development Group (GDG) reviewed, and discussed extensively, the new epidemiological and biological evidence, as well as related information about values and preferences, equity and human rights, and feasibility. After deliberating on all of the available evidence, the GDG recommended that the MEC category for DMPA and Cu-IUD should be changed to MEC Category 1. The GDG noted that there was no evidence regarding DMPA-SC and LNG-IUD, and only limited new information regarding NET-EN. Until more information becomes available, the GDG judged it was appropriate to follow the same approach as previously used, i.e. grouping all progestogen-only injectables together (DMPA- IM, DMPA-SC and NET-EN) as MEC Category 1, and to assign the same MEC category to the LNG-IUD as to the Cu-IUD (MEC Category 1). One key portion of the GDG’s deliberations related to evaluating evidence from the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Study (see Annex 3). The GDG gave particular attention to this information because of its ability to address unmeasured confounding – a major cause of uncertainty when interpreting results from observational studies. The GDG recognized that the ECHO trial did not address the etiological or causal question of whether DMPA increases the risk of HIV acquisition when compared with not using any contraception. Nevertheless, since the MEC provides guidance for women wishing to use contraception, results from the ECHO trial about the comparative risk of HIV acquisition among users of the three contraceptives tested were highly pertinent to the GDG’s deliberations. Furthermore, the GDG noted that the high incidence of HIV infection experienced by each contraceptive group during the ECHO trial was similar to the background incidence assumed when designing the trial. This was deemed to be indirect evidence addressing the question, suggesting no increased risk of HIV acquisition among users of these contraceptives compared with women not using any contraception. The ECHO trial was considered to be a well conducted study that provided high-quality evidence that superseded the low and low-to-moderate-quality observational evidence previously available to the GDG. This direct epidemiological evidence, from a trial specifically designed to address the issue, was judged to be more informative than theoretical biological evidence. The reasons for considering the ECHO trial to be of high quality included its large size; robust randomization methods; good adherence to the allocated contraceptive method; a low attrition rate; regular, standardized and objective outcome measurements; and a blinded, comprehensive analysis of the data (including sensitivity analyses for postulated confounders such as sexual activity and condom use). Although women and providers of services in the ECHO trial could not be blinded to the intervention allocation, there was no evidence that this led to the different groups of participants acting, or being managed, differently with respect to important issues such as HIV prevention counselling. This ensured that residual confounding, particularly in relation to condom use or sexual activity, was highly unlikely to have affected the ECHO trial. The GDG noted that although the ECHO trial was designed to detect a 50% increase in the risk of HIV acquisition between contraceptive groups assessed, the observed high HIV incidence and small losses to follow up meant that it could detect a 30% increase. When considering the ECHO trial results, the GDG focused on the point estimates for each primary comparison. The group noted that none of the point estimates for the primary comparisons were statistically significant. The 96% confidence intervals surrounding these point estimates included unity, and so encompassed the possibility of a small increased or decreased difference in risk between contraceptives. The GDG acknowledged, however, that for an individual woman at a high risk of HIV, any change in this risk may be important. After a full discussion, the GDG judged that unmeasured confounding was the most likely explanation for the apparent increased risk of HIV acquisition among DMPA-IM users seen in some observational studies. The GDG’s decisions to revise the MEC classifications for DMPA and IUDs were further grounded by the values and preferences of women towards optimizing informed contraceptive choice and the availability of a wide range of contraceptive options, based on a systematic review of qualitative and quantitative evidence, consultative engagements with sex workers and the perspectives of GDG members representing specific affected populations. In previous editions of the MEC, IUDs were classified as MEC Category 2 for women at a high risk of HIV. This recommendation was given because of the absence of high-quality, direct evidence about the risk of acquiring HIV among IUD users. In addition, there was an assumption that most women at a high risk of HIV were also at an increased risk of other STIs. The ECHO trial provided direct, high-quality evidence about the risk of HIV acquisition risk among women using the Cu-IUD, enabling the GDG to review its recommendation regarding these women. Any new evidence related to IUD use in women at a high risk of other STIs will be reviewed for the next MEC update. The GDG was concerned about the high rates of both HIV and STIs among women in the ECHO trial, reflecting the background risk factors among women seeking contraception in the study areas. The high incidence of HIV was particularly striking given the extensive efforts made during the ECHO trial to provide HIV prevention counselling and interventions. Thus, while the GDG concluded that the risk of HIV acquisition was not affected by the contraceptive method used, it emphasized the need for renewed efforts to reduce the incidence of HIV and STIs. | Contraceptive eligibility for women at high risk of HIV: guidance statement8 IMPLICATIONS FOR POLICY-MAKERS, PROGRAMME MANAGERS AND HEALTH-CARE PROVIDERS 5 While the main audiences for the Medical eligibility criteria for contraceptive use (MEC) are policy-makers and programme managers, a fundamental tenet of the MEC is that they are woman-centred. The following were the key messages that came from the deliberations of the Guideline Development Group. 5.1 A woman’s risk of HIV should not restrict her contraceptive choice While a risk of HIV should not restrict a woman’s choice to use hormonal contraception or an intrauterine device, it is important to note that these methods do not protect her against acquiring HIV or other sexually transmitted infection (STI). The new MEC recommendations should not be interpreted as indicating that HIV and STI testing and prevention are no longer important. Indeed, the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Study highlighted the critical need to strengthen and expand HIV and STI prevention services (10). Testing for HIV and STIs should be part of high-quality family planning services for women at risk, particularly for those living in areas of high HIV and STI incidence. 5.2 Efforts to expand access to contraceptive options must continue Women have the right to a range of short-acting, long-acting and permanent contraceptive methods, as well as to emergency contraception (1). A comprehensive range of contraceptive methods enables women to respond to changing needs and preferences during their reproductive lives. Informed decision- making and woman-centred, high-quality counselling are key components in the human rights-based provision of contraceptive information and services (2). The ECHO trial reinforced that offering a range of methods is possible and acceptable to women (10). Family planning and HIV services should be included in national universal health coverage initiatives. Efforts to expand safe and effective contraceptive options, and to ensure their availability and the access to them, must continue. Technical resources are available to support countries to introduce more contraceptive options into their programmes and services (Box 1). BOX 1. TECHNICAL RESOURCES TO SUPPORT PROGRAMMES o Medical eligibility criteria for contraceptive use (in English, French and Russian) https://apps.who.int/iris/handle/10665/181468 o Selected practice recommendations for contraceptive use (in English, French and Spanish) https://apps.who.int/iris/handle/10665/252267 o Implementation guide for the medical eligibility criteria and selected practice recommendations for contraceptive use (available in English, French, Portuguese and Spanish) https://apps.who.int/iris/handle/10665/272758 o Global handbook for family planning providers https://apps.who.int/iris/handle/10665/260156 o Training Resource Package for Family Planning website (available in English and French) https://www.fptraining.org o Mobile application for the Medical eligibility criteria for contraceptive use (free, for android and iOS platforms) https://www.who.int/reproductivehealth/mec-app o Policy brief: consolidated guidelines on HIV prevention, diagnosis, treatment and care for key populations, 2016 update https://apps.who.int/iris/handle/10665/258967 o Treat all: policy adoption and implementation status in countries (fact sheet) https://apps.who.int/iris/handle/10665/258538 Contraceptive eligibility for women at high risk of HIV: guidance statement | 9 5.3 A renewed emphasis on HIV and STI prevention services is urgently needed The ECHO trial showed high rates of both HIV and STIs in the study sites (10), highlighting the need for appropriate prevention, diagnosis and treatment of all STIs. Current HIV prevention measures remain unavailable or unsatisfactory for many women and adolescent girls living in settings of high HIV incidence. In such areas, the integration of family planning and HIV prevention services for all women is essential if the health of women and adolescent girls is to be improved. In settings of low HIV prevalence, there is a need for family planning providers to evaluate personal risk factors that may increase a woman’s risk of acquiring HIV and then to provide appropriate services. The ECHO trial also showed that syndromic management did not decrease the prevalence of STIs at baseline and at the end of follow-up. STI programmes need to be strengthened, including a move towards diagnostic management. ■ In settings with high HIV prevalence, HIV testing and prevention should be included in family planning services. HIV testing should be offered to all women and to partners of all women with HIV. HIV prevention options should be offered to all women, including pre-exposure prophylaxis (PrEP), as recommended in WHO guidelines (30). The offer of PrEP to women could also be considered where HIV incidence is high (but below 3/100 person-years overall) following, for example, a simple risk assessment. A risk assessment could include: desire to take PrEP (reflecting a self-identified risk); history of an STI; more than one sex partner in the last six months; or women with a sex partner with HIV who is not virally supressed on antiretroviral therapy. ■ In settings with low HIV prevalence, the routine offer of HIV testing and prevention services in family planning settings is unlikely to be cost-effective. HIV testing and prevention services could nonetheless be offered to women who request these services. BOX 2. WORK TO IDENTIFY WOMEN AT HIGH RISK OF HIV A person’s HIV risk depends on the incidence of HIV in the area where they live, and their individual risk factors. Family planning programmes must work closely with their national and subnational HIV programmes to use local epidemiological data to identify geographical areas and risk factors that put women at a high risk of HIV infection. 6.1 Contraceptive methods and HIV acquisition The existing body of evidence is sufficient to guide practice on intramuscular depot medroxyprogesterone acetate (DMPA-IM), levonorgestrel (LNG) implants and copper-bearing intrauterine devices; additional observational data will not add substantially to the evidence base for these methods. However, in the absence of trial data similar to those in the ECHO Study (10), observational data about subcutaneous DMPA (DMPA-SC), LNG IUDs, etonogestrel implants, or future contraceptive or multi-purpose prevention technologies could still be useful, although unmeasured confounding would likely remain a concern. Studies should consider the potential impact of contraceptive use on other sexually transmitted infections as well as HIV. Additional research on the specific effects of contraception-related bleeding changes in relation to the risk of HIV or STI acquisition is also needed. 6.2 HIV prevention The Guideline Development Group was deeply concerned by the high HIV incidence found among women seeking family planning services in the ECHO Study sites, despite the fact that trial participants received an extensive HIV prevention package (including repeated HIV testing and counselling, partner HIV testing and condom distribution, as well as pre-exposure prophylaxis (PrEP) late in the study as this became the standard of care). More research is needed on ways to increase the acceptability and uptake of effective HIV prevention strategies for women at a high risk of HIV, tailored to settings of both high and low HIV prevalence and to women with a range of personal risk factors. In the ECHO trial, the uptake (and hence impact) of PrEP was minimal as it became available only late in the trial (10). Where it was available on site, as opposed to requiring referral to another site, acceptability and uptake were high. Ways to include HIV self-testing and PrEP in family planning services should be KNOWLEDGE GAPS AND AREAS FOR RESEARCH6 | Contraceptive eligibility for women at high risk of HIV: guidance statement10 explored. This should include behavioural and implementation science research on the effective integration of HIV and contraception services. 6.3 Community involvement The ECHO trial employed a range of strategies for directly engaging with civil society at the study site, and at regional and global levels (10). An in-depth assessment of the strengths and limitations of each strategy is likely to provide models for community engagement in contraceptive and HIV prevention research that could be adopted in the future. 6.4 Increased funding for high-quality, policy-relevant research The ECHO Study demonstrated that a well conducted, adequately powered randomized controlled trial is possible in contraceptive research, and can make an important contribution to global decision-making. Global policy should be based on comprehensive high-quality evidence, but additional investment in contraceptive research is critically overdue, including research addressing whether financial barriers affect the contraceptive choices of women. DISSEMINATION OF THIS GUIDANCE STATEMENT7 The World Health Organization (WHO) will work to communicate this guidance statement clearly and widely. WHO will evaluate whether the guidance achieves its intentions. The guidance will be published on the WHO website and in a limited quantity of printed documents. The guidance will be widely disseminated through the WHO regional and country offices, WHO Member States, other United Nations agencies, civil society, the Implementing Best Practices (IBP) initiative, professional organizations, governmental and non- governmental partner organizations, and WHO collaborating centres working in the area of HIV and sexual and reproductive health. The WHO Secretariat will work closely with sexual and reproductive health and HIV focal points in regional and country offices of WHO, the United Nations Population Fund and the Joint United Nations Programme on HIV and AIDS to conduct a series of regional learning and knowledge-sharing events. This engagement will target opportunities where sexual and reproductive health issues are being discussed; examples include the 25th Conference on Population and Development in July 2019 and the 20th International Conference on AIDS and Sexually Transmitted Infections in Africa in December 2019. The Secretariat will also work closely with country task teams and working groups leading HIV and contraception programme efforts to share the guidance with grassroots and community- level organizations and providers. Additionally, webinars for stakeholders in multiple languages will be organized during 2020 to ensure Member States and stakeholders are fully informed of the new recommendations. These opportunities will enable WHO to disseminate the updated guidance effectively and efficiently. Derivative communication products highlighting key counselling issues (e.g. short briefs for front-line health-care providers and community-based organizations) will be prepared in collaboration with WHO’s implementing partners, and in consultation with the GDG during 2020. A policy brief in the six official languages used by WHO will be developed to inform policy-makers about the contraception updates. As part of the dissemination of the recommendations in this guidance statement, WHO will update its digital contraceptive decision-support tools – the MEC mobile app (31), the humanitarian contraceptive delivery app (32) and the postpartum compendium (33). These mobile applications are free to download and available for both iOS and Android platforms. Additionally, the Global handbook for family planning providers and the online Family Planning Training Resource Package will be updated accordingly (8, 34). WHO will continue to monitor the body of evidence informing these recommendations and will convene additional consultations when needed. Contraceptive eligibility for women at high risk of HIV: guidance statement | 11 REFERENCES 1. Ensuring human rights in the provision of contraceptive information and services: guidance and recommendations. Geneva: World Health Organization; 2014 (https://apps.who.int/iris/handle/10665/102539, accessed 24 August 2019). 2. Framework for ensuring human rights in the provision of contraceptive information and services. Geneva: World Health Organization; 2014 (https://apps.who.int/iris/handle/10665/133327, accessed 24 August 2019). 3. The thirteenth general programme of work, 2019–2023: promote health, keep the world safe, serve the vulnerable. Geneva: World Health Organization; 2019 (https://apps.who.int/iris/handle/10665/324775, accessed 24 August 2019). 4. Reproductive health strategy to accelerate progress towards the attainment of international development goals and targets. Geneva: World Health Organization; 2004 (https://apps.who.int/iris/handle/10665/68754, accessed 24 August 2019). 5. Medical eligibility criteria for contraceptive use, fifth edition. Geneva: World Health Organization; 2015 (https://apps.who.int/iris/ handle/10665/181468, accessed 24 August 2019). 6. Selected practice recommendations for contraceptive use: third edition. Geneva: World Health Organization; 2016 (https://apps.who.int/iris/handle/10665/252267, accessed 24 August 2019). 7. WHO medical eligibility criteria wheel for contraceptive use, 2015 update. Geneva: World Health Organization; 2004 (https://apps.who.int/iris/handle/10665/173585, accessed 24 August 2019). 8. World Health Organization, Johns Hopkins Bloomberg School of Public Health. Family planning: a global handbook for providers: evidence-based guidance developed through worldwide collaboration, third edition. Geneva: World Health Organization; 2018 (https://apps.who.int/iris/handle/10665/260156, accessed 24 August 2019). 9. Hormonal contraceptive eligibility for women at high risk of HIV: guidance statement: recommendations concerning the use of hormonal contraceptive methods by women at high risk of HIV. Geneva: World Health Organization; 2017 (https://apps.who.int/ iris/handle/10665/254662, accessed 24 August 2019). 10. Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium. HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial. Lancet. 2019;394(10195):303–13. doi: 10.1016/S0140-6736(19)31288-7. 11. WHO handbook for guideline development, second edition. Geneva: World Health Organization; 2014 (https://apps.who.int/iris/ handle/10665/145714, accessed 24 August 2019). 12. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J et al. GRADE guidelines: 1. Introduction –GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64(4):383–94. doi: 10.1016/j.jclinepi.2010.04.026. 13. Singh S. Adding it up: costs and benefits of contraceptive services – estimates for 2017. New York (NY): Guttmacher Institute; 2017. 14. Polis CB, Curtis KM, Hannaford PC, Phillips SJ, Chipato T, Kiarie JN et al. An updated systematic review of epidemiological evidence on hormonal contraceptive methods and HIV acquisition in women. AIDS. 2016;30(17):2665–83. doi: 10.1097/ QAD.0000000000001228. 15. Moher D, Liberati A, Tetzlaff J, Altman DG; The Prisma Group. Preferred reporting items for systematic reviews and meta- analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. doi: 10.1371/journal.pmed.1000097. 16. Kennedy CE, Yeh PT, Gaffield ME. Contraception values and preferences: protocol and methods for a global systematic review. Contraception. 2019 (in press). doi: 10.1016/j.contraception.2018.05.006Get. 17. Guyatt GH, Oxman AD, Vist G, Kunz R, Brozek J, Alonso-Coello P et al. GRADE guidelines: 4. Rating the quality of evidence— study limitations (risk of bias). J Clin Epidemiol. 2011;64(4):407–15. doi: 10.1016/j.jclinepi.2010.07.017. 18. Guyatt GH, Oxman AD, Kunz R, Brozek J, Alonso-Coello P, Rind D et al. GRADE guidelines 6. Rating the quality of evidence – imprecision. J Clin Epidemiol. 2011;64(12):1283–93. doi: 10.1016/j.jclinepi.2011.01.012. | Contraceptive eligibility for women at high risk of HIV: guidance statement12 19. Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M et al. GRADE guidelines: 8. Rating the quality of evidence – indirectness. J Clin Epidemiol. 2011;64(12):1303–10. doi: 10.1016/j.jclinepi.2011.04.014. 20. Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M et al. GRADE guidelines: 7. Rating the quality of evidence – inconsistency. J Clin Epidemiol. 2011;64(12):1294–302. doi: 10.1016/j.jclinepi.2011.03.017. 21. Guyatt GH, Oxman AD, Montori V, Vist G, Kunz R, Brozek J et al. GRADE guidelines: 5. Rating the quality of evidence – publication bias. J Clin Epidemiol. 2011;64(12):1277–82. doi: 10.1016/j.jclinepi.2011.01.011. 22. Guyatt GH, Oxman AD, Sultan S, Glasziou P, Akl EA, Alonso-Coello P et al. GRADE guidelines: 9. Rating up the quality of evidence. J Clin Epidemiol. 2011;64(12):1311–6. doi: 10.1016/j.jclinepi.2011.06.004. 23. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619–22. doi: 10.1097/ QAD.0000000000002260. 24. Sabo MC, Richardson BA, Lavreys L, Martin HL, Jr, Jaoko W, Mandaliya K et al. Does bacterial vaginosis modify the effect of hormonal contraception on HIV seroconversion. AIDS. 2019;33(7):1225–30. doi: 10.1097/QAD.0000000000002167. 25. Lavreys L, Baeten JM, Martin Jr HL, Overbaugh J, Mandaliya K, Ndinya-Achola J et al. Hormonal contraception and risk of HIV-1 acquisition: results of a 10-year prospective study. AIDS. 2004;18(4):695–7. 26. Wall KM, Kilembe W, Vwalika B, Htee Khu N, Brill I, Chomba E et al. Hormonal contraception does not increase women’s HIV acquisition risk in Zambian discordant couples, 1994–2012. Contraception. 2015;91(6):480–7. doi: 10.1016/j. contraception.2015.02.004. 27. Yeh PT, Kennedy CE, Gaffield ME. Contraception values and preferences: a global systematic review. Contraception. 2019; (accepted pending revisions). 28. Miller L, Ntinginya M, Makula J, Juma A, Mackay A, Wadegu E et al. Final report: a pilot study to assess training and communication materials on progestogen-only injectable use and risk of HIV acquisition in Tanzania. London: Marie Stopes International; 2019 (https://resultsforinformedchoice.org/wp-content/uploads/2019/02/Injectables-and-HIV-Pilot-Study-Report-TZ.pdf, accessed 24 August 2019). 29. Littlepage S, Dam A, Nakyanjo N, Polis C, Nalugoda F, Kennedy CE. Contraceptive decision-making in the context of HIV risk and changing World Health Organization guidelines: a qualitative study in Rakai, Uganda. 2019 (personal communication). 30. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach, second edition. Geneva: World Health Organization; 2016. (https://apps.who.int/iris/handle/10665/208825, accessed 24 August 2019). 31. New app for WHO’s medical eligibility criteria for contraceptive use. In: World Health Organization [website]. Geneva: World Health Organization; 2018 (https://www.who.int/reproductivehealth/mec-app, accessed 24 August 2019). 32. Delivering contraceptive services in humanitarian settings: new tool for front-line health care workers. In: World Health Organization [website]. Geneva: World Health Organization; 2018 (https://www.who.int/reproductivehealth/publications/ humanitarian-settings-contraception, accessed 24 August 2019). 33. New WHO tool helps guide contraception choices following childbirth. In: World Health Organization [website]. Geneva: World Health Organization; 2016 (https://www.who.int/reproductivehealth/news/pfpc, accessed 24 August 2019). 34. TRP: Training Resource Package for Family Planning [website]. Baltimore (MD): Johns Hopkins University; 2019 (https://www.fptraining.org, accessed 24 August 2019). Contraceptive eligibility for women at high risk of HIV: guidance statement | 13 ANNEX 1. GUIDELINE DEVELOPMENT GROUP AND EVIDENCE SECRETARIAT Guideline Development Group Sharon Achilles (University of Pittsburgh, United States of America), Richard Adanu (University of Ghana, Ghana), Rachid Bezad (University Roi Mohammad VI, Morocco), Sharon Cameron (University of Edinburgh, United Kingdom of Great Britain and Northern Ireland), Tsungai Chipato (University of Zimbabwe, Zimbabwe), Maria del Carmen Cravioto (National Institute of Nutrition, Salvador Zubiran, Mexico) [unable to attend], Alison Edelman (Oregon Health & Science University, United States), Mohammad Eslami (Ministry of Health and Education, Islamic Republic of Iran), Anna Glasier (University of Edinburgh, United Kingdom), Andy Gray (University of KwaZulu- Natal, South Africa), Philip Hannaford (University of Aberdeen, United Kingdom), Felicita Hikuam (AIDS and Rights Alliance for Southern Africa, Namibia), Unnop Jaisamrarn (Chulalongkorn University, Thailand), Loveleen Johri (family planning and reproductive health independent consultant, India), Natasha Kaoma (Copper Rose Zambia, Zambia), Seni Kouanda (Institute of Research in Health Sciences, Burkina Faso), Elizabeth Lule (global health and international development independent consultant, Uganda), Vimbai Magwenzi (Centre for Sexual Health and HIV/AIDS Research, Zimbabwe) [unable to attend], Loyce Maturu (Zvandiri Mentor with Africaid, Zimbabwe), Olav Meirik (Instituto Chileno de Medicina Reproductiva, Chile), Placid Mihayo (Ministry of Health, Uganda), Lilian Mworeko (International Community of Women Living with HIV Eastern Africa, Uganda), Hiromi Obara (National Center for Global Health and Medicine, Tokyo, Japan), Herbert Peterson (University of North Carolina, United States), John Pile (independent consultant, Thailand), Carolina Sales Vieira (University of Sao Paulo, Brazil), Sarah Simpson (EquiACT, France), Aminata Wurie (Youth Coalition for Sexual and Reproductive Rights, Sierra Leone). Philip Hannaford and Natasha Kaoma co-chaired the meeting Guideline Development Group (GDG) meeting. Evidence Secretariat Centre for Sexual Health and HIV/AIDS Research – Euphemia Sibanda FHI 360 – Timothy Mastro Independent Consultant – Ania Shapiro Johns Hopkins University – Caitlin Kennedy Oregon Health & Science University – Maria Isabel Rodriguez United States Centers for Disease Control and Prevention – Kathryn Curtis University of Washington – Jared Baeten Wits Reproductive Health and HIV Institute – Helen Rees Observer Zandile Mnisi (Ministry of Health, Eswatini) External Review Group Florence Anam (Doctors Without Borders, South Africa), Winfred Apio (Uganda Youth and Adolescents Forum, Uganda), Lynn Bakamjian (independent consultant, United States), Milena Brito (University of Sao Paulo, Brazil), Roy Jacobstein (IntraHealth, United States), Ernest Maya (University of Ghana, Ghana), Mari Ngai (National Center for Global Health and Medicine, Japan), Cristina Puig Borràs (European Consortium for Emergency Contraception, Spain), Nusrat Shah (Society of Obstetrics & Gynaecology, Pakistan), Bulbul Sood (Jphiego, India). WHO Secretariat The WHO Secretariat attended the meeting and several WHO staff provided background presentations (Rachel Baggaley, Mary Lyn Gaffield, James Kiarie, Nancy Kidula). The WHO Secretariat was present to serve as a background resource, if request by the GDG. Neither WHO, the Joint United Nations Programme on HIV/AIDS (UNAIDS) nor the United Nations Population Fund (UNFPA) staff participated in the decision- making or formulation of the recommendations, which was the sole responsibility of the GDG. Several WHO staff contributed to the systematic reviews (Mary Lyn Gaffield, James Kiarie, Petrus Steyn) and the writing of the statement. WHO headquarters WHO Department of Reproductive Health and Research – Ian Askew, Mary Lyn Gaffield, James Kiarie, Antonella Lavelanet, Manjulaa Narasimhan (unable to attend), Petrus Steyn WHO Department of HIV – Rachel Baggaley, Virginia MacDonald, Michele Rodolph WHO Department of Regulation of Medicines and other Health Technologies – Ray Corrin | Contraceptive eligibility for women at high risk of HIV: guidance statement14 WHO regional offices WHO Regional Office for Africa – Nancy Kidula, Léopold Ouedraogo Joint United Nations Programme on HIV/AIDS (UNAIDS) Peter Godfrey-Fausett United Nations Population Fund (UNFPA) Technical Division – Gifty Addico, Mieko Yabuta (unable to attend) Overall coordination WHO Department of Reproductive Health and Research – Mary Lyn Gaffield, with logistical support from Jane Werunga- Ndanareh. Writing The guidance statement was drafted on behalf of WHO by Caitlin Baumhart, Kathryn Curtis, Mary Lyn Gaffield, Philip Hannaford, Natasha Kaoma, Caitlin Kennedy and Maria Isabel Rodriguez. The systematic review examining the use of copper-bearing intrauterine devices and HIV acquisition was co-authored by Tsungai Chipato, Kathryn Curtis, Philip Hannaford and Angeline Ti. The update of the 2016 systematic review focusing on hormonal contraception and HIV acquisition was co-authored by Tsungai Chipato, Kathryn Curtis, Philip Hannaford, James Kiarie and Petrus Steyn. The GRADE tables and expertise on GRADE methodology were provided by Maria Isabel Rodriguez. Preparation of the evidence-to-decision table and expertise on the literature for values and preferences were provided by Caitlin Kennedy. Editing was done by Markus MacGill and Jane Patten of Green Ink (www.greenink.co.uk) and layout by Lushomo (www.lushomo.net). Contraceptive eligibility for women at high risk of HIV: guidance statement | 15 ANNEX 2. DECLARATIONS OF CONFLICTS OF INTEREST Following guidance issued on 24 September 2014 by the WHO Office of Compliance, Risk Management and Ethics (CRE), and prior to the 29–31 July 2019 meeting, the name and brief biography of each proposed Guideline Development Group (GDG) member was published on the WHO website during 27 May to 10 June 2019 (https://www.who.int/ reproductivehealth/publications/contraceptives-methods-hiv). The public was able to view and provide their comments to the WHO Secretariat using a general email address (hrx_info@who.int) regarding any perceived or real conflicts of interest of these proposed GDG members. In addition, prior to the public announcement period, the WHO Secretariat reviewed the curriculum vitae of each potential participant and conducted Internet searches (Google Scholar, Open Payments, PubMed) for information on potential financial and academic conflicts of interest related to the subject of the meeting. Following the public reporting period, and in consultation with CRE, official invitations for GDG membership were extended. Additionally, the WHO Secretariat reviewed potential financial and academic conflicts of interest related to the subject of the meeting of the proposed External Review Group: no conflicts were declared among this 11-member group. Of the 28 experts who participated in this work, six declared an interest related to contraception. The WHO Secretariat, CRE and GDG reviewed all declarations and found no conflicts of interest sufficient to preclude anyone from participating in the deliberations or the development of the recommendations relevant to hormonal contraception and HIV. Accordingly, the six participants who declared interests related to contraception, as well as the other 22 participants, fully participated in the meeting’s deliberations, discussions and final decisions. Although not all interests declared were specifically related to contraception and susceptibility to HIV, they are disclosed and summarized below. Sharon Achilles received US$ 4225 on 10 May 2016 to give expert advice on the latest HIV therapies during a one-day meeting sponsored by Merck Sharp & Dohme. Her research unit received US$ 2 638 373 from the United States National Institutes of Health/National Institute of Allergy and Infectious Diseases to conduct a study titled, Quantification of immune cells in women using contraception, during 2012–2019. For 2012–2019, her research unit is receiving US$ 4 999 999 from the Bill & Melinda Gates Foundation to conduct a study titled, HIV-target cell response in women initiating contraception in high HIV-incidence areas. During 2014–2016, Dr Achilles’s research unit received US$ 240 225 from the Bill & Melinda Gates Foundation to conduct a study addressing IFN-epsilon and hormonal contraceptive modulation of the risk of HIV acquisition. Currently, for 2018–2020, Dr Achilles’s research unit receives US$ 535 958 from the United States Food and Drug Administration (FDA) to conduct a study supporting new approaches to improve product manufacturing and quality titled, Physiologically-based model of the female reproductive tract: vaginal and intrauterine delivery components. Sharon Cameron works at a research unit that received a grant from Pfizer, UK, for £99 000, which ceased in 2016. The study was implemented to determine the feasibility and acceptability of the pharmacist administration of subcutaneous injectable contraception. Alison Edelman receives a yearly royalty of around US$ 1000 from the Internet information site, UpToDate as an author of the content. Between May 2016 and May 2017, she received US$ 10 000 a year from Agile Pharmaceuticals as an expert consultant regarding a hormonal contraceptive patch that is currently not FDA-approved. This consultation has ended. Since January 2016, she served as a trainer for Nexplanon, an FDA mandate, for Merck Sharp & Dohme, but has received no honorarium for these sessions and as an expert consultant in January 2016 for this company, receiving US$ 1500 for her services. Her research unit received US$ 540 000 from the Merck Women’s Health Investigator Initiated Studies Program to conduct research focused on treatment of breakthrough bleeding with the contraceptive implant (2016–2019). From 2015 to 2017, her research unit received a US$ 250 000 research grant from the Society for Family Planning to investigate the timing of ulipristal acetate and oral contraceptive use. Since 2002, Dr Edelman has been receiving about US$ 3000 a year from Contemporary Forums as a faculty member for its continuing medical education conferences (the amount varies depending on the number of lectures she gives). From November 2015 through June 2016, she received an honorarium of US$ 3000 from Oregon State University for expert advice on the mandated state training to allow the direct provision of contraceptives by pharmacists. Since July 2016, Dr Edelman has been receiving US$ 500 a year as an honorarium for serving on the data and safety monitoring board to FHI 360, which is developing a novel contraceptive injectable that is not yet FDA-approved. From April to September 2017, Dr Edelman was a consultant for HRA Pharma for a study investigating a progestin-only pill. Since July 2017, she had been an expert consultant for the Sugar Palm Foundation; this contract was then channelled through her institution and ended in 2019. Since June 2017, she has been providing expert consulting to Ipas to train health-care workers in Bangladesh: this contract is now administered by her institution. On an ongoing basis since 2016, Dr Edelman has received an honorarium from the University of California, San Francisco, for speaking and family planning fellowship site audits. During 2018 through to January 2019, she received an honorarium from Exeltis to provide an expert review on a contraceptive method not currently FDA- approved. This consultation has ended. Anna Glasier provides expert medical advice on the ulipristal acetate emergency contraceptive pill on a regular basis to the manufacturer (HRA Pharma). The amount was not disclosed. She works with them to try to obtain approval for the over-the- counter (OTC) use of ulipristal acetate emergency contraception and a progestin-only pill in the United States of America, and to | Contraceptive eligibility for women at high risk of HIV: guidance statement16 get a progestin-only pill approved for OTC use in the United Kingdom of Great Britain and Northern Ireland, and Europe. This is ongoing. Andy Gray is the chair of the Names and Scheduling Advisory Committee of the South African Health Products Regulatory Authority and serves on its Lega Advisory and Regulatory Advisory Committees. He is a member of the South African National Essential Medicines List Committee, responsible for medicines selection and the development of standard treatment guidelines for the public sector. Carolina Sales Vieira receives an honorarium (US$ 4000/year) for serving on Merck Sharpe & Dohme’s medical advisory board and giving ad hoc invited lectures. This role is ongoing. Dr Sales Vieira receives an honorarium (US$ 3000/year) for serving on Bayer’s medical advisory board and giving ad hoc lectures. This role is ongoing. Dr Sales Vieira received a one-time honorarium (US$ 1000) for serving on the medical advisory board for Exeltis in 2019. Contraceptive eligibility for women at high risk of HIV: guidance statement | 17 ANNEX 3. GRADE EVIDENCE PROFILES Outcome Type and number of studies (total number of participants) Limitations Inconsistency Imprecision Indirectness Overall quality Estimate of effect DMPA versus non-hormonal contraception or no method HIV acquisition 1 RCT1 (7829)a Few limitationsb No serious inconsistency No serious imprecision No indirectness High Adjusted HR 1.04 (0.82–1.33) for DMPA versus Cu-IUD HIV acquisition 10 cohort studies2–11 + 1 individual patient data meta-analysis of 7 studies12,c (40 506)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low to moderatee Adjusted HR range 0.46– 2.04, 8 studies increased risk (HR range 1.25–2.04), with statistically significant effects in 3 studies; 2 studies trended towards decreased risk (HR 0.46 and 0.75 with wide confidence intervals) Pooled adjusted HR 1.40 (1.24–1.58) NET-EN versus non-hormonal contraception or no method HIV acquisition 6 cohorts studies2,5,7,8,10,11 + 1 individual patient data meta- analysis of 7 studies12,c (29 922)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR range 0.87– 1.76, 5 studies increased risk (HR range 1.20–1.76), none statistically significant; 2 studies no effect (adjusted HR range 0.87–1.05) Pooled adjusted HR 1.14 (0.93–1.39) Implantf use versus non-hormonal contraception HIV acquisition 1 randomized trial1 (7829)a Few limitationsb No serious inconsistency No serious imprecision No indirectness High Adjusted HR 1.18 (0.91–1.53) for Cu-IUD versus LNG implant HIV acquisition 3 cohort studies2–4,c (4514)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Lowg Adjusted HR range 0.46–0.99 Adjusted HRs: 0.96 (0.29– 3.14), 0.99 (0.40–2.45), and 0.46 (0.13–1.70); none statistically significant Pooled adjusted HR 0.82 (0.44–1.53) Implantf use versus NET-EN HIV acquisition 1 cohort study2 (1136)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 0.45 (0.13–1.53) for implant use versus NET-EN Oral hormonal contraceptive use versus non-hormonal contraception or no method HIV acquisition 11 cohort studies3–6,8–14,c (43 482)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low to moderatee Adjusted HR or IRR range 0.66–1.80 3 studies increased risk (HR 1.39–1.80) Only 1 study reported a statistically significant finding (adjusted HR 1.48 [1.05– 2.09]) The remaining 8 studies reported a decreased risk (adjusted HR range 0.66–0.99), none of which was statistically significant Pooled adjusted HR 1.02 (0.88–1.19) GRADE EVIDENCE PROFILE FOR HORMONAL CONTRACEPTIVE USE IN HIV-NEGATIVE WOMEN | Contraceptive eligibility for women at high risk of HIV: guidance statement18 Outcome Type and number of studies (total number of participants) Limitations Inconsistency Imprecision Indirectness Overall quality Estimate of effect DMPA versus NET-EN HIV acquisition 2 cohort studies2,15 and 1 individual patient data meta-analysis of 17 studies12,c (42 788)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low to moderatee Adjusted HRs 1.32 (1.08– 1.61) and 0.89 (0.55–1.44) in cohort studies and 1.41 (1.06–1.89) in individual participant data meta- analysis of 17 studies Pooled adjusted HR 1.27 (1.05–1.55) DMPA versus combined oral contraceptives HIV acquisition 1 individual patient data meta-analysis of 8 studies12,c (24 853)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low to moderatee Adjusted HR 1.41 (1.23–1.67) in individual participant data meta-analysis of 8 studies NET-EN versus combined oral contraceptives HIV acquisition 1 individual patient data meta-analysis of 9 studies12,c (25 398)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 1.30 (0.99–1.17) GRADE EVIDENCE PROFILE FOR HORMONAL CONTRACEPTIVE USE IN HIV-NEGATIVE WOMEN Cu-IUD: copper-bearing intrauterine device; DMPA-IM: intramuscular depot medroxyprogesterone acetate; ETG: etonogestrel; GRADE: Grading of Recommendations Assessment, Development and Evaluation; HR: hazard ratio; IRR: incidence rate ratio; LNG: levonorgestrel; NET-EN: norethisterone enanthate; RCT: randomized controlled trial Note: Publication bias was not formally assessed; observational studies could not be upgraded for large effects; dose-response relationship, or confounders likely to increase observed effects. Estimates based on adjusted risk estimates, results from Cox model analysis used when available. a Sample size is for the entire study population. b Few limitations noted in the trial, but not serious enough to downgrade the level of evidence. While the study was unblinded for participants and health-care providers, data were analysed centrally by statisticians who were blinded to the group. c Restricted to studies classified as “informative with but with important limitations”. d Some limitations or imprecision noted across the body of evidence, but not serious enough to downgrade the level of evidence. e Evidence graded low to moderate due to consistent and precise results from well conducted observational studies, and coherence between studies of use versus non-use and head-to-head studies. f No direct evidence for ETG implants was identified for the comparisons of interest. For ETG implants, recommendations were extrapolated from other implant studies. g Upgraded from very low-quality evidence (2016 assessment). References: 1. Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium. HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial. Lancet. 2019;394(10195):303–13. doi: 10.1016/S0140-6736(19)31288-7. 2. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619–22. doi: 10.1097/ QAD.0000000000002260. 3. Sabo MC, Richardson BA, Lavreys L, Martin HL, Jr, Jaoko W, Mandaliya K et al. Does bacterial vaginosis modify the effect of hormonal contraception on HIV seroconversion. AIDS. 2019;33(7):1225–30. doi: 10.1097/QAD.0000000000002167. 4. Wall KM, Kilembe W, Vwalika B, Htee Khu N, Brill I, Chomba E et al. Hormonal contraception does not increase women’s HIV acquisition risk in Zambian discordant couples, 1994–2012. Contraception. 2015;91(6):480–7. Doi: 10.1016/j. contraception.2015.02.004. Contraceptive eligibility for women at high risk of HIV: guidance statement | 19 5. Crook AM, Ford D, Gafos M, Hayes R, Kamali A, Kapiga S et al. Injectable and oral contraceptives and risk of HIV acquisition in women: an analysis of data from the MDP301 trial. Hum Reprod. 2014;29(8):1810–7. doi: 10.1093/humrep/deu113. 6. Heffron R, Donnell D, Rees H, Celum C, Mugo N, Were E et al. Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study. Lancet Infect Dis. 2012;12(1):19–26. doi: 10.1016/S1473-3099(11)70247-X. 7. Kleinschmidt I, Rees H, Delany S, Smith D, Dinat N, Nkala B et al. Injectable progestin contraceptive use and risk of HIV infection in a South African family planning cohort. Contraception. 2007;75(6):461–7. doi: 10.1016/j.contraception.2007.02.002. 8. McCoy SI, Zheng W, Montgomery ET, Blanchard K, van der Straten A, de Bruyn G et al. Oral and injectable contraception use and risk of HIV acquisition among women in sub-Saharan Africa. AIDS. 2013;27(6):1001–9. doi: 10.1097/ QAD.0b013e32835da401. 9. Morrison CS, Richardson BA, Mmiro F, Chipato T, Celentano DD, Luoto J et al. Hormonal contraception and the risk of HIV acquisition. AIDS. 2007;21(1):85–95. doi: 10.1097/QAD.0b013e3280117c8b. 10. Morrison CS, Skoler-Karpoff S, Kwok C, Chen PL, van de Wijgert J, Gehret-Plagianos M et al. Hormonal contraception and the risk of HIV acquisition among women in South Africa. AIDS. 2012;26(4):497–504. doi: 10.1097/QAD.0b013e32834fa13d. 11. Myer L, Denny L, Wright TC, Kuhn L. Prospective study of hormonal contraception and women’s risk of HIV infection in South Africa. Int J Epidemiol. 2007;36(1):166–74. doi: 10.1093/ije/dyl251. 12. Morrison CS, Chen PL, Kwok C, Baeten JM, Brown J, Crook AM et al. Hormonal contraception and the risk of HIV acquisition: an individual participant data meta-analysis. PLoS Med. 2015;12(1):e1001778. doi: 10.1371/journal.pmed.1001778. 13. Balkus JE, Brown ER, Hillier SL, Coletti A, Ramjee G, Mgodi N et al. Oral and injectable contraceptive use and HIV acquisition risk among women in four African countries: a secondary analysis of data from a microbicide trial. Contraception. 2016;93(1):25–31. doi: 10.1016/j.contraception.2015.10.010. 14. Reid SE, Dai JY, Wang J, Sichalwe BN, Akpomiemie G, Cowan FM et al. Pregnancy, contraceptive use, and HIV acquisition in HPTN 039: relevance for HIV prevention trials among African women. J Acquir Immune Defic Syndr. 2010;53(5):606–13. doi: 10.1097/QAI.0b013e3181bc4869. 15. Noguchi LM, Richardson BA, Baeten JM, Hillier SL, Balkus JE, Chirenje ZM et al. Risk of HIV-1 acquisition among women who use different types of injectable progestin contraception in South Africa: a prospective cohort study. Lancet HIV. 2015;2(7):e279–87. doi: 10.1016/S2352-3018(15)00058-2. | Contraceptive eligibility for women at high risk of HIV: guidance statement20 Outcome Type and number of studies (total number of participants) Limitations Inconsistency Imprecision Indirectness Overall quality Estimate of effect IUDa versus no contraception or tubal ligation HIV acquisition 1 prospective study1,b (1498)c Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 1.1 (0.4–3.0) for Cu-IUD versus no contraception or tubal ligation IUDa versus implant,e DMPA, NET-EN HIV acquisition 1 prospective study2,b (1136)c Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 0.90 (0.45–1.76) for DMPA, implants, NET-EN versus Cu-IUD IUDa use versus DMPA HIV acquisition 1 RCT3,b (7829)c Few limitationsf No serious inconsistency No serious imprecision No indirectness High Adjusted HR 1.04 (0.82–1.33) for DMPA-IM versus Cu-IUD HIV acquisition 1 prospective study2,b (1136)c Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 0.91 (0.44–1.87) for DMPA versus Cu-IUD IUDa versus NET-EN HIV acquisition 1 prospective study2,b (1136)c Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 0.98 (0.47–2.03) for Cu-IUD versus NET-EN IUDa versus implante HIV acquisition 1 RCT3 (7829)c Few limitationsf No serious inconsistency No serious imprecision No indirectness High Adjusted HR 1.18 (0.91–1.53) for Cu-IUD versus LNG implant HIV acquisition 1 prospective study2,b (1136)c Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 2.17 (0.59–7.69) for Cu-IUD versus implants (LNG or ETG) GRADE EVIDENCE PROFILE FOR CU-IUD USE IN HIV-NEGATIVE WOMEN Cu-IUD: copper-bearing intrauterine device; DMPA-IM: intramuscular depot medroxyprogesterone acetate; ETG: etonogestrel; GRADE: Grading of Recommendations Assessment, Development and Evaluation; HR: hazard ratio; IUD: intrauterine device; LNG: levonorgestrel; NET-EN: norethisterone enanthate; RCT: randomized controlled trial Note: Publication bias was not formally assessed; observational studies could not be upgraded for large effects; dose-response relationship, or confounders likely to increase observed effects. Estimates based on adjusted risk estimates, results from Cox model analysis used when available. a No direct evidence for LNG-IUDs was identified for the comparisons of interest. For LNG-IUDs, recommendations were extrapolated from the evidence on Cu-IUDs and other LNG containing products. b Restricted to studies classified as “informative with but with important limitations”. c Sample size is for the entire study population. d Some limitations or imprecision was noted across the body of evidence, but not serious enough to downgrade the level of evidence. e No direct evidence for ETG implants was identified for the comparisons of interest. For ETG implants, recommendations were extrapolated from the evidence on LNG implants. f Few limitations noted in the trial, but not serious enough to downgrade the level of evidence. References: 1. Lavreys L, Baeten JM, Martin Jr HL, Overbaugh J, Mandaliya K, Ndinya-Achola J et al. Hormonal contraception and risk of HIV-1 acquisition: results of a 10-year prospective study. AIDS. 2004;18(4):695–7. 2. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619–22. doi: 10.1097/ QAD.0000000000002260. 3. Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium. HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial. Lancet. 2019;394(10195):303–13. doi: 10.1016/S0140-6736(19)31288-7. Contraceptive eligibility for women at high risk of HIV: guidance statement | 21 ANNEX 4. EVIDENCE-TO- DECISION TABLE FOR HORMONAL CONTRACEPTIVE METHODS AND INTRAUTERINE DEVICES (IUDS) Factor Explanation/evidence Judgement Quality of evidence Progestogen- only contraceptives (POCs) For the primary outcome of HIV acquisition, evidence was considered to be of high qual- ity for intramuscular depot medroxyprogesterone acetate (DMPA-IM) and for levonorge- strel (LNG) implants. Evidence was considered to be of low quality for norethisterone enanthate (NET-EN), and absent for subcutaneous DMPA (DMPA-SC), LNG intrauterine devices (IUDs) and etonogestrel (ETG) implants. For NET-EN and DMPA-SC, the recom- mendations were extrapolated from the evidence on DMPA-IM. For ETG implants, the recommendations were extrapolated from the evidence on LNG implants. High, low or absent, depending on method IUDs For the primary outcome of HIV acquisition, evidence was considered to be of high quality for copper-bearing IUDs (Cu-IUDs). Evidence was absent for LNG-IUDs. For LNG-IUDs, recommendations were extrapolated from the evidence on Cu-IUDs and other LNG-containing products. High or absent, de- pending on method Combined hormonal contraceptives (CHCs) Evidence was considered to be of low-to-moderate quality for CHCs. Low-moderate Balance of benefits versus harms POCs Contraception is a life-saving intervention with well recognized health, social and economic benefits. All POCs are effective or highly effective, reversible methods. High-quality evidence from one randomized controlled trial (RCT) observed no statistically significant differences in HIV acquisition between: DMPA-IM versus Cu-IUD, DMPA-IM versus LNG implant, and Cu-IUD versus LNG implant. Of the low-to-moderate-quality evidence from 14 observational studies, some studies suggested a possible increased risk of HIV with progestogen-only injectable use, which was most likely due to unmeasured confounding.a,b Low-quality evidence from three observational studies did not suggest an increased HIV risk for implant users.a,b No studies of sufficient quality were identified for progestogen-only pills. While no direct evidence was available for DMPA-SC or ETG implants, indirect evidence for DMPA-IM and LNG implants was used, given that there was no biological or clinical reason to believe that a lower hormonal dose, different delivery mechanism, or different progestogen would modify HIV risk. Balance is in favour of benefits of POCs IUDs Contraception is a life-saving intervention with well recognized health, social and economic benefits. All IUDs are highly effective, reversible methods. High-quality evidence from one RCT, along with low-quality evidence from two observational studies, suggested no increased risk of HIV acquisition with Cu-IUD use.c–e While no direct evidence was available for LNG-IUDs, recommendations were extrapolated from the evidence on Cu-IUDs and other LNG-containing products. Balance is in favour of benefits of IUDs CHCs Contraception is a life-saving intervention with well recognized health, social and economic benefits. All hormonal contraceptives are effective or highly effective, reversible methods. Low-moderate quality evidence from 11 observational studies suggested no association between combined oral contraceptive (COC) use (it was assumed that studies that did not specify oral contraceptive type examined mostly, if not exclusively, COC use) and HIV acquisition.a,b While no direct evidence was available for combined contraceptive patch, combined contraceptive vaginal ring or combined injectable contraceptive, indirect evidence from COCs was used given that there was no biological or clinical reason to believe that a lower hormonal dose, different delivery mechanism, or different progestogen would modify HIV risk. Balance is in favour of benefits of CHCs | Contraceptive eligibility for women at high risk of HIV: guidance statement22 Factor Explanation/evidence Judgement Values and preferences Women have the right to informed decision-making. Women prefer to have choice in methods, full information regarding benefits versus harms, and to make a final decision in conjunction with their provider (informed decision-making). Contraception is unique among medicines because a woman’s needs and preferences with regard to the characteristics of contraceptive methods will vary both between individual women and across a single individual’s lifespan. Common themes in contraceptive preferences include that they are discreet, have minimal side-effects and are long-acting, reversible and easy to use. Women who use progestogen-only injectables generally like them for these reasons, and feel comfortable using them after counselling. Women’s preferences for methods are limited by what they have knowledge of, what is available to them and other factors that foster or limit access. Offering women the choice of a range of methods is important from both a health and a rights perspective. Support for optimizing informed contraceptive choice and the availability of a wide range of contraceptive options Priority of the problem HIV is a serious illness and a major global epidemic. Unintended pregnancy is a very common problem globally, and the risks associated with it are highest where maternal mortality and severe morbidity are also common. Both are priorities for public health. Effective contraception and HIV prevention are both public health priorities Equity and human rights Human rights principles and standards from existing World Health Organization (WHO) guidelines on human rights and contraception were followed by the Guideline Development Group (GDG) in its deliberations. These include non-discrimination, availability, accessibility, acceptability, quality, informed decision-making, privacy and confidentiality, participation, and accountability. During its deliberations, the GDG considered both potential positive and negative effects of its considerations. For example, it considered and emphasized the continuing need for integrated family planning and HIV services in settings with high HIV incidence. It also emphasized the need for expanding and optimizing contraceptive options. Recommendations within WHO’s human rights guidance for contraception are paramount principles for decision-making on this topic Feasibility The importance of clear communication from WHO on this topic was underscored. This was reinforced by recent studies that suggested that messages based on the 2017 WHO guidance were difficult to explain and may not be fully understood by clients or providers. Clear guidance and a woman-centred approach are essential for successful implementation References: a. Polis CB, Curtis KM, Hannaford PC, Phillips SJ, Chipato T, Kiarie JN et al. An updated systematic review of epidemiological evidence on hormonal contraceptive methods and HIV acquisition in women. AIDS. 2016;30(17):2665–83. doi: 10.1097/ QAD.0000000000001228. b. Sabo MC, Richardson BA, Lavreys L, Martin HL, Jr, Jaoko W, Mandaliya K et al. Does bacterial vaginosis modify the effect of hormonal contraception on HIV seroconversion. AIDS. 2019;33(7):1225–30. doi: 10.1097/QAD.0000000000002167. c. Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium. HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial. Lancet. 2019;394(10195):303–13. doi: 10.1016/S0140-6736(19)31288-7. d. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619–22. doi: 10.1097/ QAD.0000000000002260. e. Lavreys L, Baeten JM, Martin Jr HL, Overbaugh J, Mandaliya K, Ndinya-Achola J et al. Hormonal contraception and risk of HIV-1 acquisition: results of a 10-year prospective study. AIDS. 2004;18(4):695–7. Contraceptive eligibility for women at high risk of HIV: guidance statement | 23 ANNEX 5: SYSTEMATIC REVIEWS Three systematic reviews were conducted as part of the development of this guidance statement. The details of the methods and search strategies are included in the reviews. Reviews published in peer-reviewed journals are available through open access. This appendix will be periodically updated as reviews are published. Access to unpublished reviews can be requested by sending an email to hrx-info@who.int. 1. Hormonal contraceptive method use and HIV acquisition in women There was a previously published review on hormonal contraceptive use and HIV acquisition. The search strategies from that review were used to search for new evidence since. The following four new publications were identified that met the inclusion criteria. PREVIOUSLY PUBLISHED REVIEW 1. Polis CB, Curtis KM, Hannaford PC, Phillips SJ, Chipato T, Kiarie JN et al. An updated systematic review of epidemiological evidence on hormonal contraceptive methods and HIV acquisition in women. AIDS. 2016;30(17):2665–83. doi: 10.1097/ QAD.0000000000001228. UNPUBLISHED REVIEW 1. Curtis KM, Hannaford PC, Rodriguez MI, Chipato T, Steyn PS, Kiarie JN. Hormonal contraceptive method use and HIV acquisition in women: an updated systematic review. Working paper developed for the World Health Organization meeting. July 2019. NEW ARTICLES 1. Haddad LB, Wall KM, Kilembe W, Vwalika B, Khu NH, Brill I et al. Bacterial vaginosis modifies the association between hormonal contraception and HIV acquisition. AIDS. 2018;32(5):595–604. doi: 10.1097/ QAD.0000000000001741. 2. Hofmeyr GJ, Singata-Madliki M, Lawrie TA, Bergel E, Temmerman M. Effects of injectable progestogen contraception versus the copper intrauterine device on HIV acquisition: sub-study of a pragmatic randomised controlled trial. J Fam Plann Reprod Health Care. 2017;43(3):175–80. doi: 10.1136/jfprhc-2016-101607. 3. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619– 22. doi: 10.1097/QAD.0000000000002260. 4. Sabo MC, Richardson BA, Lavreys L, Martin HL, Jr., Jaoko W, Mandaliya K et al. Does bacterial vaginosis modify the effect of hormonal contraception on HIV seroconversion. AIDS. 2019;33(7):1225-30. doi: 10.1097/ QAD.0000000000002167. 2. Copper-bearing intrauterine device (Cu-IUD) use and HIV acquisition in women A systematic review was conducted on Cu-IUD use and HIV acquisition in women. The following six articles met the inclusion criteria. UNPUBLISHED REVIEW 1. Hannaford PC, Ti A, Chipato T, Curtis KM. Copper intrauterine device use and HIV acquisition in women: an updated systematic review. Working paper developed for the World Health Organization meeting. July 2019. NEW ARTICLES 1. Hofmeyr GJ, Singata-Madliki M, Lawrie TA, Bergel E, Temmerman M. Effects of injectable progestogen contraception versus the copper intrauterine device on HIV acquisition: sub-study of a pragmatic randomised controlled trial. J Fam Plann Reprod Health Care. 2017;43(3):175–80. doi: 10.1136/jfprhc-2016-101607. 2. Kapiga SH, Lyamuya EF, Lwihula GK, Hunter DJ. The incidence of HIV infection among women using family planning methods in Dar es Salaam, Tanzania. AIDS. 1998;12(1):75–84. doi: 10.1097/00002030-199801000-00009. 3. Lavreys L, Baeten JM, Martin Jr HL, Overbaugh J, Mandaliya  K, Ndinya-Achola J et al. Hormonal contraception and risk of HIV-1 acquisition: results of a 10-year prospective study. AIDS. 2004;18(4):695–7. 4. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619– 22. doi: 10.1097/QAD.0000000000002260. 5. Saracco A, Musicco M, Nicolosi A, Angarano G, Arici C, Gavazzeni G et al. Man-to-woman sexual transmission of HIV: longitudinal study of 343 steady partners of infected men. J Acquir Immune Defic Syndr. 1993;6(5):497-502. 6. Sinei SK, Fortney JA, Kigondu CS, Feldblum PJ, Kuyoh M, Allen MY et al. Contraceptive use and HIV infection in Kenyan family planning clinic attenders. Int J STD AIDS. 1996;7(1):65–70. doi: 10.1258/0956462961917104. 3. Contraceptive values and preferences A systematic review was conducted on contraceptive values and preferences. The protocol and methods are published, and the manuscript presenting the main results of the review is under review for publication. As this review did not identify information specific to key populations at risk of HIV, consultative engagements were conducted in the spring of 2019, including a global online survey of sex workers, and participatory focus group discussions with female sex workers | Contraceptive eligibility for women at high risk of HIV: guidance statement24 in Zimbabwe through the Sisters with a Voice programme. Presentations showing the findings from these engagements are listed below and available on request. A presentation shared by stakeholders representing affected populations to highlight their perspectives on the topic was part of the Guideline Development Group’s discussions and is available on request. 1. Kennedy CE, Yeh PT, Gaffield ME. Contraception values and preferences: protocol and methods for a global systematic review. Contraception. 2019 (in press). doi: 10.1016/j. contraception.2018.05.006Get. 2. Yeh PT, Kennedy CE, Gaffield ME. Contraception values and preferences: a global systematic review. Contraception. 2019; (accepted pending revisions). 3. Shapiro A. Female sex workers’ contraceptive practices, values and preferences. contraception and risk of HIV infection: a WHO Guideline Development Group review of the current evidence. 29 July 2019, Geneva, World Health Organization. 4. Sibanda E. Views on contraceptive methods among female sex workers in Harare, Zimbabwe: a participatory qualitative study. 29 July 2019, Geneva, World Health Organization. 5. Mworeko L. What do recommendations on contraceptives and HIV risk mean to women?, 29 July 2019, Geneva, World Health Organization.

For more information, please contact: Department of Reproductive Health and Research, World Health Organization, Avenue Appia 20, CH-1211 Geneva 27, Switzerland. E-mail: reproductivehealth@who.int www.who.int/reproductivehealth

Contraceptive eligibility for women at high risk of HIV Guidance statement Recommendations on contraceptive methods used by women at high risk of HIV

Contraceptive eligibility for women at high risk of HIV Guidance statement Recommendations on contraceptive methods used by women at high risk of HIV Contraceptive eligibility for women at high risk of HIV. Guidance statement: recommendations on contraceptive methods used by women at high risk of HIV ISBN 978-92-4-155057-4 © World Health Organization 2019 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. Contraceptive eligibility for women at high risk of HIV. Guidance statement: recommendations on contraceptive methods used by women at high risk of HIV. Geneva: World Health Organization; 2019. Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris. Sales, rights and licensing. To purchase WHO publications, see http://apps.who.int/bookorders. To submit requests for commercial use and queries on rights and licensing, see http://www.who.int/about/licensing. Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. The views expressed in this publication are those alone of the named authors and of the collective views of an international group of experts and do not necessarily represent the decisions or the policies of WHO. Printed in Switzerland Contraceptive eligibility for women at high risk of HIV: guidance statement | iii 1 2 3 4 5 ACKNOWLEDGEMENTS V ABBREVIATIONS VI EXECUTIVE SUMMARY VII BACKGROUND 1 METHODS OF GUIDELINE REVIEW AND DEVELOPMENT 2 2.1 Guideline Development Group 2 2.2 Guideline development process 2 2.3 Evidence Retrieval 3 2.4 Evidence Synthesis 4 2.5 Formulation of recommendations 4 SUMMARY OF THE EVIDENCE 4 3.1 Progestogen-only injectables 5 3.2 Progestogen-only implants 5 3.3 Progestogen-only pills 5 3.4 Intrauterine devices 5 3.5 Combined hormonal contraceptives 5 3.6 Additional evidence considered by the GDG 5 3.6.1 Biological data 5 3.6.2 Values and preferences of contraceptive users 6 RECOMMENDATIONS 6 4.1 Recommendations for contraceptive use among women at high risk of HIV infection 6 4.2 Rationale 7 IMPLICATIONS FOR POLICY-MAKERS, PROGRAMME MANAGERS AND HEALTH-CARE PROVIDERS 8 5.1 A woman’s risk of HIV should not restrict her contraceptive choice 8 5.2 Efforts to expand access to contraceptive options must continue 8 5.3 A renewed emphasis on HIV and STI prevention services is urgently needed 9 CONTENTS | Contraceptive eligibility for women at high risk of HIV: guidance statementiv CONTENTS (continued) KNOWLEDGE GAPS AND AREAS FOR RESEARCH 9 6.1 Contraceptive methods and HIV acquisition 9 6.2 HIV prevention 9 6.3 Community involvement 10 6.4 Increased funding for high-quality, policy-relevant research 10 DISSEMINATION OF THIS GUIDANCE STATEMENT 10 REFERENCES 11 ANNEX 1. GUIDELINE DEVELOPMENT GROUP AND EVIDENCE SECRETARIAT 13 ANNEX 2. DECLARATIONS OF CONFLICTS OF INTEREST 15 ANNEX 3. GRADE EVIDENCE PROFILES 17 ANNEX 4. EVIDENCE-TO-DECISION TABLE FOR HORMONAL CONTRACEPTIVE METHODS AND INTRAUTERINE DEVICES (IUDS) 21 ANNEX 5: SYSTEMATIC REVIEWS 23 6 7 Contraceptive eligibility for women at high risk of HIV: guidance statement | v ACKNOWLEDGEMENTS The World Health Organization (WHO) would like to thank the members of the Guideline Development Group and the Evidence Secretariat (Annex 1) for their contributions throughout the development of these important recommendations for women at high risk of HIV. WHO is very grateful for the suggestions provided by colleagues who peer reviewed the draft statement as members of the External Review Group. The development of this technical statement was financially supported by the Bill & Melinda Gates Foundation, the Netherlands Ministry of Foreign Affairs, the United States Agency for International Development, and the United States National Institutes of Health. | Contraceptive eligibility for women at high risk of HIV: guidance statementvi ABBREVIATIONS CIC combined injectable contraceptive COC combined oral contraceptive CRE WHO Office of Compliance, Risk Management and Ethics Cu-IUD copper-bearing intrauterine device DMPA depot medroxyprogesterone acetate DMPA-IM intramuscular depot medroxyprogesterone acetate DMPA-SC subcutaneous depot medroxyprogesterone acetate ECHO Evidence for Contraceptive Options and HIV Outcomes (Study) ETG etonogestrel FDA United States Food and Drug Administration GDG Guideline Development Group GRADE Grading of Recommendations Assessment, Development and Evaluation HR hazard ratio IRR incidence rate ratio IUD intrauterine device LNG levonorgestrel LNG-IUD levonorgestrel-releasing intrauterine device MEC Medical eligibility criteria for contraceptive use NET-EN norethisterone enanthate OTC over the counter POP progestogen-only pill PrEP pre-exposure prophylaxis (for HIV) RCT randomized controlled trial STI sexually transmitted infection WHO World Health Organization Contraceptive eligibility for women at high risk of HIV: guidance statement | vii EXECUTIVE SUMMARY The World Health Organization (WHO) convened a Guideline Development Group (GDG) meeting from 29 to 31 July 2019 to review global guidance on contraceptive eligibility for women at high risk of HIV acquisition to and determine whether revisions to the fifth edition of the Medical eligibility criteria for contraceptive use (MEC) were needed. The issue was deemed critical, particularly for sub-Saharan Africa, given the high lifetime risk of acquiring HIV alongside the importance of hormonal contraception in offering women and adolescent girls’ choice and in reducing their risk of unintended pregnancy, a common threat to the health, well-being and lives of women and adolescent girls. The GDG consisted of 28 participants from 19 countries, including experts in family planning and HIV, representatives from affected populations, clinicians, epidemiologists, researchers, programme managers, policy-makers and guideline methodologists. The GDG considered the following factors when formulating recommendations for each contraceptive method: ■ quality of the evidence (i.e. GRADE profile)1 ■ values and preferences of contraceptive users ■ balance of benefits and harms ■ priority of the problem ■ equity and human rights ■ feasibility. In formulating these recommendations, the GDG kept at the centre of their deliberations the individuals most affected by the recommendations – that is, those women wanting to prevent pregnancy who are at a high risk of HIV acquisition. Through consensus, the GDG agreed to the following new recommendations. These revisions mean that women at a high risk of HIV can use all methods of contraception without restriction. ■ Women at a high risk of HIV infection are eligible to use all progestogen-only contraceptive methods without restriction (MEC Category 1), including progestogen-only pill (POPs), intramuscular and subcutaneous depot medroxyprogesterone acetate (DMPA-IM and DMPA-SC), norethisterone enanthate (NET-EN), levonorgestrel (LNG) implants and etonogestrel (ETG) implants. ■ Women at a high risk of HIV infection are eligible to use copper-bearing intrauterine devices (Cu-IUDs) and LNG- IUDs without restriction (MEC Category 1). In considering the 1 GRADE = Grading of Recommendations Assessment, Development and Evaluation (for further information, see: http://www.gradeworkinggroup.org). use of IUDs, many women at a high risk of HIV are also at risk of other sexually transmitted infections (STIs); for these women, providers should refer to the MEC recommendation on women at an increased risk of STIs, and the Selected practice recommendations for contraceptive use: third edition on STI screening before IUD insertion. ■ Women at a high risk of HIV infection are eligible to use all combined hormonal contraceptive methods without restriction (MEC Category 1), including combined oral contraceptives (COCs), combined injectable contraceptives (CICs), combined contraceptive patches and combined vaginal rings. These recommendations were strongly informed by new epidemiological evidence, particularly from one high-quality randomized controlled trial (the ECHO trial), which did not demonstrate a statistically significant difference in HIV acquisition among women using the three contraceptive methods studied: DMPA-IM, Cu-IUDs and LNG implants. This high-quality evidence superseded the previously available observational evidence of low and low-to-moderate quality. For COCs and NET-EN injectables, evidence of low and low-to- moderate quality from observational studies indicated no increased risk of HIV infection. While no direct evidence was available for DMPA-SC, LNG-IUDs or ETG implants, there was no biological or clinical reason to believe that a lower hormonal dose, different delivery mechanism or different progestogen would modify HIV risk. A consideration of women’s values, preferences, views and concerns regarding contraceptive methods provided support for optimizing informed contraceptive choice and the availability of a wide range of contraceptive options. There are several key messages from this guidance for policy- makers, programme managers and health-care providers. ■ A woman’s risk of HIV does not restrict her contraceptive choice. ■ Efforts to expand contraceptive method options and ensure full and equitable access to family planning services must continue. ■ A renewed emphasis on HIV/STI testing and prevention services is urgently needed, including the integration of family planning and HIV/STI services as appropriate, along with sexual and reproductive health packages. | Contraceptive eligibility for women at high risk of HIV: guidance statementviii PROGESTOGEN-ONLY CONTRACEPTIVES Progestogen-only contraceptives (POCs) do not protect against sexually transmitted infections (STIs), including HIV. If there is a risk of STI/HIV, the correct and consistent use of condoms is recommended. When used correctly and consistently, condoms offer one of the most effective methods of protection against STIs, including HIV. Female condoms are effective and safe, but are not used as widely as male condoms by national programmes. Condition MEC category Clarification/evidence POP DMPA/ NET-EN LNG/ ETG High risk of HIV 1 1 1 EVIDENCE: High-quality evidence from one randomized controlled trial observed no statistically significant differences in HIV acquisition between: DMPA-IM versus Cu-IUD, DMPA-IM versus LNG implant, and Cu-IUD versus LNG implant. Of the low-to-moderate-quality evidence from 14 observational studies, some studies sug- gested a possible increased risk of HIV with progestogen-only injectable use, which was most likely due to unmeasured confounding. Low-quality evidence from 3 obser- vational studies did not suggest an increased HIV risk for implant users. No studies of sufficient quality were identified for POPs. Cu-IUD: copper-bearing intrauterine device; DMPA: depot medroxyprogesterone acetate (injectable); IM: intramuscular; LNG/ETG: levonorgestrel and etonogestrel (implants); MEC: Medical eligibility criteria for contraceptive use; NET-EN: norethisterone enanthate (injectable); POP: progestogen-only pill INTRAUTERINE DEVICES Intrauterine devices (IUDs) do not protect against sexually transmitted infections (STIs), including HIV. If there is a risk of STI/HIV, the correct and consistent use of condoms is recommended. When used correctly and consistently, condoms offer one of the most effective methods of protec- tion against STIs, including HIV. Female condoms are effective and safe, but are not used as widely as male condoms by national programmes. Condition MEC category Clarification/evidence Cu-IUD LNG-IUD (20 μg/24 hours) High risk of HIV Initiation Continuation Initiation Continuation CLARIFICATION: Many women at a high risk of HIV are also at risk of other STIs. For these women, refer to the recommendation in the Medical eligibility criteria for contra- ceptive use on women at an increased risk of STIs, and the Selected practice recommendations for contraceptive use on STI screening before IUD insertion. EVIDENCE: High-quality evidence from one randomized controlled trial, along with low-quality evidence from two observational studies, suggested no increased risk of HIV acquisition with Cu-IUD use. No studies were identified for LNG-IUDs. 1 1 1 1 Cu-IUD: copper-bearing intrauterine device; LNG-IUD: levonorgestrel-releasing IUD; MEC: Medical eligibility criteria for contraceptive use COMBINED HORMONAL CONTRACEPTIVES Combined hormonal contraceptives (CHCs) do not protect against sexually transmitted infections (STIs), including HIV. If there is a risk of STI/ HIV, the correct and consistent use of condoms is recommended. When used correctly and consistently, condoms offer one of the most effective methods of protection against STIs, including HIV. Female condoms are effective and safe, but are not used as widely as male condoms by national programmes. Condition MEC category Clarification/evidence COC P CVR CIC High risk of HIV 1 1 1 1 EVIDENCE: Low-to-moderate-quality evidence from 11 observational studies suggested no association between COC use (it was assumed that studies that did not specify oral contraceptive type examined mostly, if not exclusively, COC use) and HIV acquisition. No studies of P, CVR or CIC were identified. COC: combined oral contraceptive; CIC: combined injectable contraceptive; CVR: combined contraceptive vaginal ring; MEC: Medical eligibility criteria for contraceptive use; P: combined contraceptive patch Contraceptive eligibility for women at high risk of HIV: guidance statement | 1 Access to sexual and reproductive health services and information, including a comprehensive range of contraceptive methods, is fundamental to the rights and well-being of women and adolescent girls (1–4). There is a wide range of hormonal and non-hormonal modern contraceptive methods providing substantial individual and public health benefits. A core part of the work of the World Health Organization (WHO) is the development and maintenance of up-to-date, evidence-based guidance on contraceptive safety for individuals with particular medical conditions or medically relevant characteristics (5). The Medical eligibility criteria for contraceptive use (the MEC), fifth edition, offers national policy-makers and family planning programmes a comprehensive set of recommendations on the medical safety of contraceptive methods, allowing for the informed development of national policies, protocols and programmes (5). Global guidance about medical safety and eligibility facilitates the removal of unnecessary medical barriers to contraception. For over 20 years, the MEC has been used by countries to maximize safety and improve the quality of contraceptive care offered. Guidance about safety is kept up to date through continuous monitoring and reviews of published literature. In 2015, WHO released the fifth edition of the MEC (5). This edition contains more than 2000 recommendations for 25 different contraceptive methods, within the context of more than 80 medical conditions or medically relevant personal characteristics. Depending on the individual, more than one condition may need to be considered when making an informed contraceptive choice (5). The recommendations in the MEC are based on several considerations, including whether the use of a contraceptive method worsens the medical condition or creates additional health risks, and whether the condition makes the contraceptive method less effective (5). The MEC is part of a set of tools aiming to improve contraceptive coverage and care throughout the world. The MEC informs decisions about who might use a particular contraceptive method, through information and guidance about the safety and appropriateness of contraceptive care. The Selected practice recommendations for contraceptive use (the SPR) provides guidance on how to safely and effectively use various contraceptive methods (6). WHO produces a range of tools to support the use and implementation of contraceptive guidance, such as the MEC wheel and the Global handbook for providers (7, 8). Since 1996, the MEC has applied a four-category scale to indicate medical eligibility for particular contraceptive methods in the presence of particular conditions or individual characteristics (e.g. at high risk of HIV). For each condition or characteristic, contraceptive methods are placed into one of four numbered categories: 1. A condition for which there is no restriction for the use of contraceptive method. 2. A condition where the advantages of using the method generally outweigh the theoretical or proven risks. 3. A condition where the theoretical or proven risks usually outweigh the advantages of using the method. 4. A condition which represents an unacceptable health risk if the contraceptive method is used. The interpretation and application of the categories in practice are shown in Table 1. In the past, there has been mixed evidence about whether hormonal contraceptive methods – particularly depot medroxyprogesterone acetate (DMPA) – are associated with an increased risk of HIV acquisition. The available evidence consisted of theoretical biological data and observational studies with important limitations. In 2016, the independent TABLE 1. INTERPRETATION AND APPLICATION OF THE MEDICAL ELIGIBILITY CRITERIA (MEC) CATEGORIES Category With good resources for clinical judgement With limited resources for clinical judgement 1 Use the method in any circumstances Yes, use the method 2 Generally use the method 3 Use of the method not usually recommended unless more appropriate methods are not available or not acceptable No, do not use the method 4 Method not to be used BACKGROUND1 | Contraceptive eligibility for women at high risk of HIV: guidance statement2 2.1 Guideline Development Group The development of this guidance statement was undertaken by the independent Guideline Development Group (GDG) and an additional panel of external reviewers. The GDG consisted of 28 participants from 19 countries, including experts in family planning and HIV, representatives from affected populations, clinicians, epidemiologists, researchers, programme managers, policy- makers and guideline methodologists (see Annex 1). Following WHO guidance, months prior to the July 2019 meeting of the GDG, the name and brief biography of each proposed GDG member was published at the WHO website (https://www.who. int/reproductivehealth/publications/contraceptives-methods-hiv). The public was able to view and provide input on any perceived or real conflicts of interest of the proposed members. WHO responded to all comments and accordingly adjusted the final composition of the GDG. Prior to the GDG meeting, the WHO Secretariat and the GDG reviewed the members’ declarations of interests (Annex 2) and found no conflicts of interest sufficient to preclude anyone from participating in the deliberations or the development of the recommendations. The members of the GDG were also asked to declare any new conflicts of interest at the start of the meeting. None were declared. 2 For further information, see: http://www.gradeworkinggroup.org 2.2 Guideline development process This guidance statement was prepared according to the standards and requirements specified in the WHO handbook for guideline development (11). This process is used to ensure that WHO guidelines are of the highest quality and follow a transparent, systematic process. Key steps of the guideline process include determining the critical questions and outcomes, retrieving the evidence, synthesizing and grading the evidence, presenting it using a structured approach, and formulating recommendations. WHO’s Family Planning Guideline Steering Group determined the critical questions and outcomes to be considered by the GDG. Distinct types of evidence were identified as essential to review. These included the health evidence (randomized trials and observational epidemiological data), the evidence on biological plausibility and the data on the values and preferences of contraceptive users. Applying the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach,2 multiple factors are considered when formulating recommendations (12). These include the quality of the epidemiological evidence (found in the GRADE evidence profiles, which are prepared based on up-to-date Guideline Development Group (GDG) for the MEC reviewed the accumulating evidence regarding women at high risk of acquiring HIV (9). The GDG concluded that there remained uncertainty about whether the increased risk of HIV acquisition seen in some observational studies was a real effect of the contraceptive method used or whether it was a statistical artefact resulting from key limitations of observational studies (residual confounding in particular) (9). There also continued to be uncertainty about the clinical relevance of the biological data. In addition, there was concern that previous attempts to inform women of the uncertainty about both the epidemiological and biological data (through the use of a MEC clarification, indicated by an asterisk [*]) had not been effective. Given these concerns, the GDG concluded that MEC guidance should be changed. Thus, in 2017, the recommendation for progestogen- only injectable use among women at high risk of HIV infection was changed from MEC Category 1* (no restrictions to use, with a clarification) to MEC Category 2 (the benefits of use outweigh the risks), with an accompanying clarification (9). This new classification indicated that progestogen-only injectables could be used by women at high risk of HIV, because the advantages of these methods generally outweighed the possible disadvantages, and it highlighted that, when choosing these methods, there might need to be extra consideration of possible HIV acquisition, and counselling. As part of the 2017 revision, WHO reaffirmed its commitment to monitoring and assessing any new evidence relevant to contraceptive safety. New information, including results from a large, multinational randomized controlled trial (RCT) (10), led WHO to convene another GDG meeting in July 2019 to review all the available evidence and assess whether the MEC guidance needed revision. METHODS OF GUIDELINE REVIEW AND DEVELOPMENT2 Contraceptive eligibility for women at high risk of HIV: guidance statement | 3 systematic reviews); the values and preferences of contraceptive users; the balance of benefit and harms; the priority of the problem; equity and human rights; acceptability; and feasibility. The human rights principles and standards described in WHO’s guidance, Ensuring human rights in the provision of contraceptive information and services, were incorporated into deliberations (1). Owing to the focus on contraceptive safety, opportunity costs were not formally assessed during the formulation of the recommendations, since costs may vary widely throughout different regions (13). The GRADE evidence-to-decision framework (a tool encompassing quality of evidence, balance of benefits versus harms, values and preferences, priority of the problem, equity and human rights, feasibility) was used to ensure that recommendations were based on the consideration of all standards (11). 2.3 Evidence Retrieval Existing WHO recommendations on the use of specific contraceptive methods by women at high risk of HIV were reviewed in accordance with procedures outlined by the WHO Guidelines Review Committee and the GRADE approach to evidence review (11, 12). Three systematic reviews were conducted in preparation for the GDG meeting: two reviews pertained to the epidemiological evidence and the third review synthesized qualitative or quantitative studies on users’ values, preferences, views and concerns regarding contraceptive methods. The two systematic reviews of epidemiological evidence conducted for the GDG meeting were: 1. An updated systematic review on hormonal contraception and risk of HIV acquisition was conducted to include new studies published since 2016, when the last systematic review was undertaken (14). The review question was: ■ Among women at risk of HIV, does use of a hormonal contraceptive method compared with non-use of a hormonal contraceptive method (or use of another specific hormonal contraceptive method) increase risk of HIV acquisition? 2. A systematic review on copper-bearing intrauterine device (Cu-IUD) use and risk of HIV acquisition was also conducted. The review questions were: ■ Among women at risk of HIV, does use of a Cu-IUD compared with use of another non-hormonal contraceptive method or no contraceptive method increase risk of HIV acquisition? ■ Among women at risk of HIV, does use of a Cu-IUD compared with use of a specific hormonal contraceptive method increase risk of HIV acquisition? The selection criteria for the systematic reviews are listed in Table 2. The same study designs, population, comparators and outcomes were considered for all the contraceptive methods reviewed. TABLE 2. SELECTION CRITERIA FOR THE SYSTEMATIC REVIEWS Study design Longitudinal studies (randomized controlled trials and observational studies or meta-analyses containing data not captured in bibliographic database searches) Population Women of reproductive age at risk of HIV infection (women who were not living with HIV at baseline) Intervention Use of a specific contraceptive method: ■ hormonal contraception (injectables, oral contraceptives, implants, patches, rings or levonorgestrel-releasing intrauterine devices) ■ copper-bearing intrauterine devices (Cu-IUDs) Comparator One of two comparison groups: 1. non-use of a hormonal contraceptive method (either no contraceptive use or use of a non-hormonal method such as condoms or other barrier method, withdrawal, Cu-IUD or tubal ligation/vasectomy) 2. use of another specific method of hormonal contraception Outcome Incident, laboratory-confirmed HIV infection in women The two systematic reviews were conducted according to the preferred reporting items for systematic reviews and meta- analyses (PRISMA) (15). The PubMed and Embase databases were searched for studies published in any language in the peer-reviewed literature up to 26 June 2019. For individual studies, the risk of bias was assessed using a quality framework described in the previous review (14). Studies were classified into three levels: 1. “Unlikely to inform the primary question”: studies that had (a) no adjustment for any measure of condom use or (b) unclear measurement of exposure to contraception. 2. “Informative but with important limitations”: studies that had none of the flaws described above, but that still had the potential for unmeasured or residual confounding. 3. “Informative with few limitations”: studies that had none of the above flaws – likely to be a randomized controlled trial (RCT) that was assessed as having a low risk of bias on standard criteria for evaluating RCTs. The focus of the systematic reviews was on information from studies that were considered “informative but with important limitations” or “informative with few limitations.” to fall into levels 2 and 3. The values and preferences of contraceptive users were incorporated in multiple ways. First, an updated systematic review of qualitative or quantitative studies on users’ values, preferences, views and concerns regarding the contraceptive methods considered under the Medical eligibility criteria for contraceptive use (MEC) guidelines was conducted (16). This review covered studies from any country published in the peer-reviewed literature between January 2005 and December 2017. Just prior to the GDG meeting in July 2019, this review was informally updated for studies in either the peer-reviewed or grey literature that specifically looked at the values and preferences of contraceptive users relating to the issue of hormonal contraception and HIV acquisition. Second, because | Contraceptive eligibility for women at high risk of HIV: guidance statement4 the updated systematic review did not identify any information specific to key populations at risk of HIV, consultative engagements were conducted in May through July of 2019, including a global online survey of sex workers and participatory focus group discussions with female sex workers in Zimbabwe (through the Sisters with a Voice programme). Third, stakeholders representing specific affected populations, including women living with HIV, and young women, contributed their perspectives through a presentation and discussion of critical perspectives at the GDG meeting. An update about the biological data on the theoretical effect that contraception may have on HIV acquisition was prepared, reviewed and discussed at the GDG meeting, including consideration of the theoretical plausibility of individual methods of hormonal contraception having an influence on HIV acquisition. 2.4 Evidence Synthesis Epidemiological data were synthesized and evaluated according to the GRADE approach to evidence review (12). Based on this, randomized trials begin with a grade for strength of evidence of “high”, and observational studies start with a grade of “low”. The risk of bias was assessed for the summarized data using standard GRADE methods (17). Factors that could lower the evidence grade were limitations in the evidence (bias), inconsistency between studies, imprecision of estimates, indirectness of evidence, and publication bias (17–22). Randomized trials were assessed for bias by systematically evaluating for inadequate randomization/ allocation concealment; inadequate blinding of treatments; attrition and failure to use intention-to-treat analyses; selective outcome reporting; and crossover/contamination (17). Observational studies were assessed for bias by examining whether there was failure to develop and apply appropriate eligibility criteria, flawed measurement of exposures or outcomes, failure to adequately address confounding, or incomplete follow-up (17). Factors that could increase the evidence grade of observational studies included the presence of a dose-response relationship, a large magnitude of observed associations, and adjustment for plausible confounders affecting observed associations (22). 2.5 Formulation of recommendations Findings from the systematic reviews and associated GRADE evidence profiles (Annex 3) were presented at the GDG meeting. A presentation on the biological plausibility of hormonal contraception modifying the risk of HIV acquisition, and several presentations on contraceptive users’ values and preferences, were also given. These inputs were used to develop an evidence-to-decision framework (Annex 4), which served as the basis for the GDG’s deliberations during the meeting (12). All recommendations were arrived at by consensus. After the GDG’s recommendations were made, a small writing group prepared a draft guidance statement summarizing the decision and associated rationale. The draft was reviewed by the entire GDG and the external review group (see Annex 1). Comments received from the GDG and the external review group were considered and addressed by the writing group. The final version of this guidance statement was approved by the WHO Guidelines Review Committee on 22 August 2019. SUMMARY OF THE EVIDENCE3 The Evidence for Contraceptive Options and HIV Outcomes (ECHO) Study3 was the primary source of new evidence since the WHO last reviewed recommendations on contraception for women at high risk of HIV (9). The ECHO Study was a large randomized controlled trial (RCT) conducted in Eswatini, Kenya, South Africa and Zambia specifically designed to compare HIV incidence among users of three contraceptive methods: intramuscular depot medroxyprogesterone acetate (DMPA-IM), levonorgestrel (LNG) implants and copper-bearing intrauterine 3 For further information, see: http://echo-consortium.com devices (Cu-IUDs) (10). The trial randomized 7829 HIV- seronegative women, aged between 16 and 35 years, who desired effective contraception and consented to be randomized to one of the three contraceptive methods. There was no group of non-users of contraception in the ECHO trial because all of the women enrolled desired effective contraception. Women returned every three months for HIV testing, contraceptive counselling, safety monitoring, behavioural assessment and a comprehensive package of HIV Contraceptive eligibility for women at high risk of HIV: guidance statement | 5 prevention services; for up to 18 months. The main (primary) comparisons used a modified intention-to-treat analysis. In addition, pre-planned (secondary) analyses were conducted, restricted to continuous use of the assigned contraceptive method and adjusted for a number of important confounders, including vaginal sex without a condom, a new sexual partner in the previous three months, and more than one sexual partner. Statistical significance in the ECHO trial was taken to be a P-value less than 0.04 for the primary comparisons. No statistically significant associations were found for any of the primary comparisons between the three contraceptive methods (Annex 3). The quality of the evidence from this RCT was rated as high, due to its large size, strong randomization and allocation procedures, high follow-up rates, high continuation of the allocated contraceptive method, objective measurement of HIV incidence and comprehensive analysis of the results. Other evidence on hormonal contraception and HIV acquisition published since the 2016 review (14) was included in the evaluation of the body of evidence, along with a systematic review on Cu-IUDs and risk of HIV acquisition (Annex 3). For hormonal contraception, one new observational study and updated estimates from a previously included study were identified (23, 24). Adding this evidence to the previous 14 observational studies (14) did not change the conclusions of the previous review. Thus, the body of observational evidence suggested some concern about an increased risk of HIV acquisition with DMPA-IM use, but was generally reassuring for other methods of hormonal contraception. For intrauterine devices (IUDs), two observational studies did not suggest an increased risk of HIV acquisition with Cu-IUD use (23, 25). The quality of evidence from these observational studies was rated as low and low-to-moderate. 3.1 Progestogen-only injectables One RCT (the ECHO trial) observed no statistically significant differences in HIV acquisition when comparing DMPA-IM versus Cu-IUD, and DMPA-IM versus LNG implant (10). The quality of the evidence from this RCT was rated as high. Evidence from 14 observational studies of DMPA-IM, norethisterone enanthate (NET-EN) or unspecified progestogen- only injectables considered to be “informative but with important limitations” was assessed (14, 23, 24). Additional data from one new observational study and updated estimates from a previously included study did not change the conclusions of the previous review of observational evidence (14). The quality of the evidence from the observational studies was rated as low and low-to-moderate due to limitations that included unmeasured confounding. 3.2 Progestogen-only implants Three observational studies considered to be “informative but with important limitations” assessed implants. One had been included in the previous review (26), one provided an updated point estimate to that used for the previous review (24) and one provided an entirely new estimate of risk (23). Two of the studies assessed LNG implants (24, 26) and the third assessed women using either LNG or etonogestrel implants (23). None of the three studies suggested an increased risk of HIV acquisition with implant use, consistent with the conclusion of the previous review (14). The quality of the evidence from these studies was rated as low. 3.3 Progestogen-only pills No studies considered “informative but with important limitations” or “informative with few limitations” were identified for progestogen-only pills. 3.4 Intrauterine devices One RCT (the ECHO trial) observed no statistically significant differences in HIV acquisition between DMPA-IM and Cu-IUD, or Cu-IUD and LNG implants (10). The quality of the evidence from this RCT was rated as high. Two observational studies considered “informative but with important limitations” did not observe an association with HIV acquisition when comparing Cu-IUD use with tubal ligation or no contraceptive method use, DMPA-IM, NET-EN or implants (23, 25). The quality of this observational evidence was rated as low. No evidence was identified for LNG-IUDs. 3.5 Combined hormonal contraceptives Eleven observational studies deemed “informative but with important limitations” assessed the use of combined oral contraceptives (COC). (It was assumed that studies that did not specify the oral contraceptive type examined mostly, if not exclusively, examined COC use.) All of these studies were included in the previous review, while an updated estimate came from one newly available study (14, 24). Overall, these studies suggested no association between COC use and HIV acquisition. The quality of the evidence was rated as low-to-moderate. No evidence was identified for the combined contraceptive patch, ring or injectable. 3.6 Additional evidence considered by the GDG 3.6.1 BIOLOGICAL DATA Biological data pertaining to the plausibility of an effect of individual methods of hormonal contraception on HIV acquisition were reviewed. Several biological mechanisms by which individual methods of hormonal contraception could theoretically modify the risk of HIV acquisition have been postulated, but | Contraceptive eligibility for women at high risk of HIV: guidance statement6 sparse and contradictory data make it unclear which, if any, of these biological mechanisms are clinically relevant. Potential mechanisms include alteration of the systemic and local immune response and changes in the genital tract environment. It was noted that different forms of hormonal contraception may change these factors in different ways. Combined contraceptives containing both ethinylestradiol and a progestogen may have a different effect than progestogen-only methods. Additionally, various progestogen-only methods, such as DMPA and NET-EN injectables, may change immune function variably. It remains uncertain to what extent data from animal and laboratory studies, including in relation to progestogen type and dosing, can be applied to clinical outcomes in humans. 3.6.2 VALUES AND PREFERENCES OF CONTRACEPTIVE USERS The systematic review identified 375 studies from all regions of the world (27). Across studies, women’s values and preferences centred on themes of choice and available options, ease of use, side-effect profiles and contraceptive efficacy. Contextual factors, such as the contraceptive methods available, counselling from providers, and the opinions of social networks, influenced decision-making. From the grey literature, two additional studies were identified that were relevant to hormonal contraception and HIV specifically (28, 29). Both found that messages from the 4 “Free” means the freedom and ability to make a voluntary decision about contraceptive use without barriers or coercion; informed means complete, correct and clear information has been given about all the options, plus details about the chosen method 2017 WHO guidance were difficult for providers to explain fully and may not be completely understood by clients. The online survey of sex workers from multiple global regions found that individual preferences around contraception varied widely and could change over time; ongoing partnership and dialogue with sex workers is essential to understanding evolving priorities. In participatory focus groups, Zimbabwean sex workers said their contraceptive choices were shaped by a wide range of factors, including cost, accessibility, the way sex workers are treated at clinics, the influence of male partners, and contraceptive side-effects. Sex without a condom was common, and there was a need to strengthen access to HIV/STI prevention and contraceptive services. The community stakeholder presentation emphasized that, for some women, any level of increased HIV risk would be too high. It also highlighted that the ECHO trial was not set up to assess the difference in the risk of HIV acquisition between contraceptive users and non-users. Community stakeholders also emphasized that there was a lack of true contraceptive choice for many women and girls, saying the guidance should emphasize full, free and informed contraceptive choice,4 the procurement of a range of contraceptive methods, and investment in integrated contraception and HIV services. RECOMMENDATIONS4 4.1 Recommendations for contraceptive use among women at high risk of HIV infection All hormonal contraceptive methods and intrauterine devices (IUDs) now fall into Category 1 of the Medical eligibility criteria for contraceptive use (MEC) (5) for women at high risk of HIV. Thus, women at high risk of HIV can use all methods of contraception without restriction. ■ Women at high a risk of HIV infection are eligible to use all progestogen-only contraceptive methods without restriction (MEC Category 1), including progestogen-only pills (POPs), intramuscular depot medroxyprogesterone acetate (DMPA-IM), subcutaneous DMPA (DMPA-SC), norethisterone enanthate (NET-EN) injectables, levonorgestrel (LNG) implants, and etonogestrel implants. ■ Women at a high risk of HIV infection are eligible to use copper-bearing IUDs (Cu-IUDs) and LNG implants without restriction (MEC Category 1). In considering the use of IUDs, many women at a high risk of HIV are also at risk of other sexually transmitted infections (STIs); for these women, providers should refer to the MEC recommendation on women at increased risk of STIs and the Selected practice recommendations for contraceptive use on STI screening before IUD insertion (5, 6). ■ Women at a high risk of HIV infection are eligible to use all combined hormonal contraceptive methods without restriction (MEC Category 1), including combined oral Contraceptive eligibility for women at high risk of HIV: guidance statement | 7 contraceptives (COCs), combined injectable contraceptives (CICs), combined contraceptive patches (P) and combined vaginal rings (CVR). 4.2 Rationale The Guideline Development Group (GDG) reviewed, and discussed extensively, the new epidemiological and biological evidence, as well as related information about values and preferences, equity and human rights, and feasibility. After deliberating on all of the available evidence, the GDG recommended that the MEC category for DMPA and Cu-IUD should be changed to MEC Category 1. The GDG noted that there was no evidence regarding DMPA-SC and LNG-IUD, and only limited new information regarding NET-EN. Until more information becomes available, the GDG judged it was appropriate to follow the same approach as previously used, i.e. grouping all progestogen-only injectables together (DMPA- IM, DMPA-SC and NET-EN) as MEC Category 1, and to assign the same MEC category to the LNG-IUD as to the Cu-IUD (MEC Category 1). One key portion of the GDG’s deliberations related to evaluating evidence from the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Study (see Annex 3). The GDG gave particular attention to this information because of its ability to address unmeasured confounding – a major cause of uncertainty when interpreting results from observational studies. The GDG recognized that the ECHO trial did not address the etiological or causal question of whether DMPA increases the risk of HIV acquisition when compared with not using any contraception. Nevertheless, since the MEC provides guidance for women wishing to use contraception, results from the ECHO trial about the comparative risk of HIV acquisition among users of the three contraceptives tested were highly pertinent to the GDG’s deliberations. Furthermore, the GDG noted that the high incidence of HIV infection experienced by each contraceptive group during the ECHO trial was similar to the background incidence assumed when designing the trial. This was deemed to be indirect evidence addressing the question, suggesting no increased risk of HIV acquisition among users of these contraceptives compared with women not using any contraception. The ECHO trial was considered to be a well conducted study that provided high-quality evidence that superseded the low and low-to-moderate-quality observational evidence previously available to the GDG. This direct epidemiological evidence, from a trial specifically designed to address the issue, was judged to be more informative than theoretical biological evidence. The reasons for considering the ECHO trial to be of high quality included its large size; robust randomization methods; good adherence to the allocated contraceptive method; a low attrition rate; regular, standardized and objective outcome measurements; and a blinded, comprehensive analysis of the data (including sensitivity analyses for postulated confounders such as sexual activity and condom use). Although women and providers of services in the ECHO trial could not be blinded to the intervention allocation, there was no evidence that this led to the different groups of participants acting, or being managed, differently with respect to important issues such as HIV prevention counselling. This ensured that residual confounding, particularly in relation to condom use or sexual activity, was highly unlikely to have affected the ECHO trial. The GDG noted that although the ECHO trial was designed to detect a 50% increase in the risk of HIV acquisition between contraceptive groups assessed, the observed high HIV incidence and small losses to follow up meant that it could detect a 30% increase. When considering the ECHO trial results, the GDG focused on the point estimates for each primary comparison. The group noted that none of the point estimates for the primary comparisons were statistically significant. The 96% confidence intervals surrounding these point estimates included unity, and so encompassed the possibility of a small increased or decreased difference in risk between contraceptives. The GDG acknowledged, however, that for an individual woman at a high risk of HIV, any change in this risk may be important. After a full discussion, the GDG judged that unmeasured confounding was the most likely explanation for the apparent increased risk of HIV acquisition among DMPA-IM users seen in some observational studies. The GDG’s decisions to revise the MEC classifications for DMPA and IUDs were further grounded by the values and preferences of women towards optimizing informed contraceptive choice and the availability of a wide range of contraceptive options, based on a systematic review of qualitative and quantitative evidence, consultative engagements with sex workers and the perspectives of GDG members representing specific affected populations. In previous editions of the MEC, IUDs were classified as MEC Category 2 for women at a high risk of HIV. This recommendation was given because of the absence of high-quality, direct evidence about the risk of acquiring HIV among IUD users. In addition, there was an assumption that most women at a high risk of HIV were also at an increased risk of other STIs. The ECHO trial provided direct, high-quality evidence about the risk of HIV acquisition risk among women using the Cu-IUD, enabling the GDG to review its recommendation regarding these women. Any new evidence related to IUD use in women at a high risk of other STIs will be reviewed for the next MEC update. The GDG was concerned about the high rates of both HIV and STIs among women in the ECHO trial, reflecting the background risk factors among women seeking contraception in the study areas. The high incidence of HIV was particularly striking given the extensive efforts made during the ECHO trial to provide HIV prevention counselling and interventions. Thus, while the GDG concluded that the risk of HIV acquisition was not affected by the contraceptive method used, it emphasized the need for renewed efforts to reduce the incidence of HIV and STIs. | Contraceptive eligibility for women at high risk of HIV: guidance statement8 IMPLICATIONS FOR POLICY-MAKERS, PROGRAMME MANAGERS AND HEALTH-CARE PROVIDERS 5 While the main audiences for the Medical eligibility criteria for contraceptive use (MEC) are policy-makers and programme managers, a fundamental tenet of the MEC is that they are woman-centred. The following were the key messages that came from the deliberations of the Guideline Development Group. 5.1 A woman’s risk of HIV should not restrict her contraceptive choice While a risk of HIV should not restrict a woman’s choice to use hormonal contraception or an intrauterine device, it is important to note that these methods do not protect her against acquiring HIV or other sexually transmitted infection (STI). The new MEC recommendations should not be interpreted as indicating that HIV and STI testing and prevention are no longer important. Indeed, the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Study highlighted the critical need to strengthen and expand HIV and STI prevention services (10). Testing for HIV and STIs should be part of high-quality family planning services for women at risk, particularly for those living in areas of high HIV and STI incidence. 5.2 Efforts to expand access to contraceptive options must continue Women have the right to a range of short-acting, long-acting and permanent contraceptive methods, as well as to emergency contraception (1). A comprehensive range of contraceptive methods enables women to respond to changing needs and preferences during their reproductive lives. Informed decision- making and woman-centred, high-quality counselling are key components in the human rights-based provision of contraceptive information and services (2). The ECHO trial reinforced that offering a range of methods is possible and acceptable to women (10). Family planning and HIV services should be included in national universal health coverage initiatives. Efforts to expand safe and effective contraceptive options, and to ensure their availability and the access to them, must continue. Technical resources are available to support countries to introduce more contraceptive options into their programmes and services (Box 1). BOX 1. TECHNICAL RESOURCES TO SUPPORT PROGRAMMES o Medical eligibility criteria for contraceptive use (in English, French and Russian) https://apps.who.int/iris/handle/10665/181468 o Selected practice recommendations for contraceptive use (in English, French and Spanish) https://apps.who.int/iris/handle/10665/252267 o Implementation guide for the medical eligibility criteria and selected practice recommendations for contraceptive use (available in English, French, Portuguese and Spanish) https://apps.who.int/iris/handle/10665/272758 o Global handbook for family planning providers https://apps.who.int/iris/handle/10665/260156 o Training Resource Package for Family Planning website (available in English and French) https://www.fptraining.org o Mobile application for the Medical eligibility criteria for contraceptive use (free, for android and iOS platforms) https://www.who.int/reproductivehealth/mec-app o Policy brief: consolidated guidelines on HIV prevention, diagnosis, treatment and care for key populations, 2016 update https://apps.who.int/iris/handle/10665/258967 o Treat all: policy adoption and implementation status in countries (fact sheet) https://apps.who.int/iris/handle/10665/258538 Contraceptive eligibility for women at high risk of HIV: guidance statement | 9 5.3 A renewed emphasis on HIV and STI prevention services is urgently needed The ECHO trial showed high rates of both HIV and STIs in the study sites (10), highlighting the need for appropriate prevention, diagnosis and treatment of all STIs. Current HIV prevention measures remain unavailable or unsatisfactory for many women and adolescent girls living in settings of high HIV incidence. In such areas, the integration of family planning and HIV prevention services for all women is essential if the health of women and adolescent girls is to be improved. In settings of low HIV prevalence, there is a need for family planning providers to evaluate personal risk factors that may increase a woman’s risk of acquiring HIV and then to provide appropriate services. The ECHO trial also showed that syndromic management did not decrease the prevalence of STIs at baseline and at the end of follow-up. STI programmes need to be strengthened, including a move towards diagnostic management. ■ In settings with high HIV prevalence, HIV testing and prevention should be included in family planning services. HIV testing should be offered to all women and to partners of all women with HIV. HIV prevention options should be offered to all women, including pre-exposure prophylaxis (PrEP), as recommended in WHO guidelines (30). The offer of PrEP to women could also be considered where HIV incidence is high (but below 3/100 person-years overall) following, for example, a simple risk assessment. A risk assessment could include: desire to take PrEP (reflecting a self-identified risk); history of an STI; more than one sex partner in the last six months; or women with a sex partner with HIV who is not virally supressed on antiretroviral therapy. ■ In settings with low HIV prevalence, the routine offer of HIV testing and prevention services in family planning settings is unlikely to be cost-effective. HIV testing and prevention services could nonetheless be offered to women who request these services. BOX 2. WORK TO IDENTIFY WOMEN AT HIGH RISK OF HIV A person’s HIV risk depends on the incidence of HIV in the area where they live, and their individual risk factors. Family planning programmes must work closely with their national and subnational HIV programmes to use local epidemiological data to identify geographical areas and risk factors that put women at a high risk of HIV infection. 6.1 Contraceptive methods and HIV acquisition The existing body of evidence is sufficient to guide practice on intramuscular depot medroxyprogesterone acetate (DMPA-IM), levonorgestrel (LNG) implants and copper-bearing intrauterine devices; additional observational data will not add substantially to the evidence base for these methods. However, in the absence of trial data similar to those in the ECHO Study (10), observational data about subcutaneous DMPA (DMPA-SC), LNG IUDs, etonogestrel implants, or future contraceptive or multi-purpose prevention technologies could still be useful, although unmeasured confounding would likely remain a concern. Studies should consider the potential impact of contraceptive use on other sexually transmitted infections as well as HIV. Additional research on the specific effects of contraception-related bleeding changes in relation to the risk of HIV or STI acquisition is also needed. 6.2 HIV prevention The Guideline Development Group was deeply concerned by the high HIV incidence found among women seeking family planning services in the ECHO Study sites, despite the fact that trial participants received an extensive HIV prevention package (including repeated HIV testing and counselling, partner HIV testing and condom distribution, as well as pre-exposure prophylaxis (PrEP) late in the study as this became the standard of care). More research is needed on ways to increase the acceptability and uptake of effective HIV prevention strategies for women at a high risk of HIV, tailored to settings of both high and low HIV prevalence and to women with a range of personal risk factors. In the ECHO trial, the uptake (and hence impact) of PrEP was minimal as it became available only late in the trial (10). Where it was available on site, as opposed to requiring referral to another site, acceptability and uptake were high. Ways to include HIV self-testing and PrEP in family planning services should be KNOWLEDGE GAPS AND AREAS FOR RESEARCH6 | Contraceptive eligibility for women at high risk of HIV: guidance statement10 explored. This should include behavioural and implementation science research on the effective integration of HIV and contraception services. 6.3 Community involvement The ECHO trial employed a range of strategies for directly engaging with civil society at the study site, and at regional and global levels (10). An in-depth assessment of the strengths and limitations of each strategy is likely to provide models for community engagement in contraceptive and HIV prevention research that could be adopted in the future. 6.4 Increased funding for high-quality, policy-relevant research The ECHO Study demonstrated that a well conducted, adequately powered randomized controlled trial is possible in contraceptive research, and can make an important contribution to global decision-making. Global policy should be based on comprehensive high-quality evidence, but additional investment in contraceptive research is critically overdue, including research addressing whether financial barriers affect the contraceptive choices of women. DISSEMINATION OF THIS GUIDANCE STATEMENT7 The World Health Organization (WHO) will work to communicate this guidance statement clearly and widely. WHO will evaluate whether the guidance achieves its intentions. The guidance will be published on the WHO website and in a limited quantity of printed documents. The guidance will be widely disseminated through the WHO regional and country offices, WHO Member States, other United Nations agencies, civil society, the Implementing Best Practices (IBP) initiative, professional organizations, governmental and non- governmental partner organizations, and WHO collaborating centres working in the area of HIV and sexual and reproductive health. The WHO Secretariat will work closely with sexual and reproductive health and HIV focal points in regional and country offices of WHO, the United Nations Population Fund and the Joint United Nations Programme on HIV and AIDS to conduct a series of regional learning and knowledge-sharing events. This engagement will target opportunities where sexual and reproductive health issues are being discussed; examples include the 25th Conference on Population and Development in July 2019 and the 20th International Conference on AIDS and Sexually Transmitted Infections in Africa in December 2019. The Secretariat will also work closely with country task teams and working groups leading HIV and contraception programme efforts to share the guidance with grassroots and community- level organizations and providers. Additionally, webinars for stakeholders in multiple languages will be organized during 2020 to ensure Member States and stakeholders are fully informed of the new recommendations. These opportunities will enable WHO to disseminate the updated guidance effectively and efficiently. Derivative communication products highlighting key counselling issues (e.g. short briefs for front-line health-care providers and community-based organizations) will be prepared in collaboration with WHO’s implementing partners, and in consultation with the GDG during 2020. A policy brief in the six official languages used by WHO will be developed to inform policy-makers about the contraception updates. As part of the dissemination of the recommendations in this guidance statement, WHO will update its digital contraceptive decision-support tools – the MEC mobile app (31), the humanitarian contraceptive delivery app (32) and the postpartum compendium (33). These mobile applications are free to download and available for both iOS and Android platforms. Additionally, the Global handbook for family planning providers and the online Family Planning Training Resource Package will be updated accordingly (8, 34). WHO will continue to monitor the body of evidence informing these recommendations and will convene additional consultations when needed. Contraceptive eligibility for women at high risk of HIV: guidance statement | 11 REFERENCES 1. Ensuring human rights in the provision of contraceptive information and services: guidance and recommendations. Geneva: World Health Organization; 2014 (https://apps.who.int/iris/handle/10665/102539, accessed 24 August 2019). 2. Framework for ensuring human rights in the provision of contraceptive information and services. Geneva: World Health Organization; 2014 (https://apps.who.int/iris/handle/10665/133327, accessed 24 August 2019). 3. The thirteenth general programme of work, 2019–2023: promote health, keep the world safe, serve the vulnerable. Geneva: World Health Organization; 2019 (https://apps.who.int/iris/handle/10665/324775, accessed 24 August 2019). 4. Reproductive health strategy to accelerate progress towards the attainment of international development goals and targets. Geneva: World Health Organization; 2004 (https://apps.who.int/iris/handle/10665/68754, accessed 24 August 2019). 5. Medical eligibility criteria for contraceptive use, fifth edition. Geneva: World Health Organization; 2015 (https://apps.who.int/iris/ handle/10665/181468, accessed 24 August 2019). 6. Selected practice recommendations for contraceptive use: third edition. Geneva: World Health Organization; 2016 (https://apps.who.int/iris/handle/10665/252267, accessed 24 August 2019). 7. WHO medical eligibility criteria wheel for contraceptive use, 2015 update. Geneva: World Health Organization; 2004 (https://apps.who.int/iris/handle/10665/173585, accessed 24 August 2019). 8. World Health Organization, Johns Hopkins Bloomberg School of Public Health. Family planning: a global handbook for providers: evidence-based guidance developed through worldwide collaboration, third edition. Geneva: World Health Organization; 2018 (https://apps.who.int/iris/handle/10665/260156, accessed 24 August 2019). 9. Hormonal contraceptive eligibility for women at high risk of HIV: guidance statement: recommendations concerning the use of hormonal contraceptive methods by women at high risk of HIV. Geneva: World Health Organization; 2017 (https://apps.who.int/ iris/handle/10665/254662, accessed 24 August 2019). 10. Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium. HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial. Lancet. 2019;394(10195):303–13. doi: 10.1016/S0140-6736(19)31288-7. 11. WHO handbook for guideline development, second edition. Geneva: World Health Organization; 2014 (https://apps.who.int/iris/ handle/10665/145714, accessed 24 August 2019). 12. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J et al. GRADE guidelines: 1. Introduction –GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64(4):383–94. doi: 10.1016/j.jclinepi.2010.04.026. 13. Singh S. Adding it up: costs and benefits of contraceptive services – estimates for 2017. New York (NY): Guttmacher Institute; 2017. 14. Polis CB, Curtis KM, Hannaford PC, Phillips SJ, Chipato T, Kiarie JN et al. An updated systematic review of epidemiological evidence on hormonal contraceptive methods and HIV acquisition in women. AIDS. 2016;30(17):2665–83. doi: 10.1097/ QAD.0000000000001228. 15. Moher D, Liberati A, Tetzlaff J, Altman DG; The Prisma Group. Preferred reporting items for systematic reviews and meta- analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. doi: 10.1371/journal.pmed.1000097. 16. Kennedy CE, Yeh PT, Gaffield ME. Contraception values and preferences: protocol and methods for a global systematic review. Contraception. 2019 (in press). doi: 10.1016/j.contraception.2018.05.006Get. 17. Guyatt GH, Oxman AD, Vist G, Kunz R, Brozek J, Alonso-Coello P et al. GRADE guidelines: 4. Rating the quality of evidence— study limitations (risk of bias). J Clin Epidemiol. 2011;64(4):407–15. doi: 10.1016/j.jclinepi.2010.07.017. 18. Guyatt GH, Oxman AD, Kunz R, Brozek J, Alonso-Coello P, Rind D et al. GRADE guidelines 6. Rating the quality of evidence – imprecision. J Clin Epidemiol. 2011;64(12):1283–93. doi: 10.1016/j.jclinepi.2011.01.012. | Contraceptive eligibility for women at high risk of HIV: guidance statement12 19. Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M et al. GRADE guidelines: 8. Rating the quality of evidence – indirectness. J Clin Epidemiol. 2011;64(12):1303–10. doi: 10.1016/j.jclinepi.2011.04.014. 20. Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M et al. GRADE guidelines: 7. Rating the quality of evidence – inconsistency. J Clin Epidemiol. 2011;64(12):1294–302. doi: 10.1016/j.jclinepi.2011.03.017. 21. Guyatt GH, Oxman AD, Montori V, Vist G, Kunz R, Brozek J et al. GRADE guidelines: 5. Rating the quality of evidence – publication bias. J Clin Epidemiol. 2011;64(12):1277–82. doi: 10.1016/j.jclinepi.2011.01.011. 22. Guyatt GH, Oxman AD, Sultan S, Glasziou P, Akl EA, Alonso-Coello P et al. GRADE guidelines: 9. Rating up the quality of evidence. J Clin Epidemiol. 2011;64(12):1311–6. doi: 10.1016/j.jclinepi.2011.06.004. 23. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619–22. doi: 10.1097/ QAD.0000000000002260. 24. Sabo MC, Richardson BA, Lavreys L, Martin HL, Jr, Jaoko W, Mandaliya K et al. Does bacterial vaginosis modify the effect of hormonal contraception on HIV seroconversion. AIDS. 2019;33(7):1225–30. doi: 10.1097/QAD.0000000000002167. 25. Lavreys L, Baeten JM, Martin Jr HL, Overbaugh J, Mandaliya K, Ndinya-Achola J et al. Hormonal contraception and risk of HIV-1 acquisition: results of a 10-year prospective study. AIDS. 2004;18(4):695–7. 26. Wall KM, Kilembe W, Vwalika B, Htee Khu N, Brill I, Chomba E et al. Hormonal contraception does not increase women’s HIV acquisition risk in Zambian discordant couples, 1994–2012. Contraception. 2015;91(6):480–7. doi: 10.1016/j. contraception.2015.02.004. 27. Yeh PT, Kennedy CE, Gaffield ME. Contraception values and preferences: a global systematic review. Contraception. 2019; (accepted pending revisions). 28. Miller L, Ntinginya M, Makula J, Juma A, Mackay A, Wadegu E et al. Final report: a pilot study to assess training and communication materials on progestogen-only injectable use and risk of HIV acquisition in Tanzania. London: Marie Stopes International; 2019 (https://resultsforinformedchoice.org/wp-content/uploads/2019/02/Injectables-and-HIV-Pilot-Study-Report-TZ.pdf, accessed 24 August 2019). 29. Littlepage S, Dam A, Nakyanjo N, Polis C, Nalugoda F, Kennedy CE. Contraceptive decision-making in the context of HIV risk and changing World Health Organization guidelines: a qualitative study in Rakai, Uganda. 2019 (personal communication). 30. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach, second edition. Geneva: World Health Organization; 2016. (https://apps.who.int/iris/handle/10665/208825, accessed 24 August 2019). 31. New app for WHO’s medical eligibility criteria for contraceptive use. In: World Health Organization [website]. Geneva: World Health Organization; 2018 (https://www.who.int/reproductivehealth/mec-app, accessed 24 August 2019). 32. Delivering contraceptive services in humanitarian settings: new tool for front-line health care workers. In: World Health Organization [website]. Geneva: World Health Organization; 2018 (https://www.who.int/reproductivehealth/publications/ humanitarian-settings-contraception, accessed 24 August 2019). 33. New WHO tool helps guide contraception choices following childbirth. In: World Health Organization [website]. Geneva: World Health Organization; 2016 (https://www.who.int/reproductivehealth/news/pfpc, accessed 24 August 2019). 34. TRP: Training Resource Package for Family Planning [website]. Baltimore (MD): Johns Hopkins University; 2019 (https://www.fptraining.org, accessed 24 August 2019). Contraceptive eligibility for women at high risk of HIV: guidance statement | 13 ANNEX 1. GUIDELINE DEVELOPMENT GROUP AND EVIDENCE SECRETARIAT Guideline Development Group Sharon Achilles (University of Pittsburgh, United States of America), Richard Adanu (University of Ghana, Ghana), Rachid Bezad (University Roi Mohammad VI, Morocco), Sharon Cameron (University of Edinburgh, United Kingdom of Great Britain and Northern Ireland), Tsungai Chipato (University of Zimbabwe, Zimbabwe), Maria del Carmen Cravioto (National Institute of Nutrition, Salvador Zubiran, Mexico) [unable to attend], Alison Edelman (Oregon Health & Science University, United States), Mohammad Eslami (Ministry of Health and Education, Islamic Republic of Iran), Anna Glasier (University of Edinburgh, United Kingdom), Andy Gray (University of KwaZulu- Natal, South Africa), Philip Hannaford (University of Aberdeen, United Kingdom), Felicita Hikuam (AIDS and Rights Alliance for Southern Africa, Namibia), Unnop Jaisamrarn (Chulalongkorn University, Thailand), Loveleen Johri (family planning and reproductive health independent consultant, India), Natasha Kaoma (Copper Rose Zambia, Zambia), Seni Kouanda (Institute of Research in Health Sciences, Burkina Faso), Elizabeth Lule (global health and international development independent consultant, Uganda), Vimbai Magwenzi (Centre for Sexual Health and HIV/AIDS Research, Zimbabwe) [unable to attend], Loyce Maturu (Zvandiri Mentor with Africaid, Zimbabwe), Olav Meirik (Instituto Chileno de Medicina Reproductiva, Chile), Placid Mihayo (Ministry of Health, Uganda), Lilian Mworeko (International Community of Women Living with HIV Eastern Africa, Uganda), Hiromi Obara (National Center for Global Health and Medicine, Tokyo, Japan), Herbert Peterson (University of North Carolina, United States), John Pile (independent consultant, Thailand), Carolina Sales Vieira (University of Sao Paulo, Brazil), Sarah Simpson (EquiACT, France), Aminata Wurie (Youth Coalition for Sexual and Reproductive Rights, Sierra Leone). Philip Hannaford and Natasha Kaoma co-chaired the meeting Guideline Development Group (GDG) meeting. Evidence Secretariat Centre for Sexual Health and HIV/AIDS Research – Euphemia Sibanda FHI 360 – Timothy Mastro Independent Consultant – Ania Shapiro Johns Hopkins University – Caitlin Kennedy Oregon Health & Science University – Maria Isabel Rodriguez United States Centers for Disease Control and Prevention – Kathryn Curtis University of Washington – Jared Baeten Wits Reproductive Health and HIV Institute – Helen Rees Observer Zandile Mnisi (Ministry of Health, Eswatini) External Review Group Florence Anam (Doctors Without Borders, South Africa), Winfred Apio (Uganda Youth and Adolescents Forum, Uganda), Lynn Bakamjian (independent consultant, United States), Milena Brito (University of Sao Paulo, Brazil), Roy Jacobstein (IntraHealth, United States), Ernest Maya (University of Ghana, Ghana), Mari Ngai (National Center for Global Health and Medicine, Japan), Cristina Puig Borràs (European Consortium for Emergency Contraception, Spain), Nusrat Shah (Society of Obstetrics & Gynaecology, Pakistan), Bulbul Sood (Jphiego, India). WHO Secretariat The WHO Secretariat attended the meeting and several WHO staff provided background presentations (Rachel Baggaley, Mary Lyn Gaffield, James Kiarie, Nancy Kidula). The WHO Secretariat was present to serve as a background resource, if request by the GDG. Neither WHO, the Joint United Nations Programme on HIV/AIDS (UNAIDS) nor the United Nations Population Fund (UNFPA) staff participated in the decision- making or formulation of the recommendations, which was the sole responsibility of the GDG. Several WHO staff contributed to the systematic reviews (Mary Lyn Gaffield, James Kiarie, Petrus Steyn) and the writing of the statement. WHO headquarters WHO Department of Reproductive Health and Research – Ian Askew, Mary Lyn Gaffield, James Kiarie, Antonella Lavelanet, Manjulaa Narasimhan (unable to attend), Petrus Steyn WHO Department of HIV – Rachel Baggaley, Virginia MacDonald, Michele Rodolph WHO Department of Regulation of Medicines and other Health Technologies – Ray Corrin | Contraceptive eligibility for women at high risk of HIV: guidance statement14 WHO regional offices WHO Regional Office for Africa – Nancy Kidula, Léopold Ouedraogo Joint United Nations Programme on HIV/AIDS (UNAIDS) Peter Godfrey-Fausett United Nations Population Fund (UNFPA) Technical Division – Gifty Addico, Mieko Yabuta (unable to attend) Overall coordination WHO Department of Reproductive Health and Research – Mary Lyn Gaffield, with logistical support from Jane Werunga- Ndanareh. Writing The guidance statement was drafted on behalf of WHO by Caitlin Baumhart, Kathryn Curtis, Mary Lyn Gaffield, Philip Hannaford, Natasha Kaoma, Caitlin Kennedy and Maria Isabel Rodriguez. The systematic review examining the use of copper-bearing intrauterine devices and HIV acquisition was co-authored by Tsungai Chipato, Kathryn Curtis, Philip Hannaford and Angeline Ti. The update of the 2016 systematic review focusing on hormonal contraception and HIV acquisition was co-authored by Tsungai Chipato, Kathryn Curtis, Philip Hannaford, James Kiarie and Petrus Steyn. The GRADE tables and expertise on GRADE methodology were provided by Maria Isabel Rodriguez. Preparation of the evidence-to-decision table and expertise on the literature for values and preferences were provided by Caitlin Kennedy. Editing was done by Markus MacGill and Jane Patten of Green Ink (www.greenink.co.uk) and layout by Lushomo (www.lushomo.net). Contraceptive eligibility for women at high risk of HIV: guidance statement | 15 ANNEX 2. DECLARATIONS OF CONFLICTS OF INTEREST Following guidance issued on 24 September 2014 by the WHO Office of Compliance, Risk Management and Ethics (CRE), and prior to the 29–31 July 2019 meeting, the name and brief biography of each proposed Guideline Development Group (GDG) member was published on the WHO website during 27 May to 10 June 2019 (https://www.who.int/ reproductivehealth/publications/contraceptives-methods-hiv). The public was able to view and provide their comments to the WHO Secretariat using a general email address (hrx_info@who.int) regarding any perceived or real conflicts of interest of these proposed GDG members. In addition, prior to the public announcement period, the WHO Secretariat reviewed the curriculum vitae of each potential participant and conducted Internet searches (Google Scholar, Open Payments, PubMed) for information on potential financial and academic conflicts of interest related to the subject of the meeting. Following the public reporting period, and in consultation with CRE, official invitations for GDG membership were extended. Additionally, the WHO Secretariat reviewed potential financial and academic conflicts of interest related to the subject of the meeting of the proposed External Review Group: no conflicts were declared among this 11-member group. Of the 28 experts who participated in this work, six declared an interest related to contraception. The WHO Secretariat, CRE and GDG reviewed all declarations and found no conflicts of interest sufficient to preclude anyone from participating in the deliberations or the development of the recommendations relevant to hormonal contraception and HIV. Accordingly, the six participants who declared interests related to contraception, as well as the other 22 participants, fully participated in the meeting’s deliberations, discussions and final decisions. Although not all interests declared were specifically related to contraception and susceptibility to HIV, they are disclosed and summarized below. Sharon Achilles received US$ 4225 on 10 May 2016 to give expert advice on the latest HIV therapies during a one-day meeting sponsored by Merck Sharp & Dohme. Her research unit received US$ 2 638 373 from the United States National Institutes of Health/National Institute of Allergy and Infectious Diseases to conduct a study titled, Quantification of immune cells in women using contraception, during 2012–2019. For 2012–2019, her research unit is receiving US$ 4 999 999 from the Bill & Melinda Gates Foundation to conduct a study titled, HIV-target cell response in women initiating contraception in high HIV-incidence areas. During 2014–2016, Dr Achilles’s research unit received US$ 240 225 from the Bill & Melinda Gates Foundation to conduct a study addressing IFN-epsilon and hormonal contraceptive modulation of the risk of HIV acquisition. Currently, for 2018–2020, Dr Achilles’s research unit receives US$ 535 958 from the United States Food and Drug Administration (FDA) to conduct a study supporting new approaches to improve product manufacturing and quality titled, Physiologically-based model of the female reproductive tract: vaginal and intrauterine delivery components. Sharon Cameron works at a research unit that received a grant from Pfizer, UK, for £99 000, which ceased in 2016. The study was implemented to determine the feasibility and acceptability of the pharmacist administration of subcutaneous injectable contraception. Alison Edelman receives a yearly royalty of around US$ 1000 from the Internet information site, UpToDate as an author of the content. Between May 2016 and May 2017, she received US$ 10 000 a year from Agile Pharmaceuticals as an expert consultant regarding a hormonal contraceptive patch that is currently not FDA-approved. This consultation has ended. Since January 2016, she served as a trainer for Nexplanon, an FDA mandate, for Merck Sharp & Dohme, but has received no honorarium for these sessions and as an expert consultant in January 2016 for this company, receiving US$ 1500 for her services. Her research unit received US$ 540 000 from the Merck Women’s Health Investigator Initiated Studies Program to conduct research focused on treatment of breakthrough bleeding with the contraceptive implant (2016–2019). From 2015 to 2017, her research unit received a US$ 250 000 research grant from the Society for Family Planning to investigate the timing of ulipristal acetate and oral contraceptive use. Since 2002, Dr Edelman has been receiving about US$ 3000 a year from Contemporary Forums as a faculty member for its continuing medical education conferences (the amount varies depending on the number of lectures she gives). From November 2015 through June 2016, she received an honorarium of US$ 3000 from Oregon State University for expert advice on the mandated state training to allow the direct provision of contraceptives by pharmacists. Since July 2016, Dr Edelman has been receiving US$ 500 a year as an honorarium for serving on the data and safety monitoring board to FHI 360, which is developing a novel contraceptive injectable that is not yet FDA-approved. From April to September 2017, Dr Edelman was a consultant for HRA Pharma for a study investigating a progestin-only pill. Since July 2017, she had been an expert consultant for the Sugar Palm Foundation; this contract was then channelled through her institution and ended in 2019. Since June 2017, she has been providing expert consulting to Ipas to train health-care workers in Bangladesh: this contract is now administered by her institution. On an ongoing basis since 2016, Dr Edelman has received an honorarium from the University of California, San Francisco, for speaking and family planning fellowship site audits. During 2018 through to January 2019, she received an honorarium from Exeltis to provide an expert review on a contraceptive method not currently FDA- approved. This consultation has ended. Anna Glasier provides expert medical advice on the ulipristal acetate emergency contraceptive pill on a regular basis to the manufacturer (HRA Pharma). The amount was not disclosed. She works with them to try to obtain approval for the over-the- counter (OTC) use of ulipristal acetate emergency contraception and a progestin-only pill in the United States of America, and to | Contraceptive eligibility for women at high risk of HIV: guidance statement16 get a progestin-only pill approved for OTC use in the United Kingdom of Great Britain and Northern Ireland, and Europe. This is ongoing. Andy Gray is the chair of the Names and Scheduling Advisory Committee of the South African Health Products Regulatory Authority and serves on its Lega Advisory and Regulatory Advisory Committees. He is a member of the South African National Essential Medicines List Committee, responsible for medicines selection and the development of standard treatment guidelines for the public sector. Carolina Sales Vieira receives an honorarium (US$ 4000/year) for serving on Merck Sharpe & Dohme’s medical advisory board and giving ad hoc invited lectures. This role is ongoing. Dr Sales Vieira receives an honorarium (US$ 3000/year) for serving on Bayer’s medical advisory board and giving ad hoc lectures. This role is ongoing. Dr Sales Vieira received a one-time honorarium (US$ 1000) for serving on the medical advisory board for Exeltis in 2019. Contraceptive eligibility for women at high risk of HIV: guidance statement | 17 ANNEX 3. GRADE EVIDENCE PROFILES Outcome Type and number of studies (total number of participants) Limitations Inconsistency Imprecision Indirectness Overall quality Estimate of effect DMPA versus non-hormonal contraception or no method HIV acquisition 1 RCT1 (7829)a Few limitationsb No serious inconsistency No serious imprecision No indirectness High Adjusted HR 1.04 (0.82–1.33) for DMPA versus Cu-IUD HIV acquisition 10 cohort studies2–11 + 1 individual patient data meta-analysis of 7 studies12,c (40 506)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low to moderatee Adjusted HR range 0.46– 2.04, 8 studies increased risk (HR range 1.25–2.04), with statistically significant effects in 3 studies; 2 studies trended towards decreased risk (HR 0.46 and 0.75 with wide confidence intervals) Pooled adjusted HR 1.40 (1.24–1.58) NET-EN versus non-hormonal contraception or no method HIV acquisition 6 cohorts studies2,5,7,8,10,11 + 1 individual patient data meta- analysis of 7 studies12,c (29 922)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR range 0.87– 1.76, 5 studies increased risk (HR range 1.20–1.76), none statistically significant; 2 studies no effect (adjusted HR range 0.87–1.05) Pooled adjusted HR 1.14 (0.93–1.39) Implantf use versus non-hormonal contraception HIV acquisition 1 randomized trial1 (7829)a Few limitationsb No serious inconsistency No serious imprecision No indirectness High Adjusted HR 1.18 (0.91–1.53) for Cu-IUD versus LNG implant HIV acquisition 3 cohort studies2–4,c (4514)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Lowg Adjusted HR range 0.46–0.99 Adjusted HRs: 0.96 (0.29– 3.14), 0.99 (0.40–2.45), and 0.46 (0.13–1.70); none statistically significant Pooled adjusted HR 0.82 (0.44–1.53) Implantf use versus NET-EN HIV acquisition 1 cohort study2 (1136)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 0.45 (0.13–1.53) for implant use versus NET-EN Oral hormonal contraceptive use versus non-hormonal contraception or no method HIV acquisition 11 cohort studies3–6,8–14,c (43 482)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low to moderatee Adjusted HR or IRR range 0.66–1.80 3 studies increased risk (HR 1.39–1.80) Only 1 study reported a statistically significant finding (adjusted HR 1.48 [1.05– 2.09]) The remaining 8 studies reported a decreased risk (adjusted HR range 0.66–0.99), none of which was statistically significant Pooled adjusted HR 1.02 (0.88–1.19) GRADE EVIDENCE PROFILE FOR HORMONAL CONTRACEPTIVE USE IN HIV-NEGATIVE WOMEN | Contraceptive eligibility for women at high risk of HIV: guidance statement18 Outcome Type and number of studies (total number of participants) Limitations Inconsistency Imprecision Indirectness Overall quality Estimate of effect DMPA versus NET-EN HIV acquisition 2 cohort studies2,15 and 1 individual patient data meta-analysis of 17 studies12,c (42 788)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low to moderatee Adjusted HRs 1.32 (1.08– 1.61) and 0.89 (0.55–1.44) in cohort studies and 1.41 (1.06–1.89) in individual participant data meta- analysis of 17 studies Pooled adjusted HR 1.27 (1.05–1.55) DMPA versus combined oral contraceptives HIV acquisition 1 individual patient data meta-analysis of 8 studies12,c (24 853)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low to moderatee Adjusted HR 1.41 (1.23–1.67) in individual participant data meta-analysis of 8 studies NET-EN versus combined oral contraceptives HIV acquisition 1 individual patient data meta-analysis of 9 studies12,c (25 398)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 1.30 (0.99–1.17) GRADE EVIDENCE PROFILE FOR HORMONAL CONTRACEPTIVE USE IN HIV-NEGATIVE WOMEN Cu-IUD: copper-bearing intrauterine device; DMPA-IM: intramuscular depot medroxyprogesterone acetate; ETG: etonogestrel; GRADE: Grading of Recommendations Assessment, Development and Evaluation; HR: hazard ratio; IRR: incidence rate ratio; LNG: levonorgestrel; NET-EN: norethisterone enanthate; RCT: randomized controlled trial Note: Publication bias was not formally assessed; observational studies could not be upgraded for large effects; dose-response relationship, or confounders likely to increase observed effects. Estimates based on adjusted risk estimates, results from Cox model analysis used when available. a Sample size is for the entire study population. b Few limitations noted in the trial, but not serious enough to downgrade the level of evidence. While the study was unblinded for participants and health-care providers, data were analysed centrally by statisticians who were blinded to the group. c Restricted to studies classified as “informative with but with important limitations”. d Some limitations or imprecision noted across the body of evidence, but not serious enough to downgrade the level of evidence. e Evidence graded low to moderate due to consistent and precise results from well conducted observational studies, and coherence between studies of use versus non-use and head-to-head studies. f No direct evidence for ETG implants was identified for the comparisons of interest. For ETG implants, recommendations were extrapolated from other implant studies. g Upgraded from very low-quality evidence (2016 assessment). References: 1. Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium. HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial. Lancet. 2019;394(10195):303–13. doi: 10.1016/S0140-6736(19)31288-7. 2. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619–22. doi: 10.1097/ QAD.0000000000002260. 3. Sabo MC, Richardson BA, Lavreys L, Martin HL, Jr, Jaoko W, Mandaliya K et al. Does bacterial vaginosis modify the effect of hormonal contraception on HIV seroconversion. AIDS. 2019;33(7):1225–30. doi: 10.1097/QAD.0000000000002167. 4. Wall KM, Kilembe W, Vwalika B, Htee Khu N, Brill I, Chomba E et al. Hormonal contraception does not increase women’s HIV acquisition risk in Zambian discordant couples, 1994–2012. Contraception. 2015;91(6):480–7. Doi: 10.1016/j. contraception.2015.02.004. Contraceptive eligibility for women at high risk of HIV: guidance statement | 19 5. Crook AM, Ford D, Gafos M, Hayes R, Kamali A, Kapiga S et al. Injectable and oral contraceptives and risk of HIV acquisition in women: an analysis of data from the MDP301 trial. Hum Reprod. 2014;29(8):1810–7. doi: 10.1093/humrep/deu113. 6. Heffron R, Donnell D, Rees H, Celum C, Mugo N, Were E et al. Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study. Lancet Infect Dis. 2012;12(1):19–26. doi: 10.1016/S1473-3099(11)70247-X. 7. Kleinschmidt I, Rees H, Delany S, Smith D, Dinat N, Nkala B et al. Injectable progestin contraceptive use and risk of HIV infection in a South African family planning cohort. Contraception. 2007;75(6):461–7. doi: 10.1016/j.contraception.2007.02.002. 8. McCoy SI, Zheng W, Montgomery ET, Blanchard K, van der Straten A, de Bruyn G et al. Oral and injectable contraception use and risk of HIV acquisition among women in sub-Saharan Africa. AIDS. 2013;27(6):1001–9. doi: 10.1097/ QAD.0b013e32835da401. 9. Morrison CS, Richardson BA, Mmiro F, Chipato T, Celentano DD, Luoto J et al. Hormonal contraception and the risk of HIV acquisition. AIDS. 2007;21(1):85–95. doi: 10.1097/QAD.0b013e3280117c8b. 10. Morrison CS, Skoler-Karpoff S, Kwok C, Chen PL, van de Wijgert J, Gehret-Plagianos M et al. Hormonal contraception and the risk of HIV acquisition among women in South Africa. AIDS. 2012;26(4):497–504. doi: 10.1097/QAD.0b013e32834fa13d. 11. Myer L, Denny L, Wright TC, Kuhn L. Prospective study of hormonal contraception and women’s risk of HIV infection in South Africa. Int J Epidemiol. 2007;36(1):166–74. doi: 10.1093/ije/dyl251. 12. Morrison CS, Chen PL, Kwok C, Baeten JM, Brown J, Crook AM et al. Hormonal contraception and the risk of HIV acquisition: an individual participant data meta-analysis. PLoS Med. 2015;12(1):e1001778. doi: 10.1371/journal.pmed.1001778. 13. Balkus JE, Brown ER, Hillier SL, Coletti A, Ramjee G, Mgodi N et al. Oral and injectable contraceptive use and HIV acquisition risk among women in four African countries: a secondary analysis of data from a microbicide trial. Contraception. 2016;93(1):25–31. doi: 10.1016/j.contraception.2015.10.010. 14. Reid SE, Dai JY, Wang J, Sichalwe BN, Akpomiemie G, Cowan FM et al. Pregnancy, contraceptive use, and HIV acquisition in HPTN 039: relevance for HIV prevention trials among African women. J Acquir Immune Defic Syndr. 2010;53(5):606–13. doi: 10.1097/QAI.0b013e3181bc4869. 15. Noguchi LM, Richardson BA, Baeten JM, Hillier SL, Balkus JE, Chirenje ZM et al. Risk of HIV-1 acquisition among women who use different types of injectable progestin contraception in South Africa: a prospective cohort study. Lancet HIV. 2015;2(7):e279–87. doi: 10.1016/S2352-3018(15)00058-2. | Contraceptive eligibility for women at high risk of HIV: guidance statement20 Outcome Type and number of studies (total number of participants) Limitations Inconsistency Imprecision Indirectness Overall quality Estimate of effect IUDa versus no contraception or tubal ligation HIV acquisition 1 prospective study1,b (1498)c Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 1.1 (0.4–3.0) for Cu-IUD versus no contraception or tubal ligation IUDa versus implant,e DMPA, NET-EN HIV acquisition 1 prospective study2,b (1136)c Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 0.90 (0.45–1.76) for DMPA, implants, NET-EN versus Cu-IUD IUDa use versus DMPA HIV acquisition 1 RCT3,b (7829)c Few limitationsf No serious inconsistency No serious imprecision No indirectness High Adjusted HR 1.04 (0.82–1.33) for DMPA-IM versus Cu-IUD HIV acquisition 1 prospective study2,b (1136)c Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 0.91 (0.44–1.87) for DMPA versus Cu-IUD IUDa versus NET-EN HIV acquisition 1 prospective study2,b (1136)c Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 0.98 (0.47–2.03) for Cu-IUD versus NET-EN IUDa versus implante HIV acquisition 1 RCT3 (7829)c Few limitationsf No serious inconsistency No serious imprecision No indirectness High Adjusted HR 1.18 (0.91–1.53) for Cu-IUD versus LNG implant HIV acquisition 1 prospective study2,b (1136)c Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 2.17 (0.59–7.69) for Cu-IUD versus implants (LNG or ETG) GRADE EVIDENCE PROFILE FOR CU-IUD USE IN HIV-NEGATIVE WOMEN Cu-IUD: copper-bearing intrauterine device; DMPA-IM: intramuscular depot medroxyprogesterone acetate; ETG: etonogestrel; GRADE: Grading of Recommendations Assessment, Development and Evaluation; HR: hazard ratio; IUD: intrauterine device; LNG: levonorgestrel; NET-EN: norethisterone enanthate; RCT: randomized controlled trial Note: Publication bias was not formally assessed; observational studies could not be upgraded for large effects; dose-response relationship, or confounders likely to increase observed effects. Estimates based on adjusted risk estimates, results from Cox model analysis used when available. a No direct evidence for LNG-IUDs was identified for the comparisons of interest. For LNG-IUDs, recommendations were extrapolated from the evidence on Cu-IUDs and other LNG containing products. b Restricted to studies classified as “informative with but with important limitations”. c Sample size is for the entire study population. d Some limitations or imprecision was noted across the body of evidence, but not serious enough to downgrade the level of evidence. e No direct evidence for ETG implants was identified for the comparisons of interest. For ETG implants, recommendations were extrapolated from the evidence on LNG implants. f Few limitations noted in the trial, but not serious enough to downgrade the level of evidence. References: 1. Lavreys L, Baeten JM, Martin Jr HL, Overbaugh J, Mandaliya K, Ndinya-Achola J et al. Hormonal contraception and risk of HIV-1 acquisition: results of a 10-year prospective study. AIDS. 2004;18(4):695–7. 2. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619–22. doi: 10.1097/ QAD.0000000000002260. 3. Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium. HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial. Lancet. 2019;394(10195):303–13. doi: 10.1016/S0140-6736(19)31288-7. Contraceptive eligibility for women at high risk of HIV: guidance statement | 21 ANNEX 4. EVIDENCE-TO- DECISION TABLE FOR HORMONAL CONTRACEPTIVE METHODS AND INTRAUTERINE DEVICES (IUDS) Factor Explanation/evidence Judgement Quality of evidence Progestogen- only contraceptives (POCs) For the primary outcome of HIV acquisition, evidence was considered to be of high qual- ity for intramuscular depot medroxyprogesterone acetate (DMPA-IM) and for levonorge- strel (LNG) implants. Evidence was considered to be of low quality for norethisterone enanthate (NET-EN), and absent for subcutaneous DMPA (DMPA-SC), LNG intrauterine devices (IUDs) and etonogestrel (ETG) implants. For NET-EN and DMPA-SC, the recom- mendations were extrapolated from the evidence on DMPA-IM. For ETG implants, the recommendations were extrapolated from the evidence on LNG implants. High, low or absent, depending on method IUDs For the primary outcome of HIV acquisition, evidence was considered to be of high quality for copper-bearing IUDs (Cu-IUDs). Evidence was absent for LNG-IUDs. For LNG-IUDs, recommendations were extrapolated from the evidence on Cu-IUDs and other LNG-containing products. High or absent, de- pending on method Combined hormonal contraceptives (CHCs) Evidence was considered to be of low-to-moderate quality for CHCs. Low-moderate Balance of benefits versus harms POCs Contraception is a life-saving intervention with well recognized health, social and economic benefits. All POCs are effective or highly effective, reversible methods. High-quality evidence from one randomized controlled trial (RCT) observed no statistically significant differences in HIV acquisition between: DMPA-IM versus Cu-IUD, DMPA-IM versus LNG implant, and Cu-IUD versus LNG implant. Of the low-to-moderate-quality evidence from 14 observational studies, some studies suggested a possible increased risk of HIV with progestogen-only injectable use, which was most likely due to unmeasured confounding.a,b Low-quality evidence from three observational studies did not suggest an increased HIV risk for implant users.a,b No studies of sufficient quality were identified for progestogen-only pills. While no direct evidence was available for DMPA-SC or ETG implants, indirect evidence for DMPA-IM and LNG implants was used, given that there was no biological or clinical reason to believe that a lower hormonal dose, different delivery mechanism, or different progestogen would modify HIV risk. Balance is in favour of benefits of POCs IUDs Contraception is a life-saving intervention with well recognized health, social and economic benefits. All IUDs are highly effective, reversible methods. High-quality evidence from one RCT, along with low-quality evidence from two observational studies, suggested no increased risk of HIV acquisition with Cu-IUD use.c–e While no direct evidence was available for LNG-IUDs, recommendations were extrapolated from the evidence on Cu-IUDs and other LNG-containing products. Balance is in favour of benefits of IUDs CHCs Contraception is a life-saving intervention with well recognized health, social and economic benefits. All hormonal contraceptives are effective or highly effective, reversible methods. Low-moderate quality evidence from 11 observational studies suggested no association between combined oral contraceptive (COC) use (it was assumed that studies that did not specify oral contraceptive type examined mostly, if not exclusively, COC use) and HIV acquisition.a,b While no direct evidence was available for combined contraceptive patch, combined contraceptive vaginal ring or combined injectable contraceptive, indirect evidence from COCs was used given that there was no biological or clinical reason to believe that a lower hormonal dose, different delivery mechanism, or different progestogen would modify HIV risk. Balance is in favour of benefits of CHCs | Contraceptive eligibility for women at high risk of HIV: guidance statement22 Factor Explanation/evidence Judgement Values and preferences Women have the right to informed decision-making. Women prefer to have choice in methods, full information regarding benefits versus harms, and to make a final decision in conjunction with their provider (informed decision-making). Contraception is unique among medicines because a woman’s needs and preferences with regard to the characteristics of contraceptive methods will vary both between individual women and across a single individual’s lifespan. Common themes in contraceptive preferences include that they are discreet, have minimal side-effects and are long-acting, reversible and easy to use. Women who use progestogen-only injectables generally like them for these reasons, and feel comfortable using them after counselling. Women’s preferences for methods are limited by what they have knowledge of, what is available to them and other factors that foster or limit access. Offering women the choice of a range of methods is important from both a health and a rights perspective. Support for optimizing informed contraceptive choice and the availability of a wide range of contraceptive options Priority of the problem HIV is a serious illness and a major global epidemic. Unintended pregnancy is a very common problem globally, and the risks associated with it are highest where maternal mortality and severe morbidity are also common. Both are priorities for public health. Effective contraception and HIV prevention are both public health priorities Equity and human rights Human rights principles and standards from existing World Health Organization (WHO) guidelines on human rights and contraception were followed by the Guideline Development Group (GDG) in its deliberations. These include non-discrimination, availability, accessibility, acceptability, quality, informed decision-making, privacy and confidentiality, participation, and accountability. During its deliberations, the GDG considered both potential positive and negative effects of its considerations. For example, it considered and emphasized the continuing need for integrated family planning and HIV services in settings with high HIV incidence. It also emphasized the need for expanding and optimizing contraceptive options. Recommendations within WHO’s human rights guidance for contraception are paramount principles for decision-making on this topic Feasibility The importance of clear communication from WHO on this topic was underscored. This was reinforced by recent studies that suggested that messages based on the 2017 WHO guidance were difficult to explain and may not be fully understood by clients or providers. Clear guidance and a woman-centred approach are essential for successful implementation References: a. Polis CB, Curtis KM, Hannaford PC, Phillips SJ, Chipato T, Kiarie JN et al. An updated systematic review of epidemiological evidence on hormonal contraceptive methods and HIV acquisition in women. AIDS. 2016;30(17):2665–83. doi: 10.1097/ QAD.0000000000001228. b. Sabo MC, Richardson BA, Lavreys L, Martin HL, Jr, Jaoko W, Mandaliya K et al. Does bacterial vaginosis modify the effect of hormonal contraception on HIV seroconversion. AIDS. 2019;33(7):1225–30. doi: 10.1097/QAD.0000000000002167. c. Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium. HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial. Lancet. 2019;394(10195):303–13. doi: 10.1016/S0140-6736(19)31288-7. d. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619–22. doi: 10.1097/ QAD.0000000000002260. e. Lavreys L, Baeten JM, Martin Jr HL, Overbaugh J, Mandaliya K, Ndinya-Achola J et al. Hormonal contraception and risk of HIV-1 acquisition: results of a 10-year prospective study. AIDS. 2004;18(4):695–7. Contraceptive eligibility for women at high risk of HIV: guidance statement | 23 ANNEX 5: SYSTEMATIC REVIEWS Three systematic reviews were conducted as part of the development of this guidance statement. The details of the methods and search strategies are included in the reviews. Reviews published in peer-reviewed journals are available through open access. This appendix will be periodically updated as reviews are published. Access to unpublished reviews can be requested by sending an email to hrx-info@who.int. 1. Hormonal contraceptive method use and HIV acquisition in women There was a previously published review on hormonal contraceptive use and HIV acquisition. The search strategies from that review were used to search for new evidence since. The following four new publications were identified that met the inclusion criteria. PREVIOUSLY PUBLISHED REVIEW 1. Polis CB, Curtis KM, Hannaford PC, Phillips SJ, Chipato T, Kiarie JN et al. An updated systematic review of epidemiological evidence on hormonal contraceptive methods and HIV acquisition in women. AIDS. 2016;30(17):2665–83. doi: 10.1097/ QAD.0000000000001228. UNPUBLISHED REVIEW 1. Curtis KM, Hannaford PC, Rodriguez MI, Chipato T, Steyn PS, Kiarie JN. Hormonal contraceptive method use and HIV acquisition in women: an updated systematic review. Working paper developed for the World Health Organization meeting. July 2019. NEW ARTICLES 1. Haddad LB, Wall KM, Kilembe W, Vwalika B, Khu NH, Brill I et al. Bacterial vaginosis modifies the association between hormonal contraception and HIV acquisition. AIDS. 2018;32(5):595–604. doi: 10.1097/ QAD.0000000000001741. 2. Hofmeyr GJ, Singata-Madliki M, Lawrie TA, Bergel E, Temmerman M. Effects of injectable progestogen contraception versus the copper intrauterine device on HIV acquisition: sub-study of a pragmatic randomised controlled trial. J Fam Plann Reprod Health Care. 2017;43(3):175–80. doi: 10.1136/jfprhc-2016-101607. 3. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619– 22. doi: 10.1097/QAD.0000000000002260. 4. Sabo MC, Richardson BA, Lavreys L, Martin HL, Jr., Jaoko W, Mandaliya K et al. Does bacterial vaginosis modify the effect of hormonal contraception on HIV seroconversion. AIDS. 2019;33(7):1225-30. doi: 10.1097/ QAD.0000000000002167. 2. Copper-bearing intrauterine device (Cu-IUD) use and HIV acquisition in women A systematic review was conducted on Cu-IUD use and HIV acquisition in women. The following six articles met the inclusion criteria. UNPUBLISHED REVIEW 1. Hannaford PC, Ti A, Chipato T, Curtis KM. Copper intrauterine device use and HIV acquisition in women: an updated systematic review. Working paper developed for the World Health Organization meeting. July 2019. NEW ARTICLES 1. Hofmeyr GJ, Singata-Madliki M, Lawrie TA, Bergel E, Temmerman M. Effects of injectable progestogen contraception versus the copper intrauterine device on HIV acquisition: sub-study of a pragmatic randomised controlled trial. J Fam Plann Reprod Health Care. 2017;43(3):175–80. doi: 10.1136/jfprhc-2016-101607. 2. Kapiga SH, Lyamuya EF, Lwihula GK, Hunter DJ. The incidence of HIV infection among women using family planning methods in Dar es Salaam, Tanzania. AIDS. 1998;12(1):75–84. doi: 10.1097/00002030-199801000-00009. 3. Lavreys L, Baeten JM, Martin Jr HL, Overbaugh J, Mandaliya  K, Ndinya-Achola J et al. Hormonal contraception and risk of HIV-1 acquisition: results of a 10-year prospective study. AIDS. 2004;18(4):695–7. 4. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619– 22. doi: 10.1097/QAD.0000000000002260. 5. Saracco A, Musicco M, Nicolosi A, Angarano G, Arici C, Gavazzeni G et al. Man-to-woman sexual transmission of HIV: longitudinal study of 343 steady partners of infected men. J Acquir Immune Defic Syndr. 1993;6(5):497-502. 6. Sinei SK, Fortney JA, Kigondu CS, Feldblum PJ, Kuyoh M, Allen MY et al. Contraceptive use and HIV infection in Kenyan family planning clinic attenders. Int J STD AIDS. 1996;7(1):65–70. doi: 10.1258/0956462961917104. 3. Contraceptive values and preferences A systematic review was conducted on contraceptive values and preferences. The protocol and methods are published, and the manuscript presenting the main results of the review is under review for publication. As this review did not identify information specific to key populations at risk of HIV, consultative engagements were conducted in the spring of 2019, including a global online survey of sex workers, and participatory focus group discussions with female sex workers | Contraceptive eligibility for women at high risk of HIV: guidance statement24 in Zimbabwe through the Sisters with a Voice programme. Presentations showing the findings from these engagements are listed below and available on request. A presentation shared by stakeholders representing affected populations to highlight their perspectives on the topic was part of the Guideline Development Group’s discussions and is available on request. 1. Kennedy CE, Yeh PT, Gaffield ME. Contraception values and preferences: protocol and methods for a global systematic review. Contraception. 2019 (in press). doi: 10.1016/j. contraception.2018.05.006Get. 2. Yeh PT, Kennedy CE, Gaffield ME. Contraception values and preferences: a global systematic review. Contraception. 2019; (accepted pending revisions). 3. Shapiro A. Female sex workers’ contraceptive practices, values and preferences. contraception and risk of HIV infection: a WHO Guideline Development Group review of the current evidence. 29 July 2019, Geneva, World Health Organization. 4. Sibanda E. Views on contraceptive methods among female sex workers in Harare, Zimbabwe: a participatory qualitative study. 29 July 2019, Geneva, World Health Organization. 5. Mworeko L. What do recommendations on contraceptives and HIV risk mean to women?, 29 July 2019, Geneva, World Health Organization.

For more information, please contact: Department of Reproductive Health and Research, World Health Organization, Avenue Appia 20, CH-1211 Geneva 27, Switzerland. E-mail: reproductivehealth@who.int www.who.int/reproductivehealth

Contraceptive eligibility for women at high risk of HIV Guidance statement Recommendations on contraceptive methods used by women at high risk of HIV

Contraceptive eligibility for women at high risk of HIV Guidance statement Recommendations on contraceptive methods used by women at high risk of HIV © World Health Organization 2019 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo) Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. Contraceptive eligibility for women at high risk of HIV: guidance statement: recommendations on contraceptive methods used by women at high risk of HIV. Geneva: World Health Organization; 2019. Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at https://apps.who.int/iris. Sales, rights and licensing. To purchase WHO publications, see https://apps.who.int/bookorders. To submit requests for commercial use and queries on rights and licensing, see https://www.who.int/about/licensing. Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. The views expressed in this publication are those alone of the named authors and of the collective views of an international group of experts and do not necessarily represent the decisions or the policies of WHO. Contraceptive eligibility for women at high risk of HIV: guidance statement | iii 1 2 3 4 5 ACKNOWLEDGEMENTS V ABBREVIATIONS VI EXECUTIVE SUMMARY VII BACKGROUND 1 METHODS OF GUIDELINE REVIEW AND DEVELOPMENT 2 2.1 Guideline Development Group 2 2.2 Guideline development process 2 2.3 Evidence Retrieval 3 2.4 Evidence Synthesis 4 2.5 Formulation of recommendations 4 SUMMARY OF THE EVIDENCE 4 3.1 Progestogen-only injectables 5 3.2 Progestogen-only implants 5 3.3 Progestogen-only pills 5 3.4 Intrauterine devices 5 3.5 Combined hormonal contraceptives 5 3.6 Additional evidence considered by the GDG 5 3.6.1 Biological data 5 3.6.2 Values and preferences of contraceptive users 6 RECOMMENDATIONS 6 4.1 Recommendations for contraceptive use among women at high risk of HIV infection 6 4.2 Rationale 7 IMPLICATIONS FOR POLICY-MAKERS, PROGRAMME MANAGERS AND HEALTH-CARE PROVIDERS 8 5.1 A woman’s risk of HIV should not restrict her contraceptive choice 8 5.2 Efforts to expand access to contraceptive options must continue 8 5.3 A renewed emphasis on HIV and STI prevention services is urgently needed 9 CONTENTS | Contraceptive eligibility for women at high risk of HIV: guidance statementiv CONTENTS (continued) KNOWLEDGE GAPS AND AREAS FOR RESEARCH 9 6.1 Contraceptive methods and HIV acquisition 9 6.2 HIV prevention 9 6.3 Community involvement 10 6.4 Increased funding for high-quality, policy-relevant research 10 DISSEMINATION OF THIS GUIDANCE STATEMENT 10 REFERENCES 11 ANNEX 1. GUIDELINE DEVELOPMENT GROUP AND EVIDENCE SECRETARIAT 13 ANNEX 2. DECLARATIONS OF CONFLICTS OF INTEREST 15 ANNEX 3. GRADE EVIDENCE PROFILES 17 ANNEX 4. EVIDENCE-TO-DECISION TABLE FOR HORMONAL CONTRACEPTIVE METHODS AND INTRAUTERINE DEVICES (IUDS) 21 ANNEX 5: SYSTEMATIC REVIEWS 23 6 7 Contraceptive eligibility for women at high risk of HIV: guidance statement | v ACKNOWLEDGEMENTS The World Health Organization (WHO) would like to thank the members of the Guideline Development Group and the Evidence Secretariat (Annex 1) for their contributions throughout the development of these important recommendations for women at high risk of HIV. WHO is very grateful for the suggestions provided by colleagues who peer reviewed the draft statement as members of the External Review Group. The development of this technical statement was financially supported by the Bill & Melinda Gates Foundation, the Netherlands Ministry of Foreign Affairs, the United States Agency for International Development, and the United States National Institutes of Health. | Contraceptive eligibility for women at high risk of HIV: guidance statementvi ABBREVIATIONS CIC combined injectable contraceptive COC combined oral contraceptive CRE WHO Office of Compliance, Risk Management and Ethics Cu-IUD copper-bearing intrauterine device DMPA depot medroxyprogesterone acetate DMPA-IM intramuscular depot medroxyprogesterone acetate DMPA-SC subcutaneous depot medroxyprogesterone acetate ECHO Evidence for Contraceptive Options and HIV Outcomes (Study) ETG etonogestrel FDA United States Food and Drug Administration GDG Guideline Development Group GRADE Grading of Recommendations Assessment, Development and Evaluation HR hazard ratio IRR incidence rate ratio IUD intrauterine device LNG levonorgestrel LNG-IUD levonorgestrel-releasing intrauterine device MEC Medical eligibility criteria for contraceptive use NET-EN norethisterone enanthate OTC over the counter POP progestogen-only pill PrEP pre-exposure prophylaxis (for HIV) RCT randomized clinical trial STI sexually transmitted infection WHO World Health Organization Contraceptive eligibility for women at high risk of HIV: guidance statement | vii EXECUTIVE SUMMARY The World Health Organization (WHO) convened a Guideline Development Group (GDG) meeting from 29 to 31 July 2019 to review global guidance on contraceptive eligibility for women at high risk of HIV acquisition to and determine whether revisions to the fifth edition of the Medical eligibility criteria for contraceptive use (MEC) were needed. The issue was deemed critical, particularly for sub-Saharan Africa, given the high lifetime risk of acquiring HIV alongside the importance of hormonal contraception in offering women and adolescent girls’ choice and in reducing their risk of unintended pregnancy, a common threat to the health, well-being and lives of women and adolescent girls. The GDG consisted of 28 participants from 19 countries, including experts in family planning and HIV, representatives from affected populations, clinicians, epidemiologists, researchers, programme managers, policy-makers and guideline methodologists. The GDG considered the following factors when formulating recommendations for each contraceptive method: ■ quality of the evidence (i.e. GRADE profile)1 ■ values and preferences of contraceptive users ■ balance of benefits and harms ■ priority of the problem ■ equity and human rights ■ feasibility. In formulating these recommendations, the GDG kept at the centre of their deliberations the individuals most affected by the recommendations – that is, those women wanting to prevent pregnancy who are at a high risk of HIV acquisition. Through consensus, the GDG agreed to the following new recommendations. These revisions mean that women at a high risk of HIV can use all methods of contraception without restriction. ■ Women at a high risk of HIV infection are eligible to use all progestogen-only contraceptive methods without restriction (MEC Category 1), including progestogen-only pill (POPs), intramuscular and subcutaneous depot medroxyprogesterone acetate (DMPA-IM and DMPA-SC), norethisterone enanthate (NET-EN), levonorgestrel (LNG) implants and etonogestrel (ETG) implants. ■ Women at a high risk of HIV infection are eligible to use copper-bearing intrauterine devices (Cu-IUDs) and LNG- IUDs without restriction (MEC Category 1). In considering the 1 GRADE = Grading of Recommendations Assessment, Development and Evaluation (for further information, see: http://www.gradeworkinggroup.org). use of IUDs, many women at a high risk of HIV are also at risk of other sexually transmitted infections (STIs); for these women, providers should refer to the MEC recommendation on women at an increased risk of STIs, and the Selected practice recommendations for contraceptive use: third edition on STI screening before IUD insertion. ■ Women at a high risk of HIV infection are eligible to use all combined hormonal contraceptive methods without restriction (MEC Category 1), including combined oral contraceptives (COCs), combined injectable contraceptives (CICs), combined contraceptive patches and combined vaginal rings. These recommendations were strongly informed by new epidemiological evidence, particularly from one high-quality randomized clinical trial (the ECHO trial), which did not demonstrate a statistically significant difference in HIV acquisition among women using the three contraceptive methods studied: DMPA-IM, Cu-IUDs and LNG implants. This high-quality evidence superseded the previously available observational evidence of low and low-to-moderate quality. For COCs and NET-EN injectables, evidence of low and low-to- moderate quality from observational studies indicated no increased risk of HIV infection. While no direct evidence was available for DMPA-SC, LNG-IUDs or ETG implants, there was no biological or clinical reason to believe that a lower hormonal dose, different delivery mechanism or different progestogen would modify HIV risk. A consideration of women’s values, preferences, views and concerns regarding contraceptive methods provided support for optimizing informed contraceptive choice and the availability of a wide range of contraceptive options. There are several key messages from this guidance for policy- makers, programme managers and health-care providers. ■ A woman’s risk of HIV does not restrict her contraceptive choice. ■ Efforts to expand contraceptive method options and ensure full and equitable access to family planning services must continue. ■ A renewed emphasis on HIV/STI testing and prevention services is urgently needed, including the integration of family planning and HIV/STI services as appropriate, along with sexual and reproductive health packages. | Contraceptive eligibility for women at high risk of HIV: guidance statementviii PROGESTOGEN-ONLY CONTRACEPTIVES Progestogen-only contraceptives (POCs) do not protect against sexually transmitted infections (STIs), including HIV. If there is a risk of STI/HIV, the correct and consistent use of condoms is recommended. When used correctly and consistently, condoms offer one of the most effective methods of protection against STIs, including HIV. Female condoms are effective and safe, but are not used as widely as male condoms by national programmes. Condition MEC category Clarification/evidence POP DMPA/ NET-EN LNG/ ETG High risk of HIV 1 1 1 EVIDENCE: High-quality evidence from one randomized clinical trial observed no sta- tistically significant differences in HIV acquisition between: DMPA-IM versus Cu-IUD, DMPA-IM versus LNG implant, and Cu-IUD versus LNG implant. Of the low-to-mod- erate-quality evidence from 14 observational studies, some studies suggested a pos- sible increased risk of HIV with progestogen-only injectable use, which was most likely due to unmeasured confounding. Low-quality evidence from 3 observational studies did not suggest an increased HIV risk for implant users. No studies of sufficient quality were identified for POPs. Cu-IUD: copper-bearing intrauterine device; DMPA: depot medroxyprogesterone acetate (injectable); IM: intramuscular; LNG/ETG: levonorgestrel and etonogestrel (implants); MEC: Medical eligibility criteria for contraceptive use; NET-EN: norethisterone enanthate (injectable); POP: progestogen-only pill INTRAUTERINE DEVICES Intrauterine devices (IUDs) do not protect against sexually transmitted infections (STIs), including HIV. If there is a risk of STI/HIV, the correct and consistent use of condoms is recommended. When used correctly and consistently, condoms offer one of the most effective methods of protec- tion against STIs, including HIV. Female condoms are effective and safe, but are not used as widely as male condoms by national programmes. Condition MEC category Clarification/evidence Cu-IUD LNG-IUD (20 μg/24 hours) High risk of HIV Initiation Continuation Initiation Continuation CLARIFICATION: Many women at a high risk of HIV are also at risk of other STIs. For these women, refer to the recommendation in the Medical eligibility criteria for contra- ceptive use on women at an increased risk of STIs, and the Selected practice recommendations for contraceptive use on STI screening before IUD insertion. EVIDENCE: High-quality evidence from one randomized clinical trial, along with low-quality evidence from two observational studies, suggested no increased risk of HIV acquisition with Cu-IUD use. No studies were identified for LNG-IUDs. 1 1 1 1 Cu-IUD: copper-bearing intrauterine device; LNG-IUD: levonorgestrel-releasing IUD; MEC: Medical eligibility criteria for contraceptive use COMBINED HORMONAL CONTRACEPTIVES Combined hormonal contraceptives (CHCs) do not protect against sexually transmitted infections (STIs), including HIV. If there is a risk of STI/ HIV, the correct and consistent use of condoms is recommended. When used correctly and consistently, condoms offer one of the most effective methods of protection against STIs, including HIV. Female condoms are effective and safe, but are not used as widely as male condoms by national programmes. Condition MEC category Clarification/evidence COC P CVR CIC High risk of HIV 1 1 1 1 EVIDENCE: Low-to-moderate-quality evidence from 11 observational studies suggested no association between COC use (it was assumed that studies that did not specify oral contraceptive type examined mostly, if not exclusively, COC use) and HIV acquisition. No studies of P, CVR or CIC were identified. COC: combined oral contraceptive; CIC: combined injectable contraceptive; CVR: combined contraceptive vaginal ring; MEC: Medical eligibility criteria for contraceptive use; P: combined contraceptive patch Contraceptive eligibility for women at high risk of HIV: guidance statement | 1 Access to sexual and reproductive health services and information, including a comprehensive range of contraceptive methods, is fundamental to the rights and well-being of women and adolescent girls (1–4). There is a wide range of hormonal and non-hormonal modern contraceptive methods providing substantial individual and public health benefits. A core part of the work of the World Health Organization (WHO) is the development and maintenance of up-to-date, evidence-based guidance on contraceptive safety for individuals with particular medical conditions or medically relevant characteristics (5). The Medical eligibility criteria for contraceptive use (the MEC), fifth edition, offers national policy-makers and family planning programmes a comprehensive set of recommendations on the medical safety of contraceptive methods, allowing for the informed development of national policies, protocols and programmes (5). Global guidance about medical safety and eligibility facilitates the removal of unnecessary medical barriers to contraception. For over 20 years, the MEC has been used by countries to maximize safety and improve the quality of contraceptive care offered. Guidance about safety is kept up to date through continuous monitoring and reviews of published literature. In 2015, WHO released the fifth edition of the MEC (5). This edition contains more than 2000 recommendations for 25 different contraceptive methods, within the context of more than 80 medical conditions or medically relevant personal characteristics. Depending on the individual, more than one condition may need to be considered when making an informed contraceptive choice (5). The recommendations in the MEC are based on several considerations, including whether the use of a contraceptive method worsens the medical condition or creates additional health risks, and whether the condition makes the contraceptive method less effective (5). The MEC is part of a set of tools aiming to improve contraceptive coverage and care throughout the world. The MEC informs decisions about who might use a particular contraceptive method, through information and guidance about the safety and appropriateness of contraceptive care. The Selected practice recommendations for contraceptive use (the SPR) provides guidance on how to safely and effectively use various contraceptive methods (6). WHO produces a range of tools to support the use and implementation of contraceptive guidance, such as the MEC wheel and the Global handbook for providers (7, 8). Since 1996, the MEC has applied a four-category scale to indicate medical eligibility for particular contraceptive methods in the presence of particular conditions or individual characteristics (e.g. at high risk of HIV). For each condition or characteristic, contraceptive methods are placed into one of four numbered categories: 1. A condition for which there is no restriction for the use of contraceptive method. 2. A condition where the advantages of using the method generally outweigh the theoretical or proven risks. 3. A condition where the theoretical or proven risks usually outweigh the advantages of using the method. 4. A condition which represents an unacceptable health risk if the contraceptive method is used. The interpretation and application of the categories in practice are shown in Table 1. In the past, there has been mixed evidence about whether hormonal contraceptive methods – particularly depot medroxyprogesterone acetate (DMPA) – are associated with an increased risk of HIV acquisition. The available evidence consisted of theoretical biological data and observational studies with important limitations. In 2016, the independent TABLE 1. INTERPRETATION AND APPLICATION OF THE MEDICAL ELIGIBILITY CRITERIA (MEC) CATEGORIES Category With good resources for clinical judgement With limited resources for clinical judgement 1 Use the method in any circumstances Yes, use the method 2 Generally use the method 3 Use of the method not usually recommended unless more appropriate methods are not available or not acceptable No, do not use the method 4 Method not to be used BACKGROUND1 | Contraceptive eligibility for women at high risk of HIV: guidance statement2 2.1 Guideline Development Group The development of this guidance statement was undertaken by the independent Guideline Development Group (GDG) and an additional panel of external reviewers. The GDG consisted of 28 participants from 19 countries, including experts in family planning and HIV, representatives from affected populations, clinicians, epidemiologists, researchers, programme managers, policy- makers and guideline methodologists (see Annex 1). Following WHO guidance, months prior to the July 2019 meeting of the GDG, the name and brief biography of each proposed GDG member was published at the WHO website (https://www.who. int/reproductivehealth/publications/contraceptives-methods-hiv). The public was able to view and provide input on any perceived or real conflicts of interest of the proposed members. WHO responded to all comments and accordingly adjusted the final composition of the GDG. Prior to the GDG meeting, the WHO Secretariat and the GDG reviewed the members’ declarations of interests (Annex 2) and found no conflicts of interest sufficient to preclude anyone from participating in the deliberations or the development of the recommendations. The members of the GDG were also asked to declare any new conflicts of interest at the start of the meeting. None were declared. 2 For further information, see: http://www.gradeworkinggroup.org 2.2 Guideline development process This guidance statement was prepared according to the standards and requirements specified in the WHO handbook for guideline development (11). This process is used to ensure that WHO guidelines are of the highest quality and follow a transparent, systematic process. Key steps of the guideline process include determining the critical questions and outcomes, retrieving the evidence, synthesizing and grading the evidence, presenting it using a structured approach, and formulating recommendations. WHO’s Family Planning Guideline Steering Group determined the critical questions and outcomes to be considered by the GDG. Distinct types of evidence were identified as essential to review. These included the health evidence (randomized trials and observational epidemiological data), the evidence on biological plausibility and the data on the values and preferences of contraceptive users. Applying the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach,2 multiple factors are considered when formulating recommendations (12). These include the quality of the epidemiological evidence (found in the GRADE evidence profiles, which are prepared based on up-to-date Guideline Development Group (GDG) for the MEC reviewed the accumulating evidence regarding women at high risk of acquiring HIV (9). The GDG concluded that there remained uncertainty about whether the increased risk of HIV acquisition seen in some observational studies was a real effect of the contraceptive method used or whether it was a statistical artefact resulting from key limitations of observational studies (residual confounding in particular) (9). There also continued to be uncertainty about the clinical relevance of the biological data. In addition, there was concern that previous attempts to inform women of the uncertainty about both the epidemiological and biological data (through the use of a MEC clarification, indicated by an asterisk [*]) had not been effective. Given these concerns, the GDG concluded that MEC guidance should be changed. Thus, in 2017, the recommendation for progestogen- only injectable use among women at high risk of HIV infection was changed from MEC Category 1* (no restrictions to use, with a clarification) to MEC Category 2 (the benefits of use outweigh the risks), with an accompanying clarification (9). This new classification indicated that progestogen-only injectables could be used by women at high risk of HIV, because the advantages of these methods generally outweighed the possible disadvantages, and it highlighted that, when choosing these methods, there might need to be extra consideration of possible HIV acquisition, and counselling. As part of the 2017 revision, WHO reaffirmed its commitment to monitoring and assessing any new evidence relevant to contraceptive safety. New information, including results from a large, multinational randomized clinical trial (RCT) (10), led WHO to convene another GDG meeting in July 2019 to review all the available evidence and assess whether the MEC guidance needed revision. METHODS OF GUIDELINE REVIEW AND DEVELOPMENT2 Contraceptive eligibility for women at high risk of HIV: guidance statement | 3 systematic reviews); the values and preferences of contraceptive users; the balance of benefit and harms; the priority of the problem; equity and human rights; acceptability; and feasibility. The human rights principles and standards described in WHO’s guidance, Ensuring human rights in the provision of contraceptive information and services, were incorporated into deliberations (1). Owing to the focus on contraceptive safety, opportunity costs were not formally assessed during the formulation of the recommendations, since costs may vary widely throughout different regions (13). The GRADE evidence-to-decision framework (a tool encompassing quality of evidence, balance of benefits versus harms, values and preferences, priority of the problem, equity and human rights, feasibility) was used to ensure that recommendations were based on the consideration of all standards (11). 2.3 Evidence Retrieval Existing WHO recommendations on the use of specific contraceptive methods by women at high risk of HIV were reviewed in accordance with procedures outlined by the WHO Guidelines Review Committee and the GRADE approach to evidence review (11, 12). Three systematic reviews were conducted in preparation for the GDG meeting: two reviews pertained to the epidemiological evidence and the third review synthesized qualitative or quantitative studies on users’ values, preferences, views and concerns regarding contraceptive methods. The two systematic reviews of epidemiological evidence conducted for the GDG meeting were: 1. An updated systematic review on hormonal contraception and risk of HIV acquisition was conducted to include new studies published since 2016, when the last systematic review was undertaken (14). The review question was: ■ Among women at risk of HIV, does use of a hormonal contraceptive method compared with non-use of a hormonal contraceptive method (or use of another specific hormonal contraceptive method) increase risk of HIV acquisition? 2. A systematic review on copper-bearing intrauterine device (Cu-IUD) use and risk of HIV acquisition was also conducted. The review questions were: ■ Among women at risk of HIV, does use of a Cu-IUD compared with use of another non-hormonal contraceptive method or no contraceptive method increase risk of HIV acquisition? ■ Among women at risk of HIV, does use of a Cu-IUD compared with use of a specific hormonal contraceptive method increase risk of HIV acquisition? The selection criteria for the systematic reviews are listed in Table 2. The same study designs, population, comparators and outcomes were considered for all the contraceptive methods reviewed. TABLE 2. SELECTION CRITERIA FOR THE SYSTEMATIC REVIEWS Study design Longitudinal studies (randomized clinical trials and observational studies or meta-analyses containing data not captured in bibliographic database searches) Population Women of reproductive age at risk of HIV infection (women who were not living with HIV at baseline) Intervention Use of a specific contraceptive method: ■ hormonal contraception (injectables, oral contraceptives, implants, patches, rings or levonorgestrel-releasing intrauterine devices) ■ copper-bearing intrauterine devices (Cu-IUDs) Comparator One of two comparison groups: 1. non-use of a hormonal contraceptive method (either no contraceptive use or use of a non-hormonal method such as condoms or other barrier method, withdrawal, Cu-IUD or tubal ligation/vasectomy) 2. use of another specific method of hormonal contraception Outcome Incident, laboratory-confirmed HIV infection in women The two systematic reviews were conducted according to the preferred reporting items for systematic reviews and meta- analyses (PRISMA) (15). The PubMed and Embase databases were searched for studies published in any language in the peer-reviewed literature up to 26 June 2019. For individual studies, the risk of bias was assessed using a quality framework described in the previous review (14). Studies were classified into three levels: 1. “Unlikely to inform the primary question”: studies that had (a) no adjustment for any measure of condom use or (b) unclear measurement of exposure to contraception. 2. “Informative but with important limitations”: studies that had none of the flaws described above, but that still had the potential for unmeasured or residual confounding. 3. “Informative with few limitations”: studies that had none of the above flaws – likely to be a randomized clinical trial (RCT) that was assessed as having a low risk of bias on standard criteria for evaluating RCTs. The focus of the systematic reviews was on information from studies that were considered “informative but with important limitations” or “informative with few limitations.” to fall into levels 2 and 3. The values and preferences of contraceptive users were incorporated in multiple ways. First, an updated systematic review of qualitative or quantitative studies on users’ values, preferences, views and concerns regarding the contraceptive methods considered under the Medical eligibility criteria for contraceptive use (MEC) guidelines was conducted (16). This review covered studies from any country published in the peer-reviewed literature between January 2005 and December 2017. Just prior to the GDG meeting in July 2019, this review was informally updated for studies in either the peer-reviewed or grey literature that specifically looked at the values and preferences of contraceptive users relating to the issue of hormonal contraception and HIV acquisition. Second, because | Contraceptive eligibility for women at high risk of HIV: guidance statement4 the updated systematic review did not identify any information specific to key populations at risk of HIV, consultative engagements were conducted in May through July of 2019, including a global online survey of sex workers and participatory focus group discussions with female sex workers in Zimbabwe (through the Sisters with a Voice programme). Third, stakeholders representing specific affected populations, including women living with HIV, and young women, contributed their perspectives through a presentation and discussion of critical perspectives at the GDG meeting. An update about the biological data on the theoretical effect that contraception may have on HIV acquisition was prepared, reviewed and discussed at the GDG meeting, including consideration of the theoretical plausibility of individual methods of hormonal contraception having an influence on HIV acquisition. 2.4 Evidence Synthesis Epidemiological data were synthesized and evaluated according to the GRADE approach to evidence review (12). Based on this, randomized trials begin with a grade for strength of evidence of “high”, and observational studies start with a grade of “low”. The risk of bias was assessed for the summarized data using standard GRADE methods (17). Factors that could lower the evidence grade were limitations in the evidence (bias), inconsistency between studies, imprecision of estimates, indirectness of evidence, and publication bias (17–22). Randomized trials were assessed for bias by systematically evaluating for inadequate randomization/ allocation concealment; inadequate blinding of treatments; attrition and failure to use intention-to-treat analyses; selective outcome reporting; and crossover/contamination (17). Observational studies were assessed for bias by examining whether there was failure to develop and apply appropriate eligibility criteria, flawed measurement of exposures or outcomes, failure to adequately address confounding, or incomplete follow-up (17). Factors that could increase the evidence grade of observational studies included the presence of a dose-response relationship, a large magnitude of observed associations, and adjustment for plausible confounders affecting observed associations (22). 2.5 Formulation of recommendations Findings from the systematic reviews and associated GRADE evidence profiles (Annex 3) were presented at the GDG meeting. A presentation on the biological plausibility of hormonal contraception modifying the risk of HIV acquisition, and several presentations on contraceptive users’ values and preferences, were also given. These inputs were used to develop an evidence-to-decision framework (Annex 4), which served as the basis for the GDG’s deliberations during the meeting (12). All recommendations were arrived at by consensus. After the GDG’s recommendations were made, a small writing group prepared a draft guidance statement summarizing the decision and associated rationale. The draft was reviewed by the entire GDG and the external review group (see Annex 1). Comments received from the GDG and the external review group were considered and addressed by the writing group. The final version of this guidance statement was approved by the WHO Guidelines Review Committee on 22 August 2019. SUMMARY OF THE EVIDENCE3 The Evidence for Contraceptive Options and HIV Outcomes (ECHO) Study3 was the primary source of new evidence since the WHO last reviewed recommendations on contraception for women at high risk of HIV (9). The ECHO Study was a large randomized clinical trial (RCT) conducted in Eswatini, Kenya, South Africa and Zambia specifically designed to compare HIV incidence among users of three contraceptive methods: intramuscular depot medroxyprogesterone acetate (DMPA-IM), levonorgestrel (LNG) implants and copper-bearing intrauterine 3 For further information, see: http://echo-consortium.com devices (Cu-IUDs) (10). The trial randomized 7829 HIV- seronegative women, aged between 16 and 35 years, who desired effective contraception and consented to be randomized to one of the three contraceptive methods. There was no group of non-users of contraception in the ECHO trial because all of the women enrolled desired effective contraception. Women returned every three months for HIV testing, contraceptive counselling, safety monitoring, behavioural assessment and a comprehensive package of HIV Contraceptive eligibility for women at high risk of HIV: guidance statement | 5 prevention services; for up to 18 months. The main (primary) comparisons used a modified intention-to-treat analysis. In addition, pre-planned (secondary) analyses were conducted, restricted to continuous use of the assigned contraceptive method and adjusted for a number of important confounders, including vaginal sex without a condom, a new sexual partner in the previous three months, and more than one sexual partner. Statistical significance in the ECHO trial was taken to be a P-value less than 0.04 for the primary comparisons. No statistically significant associations were found for any of the primary comparisons between the three contraceptive methods (Annex 3). The quality of the evidence from this RCT was rated as high, due to its large size, strong randomization and allocation procedures, high follow-up rates, high continuation of the allocated contraceptive method, objective measurement of HIV incidence and comprehensive analysis of the results. Other evidence on hormonal contraception and HIV acquisition published since the 2016 review (14) was included in the evaluation of the body of evidence, along with a systematic review on Cu-IUDs and risk of HIV acquisition (Annex 3). For hormonal contraception, one new observational study and updated estimates from a previously included study were identified (23, 24). Adding this evidence to the previous 14 observational studies (14) did not change the conclusions of the previous review. Thus, the body of observational evidence suggested some concern about an increased risk of HIV acquisition with DMPA-IM use, but was generally reassuring for other methods of hormonal contraception. For intrauterine devices (IUDs), two observational studies did not suggest an increased risk of HIV acquisition with Cu-IUD use (23, 25). The quality of evidence from these observational studies was rated as low and low-to-moderate. 3.1 Progestogen-only injectables One RCT (the ECHO trial) observed no statistically significant differences in HIV acquisition when comparing DMPA-IM versus Cu-IUD, and DMPA-IM versus LNG implant (10). The quality of the evidence from this RCT was rated as high. Evidence from 14 observational studies of DMPA-IM, norethisterone enanthate (NET-EN) or unspecified progestogen- only injectables considered to be “informative but with important limitations” was assessed (14, 23, 24). Additional data from one new observational study and updated estimates from a previously included study did not change the conclusions of the previous review of observational evidence (14). The quality of the evidence from the observational studies was rated as low and low-to-moderate due to limitations that included unmeasured confounding. 3.2 Progestogen-only implants Three observational studies considered to be “informative but with important limitations” assessed implants. One had been included in the previous review (26), one provided an updated point estimate to that used for the previous review (24) and one provided an entirely new estimate of risk (23). Two of the studies assessed LNG implants (24, 26) and the third assessed women using either LNG or etonogestrel implants (23). None of the three studies suggested an increased risk of HIV acquisition with implant use, consistent with the conclusion of the previous review (14). The quality of the evidence from these studies was rated as low. 3.3 Progestogen-only pills No studies considered “informative but with important limitations” or “informative with few limitations” were identified for progestogen-only pills. 3.4 Intrauterine devices One RCT (the ECHO trial) observed no statistically significant differences in HIV acquisition between DMPA-IM and Cu-IUD, or Cu-IUD and LNG implants (10). The quality of the evidence from this RCT was rated as high. Two observational studies considered “informative but with important limitations” did not observe an association with HIV acquisition when comparing Cu-IUD use with tubal ligation or no contraceptive method use, DMPA-IM, NET-EN or implants (23, 25). The quality of this observational evidence was rated as low. No evidence was identified for LNG-IUDs. 3.5 Combined hormonal contraceptives Eleven observational studies deemed “informative but with important limitations” assessed the use of combined oral contraceptives (COC). (It was assumed that studies that did not specify the oral contraceptive type examined mostly, if not exclusively, examined COC use.) All of these studies were included in the previous review, while an updated estimate came from one newly available study (14, 24). Overall, these studies suggested no association between COC use and HIV acquisition. The quality of the evidence was rated as low-to-moderate. No evidence was identified for the combined contraceptive patch, ring or injectable. 3.6 Additional evidence considered by the GDG 3.6.1 BIOLOGICAL DATA Biological data pertaining to the plausibility of an effect of individual methods of hormonal contraception on HIV acquisition were reviewed. Several biological mechanisms by which individual methods of hormonal contraception could theoretically modify the risk of HIV acquisition have been postulated, but | Contraceptive eligibility for women at high risk of HIV: guidance statement6 sparse and contradictory data make it unclear which, if any, of these biological mechanisms are clinically relevant. Potential mechanisms include alteration of the systemic and local immune response and changes in the genital tract environment. It was noted that different forms of hormonal contraception may change these factors in different ways. Combined contraceptives containing both ethinylestradiol and a progestogen may have a different effect than progestogen-only methods. Additionally, various progestogen-only methods, such as DMPA and NET-EN injectables, may change immune function variably. It remains uncertain to what extent data from animal and laboratory studies, including in relation to progestogen type and dosing, can be applied to clinical outcomes in humans. 3.6.2 VALUES AND PREFERENCES OF CONTRACEPTIVE USERS The systematic review identified 375 studies from all regions of the world (27). Across studies, women’s values and preferences centred on themes of choice and available options, ease of use, side-effect profiles and contraceptive efficacy. Contextual factors, such as the contraceptive methods available, counselling from providers, and the opinions of social networks, influenced decision-making. From the grey literature, two additional studies were identified that were relevant to hormonal contraception and HIV specifically (28, 29). Both found that messages from the 4 “Free” means the freedom and ability to make a voluntary decision about contraceptive use without barriers or coercion; informed means complete, correct and clear information has been given about all the options, plus details about the chosen method 2017 WHO guidance were difficult for providers to explain fully and may not be completely understood by clients. The online survey of sex workers from multiple global regions found that individual preferences around contraception varied widely and could change over time; ongoing partnership and dialogue with sex workers is essential to understanding evolving priorities. In participatory focus groups, Zimbabwean sex workers said their contraceptive choices were shaped by a wide range of factors, including cost, accessibility, the way sex workers are treated at clinics, the influence of male partners, and contraceptive side-effects. Sex without a condom was common, and there was a need to strengthen access to HIV/STI prevention and contraceptive services. The community stakeholder presentation emphasized that, for some women, any level of increased HIV risk would be too high. It also highlighted that the ECHO trial was not set up to assess the difference in the risk of HIV acquisition between contraceptive users and non-users. Community stakeholders also emphasized that there was a lack of true contraceptive choice for many women and girls, saying the guidance should emphasize full, free and informed contraceptive choice,4 the procurement of a range of contraceptive methods, and investment in integrated contraception and HIV services. RECOMMENDATIONS4 4.1 Recommendations for contraceptive use among women at high risk of HIV infection All hormonal contraceptive methods and intrauterine devices (IUDs) now fall into Category 1 of the Medical eligibility criteria for contraceptive use (MEC) (5) for women at high risk of HIV. Thus, women at high risk of HIV can use all methods of contraception without restriction. ■ Women at high a risk of HIV infection are eligible to use all progestogen-only contraceptive methods without restriction (MEC Category 1), including progestogen-only pills (POPs), intramuscular depot medroxyprogesterone acetate (DMPA-IM), subcutaneous DMPA (DMPA-SC), norethisterone enanthate (NET-EN) injectables, levonorgestrel (LNG) implants, and etonogestrel implants. ■ Women at a high risk of HIV infection are eligible to use copper-bearing IUDs (Cu-IUDs) and LNG implants without restriction (MEC Category 1). In considering the use of IUDs, many women at a high risk of HIV are also at risk of other sexually transmitted infections (STIs); for these women, providers should refer to the MEC recommendation on women at increased risk of STIs and the Selected practice recommendations for contraceptive use on STI screening before IUD insertion (5, 6). ■ Women at a high risk of HIV infection are eligible to use all combined hormonal contraceptive methods without restriction (MEC Category 1), including combined oral Contraceptive eligibility for women at high risk of HIV: guidance statement | 7 contraceptives (COCs), combined injectable contraceptives (CICs), combined contraceptive patches (P) and combined vaginal rings (CVR). 4.2 Rationale The Guideline Development Group (GDG) reviewed, and discussed extensively, the new epidemiological and biological evidence, as well as related information about values and preferences, equity and human rights, and feasibility. After deliberating on all of the available evidence, the GDG recommended that the MEC category for DMPA and Cu-IUD should be changed to MEC Category 1. The GDG noted that there was no evidence regarding DMPA-SC and LNG-IUD, and only limited new information regarding NET-EN. Until more information becomes available, the GDG judged it was appropriate to follow the same approach as previously used, i.e. grouping all progestogen-only injectables together (DMPA- IM, DMPA-SC and NET-EN) as MEC Category 1, and to assign the same MEC category to the LNG-IUD as to the Cu-IUD (MEC Category 1). One key portion of the GDG’s deliberations related to evaluating evidence from the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Study (see Annex 3). The GDG gave particular attention to this information because of its ability to address unmeasured confounding – a major cause of uncertainty when interpreting results from observational studies. The GDG recognized that the ECHO trial did not address the etiological or causal question of whether DMPA increases the risk of HIV acquisition when compared with not using any contraception. Nevertheless, since the MEC provides guidance for women wishing to use contraception, results from the ECHO trial about the comparative risk of HIV acquisition among users of the three contraceptives tested were highly pertinent to the GDG’s deliberations. Furthermore, the GDG noted that the high incidence of HIV infection experienced by each contraceptive group during the ECHO trial was similar to the background incidence assumed when designing the trial. This was deemed to be indirect evidence addressing the question, suggesting no increased risk of HIV acquisition among users of these contraceptives compared with women not using any contraception. The ECHO trial was considered to be a well conducted study that provided high-quality evidence that superseded the low and low-to-moderate-quality observational evidence previously available to the GDG. This direct epidemiological evidence, from a trial specifically designed to address the issue, was judged to be more informative than theoretical biological evidence. The reasons for considering the ECHO trial to be of high quality included its large size; robust randomization methods; good adherence to the allocated contraceptive method; a low attrition rate; regular, standardized and objective outcome measurements; and a blinded, comprehensive analysis of the data (including sensitivity analyses for postulated confounders such as sexual activity and condom use). Although women and providers of services in the ECHO trial could not be blinded to the intervention allocation, there was no evidence that this led to the different groups of participants acting, or being managed, differently with respect to important issues such as HIV prevention counselling. This ensured that residual confounding, particularly in relation to condom use or sexual activity, was highly unlikely to have affected the ECHO trial. The GDG noted that although the ECHO trial was designed to detect a 50% increase in the risk of HIV acquisition between contraceptive groups assessed, the observed high HIV incidence and small losses to follow up meant that it could detect a 30% increase. When considering the ECHO trial results, the GDG focused on the point estimates for each primary comparison. The group noted that none of the point estimates for the primary comparisons were statistically significant. The 96% confidence intervals surrounding these point estimates included unity, and so encompassed the possibility of a small increased or decreased difference in risk between contraceptives. The GDG acknowledged, however, that for an individual woman at a high risk of HIV, any change in this risk may be important. After a full discussion, the GDG judged that unmeasured confounding was the most likely explanation for the apparent increased risk of HIV acquisition among DMPA-IM users seen in some observational studies. The GDG’s decisions to revise the MEC classifications for DMPA and IUDs were further grounded by the values and preferences of women towards optimizing informed contraceptive choice and the availability of a wide range of contraceptive options, based on a systematic review of qualitative and quantitative evidence, consultative engagements with sex workers and the perspectives of GDG members representing specific affected populations. In previous editions of the MEC, IUDs were classified as MEC Category 2 for women at a high risk of HIV. This recommendation was given because of the absence of high-quality, direct evidence about the risk of acquiring HIV among IUD users. In addition, there was an assumption that most women at a high risk of HIV were also at an increased risk of other STIs. The ECHO trial provided direct, high-quality evidence about the risk of HIV acquisition risk among women using the Cu-IUD, enabling the GDG to review its recommendation regarding these women. Any new evidence related to IUD use in women at a high risk of other STIs will be reviewed for the next MEC update. The GDG was concerned about the high rates of both HIV and STIs among women in the ECHO trial, reflecting the background risk factors among women seeking contraception in the study areas. The high incidence of HIV was particularly striking given the extensive efforts made during the ECHO trial to provide HIV prevention counselling and interventions. Thus, while the GDG concluded that the risk of HIV acquisition was not affected by the contraceptive method used, it emphasized the need for renewed efforts to reduce the incidence of HIV and STIs. | Contraceptive eligibility for women at high risk of HIV: guidance statement8 IMPLICATIONS FOR POLICY-MAKERS, PROGRAMME MANAGERS AND HEALTH-CARE PROVIDERS 5 While the main audiences for the Medical eligibility criteria for contraceptive use (MEC) are policy-makers and programme managers, a fundamental tenet of the MEC is that they are woman-centred. The following were the key messages that came from the deliberations of the Guideline Development Group. 5.1 A woman’s risk of HIV should not restrict her contraceptive choice While a risk of HIV should not restrict a woman’s choice to use hormonal contraception or an intrauterine device, it is important to note that these methods do not protect her against acquiring HIV or other sexually transmitted infection (STI). The new MEC recommendations should not be interpreted as indicating that HIV and STI testing and prevention are no longer important. Indeed, the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Study highlighted the critical need to strengthen and expand HIV and STI prevention services (10). Testing for HIV and STIs should be part of high-quality family planning services for women at risk, particularly for those living in areas of high HIV and STI incidence. 5.2 Efforts to expand access to contraceptive options must continue Women have the right to a range of short-acting, long-acting and permanent contraceptive methods, as well as to emergency contraception (1). A comprehensive range of contraceptive methods enables women to respond to changing needs and preferences during their reproductive lives. Informed decision- making and woman-centred, high-quality counselling are key components in the human rights-based provision of contraceptive information and services (2). The ECHO trial reinforced that offering a range of methods is possible and acceptable to women (10). Family planning and HIV services should be included in national universal health coverage initiatives. Efforts to expand safe and effective contraceptive options, and to ensure their availability and the access to them, must continue. Technical resources are available to support countries to introduce more contraceptive options into their programmes and services (Box 1). BOX 1. TECHNICAL RESOURCES TO SUPPORT PROGRAMMES o Medical eligibility criteria for contraceptive use (in English, French and Russian) https://apps.who.int/iris/handle/10665/181468 o Selected practice recommendations for contraceptive use (in English, French and Spanish) https://apps.who.int/iris/handle/10665/252267 o Implementation guide for the medical eligibility criteria and selected practice recommendations for contraceptive use (available in English, French, Portuguese and Spanish) https://apps.who.int/iris/handle/10665/272758 o Global handbook for family planning providers https://apps.who.int/iris/handle/10665/260156 o Training Resource Package for Family Planning website (available in English and French) https://www.fptraining.org o Mobile application for the Medical eligibility criteria for contraceptive use (free, for android and iOS platforms) https://www.who.int/reproductivehealth/mec-app o Policy brief: consolidated guidelines on HIV prevention, diagnosis, treatment and care for key populations, 2016 update https://apps.who.int/iris/handle/10665/258967 o Treat all: policy adoption and implementation status in countries (fact sheet) https://apps.who.int/iris/handle/10665/258538 Contraceptive eligibility for women at high risk of HIV: guidance statement | 9 5.3 A renewed emphasis on HIV and STI prevention services is urgently needed The ECHO trial showed high rates of both HIV and STIs in the study sites (10), highlighting the need for appropriate prevention, diagnosis and treatment of all STIs. Current HIV prevention measures remain unavailable or unsatisfactory for many women and adolescent girls living in settings of high HIV incidence. In such areas, the integration of family planning and HIV prevention services for all women is essential if the health of women and adolescent girls is to be improved. In settings of low HIV prevalence, there is a need for family planning providers to evaluate personal risk factors that may increase a woman’s risk of acquiring HIV and then to provide appropriate services. The ECHO trial also showed that syndromic management did not decrease the prevalence of STIs at baseline and at the end of follow-up. STI programmes need to be strengthened, including a move towards diagnostic management. ■ In settings with high HIV prevalence, HIV testing and prevention should be included in family planning services. HIV testing should be offered to all women and to partners of all women with HIV. HIV prevention options should be offered to all women, including pre-exposure prophylaxis (PrEP), as recommended in WHO guidelines (30). The offer of PrEP to women could also be considered where HIV incidence is high (but below 3/100 person-years overall) following, for example, a simple risk assessment. A risk assessment could include: desire to take PrEP (reflecting a self-identified risk); history of an STI; more than one sex partner in the last six months; or women with a sex partner with HIV who is not virally supressed on antiretroviral therapy. ■ In settings with low HIV prevalence, the routine offer of HIV testing and prevention services in family planning settings is unlikely to be cost-effective. HIV testing and prevention services could nonetheless be offered to women who request these services. BOX 2. WORK TO IDENTIFY WOMEN AT HIGH RISK OF HIV A person’s HIV risk depends on the incidence of HIV in the area where they live, and their individual risk factors. Family planning programmes must work closely with their national and subnational HIV programmes to use local epidemiological data to identify geographical areas and risk factors that put women at a high risk of HIV infection. 6.1 Contraceptive methods and HIV acquisition The existing body of evidence is sufficient to guide practice on intramuscular depot medroxyprogesterone acetate (DMPA-IM), levonorgestrel (LNG) implants and copper-bearing intrauterine devices; additional observational data will not add substantially to the evidence base for these methods. However, in the absence of trial data similar to those in the ECHO Study (10), observational data about subcutaneous DMPA (DMPA-SC), LNG IUDs, etonogestrel implants, or future contraceptive or multi-purpose prevention technologies could still be useful, although unmeasured confounding would likely remain a concern. Studies should consider the potential impact of contraceptive use on other sexually transmitted infections as well as HIV. Additional research on the specific effects of contraception-related bleeding changes in relation to the risk of HIV or STI acquisition is also needed. 6.2 HIV prevention The Guideline Development Group was deeply concerned by the high HIV incidence found among women seeking family planning services in the ECHO Study sites, despite the fact that trial participants received an extensive HIV prevention package (including repeated HIV testing and counselling, partner HIV testing and condom distribution, as well as pre-exposure prophylaxis (PrEP) late in the study as this became the standard of care). More research is needed on ways to increase the acceptability and uptake of effective HIV prevention strategies for women at a high risk of HIV, tailored to settings of both high and low HIV prevalence and to women with a range of personal risk factors. In the ECHO trial, the uptake (and hence impact) of PrEP was minimal as it became available only late in the trial (10). Where it was available on site, as opposed to requiring referral to another site, acceptability and uptake were high. Ways to include HIV self-testing and PrEP in family planning services should be KNOWLEDGE GAPS AND AREAS FOR RESEARCH6 | Contraceptive eligibility for women at high risk of HIV: guidance statement10 explored. This should include behavioural and implementation science research on the effective integration of HIV and contraception services. 6.3 Community involvement The ECHO trial employed a range of strategies for directly engaging with civil society at the study site, and at regional and global levels (10). An in-depth assessment of the strengths and limitations of each strategy is likely to provide models for community engagement in contraceptive and HIV prevention research that could be adopted in the future. 6.4 Increased funding for high-quality, policy-relevant research The ECHO Study demonstrated that a well conducted, adequately powered randomized clinical trial is possible in contraceptive research, and can make an important contribution to global decision-making. Global policy should be based on comprehensive high-quality evidence, but additional investment in contraceptive research is critically overdue, including research addressing whether financial barriers affect the contraceptive choices of women. DISSEMINATION OF THIS GUIDANCE STATEMENT7 The World Health Organization (WHO) will work to communicate this guidance statement clearly and widely. WHO will evaluate whether the guidance achieves its intentions. The guidance will be published on the WHO website and in a limited quantity of printed documents. The guidance will be widely disseminated through the WHO regional and country offices, WHO Member States, other United Nations agencies, civil society, the Implementing Best Practices (IBP) initiative, professional organizations, governmental and non- governmental partner organizations, and WHO collaborating centres working in the area of HIV and sexual and reproductive health. The WHO Secretariat will work closely with sexual and reproductive health and HIV focal points in regional and country offices of WHO, the United Nations Population Fund and the Joint United Nations Programme on HIV and AIDS to conduct a series of regional learning and knowledge-sharing events. This engagement will target opportunities where sexual and reproductive health issues are being discussed; examples include the 25th Conference on Population and Development in July 2019 and the 20th International Conference on AIDS and Sexually Transmitted Infections in Africa in December 2019. The Secretariat will also work closely with country task teams and working groups leading HIV and contraception programme efforts to share the guidance with grassroots and community- level organizations and providers. Additionally, webinars for stakeholders in multiple languages will be organized during 2020 to ensure Member States and stakeholders are fully informed of the new recommendations. These opportunities will enable WHO to disseminate the updated guidance effectively and efficiently. Derivative communication products highlighting key counselling issues (e.g. short briefs for front-line health-care providers and community-based organizations) will be prepared in collaboration with WHO’s implementing partners, and in consultation with the GDG during 2020. A policy brief in the six official languages used by WHO will be developed to inform policy-makers about the contraception updates. As part of the dissemination of the recommendations in this guidance statement, WHO will update its digital contraceptive decision-support tools – the MEC mobile app (31), the humanitarian contraceptive delivery app (32) and the postpartum compendium (33). These mobile applications are free to download and available for both iOS and Android platforms. Additionally, the Global handbook for family planning providers and the online Family Planning Training Resource Package will be updated accordingly (8, 34). WHO will continue to monitor the body of evidence informing these recommendations and will convene additional consultations when needed. Contraceptive eligibility for women at high risk of HIV: guidance statement | 11 REFERENCES 1. Ensuring human rights in the provision of contraceptive information and services: guidance and recommendations. Geneva: World Health Organization; 2014 (https://apps.who.int/iris/handle/10665/102539, accessed 24 August 2019). 2. Framework for ensuring human rights in the provision of contraceptive information and services. Geneva: World Health Organization; 2014 (https://apps.who.int/iris/handle/10665/133327, accessed 24 August 2019). 3. The thirteenth general programme of work, 2019–2023: promote health, keep the world safe, serve the vulnerable. Geneva: World Health Organization; 2019 (https://apps.who.int/iris/handle/10665/324775, accessed 24 August 2019). 4. Reproductive health strategy to accelerate progress towards the attainment of international development goals and targets. Geneva: World Health Organization; 2004 (https://apps.who.int/iris/handle/10665/68754, accessed 24 August 2019). 5. Medical eligibility criteria for contraceptive use, fifth edition. Geneva: World Health Organization; 2015 (https://apps.who.int/iris/ handle/10665/181468, accessed 24 August 2019). 6. Selected practice recommendations for contraceptive use: third edition. Geneva: World Health Organization; 2016 (https://apps.who.int/iris/handle/10665/252267, accessed 24 August 2019). 7. WHO medical eligibility criteria wheel for contraceptive use, 2015 update. Geneva: World Health Organization; 2004 (https://apps.who.int/iris/handle/10665/173585, accessed 24 August 2019). 8. World Health Organization, Johns Hopkins Bloomberg School of Public Health. Family planning: a global handbook for providers: evidence-based guidance developed through worldwide collaboration, third edition. Geneva: World Health Organization; 2018 (https://apps.who.int/iris/handle/10665/260156, accessed 24 August 2019). 9. Hormonal contraceptive eligibility for women at high risk of HIV: guidance statement: recommendations concerning the use of hormonal contraceptive methods by women at high risk of HIV. Geneva: World Health Organization; 2017 (https://apps.who.int/ iris/handle/10665/254662, accessed 24 August 2019). 10. Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium. HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial. Lancet. 2019;394(10195):303–13. doi: 10.1016/S0140-6736(19)31288-7. 11. WHO handbook for guideline development, second edition. Geneva: World Health Organization; 2014 (https://apps.who.int/iris/ handle/10665/145714, accessed 24 August 2019). 12. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J et al. GRADE guidelines: 1. Introduction –GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64(4):383–94. doi: 10.1016/j.jclinepi.2010.04.026. 13. Singh S. Adding it up: costs and benefits of contraceptive services – estimates for 2017. New York (NY): Guttmacher Institute; 2017. 14. Polis CB, Curtis KM, Hannaford PC, Phillips SJ, Chipato T, Kiarie JN et al. An updated systematic review of epidemiological evidence on hormonal contraceptive methods and HIV acquisition in women. AIDS. 2016;30(17):2665–83. doi: 10.1097/ QAD.0000000000001228. 15. Moher D, Liberati A, Tetzlaff J, Altman DG; The Prisma Group. Preferred reporting items for systematic reviews and meta- analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. doi: 10.1371/journal.pmed.1000097. 16. Kennedy CE, Yeh PT, Gaffield ME. Contraception values and preferences: protocol and methods for a global systematic review. Contraception. 2019 (in press). doi: 10.1016/j.contraception.2018.05.006Get. 17. Guyatt GH, Oxman AD, Vist G, Kunz R, Brozek J, Alonso-Coello P et al. GRADE guidelines: 4. Rating the quality of evidence— study limitations (risk of bias). J Clin Epidemiol. 2011;64(4):407–15. doi: 10.1016/j.jclinepi.2010.07.017. 18. Guyatt GH, Oxman AD, Kunz R, Brozek J, Alonso-Coello P, Rind D et al. GRADE guidelines 6. Rating the quality of evidence – imprecision. J Clin Epidemiol. 2011;64(12):1283–93. doi: 10.1016/j.jclinepi.2011.01.012. | Contraceptive eligibility for women at high risk of HIV: guidance statement12 19. Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M et al. GRADE guidelines: 8. Rating the quality of evidence – indirectness. J Clin Epidemiol. 2011;64(12):1303–10. doi: 10.1016/j.jclinepi.2011.04.014. 20. Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M et al. GRADE guidelines: 7. Rating the quality of evidence – inconsistency. J Clin Epidemiol. 2011;64(12):1294–302. doi: 10.1016/j.jclinepi.2011.03.017. 21. Guyatt GH, Oxman AD, Montori V, Vist G, Kunz R, Brozek J et al. GRADE guidelines: 5. Rating the quality of evidence – publication bias. J Clin Epidemiol. 2011;64(12):1277–82. doi: 10.1016/j.jclinepi.2011.01.011. 22. Guyatt GH, Oxman AD, Sultan S, Glasziou P, Akl EA, Alonso-Coello P et al. GRADE guidelines: 9. Rating up the quality of evidence. J Clin Epidemiol. 2011;64(12):1311–6. doi: 10.1016/j.jclinepi.2011.06.004. 23. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619–22. doi: 10.1097/ QAD.0000000000002260. 24. Sabo MC, Richardson BA, Lavreys L, Martin HL, Jr, Jaoko W, Mandaliya K et al. Does bacterial vaginosis modify the effect of hormonal contraception on HIV seroconversion. AIDS. 2019;33(7):1225–30. doi: 10.1097/QAD.0000000000002167. 25. Lavreys L, Baeten JM, Martin Jr HL, Overbaugh J, Mandaliya K, Ndinya-Achola J et al. Hormonal contraception and risk of HIV-1 acquisition: results of a 10-year prospective study. AIDS. 2004;18(4):695–7. 26. Wall KM, Kilembe W, Vwalika B, Htee Khu N, Brill I, Chomba E et al. Hormonal contraception does not increase women’s HIV acquisition risk in Zambian discordant couples, 1994–2012. Contraception. 2015;91(6):480–7. doi: 10.1016/j. contraception.2015.02.004. 27. Yeh PT, Kennedy CE, Gaffield ME. Contraception values and preferences: a global systematic review. Contraception. 2019; (accepted pending revisions). 28. Miller L, Ntinginya M, Makula J, Juma A, Mackay A, Wadegu E et al. Final report: a pilot study to assess training and communication materials on progestogen-only injectable use and risk of HIV acquisition in Tanzania. London: Marie Stopes International; 2019 (https://resultsforinformedchoice.org/wp-content/uploads/2019/02/Injectables-and-HIV-Pilot-Study-Report-TZ.pdf, accessed 24 August 2019). 29. Littlepage S, Dam A, Nakyanjo N, Polis C, Nalugoda F, Kennedy CE. Contraceptive decision-making in the context of HIV risk and changing World Health Organization guidelines: a qualitative study in Rakai, Uganda. 2019 (personal communication). 30. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach, second edition. Geneva: World Health Organization; 2016. (https://apps.who.int/iris/handle/10665/208825, accessed 24 August 2019). 31. New app for WHO’s medical eligibility criteria for contraceptive use. In: World Health Organization [website]. Geneva: World Health Organization; 2018 (https://www.who.int/reproductivehealth/mec-app, accessed 24 August 2019). 32. Delivering contraceptive services in humanitarian settings: new tool for front-line health care workers. In: World Health Organization [website]. Geneva: World Health Organization; 2018 (https://www.who.int/reproductivehealth/publications/ humanitarian-settings-contraception, accessed 24 August 2019). 33. New WHO tool helps guide contraception choices following childbirth. In: World Health Organization [website]. Geneva: World Health Organization; 2016 (https://www.who.int/reproductivehealth/news/pfpc, accessed 24 August 2019). 34. TRP: Training Resource Package for Family Planning [website]. Baltimore (MD): Johns Hopkins University; 2019 (https://www.fptraining.org, accessed 24 August 2019). Contraceptive eligibility for women at high risk of HIV: guidance statement | 13 ANNEX 1. GUIDELINE DEVELOPMENT GROUP AND EVIDENCE SECRETARIAT Guideline Development Group Sharon Achilles (University of Pittsburgh, United States of America), Richard Adanu (University of Ghana, Ghana), Rachid Bezad (University Roi Mohammad VI, Morocco), Sharon Cameron (University of Edinburgh, United Kingdom of Great Britain and Northern Ireland), Tsungai Chipato (University of Zimbabwe, Zimbabwe), Maria del Carmen Cravioto (National Institute of Nutrition, Salvador Zubiran, Mexico) [unable to attend], Alison Edelman (Oregon Health & Science University, United States), Mohammad Eslami (Ministry of Health and Education, Islamic Republic of Iran), Anna Glasier (University of Edinburgh, United Kingdom), Andy Gray (University of KwaZulu- Natal, South Africa), Philip Hannaford (University of Aberdeen, United Kingdom), Felicita Hikuam (AIDS and Rights Alliance for Southern Africa, Namibia), Unnop Jaisamrarn (Chulalongkorn University, Thailand), Loveleen Johri (family planning and reproductive health independent consultant, India), Natasha Kaoma (Copper Rose Zambia, Zambia), Seni Kouanda (Institute of Research in Health Sciences, Burkina Faso), Elizabeth Lule (global health and international development independent consultant, Uganda), Vimbai Magwenzi (Centre for Sexual Health and HIV/AIDS Research, Zimbabwe) [unable to attend], Loyce Maturu (Zvandiri Mentor with Africaid, Zimbabwe), Olav Meirik (Instituto Chileno de Medicina Reproductiva, Chile), Placid Mihayo (Ministry of Health, Uganda), Lilian Mworeko (International Community of Women Living with HIV Eastern Africa, Uganda), Hiromi Obara (National Center for Global Health and Medicine, Tokyo, Japan), Herbert Peterson (University of North Carolina, United States), John Pile (independent consultant, Thailand), Carolina Sales Vieira (University of Sao Paulo, Brazil), Sarah Simpson (EquiACT, France), Aminata Wurie (Youth Coalition for Sexual and Reproductive Rights, Sierra Leone). Philip Hannaford and Natasha Kaoma co-chaired the meeting Guideline Development Group (GDG) meeting. Evidence Secretariat Centre for Sexual Health and HIV/AIDS Research – Euphemia Sibanda FHI 360 – Timothy Mastro Independent Consultant – Ania Shapiro Johns Hopkins University – Caitlin Kennedy Oregon Health & Science University – Maria Isabel Rodriguez United States Centers for Disease Control and Prevention – Kathryn Curtis University of Washington – Jared Baeten Wits Reproductive Health and HIV Institute – Helen Rees Observer Zandile Mnisi (Ministry of Health, Eswatini) External Review Group Florence Anam (Doctors Without Borders, South Africa), Winfred Apio (Uganda Youth and Adolescents Forum, Uganda), Lynn Bakamjian (independent consultant, United States), Milena Brito (University of Sao Paulo, Brazil), Roy Jacobstein (IntraHealth, United States), Ernest Maya (University of Ghana, Ghana), Mari Ngai (National Center for Global Health and Medicine, Japan), Cristina Puig Borràs (European Consortium for Emergency Contraception, Spain), Nusrat Shah (Society of Obstetrics & Gynaecology, Pakistan), Bulbul Sood (Jphiego, India). WHO Secretariat The WHO Secretariat attended the meeting and several WHO staff provided background presentations (Rachel Baggaley, Mary Lyn Gaffield, James Kiarie, Nancy Kidula). The WHO Secretariat was present to serve as a background resource, if request by the GDG. Neither WHO, the Joint United Nations Programme on HIV/AIDS (UNAIDS) nor the United Nations Population Fund (UNFPA) staff participated in the decision- making or formulation of the recommendations, which was the sole responsibility of the GDG. Several WHO staff contributed to the systematic reviews (Mary Lyn Gaffield, James Kiarie, Petrus Steyn) and the writing of the statement. WHO headquarters WHO Department of Reproductive Health and Research – Ian Askew, Mary Lyn Gaffield, James Kiarie, Antonella Lavelanet, Manjulaa Narasimhan (unable to attend), Petrus Steyn WHO Department of HIV – Rachel Baggaley, Virginia MacDonald, Michele Rodolph WHO Department of Regulation of Medicines and other Health Technologies – Ray Corrin | Contraceptive eligibility for women at high risk of HIV: guidance statement14 WHO regional offices WHO Regional Office for Africa – Nancy Kidula, Léopold Ouedraogo Joint United Nations Programme on HIV/AIDS (UNAIDS) Peter Godfrey-Fausett United Nations Population Fund (UNFPA) Technical Division – Gifty Addico, Mieko Yabuta (unable to attend) Overall coordination WHO Department of Reproductive Health and Research – Mary Lyn Gaffield, with logistical support from Jane Werunga- Ndanareh. Writing The guidance statement was drafted on behalf of WHO by Caitlin Baumhart, Kathryn Curtis, Mary Lyn Gaffield, Philip Hannaford, Natasha Kaoma, Caitlin Kennedy and Maria Isabel Rodriguez. The systematic review examining the use of copper-bearing intrauterine devices and HIV acquisition was co-authored by Tsungai Chipato, Kathryn Curtis, Philip Hannaford and Angeline Ti. The update of the 2016 systematic review focusing on hormonal contraception and HIV acquisition was co-authored by Tsungai Chipato, Kathryn Curtis, Philip Hannaford, James Kiarie and Petrus Steyn. The GRADE tables and expertise on GRADE methodology were provided by Maria Isabel Rodriguez. Preparation of the evidence-to-decision table and expertise on the literature for values and preferences were provided by Caitlin Kennedy. Editing was done by Markus MacGill and Jane Patten of Green Ink (www.greenink.co.uk) and layout by Lushomo (www.lushomo.net). Contraceptive eligibility for women at high risk of HIV: guidance statement | 15 ANNEX 2. DECLARATIONS OF CONFLICTS OF INTEREST Following guidance issued on 24 September 2014 by the WHO Office of Compliance, Risk Management and Ethics (CRE), and prior to the 29–31 July 2019 meeting, the name and brief biography of each proposed Guideline Development Group (GDG) member was published on the WHO website during 27 May to 10 June 2019 (https://www.who.int/ reproductivehealth/publications/contraceptives-methods-hiv). The public was able to view and provide their comments to the WHO Secretariat using a general email address (hrx_info@who.int) regarding any perceived or real conflicts of interest of these proposed GDG members. In addition, prior to the public announcement period, the WHO Secretariat reviewed the curriculum vitae of each potential participant and conducted Internet searches (Google Scholar, Open Payments, PubMed) for information on potential financial and academic conflicts of interest related to the subject of the meeting. Following the public reporting period, and in consultation with CRE, official invitations for GDG membership were extended. Additionally, the WHO Secretariat reviewed potential financial and academic conflicts of interest related to the subject of the meeting of the proposed External Review Group: no conflicts were declared among this 11-member group. Of the 28 experts who participated in this work, six declared an interest related to contraception. The WHO Secretariat, CRE and GDG reviewed all declarations and found no conflicts of interest sufficient to preclude anyone from participating in the deliberations or the development of the recommendations relevant to hormonal contraception and HIV. Accordingly, the six participants who declared interests related to contraception, as well as the other 22 participants, fully participated in the meeting’s deliberations, discussions and final decisions. Although not all interests declared were specifically related to contraception and susceptibility to HIV, they are disclosed and summarized below. Sharon Achilles received US$ 4225 on 10 May 2016 to give expert advice on the latest HIV therapies during a one-day meeting sponsored by Merck Sharp & Dohme. Her research unit received US$ 2 638 373 from the United States National Institutes of Health/National Institute of Allergy and Infectious Diseases to conduct a study titled, Quantification of immune cells in women using contraception, during 2012–2019. For 2012–2019, her research unit is receiving US$ 4 999 999 from the Bill & Melinda Gates Foundation to conduct a study titled, HIV-target cell response in women initiating contraception in high HIV-incidence areas. During 2014–2016, Dr Achilles’s research unit received US$ 240 225 from the Bill & Melinda Gates Foundation to conduct a study addressing IFN-epsilon and hormonal contraceptive modulation of the risk of HIV acquisition. Currently, for 2018–2020, Dr Achilles’s research unit receives US$ 535 958 from the United States Food and Drug Administration (FDA) to conduct a study supporting new approaches to improve product manufacturing and quality titled, Physiologically-based model of the female reproductive tract: vaginal and intrauterine delivery components. Sharon Cameron works at a research unit that received a grant from Pfizer, UK, for £99 000, which ceased in 2016. The study was implemented to determine the feasibility and acceptability of the pharmacist administration of subcutaneous injectable contraception. Alison Edelman receives a yearly royalty of around US$ 1000 from the Internet information site, UpToDate as an author of the content. Between May 2016 and May 2017, she received US$ 10 000 a year from Agile Pharmaceuticals as an expert consultant regarding a hormonal contraceptive patch that is currently not FDA-approved. This consultation has ended. Since January 2016, she served as a trainer for Nexplanon, an FDA mandate, for Merck Sharp & Dohme, but has received no honorarium for these sessions and as an expert consultant in January 2016 for this company, receiving US$ 1500 for her services. Her research unit received US$ 540 000 from the Merck Women’s Health Investigator Initiated Studies Program to conduct research focused on treatment of breakthrough bleeding with the contraceptive implant (2016–2019). From 2015 to 2017, her research unit received a US$ 250 000 research grant from the Society for Family Planning to investigate the timing of ulipristal acetate and oral contraceptive use. Since 2002, Dr Edelman has been receiving about US$ 3000 a year from Contemporary Forums as a faculty member for its continuing medical education conferences (the amount varies depending on the number of lectures she gives). From November 2015 through June 2016, she received an honorarium of US$ 3000 from Oregon State University for expert advice on the mandated state training to allow the direct provision of contraceptives by pharmacists. Since July 2016, Dr Edelman has been receiving US$ 500 a year as an honorarium for serving on the data and safety monitoring board to FHI 360, which is developing a novel contraceptive injectable that is not yet FDA-approved. From April to September 2017, Dr Edelman was a consultant for HRA Pharma for a study investigating a progestin-only pill. Since July 2017, she had been an expert consultant for the Sugar Palm Foundation; this contract was then channelled through her institution and ended in 2019. Since June 2017, she has been providing expert consulting to Ipas to train health-care workers in Bangladesh: this contract is now administered by her institution. On an ongoing basis since 2016, Dr Edelman has received an honorarium from the University of California, San Francisco, for speaking and family planning fellowship site audits. During 2018 through to January 2019, she received an honorarium from Exeltis to provide an expert review on a contraceptive method not currently FDA- approved. This consultation has ended. Anna Glasier provides expert medical advice on the ulipristal acetate emergency contraceptive pill on a regular basis to the manufacturer (HRA Pharma). The amount was not disclosed. She works with them to try to obtain approval for the over-the- counter (OTC) use of ulipristal acetate emergency contraception and a progestin-only pill in the United States of America, and to | Contraceptive eligibility for women at high risk of HIV: guidance statement16 get a progestin-only pill approved for OTC use in the United Kingdom of Great Britain and Northern Ireland, and Europe. This is ongoing. Andy Gray is the chair of the Names and Scheduling Advisory Committee of the South African Health Products Regulatory Authority and serves on its Lega Advisory and Regulatory Advisory Committees. He is a member of the South African National Essential Medicines List Committee, responsible for medicines selection and the development of standard treatment guidelines for the public sector. Carolina Sales Vieira receives an honorarium (US$ 4000/year) for serving on Merck Sharpe & Dohme’s medical advisory board and giving ad hoc invited lectures. This role is ongoing. Dr Sales Vieira receives an honorarium (US$ 3000/year) for serving on Bayer’s medical advisory board and giving ad hoc lectures. This role is ongoing. Dr Sales Vieira received a one-time honorarium (US$ 1000) for serving on the medical advisory board for Exeltis in 2019. Contraceptive eligibility for women at high risk of HIV: guidance statement | 17 ANNEX 3. GRADE EVIDENCE PROFILES Outcome Type and number of studies (total number of participants) Limitations Inconsistency Imprecision Indirectness Overall quality Estimate of effect DMPA versus non-hormonal contraception or no method HIV acquisition 1 RCT1 (7829)a Few limitationsb No serious inconsistency No serious imprecision No indirectness High Adjusted HR 1.04 (0.82–1.33) for DMPA versus Cu-IUD HIV acquisition 10 cohort studies2–11 + 1 individual patient data meta-analysis of 7 studies12,c (40 506)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low to moderatee Adjusted HR range 0.46– 2.04, 8 studies increased risk (HR range 1.25–2.04), with statistically significant effects in 3 studies; 2 studies trended towards decreased risk (HR 0.46 and 0.75 with wide confidence intervals) Pooled adjusted HR 1.40 (1.24–1.58) NET-EN versus non-hormonal contraception or no method HIV acquisition 6 cohorts studies2,5,7,8,10,11 + 1 individual patient data meta- analysis of 7 studies12,c (29 922)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR range 0.87– 1.76, 5 studies increased risk (HR range 1.20–1.76), none statistically significant; 2 studies no effect (adjusted HR range 0.87–1.05) Pooled adjusted HR 1.14 (0.93–1.39) Implantf use versus non-hormonal contraception HIV acquisition 1 randomized trial1 (7829)a Few limitationsb No serious inconsistency No serious imprecision No indirectness High Adjusted HR 1.18 (0.91–1.53) for Cu-IUD versus LNG implant HIV acquisition 3 cohort studies2–4,c (4514)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Lowg Adjusted HR range 0.46–0.99 Adjusted HRs: 0.96 (0.29– 3.14), 0.99 (0.40–2.45), and 0.46 (0.13–1.70); none statistically significant Pooled adjusted HR 0.82 (0.44–1.53) Implantf use versus NET-EN HIV acquisition 1 cohort study2 (1136)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 0.45 (0.13–1.53) for implant use versus NET-EN Oral hormonal contraceptive use versus non-hormonal contraception or no method HIV acquisition 11 cohort studies3–6,8–14,c (43 482)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low to moderatee Adjusted HR or IRR range 0.66–1.80 3 studies increased risk (HR 1.39–1.80) Only 1 study reported a statistically significant finding (adjusted HR 1.48 [1.05– 2.09]) The remaining 8 studies reported a decreased risk (adjusted HR range 0.66–0.99), none of which was statistically significant Pooled adjusted HR 1.02 (0.88–1.19) GRADE EVIDENCE PROFILE FOR HORMONAL CONTRACEPTIVE USE IN HIV-NEGATIVE WOMEN | Contraceptive eligibility for women at high risk of HIV: guidance statement18 Outcome Type and number of studies (total number of participants) Limitations Inconsistency Imprecision Indirectness Overall quality Estimate of effect DMPA versus NET-EN HIV acquisition 2 cohort studies2,15 and 1 individual patient data meta-analysis of 17 studies12,c (42 788)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low to moderatee Adjusted HRs 1.32 (1.08– 1.61) and 0.89 (0.55–1.44) in cohort studies and 1.41 (1.06–1.89) in individual participant data meta- analysis of 17 studies Pooled adjusted HR 1.27 (1.05–1.55) DMPA versus combined oral contraceptives HIV acquisition 1 individual patient data meta-analysis of 8 studies12,c (24 853)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low to moderatee Adjusted HR 1.41 (1.23–1.67) in individual participant data meta-analysis of 8 studies NET-EN versus combined oral contraceptives HIV acquisition 1 individual patient data meta-analysis of 9 studies12,c (25 398)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 1.30 (0.99–1.17) GRADE EVIDENCE PROFILE FOR HORMONAL CONTRACEPTIVE USE IN HIV-NEGATIVE WOMEN Cu-IUD: copper-bearing intrauterine device; DMPA-IM: intramuscular depot medroxyprogesterone acetate; ETG: etonogestrel; GRADE: Grading of Recommendations Assessment, Development and Evaluation; HR: hazard ratio; IRR: incidence rate ratio; LNG: levonorgestrel; NET-EN: norethisterone enanthate; RCT: randomized clinical trial Note: Publication bias was not formally assessed; observational studies could not be upgraded for large effects; dose-response relationship, or confounders likely to increase observed effects. Estimates based on adjusted risk estimates, results from Cox model analysis used when available. a Sample size is for the entire study population. b Few limitations noted in the trial, but not serious enough to downgrade the level of evidence. While the study was unblinded for participants and health-care providers, data were analysed centrally by statisticians who were blinded to the group. c Restricted to studies classified as “informative with but with important limitations”. d Some limitations or imprecision noted across the body of evidence, but not serious enough to downgrade the level of evidence. e Evidence graded low to moderate due to consistent and precise results from well conducted observational studies, and coherence between studies of use versus non-use and head-to-head studies. f No direct evidence for ETG implants was identified for the comparisons of interest. For ETG implants, recommendations were extrapolated from other implant studies. g Upgraded from very low-quality evidence (2016 assessment). References: 1. Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium. HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial. Lancet. 2019;394(10195):303–13. doi: 10.1016/S0140-6736(19)31288-7. 2. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619–22. doi: 10.1097/ QAD.0000000000002260. 3. Sabo MC, Richardson BA, Lavreys L, Martin HL, Jr, Jaoko W, Mandaliya K et al. Does bacterial vaginosis modify the effect of hormonal contraception on HIV seroconversion. AIDS. 2019;33(7):1225–30. doi: 10.1097/QAD.0000000000002167. 4. Wall KM, Kilembe W, Vwalika B, Htee Khu N, Brill I, Chomba E et al. Hormonal contraception does not increase women’s HIV acquisition risk in Zambian discordant couples, 1994–2012. Contraception. 2015;91(6):480–7. Doi: 10.1016/j. contraception.2015.02.004. Contraceptive eligibility for women at high risk of HIV: guidance statement | 19 5. Crook AM, Ford D, Gafos M, Hayes R, Kamali A, Kapiga S et al. Injectable and oral contraceptives and risk of HIV acquisition in women: an analysis of data from the MDP301 trial. Hum Reprod. 2014;29(8):1810–7. doi: 10.1093/humrep/deu113. 6. Heffron R, Donnell D, Rees H, Celum C, Mugo N, Were E et al. Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study. Lancet Infect Dis. 2012;12(1):19–26. doi: 10.1016/S1473-3099(11)70247-X. 7. Kleinschmidt I, Rees H, Delany S, Smith D, Dinat N, Nkala B et al. Injectable progestin contraceptive use and risk of HIV infection in a South African family planning cohort. Contraception. 2007;75(6):461–7. doi: 10.1016/j.contraception.2007.02.002. 8. McCoy SI, Zheng W, Montgomery ET, Blanchard K, van der Straten A, de Bruyn G et al. Oral and injectable contraception use and risk of HIV acquisition among women in sub-Saharan Africa. AIDS. 2013;27(6):1001–9. doi: 10.1097/ QAD.0b013e32835da401. 9. Morrison CS, Richardson BA, Mmiro F, Chipato T, Celentano DD, Luoto J et al. Hormonal contraception and the risk of HIV acquisition. AIDS. 2007;21(1):85–95. doi: 10.1097/QAD.0b013e3280117c8b. 10. Morrison CS, Skoler-Karpoff S, Kwok C, Chen PL, van de Wijgert J, Gehret-Plagianos M et al. Hormonal contraception and the risk of HIV acquisition among women in South Africa. AIDS. 2012;26(4):497–504. doi: 10.1097/QAD.0b013e32834fa13d. 11. Myer L, Denny L, Wright TC, Kuhn L. Prospective study of hormonal contraception and women’s risk of HIV infection in South Africa. Int J Epidemiol. 2007;36(1):166–74. doi: 10.1093/ije/dyl251. 12. Morrison CS, Chen PL, Kwok C, Baeten JM, Brown J, Crook AM et al. Hormonal contraception and the risk of HIV acquisition: an individual participant data meta-analysis. PLoS Med. 2015;12(1):e1001778. doi: 10.1371/journal.pmed.1001778. 13. Balkus JE, Brown ER, Hillier SL, Coletti A, Ramjee G, Mgodi N et al. Oral and injectable contraceptive use and HIV acquisition risk among women in four African countries: a secondary analysis of data from a microbicide trial. Contraception. 2016;93(1):25–31. doi: 10.1016/j.contraception.2015.10.010. 14. Reid SE, Dai JY, Wang J, Sichalwe BN, Akpomiemie G, Cowan FM et al. Pregnancy, contraceptive use, and HIV acquisition in HPTN 039: relevance for HIV prevention trials among African women. J Acquir Immune Defic Syndr. 2010;53(5):606–13. doi: 10.1097/QAI.0b013e3181bc4869. 15. Noguchi LM, Richardson BA, Baeten JM, Hillier SL, Balkus JE, Chirenje ZM et al. Risk of HIV-1 acquisition among women who use different types of injectable progestin contraception in South Africa: a prospective cohort study. Lancet HIV. 2015;2(7):e279–87. doi: 10.1016/S2352-3018(15)00058-2. | Contraceptive eligibility for women at high risk of HIV: guidance statement20 Outcome Type and number of studies (total number of participants) Limitations Inconsistency Imprecision Indirectness Overall quality Estimate of effect IUDa versus no contraception or tubal ligation HIV acquisition 1 prospective study1,b (1498)c Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 1.1 (0.4–3.0) for Cu-IUD versus no contraception or tubal ligation IUDa versus implant,e DMPA, NET-EN HIV acquisition 1 prospective study2,b (1136)c Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 0.90 (0.45–1.76) for DMPA, implants, NET-EN versus Cu-IUD IUDa use versus DMPA HIV acquisition 1 RCT3,b (7829)c Few limitationsf No serious inconsistency No serious imprecision No indirectness High Adjusted HR 1.04 (0.82–1.33) for DMPA-IM versus Cu-IUD HIV acquisition 1 prospective study2,b (1136)c Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 0.91 (0.44–1.87) for DMPA versus Cu-IUD IUDa versus NET-EN HIV acquisition 1 prospective study2,b (1136)c Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 0.98 (0.47–2.03) for Cu-IUD versus NET-EN IUDa versus implante HIV acquisition 1 RCT3 (7829)c Few limitationsf No serious inconsistency No serious imprecision No indirectness High Adjusted HR 1.18 (0.91–1.53) for Cu-IUD versus LNG implant HIV acquisition 1 prospective study2,b (1136)c Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 2.17 (0.59–7.69) for Cu-IUD versus implants (LNG or ETG) GRADE EVIDENCE PROFILE FOR CU-IUD USE IN HIV-NEGATIVE WOMEN Cu-IUD: copper-bearing intrauterine device; DMPA-IM: intramuscular depot medroxyprogesterone acetate; ETG: etonogestrel; GRADE: Grading of Recommendations Assessment, Development and Evaluation; HR: hazard ratio; IUD: intrauterine device; LNG: levonorgestrel; NET-EN: norethisterone enanthate; RCT: randomized clinical trial Note: Publication bias was not formally assessed; observational studies could not be upgraded for large effects; dose-response relationship, or confounders likely to increase observed effects. Estimates based on adjusted risk estimates, results from Cox model analysis used when available. a No direct evidence for LNG-IUDs was identified for the comparisons of interest. For LNG-IUDs, recommendations were extrapolated from the evidence on Cu-IUDs and other LNG containing products. b Restricted to studies classified as “informative with but with important limitations”. c Sample size is for the entire study population. d Some limitations or imprecision was noted across the body of evidence, but not serious enough to downgrade the level of evidence. e No direct evidence for ETG implants was identified for the comparisons of interest. For ETG implants, recommendations were extrapolated from the evidence on LNG implants. f Few limitations noted in the trial, but not serious enough to downgrade the level of evidence. References: 1. Lavreys L, Baeten JM, Martin Jr HL, Overbaugh J, Mandaliya K, Ndinya-Achola J et al. Hormonal contraception and risk of HIV-1 acquisition: results of a 10-year prospective study. AIDS. 2004;18(4):695–7. 2. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619–22. doi: 10.1097/ QAD.0000000000002260. 3. Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium. HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial. Lancet. 2019;394(10195):303–13. doi: 10.1016/S0140-6736(19)31288-7. Contraceptive eligibility for women at high risk of HIV: guidance statement | 21 ANNEX 4. EVIDENCE-TO- DECISION TABLE FOR HORMONAL CONTRACEPTIVE METHODS AND INTRAUTERINE DEVICES (IUDS) Factor Explanation/evidence Judgement Quality of evidence Progestogen- only contraceptives (POCs) For the primary outcome of HIV acquisition, evidence was considered to be of high qual- ity for intramuscular depot medroxyprogesterone acetate (DMPA-IM) and for levonorge- strel (LNG) implants. Evidence was considered to be of low quality for norethisterone enanthate (NET-EN), and absent for subcutaneous DMPA (DMPA-SC), LNG intrauterine devices (IUDs) and etonogestrel (ETG) implants. For NET-EN and DMPA-SC, the recom- mendations were extrapolated from the evidence on DMPA-IM. For ETG implants, the recommendations were extrapolated from the evidence on LNG implants. High, low or absent, depending on method IUDs For the primary outcome of HIV acquisition, evidence was considered to be of high quality for copper-bearing IUDs (Cu-IUDs). Evidence was absent for LNG-IUDs. For LNG-IUDs, recommendations were extrapolated from the evidence on Cu-IUDs and other LNG-containing products. High or absent, de- pending on method Combined hormonal contraceptives (CHCs) Evidence was considered to be of low-to-moderate quality for CHCs. Low-moderate Balance of benefits versus harms POCs Contraception is a life-saving intervention with well recognized health, social and economic benefits. All POCs are effective or highly effective, reversible methods. High-quality evidence from one randomized clinical trial (RCT) observed no statistically significant differences in HIV acquisition between: DMPA-IM versus Cu-IUD, DMPA-IM versus LNG implant, and Cu-IUD versus LNG implant. Of the low-to-moderate-quality evidence from 14 observational studies, some studies suggested a possible increased risk of HIV with progestogen-only injectable use, which was most likely due to unmeasured confounding.a,b Low-quality evidence from three observational studies did not suggest an increased HIV risk for implant users.a,b No studies of sufficient quality were identified for progestogen-only pills. While no direct evidence was available for DMPA-SC or ETG implants, indirect evidence for DMPA-IM and LNG implants was used, given that there was no biological or clinical reason to believe that a lower hormonal dose, different delivery mechanism, or different progestogen would modify HIV risk. Balance is in favour of benefits of POCs IUDs Contraception is a life-saving intervention with well recognized health, social and economic benefits. All IUDs are highly effective, reversible methods. High-quality evidence from one RCT, along with low-quality evidence from two observational studies, suggested no increased risk of HIV acquisition with Cu-IUD use.c–e While no direct evidence was available for LNG-IUDs, recommendations were extrapolated from the evidence on Cu-IUDs and other LNG-containing products. Balance is in favour of benefits of IUDs CHCs Contraception is a life-saving intervention with well recognized health, social and economic benefits. All hormonal contraceptives are effective or highly effective, reversible methods. Low-moderate quality evidence from 11 observational studies suggested no association between combined oral contraceptive (COC) use (it was assumed that studies that did not specify oral contraceptive type examined mostly, if not exclusively, COC use) and HIV acquisition.a,b While no direct evidence was available for combined contraceptive patch, combined contraceptive vaginal ring or combined injectable contraceptive, indirect evidence from COCs was used given that there was no biological or clinical reason to believe that a lower hormonal dose, different delivery mechanism, or different progestogen would modify HIV risk. Balance is in favour of benefits of CHCs | Contraceptive eligibility for women at high risk of HIV: guidance statement22 Factor Explanation/evidence Judgement Values and preferences Women have the right to informed decision-making. Women prefer to have choice in methods, full information regarding benefits versus harms, and to make a final decision in conjunction with their provider (informed decision-making). Contraception is unique among medicines because a woman’s needs and preferences with regard to the characteristics of contraceptive methods will vary both between individual women and across a single individual’s lifespan. Common themes in contraceptive preferences include that they are discreet, have minimal side-effects and are long-acting, reversible and easy to use. Women who use progestogen-only injectables generally like them for these reasons, and feel comfortable using them after counselling. Women’s preferences for methods are limited by what they have knowledge of, what is available to them and other factors that foster or limit access. Offering women the choice of a range of methods is important from both a health and a rights perspective. Support for optimizing informed contraceptive choice and the availability of a wide range of contraceptive options Priority of the problem HIV is a serious illness and a major global epidemic. Unintended pregnancy is a very common problem globally, and the risks associated with it are highest where maternal mortality and severe morbidity are also common. Both are priorities for public health. Effective contraception and HIV prevention are both public health priorities Equity and human rights Human rights principles and standards from existing World Health Organization (WHO) guidelines on human rights and contraception were followed by the Guideline Development Group (GDG) in its deliberations. These include non-discrimination, availability, accessibility, acceptability, quality, informed decision-making, privacy and confidentiality, participation, and accountability. During its deliberations, the GDG considered both potential positive and negative effects of its considerations. For example, it considered and emphasized the continuing need for integrated family planning and HIV services in settings with high HIV incidence. It also emphasized the need for expanding and optimizing contraceptive options. Recommendations within WHO’s human rights guidance for contraception are paramount principles for decision-making on this topic Feasibility The importance of clear communication from WHO on this topic was underscored. This was reinforced by recent studies that suggested that messages based on the 2017 WHO guidance were difficult to explain and may not be fully understood by clients or providers. Clear guidance and a woman-centred approach are essential for successful implementation References: a. Polis CB, Curtis KM, Hannaford PC, Phillips SJ, Chipato T, Kiarie JN et al. An updated systematic review of epidemiological evidence on hormonal contraceptive methods and HIV acquisition in women. AIDS. 2016;30(17):2665–83. doi: 10.1097/ QAD.0000000000001228. b. Sabo MC, Richardson BA, Lavreys L, Martin HL, Jr, Jaoko W, Mandaliya K et al. Does bacterial vaginosis modify the effect of hormonal contraception on HIV seroconversion. AIDS. 2019;33(7):1225–30. doi: 10.1097/QAD.0000000000002167. c. Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium. HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial. Lancet. 2019;394(10195):303–13. doi: 10.1016/S0140-6736(19)31288-7. d. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619–22. doi: 10.1097/ QAD.0000000000002260. e. Lavreys L, Baeten JM, Martin Jr HL, Overbaugh J, Mandaliya K, Ndinya-Achola J et al. Hormonal contraception and risk of HIV-1 acquisition: results of a 10-year prospective study. AIDS. 2004;18(4):695–7. Contraceptive eligibility for women at high risk of HIV: guidance statement | 23 ANNEX 5: SYSTEMATIC REVIEWS Three systematic reviews were conducted as part of the development of this guidance statement. The details of the methods and search strategies are included in the reviews. Reviews published in peer-reviewed journals are available through open access. This appendix will be periodically updated as reviews are published. Access to unpublished reviews can be requested by sending an email to hrx-info@who.int. 1. Hormonal contraceptive method use and HIV acquisition in women There was a previously published review on hormonal contraceptive use and HIV acquisition. The search strategies from that review were used to search for new evidence since. The following four new publications were identified that met the inclusion criteria. PREVIOUSLY PUBLISHED REVIEW 1. Polis CB, Curtis KM, Hannaford PC, Phillips SJ, Chipato T, Kiarie JN et al. An updated systematic review of epidemiological evidence on hormonal contraceptive methods and HIV acquisition in women. AIDS. 2016;30(17):2665–83. doi: 10.1097/ QAD.0000000000001228. UNPUBLISHED REVIEW 1. Curtis KM, Hannaford PC, Rodriguez MI, Chipato T, Steyn PS, Kiarie JN. Hormonal contraceptive method use and HIV acquisition in women: an updated systematic review. Working paper developed for the World Health Organization meeting. July 2019. NEW ARTICLES 1. Haddad LB, Wall KM, Kilembe W, Vwalika B, Khu NH, Brill I et al. Bacterial vaginosis modifies the association between hormonal contraception and HIV acquisition. AIDS. 2018;32(5):595–604. doi: 10.1097/ QAD.0000000000001741. 2. Hofmeyr GJ, Singata-Madliki M, Lawrie TA, Bergel E, Temmerman M. Effects of injectable progestogen contraception versus the copper intrauterine device on HIV acquisition: sub-study of a pragmatic randomised controlled trial. J Fam Plann Reprod Health Care. 2017;43(3):175–80. doi: 10.1136/jfprhc-2016-101607. 3. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619– 22. doi: 10.1097/QAD.0000000000002260. 4. Sabo MC, Richardson BA, Lavreys L, Martin HL, Jr., Jaoko W, Mandaliya K et al. Does bacterial vaginosis modify the effect of hormonal contraception on HIV seroconversion. AIDS. 2019;33(7):1225-30. doi: 10.1097/ QAD.0000000000002167. 2. Copper-bearing intrauterine device (Cu-IUD) use and HIV acquisition in women A systematic review was conducted on Cu-IUD use and HIV acquisition in women. The following six articles met the inclusion criteria. UNPUBLISHED REVIEW 1. Hannaford PC, Ti A, Chipato T, Curtis KM. Copper intrauterine device use and HIV acquisition in women: an updated systematic review. Working paper developed for the World Health Organization meeting. July 2019. NEW ARTICLES 1. Hofmeyr GJ, Singata-Madliki M, Lawrie TA, Bergel E, Temmerman M. Effects of injectable progestogen contraception versus the copper intrauterine device on HIV acquisition: sub-study of a pragmatic randomised controlled trial. J Fam Plann Reprod Health Care. 2017;43(3):175–80. doi: 10.1136/jfprhc-2016-101607. 2. Kapiga SH, Lyamuya EF, Lwihula GK, Hunter DJ. The incidence of HIV infection among women using family planning methods in Dar es Salaam, Tanzania. AIDS. 1998;12(1):75–84. doi: 10.1097/00002030-199801000-00009. 3. Lavreys L, Baeten JM, Martin Jr HL, Overbaugh J, Mandaliya  K, Ndinya-Achola J et al. Hormonal contraception and risk of HIV-1 acquisition: results of a 10-year prospective study. AIDS. 2004;18(4):695–7. 4. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619– 22. doi: 10.1097/QAD.0000000000002260. 5. Saracco A, Musicco M, Nicolosi A, Angarano G, Arici C, Gavazzeni G et al. Man-to-woman sexual transmission of HIV: longitudinal study of 343 steady partners of infected men. J Acquir Immune Defic Syndr. 1993;6(5):497-502. 6. Sinei SK, Fortney JA, Kigondu CS, Feldblum PJ, Kuyoh M, Allen MY et al. Contraceptive use and HIV infection in Kenyan family planning clinic attenders. Int J STD AIDS. 1996;7(1):65–70. doi: 10.1258/0956462961917104. 3. Contraceptive values and preferences A systematic review was conducted on contraceptive values and preferences. The protocol and methods are published, and the manuscript presenting the main results of the review is under review for publication. As this review did not identify information specific to key populations at risk of HIV, consultative engagements were conducted in the spring of 2019, including a global online survey of sex workers, and participatory focus group discussions with female sex workers | Contraceptive eligibility for women at high risk of HIV: guidance statement24 in Zimbabwe through the Sisters with a Voice programme. Presentations showing the findings from these engagements are listed below and available on request. A presentation shared by stakeholders representing affected populations to highlight their perspectives on the topic was part of the Guideline Development Group’s discussions and is available on request. 1. Kennedy CE, Yeh PT, Gaffield ME. Contraception values and preferences: protocol and methods for a global systematic review. Contraception. 2019 (in press). doi: 10.1016/j. contraception.2018.05.006Get. 2. Yeh PT, Kennedy CE, Gaffield ME. Contraception values and preferences: a global systematic review. Contraception. 2019; (accepted pending revisions). 3. Shapiro A. Female sex workers’ contraceptive practices, values and preferences. contraception and risk of HIV infection: a WHO Guideline Development Group review of the current evidence. 29 July 2019, Geneva, World Health Organization. 4. Sibanda E. Views on contraceptive methods among female sex workers in Harare, Zimbabwe: a participatory qualitative study. 29 July 2019, Geneva, World Health Organization. 5. Mworeko L. What do recommendations on contraceptives and HIV risk mean to women?, 29 July 2019, Geneva, World Health Organization.

For more information, please contact: Department of Reproductive Health and Research, World Health Organization, Avenue Appia 20, CH-1211 Geneva 27, Switzerland. E-mail: reproductivehealth@who.int www.who.int/reproductivehealth [Bar code if ISBN]

Contraceptive eligibility for women at high risk of HIV Guidance statement Recommendations on contraceptive methods used by women at high risk of HIV

Contraceptive eligibility for women at high risk of HIV Guidance statement Recommendations on contraceptive methods used by women at high risk of HIV Contraceptive eligibility for women at high risk of HIV. Guidance statement: recommendations on contraceptive methods used by women at high risk of HIV ISBN 978-92-4-155057-4 © World Health Organization 2019 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. Contraceptive eligibility for women at high risk of HIV. Guidance statement: recommendations on contraceptive methods used by women at high risk of HIV. Geneva: World Health Organization; 2019. Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris. Sales, rights and licensing. To purchase WHO publications, see http://apps.who.int/bookorders. To submit requests for commercial use and queries on rights and licensing, see http://www.who.int/about/licensing. Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. The views expressed in this publication are those alone of the named authors and of the collective views of an international group of experts and do not necessarily represent the decisions or the policies of WHO. Printed in Switzerland Contraceptive eligibility for women at high risk of HIV: guidance statement | iii 1 2 3 4 5 ACKNOWLEDGEMENTS V ABBREVIATIONS VI EXECUTIVE SUMMARY VII BACKGROUND 1 METHODS OF GUIDELINE REVIEW AND DEVELOPMENT 2 2.1 Guideline Development Group 2 2.2 Guideline development process 2 2.3 Evidence Retrieval 3 2.4 Evidence Synthesis 4 2.5 Formulation of recommendations 4 SUMMARY OF THE EVIDENCE 4 3.1 Progestogen-only injectables 5 3.2 Progestogen-only implants 5 3.3 Progestogen-only pills 5 3.4 Intrauterine devices 5 3.5 Combined hormonal contraceptives 5 3.6 Additional evidence considered by the GDG 5 3.6.1 Biological data 5 3.6.2 Values and preferences of contraceptive users 6 RECOMMENDATIONS 6 4.1 Recommendations for contraceptive use among women at high risk of HIV infection 6 4.2 Rationale 7 IMPLICATIONS FOR POLICY-MAKERS, PROGRAMME MANAGERS AND HEALTH-CARE PROVIDERS 8 5.1 A woman’s risk of HIV should not restrict her contraceptive choice 8 5.2 Efforts to expand access to contraceptive options must continue 8 5.3 A renewed emphasis on HIV and STI prevention services is urgently needed 9 CONTENTS | Contraceptive eligibility for women at high risk of HIV: guidance statementiv CONTENTS (continued) KNOWLEDGE GAPS AND AREAS FOR RESEARCH 9 6.1 Contraceptive methods and HIV acquisition 9 6.2 HIV prevention 9 6.3 Community involvement 10 6.4 Increased funding for high-quality, policy-relevant research 10 DISSEMINATION OF THIS GUIDANCE STATEMENT 10 REFERENCES 11 ANNEX 1. GUIDELINE DEVELOPMENT GROUP AND EVIDENCE SECRETARIAT 13 ANNEX 2. DECLARATIONS OF CONFLICTS OF INTEREST 15 ANNEX 3. GRADE EVIDENCE PROFILES 17 ANNEX 4. EVIDENCE-TO-DECISION TABLE FOR HORMONAL CONTRACEPTIVE METHODS AND INTRAUTERINE DEVICES (IUDS) 21 ANNEX 5: SYSTEMATIC REVIEWS 23 6 7 Contraceptive eligibility for women at high risk of HIV: guidance statement | v ACKNOWLEDGEMENTS The World Health Organization (WHO) would like to thank the members of the Guideline Development Group and the Evidence Secretariat (Annex 1) for their contributions throughout the development of these important recommendations for women at high risk of HIV. WHO is very grateful for the suggestions provided by colleagues who peer reviewed the draft statement as members of the External Review Group. The development of this technical statement was financially supported by the Bill & Melinda Gates Foundation, the Netherlands Ministry of Foreign Affairs, the United States Agency for International Development, and the United States National Institutes of Health. | Contraceptive eligibility for women at high risk of HIV: guidance statementvi ABBREVIATIONS CIC combined injectable contraceptive COC combined oral contraceptive CRE WHO Office of Compliance, Risk Management and Ethics Cu-IUD copper-bearing intrauterine device DMPA depot medroxyprogesterone acetate DMPA-IM intramuscular depot medroxyprogesterone acetate DMPA-SC subcutaneous depot medroxyprogesterone acetate ECHO Evidence for Contraceptive Options and HIV Outcomes (Study) ETG etonogestrel FDA United States Food and Drug Administration GDG Guideline Development Group GRADE Grading of Recommendations Assessment, Development and Evaluation HR hazard ratio IRR incidence rate ratio IUD intrauterine device LNG levonorgestrel LNG-IUD levonorgestrel-releasing intrauterine device MEC Medical eligibility criteria for contraceptive use NET-EN norethisterone enanthate OTC over the counter POP progestogen-only pill PrEP pre-exposure prophylaxis (for HIV) RCT randomized controlled trial STI sexually transmitted infection WHO World Health Organization Contraceptive eligibility for women at high risk of HIV: guidance statement | vii EXECUTIVE SUMMARY The World Health Organization (WHO) convened a Guideline Development Group (GDG) meeting from 29 to 31 July 2019 to review global guidance on contraceptive eligibility for women at high risk of HIV acquisition to and determine whether revisions to the fifth edition of the Medical eligibility criteria for contraceptive use (MEC) were needed. The issue was deemed critical, particularly for sub-Saharan Africa, given the high lifetime risk of acquiring HIV alongside the importance of hormonal contraception in offering women and adolescent girls’ choice and in reducing their risk of unintended pregnancy, a common threat to the health, well-being and lives of women and adolescent girls. The GDG consisted of 28 participants from 19 countries, including experts in family planning and HIV, representatives from affected populations, clinicians, epidemiologists, researchers, programme managers, policy-makers and guideline methodologists. The GDG considered the following factors when formulating recommendations for each contraceptive method: ■ quality of the evidence (i.e. GRADE profile)1 ■ values and preferences of contraceptive users ■ balance of benefits and harms ■ priority of the problem ■ equity and human rights ■ feasibility. In formulating these recommendations, the GDG kept at the centre of their deliberations the individuals most affected by the recommendations – that is, those women wanting to prevent pregnancy who are at a high risk of HIV acquisition. Through consensus, the GDG agreed to the following new recommendations. These revisions mean that women at a high risk of HIV can use all methods of contraception without restriction. ■ Women at a high risk of HIV infection are eligible to use all progestogen-only contraceptive methods without restriction (MEC Category 1), including progestogen-only pill (POPs), intramuscular and subcutaneous depot medroxyprogesterone acetate (DMPA-IM and DMPA-SC), norethisterone enanthate (NET-EN), levonorgestrel (LNG) implants and etonogestrel (ETG) implants. ■ Women at a high risk of HIV infection are eligible to use copper-bearing intrauterine devices (Cu-IUDs) and LNG- IUDs without restriction (MEC Category 1). In considering the 1 GRADE = Grading of Recommendations Assessment, Development and Evaluation (for further information, see: http://www.gradeworkinggroup.org). use of IUDs, many women at a high risk of HIV are also at risk of other sexually transmitted infections (STIs); for these women, providers should refer to the MEC recommendation on women at an increased risk of STIs, and the Selected practice recommendations for contraceptive use: third edition on STI screening before IUD insertion. ■ Women at a high risk of HIV infection are eligible to use all combined hormonal contraceptive methods without restriction (MEC Category 1), including combined oral contraceptives (COCs), combined injectable contraceptives (CICs), combined contraceptive patches and combined vaginal rings. These recommendations were strongly informed by new epidemiological evidence, particularly from one high-quality randomized controlled trial (the ECHO trial), which did not demonstrate a statistically significant difference in HIV acquisition among women using the three contraceptive methods studied: DMPA-IM, Cu-IUDs and LNG implants. This high-quality evidence superseded the previously available observational evidence of low and low-to-moderate quality. For COCs and NET-EN injectables, evidence of low and low-to- moderate quality from observational studies indicated no increased risk of HIV infection. While no direct evidence was available for DMPA-SC, LNG-IUDs or ETG implants, there was no biological or clinical reason to believe that a lower hormonal dose, different delivery mechanism or different progestogen would modify HIV risk. A consideration of women’s values, preferences, views and concerns regarding contraceptive methods provided support for optimizing informed contraceptive choice and the availability of a wide range of contraceptive options. There are several key messages from this guidance for policy- makers, programme managers and health-care providers. ■ A woman’s risk of HIV does not restrict her contraceptive choice. ■ Efforts to expand contraceptive method options and ensure full and equitable access to family planning services must continue. ■ A renewed emphasis on HIV/STI testing and prevention services is urgently needed, including the integration of family planning and HIV/STI services as appropriate, along with sexual and reproductive health packages. | Contraceptive eligibility for women at high risk of HIV: guidance statementviii PROGESTOGEN-ONLY CONTRACEPTIVES Progestogen-only contraceptives (POCs) do not protect against sexually transmitted infections (STIs), including HIV. If there is a risk of STI/HIV, the correct and consistent use of condoms is recommended. When used correctly and consistently, condoms offer one of the most effective methods of protection against STIs, including HIV. Female condoms are effective and safe, but are not used as widely as male condoms by national programmes. Condition MEC category Clarification/evidence POP DMPA/ NET-EN LNG/ ETG High risk of HIV 1 1 1 EVIDENCE: High-quality evidence from one randomized controlled trial observed no statistically significant differences in HIV acquisition between: DMPA-IM versus Cu-IUD, DMPA-IM versus LNG implant, and Cu-IUD versus LNG implant. Of the low-to-moderate-quality evidence from 14 observational studies, some studies sug- gested a possible increased risk of HIV with progestogen-only injectable use, which was most likely due to unmeasured confounding. Low-quality evidence from 3 obser- vational studies did not suggest an increased HIV risk for implant users. No studies of sufficient quality were identified for POPs. Cu-IUD: copper-bearing intrauterine device; DMPA: depot medroxyprogesterone acetate (injectable); IM: intramuscular; LNG/ETG: levonorgestrel and etonogestrel (implants); MEC: Medical eligibility criteria for contraceptive use; NET-EN: norethisterone enanthate (injectable); POP: progestogen-only pill INTRAUTERINE DEVICES Intrauterine devices (IUDs) do not protect against sexually transmitted infections (STIs), including HIV. If there is a risk of STI/HIV, the correct and consistent use of condoms is recommended. When used correctly and consistently, condoms offer one of the most effective methods of protec- tion against STIs, including HIV. Female condoms are effective and safe, but are not used as widely as male condoms by national programmes. Condition MEC category Clarification/evidence Cu-IUD LNG-IUD (20 μg/24 hours) High risk of HIV Initiation Continuation Initiation Continuation CLARIFICATION: Many women at a high risk of HIV are also at risk of other STIs. For these women, refer to the recommendation in the Medical eligibility criteria for contra- ceptive use on women at an increased risk of STIs, and the Selected practice recommendations for contraceptive use on STI screening before IUD insertion. EVIDENCE: High-quality evidence from one randomized controlled trial, along with low-quality evidence from two observational studies, suggested no increased risk of HIV acquisition with Cu-IUD use. No studies were identified for LNG-IUDs. 1 1 1 1 Cu-IUD: copper-bearing intrauterine device; LNG-IUD: levonorgestrel-releasing IUD; MEC: Medical eligibility criteria for contraceptive use COMBINED HORMONAL CONTRACEPTIVES Combined hormonal contraceptives (CHCs) do not protect against sexually transmitted infections (STIs), including HIV. If there is a risk of STI/ HIV, the correct and consistent use of condoms is recommended. When used correctly and consistently, condoms offer one of the most effective methods of protection against STIs, including HIV. Female condoms are effective and safe, but are not used as widely as male condoms by national programmes. Condition MEC category Clarification/evidence COC P CVR CIC High risk of HIV 1 1 1 1 EVIDENCE: Low-to-moderate-quality evidence from 11 observational studies suggested no association between COC use (it was assumed that studies that did not specify oral contraceptive type examined mostly, if not exclusively, COC use) and HIV acquisition. No studies of P, CVR or CIC were identified. COC: combined oral contraceptive; CIC: combined injectable contraceptive; CVR: combined contraceptive vaginal ring; MEC: Medical eligibility criteria for contraceptive use; P: combined contraceptive patch Contraceptive eligibility for women at high risk of HIV: guidance statement | 1 Access to sexual and reproductive health services and information, including a comprehensive range of contraceptive methods, is fundamental to the rights and well-being of women and adolescent girls (1–4). There is a wide range of hormonal and non-hormonal modern contraceptive methods providing substantial individual and public health benefits. A core part of the work of the World Health Organization (WHO) is the development and maintenance of up-to-date, evidence-based guidance on contraceptive safety for individuals with particular medical conditions or medically relevant characteristics (5). The Medical eligibility criteria for contraceptive use (the MEC), fifth edition, offers national policy-makers and family planning programmes a comprehensive set of recommendations on the medical safety of contraceptive methods, allowing for the informed development of national policies, protocols and programmes (5). Global guidance about medical safety and eligibility facilitates the removal of unnecessary medical barriers to contraception. For over 20 years, the MEC has been used by countries to maximize safety and improve the quality of contraceptive care offered. Guidance about safety is kept up to date through continuous monitoring and reviews of published literature. In 2015, WHO released the fifth edition of the MEC (5). This edition contains more than 2000 recommendations for 25 different contraceptive methods, within the context of more than 80 medical conditions or medically relevant personal characteristics. Depending on the individual, more than one condition may need to be considered when making an informed contraceptive choice (5). The recommendations in the MEC are based on several considerations, including whether the use of a contraceptive method worsens the medical condition or creates additional health risks, and whether the condition makes the contraceptive method less effective (5). The MEC is part of a set of tools aiming to improve contraceptive coverage and care throughout the world. The MEC informs decisions about who might use a particular contraceptive method, through information and guidance about the safety and appropriateness of contraceptive care. The Selected practice recommendations for contraceptive use (the SPR) provides guidance on how to safely and effectively use various contraceptive methods (6). WHO produces a range of tools to support the use and implementation of contraceptive guidance, such as the MEC wheel and the Global handbook for providers (7, 8). Since 1996, the MEC has applied a four-category scale to indicate medical eligibility for particular contraceptive methods in the presence of particular conditions or individual characteristics (e.g. at high risk of HIV). For each condition or characteristic, contraceptive methods are placed into one of four numbered categories: 1. A condition for which there is no restriction for the use of contraceptive method. 2. A condition where the advantages of using the method generally outweigh the theoretical or proven risks. 3. A condition where the theoretical or proven risks usually outweigh the advantages of using the method. 4. A condition which represents an unacceptable health risk if the contraceptive method is used. The interpretation and application of the categories in practice are shown in Table 1. In the past, there has been mixed evidence about whether hormonal contraceptive methods – particularly depot medroxyprogesterone acetate (DMPA) – are associated with an increased risk of HIV acquisition. The available evidence consisted of theoretical biological data and observational studies with important limitations. In 2016, the independent TABLE 1. INTERPRETATION AND APPLICATION OF THE MEDICAL ELIGIBILITY CRITERIA (MEC) CATEGORIES Category With good resources for clinical judgement With limited resources for clinical judgement 1 Use the method in any circumstances Yes, use the method 2 Generally use the method 3 Use of the method not usually recommended unless more appropriate methods are not available or not acceptable No, do not use the method 4 Method not to be used BACKGROUND1 | Contraceptive eligibility for women at high risk of HIV: guidance statement2 2.1 Guideline Development Group The development of this guidance statement was undertaken by the independent Guideline Development Group (GDG) and an additional panel of external reviewers. The GDG consisted of 28 participants from 19 countries, including experts in family planning and HIV, representatives from affected populations, clinicians, epidemiologists, researchers, programme managers, policy- makers and guideline methodologists (see Annex 1). Following WHO guidance, months prior to the July 2019 meeting of the GDG, the name and brief biography of each proposed GDG member was published at the WHO website (https://www.who. int/reproductivehealth/publications/contraceptives-methods-hiv). The public was able to view and provide input on any perceived or real conflicts of interest of the proposed members. WHO responded to all comments and accordingly adjusted the final composition of the GDG. Prior to the GDG meeting, the WHO Secretariat and the GDG reviewed the members’ declarations of interests (Annex 2) and found no conflicts of interest sufficient to preclude anyone from participating in the deliberations or the development of the recommendations. The members of the GDG were also asked to declare any new conflicts of interest at the start of the meeting. None were declared. 2 For further information, see: http://www.gradeworkinggroup.org 2.2 Guideline development process This guidance statement was prepared according to the standards and requirements specified in the WHO handbook for guideline development (11). This process is used to ensure that WHO guidelines are of the highest quality and follow a transparent, systematic process. Key steps of the guideline process include determining the critical questions and outcomes, retrieving the evidence, synthesizing and grading the evidence, presenting it using a structured approach, and formulating recommendations. WHO’s Family Planning Guideline Steering Group determined the critical questions and outcomes to be considered by the GDG. Distinct types of evidence were identified as essential to review. These included the health evidence (randomized trials and observational epidemiological data), the evidence on biological plausibility and the data on the values and preferences of contraceptive users. Applying the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach,2 multiple factors are considered when formulating recommendations (12). These include the quality of the epidemiological evidence (found in the GRADE evidence profiles, which are prepared based on up-to-date Guideline Development Group (GDG) for the MEC reviewed the accumulating evidence regarding women at high risk of acquiring HIV (9). The GDG concluded that there remained uncertainty about whether the increased risk of HIV acquisition seen in some observational studies was a real effect of the contraceptive method used or whether it was a statistical artefact resulting from key limitations of observational studies (residual confounding in particular) (9). There also continued to be uncertainty about the clinical relevance of the biological data. In addition, there was concern that previous attempts to inform women of the uncertainty about both the epidemiological and biological data (through the use of a MEC clarification, indicated by an asterisk [*]) had not been effective. Given these concerns, the GDG concluded that MEC guidance should be changed. Thus, in 2017, the recommendation for progestogen- only injectable use among women at high risk of HIV infection was changed from MEC Category 1* (no restrictions to use, with a clarification) to MEC Category 2 (the benefits of use outweigh the risks), with an accompanying clarification (9). This new classification indicated that progestogen-only injectables could be used by women at high risk of HIV, because the advantages of these methods generally outweighed the possible disadvantages, and it highlighted that, when choosing these methods, there might need to be extra consideration of possible HIV acquisition, and counselling. As part of the 2017 revision, WHO reaffirmed its commitment to monitoring and assessing any new evidence relevant to contraceptive safety. New information, including results from a large, multinational randomized controlled trial (RCT) (10), led WHO to convene another GDG meeting in July 2019 to review all the available evidence and assess whether the MEC guidance needed revision. METHODS OF GUIDELINE REVIEW AND DEVELOPMENT2 Contraceptive eligibility for women at high risk of HIV: guidance statement | 3 systematic reviews); the values and preferences of contraceptive users; the balance of benefit and harms; the priority of the problem; equity and human rights; acceptability; and feasibility. The human rights principles and standards described in WHO’s guidance, Ensuring human rights in the provision of contraceptive information and services, were incorporated into deliberations (1). Owing to the focus on contraceptive safety, opportunity costs were not formally assessed during the formulation of the recommendations, since costs may vary widely throughout different regions (13). The GRADE evidence-to-decision framework (a tool encompassing quality of evidence, balance of benefits versus harms, values and preferences, priority of the problem, equity and human rights, feasibility) was used to ensure that recommendations were based on the consideration of all standards (11). 2.3 Evidence Retrieval Existing WHO recommendations on the use of specific contraceptive methods by women at high risk of HIV were reviewed in accordance with procedures outlined by the WHO Guidelines Review Committee and the GRADE approach to evidence review (11, 12). Three systematic reviews were conducted in preparation for the GDG meeting: two reviews pertained to the epidemiological evidence and the third review synthesized qualitative or quantitative studies on users’ values, preferences, views and concerns regarding contraceptive methods. The two systematic reviews of epidemiological evidence conducted for the GDG meeting were: 1. An updated systematic review on hormonal contraception and risk of HIV acquisition was conducted to include new studies published since 2016, when the last systematic review was undertaken (14). The review question was: ■ Among women at risk of HIV, does use of a hormonal contraceptive method compared with non-use of a hormonal contraceptive method (or use of another specific hormonal contraceptive method) increase risk of HIV acquisition? 2. A systematic review on copper-bearing intrauterine device (Cu-IUD) use and risk of HIV acquisition was also conducted. The review questions were: ■ Among women at risk of HIV, does use of a Cu-IUD compared with use of another non-hormonal contraceptive method or no contraceptive method increase risk of HIV acquisition? ■ Among women at risk of HIV, does use of a Cu-IUD compared with use of a specific hormonal contraceptive method increase risk of HIV acquisition? The selection criteria for the systematic reviews are listed in Table 2. The same study designs, population, comparators and outcomes were considered for all the contraceptive methods reviewed. TABLE 2. SELECTION CRITERIA FOR THE SYSTEMATIC REVIEWS Study design Longitudinal studies (randomized controlled trials and observational studies or meta-analyses containing data not captured in bibliographic database searches) Population Women of reproductive age at risk of HIV infection (women who were not living with HIV at baseline) Intervention Use of a specific contraceptive method: ■ hormonal contraception (injectables, oral contraceptives, implants, patches, rings or levonorgestrel-releasing intrauterine devices) ■ copper-bearing intrauterine devices (Cu-IUDs) Comparator One of two comparison groups: 1. non-use of a hormonal contraceptive method (either no contraceptive use or use of a non-hormonal method such as condoms or other barrier method, withdrawal, Cu-IUD or tubal ligation/vasectomy) 2. use of another specific method of hormonal contraception Outcome Incident, laboratory-confirmed HIV infection in women The two systematic reviews were conducted according to the preferred reporting items for systematic reviews and meta- analyses (PRISMA) (15). The PubMed and Embase databases were searched for studies published in any language in the peer-reviewed literature up to 26 June 2019. For individual studies, the risk of bias was assessed using a quality framework described in the previous review (14). Studies were classified into three levels: 1. “Unlikely to inform the primary question”: studies that had (a) no adjustment for any measure of condom use or (b) unclear measurement of exposure to contraception. 2. “Informative but with important limitations”: studies that had none of the flaws described above, but that still had the potential for unmeasured or residual confounding. 3. “Informative with few limitations”: studies that had none of the above flaws – likely to be a randomized controlled trial (RCT) that was assessed as having a low risk of bias on standard criteria for evaluating RCTs. The focus of the systematic reviews was on information from studies that were considered “informative but with important limitations” or “informative with few limitations.” to fall into levels 2 and 3. The values and preferences of contraceptive users were incorporated in multiple ways. First, an updated systematic review of qualitative or quantitative studies on users’ values, preferences, views and concerns regarding the contraceptive methods considered under the Medical eligibility criteria for contraceptive use (MEC) guidelines was conducted (16). This review covered studies from any country published in the peer-reviewed literature between January 2005 and December 2017. Just prior to the GDG meeting in July 2019, this review was informally updated for studies in either the peer-reviewed or grey literature that specifically looked at the values and preferences of contraceptive users relating to the issue of hormonal contraception and HIV acquisition. Second, because | Contraceptive eligibility for women at high risk of HIV: guidance statement4 the updated systematic review did not identify any information specific to key populations at risk of HIV, consultative engagements were conducted in May through July of 2019, including a global online survey of sex workers and participatory focus group discussions with female sex workers in Zimbabwe (through the Sisters with a Voice programme). Third, stakeholders representing specific affected populations, including women living with HIV, and young women, contributed their perspectives through a presentation and discussion of critical perspectives at the GDG meeting. An update about the biological data on the theoretical effect that contraception may have on HIV acquisition was prepared, reviewed and discussed at the GDG meeting, including consideration of the theoretical plausibility of individual methods of hormonal contraception having an influence on HIV acquisition. 2.4 Evidence Synthesis Epidemiological data were synthesized and evaluated according to the GRADE approach to evidence review (12). Based on this, randomized trials begin with a grade for strength of evidence of “high”, and observational studies start with a grade of “low”. The risk of bias was assessed for the summarized data using standard GRADE methods (17). Factors that could lower the evidence grade were limitations in the evidence (bias), inconsistency between studies, imprecision of estimates, indirectness of evidence, and publication bias (17–22). Randomized trials were assessed for bias by systematically evaluating for inadequate randomization/ allocation concealment; inadequate blinding of treatments; attrition and failure to use intention-to-treat analyses; selective outcome reporting; and crossover/contamination (17). Observational studies were assessed for bias by examining whether there was failure to develop and apply appropriate eligibility criteria, flawed measurement of exposures or outcomes, failure to adequately address confounding, or incomplete follow-up (17). Factors that could increase the evidence grade of observational studies included the presence of a dose-response relationship, a large magnitude of observed associations, and adjustment for plausible confounders affecting observed associations (22). 2.5 Formulation of recommendations Findings from the systematic reviews and associated GRADE evidence profiles (Annex 3) were presented at the GDG meeting. A presentation on the biological plausibility of hormonal contraception modifying the risk of HIV acquisition, and several presentations on contraceptive users’ values and preferences, were also given. These inputs were used to develop an evidence-to-decision framework (Annex 4), which served as the basis for the GDG’s deliberations during the meeting (12). All recommendations were arrived at by consensus. After the GDG’s recommendations were made, a small writing group prepared a draft guidance statement summarizing the decision and associated rationale. The draft was reviewed by the entire GDG and the external review group (see Annex 1). Comments received from the GDG and the external review group were considered and addressed by the writing group. The final version of this guidance statement was approved by the WHO Guidelines Review Committee on 22 August 2019. SUMMARY OF THE EVIDENCE3 The Evidence for Contraceptive Options and HIV Outcomes (ECHO) Study3 was the primary source of new evidence since the WHO last reviewed recommendations on contraception for women at high risk of HIV (9). The ECHO Study was a large randomized controlled trial (RCT) conducted in Eswatini, Kenya, South Africa and Zambia specifically designed to compare HIV incidence among users of three contraceptive methods: intramuscular depot medroxyprogesterone acetate (DMPA-IM), levonorgestrel (LNG) implants and copper-bearing intrauterine 3 For further information, see: http://echo-consortium.com devices (Cu-IUDs) (10). The trial randomized 7829 HIV- seronegative women, aged between 16 and 35 years, who desired effective contraception and consented to be randomized to one of the three contraceptive methods. There was no group of non-users of contraception in the ECHO trial because all of the women enrolled desired effective contraception. Women returned every three months for HIV testing, contraceptive counselling, safety monitoring, behavioural assessment and a comprehensive package of HIV Contraceptive eligibility for women at high risk of HIV: guidance statement | 5 prevention services; for up to 18 months. The main (primary) comparisons used a modified intention-to-treat analysis. In addition, pre-planned (secondary) analyses were conducted, restricted to continuous use of the assigned contraceptive method and adjusted for a number of important confounders, including vaginal sex without a condom, a new sexual partner in the previous three months, and more than one sexual partner. Statistical significance in the ECHO trial was taken to be a P-value less than 0.04 for the primary comparisons. No statistically significant associations were found for any of the primary comparisons between the three contraceptive methods (Annex 3). The quality of the evidence from this RCT was rated as high, due to its large size, strong randomization and allocation procedures, high follow-up rates, high continuation of the allocated contraceptive method, objective measurement of HIV incidence and comprehensive analysis of the results. Other evidence on hormonal contraception and HIV acquisition published since the 2016 review (14) was included in the evaluation of the body of evidence, along with a systematic review on Cu-IUDs and risk of HIV acquisition (Annex 3). For hormonal contraception, one new observational study and updated estimates from a previously included study were identified (23, 24). Adding this evidence to the previous 14 observational studies (14) did not change the conclusions of the previous review. Thus, the body of observational evidence suggested some concern about an increased risk of HIV acquisition with DMPA-IM use, but was generally reassuring for other methods of hormonal contraception. For intrauterine devices (IUDs), two observational studies did not suggest an increased risk of HIV acquisition with Cu-IUD use (23, 25). The quality of evidence from these observational studies was rated as low and low-to-moderate. 3.1 Progestogen-only injectables One RCT (the ECHO trial) observed no statistically significant differences in HIV acquisition when comparing DMPA-IM versus Cu-IUD, and DMPA-IM versus LNG implant (10). The quality of the evidence from this RCT was rated as high. Evidence from 14 observational studies of DMPA-IM, norethisterone enanthate (NET-EN) or unspecified progestogen- only injectables considered to be “informative but with important limitations” was assessed (14, 23, 24). Additional data from one new observational study and updated estimates from a previously included study did not change the conclusions of the previous review of observational evidence (14). The quality of the evidence from the observational studies was rated as low and low-to-moderate due to limitations that included unmeasured confounding. 3.2 Progestogen-only implants Three observational studies considered to be “informative but with important limitations” assessed implants. One had been included in the previous review (26), one provided an updated point estimate to that used for the previous review (24) and one provided an entirely new estimate of risk (23). Two of the studies assessed LNG implants (24, 26) and the third assessed women using either LNG or etonogestrel implants (23). None of the three studies suggested an increased risk of HIV acquisition with implant use, consistent with the conclusion of the previous review (14). The quality of the evidence from these studies was rated as low. 3.3 Progestogen-only pills No studies considered “informative but with important limitations” or “informative with few limitations” were identified for progestogen-only pills. 3.4 Intrauterine devices One RCT (the ECHO trial) observed no statistically significant differences in HIV acquisition between DMPA-IM and Cu-IUD, or Cu-IUD and LNG implants (10). The quality of the evidence from this RCT was rated as high. Two observational studies considered “informative but with important limitations” did not observe an association with HIV acquisition when comparing Cu-IUD use with tubal ligation or no contraceptive method use, DMPA-IM, NET-EN or implants (23, 25). The quality of this observational evidence was rated as low. No evidence was identified for LNG-IUDs. 3.5 Combined hormonal contraceptives Eleven observational studies deemed “informative but with important limitations” assessed the use of combined oral contraceptives (COC). (It was assumed that studies that did not specify the oral contraceptive type examined mostly, if not exclusively, examined COC use.) All of these studies were included in the previous review, while an updated estimate came from one newly available study (14, 24). Overall, these studies suggested no association between COC use and HIV acquisition. The quality of the evidence was rated as low-to-moderate. No evidence was identified for the combined contraceptive patch, ring or injectable. 3.6 Additional evidence considered by the GDG 3.6.1 BIOLOGICAL DATA Biological data pertaining to the plausibility of an effect of individual methods of hormonal contraception on HIV acquisition were reviewed. Several biological mechanisms by which individual methods of hormonal contraception could theoretically modify the risk of HIV acquisition have been postulated, but | Contraceptive eligibility for women at high risk of HIV: guidance statement6 sparse and contradictory data make it unclear which, if any, of these biological mechanisms are clinically relevant. Potential mechanisms include alteration of the systemic and local immune response and changes in the genital tract environment. It was noted that different forms of hormonal contraception may change these factors in different ways. Combined contraceptives containing both ethinylestradiol and a progestogen may have a different effect than progestogen-only methods. Additionally, various progestogen-only methods, such as DMPA and NET-EN injectables, may change immune function variably. It remains uncertain to what extent data from animal and laboratory studies, including in relation to progestogen type and dosing, can be applied to clinical outcomes in humans. 3.6.2 VALUES AND PREFERENCES OF CONTRACEPTIVE USERS The systematic review identified 375 studies from all regions of the world (27). Across studies, women’s values and preferences centred on themes of choice and available options, ease of use, side-effect profiles and contraceptive efficacy. Contextual factors, such as the contraceptive methods available, counselling from providers, and the opinions of social networks, influenced decision-making. From the grey literature, two additional studies were identified that were relevant to hormonal contraception and HIV specifically (28, 29). Both found that messages from the 4 “Free” means the freedom and ability to make a voluntary decision about contraceptive use without barriers or coercion; informed means complete, correct and clear information has been given about all the options, plus details about the chosen method 2017 WHO guidance were difficult for providers to explain fully and may not be completely understood by clients. The online survey of sex workers from multiple global regions found that individual preferences around contraception varied widely and could change over time; ongoing partnership and dialogue with sex workers is essential to understanding evolving priorities. In participatory focus groups, Zimbabwean sex workers said their contraceptive choices were shaped by a wide range of factors, including cost, accessibility, the way sex workers are treated at clinics, the influence of male partners, and contraceptive side-effects. Sex without a condom was common, and there was a need to strengthen access to HIV/STI prevention and contraceptive services. The community stakeholder presentation emphasized that, for some women, any level of increased HIV risk would be too high. It also highlighted that the ECHO trial was not set up to assess the difference in the risk of HIV acquisition between contraceptive users and non-users. Community stakeholders also emphasized that there was a lack of true contraceptive choice for many women and girls, saying the guidance should emphasize full, free and informed contraceptive choice,4 the procurement of a range of contraceptive methods, and investment in integrated contraception and HIV services. RECOMMENDATIONS4 4.1 Recommendations for contraceptive use among women at high risk of HIV infection All hormonal contraceptive methods and intrauterine devices (IUDs) now fall into Category 1 of the Medical eligibility criteria for contraceptive use (MEC) (5) for women at high risk of HIV. Thus, women at high risk of HIV can use all methods of contraception without restriction. ■ Women at high a risk of HIV infection are eligible to use all progestogen-only contraceptive methods without restriction (MEC Category 1), including progestogen-only pills (POPs), intramuscular depot medroxyprogesterone acetate (DMPA-IM), subcutaneous DMPA (DMPA-SC), norethisterone enanthate (NET-EN) injectables, levonorgestrel (LNG) implants, and etonogestrel implants. ■ Women at a high risk of HIV infection are eligible to use copper-bearing IUDs (Cu-IUDs) and LNG implants without restriction (MEC Category 1). In considering the use of IUDs, many women at a high risk of HIV are also at risk of other sexually transmitted infections (STIs); for these women, providers should refer to the MEC recommendation on women at increased risk of STIs and the Selected practice recommendations for contraceptive use on STI screening before IUD insertion (5, 6). ■ Women at a high risk of HIV infection are eligible to use all combined hormonal contraceptive methods without restriction (MEC Category 1), including combined oral Contraceptive eligibility for women at high risk of HIV: guidance statement | 7 contraceptives (COCs), combined injectable contraceptives (CICs), combined contraceptive patches (P) and combined vaginal rings (CVR). 4.2 Rationale The Guideline Development Group (GDG) reviewed, and discussed extensively, the new epidemiological and biological evidence, as well as related information about values and preferences, equity and human rights, and feasibility. After deliberating on all of the available evidence, the GDG recommended that the MEC category for DMPA and Cu-IUD should be changed to MEC Category 1. The GDG noted that there was no evidence regarding DMPA-SC and LNG-IUD, and only limited new information regarding NET-EN. Until more information becomes available, the GDG judged it was appropriate to follow the same approach as previously used, i.e. grouping all progestogen-only injectables together (DMPA- IM, DMPA-SC and NET-EN) as MEC Category 1, and to assign the same MEC category to the LNG-IUD as to the Cu-IUD (MEC Category 1). One key portion of the GDG’s deliberations related to evaluating evidence from the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Study (see Annex 3). The GDG gave particular attention to this information because of its ability to address unmeasured confounding – a major cause of uncertainty when interpreting results from observational studies. The GDG recognized that the ECHO trial did not address the etiological or causal question of whether DMPA increases the risk of HIV acquisition when compared with not using any contraception. Nevertheless, since the MEC provides guidance for women wishing to use contraception, results from the ECHO trial about the comparative risk of HIV acquisition among users of the three contraceptives tested were highly pertinent to the GDG’s deliberations. Furthermore, the GDG noted that the high incidence of HIV infection experienced by each contraceptive group during the ECHO trial was similar to the background incidence assumed when designing the trial. This was deemed to be indirect evidence addressing the question, suggesting no increased risk of HIV acquisition among users of these contraceptives compared with women not using any contraception. The ECHO trial was considered to be a well conducted study that provided high-quality evidence that superseded the low and low-to-moderate-quality observational evidence previously available to the GDG. This direct epidemiological evidence, from a trial specifically designed to address the issue, was judged to be more informative than theoretical biological evidence. The reasons for considering the ECHO trial to be of high quality included its large size; robust randomization methods; good adherence to the allocated contraceptive method; a low attrition rate; regular, standardized and objective outcome measurements; and a blinded, comprehensive analysis of the data (including sensitivity analyses for postulated confounders such as sexual activity and condom use). Although women and providers of services in the ECHO trial could not be blinded to the intervention allocation, there was no evidence that this led to the different groups of participants acting, or being managed, differently with respect to important issues such as HIV prevention counselling. This ensured that residual confounding, particularly in relation to condom use or sexual activity, was highly unlikely to have affected the ECHO trial. The GDG noted that although the ECHO trial was designed to detect a 50% increase in the risk of HIV acquisition between contraceptive groups assessed, the observed high HIV incidence and small losses to follow up meant that it could detect a 30% increase. When considering the ECHO trial results, the GDG focused on the point estimates for each primary comparison. The group noted that none of the point estimates for the primary comparisons were statistically significant. The 96% confidence intervals surrounding these point estimates included unity, and so encompassed the possibility of a small increased or decreased difference in risk between contraceptives. The GDG acknowledged, however, that for an individual woman at a high risk of HIV, any change in this risk may be important. After a full discussion, the GDG judged that unmeasured confounding was the most likely explanation for the apparent increased risk of HIV acquisition among DMPA-IM users seen in some observational studies. The GDG’s decisions to revise the MEC classifications for DMPA and IUDs were further grounded by the values and preferences of women towards optimizing informed contraceptive choice and the availability of a wide range of contraceptive options, based on a systematic review of qualitative and quantitative evidence, consultative engagements with sex workers and the perspectives of GDG members representing specific affected populations. In previous editions of the MEC, IUDs were classified as MEC Category 2 for women at a high risk of HIV. This recommendation was given because of the absence of high-quality, direct evidence about the risk of acquiring HIV among IUD users. In addition, there was an assumption that most women at a high risk of HIV were also at an increased risk of other STIs. The ECHO trial provided direct, high-quality evidence about the risk of HIV acquisition risk among women using the Cu-IUD, enabling the GDG to review its recommendation regarding these women. Any new evidence related to IUD use in women at a high risk of other STIs will be reviewed for the next MEC update. The GDG was concerned about the high rates of both HIV and STIs among women in the ECHO trial, reflecting the background risk factors among women seeking contraception in the study areas. The high incidence of HIV was particularly striking given the extensive efforts made during the ECHO trial to provide HIV prevention counselling and interventions. Thus, while the GDG concluded that the risk of HIV acquisition was not affected by the contraceptive method used, it emphasized the need for renewed efforts to reduce the incidence of HIV and STIs. | Contraceptive eligibility for women at high risk of HIV: guidance statement8 IMPLICATIONS FOR POLICY-MAKERS, PROGRAMME MANAGERS AND HEALTH-CARE PROVIDERS 5 While the main audiences for the Medical eligibility criteria for contraceptive use (MEC) are policy-makers and programme managers, a fundamental tenet of the MEC is that they are woman-centred. The following were the key messages that came from the deliberations of the Guideline Development Group. 5.1 A woman’s risk of HIV should not restrict her contraceptive choice While a risk of HIV should not restrict a woman’s choice to use hormonal contraception or an intrauterine device, it is important to note that these methods do not protect her against acquiring HIV or other sexually transmitted infection (STI). The new MEC recommendations should not be interpreted as indicating that HIV and STI testing and prevention are no longer important. Indeed, the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Study highlighted the critical need to strengthen and expand HIV and STI prevention services (10). Testing for HIV and STIs should be part of high-quality family planning services for women at risk, particularly for those living in areas of high HIV and STI incidence. 5.2 Efforts to expand access to contraceptive options must continue Women have the right to a range of short-acting, long-acting and permanent contraceptive methods, as well as to emergency contraception (1). A comprehensive range of contraceptive methods enables women to respond to changing needs and preferences during their reproductive lives. Informed decision- making and woman-centred, high-quality counselling are key components in the human rights-based provision of contraceptive information and services (2). The ECHO trial reinforced that offering a range of methods is possible and acceptable to women (10). Family planning and HIV services should be included in national universal health coverage initiatives. Efforts to expand safe and effective contraceptive options, and to ensure their availability and the access to them, must continue. Technical resources are available to support countries to introduce more contraceptive options into their programmes and services (Box 1). BOX 1. TECHNICAL RESOURCES TO SUPPORT PROGRAMMES o Medical eligibility criteria for contraceptive use (in English, French and Russian) https://apps.who.int/iris/handle/10665/181468 o Selected practice recommendations for contraceptive use (in English, French and Spanish) https://apps.who.int/iris/handle/10665/252267 o Implementation guide for the medical eligibility criteria and selected practice recommendations for contraceptive use (available in English, French, Portuguese and Spanish) https://apps.who.int/iris/handle/10665/272758 o Global handbook for family planning providers https://apps.who.int/iris/handle/10665/260156 o Training Resource Package for Family Planning website (available in English and French) https://www.fptraining.org o Mobile application for the Medical eligibility criteria for contraceptive use (free, for android and iOS platforms) https://www.who.int/reproductivehealth/mec-app o Policy brief: consolidated guidelines on HIV prevention, diagnosis, treatment and care for key populations, 2016 update https://apps.who.int/iris/handle/10665/258967 o Treat all: policy adoption and implementation status in countries (fact sheet) https://apps.who.int/iris/handle/10665/258538 Contraceptive eligibility for women at high risk of HIV: guidance statement | 9 5.3 A renewed emphasis on HIV and STI prevention services is urgently needed The ECHO trial showed high rates of both HIV and STIs in the study sites (10), highlighting the need for appropriate prevention, diagnosis and treatment of all STIs. Current HIV prevention measures remain unavailable or unsatisfactory for many women and adolescent girls living in settings of high HIV incidence. In such areas, the integration of family planning and HIV prevention services for all women is essential if the health of women and adolescent girls is to be improved. In settings of low HIV prevalence, there is a need for family planning providers to evaluate personal risk factors that may increase a woman’s risk of acquiring HIV and then to provide appropriate services. The ECHO trial also showed that syndromic management did not decrease the prevalence of STIs at baseline and at the end of follow-up. STI programmes need to be strengthened, including a move towards diagnostic management. ■ In settings with high HIV prevalence, HIV testing and prevention should be included in family planning services. HIV testing should be offered to all women and to partners of all women with HIV. HIV prevention options should be offered to all women, including pre-exposure prophylaxis (PrEP), as recommended in WHO guidelines (30). The offer of PrEP to women could also be considered where HIV incidence is high (but below 3/100 person-years overall) following, for example, a simple risk assessment. A risk assessment could include: desire to take PrEP (reflecting a self-identified risk); history of an STI; more than one sex partner in the last six months; or women with a sex partner with HIV who is not virally supressed on antiretroviral therapy. ■ In settings with low HIV prevalence, the routine offer of HIV testing and prevention services in family planning settings is unlikely to be cost-effective. HIV testing and prevention services could nonetheless be offered to women who request these services. BOX 2. WORK TO IDENTIFY WOMEN AT HIGH RISK OF HIV A person’s HIV risk depends on the incidence of HIV in the area where they live, and their individual risk factors. Family planning programmes must work closely with their national and subnational HIV programmes to use local epidemiological data to identify geographical areas and risk factors that put women at a high risk of HIV infection. 6.1 Contraceptive methods and HIV acquisition The existing body of evidence is sufficient to guide practice on intramuscular depot medroxyprogesterone acetate (DMPA-IM), levonorgestrel (LNG) implants and copper-bearing intrauterine devices; additional observational data will not add substantially to the evidence base for these methods. However, in the absence of trial data similar to those in the ECHO Study (10), observational data about subcutaneous DMPA (DMPA-SC), LNG IUDs, etonogestrel implants, or future contraceptive or multi-purpose prevention technologies could still be useful, although unmeasured confounding would likely remain a concern. Studies should consider the potential impact of contraceptive use on other sexually transmitted infections as well as HIV. Additional research on the specific effects of contraception-related bleeding changes in relation to the risk of HIV or STI acquisition is also needed. 6.2 HIV prevention The Guideline Development Group was deeply concerned by the high HIV incidence found among women seeking family planning services in the ECHO Study sites, despite the fact that trial participants received an extensive HIV prevention package (including repeated HIV testing and counselling, partner HIV testing and condom distribution, as well as pre-exposure prophylaxis (PrEP) late in the study as this became the standard of care). More research is needed on ways to increase the acceptability and uptake of effective HIV prevention strategies for women at a high risk of HIV, tailored to settings of both high and low HIV prevalence and to women with a range of personal risk factors. In the ECHO trial, the uptake (and hence impact) of PrEP was minimal as it became available only late in the trial (10). Where it was available on site, as opposed to requiring referral to another site, acceptability and uptake were high. Ways to include HIV self-testing and PrEP in family planning services should be KNOWLEDGE GAPS AND AREAS FOR RESEARCH6 | Contraceptive eligibility for women at high risk of HIV: guidance statement10 explored. This should include behavioural and implementation science research on the effective integration of HIV and contraception services. 6.3 Community involvement The ECHO trial employed a range of strategies for directly engaging with civil society at the study site, and at regional and global levels (10). An in-depth assessment of the strengths and limitations of each strategy is likely to provide models for community engagement in contraceptive and HIV prevention research that could be adopted in the future. 6.4 Increased funding for high-quality, policy-relevant research The ECHO Study demonstrated that a well conducted, adequately powered randomized controlled trial is possible in contraceptive research, and can make an important contribution to global decision-making. Global policy should be based on comprehensive high-quality evidence, but additional investment in contraceptive research is critically overdue, including research addressing whether financial barriers affect the contraceptive choices of women. DISSEMINATION OF THIS GUIDANCE STATEMENT7 The World Health Organization (WHO) will work to communicate this guidance statement clearly and widely. WHO will evaluate whether the guidance achieves its intentions. The guidance will be published on the WHO website and in a limited quantity of printed documents. The guidance will be widely disseminated through the WHO regional and country offices, WHO Member States, other United Nations agencies, civil society, the Implementing Best Practices (IBP) initiative, professional organizations, governmental and non- governmental partner organizations, and WHO collaborating centres working in the area of HIV and sexual and reproductive health. The WHO Secretariat will work closely with sexual and reproductive health and HIV focal points in regional and country offices of WHO, the United Nations Population Fund and the Joint United Nations Programme on HIV and AIDS to conduct a series of regional learning and knowledge-sharing events. This engagement will target opportunities where sexual and reproductive health issues are being discussed; examples include the 25th Conference on Population and Development in July 2019 and the 20th International Conference on AIDS and Sexually Transmitted Infections in Africa in December 2019. The Secretariat will also work closely with country task teams and working groups leading HIV and contraception programme efforts to share the guidance with grassroots and community- level organizations and providers. Additionally, webinars for stakeholders in multiple languages will be organized during 2020 to ensure Member States and stakeholders are fully informed of the new recommendations. These opportunities will enable WHO to disseminate the updated guidance effectively and efficiently. Derivative communication products highlighting key counselling issues (e.g. short briefs for front-line health-care providers and community-based organizations) will be prepared in collaboration with WHO’s implementing partners, and in consultation with the GDG during 2020. A policy brief in the six official languages used by WHO will be developed to inform policy-makers about the contraception updates. As part of the dissemination of the recommendations in this guidance statement, WHO will update its digital contraceptive decision-support tools – the MEC mobile app (31), the humanitarian contraceptive delivery app (32) and the postpartum compendium (33). These mobile applications are free to download and available for both iOS and Android platforms. Additionally, the Global handbook for family planning providers and the online Family Planning Training Resource Package will be updated accordingly (8, 34). WHO will continue to monitor the body of evidence informing these recommendations and will convene additional consultations when needed. Contraceptive eligibility for women at high risk of HIV: guidance statement | 11 REFERENCES 1. Ensuring human rights in the provision of contraceptive information and services: guidance and recommendations. Geneva: World Health Organization; 2014 (https://apps.who.int/iris/handle/10665/102539, accessed 24 August 2019). 2. Framework for ensuring human rights in the provision of contraceptive information and services. Geneva: World Health Organization; 2014 (https://apps.who.int/iris/handle/10665/133327, accessed 24 August 2019). 3. The thirteenth general programme of work, 2019–2023: promote health, keep the world safe, serve the vulnerable. Geneva: World Health Organization; 2019 (https://apps.who.int/iris/handle/10665/324775, accessed 24 August 2019). 4. Reproductive health strategy to accelerate progress towards the attainment of international development goals and targets. Geneva: World Health Organization; 2004 (https://apps.who.int/iris/handle/10665/68754, accessed 24 August 2019). 5. Medical eligibility criteria for contraceptive use, fifth edition. Geneva: World Health Organization; 2015 (https://apps.who.int/iris/ handle/10665/181468, accessed 24 August 2019). 6. Selected practice recommendations for contraceptive use: third edition. Geneva: World Health Organization; 2016 (https://apps.who.int/iris/handle/10665/252267, accessed 24 August 2019). 7. WHO medical eligibility criteria wheel for contraceptive use, 2015 update. Geneva: World Health Organization; 2004 (https://apps.who.int/iris/handle/10665/173585, accessed 24 August 2019). 8. World Health Organization, Johns Hopkins Bloomberg School of Public Health. Family planning: a global handbook for providers: evidence-based guidance developed through worldwide collaboration, third edition. Geneva: World Health Organization; 2018 (https://apps.who.int/iris/handle/10665/260156, accessed 24 August 2019). 9. Hormonal contraceptive eligibility for women at high risk of HIV: guidance statement: recommendations concerning the use of hormonal contraceptive methods by women at high risk of HIV. Geneva: World Health Organization; 2017 (https://apps.who.int/ iris/handle/10665/254662, accessed 24 August 2019). 10. Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium. HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial. Lancet. 2019;394(10195):303–13. doi: 10.1016/S0140-6736(19)31288-7. 11. WHO handbook for guideline development, second edition. Geneva: World Health Organization; 2014 (https://apps.who.int/iris/ handle/10665/145714, accessed 24 August 2019). 12. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J et al. GRADE guidelines: 1. Introduction –GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64(4):383–94. doi: 10.1016/j.jclinepi.2010.04.026. 13. Singh S. Adding it up: costs and benefits of contraceptive services – estimates for 2017. New York (NY): Guttmacher Institute; 2017. 14. Polis CB, Curtis KM, Hannaford PC, Phillips SJ, Chipato T, Kiarie JN et al. An updated systematic review of epidemiological evidence on hormonal contraceptive methods and HIV acquisition in women. AIDS. 2016;30(17):2665–83. doi: 10.1097/ QAD.0000000000001228. 15. Moher D, Liberati A, Tetzlaff J, Altman DG; The Prisma Group. Preferred reporting items for systematic reviews and meta- analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. doi: 10.1371/journal.pmed.1000097. 16. Kennedy CE, Yeh PT, Gaffield ME. Contraception values and preferences: protocol and methods for a global systematic review. Contraception. 2019 (in press). doi: 10.1016/j.contraception.2018.05.006Get. 17. Guyatt GH, Oxman AD, Vist G, Kunz R, Brozek J, Alonso-Coello P et al. GRADE guidelines: 4. Rating the quality of evidence— study limitations (risk of bias). J Clin Epidemiol. 2011;64(4):407–15. doi: 10.1016/j.jclinepi.2010.07.017. 18. Guyatt GH, Oxman AD, Kunz R, Brozek J, Alonso-Coello P, Rind D et al. GRADE guidelines 6. Rating the quality of evidence – imprecision. J Clin Epidemiol. 2011;64(12):1283–93. doi: 10.1016/j.jclinepi.2011.01.012. | Contraceptive eligibility for women at high risk of HIV: guidance statement12 19. Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M et al. GRADE guidelines: 8. Rating the quality of evidence – indirectness. J Clin Epidemiol. 2011;64(12):1303–10. doi: 10.1016/j.jclinepi.2011.04.014. 20. Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M et al. GRADE guidelines: 7. Rating the quality of evidence – inconsistency. J Clin Epidemiol. 2011;64(12):1294–302. doi: 10.1016/j.jclinepi.2011.03.017. 21. Guyatt GH, Oxman AD, Montori V, Vist G, Kunz R, Brozek J et al. GRADE guidelines: 5. Rating the quality of evidence – publication bias. J Clin Epidemiol. 2011;64(12):1277–82. doi: 10.1016/j.jclinepi.2011.01.011. 22. Guyatt GH, Oxman AD, Sultan S, Glasziou P, Akl EA, Alonso-Coello P et al. GRADE guidelines: 9. Rating up the quality of evidence. J Clin Epidemiol. 2011;64(12):1311–6. doi: 10.1016/j.jclinepi.2011.06.004. 23. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619–22. doi: 10.1097/ QAD.0000000000002260. 24. Sabo MC, Richardson BA, Lavreys L, Martin HL, Jr, Jaoko W, Mandaliya K et al. Does bacterial vaginosis modify the effect of hormonal contraception on HIV seroconversion. AIDS. 2019;33(7):1225–30. doi: 10.1097/QAD.0000000000002167. 25. Lavreys L, Baeten JM, Martin Jr HL, Overbaugh J, Mandaliya K, Ndinya-Achola J et al. Hormonal contraception and risk of HIV-1 acquisition: results of a 10-year prospective study. AIDS. 2004;18(4):695–7. 26. Wall KM, Kilembe W, Vwalika B, Htee Khu N, Brill I, Chomba E et al. Hormonal contraception does not increase women’s HIV acquisition risk in Zambian discordant couples, 1994–2012. Contraception. 2015;91(6):480–7. doi: 10.1016/j. contraception.2015.02.004. 27. Yeh PT, Kennedy CE, Gaffield ME. Contraception values and preferences: a global systematic review. Contraception. 2019; (accepted pending revisions). 28. Miller L, Ntinginya M, Makula J, Juma A, Mackay A, Wadegu E et al. Final report: a pilot study to assess training and communication materials on progestogen-only injectable use and risk of HIV acquisition in Tanzania. London: Marie Stopes International; 2019 (https://resultsforinformedchoice.org/wp-content/uploads/2019/02/Injectables-and-HIV-Pilot-Study-Report-TZ.pdf, accessed 24 August 2019). 29. Littlepage S, Dam A, Nakyanjo N, Polis C, Nalugoda F, Kennedy CE. Contraceptive decision-making in the context of HIV risk and changing World Health Organization guidelines: a qualitative study in Rakai, Uganda. 2019 (personal communication). 30. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach, second edition. Geneva: World Health Organization; 2016. (https://apps.who.int/iris/handle/10665/208825, accessed 24 August 2019). 31. New app for WHO’s medical eligibility criteria for contraceptive use. In: World Health Organization [website]. Geneva: World Health Organization; 2018 (https://www.who.int/reproductivehealth/mec-app, accessed 24 August 2019). 32. Delivering contraceptive services in humanitarian settings: new tool for front-line health care workers. In: World Health Organization [website]. Geneva: World Health Organization; 2018 (https://www.who.int/reproductivehealth/publications/ humanitarian-settings-contraception, accessed 24 August 2019). 33. New WHO tool helps guide contraception choices following childbirth. In: World Health Organization [website]. Geneva: World Health Organization; 2016 (https://www.who.int/reproductivehealth/news/pfpc, accessed 24 August 2019). 34. TRP: Training Resource Package for Family Planning [website]. Baltimore (MD): Johns Hopkins University; 2019 (https://www.fptraining.org, accessed 24 August 2019). Contraceptive eligibility for women at high risk of HIV: guidance statement | 13 ANNEX 1. GUIDELINE DEVELOPMENT GROUP AND EVIDENCE SECRETARIAT Guideline Development Group Sharon Achilles (University of Pittsburgh, United States of America), Richard Adanu (University of Ghana, Ghana), Rachid Bezad (University Roi Mohammad VI, Morocco), Sharon Cameron (University of Edinburgh, United Kingdom of Great Britain and Northern Ireland), Tsungai Chipato (University of Zimbabwe, Zimbabwe), Maria del Carmen Cravioto (National Institute of Nutrition, Salvador Zubiran, Mexico) [unable to attend], Alison Edelman (Oregon Health & Science University, United States), Mohammad Eslami (Ministry of Health and Education, Islamic Republic of Iran), Anna Glasier (University of Edinburgh, United Kingdom), Andy Gray (University of KwaZulu- Natal, South Africa), Philip Hannaford (University of Aberdeen, United Kingdom), Felicita Hikuam (AIDS and Rights Alliance for Southern Africa, Namibia), Unnop Jaisamrarn (Chulalongkorn University, Thailand), Loveleen Johri (family planning and reproductive health independent consultant, India), Natasha Kaoma (Copper Rose Zambia, Zambia), Seni Kouanda (Institute of Research in Health Sciences, Burkina Faso), Elizabeth Lule (global health and international development independent consultant, Uganda), Vimbai Magwenzi (Centre for Sexual Health and HIV/AIDS Research, Zimbabwe) [unable to attend], Loyce Maturu (Zvandiri Mentor with Africaid, Zimbabwe), Olav Meirik (Instituto Chileno de Medicina Reproductiva, Chile), Placid Mihayo (Ministry of Health, Uganda), Lilian Mworeko (International Community of Women Living with HIV Eastern Africa, Uganda), Hiromi Obara (National Center for Global Health and Medicine, Tokyo, Japan), Herbert Peterson (University of North Carolina, United States), John Pile (independent consultant, Thailand), Carolina Sales Vieira (University of Sao Paulo, Brazil), Sarah Simpson (EquiACT, France), Aminata Wurie (Youth Coalition for Sexual and Reproductive Rights, Sierra Leone). Philip Hannaford and Natasha Kaoma co-chaired the meeting Guideline Development Group (GDG) meeting. Evidence Secretariat Centre for Sexual Health and HIV/AIDS Research – Euphemia Sibanda FHI 360 – Timothy Mastro Independent Consultant – Ania Shapiro Johns Hopkins University – Caitlin Kennedy Oregon Health & Science University – Maria Isabel Rodriguez United States Centers for Disease Control and Prevention – Kathryn Curtis University of Washington – Jared Baeten Wits Reproductive Health and HIV Institute – Helen Rees Observer Zandile Mnisi (Ministry of Health, Eswatini) External Review Group Florence Anam (Doctors Without Borders, South Africa), Winfred Apio (Uganda Youth and Adolescents Forum, Uganda), Lynn Bakamjian (independent consultant, United States), Milena Brito (University of Sao Paulo, Brazil), Roy Jacobstein (IntraHealth, United States), Ernest Maya (University of Ghana, Ghana), Mari Ngai (National Center for Global Health and Medicine, Japan), Cristina Puig Borràs (European Consortium for Emergency Contraception, Spain), Nusrat Shah (Society of Obstetrics & Gynaecology, Pakistan), Bulbul Sood (Jphiego, India). WHO Secretariat The WHO Secretariat attended the meeting and several WHO staff provided background presentations (Rachel Baggaley, Mary Lyn Gaffield, James Kiarie, Nancy Kidula). The WHO Secretariat was present to serve as a background resource, if request by the GDG. Neither WHO, the Joint United Nations Programme on HIV/AIDS (UNAIDS) nor the United Nations Population Fund (UNFPA) staff participated in the decision- making or formulation of the recommendations, which was the sole responsibility of the GDG. Several WHO staff contributed to the systematic reviews (Mary Lyn Gaffield, James Kiarie, Petrus Steyn) and the writing of the statement. WHO headquarters WHO Department of Reproductive Health and Research – Ian Askew, Mary Lyn Gaffield, James Kiarie, Antonella Lavelanet, Manjulaa Narasimhan (unable to attend), Petrus Steyn WHO Department of HIV – Rachel Baggaley, Virginia MacDonald, Michele Rodolph WHO Department of Regulation of Medicines and other Health Technologies – Ray Corrin | Contraceptive eligibility for women at high risk of HIV: guidance statement14 WHO regional offices WHO Regional Office for Africa – Nancy Kidula, Léopold Ouedraogo Joint United Nations Programme on HIV/AIDS (UNAIDS) Peter Godfrey-Fausett United Nations Population Fund (UNFPA) Technical Division – Gifty Addico, Mieko Yabuta (unable to attend) Overall coordination WHO Department of Reproductive Health and Research – Mary Lyn Gaffield, with logistical support from Jane Werunga- Ndanareh. Writing The guidance statement was drafted on behalf of WHO by Caitlin Baumhart, Kathryn Curtis, Mary Lyn Gaffield, Philip Hannaford, Natasha Kaoma, Caitlin Kennedy and Maria Isabel Rodriguez. The systematic review examining the use of copper-bearing intrauterine devices and HIV acquisition was co-authored by Tsungai Chipato, Kathryn Curtis, Philip Hannaford and Angeline Ti. The update of the 2016 systematic review focusing on hormonal contraception and HIV acquisition was co-authored by Tsungai Chipato, Kathryn Curtis, Philip Hannaford, James Kiarie and Petrus Steyn. The GRADE tables and expertise on GRADE methodology were provided by Maria Isabel Rodriguez. Preparation of the evidence-to-decision table and expertise on the literature for values and preferences were provided by Caitlin Kennedy. Editing was done by Markus MacGill and Jane Patten of Green Ink (www.greenink.co.uk) and layout by Lushomo (www.lushomo.net). Contraceptive eligibility for women at high risk of HIV: guidance statement | 15 ANNEX 2. DECLARATIONS OF CONFLICTS OF INTEREST Following guidance issued on 24 September 2014 by the WHO Office of Compliance, Risk Management and Ethics (CRE), and prior to the 29–31 July 2019 meeting, the name and brief biography of each proposed Guideline Development Group (GDG) member was published on the WHO website during 27 May to 10 June 2019 (https://www.who.int/ reproductivehealth/publications/contraceptives-methods-hiv). The public was able to view and provide their comments to the WHO Secretariat using a general email address (hrx_info@who.int) regarding any perceived or real conflicts of interest of these proposed GDG members. In addition, prior to the public announcement period, the WHO Secretariat reviewed the curriculum vitae of each potential participant and conducted Internet searches (Google Scholar, Open Payments, PubMed) for information on potential financial and academic conflicts of interest related to the subject of the meeting. Following the public reporting period, and in consultation with CRE, official invitations for GDG membership were extended. Additionally, the WHO Secretariat reviewed potential financial and academic conflicts of interest related to the subject of the meeting of the proposed External Review Group: no conflicts were declared among this 11-member group. Of the 28 experts who participated in this work, six declared an interest related to contraception. The WHO Secretariat, CRE and GDG reviewed all declarations and found no conflicts of interest sufficient to preclude anyone from participating in the deliberations or the development of the recommendations relevant to hormonal contraception and HIV. Accordingly, the six participants who declared interests related to contraception, as well as the other 22 participants, fully participated in the meeting’s deliberations, discussions and final decisions. Although not all interests declared were specifically related to contraception and susceptibility to HIV, they are disclosed and summarized below. Sharon Achilles received US$ 4225 on 10 May 2016 to give expert advice on the latest HIV therapies during a one-day meeting sponsored by Merck Sharp & Dohme. Her research unit received US$ 2 638 373 from the United States National Institutes of Health/National Institute of Allergy and Infectious Diseases to conduct a study titled, Quantification of immune cells in women using contraception, during 2012–2019. For 2012–2019, her research unit is receiving US$ 4 999 999 from the Bill & Melinda Gates Foundation to conduct a study titled, HIV-target cell response in women initiating contraception in high HIV-incidence areas. During 2014–2016, Dr Achilles’s research unit received US$ 240 225 from the Bill & Melinda Gates Foundation to conduct a study addressing IFN-epsilon and hormonal contraceptive modulation of the risk of HIV acquisition. Currently, for 2018–2020, Dr Achilles’s research unit receives US$ 535 958 from the United States Food and Drug Administration (FDA) to conduct a study supporting new approaches to improve product manufacturing and quality titled, Physiologically-based model of the female reproductive tract: vaginal and intrauterine delivery components. Sharon Cameron works at a research unit that received a grant from Pfizer, UK, for £99 000, which ceased in 2016. The study was implemented to determine the feasibility and acceptability of the pharmacist administration of subcutaneous injectable contraception. Alison Edelman receives a yearly royalty of around US$ 1000 from the Internet information site, UpToDate as an author of the content. Between May 2016 and May 2017, she received US$ 10 000 a year from Agile Pharmaceuticals as an expert consultant regarding a hormonal contraceptive patch that is currently not FDA-approved. This consultation has ended. Since January 2016, she served as a trainer for Nexplanon, an FDA mandate, for Merck Sharp & Dohme, but has received no honorarium for these sessions and as an expert consultant in January 2016 for this company, receiving US$ 1500 for her services. Her research unit received US$ 540 000 from the Merck Women’s Health Investigator Initiated Studies Program to conduct research focused on treatment of breakthrough bleeding with the contraceptive implant (2016–2019). From 2015 to 2017, her research unit received a US$ 250 000 research grant from the Society for Family Planning to investigate the timing of ulipristal acetate and oral contraceptive use. Since 2002, Dr Edelman has been receiving about US$ 3000 a year from Contemporary Forums as a faculty member for its continuing medical education conferences (the amount varies depending on the number of lectures she gives). From November 2015 through June 2016, she received an honorarium of US$ 3000 from Oregon State University for expert advice on the mandated state training to allow the direct provision of contraceptives by pharmacists. Since July 2016, Dr Edelman has been receiving US$ 500 a year as an honorarium for serving on the data and safety monitoring board to FHI 360, which is developing a novel contraceptive injectable that is not yet FDA-approved. From April to September 2017, Dr Edelman was a consultant for HRA Pharma for a study investigating a progestin-only pill. Since July 2017, she had been an expert consultant for the Sugar Palm Foundation; this contract was then channelled through her institution and ended in 2019. Since June 2017, she has been providing expert consulting to Ipas to train health-care workers in Bangladesh: this contract is now administered by her institution. On an ongoing basis since 2016, Dr Edelman has received an honorarium from the University of California, San Francisco, for speaking and family planning fellowship site audits. During 2018 through to January 2019, she received an honorarium from Exeltis to provide an expert review on a contraceptive method not currently FDA- approved. This consultation has ended. Anna Glasier provides expert medical advice on the ulipristal acetate emergency contraceptive pill on a regular basis to the manufacturer (HRA Pharma). The amount was not disclosed. She works with them to try to obtain approval for the over-the- counter (OTC) use of ulipristal acetate emergency contraception and a progestin-only pill in the United States of America, and to | Contraceptive eligibility for women at high risk of HIV: guidance statement16 get a progestin-only pill approved for OTC use in the United Kingdom of Great Britain and Northern Ireland, and Europe. This is ongoing. Andy Gray is the chair of the Names and Scheduling Advisory Committee of the South African Health Products Regulatory Authority and serves on its Lega Advisory and Regulatory Advisory Committees. He is a member of the South African National Essential Medicines List Committee, responsible for medicines selection and the development of standard treatment guidelines for the public sector. Carolina Sales Vieira receives an honorarium (US$ 4000/year) for serving on Merck Sharpe & Dohme’s medical advisory board and giving ad hoc invited lectures. This role is ongoing. Dr Sales Vieira receives an honorarium (US$ 3000/year) for serving on Bayer’s medical advisory board and giving ad hoc lectures. This role is ongoing. Dr Sales Vieira received a one-time honorarium (US$ 1000) for serving on the medical advisory board for Exeltis in 2019. Contraceptive eligibility for women at high risk of HIV: guidance statement | 17 ANNEX 3. GRADE EVIDENCE PROFILES Outcome Type and number of studies (total number of participants) Limitations Inconsistency Imprecision Indirectness Overall quality Estimate of effect DMPA versus non-hormonal contraception or no method HIV acquisition 1 RCT1 (7829)a Few limitationsb No serious inconsistency No serious imprecision No indirectness High Adjusted HR 1.04 (0.82–1.33) for DMPA versus Cu-IUD HIV acquisition 10 cohort studies2–11 + 1 individual patient data meta-analysis of 7 studies12,c (40 506)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low to moderatee Adjusted HR range 0.46– 2.04, 8 studies increased risk (HR range 1.25–2.04), with statistically significant effects in 3 studies; 2 studies trended towards decreased risk (HR 0.46 and 0.75 with wide confidence intervals) Pooled adjusted HR 1.40 (1.24–1.58) NET-EN versus non-hormonal contraception or no method HIV acquisition 6 cohorts studies2,5,7,8,10,11 + 1 individual patient data meta- analysis of 7 studies12,c (29 922)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR range 0.87– 1.76, 5 studies increased risk (HR range 1.20–1.76), none statistically significant; 2 studies no effect (adjusted HR range 0.87–1.05) Pooled adjusted HR 1.14 (0.93–1.39) Implantf use versus non-hormonal contraception HIV acquisition 1 randomized trial1 (7829)a Few limitationsb No serious inconsistency No serious imprecision No indirectness High Adjusted HR 1.18 (0.91–1.53) for Cu-IUD versus LNG implant HIV acquisition 3 cohort studies2–4,c (4514)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Lowg Adjusted HR range 0.46–0.99 Adjusted HRs: 0.96 (0.29– 3.14), 0.99 (0.40–2.45), and 0.46 (0.13–1.70); none statistically significant Pooled adjusted HR 0.82 (0.44–1.53) Implantf use versus NET-EN HIV acquisition 1 cohort study2 (1136)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 0.45 (0.13–1.53) for implant use versus NET-EN Oral hormonal contraceptive use versus non-hormonal contraception or no method HIV acquisition 11 cohort studies3–6,8–14,c (43 482)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low to moderatee Adjusted HR or IRR range 0.66–1.80 3 studies increased risk (HR 1.39–1.80) Only 1 study reported a statistically significant finding (adjusted HR 1.48 [1.05– 2.09]) The remaining 8 studies reported a decreased risk (adjusted HR range 0.66–0.99), none of which was statistically significant Pooled adjusted HR 1.02 (0.88–1.19) GRADE EVIDENCE PROFILE FOR HORMONAL CONTRACEPTIVE USE IN HIV-NEGATIVE WOMEN | Contraceptive eligibility for women at high risk of HIV: guidance statement18 Outcome Type and number of studies (total number of participants) Limitations Inconsistency Imprecision Indirectness Overall quality Estimate of effect DMPA versus NET-EN HIV acquisition 2 cohort studies2,15 and 1 individual patient data meta-analysis of 17 studies12,c (42 788)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low to moderatee Adjusted HRs 1.32 (1.08– 1.61) and 0.89 (0.55–1.44) in cohort studies and 1.41 (1.06–1.89) in individual participant data meta- analysis of 17 studies Pooled adjusted HR 1.27 (1.05–1.55) DMPA versus combined oral contraceptives HIV acquisition 1 individual patient data meta-analysis of 8 studies12,c (24 853)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low to moderatee Adjusted HR 1.41 (1.23–1.67) in individual participant data meta-analysis of 8 studies NET-EN versus combined oral contraceptives HIV acquisition 1 individual patient data meta-analysis of 9 studies12,c (25 398)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 1.30 (0.99–1.17) GRADE EVIDENCE PROFILE FOR HORMONAL CONTRACEPTIVE USE IN HIV-NEGATIVE WOMEN Cu-IUD: copper-bearing intrauterine device; DMPA-IM: intramuscular depot medroxyprogesterone acetate; ETG: etonogestrel; GRADE: Grading of Recommendations Assessment, Development and Evaluation; HR: hazard ratio; IRR: incidence rate ratio; LNG: levonorgestrel; NET-EN: norethisterone enanthate; RCT: randomized controlled trial Note: Publication bias was not formally assessed; observational studies could not be upgraded for large effects; dose-response relationship, or confounders likely to increase observed effects. Estimates based on adjusted risk estimates, results from Cox model analysis used when available. a Sample size is for the entire study population. b Few limitations noted in the trial, but not serious enough to downgrade the level of evidence. While the study was unblinded for participants and health-care providers, data were analysed centrally by statisticians who were blinded to the group. c Restricted to studies classified as “informative with but with important limitations”. d Some limitations or imprecision noted across the body of evidence, but not serious enough to downgrade the level of evidence. e Evidence graded low to moderate due to consistent and precise results from well conducted observational studies, and coherence between studies of use versus non-use and head-to-head studies. f No direct evidence for ETG implants was identified for the comparisons of interest. For ETG implants, recommendations were extrapolated from other implant studies. g Upgraded from very low-quality evidence (2016 assessment). References: 1. Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium. HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial. Lancet. 2019;394(10195):303–13. doi: 10.1016/S0140-6736(19)31288-7. 2. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619–22. doi: 10.1097/ QAD.0000000000002260. 3. Sabo MC, Richardson BA, Lavreys L, Martin HL, Jr, Jaoko W, Mandaliya K et al. Does bacterial vaginosis modify the effect of hormonal contraception on HIV seroconversion. AIDS. 2019;33(7):1225–30. doi: 10.1097/QAD.0000000000002167. 4. Wall KM, Kilembe W, Vwalika B, Htee Khu N, Brill I, Chomba E et al. Hormonal contraception does not increase women’s HIV acquisition risk in Zambian discordant couples, 1994–2012. Contraception. 2015;91(6):480–7. Doi: 10.1016/j. contraception.2015.02.004. Contraceptive eligibility for women at high risk of HIV: guidance statement | 19 5. Crook AM, Ford D, Gafos M, Hayes R, Kamali A, Kapiga S et al. Injectable and oral contraceptives and risk of HIV acquisition in women: an analysis of data from the MDP301 trial. Hum Reprod. 2014;29(8):1810–7. doi: 10.1093/humrep/deu113. 6. Heffron R, Donnell D, Rees H, Celum C, Mugo N, Were E et al. Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study. Lancet Infect Dis. 2012;12(1):19–26. doi: 10.1016/S1473-3099(11)70247-X. 7. Kleinschmidt I, Rees H, Delany S, Smith D, Dinat N, Nkala B et al. Injectable progestin contraceptive use and risk of HIV infection in a South African family planning cohort. Contraception. 2007;75(6):461–7. doi: 10.1016/j.contraception.2007.02.002. 8. McCoy SI, Zheng W, Montgomery ET, Blanchard K, van der Straten A, de Bruyn G et al. Oral and injectable contraception use and risk of HIV acquisition among women in sub-Saharan Africa. AIDS. 2013;27(6):1001–9. doi: 10.1097/ QAD.0b013e32835da401. 9. Morrison CS, Richardson BA, Mmiro F, Chipato T, Celentano DD, Luoto J et al. Hormonal contraception and the risk of HIV acquisition. AIDS. 2007;21(1):85–95. doi: 10.1097/QAD.0b013e3280117c8b. 10. Morrison CS, Skoler-Karpoff S, Kwok C, Chen PL, van de Wijgert J, Gehret-Plagianos M et al. Hormonal contraception and the risk of HIV acquisition among women in South Africa. AIDS. 2012;26(4):497–504. doi: 10.1097/QAD.0b013e32834fa13d. 11. Myer L, Denny L, Wright TC, Kuhn L. Prospective study of hormonal contraception and women’s risk of HIV infection in South Africa. Int J Epidemiol. 2007;36(1):166–74. doi: 10.1093/ije/dyl251. 12. Morrison CS, Chen PL, Kwok C, Baeten JM, Brown J, Crook AM et al. Hormonal contraception and the risk of HIV acquisition: an individual participant data meta-analysis. PLoS Med. 2015;12(1):e1001778. doi: 10.1371/journal.pmed.1001778. 13. Balkus JE, Brown ER, Hillier SL, Coletti A, Ramjee G, Mgodi N et al. Oral and injectable contraceptive use and HIV acquisition risk among women in four African countries: a secondary analysis of data from a microbicide trial. Contraception. 2016;93(1):25–31. doi: 10.1016/j.contraception.2015.10.010. 14. Reid SE, Dai JY, Wang J, Sichalwe BN, Akpomiemie G, Cowan FM et al. Pregnancy, contraceptive use, and HIV acquisition in HPTN 039: relevance for HIV prevention trials among African women. J Acquir Immune Defic Syndr. 2010;53(5):606–13. doi: 10.1097/QAI.0b013e3181bc4869. 15. Noguchi LM, Richardson BA, Baeten JM, Hillier SL, Balkus JE, Chirenje ZM et al. Risk of HIV-1 acquisition among women who use different types of injectable progestin contraception in South Africa: a prospective cohort study. Lancet HIV. 2015;2(7):e279–87. doi: 10.1016/S2352-3018(15)00058-2. | Contraceptive eligibility for women at high risk of HIV: guidance statement20 Outcome Type and number of studies (total number of participants) Limitations Inconsistency Imprecision Indirectness Overall quality Estimate of effect IUDa versus no contraception or tubal ligation HIV acquisition 1 prospective study1,b (1498)c Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 1.1 (0.4–3.0) for Cu-IUD versus no contraception or tubal ligation IUDa versus implant,e DMPA, NET-EN HIV acquisition 1 prospective study2,b (1136)c Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 0.90 (0.45–1.76) for DMPA, implants, NET-EN versus Cu-IUD IUDa use versus DMPA HIV acquisition 1 RCT3,b (7829)c Few limitationsf No serious inconsistency No serious imprecision No indirectness High Adjusted HR 1.04 (0.82–1.33) for DMPA-IM versus Cu-IUD HIV acquisition 1 prospective study2,b (1136)c Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 0.91 (0.44–1.87) for DMPA versus Cu-IUD IUDa versus NET-EN HIV acquisition 1 prospective study2,b (1136)c Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 0.98 (0.47–2.03) for Cu-IUD versus NET-EN IUDa versus implante HIV acquisition 1 RCT3 (7829)c Few limitationsf No serious inconsistency No serious imprecision No indirectness High Adjusted HR 1.18 (0.91–1.53) for Cu-IUD versus LNG implant HIV acquisition 1 prospective study2,b (1136)c Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 2.17 (0.59–7.69) for Cu-IUD versus implants (LNG or ETG) GRADE EVIDENCE PROFILE FOR CU-IUD USE IN HIV-NEGATIVE WOMEN Cu-IUD: copper-bearing intrauterine device; DMPA-IM: intramuscular depot medroxyprogesterone acetate; ETG: etonogestrel; GRADE: Grading of Recommendations Assessment, Development and Evaluation; HR: hazard ratio; IUD: intrauterine device; LNG: levonorgestrel; NET-EN: norethisterone enanthate; RCT: randomized controlled trial Note: Publication bias was not formally assessed; observational studies could not be upgraded for large effects; dose-response relationship, or confounders likely to increase observed effects. Estimates based on adjusted risk estimates, results from Cox model analysis used when available. a No direct evidence for LNG-IUDs was identified for the comparisons of interest. For LNG-IUDs, recommendations were extrapolated from the evidence on Cu-IUDs and other LNG containing products. b Restricted to studies classified as “informative with but with important limitations”. c Sample size is for the entire study population. d Some limitations or imprecision was noted across the body of evidence, but not serious enough to downgrade the level of evidence. e No direct evidence for ETG implants was identified for the comparisons of interest. For ETG implants, recommendations were extrapolated from the evidence on LNG implants. f Few limitations noted in the trial, but not serious enough to downgrade the level of evidence. References: 1. Lavreys L, Baeten JM, Martin Jr HL, Overbaugh J, Mandaliya K, Ndinya-Achola J et al. Hormonal contraception and risk of HIV-1 acquisition: results of a 10-year prospective study. AIDS. 2004;18(4):695–7. 2. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619–22. doi: 10.1097/ QAD.0000000000002260. 3. Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium. HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial. Lancet. 2019;394(10195):303–13. doi: 10.1016/S0140-6736(19)31288-7. Contraceptive eligibility for women at high risk of HIV: guidance statement | 21 ANNEX 4. EVIDENCE-TO- DECISION TABLE FOR HORMONAL CONTRACEPTIVE METHODS AND INTRAUTERINE DEVICES (IUDS) Factor Explanation/evidence Judgement Quality of evidence Progestogen- only contraceptives (POCs) For the primary outcome of HIV acquisition, evidence was considered to be of high qual- ity for intramuscular depot medroxyprogesterone acetate (DMPA-IM) and for levonorge- strel (LNG) implants. Evidence was considered to be of low quality for norethisterone enanthate (NET-EN), and absent for subcutaneous DMPA (DMPA-SC), LNG intrauterine devices (IUDs) and etonogestrel (ETG) implants. For NET-EN and DMPA-SC, the recom- mendations were extrapolated from the evidence on DMPA-IM. For ETG implants, the recommendations were extrapolated from the evidence on LNG implants. High, low or absent, depending on method IUDs For the primary outcome of HIV acquisition, evidence was considered to be of high quality for copper-bearing IUDs (Cu-IUDs). Evidence was absent for LNG-IUDs. For LNG-IUDs, recommendations were extrapolated from the evidence on Cu-IUDs and other LNG-containing products. High or absent, de- pending on method Combined hormonal contraceptives (CHCs) Evidence was considered to be of low-to-moderate quality for CHCs. Low-moderate Balance of benefits versus harms POCs Contraception is a life-saving intervention with well recognized health, social and economic benefits. All POCs are effective or highly effective, reversible methods. High-quality evidence from one randomized controlled trial (RCT) observed no statistically significant differences in HIV acquisition between: DMPA-IM versus Cu-IUD, DMPA-IM versus LNG implant, and Cu-IUD versus LNG implant. Of the low-to-moderate-quality evidence from 14 observational studies, some studies suggested a possible increased risk of HIV with progestogen-only injectable use, which was most likely due to unmeasured confounding.a,b Low-quality evidence from three observational studies did not suggest an increased HIV risk for implant users.a,b No studies of sufficient quality were identified for progestogen-only pills. While no direct evidence was available for DMPA-SC or ETG implants, indirect evidence for DMPA-IM and LNG implants was used, given that there was no biological or clinical reason to believe that a lower hormonal dose, different delivery mechanism, or different progestogen would modify HIV risk. Balance is in favour of benefits of POCs IUDs Contraception is a life-saving intervention with well recognized health, social and economic benefits. All IUDs are highly effective, reversible methods. High-quality evidence from one RCT, along with low-quality evidence from two observational studies, suggested no increased risk of HIV acquisition with Cu-IUD use.c–e While no direct evidence was available for LNG-IUDs, recommendations were extrapolated from the evidence on Cu-IUDs and other LNG-containing products. Balance is in favour of benefits of IUDs CHCs Contraception is a life-saving intervention with well recognized health, social and economic benefits. All hormonal contraceptives are effective or highly effective, reversible methods. Low-moderate quality evidence from 11 observational studies suggested no association between combined oral contraceptive (COC) use (it was assumed that studies that did not specify oral contraceptive type examined mostly, if not exclusively, COC use) and HIV acquisition.a,b While no direct evidence was available for combined contraceptive patch, combined contraceptive vaginal ring or combined injectable contraceptive, indirect evidence from COCs was used given that there was no biological or clinical reason to believe that a lower hormonal dose, different delivery mechanism, or different progestogen would modify HIV risk. Balance is in favour of benefits of CHCs | Contraceptive eligibility for women at high risk of HIV: guidance statement22 Factor Explanation/evidence Judgement Values and preferences Women have the right to informed decision-making. Women prefer to have choice in methods, full information regarding benefits versus harms, and to make a final decision in conjunction with their provider (informed decision-making). Contraception is unique among medicines because a woman’s needs and preferences with regard to the characteristics of contraceptive methods will vary both between individual women and across a single individual’s lifespan. Common themes in contraceptive preferences include that they are discreet, have minimal side-effects and are long-acting, reversible and easy to use. Women who use progestogen-only injectables generally like them for these reasons, and feel comfortable using them after counselling. Women’s preferences for methods are limited by what they have knowledge of, what is available to them and other factors that foster or limit access. Offering women the choice of a range of methods is important from both a health and a rights perspective. Support for optimizing informed contraceptive choice and the availability of a wide range of contraceptive options Priority of the problem HIV is a serious illness and a major global epidemic. Unintended pregnancy is a very common problem globally, and the risks associated with it are highest where maternal mortality and severe morbidity are also common. Both are priorities for public health. Effective contraception and HIV prevention are both public health priorities Equity and human rights Human rights principles and standards from existing World Health Organization (WHO) guidelines on human rights and contraception were followed by the Guideline Development Group (GDG) in its deliberations. These include non-discrimination, availability, accessibility, acceptability, quality, informed decision-making, privacy and confidentiality, participation, and accountability. During its deliberations, the GDG considered both potential positive and negative effects of its considerations. For example, it considered and emphasized the continuing need for integrated family planning and HIV services in settings with high HIV incidence. It also emphasized the need for expanding and optimizing contraceptive options. Recommendations within WHO’s human rights guidance for contraception are paramount principles for decision-making on this topic Feasibility The importance of clear communication from WHO on this topic was underscored. This was reinforced by recent studies that suggested that messages based on the 2017 WHO guidance were difficult to explain and may not be fully understood by clients or providers. Clear guidance and a woman-centred approach are essential for successful implementation References: a. Polis CB, Curtis KM, Hannaford PC, Phillips SJ, Chipato T, Kiarie JN et al. An updated systematic review of epidemiological evidence on hormonal contraceptive methods and HIV acquisition in women. AIDS. 2016;30(17):2665–83. doi: 10.1097/ QAD.0000000000001228. b. Sabo MC, Richardson BA, Lavreys L, Martin HL, Jr, Jaoko W, Mandaliya K et al. Does bacterial vaginosis modify the effect of hormonal contraception on HIV seroconversion. AIDS. 2019;33(7):1225–30. doi: 10.1097/QAD.0000000000002167. c. Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium. HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial. Lancet. 2019;394(10195):303–13. doi: 10.1016/S0140-6736(19)31288-7. d. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619–22. doi: 10.1097/ QAD.0000000000002260. e. Lavreys L, Baeten JM, Martin Jr HL, Overbaugh J, Mandaliya K, Ndinya-Achola J et al. Hormonal contraception and risk of HIV-1 acquisition: results of a 10-year prospective study. AIDS. 2004;18(4):695–7. Contraceptive eligibility for women at high risk of HIV: guidance statement | 23 ANNEX 5: SYSTEMATIC REVIEWS Three systematic reviews were conducted as part of the development of this guidance statement. The details of the methods and search strategies are included in the reviews. Reviews published in peer-reviewed journals are available through open access. This appendix will be periodically updated as reviews are published. Access to unpublished reviews can be requested by sending an email to hrx-info@who.int. 1. Hormonal contraceptive method use and HIV acquisition in women There was a previously published review on hormonal contraceptive use and HIV acquisition. The search strategies from that review were used to search for new evidence since. The following four new publications were identified that met the inclusion criteria. PREVIOUSLY PUBLISHED REVIEW 1. Polis CB, Curtis KM, Hannaford PC, Phillips SJ, Chipato T, Kiarie JN et al. An updated systematic review of epidemiological evidence on hormonal contraceptive methods and HIV acquisition in women. AIDS. 2016;30(17):2665–83. doi: 10.1097/ QAD.0000000000001228. UNPUBLISHED REVIEW 1. Curtis KM, Hannaford PC, Rodriguez MI, Chipato T, Steyn PS, Kiarie JN. Hormonal contraceptive method use and HIV acquisition in women: an updated systematic review. Working paper developed for the World Health Organization meeting. July 2019. NEW ARTICLES 1. Haddad LB, Wall KM, Kilembe W, Vwalika B, Khu NH, Brill I et al. Bacterial vaginosis modifies the association between hormonal contraception and HIV acquisition. AIDS. 2018;32(5):595–604. doi: 10.1097/ QAD.0000000000001741. 2. Hofmeyr GJ, Singata-Madliki M, Lawrie TA, Bergel E, Temmerman M. Effects of injectable progestogen contraception versus the copper intrauterine device on HIV acquisition: sub-study of a pragmatic randomised controlled trial. J Fam Plann Reprod Health Care. 2017;43(3):175–80. doi: 10.1136/jfprhc-2016-101607. 3. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619– 22. doi: 10.1097/QAD.0000000000002260. 4. Sabo MC, Richardson BA, Lavreys L, Martin HL, Jr., Jaoko W, Mandaliya K et al. Does bacterial vaginosis modify the effect of hormonal contraception on HIV seroconversion. AIDS. 2019;33(7):1225-30. doi: 10.1097/ QAD.0000000000002167. 2. Copper-bearing intrauterine device (Cu-IUD) use and HIV acquisition in women A systematic review was conducted on Cu-IUD use and HIV acquisition in women. The following six articles met the inclusion criteria. UNPUBLISHED REVIEW 1. Hannaford PC, Ti A, Chipato T, Curtis KM. Copper intrauterine device use and HIV acquisition in women: an updated systematic review. Working paper developed for the World Health Organization meeting. July 2019. NEW ARTICLES 1. Hofmeyr GJ, Singata-Madliki M, Lawrie TA, Bergel E, Temmerman M. Effects of injectable progestogen contraception versus the copper intrauterine device on HIV acquisition: sub-study of a pragmatic randomised controlled trial. J Fam Plann Reprod Health Care. 2017;43(3):175–80. doi: 10.1136/jfprhc-2016-101607. 2. Kapiga SH, Lyamuya EF, Lwihula GK, Hunter DJ. The incidence of HIV infection among women using family planning methods in Dar es Salaam, Tanzania. AIDS. 1998;12(1):75–84. doi: 10.1097/00002030-199801000-00009. 3. Lavreys L, Baeten JM, Martin Jr HL, Overbaugh J, Mandaliya  K, Ndinya-Achola J et al. Hormonal contraception and risk of HIV-1 acquisition: results of a 10-year prospective study. AIDS. 2004;18(4):695–7. 4. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619– 22. doi: 10.1097/QAD.0000000000002260. 5. Saracco A, Musicco M, Nicolosi A, Angarano G, Arici C, Gavazzeni G et al. Man-to-woman sexual transmission of HIV: longitudinal study of 343 steady partners of infected men. J Acquir Immune Defic Syndr. 1993;6(5):497-502. 6. Sinei SK, Fortney JA, Kigondu CS, Feldblum PJ, Kuyoh M, Allen MY et al. Contraceptive use and HIV infection in Kenyan family planning clinic attenders. Int J STD AIDS. 1996;7(1):65–70. doi: 10.1258/0956462961917104. 3. Contraceptive values and preferences A systematic review was conducted on contraceptive values and preferences. The protocol and methods are published, and the manuscript presenting the main results of the review is under review for publication. As this review did not identify information specific to key populations at risk of HIV, consultative engagements were conducted in the spring of 2019, including a global online survey of sex workers, and participatory focus group discussions with female sex workers | Contraceptive eligibility for women at high risk of HIV: guidance statement24 in Zimbabwe through the Sisters with a Voice programme. Presentations showing the findings from these engagements are listed below and available on request. A presentation shared by stakeholders representing affected populations to highlight their perspectives on the topic was part of the Guideline Development Group’s discussions and is available on request. 1. Kennedy CE, Yeh PT, Gaffield ME. Contraception values and preferences: protocol and methods for a global systematic review. Contraception. 2019 (in press). doi: 10.1016/j. contraception.2018.05.006Get. 2. Yeh PT, Kennedy CE, Gaffield ME. Contraception values and preferences: a global systematic review. Contraception. 2019; (accepted pending revisions). 3. Shapiro A. Female sex workers’ contraceptive practices, values and preferences. contraception and risk of HIV infection: a WHO Guideline Development Group review of the current evidence. 29 July 2019, Geneva, World Health Organization. 4. Sibanda E. Views on contraceptive methods among female sex workers in Harare, Zimbabwe: a participatory qualitative study. 29 July 2019, Geneva, World Health Organization. 5. Mworeko L. What do recommendations on contraceptives and HIV risk mean to women?, 29 July 2019, Geneva, World Health Organization.

For more information, please contact: Department of Reproductive Health and Research, World Health Organization, Avenue Appia 20, CH-1211 Geneva 27, Switzerland. E-mail: reproductivehealth@who.int www.who.int/reproductivehealth

Contraceptive eligibility for women at high risk of HIV Guidance statement Recommendations on contraceptive methods used by women at high risk of HIV

Contraceptive eligibility for women at high risk of HIV Guidance statement Recommendations on contraceptive methods used by women at high risk of HIV Contraceptive eligibility for women at high risk of HIV. Guidance statement: recommendations on contraceptive methods used by women at high risk of HIV ISBN 978-92-4-155057-4 © World Health Organization 2019 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. Contraceptive eligibility for women at high risk of HIV. Guidance statement: recommendations on contraceptive methods used by women at high risk of HIV. Geneva: World Health Organization; 2019. Licence: CC BY- NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris. Sales, rights and licensing. To purchase WHO publications, see http://apps.who.int/bookorders. To submit requests for commercial use and queries on rights and licensing, see http://www.who.int/about/licensing. Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. The views expressed in this publication are those alone of the named authors and of the collective views of an international group of experts and do not necessarily represent the decisions or the policies of WHO. Printed in Switzerland Contraceptive eligibility for women at high risk of HIV: guidance statement | iii 1 2 3 4 5 ACKNOWLEDGEMENTS V ABBREVIATIONS VI EXECUTIVE SUMMARY VII BACKGROUND 1 METHODS OF GUIDELINE REVIEW AND DEVELOPMENT 2 2.1 Guideline Development Group 2 2.2 Guideline development process 2 2.3 Evidence Retrieval 3 2.4 Evidence Synthesis 4 2.5 Formulation of recommendations 4 SUMMARY OF THE EVIDENCE 4 3.1 Progestogen-only injectables 5 3.2 Progestogen-only implants 5 3.3 Progestogen-only pills 5 3.4 Intrauterine devices 5 3.5 Combined hormonal contraceptives 5 3.6 Additional evidence considered by the GDG 5 3.6.1 Biological data 5 3.6.2 Values and preferences of contraceptive users 6 RECOMMENDATIONS 6 4.1 Recommendations for contraceptive use among women at high risk of HIV infection 6 4.2 Rationale 7 IMPLICATIONS FOR POLICY-MAKERS, PROGRAMME MANAGERS AND HEALTH-CARE PROVIDERS 8 5.1 A woman’s risk of HIV should not restrict her contraceptive choice 8 5.2 Efforts to expand access to contraceptive options must continue 8 5.3 A renewed emphasis on HIV and STI prevention services is urgently needed 9 CONTENTS | Contraceptive eligibility for women at high risk of HIV: guidance statementiv CONTENTS (continued) KNOWLEDGE GAPS AND AREAS FOR RESEARCH 9 6.1 Contraceptive methods and HIV acquisition 9 6.2 HIV prevention 9 6.3 Community involvement 10 6.4 Increased funding for high-quality, policy-relevant research 10 DISSEMINATION OF THIS GUIDANCE STATEMENT 10 REFERENCES 11 ANNEX 1. GUIDELINE DEVELOPMENT GROUP AND EVIDENCE SECRETARIAT 13 ANNEX 2. DECLARATIONS OF CONFLICTS OF INTEREST 15 ANNEX 3. GRADE EVIDENCE PROFILES 17 ANNEX 4. EVIDENCE-TO-DECISION TABLE FOR HORMONAL CONTRACEPTIVE METHODS AND INTRAUTERINE DEVICES (IUDS) 21 ANNEX 5: SYSTEMATIC REVIEWS 23 6 7 Contraceptive eligibility for women at high risk of HIV: guidance statement | v ACKNOWLEDGEMENTS The World Health Organization (WHO) would like to thank the members of the Guideline Development Group and the Evidence Secretariat (Annex 1) for their contributions throughout the development of these important recommendations for women at high risk of HIV. WHO is very grateful for the suggestions provided by colleagues who peer reviewed the draft statement as members of the External Review Group. The development of this technical statement was financially supported by the Bill & Melinda Gates Foundation, the Netherlands Ministry of Foreign Affairs, the United States Agency for International Development, and the United States National Institutes of Health. | Contraceptive eligibility for women at high risk of HIV: guidance statementvi ABBREVIATIONS CIC combined injectable contraceptive COC combined oral contraceptive CRE WHO Office of Compliance, Risk Management and Ethics Cu-IUD copper-bearing intrauterine device DMPA depot medroxyprogesterone acetate DMPA-IM intramuscular depot medroxyprogesterone acetate DMPA-SC subcutaneous depot medroxyprogesterone acetate ECHO Evidence for Contraceptive Options and HIV Outcomes (Study) ETG etonogestrel FDA United States Food and Drug Administration GDG Guideline Development Group GRADE Grading of Recommendations Assessment, Development and Evaluation HR hazard ratio IRR incidence rate ratio IUD intrauterine device LNG levonorgestrel LNG-IUD levonorgestrel-releasing intrauterine device MEC Medical eligibility criteria for contraceptive use NET-EN norethisterone enanthate OTC over the counter POP progestogen-only pill PrEP pre-exposure prophylaxis (for HIV) RCT randomized clinical trial STI sexually transmitted infection WHO World Health Organization Contraceptive eligibility for women at high risk of HIV: guidance statement | vii EXECUTIVE SUMMARY The World Health Organization (WHO) convened a Guideline Development Group (GDG) meeting from 29 to 31 July 2019 to review global guidance on contraceptive eligibility for women at high risk of HIV acquisition to and determine whether revisions to the fifth edition of the Medical eligibility criteria for contraceptive use (MEC) were needed. The issue was deemed critical, particularly for sub-Saharan Africa, given the high lifetime risk of acquiring HIV alongside the importance of hormonal contraception in offering women and adolescent girls’ choice and in reducing their risk of unintended pregnancy, a common threat to the health, well-being and lives of women and adolescent girls. The GDG consisted of 28 participants from 19 countries, including experts in family planning and HIV, representatives from affected populations, clinicians, epidemiologists, researchers, programme managers, policy-makers and guideline methodologists. The GDG considered the following factors when formulating recommendations for each contraceptive method: ■ quality of the evidence (i.e. GRADE profile)1 ■ values and preferences of contraceptive users ■ balance of benefits and harms ■ priority of the problem ■ equity and human rights ■ feasibility. In formulating these recommendations, the GDG kept at the centre of their deliberations the individuals most affected by the recommendations – that is, those women wanting to prevent pregnancy who are at a high risk of HIV acquisition. Through consensus, the GDG agreed to the following new recommendations. These revisions mean that women at a high risk of HIV can use all methods of contraception without restriction. ■ Women at a high risk of HIV infection are eligible to use all progestogen-only contraceptive methods without restriction (MEC Category 1), including progestogen-only pill (POPs), intramuscular and subcutaneous depot medroxyprogesterone acetate (DMPA-IM and DMPA-SC), norethisterone enanthate (NET-EN), levonorgestrel (LNG) implants and etonogestrel (ETG) implants. ■ Women at a high risk of HIV infection are eligible to use copper-bearing intrauterine devices (Cu-IUDs) and LNG- IUDs without restriction (MEC Category 1). In considering the 1 GRADE = Grading of Recommendations Assessment, Development and Evaluation (for further information, see: http://www.gradeworkinggroup.org). use of IUDs, many women at a high risk of HIV are also at risk of other sexually transmitted infections (STIs); for these women, providers should refer to the MEC recommendation on women at an increased risk of STIs, and the Selected practice recommendations for contraceptive use: third edition on STI screening before IUD insertion. ■ Women at a high risk of HIV infection are eligible to use all combined hormonal contraceptive methods without restriction (MEC Category 1), including combined oral contraceptives (COCs), combined injectable contraceptives (CICs), combined contraceptive patches and combined vaginal rings. These recommendations were strongly informed by new epidemiological evidence, particularly from one high-quality randomized clinical trial (the ECHO trial), which did not demonstrate a statistically significant difference in HIV acquisition among women using the three contraceptive methods studied: DMPA-IM, Cu-IUDs and LNG implants. This high-quality evidence superseded the previously available observational evidence of low and low-to-moderate quality. For COCs and NET-EN injectables, evidence of low and low-to- moderate quality from observational studies indicated no increased risk of HIV infection. While no direct evidence was available for DMPA-SC, LNG-IUDs or ETG implants, there was no biological or clinical reason to believe that a lower hormonal dose, different delivery mechanism or different progestogen would modify HIV risk. A consideration of women’s values, preferences, views and concerns regarding contraceptive methods provided support for optimizing informed contraceptive choice and the availability of a wide range of contraceptive options. There are several key messages from this guidance for policy- makers, programme managers and health-care providers. ■ A woman’s risk of HIV does not restrict her contraceptive choice. ■ Efforts to expand contraceptive method options and ensure full and equitable access to family planning services must continue. ■ A renewed emphasis on HIV/STI testing and prevention services is urgently needed, including the integration of family planning and HIV/STI services as appropriate, along with sexual and reproductive health packages. | Contraceptive eligibility for women at high risk of HIV: guidance statementviii PROGESTOGEN-ONLY CONTRACEPTIVES Progestogen-only contraceptives (POCs) do not protect against sexually transmitted infections (STIs), including HIV. If there is a risk of STI/HIV, the correct and consistent use of condoms is recommended. When used correctly and consistently, condoms offer one of the most effective methods of protection against STIs, including HIV. Female condoms are effective and safe, but are not used as widely as male condoms by national programmes. Condition MEC category Clarification/evidence POP DMPA/ NET-EN LNG/ ETG High risk of HIV 1 1 1 EVIDENCE: High-quality evidence from one randomized clinical trial observed no sta- tistically significant differences in HIV acquisition between: DMPA-IM versus Cu-IUD, DMPA-IM versus LNG implant, and Cu-IUD versus LNG implant. Of the low-to-mod- erate-quality evidence from 14 observational studies, some studies suggested a pos- sible increased risk of HIV with progestogen-only injectable use, which was most likely due to unmeasured confounding. Low-quality evidence from 3 observational studies did not suggest an increased HIV risk for implant users. No studies of sufficient quality were identified for POPs. Cu-IUD: copper-bearing intrauterine device; DMPA: depot medroxyprogesterone acetate (injectable); IM: intramuscular; LNG/ETG: levonorgestrel and etonogestrel (implants); MEC: Medical eligibility criteria for contraceptive use; NET-EN: norethisterone enanthate (injectable); POP: progestogen-only pill INTRAUTERINE DEVICES Intrauterine devices (IUDs) do not protect against sexually transmitted infections (STIs), including HIV. If there is a risk of STI/HIV, the correct and consistent use of condoms is recommended. When used correctly and consistently, condoms offer one of the most effective methods of protec- tion against STIs, including HIV. Female condoms are effective and safe, but are not used as widely as male condoms by national programmes. Condition MEC category Clarification/evidence Cu-IUD LNG-IUD (20 μg/24 hours) High risk of HIV Initiation Continuation Initiation Continuation CLARIFICATION: Many women at a high risk of HIV are also at risk of other STIs. For these women, refer to the recommendation in the Medical eligibility criteria for contra- ceptive use on women at an increased risk of STIs, and the Selected practice recommendations for contraceptive use on STI screening before IUD insertion. EVIDENCE: High-quality evidence from one randomized clinical trial, along with low-quality evidence from two observational studies, suggested no increased risk of HIV acquisition with Cu-IUD use. No studies were identified for LNG-IUDs. 1 1 1 1 Cu-IUD: copper-bearing intrauterine device; LNG-IUD: levonorgestrel-releasing IUD; MEC: Medical eligibility criteria for contraceptive use COMBINED HORMONAL CONTRACEPTIVES Combined hormonal contraceptives (CHCs) do not protect against sexually transmitted infections (STIs), including HIV. If there is a risk of STI/ HIV, the correct and consistent use of condoms is recommended. When used correctly and consistently, condoms offer one of the most effective methods of protection against STIs, including HIV. Female condoms are effective and safe, but are not used as widely as male condoms by national programmes. Condition MEC category Clarification/evidence COC P CVR CIC High risk of HIV 1 1 1 1 EVIDENCE: Low-to-moderate-quality evidence from 11 observational studies suggested no association between COC use (it was assumed that studies that did not specify oral contraceptive type examined mostly, if not exclusively, COC use) and HIV acquisition. No studies of P, CVR or CIC were identified. COC: combined oral contraceptive; CIC: combined injectable contraceptive; CVR: combined contraceptive vaginal ring; MEC: Medical eligibility criteria for contraceptive use; P: combined contraceptive patch Contraceptive eligibility for women at high risk of HIV: guidance statement | 1 Access to sexual and reproductive health services and information, including a comprehensive range of contraceptive methods, is fundamental to the rights and well-being of women and adolescent girls (1–4). There is a wide range of hormonal and non-hormonal modern contraceptive methods providing substantial individual and public health benefits. A core part of the work of the World Health Organization (WHO) is the development and maintenance of up-to-date, evidence-based guidance on contraceptive safety for individuals with particular medical conditions or medically relevant characteristics (5). The Medical eligibility criteria for contraceptive use (the MEC), fifth edition, offers national policy-makers and family planning programmes a comprehensive set of recommendations on the medical safety of contraceptive methods, allowing for the informed development of national policies, protocols and programmes (5). Global guidance about medical safety and eligibility facilitates the removal of unnecessary medical barriers to contraception. For over 20 years, the MEC has been used by countries to maximize safety and improve the quality of contraceptive care offered. Guidance about safety is kept up to date through continuous monitoring and reviews of published literature. In 2015, WHO released the fifth edition of the MEC (5). This edition contains more than 2000 recommendations for 25 different contraceptive methods, within the context of more than 80 medical conditions or medically relevant personal characteristics. Depending on the individual, more than one condition may need to be considered when making an informed contraceptive choice (5). The recommendations in the MEC are based on several considerations, including whether the use of a contraceptive method worsens the medical condition or creates additional health risks, and whether the condition makes the contraceptive method less effective (5). The MEC is part of a set of tools aiming to improve contraceptive coverage and care throughout the world. The MEC informs decisions about who might use a particular contraceptive method, through information and guidance about the safety and appropriateness of contraceptive care. The Selected practice recommendations for contraceptive use (the SPR) provides guidance on how to safely and effectively use various contraceptive methods (6). WHO produces a range of tools to support the use and implementation of contraceptive guidance, such as the MEC wheel and the Global handbook for providers (7, 8). Since 1996, the MEC has applied a four-category scale to indicate medical eligibility for particular contraceptive methods in the presence of particular conditions or individual characteristics (e.g. at high risk of HIV). For each condition or characteristic, contraceptive methods are placed into one of four numbered categories: 1. A condition for which there is no restriction for the use of contraceptive method. 2. A condition where the advantages of using the method generally outweigh the theoretical or proven risks. 3. A condition where the theoretical or proven risks usually outweigh the advantages of using the method. 4. A condition which represents an unacceptable health risk if the contraceptive method is used. The interpretation and application of the categories in practice are shown in Table 1. In the past, there has been mixed evidence about whether hormonal contraceptive methods – particularly depot medroxyprogesterone acetate (DMPA) – are associated with an increased risk of HIV acquisition. The available evidence consisted of theoretical biological data and observational studies with important limitations. In 2016, the independent TABLE 1. INTERPRETATION AND APPLICATION OF THE MEDICAL ELIGIBILITY CRITERIA (MEC) CATEGORIES Category With good resources for clinical judgement With limited resources for clinical judgement 1 Use the method in any circumstances Yes, use the method 2 Generally use the method 3 Use of the method not usually recommended unless more appropriate methods are not available or not acceptable No, do not use the method 4 Method not to be used BACKGROUND1 | Contraceptive eligibility for women at high risk of HIV: guidance statement2 2.1 Guideline Development Group The development of this guidance statement was undertaken by the independent Guideline Development Group (GDG) and an additional panel of external reviewers. The GDG consisted of 28 participants from 19 countries, including experts in family planning and HIV, representatives from affected populations, clinicians, epidemiologists, researchers, programme managers, policy- makers and guideline methodologists (see Annex 1). Following WHO guidance, months prior to the July 2019 meeting of the GDG, the name and brief biography of each proposed GDG member was published at the WHO website (https://www.who. int/reproductivehealth/publications/contraceptives-methods-hiv). The public was able to view and provide input on any perceived or real conflicts of interest of the proposed members. WHO responded to all comments and accordingly adjusted the final composition of the GDG. Prior to the GDG meeting, the WHO Secretariat and the GDG reviewed the members’ declarations of interests (Annex 2) and found no conflicts of interest sufficient to preclude anyone from participating in the deliberations or the development of the recommendations. The members of the GDG were also asked to declare any new conflicts of interest at the start of the meeting. None were declared. 2 For further information, see: http://www.gradeworkinggroup.org 2.2 Guideline development process This guidance statement was prepared according to the standards and requirements specified in the WHO handbook for guideline development (11). This process is used to ensure that WHO guidelines are of the highest quality and follow a transparent, systematic process. Key steps of the guideline process include determining the critical questions and outcomes, retrieving the evidence, synthesizing and grading the evidence, presenting it using a structured approach, and formulating recommendations. WHO’s Family Planning Guideline Steering Group determined the critical questions and outcomes to be considered by the GDG. Distinct types of evidence were identified as essential to review. These included the health evidence (randomized trials and observational epidemiological data), the evidence on biological plausibility and the data on the values and preferences of contraceptive users. Applying the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach,2 multiple factors are considered when formulating recommendations (12). These include the quality of the epidemiological evidence (found in the GRADE evidence profiles, which are prepared based on up-to-date Guideline Development Group (GDG) for the MEC reviewed the accumulating evidence regarding women at high risk of acquiring HIV (9). The GDG concluded that there remained uncertainty about whether the increased risk of HIV acquisition seen in some observational studies was a real effect of the contraceptive method used or whether it was a statistical artefact resulting from key limitations of observational studies (residual confounding in particular) (9). There also continued to be uncertainty about the clinical relevance of the biological data. In addition, there was concern that previous attempts to inform women of the uncertainty about both the epidemiological and biological data (through the use of a MEC clarification, indicated by an asterisk [*]) had not been effective. Given these concerns, the GDG concluded that MEC guidance should be changed. Thus, in 2017, the recommendation for progestogen- only injectable use among women at high risk of HIV infection was changed from MEC Category 1* (no restrictions to use, with a clarification) to MEC Category 2 (the benefits of use outweigh the risks), with an accompanying clarification (9). This new classification indicated that progestogen-only injectables could be used by women at high risk of HIV, because the advantages of these methods generally outweighed the possible disadvantages, and it highlighted that, when choosing these methods, there might need to be extra consideration of possible HIV acquisition, and counselling. As part of the 2017 revision, WHO reaffirmed its commitment to monitoring and assessing any new evidence relevant to contraceptive safety. New information, including results from a large, multinational randomized clinical trial (RCT) (10), led WHO to convene another GDG meeting in July 2019 to review all the available evidence and assess whether the MEC guidance needed revision. METHODS OF GUIDELINE REVIEW AND DEVELOPMENT2 Contraceptive eligibility for women at high risk of HIV: guidance statement | 3 systematic reviews); the values and preferences of contraceptive users; the balance of benefit and harms; the priority of the problem; equity and human rights; acceptability; and feasibility. The human rights principles and standards described in WHO’s guidance, Ensuring human rights in the provision of contraceptive information and services, were incorporated into deliberations (1). Owing to the focus on contraceptive safety, opportunity costs were not formally assessed during the formulation of the recommendations, since costs may vary widely throughout different regions (13). The GRADE evidence-to-decision framework (a tool encompassing quality of evidence, balance of benefits versus harms, values and preferences, priority of the problem, equity and human rights, feasibility) was used to ensure that recommendations were based on the consideration of all standards (11). 2.3 Evidence Retrieval Existing WHO recommendations on the use of specific contraceptive methods by women at high risk of HIV were reviewed in accordance with procedures outlined by the WHO Guidelines Review Committee and the GRADE approach to evidence review (11, 12). Three systematic reviews were conducted in preparation for the GDG meeting: two reviews pertained to the epidemiological evidence and the third review synthesized qualitative or quantitative studies on users’ values, preferences, views and concerns regarding contraceptive methods. The two systematic reviews of epidemiological evidence conducted for the GDG meeting were: 1. An updated systematic review on hormonal contraception and risk of HIV acquisition was conducted to include new studies published since 2016, when the last systematic review was undertaken (14). The review question was: ■ Among women at risk of HIV, does use of a hormonal contraceptive method compared with non-use of a hormonal contraceptive method (or use of another specific hormonal contraceptive method) increase risk of HIV acquisition? 2. A systematic review on copper-bearing intrauterine device (Cu-IUD) use and risk of HIV acquisition was also conducted. The review questions were: ■ Among women at risk of HIV, does use of a Cu-IUD compared with use of another non-hormonal contraceptive method or no contraceptive method increase risk of HIV acquisition? ■ Among women at risk of HIV, does use of a Cu-IUD compared with use of a specific hormonal contraceptive method increase risk of HIV acquisition? The selection criteria for the systematic reviews are listed in Table 2. The same study designs, population, comparators and outcomes were considered for all the contraceptive methods reviewed. TABLE 2. SELECTION CRITERIA FOR THE SYSTEMATIC REVIEWS Study design Longitudinal studies (randomized clinical trials and observational studies or meta-analyses containing data not captured in bibliographic database searches) Population Women of reproductive age at risk of HIV infection (women who were not living with HIV at baseline) Intervention Use of a specific contraceptive method: ■ hormonal contraception (injectables, oral contraceptives, implants, patches, rings or levonorgestrel-releasing intrauterine devices) ■ copper-bearing intrauterine devices (Cu-IUDs) Comparator One of two comparison groups: 1. non-use of a hormonal contraceptive method (either no contraceptive use or use of a non-hormonal method such as condoms or other barrier method, withdrawal, Cu-IUD or tubal ligation/vasectomy) 2. use of another specific method of hormonal contraception Outcome Incident, laboratory-confirmed HIV infection in women The two systematic reviews were conducted according to the preferred reporting items for systematic reviews and meta- analyses (PRISMA) (15). The PubMed and Embase databases were searched for studies published in any language in the peer-reviewed literature up to 26 June 2019. For individual studies, the risk of bias was assessed using a quality framework described in the previous review (14). Studies were classified into three levels: 1. “Unlikely to inform the primary question”: studies that had (a) no adjustment for any measure of condom use or (b) unclear measurement of exposure to contraception. 2. “Informative but with important limitations”: studies that had none of the flaws described above, but that still had the potential for unmeasured or residual confounding. 3. “Informative with few limitations”: studies that had none of the above flaws – likely to be a randomized clinical trial (RCT) that was assessed as having a low risk of bias on standard criteria for evaluating RCTs. The focus of the systematic reviews was on information from studies that were considered “informative but with important limitations” or “informative with few limitations.” to fall into levels 2 and 3. The values and preferences of contraceptive users were incorporated in multiple ways. First, an updated systematic review of qualitative or quantitative studies on users’ values, preferences, views and concerns regarding the contraceptive methods considered under the Medical eligibility criteria for contraceptive use (MEC) guidelines was conducted (16). This review covered studies from any country published in the peer-reviewed literature between January 2005 and December 2017. Just prior to the GDG meeting in July 2019, this review was informally updated for studies in either the peer-reviewed or grey literature that specifically looked at the values and preferences of contraceptive users relating to the issue of hormonal contraception and HIV acquisition. Second, because | Contraceptive eligibility for women at high risk of HIV: guidance statement4 the updated systematic review did not identify any information specific to key populations at risk of HIV, consultative engagements were conducted in May through July of 2019, including a global online survey of sex workers and participatory focus group discussions with female sex workers in Zimbabwe (through the Sisters with a Voice programme). Third, stakeholders representing specific affected populations, including women living with HIV, and young women, contributed their perspectives through a presentation and discussion of critical perspectives at the GDG meeting. An update about the biological data on the theoretical effect that contraception may have on HIV acquisition was prepared, reviewed and discussed at the GDG meeting, including consideration of the theoretical plausibility of individual methods of hormonal contraception having an influence on HIV acquisition. 2.4 Evidence Synthesis Epidemiological data were synthesized and evaluated according to the GRADE approach to evidence review (12). Based on this, randomized trials begin with a grade for strength of evidence of “high”, and observational studies start with a grade of “low”. The risk of bias was assessed for the summarized data using standard GRADE methods (17). Factors that could lower the evidence grade were limitations in the evidence (bias), inconsistency between studies, imprecision of estimates, indirectness of evidence, and publication bias (17–22). Randomized trials were assessed for bias by systematically evaluating for inadequate randomization/ allocation concealment; inadequate blinding of treatments; attrition and failure to use intention-to-treat analyses; selective outcome reporting; and crossover/contamination (17). Observational studies were assessed for bias by examining whether there was failure to develop and apply appropriate eligibility criteria, flawed measurement of exposures or outcomes, failure to adequately address confounding, or incomplete follow-up (17). Factors that could increase the evidence grade of observational studies included the presence of a dose-response relationship, a large magnitude of observed associations, and adjustment for plausible confounders affecting observed associations (22). 2.5 Formulation of recommendations Findings from the systematic reviews and associated GRADE evidence profiles (Annex 3) were presented at the GDG meeting. A presentation on the biological plausibility of hormonal contraception modifying the risk of HIV acquisition, and several presentations on contraceptive users’ values and preferences, were also given. These inputs were used to develop an evidence-to-decision framework (Annex 4), which served as the basis for the GDG’s deliberations during the meeting (12). All recommendations were arrived at by consensus. After the GDG’s recommendations were made, a small writing group prepared a draft guidance statement summarizing the decision and associated rationale. The draft was reviewed by the entire GDG and the external review group (see Annex 1). Comments received from the GDG and the external review group were considered and addressed by the writing group. The final version of this guidance statement was approved by the WHO Guidelines Review Committee on 22 August 2019. SUMMARY OF THE EVIDENCE3 The Evidence for Contraceptive Options and HIV Outcomes (ECHO) Study3 was the primary source of new evidence since the WHO last reviewed recommendations on contraception for women at high risk of HIV (9). The ECHO Study was a large randomized clinical trial (RCT) conducted in Eswatini, Kenya, South Africa and Zambia specifically designed to compare HIV incidence among users of three contraceptive methods: intramuscular depot medroxyprogesterone acetate (DMPA-IM), levonorgestrel (LNG) implants and copper-bearing intrauterine 3 For further information, see: http://echo-consortium.com devices (Cu-IUDs) (10). The trial randomized 7829 HIV- seronegative women, aged between 16 and 35 years, who desired effective contraception and consented to be randomized to one of the three contraceptive methods. There was no group of non-users of contraception in the ECHO trial because all of the women enrolled desired effective contraception. Women returned every three months for HIV testing, contraceptive counselling, safety monitoring, behavioural assessment and a comprehensive package of HIV Contraceptive eligibility for women at high risk of HIV: guidance statement | 5 prevention services; for up to 18 months. The main (primary) comparisons used a modified intention-to-treat analysis. In addition, pre-planned (secondary) analyses were conducted, restricted to continuous use of the assigned contraceptive method and adjusted for a number of important confounders, including vaginal sex without a condom, a new sexual partner in the previous three months, and more than one sexual partner. Statistical significance in the ECHO trial was taken to be a P-value less than 0.04 for the primary comparisons. No statistically significant associations were found for any of the primary comparisons between the three contraceptive methods (Annex 3). The quality of the evidence from this RCT was rated as high, due to its large size, strong randomization and allocation procedures, high follow-up rates, high continuation of the allocated contraceptive method, objective measurement of HIV incidence and comprehensive analysis of the results. Other evidence on hormonal contraception and HIV acquisition published since the 2016 review (14) was included in the evaluation of the body of evidence, along with a systematic review on Cu-IUDs and risk of HIV acquisition (Annex 3). For hormonal contraception, one new observational study and updated estimates from a previously included study were identified (23, 24). Adding this evidence to the previous 14 observational studies (14) did not change the conclusions of the previous review. Thus, the body of observational evidence suggested some concern about an increased risk of HIV acquisition with DMPA-IM use, but was generally reassuring for other methods of hormonal contraception. For intrauterine devices (IUDs), two observational studies did not suggest an increased risk of HIV acquisition with Cu-IUD use (23, 25). The quality of evidence from these observational studies was rated as low and low-to-moderate. 3.1 Progestogen-only injectables One RCT (the ECHO trial) observed no statistically significant differences in HIV acquisition when comparing DMPA-IM versus Cu-IUD, and DMPA-IM versus LNG implant (10). The quality of the evidence from this RCT was rated as high. Evidence from 14 observational studies of DMPA-IM, norethisterone enanthate (NET-EN) or unspecified progestogen- only injectables considered to be “informative but with important limitations” was assessed (14, 23, 24). Additional data from one new observational study and updated estimates from a previously included study did not change the conclusions of the previous review of observational evidence (14). The quality of the evidence from the observational studies was rated as low and low-to-moderate due to limitations that included unmeasured confounding. 3.2 Progestogen-only implants Three observational studies considered to be “informative but with important limitations” assessed implants. One had been included in the previous review (26), one provided an updated point estimate to that used for the previous review (24) and one provided an entirely new estimate of risk (23). Two of the studies assessed LNG implants (24, 26) and the third assessed women using either LNG or etonogestrel implants (23). None of the three studies suggested an increased risk of HIV acquisition with implant use, consistent with the conclusion of the previous review (14). The quality of the evidence from these studies was rated as low. 3.3 Progestogen-only pills No studies considered “informative but with important limitations” or “informative with few limitations” were identified for progestogen-only pills. 3.4 Intrauterine devices One RCT (the ECHO trial) observed no statistically significant differences in HIV acquisition between DMPA-IM and Cu-IUD, or Cu-IUD and LNG implants (10). The quality of the evidence from this RCT was rated as high. Two observational studies considered “informative but with important limitations” did not observe an association with HIV acquisition when comparing Cu-IUD use with tubal ligation or no contraceptive method use, DMPA-IM, NET-EN or implants (23, 25). The quality of this observational evidence was rated as low. No evidence was identified for LNG-IUDs. 3.5 Combined hormonal contraceptives Eleven observational studies deemed “informative but with important limitations” assessed the use of combined oral contraceptives (COC). (It was assumed that studies that did not specify the oral contraceptive type examined mostly, if not exclusively, examined COC use.) All of these studies were included in the previous review, while an updated estimate came from one newly available study (14, 24). Overall, these studies suggested no association between COC use and HIV acquisition. The quality of the evidence was rated as low-to-moderate. No evidence was identified for the combined contraceptive patch, ring or injectable. 3.6 Additional evidence considered by the GDG 3.6.1 BIOLOGICAL DATA Biological data pertaining to the plausibility of an effect of individual methods of hormonal contraception on HIV acquisition were reviewed. Several biological mechanisms by which individual methods of hormonal contraception could theoretically modify the risk of HIV acquisition have been postulated, but | Contraceptive eligibility for women at high risk of HIV: guidance statement6 sparse and contradictory data make it unclear which, if any, of these biological mechanisms are clinically relevant. Potential mechanisms include alteration of the systemic and local immune response and changes in the genital tract environment. It was noted that different forms of hormonal contraception may change these factors in different ways. Combined contraceptives containing both ethinylestradiol and a progestogen may have a different effect than progestogen-only methods. Additionally, various progestogen-only methods, such as DMPA and NET-EN injectables, may change immune function variably. It remains uncertain to what extent data from animal and laboratory studies, including in relation to progestogen type and dosing, can be applied to clinical outcomes in humans. 3.6.2 VALUES AND PREFERENCES OF CONTRACEPTIVE USERS The systematic review identified 375 studies from all regions of the world (27). Across studies, women’s values and preferences centred on themes of choice and available options, ease of use, side-effect profiles and contraceptive efficacy. Contextual factors, such as the contraceptive methods available, counselling from providers, and the opinions of social networks, influenced decision-making. From the grey literature, two additional studies were identified that were relevant to hormonal contraception and HIV specifically (28, 29). Both found that messages from the 4 “Free” means the freedom and ability to make a voluntary decision about contraceptive use without barriers or coercion; informed means complete, correct and clear information has been given about all the options, plus details about the chosen method 2017 WHO guidance were difficult for providers to explain fully and may not be completely understood by clients. The online survey of sex workers from multiple global regions found that individual preferences around contraception varied widely and could change over time; ongoing partnership and dialogue with sex workers is essential to understanding evolving priorities. In participatory focus groups, Zimbabwean sex workers said their contraceptive choices were shaped by a wide range of factors, including cost, accessibility, the way sex workers are treated at clinics, the influence of male partners, and contraceptive side-effects. Sex without a condom was common, and there was a need to strengthen access to HIV/STI prevention and contraceptive services. The community stakeholder presentation emphasized that, for some women, any level of increased HIV risk would be too high. It also highlighted that the ECHO trial was not set up to assess the difference in the risk of HIV acquisition between contraceptive users and non-users. Community stakeholders also emphasized that there was a lack of true contraceptive choice for many women and girls, saying the guidance should emphasize full, free and informed contraceptive choice,4 the procurement of a range of contraceptive methods, and investment in integrated contraception and HIV services. RECOMMENDATIONS4 4.1 Recommendations for contraceptive use among women at high risk of HIV infection All hormonal contraceptive methods and intrauterine devices (IUDs) now fall into Category 1 of the Medical eligibility criteria for contraceptive use (MEC) (5) for women at high risk of HIV. Thus, women at high risk of HIV can use all methods of contraception without restriction. ■ Women at high a risk of HIV infection are eligible to use all progestogen-only contraceptive methods without restriction (MEC Category 1), including progestogen-only pills (POPs), intramuscular depot medroxyprogesterone acetate (DMPA-IM), subcutaneous DMPA (DMPA-SC), norethisterone enanthate (NET-EN) injectables, levonorgestrel (LNG) implants, and etonogestrel implants. ■ Women at a high risk of HIV infection are eligible to use copper-bearing IUDs (Cu-IUDs) and LNG-IUDs without restriction (MEC Category 1). In considering the use of IUDs, many women at a high risk of HIV are also at risk of other sexually transmitted infections (STIs); for these women, providers should refer to the MEC recommendation on women at increased risk of STIs and the Selected practice recommendations for contraceptive use on STI screening before IUD insertion (5, 6). ■ Women at a high risk of HIV infection are eligible to use all combined hormonal contraceptive methods without restriction (MEC Category 1), including combined oral Contraceptive eligibility for women at high risk of HIV: guidance statement | 7 contraceptives (COCs), combined injectable contraceptives (CICs), combined contraceptive patches (P) and combined vaginal rings (CVR). 4.2 Rationale The Guideline Development Group (GDG) reviewed, and discussed extensively, the new epidemiological and biological evidence, as well as related information about values and preferences, equity and human rights, and feasibility. After deliberating on all of the available evidence, the GDG recommended that the MEC category for DMPA and Cu-IUD should be changed to MEC Category 1. The GDG noted that there was no evidence regarding DMPA-SC and LNG-IUD, and only limited new information regarding NET-EN. Until more information becomes available, the GDG judged it was appropriate to follow the same approach as previously used, i.e. grouping all progestogen-only injectables together (DMPA- IM, DMPA-SC and NET-EN) as MEC Category 1, and to assign the same MEC category to the LNG-IUD as to the Cu-IUD (MEC Category 1). One key portion of the GDG’s deliberations related to evaluating evidence from the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Study (see Annex 3). The GDG gave particular attention to this information because of its ability to address unmeasured confounding – a major cause of uncertainty when interpreting results from observational studies. The GDG recognized that the ECHO trial did not address the etiological or causal question of whether DMPA increases the risk of HIV acquisition when compared with not using any contraception. Nevertheless, since the MEC provides guidance for women wishing to use contraception, results from the ECHO trial about the comparative risk of HIV acquisition among users of the three contraceptives tested were highly pertinent to the GDG’s deliberations. Furthermore, the GDG noted that the high incidence of HIV infection experienced by each contraceptive group during the ECHO trial was similar to the background incidence assumed when designing the trial. This was deemed to be indirect evidence addressing the question, suggesting no increased risk of HIV acquisition among users of these contraceptives compared with women not using any contraception. The ECHO trial was considered to be a well conducted study that provided high-quality evidence that superseded the low and low-to-moderate-quality observational evidence previously available to the GDG. This direct epidemiological evidence, from a trial specifically designed to address the issue, was judged to be more informative than theoretical biological evidence. The reasons for considering the ECHO trial to be of high quality included its large size; robust randomization methods; good adherence to the allocated contraceptive method; a low attrition rate; regular, standardized and objective outcome measurements; and a blinded, comprehensive analysis of the data (including sensitivity analyses for postulated confounders such as sexual activity and condom use). Although women and providers of services in the ECHO trial could not be blinded to the intervention allocation, there was no evidence that this led to the different groups of participants acting, or being managed, differently with respect to important issues such as HIV prevention counselling. This ensured that residual confounding, particularly in relation to condom use or sexual activity, was highly unlikely to have affected the ECHO trial. The GDG noted that although the ECHO trial was designed to detect a 50% increase in the risk of HIV acquisition between contraceptive groups assessed, the observed high HIV incidence and small losses to follow up meant that it could detect a 30% increase. When considering the ECHO trial results, the GDG focused on the point estimates for each primary comparison. The group noted that none of the point estimates for the primary comparisons were statistically significant. The 96% confidence intervals surrounding these point estimates included unity, and so encompassed the possibility of a small increased or decreased difference in risk between contraceptives. The GDG acknowledged, however, that for an individual woman at a high risk of HIV, any change in this risk may be important. After a full discussion, the GDG judged that unmeasured confounding was the most likely explanation for the apparent increased risk of HIV acquisition among DMPA-IM users seen in some observational studies. The GDG’s decisions to revise the MEC classifications for DMPA and IUDs were further grounded by the values and preferences of women towards optimizing informed contraceptive choice and the availability of a wide range of contraceptive options, based on a systematic review of qualitative and quantitative evidence, consultative engagements with sex workers and the perspectives of GDG members representing specific affected populations. In previous editions of the MEC, IUDs were classified as MEC Category 2 for women at a high risk of HIV. This recommendation was given because of the absence of high-quality, direct evidence about the risk of acquiring HIV among IUD users. In addition, there was an assumption that most women at a high risk of HIV were also at an increased risk of other STIs. The ECHO trial provided direct, high-quality evidence about the risk of HIV acquisition risk among women using the Cu-IUD, enabling the GDG to review its recommendation regarding these women. Any new evidence related to IUD use in women at a high risk of other STIs will be reviewed for the next MEC update. The GDG was concerned about the high rates of both HIV and STIs among women in the ECHO trial, reflecting the background risk factors among women seeking contraception in the study areas. The high incidence of HIV was particularly striking given the extensive efforts made during the ECHO trial to provide HIV prevention counselling and interventions. Thus, while the GDG concluded that the risk of HIV acquisition was not affected by the contraceptive method used, it emphasized the need for renewed efforts to reduce the incidence of HIV and STIs. | Contraceptive eligibility for women at high risk of HIV: guidance statement8 IMPLICATIONS FOR POLICY-MAKERS, PROGRAMME MANAGERS AND HEALTH-CARE PROVIDERS 5 While the main audiences for the Medical eligibility criteria for contraceptive use (MEC) are policy-makers and programme managers, a fundamental tenet of the MEC is that they are woman-centred. The following were the key messages that came from the deliberations of the Guideline Development Group. 5.1 A woman’s risk of HIV should not restrict her contraceptive choice While a risk of HIV should not restrict a woman’s choice to use hormonal contraception or an intrauterine device, it is important to note that these methods do not protect her against acquiring HIV or other sexually transmitted infection (STI). The new MEC recommendations should not be interpreted as indicating that HIV and STI testing and prevention are no longer important. Indeed, the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Study highlighted the critical need to strengthen and expand HIV and STI prevention services (10). Testing for HIV and STIs should be part of high-quality family planning services for women at risk, particularly for those living in areas of high HIV and STI incidence. 5.2 Efforts to expand access to contraceptive options must continue Women have the right to a range of short-acting, long-acting and permanent contraceptive methods, as well as to emergency contraception (1). A comprehensive range of contraceptive methods enables women to respond to changing needs and preferences during their reproductive lives. Informed decision- making and woman-centred, high-quality counselling are key components in the human rights-based provision of contraceptive information and services (2). The ECHO trial reinforced that offering a range of methods is possible and acceptable to women (10). Family planning and HIV services should be included in national universal health coverage initiatives. Efforts to expand safe and effective contraceptive options, and to ensure their availability and the access to them, must continue. Technical resources are available to support countries to introduce more contraceptive options into their programmes and services (Box 1). BOX 1. TECHNICAL RESOURCES TO SUPPORT PROGRAMMES o Medical eligibility criteria for contraceptive use (in English, French and Russian) https://apps.who.int/iris/handle/10665/181468 o Selected practice recommendations for contraceptive use (in English, French and Spanish) https://apps.who.int/iris/handle/10665/252267 o Implementation guide for the medical eligibility criteria and selected practice recommendations for contraceptive use (available in English, French, Portuguese and Spanish) https://apps.who.int/iris/handle/10665/272758 o Global handbook for family planning providers https://apps.who.int/iris/handle/10665/260156 o Training Resource Package for Family Planning website (available in English and French) https://www.fptraining.org o Mobile application for the Medical eligibility criteria for contraceptive use (free, for android and iOS platforms) https://www.who.int/reproductivehealth/mec-app o Policy brief: consolidated guidelines on HIV prevention, diagnosis, treatment and care for key populations, 2016 update https://apps.who.int/iris/handle/10665/258967 o Treat all: policy adoption and implementation status in countries (fact sheet) https://apps.who.int/iris/handle/10665/258538 Contraceptive eligibility for women at high risk of HIV: guidance statement | 9 5.3 A renewed emphasis on HIV and STI prevention services is urgently needed The ECHO trial showed high rates of both HIV and STIs in the study sites (10), highlighting the need for appropriate prevention, diagnosis and treatment of all STIs. Current HIV prevention measures remain unavailable or unsatisfactory for many women and adolescent girls living in settings of high HIV incidence. In such areas, the integration of family planning and HIV prevention services for all women is essential if the health of women and adolescent girls is to be improved. In settings of low HIV prevalence, there is a need for family planning providers to evaluate personal risk factors that may increase a woman’s risk of acquiring HIV and then to provide appropriate services. The ECHO trial also showed that syndromic management did not decrease the prevalence of STIs at baseline and at the end of follow-up. STI programmes need to be strengthened, including a move towards diagnostic management. ■ In settings with high HIV prevalence, HIV testing and prevention should be included in family planning services. HIV testing should be offered to all women and to partners of all women with HIV. HIV prevention options should be offered to all women, including pre-exposure prophylaxis (PrEP), as recommended in WHO guidelines (30). The offer of PrEP to women could also be considered where HIV incidence is high (but below 3/100 person-years overall) following, for example, a simple risk assessment. A risk assessment could include: desire to take PrEP (reflecting a self-identified risk); history of an STI; more than one sex partner in the last six months; or women with a sex partner with HIV who is not virally supressed on antiretroviral therapy. ■ In settings with low HIV prevalence, the routine offer of HIV testing and prevention services in family planning settings is unlikely to be cost-effective. HIV testing and prevention services could nonetheless be offered to women who request these services. BOX 2. WORK TO IDENTIFY WOMEN AT HIGH RISK OF HIV A person’s HIV risk depends on the incidence of HIV in the area where they live, and their individual risk factors. Family planning programmes must work closely with their national and subnational HIV programmes to use local epidemiological data to identify geographical areas and risk factors that put women at a high risk of HIV infection. 6.1 Contraceptive methods and HIV acquisition The existing body of evidence is sufficient to guide practice on intramuscular depot medroxyprogesterone acetate (DMPA-IM), levonorgestrel (LNG) implants and copper-bearing intrauterine devices; additional observational data will not add substantially to the evidence base for these methods. However, in the absence of trial data similar to those in the ECHO Study (10), observational data about subcutaneous DMPA (DMPA-SC), LNG IUDs, etonogestrel implants, or future contraceptive or multi-purpose prevention technologies could still be useful, although unmeasured confounding would likely remain a concern. Studies should consider the potential impact of contraceptive use on other sexually transmitted infections as well as HIV. Additional research on the specific effects of contraception-related bleeding changes in relation to the risk of HIV or STI acquisition is also needed. 6.2 HIV prevention The Guideline Development Group was deeply concerned by the high HIV incidence found among women seeking family planning services in the ECHO Study sites, despite the fact that trial participants received an extensive HIV prevention package (including repeated HIV testing and counselling, partner HIV testing and condom distribution, as well as pre-exposure prophylaxis (PrEP) late in the study as this became the standard of care). More research is needed on ways to increase the acceptability and uptake of effective HIV prevention strategies for women at a high risk of HIV, tailored to settings of both high and low HIV prevalence and to women with a range of personal risk factors. In the ECHO trial, the uptake (and hence impact) of PrEP was minimal as it became available only late in the trial (10). Where it was available on site, as opposed to requiring referral to another site, acceptability and uptake were high. Ways to include HIV self-testing and PrEP in family planning services should be KNOWLEDGE GAPS AND AREAS FOR RESEARCH6 | Contraceptive eligibility for women at high risk of HIV: guidance statement10 explored. This should include behavioural and implementation science research on the effective integration of HIV and contraception services. 6.3 Community involvement The ECHO trial employed a range of strategies for directly engaging with civil society at the study site, and at regional and global levels (10). An in-depth assessment of the strengths and limitations of each strategy is likely to provide models for community engagement in contraceptive and HIV prevention research that could be adopted in the future. 6.4 Increased funding for high-quality, policy-relevant research The ECHO Study demonstrated that a well conducted, adequately powered randomized clinical trial is possible in contraceptive research, and can make an important contribution to global decision-making. Global policy should be based on comprehensive high-quality evidence, but additional investment in contraceptive research is critically overdue, including research addressing whether financial barriers affect the contraceptive choices of women. DISSEMINATION OF THIS GUIDANCE STATEMENT7 The World Health Organization (WHO) will work to communicate this guidance statement clearly and widely. WHO will evaluate whether the guidance achieves its intentions. The guidance will be published on the WHO website and in a limited quantity of printed documents. The guidance will be widely disseminated through the WHO regional and country offices, WHO Member States, other United Nations agencies, civil society, the Implementing Best Practices (IBP) initiative, professional organizations, governmental and non- governmental partner organizations, and WHO collaborating centres working in the area of HIV and sexual and reproductive health. The WHO Secretariat will work closely with sexual and reproductive health and HIV focal points in regional and country offices of WHO, the United Nations Population Fund and the Joint United Nations Programme on HIV and AIDS to conduct a series of regional learning and knowledge-sharing events. This engagement will target opportunities where sexual and reproductive health issues are being discussed; examples include the 25th Conference on Population and Development in July 2019 and the 20th International Conference on AIDS and Sexually Transmitted Infections in Africa in December 2019. The Secretariat will also work closely with country task teams and working groups leading HIV and contraception programme efforts to share the guidance with grassroots and community- level organizations and providers. Additionally, webinars for stakeholders in multiple languages will be organized during 2020 to ensure Member States and stakeholders are fully informed of the new recommendations. These opportunities will enable WHO to disseminate the updated guidance effectively and efficiently. Derivative communication products highlighting key counselling issues (e.g. short briefs for front-line health-care providers and community-based organizations) will be prepared in collaboration with WHO’s implementing partners, and in consultation with the GDG during 2020. A policy brief in the six official languages used by WHO will be developed to inform policy-makers about the contraception updates. As part of the dissemination of the recommendations in this guidance statement, WHO will update its digital contraceptive decision-support tools – the MEC mobile app (31), the humanitarian contraceptive delivery app (32) and the postpartum compendium (33). These mobile applications are free to download and available for both iOS and Android platforms. Additionally, the Global handbook for family planning providers and the online Family Planning Training Resource Package will be updated accordingly (8, 34). WHO will continue to monitor the body of evidence informing these recommendations and will convene additional consultations when needed. Contraceptive eligibility for women at high risk of HIV: guidance statement | 11 REFERENCES 1. Ensuring human rights in the provision of contraceptive information and services: guidance and recommendations. Geneva: World Health Organization; 2014 (https://apps.who.int/iris/handle/10665/102539, accessed 24 August 2019). 2. Framework for ensuring human rights in the provision of contraceptive information and services. Geneva: World Health Organization; 2014 (https://apps.who.int/iris/handle/10665/133327, accessed 24 August 2019). 3. The thirteenth general programme of work, 2019–2023: promote health, keep the world safe, serve the vulnerable. Geneva: World Health Organization; 2019 (https://apps.who.int/iris/handle/10665/324775, accessed 24 August 2019). 4. Reproductive health strategy to accelerate progress towards the attainment of international development goals and targets. Geneva: World Health Organization; 2004 (https://apps.who.int/iris/handle/10665/68754, accessed 24 August 2019). 5. Medical eligibility criteria for contraceptive use, fifth edition. Geneva: World Health Organization; 2015 (https://apps.who.int/iris/ handle/10665/181468, accessed 24 August 2019). 6. Selected practice recommendations for contraceptive use: third edition. Geneva: World Health Organization; 2016 (https://apps.who.int/iris/handle/10665/252267, accessed 24 August 2019). 7. WHO medical eligibility criteria wheel for contraceptive use, 2015 update. Geneva: World Health Organization; 2004 (https://apps.who.int/iris/handle/10665/173585, accessed 24 August 2019). 8. World Health Organization, Johns Hopkins Bloomberg School of Public Health. Family planning: a global handbook for providers: evidence-based guidance developed through worldwide collaboration, third edition. Geneva: World Health Organization; 2018 (https://apps.who.int/iris/handle/10665/260156, accessed 24 August 2019). 9. Hormonal contraceptive eligibility for women at high risk of HIV: guidance statement: recommendations concerning the use of hormonal contraceptive methods by women at high risk of HIV. Geneva: World Health Organization; 2017 (https://apps.who.int/ iris/handle/10665/254662, accessed 24 August 2019). 10. Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium. HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial. Lancet. 2019;394(10195):303–13. doi: 10.1016/S0140-6736(19)31288-7. 11. WHO handbook for guideline development, second edition. Geneva: World Health Organization; 2014 (https://apps.who.int/iris/ handle/10665/145714, accessed 24 August 2019). 12. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J et al. GRADE guidelines: 1. Introduction –GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64(4):383–94. doi: 10.1016/j.jclinepi.2010.04.026. 13. Singh S. Adding it up: costs and benefits of contraceptive services – estimates for 2017. New York (NY): Guttmacher Institute; 2017. 14. Polis CB, Curtis KM, Hannaford PC, Phillips SJ, Chipato T, Kiarie JN et al. An updated systematic review of epidemiological evidence on hormonal contraceptive methods and HIV acquisition in women. AIDS. 2016;30(17):2665–83. doi: 10.1097/ QAD.0000000000001228. 15. Moher D, Liberati A, Tetzlaff J, Altman DG; The Prisma Group. Preferred reporting items for systematic reviews and meta- analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. doi: 10.1371/journal.pmed.1000097. 16. Kennedy CE, Yeh PT, Gaffield ME. Contraception values and preferences: protocol and methods for a global systematic review. Contraception. 2019 (in press). doi: 10.1016/j.contraception.2018.05.006Get. 17. Guyatt GH, Oxman AD, Vist G, Kunz R, Brozek J, Alonso-Coello P et al. GRADE guidelines: 4. Rating the quality of evidence— study limitations (risk of bias). J Clin Epidemiol. 2011;64(4):407–15. doi: 10.1016/j.jclinepi.2010.07.017. 18. Guyatt GH, Oxman AD, Kunz R, Brozek J, Alonso-Coello P, Rind D et al. GRADE guidelines 6. Rating the quality of evidence – imprecision. J Clin Epidemiol. 2011;64(12):1283–93. doi: 10.1016/j.jclinepi.2011.01.012. | Contraceptive eligibility for women at high risk of HIV: guidance statement12 19. Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M et al. GRADE guidelines: 8. Rating the quality of evidence – indirectness. J Clin Epidemiol. 2011;64(12):1303–10. doi: 10.1016/j.jclinepi.2011.04.014. 20. Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M et al. GRADE guidelines: 7. Rating the quality of evidence – inconsistency. J Clin Epidemiol. 2011;64(12):1294–302. doi: 10.1016/j.jclinepi.2011.03.017. 21. Guyatt GH, Oxman AD, Montori V, Vist G, Kunz R, Brozek J et al. GRADE guidelines: 5. Rating the quality of evidence – publication bias. J Clin Epidemiol. 2011;64(12):1277–82. doi: 10.1016/j.jclinepi.2011.01.011. 22. Guyatt GH, Oxman AD, Sultan S, Glasziou P, Akl EA, Alonso-Coello P et al. GRADE guidelines: 9. Rating up the quality of evidence. J Clin Epidemiol. 2011;64(12):1311–6. doi: 10.1016/j.jclinepi.2011.06.004. 23. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619–22. doi: 10.1097/ QAD.0000000000002260. 24. Sabo MC, Richardson BA, Lavreys L, Martin HL, Jr, Jaoko W, Mandaliya K et al. Does bacterial vaginosis modify the effect of hormonal contraception on HIV seroconversion. AIDS. 2019;33(7):1225–30. doi: 10.1097/QAD.0000000000002167. 25. Lavreys L, Baeten JM, Martin Jr HL, Overbaugh J, Mandaliya K, Ndinya-Achola J et al. Hormonal contraception and risk of HIV-1 acquisition: results of a 10-year prospective study. AIDS. 2004;18(4):695–7. 26. Wall KM, Kilembe W, Vwalika B, Htee Khu N, Brill I, Chomba E et al. Hormonal contraception does not increase women’s HIV acquisition risk in Zambian discordant couples, 1994–2012. Contraception. 2015;91(6):480–7. doi: 10.1016/j. contraception.2015.02.004. 27. Yeh PT, Kennedy CE, Gaffield ME. Contraception values and preferences: a global systematic review. Contraception. 2019; (accepted pending revisions). 28. Miller L, Ntinginya M, Makula J, Juma A, Mackay A, Wadegu E et al. Final report: a pilot study to assess training and communication materials on progestogen-only injectable use and risk of HIV acquisition in Tanzania. London: Marie Stopes International; 2019 (https://resultsforinformedchoice.org/wp-content/uploads/2019/02/Injectables-and-HIV-Pilot-Study-Report-TZ.pdf, accessed 24 August 2019). 29. Littlepage S, Dam A, Nakyanjo N, Polis C, Nalugoda F, Kennedy CE. Contraceptive decision-making in the context of HIV risk and changing World Health Organization guidelines: a qualitative study in Rakai, Uganda. 2019 (personal communication). 30. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach, second edition. Geneva: World Health Organization; 2016. (https://apps.who.int/iris/handle/10665/208825, accessed 24 August 2019). 31. New app for WHO’s medical eligibility criteria for contraceptive use. In: World Health Organization [website]. Geneva: World Health Organization; 2018 (https://www.who.int/reproductivehealth/mec-app, accessed 24 August 2019). 32. Delivering contraceptive services in humanitarian settings: new tool for front-line health care workers. In: World Health Organization [website]. Geneva: World Health Organization; 2018 (https://www.who.int/reproductivehealth/publications/ humanitarian-settings-contraception, accessed 24 August 2019). 33. New WHO tool helps guide contraception choices following childbirth. In: World Health Organization [website]. Geneva: World Health Organization; 2016 (https://www.who.int/reproductivehealth/news/pfpc, accessed 24 August 2019). 34. TRP: Training Resource Package for Family Planning [website]. Baltimore (MD): Johns Hopkins University; 2019 (https://www.fptraining.org, accessed 24 August 2019). Contraceptive eligibility for women at high risk of HIV: guidance statement | 13 ANNEX 1. GUIDELINE DEVELOPMENT GROUP AND EVIDENCE SECRETARIAT Guideline Development Group Sharon Achilles (University of Pittsburgh, United States of America), Richard Adanu (University of Ghana, Ghana), Rachid Bezad (University Roi Mohammad VI, Morocco), Sharon Cameron (University of Edinburgh, United Kingdom of Great Britain and Northern Ireland), Tsungai Chipato (University of Zimbabwe, Zimbabwe), Maria del Carmen Cravioto (National Institute of Nutrition, Salvador Zubiran, Mexico) [unable to attend], Alison Edelman (Oregon Health & Science University, United States), Mohammad Eslami (Ministry of Health and Education, Islamic Republic of Iran), Anna Glasier (University of Edinburgh, United Kingdom), Andy Gray (University of KwaZulu- Natal, South Africa), Philip Hannaford (University of Aberdeen, United Kingdom), Felicita Hikuam (AIDS and Rights Alliance for Southern Africa, Namibia), Unnop Jaisamrarn (Chulalongkorn University, Thailand), Loveleen Johri (family planning and reproductive health independent consultant, India), Natasha Kaoma (Copper Rose Zambia, Zambia), Seni Kouanda (Institute of Research in Health Sciences, Burkina Faso), Elizabeth Lule (global health and international development independent consultant, Uganda), Vimbai Magwenzi (Centre for Sexual Health and HIV/AIDS Research, Zimbabwe) [unable to attend], Loyce Maturu (Zvandiri Mentor with Africaid, Zimbabwe), Olav Meirik (Instituto Chileno de Medicina Reproductiva, Chile), Placid Mihayo (Ministry of Health, Uganda), Lilian Mworeko (International Community of Women Living with HIV Eastern Africa, Uganda), Hiromi Obara (National Center for Global Health and Medicine, Tokyo, Japan), Herbert Peterson (University of North Carolina, United States), John Pile (independent consultant, Thailand), Carolina Sales Vieira (University of Sao Paulo, Brazil), Sarah Simpson (EquiACT, France), Aminata Wurie (Youth Coalition for Sexual and Reproductive Rights, Sierra Leone). Philip Hannaford and Natasha Kaoma co-chaired the meeting Guideline Development Group (GDG) meeting. Evidence Secretariat Centre for Sexual Health and HIV/AIDS Research – Euphemia Sibanda FHI 360 – Timothy Mastro Independent Consultant – Ania Shapiro Johns Hopkins University – Caitlin Kennedy Oregon Health & Science University – Maria Isabel Rodriguez United States Centers for Disease Control and Prevention – Kathryn Curtis University of Washington – Jared Baeten Wits Reproductive Health and HIV Institute – Helen Rees Observer Zandile Mnisi (Ministry of Health, Eswatini) External Review Group Florence Anam (Doctors Without Borders, South Africa), Winfred Apio (Uganda Youth and Adolescents Forum, Uganda), Lynn Bakamjian (independent consultant, United States), Milena Brito (University of Sao Paulo, Brazil), Roy Jacobstein (IntraHealth, United States), Ernest Maya (University of Ghana, Ghana), Mari Ngai (National Center for Global Health and Medicine, Japan), Cristina Puig Borràs (European Consortium for Emergency Contraception, Spain), Nusrat Shah (Society of Obstetrics & Gynaecology, Pakistan), Bulbul Sood (Jphiego, India). WHO Secretariat The WHO Secretariat attended the meeting and several WHO staff provided background presentations (Rachel Baggaley, Mary Lyn Gaffield, James Kiarie, Nancy Kidula). The WHO Secretariat was present to serve as a background resource, if request by the GDG. Neither WHO, the Joint United Nations Programme on HIV/AIDS (UNAIDS) nor the United Nations Population Fund (UNFPA) staff participated in the decision- making or formulation of the recommendations, which was the sole responsibility of the GDG. Several WHO staff contributed to the systematic reviews (Mary Lyn Gaffield, James Kiarie, Petrus Steyn) and the writing of the statement. WHO headquarters WHO Department of Reproductive Health and Research – Ian Askew, Mary Lyn Gaffield, James Kiarie, Antonella Lavelanet, Manjulaa Narasimhan (unable to attend), Petrus Steyn WHO Department of HIV – Rachel Baggaley, Virginia MacDonald, Michele Rodolph WHO Department of Regulation of Medicines and other Health Technologies – Ray Corrin | Contraceptive eligibility for women at high risk of HIV: guidance statement14 WHO regional offices WHO Regional Office for Africa – Nancy Kidula, Léopold Ouedraogo Joint United Nations Programme on HIV/AIDS (UNAIDS) Peter Godfrey-Fausett United Nations Population Fund (UNFPA) Technical Division – Gifty Addico, Mieko Yabuta (unable to attend) Overall coordination WHO Department of Reproductive Health and Research – Mary Lyn Gaffield, with logistical support from Jane Werunga- Ndanareh. Writing The guidance statement was drafted on behalf of WHO by Caitlin Baumhart, Kathryn Curtis, Mary Lyn Gaffield, Philip Hannaford, Natasha Kaoma, Caitlin Kennedy and Maria Isabel Rodriguez. The systematic review examining the use of copper-bearing intrauterine devices and HIV acquisition was co-authored by Tsungai Chipato, Kathryn Curtis, Philip Hannaford and Angeline Ti. The update of the 2016 systematic review focusing on hormonal contraception and HIV acquisition was co-authored by Tsungai Chipato, Kathryn Curtis, Philip Hannaford, James Kiarie and Petrus Steyn. The GRADE tables and expertise on GRADE methodology were provided by Maria Isabel Rodriguez. Preparation of the evidence-to-decision table and expertise on the literature for values and preferences were provided by Caitlin Kennedy. Editing was done by Markus MacGill and Jane Patten of Green Ink (www.greenink.co.uk) and layout by Lushomo (www.lushomo.net). Contraceptive eligibility for women at high risk of HIV: guidance statement | 15 ANNEX 2. DECLARATIONS OF CONFLICTS OF INTEREST Following guidance issued on 24 September 2014 by the WHO Office of Compliance, Risk Management and Ethics (CRE), and prior to the 29–31 July 2019 meeting, the name and brief biography of each proposed Guideline Development Group (GDG) member was published on the WHO website during 27 May to 10 June 2019 (https://www.who.int/ reproductivehealth/publications/contraceptives-methods-hiv). The public was able to view and provide their comments to the WHO Secretariat using a general email address (hrx_info@who.int) regarding any perceived or real conflicts of interest of these proposed GDG members. In addition, prior to the public announcement period, the WHO Secretariat reviewed the curriculum vitae of each potential participant and conducted Internet searches (Google Scholar, Open Payments, PubMed) for information on potential financial and academic conflicts of interest related to the subject of the meeting. Following the public reporting period, and in consultation with CRE, official invitations for GDG membership were extended. Additionally, the WHO Secretariat reviewed potential financial and academic conflicts of interest related to the subject of the meeting of the proposed External Review Group: no conflicts were declared among this 11-member group. Of the 28 experts who participated in this work, six declared an interest related to contraception. The WHO Secretariat, CRE and GDG reviewed all declarations and found no conflicts of interest sufficient to preclude anyone from participating in the deliberations or the development of the recommendations relevant to hormonal contraception and HIV. Accordingly, the six participants who declared interests related to contraception, as well as the other 22 participants, fully participated in the meeting’s deliberations, discussions and final decisions. Although not all interests declared were specifically related to contraception and susceptibility to HIV, they are disclosed and summarized below. Sharon Achilles received US$ 4225 on 10 May 2016 to give expert advice on the latest HIV therapies during a one-day meeting sponsored by Merck Sharp & Dohme. Her research unit received US$ 2 638 373 from the United States National Institutes of Health/National Institute of Allergy and Infectious Diseases to conduct a study titled, Quantification of immune cells in women using contraception, during 2012–2019. For 2012–2019, her research unit is receiving US$ 4 999 999 from the Bill & Melinda Gates Foundation to conduct a study titled, HIV-target cell response in women initiating contraception in high HIV-incidence areas. During 2014–2016, Dr Achilles’s research unit received US$ 240 225 from the Bill & Melinda Gates Foundation to conduct a study addressing IFN-epsilon and hormonal contraceptive modulation of the risk of HIV acquisition. Currently, for 2018–2020, Dr Achilles’s research unit receives US$ 535 958 from the United States Food and Drug Administration (FDA) to conduct a study supporting new approaches to improve product manufacturing and quality titled, Physiologically-based model of the female reproductive tract: vaginal and intrauterine delivery components. Sharon Cameron works at a research unit that received a grant from Pfizer, UK, for £99 000, which ceased in 2016. The study was implemented to determine the feasibility and acceptability of the pharmacist administration of subcutaneous injectable contraception. Alison Edelman receives a yearly royalty of around US$ 1000 from the Internet information site, UpToDate as an author of the content. Between May 2016 and May 2017, she received US$ 10 000 a year from Agile Pharmaceuticals as an expert consultant regarding a hormonal contraceptive patch that is currently not FDA-approved. This consultation has ended. Since January 2016, she served as a trainer for Nexplanon, an FDA mandate, for Merck Sharp & Dohme, but has received no honorarium for these sessions and as an expert consultant in January 2016 for this company, receiving US$ 1500 for her services. Her research unit received US$ 540 000 from the Merck Women’s Health Investigator Initiated Studies Program to conduct research focused on treatment of breakthrough bleeding with the contraceptive implant (2016–2019). From 2015 to 2017, her research unit received a US$ 250 000 research grant from the Society for Family Planning to investigate the timing of ulipristal acetate and oral contraceptive use. Since 2002, Dr Edelman has been receiving about US$ 3000 a year from Contemporary Forums as a faculty member for its continuing medical education conferences (the amount varies depending on the number of lectures she gives). From November 2015 through June 2016, she received an honorarium of US$ 3000 from Oregon State University for expert advice on the mandated state training to allow the direct provision of contraceptives by pharmacists. Since July 2016, Dr Edelman has been receiving US$ 500 a year as an honorarium for serving on the data and safety monitoring board to FHI 360, which is developing a novel contraceptive injectable that is not yet FDA-approved. From April to September 2017, Dr Edelman was a consultant for HRA Pharma for a study investigating a progestin-only pill. Since July 2017, she had been an expert consultant for the Sugar Palm Foundation; this contract was then channelled through her institution and ended in 2019. Since June 2017, she has been providing expert consulting to Ipas to train health-care workers in Bangladesh: this contract is now administered by her institution. On an ongoing basis since 2016, Dr Edelman has received an honorarium from the University of California, San Francisco, for speaking and family planning fellowship site audits. During 2018 through to January 2019, she received an honorarium from Exeltis to provide an expert review on a contraceptive method not currently FDA- approved. This consultation has ended. Anna Glasier provides expert medical advice on the ulipristal acetate emergency contraceptive pill on a regular basis to the manufacturer (HRA Pharma). The amount was not disclosed. She works with them to try to obtain approval for the over-the- counter (OTC) use of ulipristal acetate emergency contraception and a progestin-only pill in the United States of America, and to | Contraceptive eligibility for women at high risk of HIV: guidance statement16 get a progestin-only pill approved for OTC use in the United Kingdom of Great Britain and Northern Ireland, and Europe. This is ongoing. Andy Gray is the chair of the Names and Scheduling Advisory Committee of the South African Health Products Regulatory Authority and serves on its Lega Advisory and Regulatory Advisory Committees. He is a member of the South African National Essential Medicines List Committee, responsible for medicines selection and the development of standard treatment guidelines for the public sector. Carolina Sales Vieira receives an honorarium (US$ 4000/year) for serving on Merck Sharpe & Dohme’s medical advisory board and giving ad hoc invited lectures. This role is ongoing. Dr Sales Vieira receives an honorarium (US$ 3000/year) for serving on Bayer’s medical advisory board and giving ad hoc lectures. This role is ongoing. Dr Sales Vieira received a one-time honorarium (US$ 1000) for serving on the medical advisory board for Exeltis in 2019. Contraceptive eligibility for women at high risk of HIV: guidance statement | 17 ANNEX 3. GRADE EVIDENCE PROFILES Outcome Type and number of studies (total number of participants) Limitations Inconsistency Imprecision Indirectness Overall quality Estimate of effect DMPA versus non-hormonal contraception or no method HIV acquisition 1 RCT1 (7829)a Few limitationsb No serious inconsistency No serious imprecision No indirectness High Adjusted HR 1.04 (0.82–1.33) for DMPA versus Cu-IUD HIV acquisition 10 cohort studies2–11 + 1 individual patient data meta-analysis of 7 studies12,c (40 506)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low to moderatee Adjusted HR range 0.46– 2.04, 8 studies increased risk (HR range 1.25–2.04), with statistically significant effects in 3 studies; 2 studies trended towards decreased risk (HR 0.46 and 0.75 with wide confidence intervals) Pooled adjusted HR 1.40 (1.24–1.58) NET-EN versus non-hormonal contraception or no method HIV acquisition 6 cohorts studies2,5,7,8,10,11 + 1 individual patient data meta- analysis of 7 studies12,c (29 922)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR range 0.87– 1.76, 5 studies increased risk (HR range 1.20–1.76), none statistically significant; 2 studies no effect (adjusted HR range 0.87–1.05) Pooled adjusted HR 1.14 (0.93–1.39) Implantf use versus non-hormonal contraception HIV acquisition 1 randomized trial1 (7829)a Few limitationsb No serious inconsistency No serious imprecision No indirectness High Adjusted HR 1.18 (0.91–1.53) for Cu-IUD versus LNG implant HIV acquisition 3 cohort studies2–4,c (4514)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Lowg Adjusted HR range 0.46–0.99 Adjusted HRs: 0.96 (0.29– 3.14), 0.99 (0.40–2.45), and 0.46 (0.13–1.70); none statistically significant Pooled adjusted HR 0.82 (0.44–1.53) Implantf use versus NET-EN HIV acquisition 1 cohort study2 (1136)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 0.45 (0.13–1.53) for implant use versus NET-EN Oral hormonal contraceptive use versus non-hormonal contraception or no method HIV acquisition 11 cohort studies3–6,8–14,c (43 482)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low to moderatee Adjusted HR or IRR range 0.66–1.80 3 studies increased risk (HR 1.39–1.80) Only 1 study reported a statistically significant finding (adjusted HR 1.48 [1.05– 2.09]) The remaining 8 studies reported a decreased risk (adjusted HR range 0.66–0.99), none of which was statistically significant Pooled adjusted HR 1.02 (0.88–1.19) GRADE EVIDENCE PROFILE FOR HORMONAL CONTRACEPTIVE USE IN HIV-NEGATIVE WOMEN | Contraceptive eligibility for women at high risk of HIV: guidance statement18 Outcome Type and number of studies (total number of participants) Limitations Inconsistency Imprecision Indirectness Overall quality Estimate of effect DMPA versus NET-EN HIV acquisition 2 cohort studies2,15 and 1 individual patient data meta-analysis of 17 studies12,c (42 788)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low to moderatee Adjusted HRs 1.32 (1.08– 1.61) and 0.89 (0.55–1.44) in cohort studies and 1.41 (1.06–1.89) in individual participant data meta- analysis of 17 studies Pooled adjusted HR 1.27 (1.05–1.55) DMPA versus combined oral contraceptives HIV acquisition 1 individual patient data meta-analysis of 8 studies12,c (24 853)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low to moderatee Adjusted HR 1.41 (1.23–1.67) in individual participant data meta-analysis of 8 studies NET-EN versus combined oral contraceptives HIV acquisition 1 individual patient data meta-analysis of 9 studies12,c (25 398)a Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 1.30 (0.99–1.17) GRADE EVIDENCE PROFILE FOR HORMONAL CONTRACEPTIVE USE IN HIV-NEGATIVE WOMEN Cu-IUD: copper-bearing intrauterine device; DMPA-IM: intramuscular depot medroxyprogesterone acetate; ETG: etonogestrel; GRADE: Grading of Recommendations Assessment, Development and Evaluation; HR: hazard ratio; IRR: incidence rate ratio; LNG: levonorgestrel; NET-EN: norethisterone enanthate; RCT: randomized clinical trial Note: Publication bias was not formally assessed; observational studies could not be upgraded for large effects; dose-response relationship, or confounders likely to increase observed effects. Estimates based on adjusted risk estimates, results from Cox model analysis used when available. a Sample size is for the entire study population. b Few limitations noted in the trial, but not serious enough to downgrade the level of evidence. While the study was unblinded for participants and health-care providers, data were analysed centrally by statisticians who were blinded to the group. c Restricted to studies classified as “informative with but with important limitations”. d Some limitations or imprecision noted across the body of evidence, but not serious enough to downgrade the level of evidence. e Evidence graded low to moderate due to consistent and precise results from well conducted observational studies, and coherence between studies of use versus non-use and head-to-head studies. f No direct evidence for ETG implants was identified for the comparisons of interest. For ETG implants, recommendations were extrapolated from other implant studies. g Upgraded from very low-quality evidence (2016 assessment). References: 1. Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium. HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial. Lancet. 2019;394(10195):303–13. doi: 10.1016/S0140-6736(19)31288-7. 2. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619–22. doi: 10.1097/ QAD.0000000000002260. 3. Sabo MC, Richardson BA, Lavreys L, Martin HL, Jr, Jaoko W, Mandaliya K et al. Does bacterial vaginosis modify the effect of hormonal contraception on HIV seroconversion. AIDS. 2019;33(7):1225–30. doi: 10.1097/QAD.0000000000002167. 4. Wall KM, Kilembe W, Vwalika B, Htee Khu N, Brill I, Chomba E et al. Hormonal contraception does not increase women’s HIV acquisition risk in Zambian discordant couples, 1994–2012. Contraception. 2015;91(6):480–7. Doi: 10.1016/j. contraception.2015.02.004. Contraceptive eligibility for women at high risk of HIV: guidance statement | 19 5. Crook AM, Ford D, Gafos M, Hayes R, Kamali A, Kapiga S et al. Injectable and oral contraceptives and risk of HIV acquisition in women: an analysis of data from the MDP301 trial. Hum Reprod. 2014;29(8):1810–7. doi: 10.1093/humrep/deu113. 6. Heffron R, Donnell D, Rees H, Celum C, Mugo N, Were E et al. Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study. Lancet Infect Dis. 2012;12(1):19–26. doi: 10.1016/S1473-3099(11)70247-X. 7. Kleinschmidt I, Rees H, Delany S, Smith D, Dinat N, Nkala B et al. Injectable progestin contraceptive use and risk of HIV infection in a South African family planning cohort. Contraception. 2007;75(6):461–7. doi: 10.1016/j.contraception.2007.02.002. 8. McCoy SI, Zheng W, Montgomery ET, Blanchard K, van der Straten A, de Bruyn G et al. Oral and injectable contraception use and risk of HIV acquisition among women in sub-Saharan Africa. AIDS. 2013;27(6):1001–9. doi: 10.1097/ QAD.0b013e32835da401. 9. Morrison CS, Richardson BA, Mmiro F, Chipato T, Celentano DD, Luoto J et al. Hormonal contraception and the risk of HIV acquisition. AIDS. 2007;21(1):85–95. doi: 10.1097/QAD.0b013e3280117c8b. 10. Morrison CS, Skoler-Karpoff S, Kwok C, Chen PL, van de Wijgert J, Gehret-Plagianos M et al. Hormonal contraception and the risk of HIV acquisition among women in South Africa. AIDS. 2012;26(4):497–504. doi: 10.1097/QAD.0b013e32834fa13d. 11. Myer L, Denny L, Wright TC, Kuhn L. Prospective study of hormonal contraception and women’s risk of HIV infection in South Africa. Int J Epidemiol. 2007;36(1):166–74. doi: 10.1093/ije/dyl251. 12. Morrison CS, Chen PL, Kwok C, Baeten JM, Brown J, Crook AM et al. Hormonal contraception and the risk of HIV acquisition: an individual participant data meta-analysis. PLoS Med. 2015;12(1):e1001778. doi: 10.1371/journal.pmed.1001778. 13. Balkus JE, Brown ER, Hillier SL, Coletti A, Ramjee G, Mgodi N et al. Oral and injectable contraceptive use and HIV acquisition risk among women in four African countries: a secondary analysis of data from a microbicide trial. Contraception. 2016;93(1):25–31. doi: 10.1016/j.contraception.2015.10.010. 14. Reid SE, Dai JY, Wang J, Sichalwe BN, Akpomiemie G, Cowan FM et al. Pregnancy, contraceptive use, and HIV acquisition in HPTN 039: relevance for HIV prevention trials among African women. J Acquir Immune Defic Syndr. 2010;53(5):606–13. doi: 10.1097/QAI.0b013e3181bc4869. 15. Noguchi LM, Richardson BA, Baeten JM, Hillier SL, Balkus JE, Chirenje ZM et al. Risk of HIV-1 acquisition among women who use different types of injectable progestin contraception in South Africa: a prospective cohort study. Lancet HIV. 2015;2(7):e279–87. doi: 10.1016/S2352-3018(15)00058-2. | Contraceptive eligibility for women at high risk of HIV: guidance statement20 Outcome Type and number of studies (total number of participants) Limitations Inconsistency Imprecision Indirectness Overall quality Estimate of effect IUDa versus no contraception or tubal ligation HIV acquisition 1 prospective study1,b (1498)c Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 1.1 (0.4–3.0) for Cu-IUD versus no contraception or tubal ligation IUDa versus implant,e DMPA, NET-EN HIV acquisition 1 prospective study2,b (1136)c Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 0.90 (0.45–1.76) for DMPA, implants, NET-EN versus Cu-IUD IUDa use versus DMPA HIV acquisition 1 RCT3,b (7829)c Few limitationsf No serious inconsistency No serious imprecision No indirectness High Adjusted HR 1.04 (0.82–1.33) for DMPA-IM versus Cu-IUD HIV acquisition 1 prospective study2,b (1136)c Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 0.91 (0.44–1.87) for DMPA versus Cu-IUD IUDa versus NET-EN HIV acquisition 1 prospective study2,b (1136)c Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 0.98 (0.47–2.03) for Cu-IUD versus NET-EN IUDa versus implante HIV acquisition 1 RCT3 (7829)c Few limitationsf No serious inconsistency No serious imprecision No indirectness High Adjusted HR 1.18 (0.91–1.53) for Cu-IUD versus LNG implant HIV acquisition 1 prospective study2,b (1136)c Some limitationsd No serious inconsistency No serious imprecision No indirectness Low Adjusted HR 2.17 (0.59–7.69) for Cu-IUD versus implants (LNG or ETG) GRADE EVIDENCE PROFILE FOR CU-IUD USE IN HIV-NEGATIVE WOMEN Cu-IUD: copper-bearing intrauterine device; DMPA-IM: intramuscular depot medroxyprogesterone acetate; ETG: etonogestrel; GRADE: Grading of Recommendations Assessment, Development and Evaluation; HR: hazard ratio; IUD: intrauterine device; LNG: levonorgestrel; NET-EN: norethisterone enanthate; RCT: randomized clinical trial Note: Publication bias was not formally assessed; observational studies could not be upgraded for large effects; dose-response relationship, or confounders likely to increase observed effects. Estimates based on adjusted risk estimates, results from Cox model analysis used when available. a No direct evidence for LNG-IUDs was identified for the comparisons of interest. For LNG-IUDs, recommendations were extrapolated from the evidence on Cu-IUDs and other LNG containing products. b Restricted to studies classified as “informative with but with important limitations”. c Sample size is for the entire study population. d Some limitations or imprecision was noted across the body of evidence, but not serious enough to downgrade the level of evidence. e No direct evidence for ETG implants was identified for the comparisons of interest. For ETG implants, recommendations were extrapolated from the evidence on LNG implants. f Few limitations noted in the trial, but not serious enough to downgrade the level of evidence. References: 1. Lavreys L, Baeten JM, Martin Jr HL, Overbaugh J, Mandaliya K, Ndinya-Achola J et al. Hormonal contraception and risk of HIV-1 acquisition: results of a 10-year prospective study. AIDS. 2004;18(4):695–7. 2. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619–22. doi: 10.1097/ QAD.0000000000002260. 3. Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium. HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial. Lancet. 2019;394(10195):303–13. doi: 10.1016/S0140-6736(19)31288-7. Contraceptive eligibility for women at high risk of HIV: guidance statement | 21 ANNEX 4. EVIDENCE-TO- DECISION TABLE FOR HORMONAL CONTRACEPTIVE METHODS AND INTRAUTERINE DEVICES (IUDS) Factor Explanation/evidence Judgement Quality of evidence Progestogen- only contraceptives (POCs) For the primary outcome of HIV acquisition, evidence was considered to be of high qual- ity for intramuscular depot medroxyprogesterone acetate (DMPA-IM) and for levonorge- strel (LNG) implants. Evidence was considered to be of low quality for norethisterone enanthate (NET-EN), and absent for subcutaneous DMPA (DMPA-SC), LNG intrauterine devices (IUDs) and etonogestrel (ETG) implants. For NET-EN and DMPA-SC, the recom- mendations were extrapolated from the evidence on DMPA-IM. For ETG implants, the recommendations were extrapolated from the evidence on LNG implants. High, low or absent, depending on method IUDs For the primary outcome of HIV acquisition, evidence was considered to be of high quality for copper-bearing IUDs (Cu-IUDs). Evidence was absent for LNG-IUDs. For LNG-IUDs, recommendations were extrapolated from the evidence on Cu-IUDs and other LNG-containing products. High or absent, de- pending on method Combined hormonal contraceptives (CHCs) Evidence was considered to be of low-to-moderate quality for CHCs. Low-moderate Balance of benefits versus harms POCs Contraception is a life-saving intervention with well recognized health, social and economic benefits. All POCs are effective or highly effective, reversible methods. High-quality evidence from one randomized clinical trial (RCT) observed no statistically significant differences in HIV acquisition between: DMPA-IM versus Cu-IUD, DMPA-IM versus LNG implant, and Cu-IUD versus LNG implant. Of the low-to-moderate-quality evidence from 14 observational studies, some studies suggested a possible increased risk of HIV with progestogen-only injectable use, which was most likely due to unmeasured confounding.a,b Low-quality evidence from three observational studies did not suggest an increased HIV risk for implant users.a,b No studies of sufficient quality were identified for progestogen-only pills. While no direct evidence was available for DMPA-SC or ETG implants, indirect evidence for DMPA-IM and LNG implants was used, given that there was no biological or clinical reason to believe that a lower hormonal dose, different delivery mechanism, or different progestogen would modify HIV risk. Balance is in favour of benefits of POCs IUDs Contraception is a life-saving intervention with well recognized health, social and economic benefits. All IUDs are highly effective, reversible methods. High-quality evidence from one RCT, along with low-quality evidence from two observational studies, suggested no increased risk of HIV acquisition with Cu-IUD use.c–e While no direct evidence was available for LNG-IUDs, recommendations were extrapolated from the evidence on Cu-IUDs and other LNG-containing products. Balance is in favour of benefits of IUDs CHCs Contraception is a life-saving intervention with well recognized health, social and economic benefits. All hormonal contraceptives are effective or highly effective, reversible methods. Low-moderate quality evidence from 11 observational studies suggested no association between combined oral contraceptive (COC) use (it was assumed that studies that did not specify oral contraceptive type examined mostly, if not exclusively, COC use) and HIV acquisition.a,b While no direct evidence was available for combined contraceptive patch, combined contraceptive vaginal ring or combined injectable contraceptive, indirect evidence from COCs was used given that there was no biological or clinical reason to believe that a lower hormonal dose, different delivery mechanism, or different progestogen would modify HIV risk. Balance is in favour of benefits of CHCs | Contraceptive eligibility for women at high risk of HIV: guidance statement22 Factor Explanation/evidence Judgement Values and preferences Women have the right to informed decision-making. Women prefer to have choice in methods, full information regarding benefits versus harms, and to make a final decision in conjunction with their provider (informed decision-making). Contraception is unique among medicines because a woman’s needs and preferences with regard to the characteristics of contraceptive methods will vary both between individual women and across a single individual’s lifespan. Common themes in contraceptive preferences include that they are discreet, have minimal side-effects and are long-acting, reversible and easy to use. Women who use progestogen-only injectables generally like them for these reasons, and feel comfortable using them after counselling. Women’s preferences for methods are limited by what they have knowledge of, what is available to them and other factors that foster or limit access. Offering women the choice of a range of methods is important from both a health and a rights perspective. Support for optimizing informed contraceptive choice and the availability of a wide range of contraceptive options Priority of the problem HIV is a serious illness and a major global epidemic. Unintended pregnancy is a very common problem globally, and the risks associated with it are highest where maternal mortality and severe morbidity are also common. Both are priorities for public health. Effective contraception and HIV prevention are both public health priorities Equity and human rights Human rights principles and standards from existing World Health Organization (WHO) guidelines on human rights and contraception were followed by the Guideline Development Group (GDG) in its deliberations. These include non-discrimination, availability, accessibility, acceptability, quality, informed decision-making, privacy and confidentiality, participation, and accountability. During its deliberations, the GDG considered both potential positive and negative effects of its considerations. For example, it considered and emphasized the continuing need for integrated family planning and HIV services in settings with high HIV incidence. It also emphasized the need for expanding and optimizing contraceptive options. Recommendations within WHO’s human rights guidance for contraception are paramount principles for decision-making on this topic Feasibility The importance of clear communication from WHO on this topic was underscored. This was reinforced by recent studies that suggested that messages based on the 2017 WHO guidance were difficult to explain and may not be fully understood by clients or providers. Clear guidance and a woman-centred approach are essential for successful implementation References: a. Polis CB, Curtis KM, Hannaford PC, Phillips SJ, Chipato T, Kiarie JN et al. An updated systematic review of epidemiological evidence on hormonal contraceptive methods and HIV acquisition in women. AIDS. 2016;30(17):2665–83. doi: 10.1097/ QAD.0000000000001228. b. Sabo MC, Richardson BA, Lavreys L, Martin HL, Jr, Jaoko W, Mandaliya K et al. Does bacterial vaginosis modify the effect of hormonal contraception on HIV seroconversion. AIDS. 2019;33(7):1225–30. doi: 10.1097/QAD.0000000000002167. c. Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium. HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial. Lancet. 2019;394(10195):303–13. doi: 10.1016/S0140-6736(19)31288-7. d. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619–22. doi: 10.1097/ QAD.0000000000002260. e. Lavreys L, Baeten JM, Martin Jr HL, Overbaugh J, Mandaliya K, Ndinya-Achola J et al. Hormonal contraception and risk of HIV-1 acquisition: results of a 10-year prospective study. AIDS. 2004;18(4):695–7. Contraceptive eligibility for women at high risk of HIV: guidance statement | 23 ANNEX 5: SYSTEMATIC REVIEWS Three systematic reviews were conducted as part of the development of this guidance statement. The details of the methods and search strategies are included in the reviews. Reviews published in peer-reviewed journals are available through open access. This appendix will be periodically updated as reviews are published. Access to unpublished reviews can be requested by sending an email to hrx-info@who.int. 1. Hormonal contraceptive method use and HIV acquisition in women There was a previously published review on hormonal contraceptive use and HIV acquisition. The search strategies from that review were used to search for new evidence since. The following four new publications were identified that met the inclusion criteria. PREVIOUSLY PUBLISHED REVIEW 1. Polis CB, Curtis KM, Hannaford PC, Phillips SJ, Chipato T, Kiarie JN et al. An updated systematic review of epidemiological evidence on hormonal contraceptive methods and HIV acquisition in women. AIDS. 2016;30(17):2665–83. doi: 10.1097/ QAD.0000000000001228. PUBLISHED REVIEW 1. Curtis KM, Hannaford PC, Rodriguez MI, Chipato T, Steyn PS, Kiarie JN. Hormonal contraceptive method use and HIV acquisition in women: an updated systematic review. BMJ Sex Reprod Health. 2020; 46:8-16. (http://dx.doi. org/10.1136/bmjsrh-2019-200509). NEW ARTICLES 1. Haddad LB, Wall KM, Kilembe W, Vwalika B, Khu NH, Brill I et al. Bacterial vaginosis modifies the association between hormonal contraception and HIV acquisition. AIDS. 2018;32(5):595–604. doi: 10.1097/ QAD.0000000000001741. 2. Hofmeyr GJ, Singata-Madliki M, Lawrie TA, Bergel E, Temmerman M. Effects of injectable progestogen contraception versus the copper intrauterine device on HIV acquisition: sub-study of a pragmatic randomised controlled trial. J Fam Plann Reprod Health Care. 2017;43(3):175–80. doi: 10.1136/jfprhc-2016-101607. 3. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619– 22. doi: 10.1097/QAD.0000000000002260. 4. Sabo MC, Richardson BA, Lavreys L, Martin HL, Jr., Jaoko W, Mandaliya K et al. Does bacterial vaginosis modify the effect of hormonal contraception on HIV seroconversion. AIDS. 2019;33(7):1225-30. doi: 10.1097/ QAD.0000000000002167. 2. Copper-bearing intrauterine device (Cu-IUD) use and HIV acquisition in women A systematic review was conducted on Cu-IUD use and HIV acquisition in women. The following six articles met the inclusion criteria. PUBLISHED REVIEW 1. Hannaford PC, Ti A, Chipato T, Curtis KM. Copper intrauterine device use and HIV acquisition in women: an updated systematic review. BMJ Sex Reprod Health 2020; 46:17-25. (http://dx.doi.org/10.1136/bmjsrh-2019-200512). NEW ARTICLES 1. Hofmeyr GJ, Singata-Madliki M, Lawrie TA, Bergel E, Temmerman M. Effects of injectable progestogen contraception versus the copper intrauterine device on HIV acquisition: sub-study of a pragmatic randomised controlled trial. J Fam Plann Reprod Health Care. 2017;43(3):175–80. doi: 10.1136/jfprhc-2016-101607. 2. Kapiga SH, Lyamuya EF, Lwihula GK, Hunter DJ. The incidence of HIV infection among women using family planning methods in Dar es Salaam, Tanzania. AIDS. 1998;12(1):75–84. doi: 10.1097/00002030-199801000-00009. 3. Lavreys L, Baeten JM, Martin Jr HL, Overbaugh J, Mandaliya  K, Ndinya-Achola J et al. Hormonal contraception and risk of HIV-1 acquisition: results of a 10-year prospective study. AIDS. 2004;18(4):695–7. 4. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619– 22. doi: 10.1097/QAD.0000000000002260. 5. Saracco A, Musicco M, Nicolosi A, Angarano G, Arici C, Gavazzeni G et al. Man-to-woman sexual transmission of HIV: longitudinal study of 343 steady partners of infected men. J Acquir Immune Defic Syndr. 1993;6(5):497-502. 6. Sinei SK, Fortney JA, Kigondu CS, Feldblum PJ, Kuyoh M, Allen MY et al. Contraceptive use and HIV infection in Kenyan family planning clinic attenders. Int J STD AIDS. 1996;7(1):65–70. doi: 10.1258/0956462961917104. 3. Contraceptive values and preferences A systematic review was conducted on contraceptive values and preferences. The protocol and methods are published, and the manuscript presenting the main results of the review is under review for publication. As this review did not identify information specific to key populations at risk of HIV, consultative engagements were conducted in the spring of 2019, including a global online survey of sex workers, and participatory focus group discussions with female sex workers | Contraceptive eligibility for women at high risk of HIV: guidance statement24 in Zimbabwe through the Sisters with a Voice programme. Presentations showing the findings from these engagements are listed below and available on request. A presentation shared by stakeholders representing affected populations to highlight their perspectives on the topic was part of the Guideline Development Group’s discussions and is available on request. 1. Kennedy CE, Yeh PT, Gaffield ME. Contraception values and preferences: protocol and methods for a global systematic review. Contraception. 2019 (in press). doi: 10.1016/j. contraception.2018.05.006Get. 2. Yeh PT, Kennedy CE, Gaffield ME. Contraception values and preferences: a global systematic review. Contraception. 2019; (accepted pending revisions). 3. Shapiro A. Female sex workers’ contraceptive practices, values and preferences. contraception and risk of HIV infection: a WHO Guideline Development Group review of the current evidence. 29 July 2019, Geneva, World Health Organization. 4. Sibanda E. Views on contraceptive methods among female sex workers in Harare, Zimbabwe: a participatory qualitative study. 29 July 2019, Geneva, World Health Organization. 5. Mworeko L. What do recommendations on contraceptives and HIV risk mean to women?, 29 July 2019, Geneva, World Health Organization.

For more information, please contact: Department of Reproductive Health and Research, World Health Organization, Avenue Appia 20, CH-1211 Geneva 27, Switzerland. E-mail: reproductivehealth@who.int www.who.int/reproductivehealth ISBN 978-92-4-155057-4

Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV Diretrizes Recomendações sobre o uso de métodos contraceptivos por mulheres com alto risco de infecção pelo HIV

Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV Diretrizes Recomendações sobre o uso de métodos contraceptivos por mulheres com alto risco de infecção pelo HIV Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV. Diretriz: recomendações sobre o uso de métodos contraceptivos por mulheres com alto risco de infecção pelo HIV [Contraceptive eligibility for women at high risk of HIV. Guidance statement: recommendations on contraceptive methods used by women at high risk of HIV] ISBN 978-92-4-000460-3 (versão electrónica) ISBN 978-92-4-000461-0 (versão impressa) © Organização Mundial da Saúde 2020 Alguns direitos reservados. Este trabalho é disponibilizado sob licença de Creative Commons Attribution-NonCommercial- ShareAlike 3.0 IGO (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo/deed.pt). Nos termos desta licença, é possível copiar, redistribuir e adaptar o trabalho para fins não comerciais, desde que dele se faça a devida menção, como abaixo se indica. Em nenhuma circunstância, deve este trabalho sugerir que a OMS aprova uma determinada organização, produtos ou serviços. O uso do logótipo da OMS não é autorizado. Para adaptação do trabalho, é preciso obter a mesma licença de Creative Commons ou equivalente. Numa tradução deste trabalho, é necessário acrescentar a seguinte isenção de responsabilidade, juntamente com a citação sugerida: “Esta tradução não foi criada pela Organização Mundial da Saúde (OMS). A OMS não é responsável, nem pelo conteúdo, nem pelo rigor desta tradução. A edição original em inglês será a única autêntica e vinculativa”. Qualquer mediação relacionada com litígios resultantes da licença deverá ser conduzida em conformidade com o Regulamento de Mediação da Organização Mundial da Propriedade Intelectual. Citação sugerida. Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV. Diretriz: recomendações sobre o uso de métodos contraceptivos por mulheres com alto risco de infecção pelo HIV [Contraceptive eligibility for women at high risk of HIV. Guidance statement: recommendations on contraceptive methods used by women at high risk of HIV]. Genebra: Organização Mundial da Saúde; 2020. Licença: CC BY-NC-SA 3.0 IGO. Dados da catalogação na fonte (CIP). Os dados da CIP estão disponíveis em http://apps.who.int/iris/. Vendas, direitos e licenças. Para comprar as publicações da OMS, ver http://apps.who.int/bookorders. Para apresentar pedidos para uso comercial e esclarecer dúvidas sobre direitos e licenças, consultar http://www.who.int/about/licensing. Materiais de partes terceiras. Para utilizar materiais desta publicação, tais como quadros, figuras ou imagens, que sejam atribuídos a uma parte terceira, compete ao utilizador determinar se é necessária autorização para esse uso e obter a devida autorização do titular dos direitos de autor. O risco de pedidos de indemnização resultantes de irregularidades pelo uso de componentes da autoria de uma parte terceira é da responsabilidade exclusiva do utilizador. Isenção geral de responsabilidade. As denominações utilizadas nesta publicação e a apresentação do material nela contido não significam, por parte da Organização Mundial da Saúde, nenhum julgamento sobre o estatuto jurídico ou as autoridades de qualquer país, território, cidade ou zona, nem tampouco sobre a demarcação das suas fronteiras ou limites. As linhas ponteadas e tracejadas nos mapas representam de modo aproximativo fronteiras sobre as quais pode não existir ainda acordo total. A menção de determinadas companhias ou do nome comercial de certos produtos não implica que a Organização Mundial da Saúde os aprove ou recomende, dando-lhes preferência a outros análogos não mencionados. Salvo erros ou omissões, uma letra maiúscula inicial indica que se trata dum produto de marca registado. A OMS tomou todas as precauções razoáveis para verificar a informação contida nesta publicação. No entanto, o material publicado é distribuído sem nenhum tipo de garantia, nem expressa nem implícita. A responsabilidade pela interpretação e utilização deste material recai sobre o leitor. Em nenhum caso se poderá responsabilizar a OMS por qualquer prejuízo resultante da sua utilização. Tradução por Dra Carolina Sales Vieira, associação de Obstetrícia e Ginecologia do Estado de São Paulo, SOGESP, Brasil. Em caso de discrepância entre a versão em inglês e a versão portuguesa, o texto original em inglês será a versão vinculativa e autêntica. Printed in Switzerland Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz | iii 1 2 3 4 5 AGRADECIMENTOS V SIGLAS E ACRÔNIMOS V RESUMO EXECUTIVO VI CONTEXTO 1 MÉTODOS DE REVISÃO E DESENVOLVIMENTO DAS DIRETRIZES 2 2.1 Grupo de desenvolvimento das diretrizes 2 2.2 Processo de desenvolvimento das diretrizes 2 2.3 Busca e obtenção de evidências 3 2.4 Síntese de evidências 4 2.5 Formulação das recomendações 5 RESUMO DAS EVIDÊNCIAS 5 3.1 Injetáveis contendo apenas progestagênio 6 3.2 Implantes contendo apenas progestagênio 6 3.3 Pílulas de progestagênio 6 3.4 Dispositivos intrauterinos 6 3.5 Contraceptivos hormonais combinados 6 3.6 Evidências adicionais consideradas pelo GDD 6 3.6.1 Dados biológicos 6 3.6.2 Valores e preferências das usuárias de contraceptivos 7 RECOMENDAÇÕES 7 4.1 Recomendações para uso de contraceptivos entre mulheres com alto risco de infecção pelo HIV 7 4.2 Fundamentação 8 IMPLICAÇÕES PARA FORMULADORES DE POLÍTICAS, DIRETORES DE PROGRAMAS E PROFISSIONAIS DE SAÚDE 9 5.1 O risco de uma mulher para o HIV não deve restringir sua escolha contraceptiva 9 5.2 Os esforços para expandir o acesso às opções contraceptivas devem continuar 9 5.3 Uma nova ênfase nos serviços de prevenção de HIV e ISTs é urgentemente necessária 10 ÍNDICE | Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriziv SUMÁRIO LACUNAS DE CONHECIMENTO E ÁREAS DE PESQUISA 11 6.1 Métodos contraceptivos e aquisição do HIV 11 6.2 Prevenção do HIV 11 6.3 Envolvimento da comunidade 11 6.4 Maior financiamento para pesquisa de alta qualidade e relevante para elaboração de políticas 11 DIVULGAÇÃO DESTA DIRETRIZ 12 REFERÊNCIAS 13 ANEXO 1: GRUPO DE DESENVOLVIMENTO DAS DIRETRIZES E SECRETARIADO DE EVIDÊNCIAS 15 ANEXO 2: DECLARAÇÕES DE CONFLITOS DE INTERESSE 17 ANEXO 3: PERFIS DE EVIDÊNCIA GRADE 19 ANEXO 4: TABELA DE EVIDÊNCIAS PARA A TOMADA DE DECISÃO PARA MÉTODOS CONTRACEPTIVOS HORMONAIS E DISPOSITIVOS INTRAUTERINOS (DIU) 24 ANEXO 5: REVISÕES SISTEMÁTICAS 27 6 7 Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz | v AGRADECIMENTOS A Organização Mundial da Saúde (OMS) gostaria de agradecer aos membros do Grupo de Desenvolvimento das Diretrizes e do Secretariado de Evidências (Anexo 1) por suas contribuições ao longo do desenvolvimento dessas importantes recomendações para mulheres com alto risco de infecção pelo HIV. A OMS está muito agradecida pelas sugestões fornecidas pelos colegas que revisaram o esboço da declaração como membros do Grupo de Revisores Externos. O desenvolvimento desta declaração técnica foi apoiado financeiramente pela Fundação Bill & Melinda Gates, pelo Ministério de Relações Exteriores da Holanda, pela Agência dos Estados Unidos para o Desenvolvimento Internacional (United States Agency for International Development - USAID) e pelos Institutos Nacionais de Saúde dos Estados Unidos (United States National Institutes of Health - NIH). SIGLAS E ACRÔNIMOS AMPD-IM acetato de medroxiprogesterona de depósito intramuscular AMPD-SC acetato de medroxiprogesterona de depósito subcutâneo CIC contraceptivo injetável combinado CME Critérios Médicos de Elegibilidade para uso de contraceptivos (publicação da OMS) COC contraceptivo oral combinado CRE WHO Office of Compliance, Risk Management and Ethics (Departamento da OMS para a Conformidade, Gestão de Riscos e Ética) DIU dispositivo intrauterino DIU-Cu dispositivo intrauterino de cobre DIU-LNG dispositivo intrauterino liberador de levonorgestrel ECHO Evidence for Contraceptive Options and HIV (Evidências para Opções Contraceptivas e HIV) ECR Ensaio clínico randomizado ETG etonogestrel FDA United States Food and Drug Administration (Agência Regulatória Americana de Medicamentos e Alimentos) GDD Grupo de Desenvolvimento das Diretrizes GRADE Grading Recommendations, Assessment, Development and Evaluation (Sistema GRADE – graduação da qualidade das evidências e força das recomendações para tomada de decisões em saúde) HR hazard ratio (razão de risco) IRR incidence rate ratio (razão da taxa de incidência) IST Infecção sexualmente transmissível LNG levonorgestrel NET-EN enantato de norestisterona OMS Organização Mundial de Saúde PP pílula de progestagênio PrEP Profilaxia pré-exposição (para HIV) | Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretrizvi RESUMO EXECUTIVO A Organização Mundial da Saúde (OMS) convocou uma reunião do Grupo de Desenvolvimento das Diretrizes (GDD) de 29 a 31 de julho de 2019 para revisar as orientações sobre a elegibilidade dos métodos contraceptivos para mulheres com alto risco de aquisição do HIV e determinar se a quinta edição dos Critérios Médicos de Elegibilidade (CME) para uso de contraceptivos necessitava alterar essas orientações. Essas orientações foram consideradas críticas, particularmente para a África Subsaariana, dado o alto risco de contrair o vírus ao longo da vida nesta região e a importância da contracepção hormonal para oferecer escolhas às mulheres e adolescentes e para reduzir o risco de uma gravidez não planejada, que é uma ameaça comum à saúde, ao bem-estar e à vida de mulheres e adolescentes. O GDD era constituído por 28 participantes de 19 países, incluindo especialistas em planejamento familiar e HIV, representantes de populações afetadas, clínicos, epidemiologistas, pesquisadores, gestores de programas, formuladores de políticas e especialistas em metodologia de diretrizes. O GDD considerou os seguintes fatores ao formular recomendações para cada método contraceptivo: ■ qualidade das evidências (ou seja, o perfil GRADE)1 ■ valores e preferências das usuárias de contraceptivos ■ balanço entre benefícios e malefícios ■ prioridade do problema ■ equidade e direitos humanos ■ viabilidade. Ao formular essas recomendações, o GDD manteve no centro de suas deliberações os indivíduos mais afetados pelas recomendações, ou seja, as mulheres que desejam evitar uma gravidez e possuem um alto risco de adquirir o HIV. Por consenso, o GDD concordou com as novas recomendações apresentadas a seguir. Pelas novas recomendações, as mulheres com alto risco de adquirir o HIV podem usar todos os métodos contraceptivos sem restrição. ■ Mulheres com alto risco de infecção pelo HIV são elegíveis para usar todos os métodos contraceptivos exclusivos de progestagênio sem restrição (Categoria 1 dos CME), incluindo pílulas de progestagênio (PP), acetato de medroxiprogesterona de depósito de administração intramuscular e subcutânea (AMPD-IM e AMPD-SC ), enantato de noretisterona (NET-EN) injetável e implantes liberadores de levonorgestrel (LNG) ou de etonogestrel (ETG). 1 GRADE = Grading of Recommendations Assessment, Development and Evaluation (for further information, see: http://www.gradeworkinggroup.org). ■ Mulheres com alto risco de infecção pelo HIV são elegíveis para usar dispositivos intrauterinos contendo cobre (DIU-Cu) e liberadores de levonorgestrel (DIU-LNG) sem restrição (Categoria 1 dos CME). Ao considerar o uso de DIU, muitas mulheres com alto risco de infecção pelo HIV também correm risco de outras infecções sexualmente transmissíveis (IST); para essas mulheres, os profissionais de saúde devem consultar as recomendações dos CME sobre uso de contraceptivos em mulheres de risco aumentado para IST e as recomendações sobre a triagem de IST antes da inserção de DIU contidas na terceira edição das Recomendações sobre Práticas Selecionadas para uso de Contraceptivos (Selected practice recommendations for contraceptive use: third edition). ■ Mulheres com alto risco de infecção pelo HIV são elegíveis para usar todos os métodos contraceptivos hormonais combinados sem restrição (CME Categoria 1), incluindo contraceptivos orais combinados (COC), contraceptivos injetáveis combinados (CIC), adesivos contraceptivos combinados e anéis vaginais combinados. Essas recomendações foram fortemente baseadas em novas evidências epidemiológicas, particularmente em um estudo controlado randomizado de alta qualidade (estudo ECHO), que não mostrou diferença estatisticamente significativa na aquisição do HIV entre mulheres usando um dos três métodos contraceptivos estudados: AMPD-IM, DIU-Cu e Implante de LNG. Essa evidência de alta qualidade substituiu a evidência observacional anteriormente disponível, que era considerada de qualidade baixa e de baixa a moderada, dependendo do método contraceptivo. Para os COC e o NET-EN injetável, as evidências de qualidade baixa e baixa a moderada de estudos observacionais não indicaram aumento do risco de infecção pelo HIV. Embora nenhuma evidência direta estivesse disponível para o AMPD-SC, o DIU-LNG ou implantes de ETG, não havia razão biológica ou clínica para acreditar que uma dose hormonal mais baixa, um mecanismo de administração diferente ou um progestagênio diferente modificassem o risco de HIV. A consideração dos valores, preferências, opiniões e preocupações das mulheres em relação aos métodos contraceptivos forneceu suporte para otimizar a escolha contraceptiva informada e a disponibilidade de uma ampla gama de opções contraceptivas. Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz | vii Existem várias mensagens importantes desta diretriz para os formuladores de políticas, diretores de programas e profissionais de saúde. ■ O risco de uma mulher adquirir o HIV não restringe sua escolha contraceptiva. ■ Os esforços para expandir as opções de métodos contraceptivos e garantir o acesso total e equitativo aos serviços de planejamento familiar devem continuar. ■ Uma ênfase reforçada nos serviços de testagem e prevenção de HIV/IST é urgentemente necessária, incluindo a integração do planejamento familiar com serviços de HIV/ IST, conforme apropriado, juntamente com pacotes de saúde sexual e reprodutiva. CONTRACEPTIVOS CONTENDO APENAS PROGESTAGÊNIOS (CAP) Os contraceptivos contendo apenas progestagênio (CAP) não protegem contra infecções sexualmente transmissíveis (IST), incluindo o HIV. Se houver risco de IST/HIV, recomenda-se o uso correto e consistente de preservativos. Quando usados de maneira correta e consistente, os preservativos são um dos métodos mais eficazes de proteção contra as IST, incluindo o HIV. Os preservativos femininos são tão eficazes e seguros quanto os masculinos, mas não são usados tão amplamente quanto os masculinos pelos programas nacionais. Condição Categoria dos CME Esclarecimentos / evidências PP AMPD/ NET-EN LNG/ETG implantes Alto risco de infecção pelo HIV 1 1 1 Evidências: Evidências de alta qualidade de um estudo controlado randomizado não observaram diferenças estatisticamente significativas na aquisição do HIV entre: AMPD-IM versus DIU-Cu, AMPD-IM versus implante de LNG e DIU-Cu versus implante de LNG. Das evidências de qualidade baixa a moderada de 14 estudos observacionais, alguns estudos sugeriram um possível aumento do risco de aquisição do HIV com uso do injetável contendo apenas progestagênio (AMPD), o que provavelmente ocorreu devido a fatores de confusão não medidos nestes estudos. Evidências de baixa qualidade de três estudos observacionais não sugeriram aumento de risco para aquisição de HIV para usuárias de implantes. Não foram identificados estudos de qualidade suficiente para as PP. AMPD: acetato de medroxiprogesterona de depósito (injetável); CME: Critérios médicos de elegibilidade para uso de contraceptivos; DIU-Cu: dispositivo intrauterino de cobre; IM: intramuscular; LNG/ ETG: levonorgestrel e etonogestrel (implantes); NET-EN: enantato de noretisterona (injetável); PP: pílula de progestagênio DISPOSITIVOS INTRAUTERINOS Os dispositivos intrauterinos (DIU) não protegem contra infecções sexualmente transmissíveis (IST), incluindo o HIV. Se houver risco de IST/HIV, recomenda-se o uso correto e consistente de preservativos. Quando usados de maneira correta e consistente, os preservativos são um dos métodos mais eficazes de proteção contra as IST, incluindo o HIV. Os preservativos femininos são tão eficazes e seguros quanto os masculinos, mas não são usados tão amplamente quanto os masculinos pelos programas nacionais. Condição Categoria dos CME Esclarecimentos / evidências DIU-Cu DIU-LNG (20 μg/24 horas) Alto risco de infecção pelo HIV Iniciar Continuar Iniciar Continuar Esclarecimento: Muitas mulheres com alto risco de adquirir o HIV também correm risco de adquirir outras IST. Para essas mulheres, consulte a recomendação nos critérios de elegibilidade médica para uso de contraceptivos em mulheres com risco aumentado de adquirir IST e as recomendações da 3ª edição das Práticas Selecionadas para uso de Contraceptivos sobre o rastreamento de IST antes da inserção de DIU. Evidências: Evidências de alta qualidade de um estudo controlado randomizado, juntamente com evidências de baixa qualidade de dois estudos observacionais, não sugeriram aumento de risco de aquisição do HIV com o uso do DIU- Cu. Não foram identificados estudos para os DIU-LNG. 1 1 1 1 CME: Critérios médicos de elegibilidade para uso de contraceptivos; DIU-Cu: dispositivo intrauterino de cobre; DIU-LNG: DIU liberador de levonorgestrel | Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretrizviii CONTRACEPTIVOS HORMONAIS COMBINADOS Os contraceptivos hormonais combinados (CHC) não protegem contra infecções sexualmente transmissíveis (IST), incluindo o HIV. Se houver risco de IST/HIV, recomenda-se o uso correto e consistente de preservativos. Quando usados de maneira correta e consistente, os preservati- vos são um dos métodos mais eficazes de proteção contra IST, incluindo o HIV. Os preservativos femininos são tão eficazes e seguros quanto os masculinos, mas não são usados tão amplamente quanto os masculinos pelos programas nacionais. Condição Categoria dos CME Esclarecimentos / evidências COC A AVC CIC Alto risco de infecção pelo HIV 1 1 1 1 Evidências: Evidências de qualidade baixa a moderada de 11 estudos observacionais, não sugeriram associação entre o uso de COC e a aquisição do HIV (nesses casos, assumiu-se que estudos que não especificavam o tipo de contracep- tivo oral examinaram principalmente, se não exclusivamente, o uso de COC). Não foram identificados estudos de adesivos (A), AVC e CIC. A = adesivo combinado; AVC = anel vaginal combinado; CIC = contraceptivo injetável combinado; CME: Critérios médicos de elegibilidade para uso de contraceptivos; COC = contraceptivo oral combinado Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz | 1 TABELA 1. INTERPRETAÇÃO E APLICAÇÃO DAS CATEGORIAS DOS CRITÉRIOS MÉDICOS DE ELEGIBILIDADE (CME) Categoria Com bons recursos para o julgamento clínico Com recursos limitados para o julgamento clínico 1 Usar o método contraceptivo em qualquer circunstância Usar o método contraceptivo 2 Geralmente, usar o método contraceptivo 3 O uso do método contraceptivo não é geralmente recomendado, a não ser que métodos mais apropriados não estejam disponíveis ou não sejam aceitos Não usar o método contraceptivo 4 O método contraceptivo não pode ser usado O acesso a serviços e informações sobre saúde sexual e reprodutiva, incluindo uma ampla variedade de métodos contraceptivos, é fundamental para os direitos e o bem-estar das mulheres e adolescentes (1–4). Existe uma ampla gama de métodos contraceptivos modernos hormonais e não hormonais, que fornecem benefícios substanciais a nível individual e de saúde pública. Uma parte central do trabalho da Organização Mundial da Saúde (OMS) é o desenvolvimento e a manutenção de orientações atualizadas e baseadas em evidências sobre a segurança do uso de contraceptivos para indivíduos com condições médicas específicas ou características clinicamente relevantes (5). A quinta edição dos critérios médicos de elegibilidade para uso contraceptivo (CME) oferece aos formuladores de políticas nacionais e programas de planejamento familiar um conjunto abrangente de recomendações sobre a segurança médica dos métodos contraceptivos, permitindo o desenvolvimento informado de políticas, protocolos e programas nacionais (5). As orientações globais sobre segurança médica e elegibilidade facilitam a remoção de barreiras médicas desnecessárias para o acesso à contracepção. Por mais de 20 anos, os CME têm sido usados pelos países para maximizar a segurança e melhorar a qualidade dos cuidados contraceptivos oferecidos. As orientações sobre segurança são mantidas atualizadas por meio de monitoramento contínuo e revisões da literatura publicada. Em 2015, a OMS lançou a quinta edição dos CME (5). Esta edição contém mais de 2000 recomendações para 25 métodos contraceptivos diferentes, dentro do contexto de mais de 80 condições médicas ou características pessoais clinicamente relevantes. Dependendo do indivíduo, pode ser necessário considerar mais de uma condição ao fazer uma escolha contraceptiva informada (5). As recomendações dos CME são baseadas em várias considerações, incluindo se o uso de um método contraceptivo piora a condição médica ou cria riscos adicionais à saúde e se a condição torna o método contraceptivo menos eficaz (5). Os CME fazem parte de um conjunto de ferramentas com o objetivo de melhorar a cobertura e os cuidados contraceptivos em todo o mundo. Os CME informam as decisões sobre quem pode usar um método contraceptivo específico, por meio de informações e orientações sobre a segurança e adequação dos contraceptivos. As recomendações das Práticas Selecionadas para uso de Contraceptivos [Selected Practice Recommendations (SPR) for Contraceptive use: third edition, não disponível em português] fornecem orientações sobre como usar com segurança e eficácia vários métodos contraceptivos (6). A OMS produz uma gama de ferramentas para apoiar o uso e a implementação de orientações contraceptivas, como a roda dos CME (disponível em português) e o Manual Global para profissionais de saúde (Global Handbook for providers, não disponível em português) (7,8). Desde 1996, os CME aplicam uma escala de quatro categorias para indicar elegibilidade médica para métodos contraceptivos específicos na presença de condições particulares ou características individuais (por exemplo, alto risco de infecção pelo HIV). Para cada condição ou característica, os métodos contraceptivos são classificados em uma das quatro categorias numeradas: 1. Condição para a qual não há restrição ao uso do método contraceptivo. 2. Condição em que as vantagens do uso do método geralmente superam os riscos teóricos ou comprovados. 3. Condição em que os riscos teóricos ou comprovados geralmente superam as vantagens de se usar o método. 4. Condição que representa um risco inaceitável para a saúde se o método contraceptivo for usado. A interpretação e aplicação das categorias na prática são mostradas na Tabela 1. CONTEXTO1 | Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz2 2.1 Grupo de desenvolvimento das diretrizes O desenvolvimento destas diretrizes foi realizado por um grupo independente chamado Grupo de Desenvolvimento das Diretrizes (GDD) e por um painel adicional de revisores externos. O GDD era constituído por 28 participantes de 19 países, incluindo especialistas em planejamento familiar e HIV, representantes de populações afetadas, clínicos, epidemiologistas, pesquisadores, gestores de programas, formuladores de políticas e especialistas em metodologia de diretrizes (ver Anexo 1). Seguindo as orientações da OMS, meses antes da reunião do GDD, em julho de 2019, o nome e uma breve biografia de cada membro proposto do GDD foram publicados no site da OMS (https://www. who.int/reproductivehealth/publications/contraceptives-methods- hiv). O público podia consultar o site e apresentar opiniões sobre quaisquer conflitos de interesse reais ou percepcionados dos membros propostos. A OMS respondeu a todos os comentários e, consequentemente, ajustou a composição final do GDD. Antes da reunião do GDD, o Secretariado da OMS e o GDD analisaram as declarações de interesses dos membros (Anexo 2) e não encontraram conflitos de interesse suficientes para impedir que alguém participasse nas deliberações ou no desenvolvimento das recomendações. Os membros do GDD também foram convidados a declarar novos conflitos de interesse no início da reunião. Nenhum conflito adicional foi declarado. 2.2 Processo de desenvolvimento das diretrizes Esta declaração de orientação foi preparada de acordo com os padrões e requisitos especificados no manual da OMS para o No passado, a presença de evidências mistas questionava se os métodos contraceptivos hormonais, particularmente o acetato de medroxiprogesterona de depósito (AMPD), estariam associados a um risco aumentado de aquisição do HIV. As evidências disponíveis, naquela época, consistiam em dados biológicos teóricos e estudos observacionais com limitações importantes. Em 2016, o Grupo de Desenvolvimento das Diretrizes (GDD) dos CME, que é um grupo independente, revisou as evidências acumuladas sobre mulheres com alto risco de adquirir o HIV (9). O GDD concluiu que ainda havia incerteza sobre se o aumento do risco de aquisição do HIV, registado em alguns estudos observacionais, era um efeito real do método contraceptivo usado ou se era um artefato estatístico resultante das principais limitações dos estudos observacionais (confundidores residuais em particular) (9). Existiam ainda dúvidas sobre a relevância clínica dos dados biológicos disponíveis. Além disto, havia a preocupação de que as tentativas anteriores de informar as mulheres da incerteza sobre os dados epidemiológicos e biológicos [através do esclarecimento contido nos CME, indicado por um asterisco (*)] não haviam sido eficazes. Dadas essas preocupações, o GDD concluiu que as recomendações dos CME deveriam ser alteradas. Assim, em 2017, a recomendação para uso de injetável somente de progestagênio entre mulheres com alto risco de infecção pelo HIV foi alterada da Categoria 1 dos CME* (sem restrições de uso, com esclarecimentos) para a Categoria 2 dos CME (os benefícios do uso superam os riscos) acompanhada de um esclarecimento (9). Essa nova classificação indicava que os contraceptivos injetáveis contendo apenas progestagênio poderiam ser usados por mulheres com alto risco de infecção pelo HIV, porque as vantagens desses métodos geralmente superavam as possíveis desvantagens, mas indicava também que, ao escolher esses métodos, seria necessário ter igualmente em consideração o risco de aquisição do HIV e oferecer aconselhamento. Como parte da revisão de 2017, a OMS reafirmou seu compromisso de monitorar e avaliar qualquer nova evidência relevante para a segurança contraceptiva. Novas informações, incluindo resultados de um grande ensaio clínico multinacional, randomizado e controlado (10), levaram a OMS a convocar outra reunião do GDD em julho de 2019, para analisar todas as evidências disponíveis e avaliar se as recomendações dos CME sobre este tópico precisavam de revisão. MÉTODOS DE REVISÃO E DESENVOLVIMENTO DAS DIRETRIZES2 Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz | 3 desenvolvimento de diretrizes (WHO handbook for guideline development) (11). Esse processo é usado para garantir que as diretrizes da OMS sejam da mais alta qualidade e sigam um processo sistemático e transparente. As principais etapas do processo de elaboração das diretrizes incluem: a) determinar as questões e resultados críticos; b) buscar as evidências; c) sintetizar e classificar as evidências, apresentando-as através de uma abordagem estruturada e d) formular recomendações. O Comitê Diretor de Diretrizes (CDD) de Planejamento Familiar da OMS determinou as questões e resultados críticos a serem considerados pelo GDD. Tipos distintos de evidências foram identificados como essenciais para a revisão: as evidências de saúde (dados de estudos randomizados e de estudos epidemiológicos observacionais), as evidências de plausibilidade biológica e os dados sobre os valores e preferências das usuárias de contraceptivos. Aplicando o sistema GRADE (Grading Recommendations, Assessment, Development and Evaluation – graduação da qualidade das evidências e força das recomendações para tomada de decisões em saúde) 2 para avaliação das evidências, vários fatores são considerados na formulação de recomendações (12). Isso inclui: a qualidade das evidências epidemiológicas (encontradas nos perfis de evidências GRADE, que são preparados com base em revisões sistemáticas atualizadas); os valores e preferências das usuárias de contraceptivos; o balanço entre os benefícios e danos; a prioridade do problema; equidade e direitos humanos; aceitabilidade; e viabilidade. Os princípios e padrões de direitos humanos descritos nas orientações da OMS, “Ensuring human rights in the provision of contraceptive information and services”, foram incorporados nas deliberações (1). Devido ao foco na segurança contraceptiva, os custos não foram formalmente avaliados durante a formulação das recomendações, uma vez que eles podem variar amplamente em diferentes regiões (13). O sistema GRADE que faz a graduação da qualidade da evidência e força de recomendação para tomada de decisão em saúde (uma ferramenta que engloba qualidade da evidência, equilíbrio de benefícios versus danos, valores e preferências, prioridade do problema, equidade e direitos humanos, viabilidade) foi usada para garantir que as recomendações fossem baseadas considerando todos estes padrões (11). 2 Para mais informações, consultar: http://www.gradeworkinggroup.org 2.3 Busca e obtenção de evidências As recomendações existentes da OMS sobre o uso de métodos contraceptivos específicos por mulheres com alto risco de infecção pelo HIV foram analisadas de acordo com os procedimentos descritos pelo Comitê de Revisão das Diretrizes da OMS e pelo sistema GRADE para graduação e força de recomendação das evidências (11,12). Três revisões sistemáticas foram conduzidas em preparação para a reunião do GDD: duas referentes às evidências epidemiológicas e a terceira revisão sintetizou estudos qualitativos ou quantitativos sobre os valores, preferências, opiniões e preocupações das usuárias sobre métodos contraceptivos. As duas revisões sistemáticas de evidências epidemiológicas conduzidas para a reunião do GDD foram: 1. Uma revisão sistemática atualizada sobre contracepção hormonal e risco de aquisição do HIV para incluir os novos estudos publicados desde 2016, ano em que foi realizada a última revisão sistemática (14). A pergunta da revisão foi: ■ Entre as mulheres em risco de infecção pelo HIV, o uso de um método contraceptivo hormonal em comparação com o não uso de um método contraceptivo hormonal (ou o uso de outro método contraceptivo hormonal específico) aumenta o risco de aquisição do HIV? 2. Também foi realizada uma revisão sistemática sobre o uso do dispositivo intrauterino de cobre (DIU-Cu) e o risco de aquisição do HIV. As perguntas da revisão foram: ■ Entre as mulheres em risco de infecção pelo HIV, o uso do DIU-Cu comparado ao uso de outro método contraceptivo não hormonal ou nenhum método contraceptivo aumenta o risco de aquisição do HIV? ■ Entre as mulheres em risco de infecção pelo HIV, o uso do DIU-Cu em comparação ao uso de um método contraceptivo hormonal específico aumenta o risco de aquisição do HIV? Os critérios de seleção para as revisões sistemáticas estão listados na Tabela 2. Os mesmos desenhos, população, comparadores e resultados do estudo foram considerados para todos os métodos contraceptivos estudados. | Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz4 TABELA 2. CRITÉRIOS DE SELEÇÃO PARA AS REVISÕES SISTEMÁTICAS Desenho dos estudos Estudos longitudinais (ensaios clínicos randomizados e estudos observacionais ou meta-análises contendo dados não captur- ados em pesquisas bibliográficas nos bancos de dados) População Mulheres em idade reprodutiva em risco de infecção pelo HIV (mulheres que não viviam com HIV na linha de base) Intervenção Uso de um método contraceptivo específico: ■ contracepção hormonal (injetáveis, contraceptivos orais, implantes, adesivos, anéis ou dispositivos intrauterinos liberadores de levonorgestrel) ■ dispositivos intrauterinos de cobre (DIU-Cu) Comparador Um dos dois grupos de comparação: 1. não uso de um método contraceptivo hormonal (não uso de contraceptivo ou uso de um método não hormonal, como preservativos ou outro método de barreira, abstinência, DIU-Cu ou laqueadura tubária / vasectomia) 2. uso de outro método contraceptivo hormonal específico Resultados Infecção incidente pelo HIV confirmada por exame laboratorial em mulheres As duas revisões sistemáticas foram realizadas de acordo com o guia apropriado, chamado de PRISMA (preferred reporting items for systematic reviews and meta-analyses) (15). As bases de dados PubMed e Embase foram pesquisadas para estudos publicados em qualquer idioma na literatura revisada por pares até 26 de junho de 2019. Para estudos individuais, o risco de viés foi avaliado usando um sistema de qualidade descrito na revisão anterior (14). Os estudos foram classificados em três níveis: 1. “Improvável de informar a questão principal da revisão”: estudos que (a) não fizeram ajustes para qualquer medida de uso de preservativo ou (b) fizeram uma medição pouco clara da exposição ao uso de contraceptivos. 2. “Informativo, mas com limitações importantes”: estudos que não apresentavam nenhuma das falhas descritas acima, mas que ainda tinham potencial para fatores de confusão não mensurados ou residuais. 3. “Informativo com poucas limitações”: estudos que não apresentavam nenhuma das falhas acima, provavelmente um ensaio clínico randomizado que foi avaliado como tendo baixo risco de viés nos critérios padronizados para avaliação desses estudos. O foco das revisões sistemáticas estava nas informações de estudos considerados “informativos, mas com limitações importantes” ou “informativos com poucas limitações”, os quais foram classificados como níveis 2 e 3. Os valores e preferências das usuárias de contraceptivos foram incorporados de várias maneiras. Primeiro, foi realizada uma revisão sistemática atualizada de estudos qualitativos e quantitativos sobre os valores, preferências, visões e preocupações das usuárias em relação aos métodos contraceptivos considerados de acordo as orientações dos Critérios Médicos de Elegibilidade para o Uso de Contraceptivos (CME) (16). Esta revisão abrangeu estudos de qualquer país publicado na literatura revisada por pares, entre janeiro de 2005 e dezembro de 2017. Pouco antes da reunião do GDD em julho de 2019, essa revisão foi informalmente atualizada com estudos da literatura revisada por pares e da literatura cinza que avaliaram especificamente os valores e preferências das usuárias de contraceptivos relacionados à questão da contracepção hormonal e aquisição do HIV. Segundo, como a revisão sistemática atualizada não identificou nenhuma informação específica para populações-chave em risco de infecção pelo HIV, foram realizados estudos consultivos de maio a julho de 2019, incluindo um inquérito online global a profissionais do sexo e discussões em grupos focais com a participação de mulheres profissionais do sexo em Zimbábue (através do “Sisters with a Voice programme”). Terceiro, as partes interessadas que representam populações afetadas específicas, incluindo mulheres vivendo com HIV e mulheres jovens, contribuíram com suas perspectivas por meio de uma apresentação e discussão de perspectivas críticas na reunião do GDD. Uma atualização dos dados biológicos sobre o efeito teórico que a contracepção pode ter na aquisição do HIV foi preparada, revisada e discutida na reunião do GDD, incluindo a consideração da plausibilidade teórica de cada método de contracepção hormonal ter influência na aquisição do HIV. 2.4 Síntese de evidências Os dados epidemiológicos foram sintetizados e avaliados de acordo com o sistema GRADE para revisão de evidências (12). Baseado neste sistema, a qualidade das evidências provenientes dos ensaios clínicos randomizados é graduada inicialmente como alta. Já a qualidade da evidência de estudos observacionais é graduada inicialmente como baixa. O risco de viés foi avaliado para os resultados resumidos do conjunto de estudos incluídos usando os métodos padronizados pelo sistema GRADE (17). Os fatores que poderiam reduzir o nível de evidência foram limitações na metodologia da evidência (risco de viés), inconsistência entre os estudos, imprecisão de estimativas, evidência indireta e viés de publicação (17–22). O risco de viés dos ensaios randomizados foram avaliados de forma sistemática através da ocultação inadequada da randomização/alocação; cegamento inadequado dos tratamentos; alta taxa de perda de pacientes no estudo (seguimento incompleto); falha em usar análises de intenção de tratar; apresentação seletiva dos resultados; e contaminação entre os grupos (17). Já o risco de viés dos estudos observacionais foi avaliado examinando se houve falha no desenvolvimento e na aplicação de critérios de elegibilidade apropriados, na medição da exposição ou dos resultados, no tratamento adequado dos fatores de confusão e se houve seguimento incompleto (alta taxa de perda de pacientes no estudo) (17). Os fatores que poderiam aumentar o nível de Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz | 5 RESUMO DAS EVIDÊNCIAS3 evidência dos estudos observacionais incluíram a presença de uma relação dose-resposta, uma grande magnitude de associações observadas e ajuste para fatores de confusão plausíveis que afetam as associações observadas (22). 2.5 Formulação das recomendações As conclusões das revisões sistemáticas e os perfis de evidências GRADE (Anexo 3) foram apresentados na reunião do GDD. Também foram apresentados os seguintes tópicos: uma apresentação sobre a plausibilidade biológica da contracepção hormonal modificar o risco de aquisição do HIV e várias apresentações sobre os valores e preferências das usuárias de contraceptivos. Estes conteúdos foram usados para desenvolver uma estrutura de evidências para decisão (Anexo 4), que serviu de base para as deliberações do GDD durante a reunião (12). Todas as recomendações foram aprovadas por consenso. Depois que as recomendações do GDD foram feitas, um pequeno grupo de redação preparou um esboço das diretrizes resumindo a decisão e a fundamentação. Este esboço foi revisado por todo o GDD e pelo grupo de revisão externa (ver Anexo 1). Os comentários recebidos do GDD e do grupo de revisão externa foram considerados e abordados pelo grupo de redação. A versão final desta diretriz foi aprovada pelo Comitê de Revisão das Diretrizes da OMS, em 22 de agosto de 2019. O estudo Evidence for Options Contraceptive and HIV Results (ECHO)3 foi a principal fonte de novas evidências, desde que a OMS revisou as recomendações sobre contracepção para mulheres com alto risco de infecção pelo HIV (9). O Estudo ECHO foi um grande ensaio clínico randomizado (ECR) realizado em Reino de Essuatíni, Quênia, África do Sul e Zâmbia, desenhado especificamente para comparar a incidência de HIV entre usuárias de três métodos contraceptivos: acetato de medroxiprogesterona de depósito intramuscular (AMPD-IM), implantes de levonorgestrel (LNG) e dispositivos intrauterinos contendo cobre (DIU-Cu) (10). O estudo randomizou 7829 mulheres soronegativas para o HIV, com idades entre 16 e 35 anos, que desejavam contracepção eficaz e consentiram em ser randomizadas para um dos três métodos contraceptivos. Não houve grupo de não usuárias de métodos contraceptivos no estudo ECHO, porque todas as mulheres inscritas desejavam contracepção eficaz. As mulheres retornavam a cada três meses para testes de HIV, aconselhamento contraceptivo, monitoramento de segurança, avaliação comportamental e um pacote abrangente de serviços de prevenção de HIV; por até 18 meses. As principais comparações (primárias) usaram uma análise modificada da intenção de tratar. Além disso, foram realizadas análises pré-planejadas (secundárias), restritas ao uso contínuo do 3 Para mais informações, consultar: http://echo-consortium.com método contraceptivo designado e ajustadas para vários fatores de confusão importantes, incluindo sexo vaginal sem preservativo, um novo parceiro sexual nos últimos três meses e mais de um parceiro sexual. No estudo ECHO, a significância estatística considerada foi um valor de P menor que 0,04 para as comparações primárias. Não foram encontradas associações estatisticamente significativas para nenhuma das comparações primárias entre os três métodos contraceptivos (Anexo 3). A qualidade das evidências deste ECR foi classificada como alta, devido ao seu grande tamanho, procedimentos de randomização e alocação robustos, altas taxas de seguimento, alta taxa de continuidade do método contraceptivo alocado, medição objetiva da incidência do HIV e análise abrangente dos resultados. Outras evidências sobre contracepção hormonal e aquisição do HIV publicadas desde a revisão de 2016 (14) foram incluídas na avaliação do corpo de evidências, juntamente com uma revisão sistemática sobre DIU-Cu e risco de aquisição do HIV (Anexo 3). Para a contracepção hormonal, foram identificados um novo estudo observacional e estimativas atualizadas de um estudo anteriormente incluído (23,24). A adição dessa evidência aos 14 estudos observacionais anteriores (14) não | Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz6 alterou as conclusões da revisão anterior. Assim, o corpo de evidências observacionais sugeriu alguma preocupação sobre o aumento de risco de aquisição do HIV com o uso de AMPD-IM, mas, de modo geral, foi tranquilizador para outros métodos de contracepção hormonal em relação ao risco de aquisição do HIV. Para dispositivos intrauterinos (DIU), dois estudos observacionais não sugeriram aumento do risco de aquisição do HIV com o uso de DIU-Cu (23,25). A qualidade das evidências desses estudos observacionais foi classificada como baixa e baixa a moderada. 3.1 Injetáveis contendo apenas progestagênio Um ECR (estudo ECHO) não observou diferenças estatisticamente significativas na aquisição do HIV ao comparar o AMPD-IM versus o DIU-Cu e o AMPD-IM versus o implante de LNG (10). A qualidade das evidências deste ECR foi classificada como alta. Foram avaliadas as evidências de 14 estudos observacionais sobre AMPD-IM, enantato de noretisterona (NET-EN) ou injetáveis contendo apenas progestagênio (não especificado quais injetáveis). Estes estudos foram considerados “informativos, mas com limitações importantes” (14,23,24). Dados adicionais de um novo estudo observacional e estimativas atualizadas com o novo estudo incluído não alteraram as conclusões da revisão anterior de evidências observacionais (14). A qualidade das evidências dos estudos observacionais foi classificada como baixa e baixa a moderada, devido a limitações que incluíam fatores de confusão não medidos. 3.2 Implantes contendo apenas progestagênio Três estudos observacionais considerados “informativos, mas com limitações importantes” avaliaram os implantes. Um foi incluído na revisão anterior (26), um forneceu uma estimativa atualizada à utilizada na revisão anterior (24) e um forneceu uma estimativa de risco totalmente nova (23). Dois dos estudos avaliaram implantes de LNG (24,26) e o terceiro avaliou mulheres usando implantes de LNG ou etonogestrel (23). Nenhum dos três estudos sugeriu um risco aumentado de aquisição do HIV com o uso de implantes, consistente com a conclusão da revisão anterior (14). A qualidade das evidências desses estudos foi classificada como baixa. 3.3 Pílulas apenas de progestagênio Não foram identificados estudos considerados “informativos, mas com limitações importantes” ou “informativos com poucas limitações” para as pílulas apenas de progestagênio. 3.4 Dispositivos intrauterinos Um ECR (estudo ECHO) não observou diferenças estatisticamente significativas na aquisição do HIV entre AMPD- IM e DIU-Cu, ou implantes LNG e DIU-Cu (10). A qualidade das evidências deste ECR foi classificada como alta. Dois estudos observacionais considerados “informativos, mas com importantes limitações” não observaram associação com a aquisição do HIV ao comparar o uso de DIU-Cu com a ligadura tubária ou sem uso de método contraceptivo, AMPD- IM, NET-EN ou implantes (23,25). A qualidade dessa evidência observacional foi classificada como baixa. Nenhuma evidência foi identificada para o DIU-LNG. 3.5 Contraceptivos hormonais combinados Onze estudos observacionais considerados “informativos, mas com limitações importantes” avaliaram o uso de contraceptivos orais combinados (COC). (Foi assumido que estudos que não especificaram o tipo de contraceptivo oral utilizado, avaliaram principalmente, se não exclusivamente, os COC). Todos esses estudos foram incluídos na revisão anterior, enquanto uma estimativa atualizada veio de um novo estudo disponível (14, 24). No geral, esses estudos não sugeriram associação entre o uso de COC e a aquisição de HIV. A qualidade da evidência foi classificada como baixa a moderada. Não foi identificada evidência para o adesivo contraceptivo combinado, o anel combinado e o injetável combinado. 3.6 Evidências adicionais consideradas pelo GDD 3.6.1 DADOS BIOLÓGICOS Os dados biológicos relativos à plausibilidade do efeito de cada método de contracepção hormonal na aquisição do HIV foram revisados. Foram postulados vários mecanismos biológicos pelos quais os métodos contraceptivos hormonais poderiam modificar teoricamente o risco de aquisição do HIV, mas dados esparsos e contraditórios não esclarecem quais, se houver algum desses mecanismos biológicos, seriam clinicamente relevantes. Os mecanismos potenciais incluem alteração da resposta imune sistêmica e local e alterações no ambiente do trato genital. Observou-se que diferentes formas de contracepção hormonal podem alterar esses fatores de diferentes maneiras. Os contraceptivos combinados contendo etinilestradiol e progestagênio podem ter um efeito diferente dos métodos contendo apenas progestagênio. Além disso, vários métodos contendo apenas progestagênio, como os injetáveis AMPD e NET-EN, podem alterar a função imunológica de maneira variável. Ainda não se sabe até que ponto os dados de estudos em animais e em laboratório, inclusive em relação ao Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz | 7 RECOMENDAÇÕES4 tipo e dosagem de progestagênio, podem ser aplicados aos resultados clínicos em humanos. 3.6.2 VALORES E PREFERÊNCIAS DAS USUÁRIAS DE CONTRACEPTIVOS A revisão sistemática identificou 375 estudos de todas as regiões do mundo (27). Entre os estudos, os valores e preferências das mulheres se concentraram em temas de escolha e opções disponíveis, facilidade de uso, perfis de efeitos colaterais e eficácia contraceptiva. Fatores contextuais, como métodos contraceptivos disponíveis, aconselhamento de profissionais e opiniões de redes sociais, influenciaram a tomada de decisão. Na literatura cinzenta, foram identificados dois estudos adicionais relevantes para a contracepção hormonal e o HIV, especificamente (28,29). Ambos consideraram que as mensagens das diretrizes de 2017 da OMS eram difíceis de ser integralmente explicadas pelos profissionais, podendo não ser completamente compreendidas pelas usuárias. O inquérito online a profissionais do sexo de várias regiões do mundo mostrou que as preferências individuais em relação à contracepção variavam bastante e poderiam mudar com o 4 “Livre” significa liberdade e capacidade para tomar uma decisão voluntária acerca do uso de contraceptivos, sem barreiras ou coerção; “informado” significa que foi dada informação completa, correta e clara sobre todas as opções e também informações sobre o método escolhido. tempo; a parceria atual e o diálogo contínuo com profissionais do sexo são essenciais para entender a evolução das prioridades. Em grupos focais, as profissionais do sexo do Zimbábue disseram que suas escolhas contraceptivas foram moldadas por uma ampla gama de fatores, incluindo custo, acessibilidade, forma como as profissionais do sexo são tratadas nas clínicas, influência de parceiros masculinos e efeitos colaterais contraceptivos. O sexo sem preservativo era comum e havia a necessidade de fortalecer o acesso aos serviços de contracepção e de prevenção de HIV/IST. A apresentação da representante da comunidade enfatizou que, para algumas mulheres, qualquer nível de risco aumentado de HIV seria muito alto. Ela também destacou que o estudo ECHO não foi criado para avaliar a diferença no risco de aquisição do HIV entre usuárias de contraceptivos e não usuárias. As representantes da comunidade também enfatizaram que havia uma falta real de opções contraceptivas para muitas mulheres e adolescentes, dizendo que a diretriz deveria enfatizar a escolha contraceptiva livre e informadas4, a aquisição de uma variedade de métodos contraceptivos e o investimento em serviços integrados de contracepção e de HIV. 4.1 Recomendações para uso de contraceptivos entre mulheres com alto risco de infecção pelo HIV Atualmente, todos os métodos contraceptivos hormonais e dispositivos intrauterinos (DIU) se enquadram na categoria 1 dos critérios médicos de elegibilidade para uso de contraceptivos (MEC) (5) por mulheres com alto risco de infecção pelo HIV. Assim, as mulheres com alto risco de infecção pelo HIV podem usar todos os contraceptivos sem restrição. ■ Mulheres com alto risco de infecção pelo HIV são elegíveis para usar todos os métodos contraceptivos contendo apenas progestagênio, sem qualquer restrição (CME Categoria 1), incluindo pílulas apenas de progestagênio (PPs), acetato de medroxiprogesterona de depósito intramuscular (AMPD-IM), AMPD subcutâneo (AMPD -SC), enantato de noretisterona (NET-EN) injetável, implantes de levonorgestrel (LNG) e implantes de etonogestrel. ■ Mulheres com alto risco de infecção pelo HIV são elegíveis para usar DIU contendo cobre (DIU-Cu) e o DIU liberador de LNG sem restrição (Categoria 1 dos CME). Ao considerar o uso de DIU, muitas mulheres com alto risco de HIV também correm risco de outras infecções sexualmente transmissíveis (IST); para essas mulheres, os profissionais de saúde devem consultar as recomendações dos CME sobre uso de | Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz8 contraceptivos em mulheres de risco aumentado para IST e as recomendações sobre rastreamento de IST, antes da inserção de DIU, contidas nas recomendações das Práticas Selecionadas para uso de Contraceptivos (Selected Practice Recommendations for Contraceptive use: third edition, não disponível em português) (5,6). ■ Mulheres com alto risco de infecção pelo HIV são elegíveis para usar todos os métodos contraceptivos hormonais combinados sem restrição (Categoria 1 dos CME), incluindo contraceptivos orais combinados (COC), contraceptivos injetáveis combinados (CIC), adesivos contraceptivos combinados (A) e anel vaginal combinado (AVC). 4.2 Fundamentação O Grupo de Desenvolvimento das Diretrizes (GDD) revisou e discutiu extensivamente as novas evidências epidemiológicas e biológicas, bem como as informações sobre valores e preferências, equidade e direitos humanos e viabilidade. Após deliberar sobre todas as evidências disponíveis, o GDD recomendou que as categorias dos CME do AMPD e do DIU-Cu fossem alteradas para Categoria 1 dos CME. O GDD observou que não havia evidências sobre o AMPD-SC e o DIU-LNG, apenas informações novas limitadas sobre o NET-EN. Até que mais informações sejam disponibilizadas, o GDD julgou apropriado seguir a mesma abordagem usada anteriormente, ou seja, agrupar todos os injetáveis somente de progestagênio (AMPD-IM, AMPD-SC e NET-EN) como Categoria 1 dos CME, e atribuir mesma categoria ao DIU-LNG e ao DIU-Cu (categoria 1 dos CME). Uma parte importante das deliberações do GDD envolveu a avaliação das evidências do estudo Evidence for Contraceptive Options and HIV Outcomes (ECHO) (ver Anexo 3). O GDD deu atenção especial a essas informações devido à capacidade do estudo, por ser randomizado, de abordar os fatores de confusão não medidos, uma das principais causas de incerteza ao interpretar resultados de estudos observacionais. O GDD reconheceu que o estudo ECHO não abordou a questão etiológica ou causal de saber se o AMPD aumenta o risco de aquisição do HIV, quando comparado ao não uso de contraceptivos. No entanto, como os CME fornecem orientação para mulheres que desejam usar contraceptivos, os resultados do estudo ECHO sobre o risco comparativo de aquisição do HIV entre as usuárias dos três contraceptivos avaliados foram altamente pertinentes para as deliberações do GDD. Além disso, o GDD observou que a alta incidência de infecção pelo HIV experimentada em cada grupo contraceptivo durante o estudo ECHO foi semelhante à incidência basal assumida ao desenhar o estudo. Isso foi considerado uma evidência indireta que aborda a questão, sugerindo que não há risco aumentado de aquisição do HIV entre as usuárias desses contraceptivos, em comparação com as mulheres que não usam nenhum método contraceptivo. O estudo ECHO foi considerado um estudo bem conduzido que forneceu evidências de alta qualidade que substituíram as evidências observacionais de baixa e baixa a moderada qualidade anteriormente disponíveis para o GDD. Essa evidência epidemiológica direta, de um estudo especificamente desenhado para abordar a questão, foi considerada mais informativa do que a evidência biológica teórica. As razões para considerar o estudo ECHO de alta qualidade incluíram: seu grande número de participantes; métodos robustos de randomização; boa adesão ao método contraceptivo alocado; uma baixa taxa de descontinuidade; medições regulares, padronizadas e objetivas dos resultados; e uma análise abrangente e cega dos dados (incluindo análises de sensibilidade para fatores de confusão conhecidos, como atividade sexual e uso de preservativo). Embora as mulheres e os profissionais de saúde do estudo ECHO não foram cegados para a alocação da intervenção, não havia evidências de que isso levasse os diferentes grupos de participantes a agirem ou serem gerenciados de maneira diferente em relação a questões importantes, como aconselhamento sobre prevenção do HIV. Isso garantiu que os fatores de confusão residual, particularmente em relação ao uso de preservativos ou atividade sexual, tivessem alta probabilidade de não afetar o estudo ECHO. O GDD observou que, embora o estudo ECHO tenha sido projetado para detectar um aumento de 50% no risco de aquisição do HIV entre os grupos contraceptivos avaliados, a alta incidência de HIV observada e as pequenas perdas no seguimento fizeram com que ele pudesse detectar um aumento de 30%. Ao considerar os resultados do estudo ECHO, o GDD concentrou-se nas estimativas pontuais para cada comparação primária. O grupo observou que nenhuma das estimativas pontuais para as comparações primárias foi estatisticamente significativa. Os intervalos de confiança de 96% dessas estimativas pontuais incluíram a unidade e, portanto, incluíram a possibilidade de uma pequena diferença aumentada ou diminuída do risco entre os contraceptivos. O GDD reconheceu, no entanto, que para uma mulher individualmente com alto risco de infecção pelo HIV, qualquer mudança nesse risco pode ser importante. Após uma discussão completa, o GDD julgou que a presença de fatores de confusão não medidos era a explicação mais provável para o aparente aumento do risco de aquisição do HIV entre usuárias de AMPD-IM visto em alguns estudos observacionais. A decisão do GDD de revisar as classificações dos CME para o AMPD e o DIU foram adicionalmente fundamentadas pelos valores e preferências das mulheres em otimizar a escolha contraceptiva informada e a disponibilidade de uma ampla gama de opções contraceptivas, com base em uma revisão sistemática de evidências qualitativas e quantitativas, estudos com profissionais do sexo e as perspectivas dos membros do GDD que representavam populações afetadas específicas. Nas edições anteriores dos CME, o DIU foi classificado como categoria 2 dos CME para mulheres com alto risco de infecção pelo HIV. Essa recomendação foi dada devido à ausência de evidências diretas de alta qualidade sobre o risco de adquirir o HIV entre as usuárias de DIU. Além disso, havia uma suposição de que a maioria das mulheres com alto risco de adquirir HIV também apresentava um risco aumentado de contrair outras IST. O estudo ECHO forneceu evidências diretas e de alta qualidade sobre o risco de adquirir HIV entre mulheres que Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz | 9 usaram o DIU-Cu, permitindo que o GDD revisasse sua recomendação sobre essas mulheres. Quaisquer novas evidências relacionadas ao uso do DIU em mulheres com alto risco de outras IST serão analisadas na próxima atualização dos CME. O GDD ficou preocupado com as altas taxas de HIV e IST entre as mulheres do estudo ECHO, refletindo os fatores de risco conhecidos entre as mulheres que buscam contracepção nas áreas de estudo. A alta incidência de HIV foi particularmente notória, dados os extensos esforços feitos durante o estudo ECHO para fornecer aconselhamento e intervenções de prevenção do HIV. Assim, embora o GDD tivesse concluído que o risco de aquisição do HIV não foi afetado pelo método contraceptivo usado, enfatizou a necessidade de esforços renovados para reduzir a incidência de HIV e IST. IMPLICAÇÕES PARA FORMULADORES DE POLÍTICAS, DIRETORES DE PROGRAMAS E PROFISSIONAIS DE SAÚDE 5 Embora os principais públicos-alvos dos Critérios Médicos de Elegibilidade para uso de contraceptivos (CME) sejam formuladores de políticas e diretores de programas, um princípio fundamental dos CME é que eles são centrados na mulher. A seguir, foram apresentadas as principais mensagens provenientes das deliberações do Grupo de Desenvolvimento das Diretrizes. 5.1 O risco de uma mulher contrair o HIV não deve restringir sua escolha contraceptiva Embora o risco de HIV não deva restringir a escolha de uma mulher de usar contracepção hormonal ou um dispositivo intrauterino, é importante observar que esses métodos não a protegem contra a aquisição de HIV ou outras infecções sexualmente transmissíveis (IST). As novas recomendações dos CME não devem ser interpretadas como indicando que a testagem e a prevenção do HIV e outras IST não são mais importantes. De fato, o estudo Evidence for Contraceptive Options and HIV Outcomes (ECHO) destacou a necessidade crítica de fortalecer e expandir os serviços de prevenção de HIV e IST (10). Os testes de HIV e IST devem fazer parte dos serviços de planejamento familiar de alta qualidade para mulheres em risco de adquirir estas infecções, principalmente para aquelas que vivem em áreas com alta incidência de HIV e IST. 5.2 Os esforços para expandir o acesso às opções contraceptivas devem continuar As mulheres têm direito a uma variedade de métodos contraceptivos de curta ação, longa ação e permanentes, bem como à contracepção de emergência (1). Uma variedade de métodos contraceptivos permite que as mulheres respondam às mudanças de necessidades e preferências durante a vida reprodutiva. A tomada de decisão informada e o aconselhamento de alta qualidade, centrado na mulher, são componentes essenciais no fornecimento de informações e serviços contraceptivos baseados em direitos humanos (2). O estudo ECHO reforçou que a oferta de uma variedade de métodos é possível e aceitável para as mulheres (10). O planejamento familiar e os serviços de atendimento de pessoas com HIV devem ser | Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz10 incluídos nas iniciativas nacionais da cobertura universal de saúde. Os esforços para expandir as opções contraceptivas seguras e eficazes e para garantir a disponibilidade e acesso a estas opções devem continuar. Estão disponíveis recursos técnicos para apoiar os países a introduzir mais opções contraceptivas em seus programas e serviços (Quadro 1). QUADRO 1. RECURSOS TÉCNICOS PARA APOIAR PROGRAMAS DE SAÚDE o Medical eligibility criteria for contraceptive use – Critérios Médicos de Elegibilidade para uso de contraceptivos (disponível em Inglês, Francês e Russo) https://apps.who.int/iris/handle/10665/181468 o Selected practice recommendations for contraceptive use (disponível em Inglês, Francês e Espanhol) https:// apps.who.int/iris/handle/10665/252267 o Implementation guide for the medical eligibility criteria and selected practice recommendations for contraceptive use (disponível em Inglês, Francês, Português e Espanhol) https://apps.who.int/iris/handle/10665/272758 o Global handbook for family planning providers https://apps.who.int/iris/handle/10665/260156 o Training Resource Package for Family Planning website (disponível em Inglês e Francês) https://www.fptraining.org o Aplicativo para celular para os Critérios Médicos de Elegibilidade para uso de contraceptivos (gratuito, para android e iOS) https://www.who.int/reproductivehealth/mec-app o Policy brief: consolidated guidelines on HIV prevention, diagnosis, treatment and care for key populations, 2016 update https://apps.who.int/iris/handle/10665/258967 o Treat all: policy adoption and implementation status in countries (fact sheet) https://apps.who.int/iris/handle/10665/258538 5.3 Uma nova ênfase nos serviços de prevenção de HIV e IST é urgentemente necessária O estudo ECHO mostrou altas taxas de HIV e IST nos locais do estudo (10), destacando a necessidade de prevenção, diagnóstico e tratamento adequados para todas as IST. As atuais medidas de prevenção do HIV permanecem indisponíveis ou insatisfatórias para muitas mulheres e adolescentes que vivem em contextos de alta incidência de HIV. Nessas áreas, a integração de serviços de planejamento familiar e prevenção do HIV para todas as mulheres é essencial para melhorar a saúde das mulheres e adolescentes. Em ambientes com baixa prevalência de HIV, é necessário que os profissionais que trabalham com planejamento familiar avaliem fatores de risco pessoais que podem aumentar o risco de uma mulher adquirir o HIV e, então, fornecer os serviços adequados. O estudo ECHO também mostrou que o tratamento sindrômico não diminuiu a prevalência de IST na avaliação basal e no final do seguimento. Os programas de IST precisam ser fortalecidos, incluindo uma mudança em direção ao gerenciamento de diagnóstico. ■ Em locais com alta prevalência de HIV, a testagem e a prevenção devem ser incluídas nos serviços de planejamento familiar. O teste de HIV deve ser oferecido a todas as mulheres e aos parceiros de todas as mulheres com HIV. As opções de prevenção do HIV devem ser oferecidas a todas as mulheres, incluindo a profilaxia pré-exposição (PrEP), conforme recomendado nas diretrizes da OMS (30). A oferta de PrEP para as mulheres também pode ser considerada onde a incidência de HIV é alta (mas abaixo de 3/100 pessoas-ano no total), seguindo, por exemplo, uma simples avaliação de risco. Uma avaliação de risco pode incluir: desejo de tomar PrEP (refletindo um risco auto-identificado); história de uma IST; mais de um parceiro sexual nos últimos seis meses; ou mulheres com parceiro sexual com HIV que não está com carga viral suprimida em terapia antirretroviral. ■ Em ambientes com baixa prevalência de HIV, é improvável que a oferta rotineira de serviços de testagem e prevenção de HIV em ambientes de planejamento familiar seja custo- efetiva. No entanto, os serviços de testagem e prevenção do HIV podem ser oferecidos às mulheres que solicitam esses serviços. QUADRO 2. COMO IDENTIFICAR MULHERES COM ALTO RISCO DE HIV O risco de infecção pelo HIV de uma pessoa depende da incidência do vírus na área em que vive e de seus fatores de risco individuais. Os programas de planejamento familiar devem trabalhar em estreita colaboração com seus programas nacionais, regionais e locais de HIV para usar dados epidemiológicos locais destinados a identificar áreas geográficas e fatores de risco que coloquem as mulheres em alto risco de infecção pelo HIV Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz | 11 6.1 Métodos contraceptivos e aquisição do HIV O corpo de evidências existente é suficiente para orientar a prática quando ao acetato de medroxiprogesterona de depósito (AMPD-IM), implantes de levonorgestrel (LNG) e os dispositivos intrauterinos contendo cobre; dados observacionais adicionais não aumentarão substancialmente a base de evidências desses métodos. No entanto, na ausência de dados oriundos de ensaios semelhantes aos do estudo ECHO (10), dados observacionais sobre AMPD subcutâneo (AMPD-SC), DIU de LNG, implantes de etonogestrel ou futuras tecnologias contraceptivas ou de prevenção de múltiplos propósitos ainda podem ser úteis, embora os fatores de confusão não medidos provavelmente continuarão sendo uma preocupação. Os estudos devem considerar o impacto potencial do uso de contraceptivos em outras infecções sexualmente transmissíveis, bem como no HIV. Também são necessárias pesquisas adicionais sobre os efeitos específicos das alterações dos padrões de sangramento relacionadas ao uso de contraceptivos em relação ao risco de aquisição de HIV ou IST. 6.2 Prevenção do HIV O Grupo de Desenvolvimento das Diretrizes ficou profundamente preocupado com a alta incidência de HIV encontrada entre as mulheres que procuraram os serviços de planejamento familiar nos locais do Estudo ECHO, apesar do fato das participantes do estudo receberem um amplo pacote de prevenção do HIV [incluindo repetidos testes e aconselhamento, testagem de HIV para parceiros, distribuição de preservativos, bem como profilaxia pré- exposição (PrEP) no final do estudo, quando esta se tornou o padrão de atendimento]. São necessárias mais pesquisas sobre maneiras de aumentar a aceitabilidade e a adoção de estratégias eficazes de prevenção do HIV para mulheres com alto risco de infecção pelo HIV, adaptadas a contextos de alta e baixa prevalência de HIV e a mulheres com uma variedade de fatores de risco pessoais. No estudo ECHO, a busca (e, portanto, o impacto) da PrEP foi mínima, uma vez que esta ficou disponível apenas no final do estudo (10). Onde a PrEP estava disponível no local, em vez de ser necessário o encaminhamento para outro lugar para obtenção da medicação, a busca e a aceitabilidade foram altas. Devem ser exploradas maneiras para incluir o auto- teste de HIV e a PrEP nos serviços de planejamento familiar. Isso deve incluir pesquisas científicas comportamentais e de implementação sobre a integração efetiva dos serviços de HIV e contracepção. 6.3 Envolvimento da comunidade O estudo ECHO empregou uma série de estratégias para se envolver diretamente com a sociedade civil no local do estudo e nos níveis regional e global (10). É provável que uma avaliação aprofundada dos pontos fortes e das limitações de cada estratégia forneça modelos para o envolvimento da comunidade em pesquisas sobre contraceptivos e prevenção do HIV que possam ser adotadas no futuro. 6.4 Maior financiamento para pesquisa de alta qualidade e relevante para a elaboração de políticas O estudo ECHO demonstrou que um estudo controlado randomizado, bem conduzido e com poder estatístico adequado é possível na área de contracepção, podendo dar uma contribuição importante para a tomada de decisões global. A política global deve se basear em evidências abrangentes de alta qualidade, mas o investimento em pesquisas na área de contracepção está muito atrasado, incluindo pesquisas que investigam se as barreiras financeiras afetam as escolhas contraceptivas das mulheres. LACUNAS DE CONHECIMENTO E ÁREAS DE PESQUISA6 | Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz12 DIVULGAÇÃO DESTA DIRETRIZ7 A Organização Mundial da Saúde (OMS) trabalhará para divulgar esta diretriz amplamente e de forma clara. A OMS avaliará se a diretriz alcançará suas intenções e publicá-la-á no seu site, bem como em uma quantidade limitada de documentos impressos. A diretriz será amplamente divulgada através dos escritórios regionais e nacionais da OMS, Estados Membros da OMS, outras agências das Nações Unidas, sociedade civil, iniciativa de Implementação de Melhores Práticas (IBP), organizações profissionais, organizações governamentais e não governamentais parceiras e centros colaboradores da OMS que trabalham na área do HIV e da saúde sexual e reprodutiva. O Secretariado da OMS trabalhará em estreita colaboração com os pontos focais de saúde sexual e reprodutiva e HIV nos escritórios regionais e nacionais da OMS, o Fundo de População das Nações Unidas e o Programa Conjunto das Nações Unidas sobre HIV e AIDS para conduzir uma série de eventos regionais de aprendizado e partilha de conhecimentos. Essa relação visará oportunidades nas quais questões de saúde sexual e reprodutiva estão sendo discutidas, como, por exemplo, a 25ª Conferência sobre População e Desenvolvimento (25th Conference on Population and Development), em julho de 2019, e a 20ª Conferência Internacional sobre Aids e Infecções Sexualmente Transmissíveis (20th International Conference on AIDS and Sexually Transmitted Infections) na África, em dezembro de 2019. O Secretariado também trabalhará em estreita colaboração com as equipes operacionais dos países e os grupos de trabalho que lideram os programas de HIV e de contracepção, para compartilhar a diretriz com as bases, organizações e profissionais ao nível comunitário. Além disso, em 2020, serão organizados seminários on-line, em vários idiomas, para garantir que os Estados-Membros e as partes interessadas sejam totalmente informados sobre as novas recomendações. Essas oportunidades permitirão à OMS disseminar a diretriz atualizada de maneira eficaz e eficiente. Produtos derivados da comunicação, que destaquem as principais questões de aconselhamento (por exemplo, breves resumos para profissionais de saúde da linha de frente dos serviços de saúde e organizações comunitárias), serão preparados em colaboração com os parceiros de implementação da OMS e em consulta com o GDD em 2020. Um resumo de políticas nos seis idiomas oficiais usados pela OMS será desenvolvido para informar os formuladores de políticas sobre as atualizações em matéria de contracepção. Como parte da divulgação das recomendações desta diretriz, a OMS atualizará suas ferramentas digitais de apoio à decisão contraceptiva - o aplicativo móvel dos CME (31), o aplicativo de distribuição humanitária de contraceptivos (32) e o compêndio pós-parto (33). Esses aplicativos móveis são gratuitos para download e estão disponíveis para as plataformas iOS e Android. Além disso, o Global Handbook for family planning providers e o online Family Planning Training Resource Package serão atualizados de acordo com as novas recomendações (8,34). A OMS continuará monitorando o conjunto de evidências que sustenta essas recomendações e convocará consultas adicionais, quando necessário. Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz | 13 REFERÊNCIAS 1. Ensuring human rights in the provision of contraceptive information and services: guidance and recommendations. Geneva: World Health Organization; 2014 (https://apps.who.int/iris/handle/10665/102539, accessed 24 August 2019). 2. Framework for ensuring human rights in the provision of contraceptive information and services. Geneva: World Health Organization; 2014 (https://apps.who.int/iris/handle/10665/133327, accessed 24 August 2019). 3. The thirteenth general programme of work, 2019–2023: promote health, keep the world safe, serve the vulnerable. Geneva: World Health Organization; 2019 (https://apps.who.int/iris/handle/10665/324775, accessed 24 August 2019). 4. Reproductive health strategy to accelerate progress towards the attainment of international development goals and targets. Geneva: World Health Organization; 2004 (https://apps.who.int/iris/handle/10665/68754, accessed 24 August 2019). 5. Medical eligibility criteria for contraceptive use, fifth edition. Geneva: World Health Organization; 2015 (https://apps.who.int/iris/handle/10665/181468, accessed 24 August 2019). 6. Selected practice recommendations for contraceptive use: third edition. Geneva: World Health Organization; 2016 (https://apps.who.int/iris/handle/10665/252267, accessed 24 August 2019). 7. WHO medical eligibility criteria wheel for contraceptive use, 2015 update. Geneva: World Health Organization; 2004 (https://apps.who.int/iris/handle/10665/173585, accessed 24 August 2019). 8. World Health Organization, Johns Hopkins Bloomberg School of Public Health. Family planning: a global handbook for providers: evidence-based guidance developed through worldwide collaboration, third edition. Geneva: World Health Organization; 2018 (https://apps.who.int/iris/handle/10665/260156, accessed 24 August 2019). 9. Hormonal contraceptive eligibility for women at high risk of HIV: guidance statement: recommendations concerning the use of hormonal contraceptive methods by women at high risk of HIV. Geneva: World Health Organization; 2017 (https://apps.who.int/iris/handle/10665/254662, accessed 24 August 2019). 10. Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium. HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial. Lancet. 2019;394(10195):303–13. doi: 10.1016/S0140-6736(19)31288-7. 11. WHO handbook for guideline development, second edition. Geneva: World Health Organization; 2014 (https://apps.who.int/iris/handle/10665/145714, accessed 24 August 2019). 12. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J et al. GRADE guidelines: 1. Introduction –GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64(4):383–94. doi: 10.1016/j.jclinepi.2010.04.026. 13. Singh S. Adding it up: costs and benefits of contraceptive services – estimates for 2017. New York (NY): Guttmacher Institute; 2017. 14. Polis CB, Curtis KM, Hannaford PC, Phillips SJ, Chipato T, Kiarie JN et al. An updated systematic review of epidemiological evidence on hormonal contraceptive methods and HIV acquisition in women. AIDS. 2016;30(17):2665–83. doi: 10.1097/ QAD.0000000000001228. 15. Moher D, Liberati A, Tetzlaff J, Altman DG; The Prisma Group. Preferred reporting items for systematic reviews and meta- analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. doi: 10.1371/journal.pmed.1000097. 16. Kennedy CE, Yeh PT, Gaffield ME. Contraception values and preferences: protocol and methods for a global systematic review. Contraception. 2019 (in press). doi: 10.1016/j.contraception.2018.05.006Get. 17. Guyatt GH, Oxman AD, Vist G, Kunz R, Brozek J, Alonso-Coello P et al. GRADE guidelines: 4. Rating the quality of evidence— study limitations (risk of bias). J Clin Epidemiol. 2011;64(4):407–15. doi: 10.1016/j.jclinepi.2010.07.017. 18. Guyatt GH, Oxman AD, Kunz R, Brozek J, Alonso-Coello P, Rind D et al. GRADE guidelines 6. Rating the quality of evidence – imprecision. J Clin Epidemiol. 2011;64(12):1283–93. doi: 10.1016/j.jclinepi.2011.01.012. | Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz14 19. Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M et al. GRADE guidelines: 8. Rating the quality of evidence – indirectness. J Clin Epidemiol. 2011;64(12):1303–10. doi: 10.1016/j.jclinepi.2011.04.014. 20. Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M et al. GRADE guidelines: 7. Rating the quality of evidence – inconsistency. J Clin Epidemiol. 2011;64(12):1294–302. doi: 10.1016/j.jclinepi.2011.03.017. 21. Guyatt GH, Oxman AD, Montori V, Vist G, Kunz R, Brozek J et al. GRADE guidelines: 5. Rating the quality of evidence – publication bias. J Clin Epidemiol. 2011;64(12):1277–82. doi: 10.1016/j.jclinepi.2011.01.011. 22. Guyatt GH, Oxman AD, Sultan S, Glasziou P, Akl EA, Alonso-Coello P et al. GRADE guidelines: 9. Rating up the quality of evidence. J Clin Epidemiol. 2011;64(12):1311–6. doi: 10.1016/j.jclinepi.2011.06.004. 23. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619–22. doi: 10.1097/ QAD.0000000000002260. 24. Sabo MC, Richardson BA, Lavreys L, Martin HL, Jr, Jaoko W, Mandaliya K et al. Does bacterial vaginosis modify the effect of hormonal contraception on HIV seroconversion. AIDS. 2019;33(7):1225–30. doi: 10.1097/QAD.0000000000002167. 25. Lavreys L, Baeten JM, Martin Jr HL, Overbaugh J, Mandaliya K, Ndinya-Achola J et al. Hormonal contraception and risk of HIV-1 acquisition: results of a 10-year prospective study. AIDS. 2004;18(4):695–7. 26. Wall KM, Kilembe W, Vwalika B, Htee Khu N, Brill I, Chomba E et al. Hormonal contraception does not increase women’s HIV acquisition risk in Zambian discordant couples, 1994–2012. Contraception. 2015;91(6):480–7. doi: 10.1016/j. contraception.2015.02.004. 27. Yeh PT, Kennedy CE, Gaffield ME. Contraception values and preferences: a global systematic review. Contraception. 2019; (accepted pending revisions). 28. Miller L, Ntinginya M, Makula J, Juma A, Mackay A, Wadegu E et al. Final report: a pilot study to assess training and communication materials on progestogen-only injectable use and risk of HIV acquisition in Tanzania. London: Marie Stopes International; 2019 (https://resultsforinformedchoice.org/wp-content/uploads/2019/02/Injectables-and-HIV-Pilot-Study-Report-TZ.pdf, accessed 24 August 2019). 29. Littlepage S, Dam A, Nakyanjo N, Polis C, Nalugoda F, Kennedy CE. Contraceptive decision-making in the context of HIV risk and changing World Health Organization guidelines: a qualitative study in Rakai, Uganda. 2019 (personal communication). 30. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach, second edition. Geneva: World Health Organization; 2016. (https://apps.who.int/iris/handle/10665/208825, accessed 24 August 2019). 31. New app for WHO’s medical eligibility criteria for contraceptive use. In: World Health Organization [website]. Geneva: World Health Organization; 2018 (https://www.who.int/reproductivehealth/mec-app, accessed 24 August 2019). 32. Delivering contraceptive services in humanitarian settings: new tool for front-line health care workers. In: World Health Organization [website]. Geneva: World Health Organization; 2018 (https://www.who.int/reproductivehealth/publications/ humanitarian-settings-contraception, accessed 24 August 2019). 33. New WHO tool helps guide contraception choices following childbirth. In: World Health Organization [website]. Geneva: World Health Organization; 2016 (https://www.who.int/reproductivehealth/news/pfpc, accessed 24 August 2019). 34. TRP: Training Resource Package for Family Planning [website]. Baltimore (MD): Johns Hopkins University; 2019 (https://www.fptraining.org, accessed 24 August 2019). Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz | 15 ANEXO 1: GRUPO DE DESENVOLVIMENTO DAS DIRETRIZES E SECRETARIADO DE EVIDÊNCIAS Grupo de Desenvolvimento das Diretrizes Sharon Achilles (Universidade de Pittsburgh, Estados Unidos da América), Richard Adanu (Universidade do Gana, Gana), Rachid Bezad (Universidade Roi Mohammad VI, Marrocos), Sharon Cameron (Universidade de Edimburgo, Reino Unido da Grã-Bretanha e Irlanda do Norte), Tsungai Chipato (Universidade do Zimbabué, Zimbabuê), Maria del Carmen Cravioto (Instituto Nacional de Nutrição, Salvador Zubiran, México) [impossibilitada de comparecer], Alison Edelman (Universidade de Saúde e Ciência do Oregon, Estados Unidos da América), Mohammad Eslami (Ministro da Saúde e Educação, República Islâmica do Irã), Anna Glasier (Universidade de Edimburgo, Reino Unido), Andy Gray (Universidade de KwaZulu-Natal, África do Sul), Philip Hannaford (Universidade de Aberdeen, Reino Unido), Felicita Hikuam (Aliança para a AIDS e Direitos na África Austral, Namíbia), Unnop Jaisamrarn (Universidade Chulalongkorn, Tailândia), Loveleen Johri (consultora independente de planejamento familiar e saúde reprodutiva, Índia), Natasha Kaoma (Copper Rose Zambia, Zâmbia), Seni Kouanda (Instituto de Investigação em Ciências da Saúde, Burquina Faso), Elizabeth Lule (consultor independente de saúde global e desenvolvimento internacional, Uganda), Vimbai Magwenzi (Centre for Sexual Health and HIV/AIDS Research, Zimbabuê) [impossibilitada de comparecer], Loyce Maturu (Zvandiri Mentor with Africaid, Zimbabuê), Olav Meirik (Instituto Chileno de Medicina Reprodutiva, Chile), Placid Mihayo (Ministro da Saúde, Uganda), Lilian Mworeko (Comunidade Internacional das Mulheres que vivem com o HIV na África Oriental, Uganda), Hiromi Obara (Centro Nacional para a Saúde e Medicina Global, Tóquio, Japão), Herbert Peterson (Universidade da Carolina do Norte, Estados Unidos da América), John Pile (Consultor independente, Tailândia), Carolina Sales Vieira (Universidade de São Paulo, Brasil), Sarah Simpson (EquiACT, França), Aminata Wurie (Coligação de Jovens para os Direitos na área da Saúde Sexual e Reprodutiva, Serra Leoa). Philip Hannaford e Natasha Kaoma co-presidiram a reunião do Grupo de Desenvolvimento das Diretrizes (GDG) Secretariado de Evidências Centro de Investigação em Saúde Sexual e HIV/AIDS – Euphemia Sibanda FHI 360 – Timothy Mastro Consultora independente – Ania Shapiro Universidade Johns Hopkins – Caitlin Kennedy Universidade de Saúde e Ciência do Oregon – Maria Isabel Rodriguez Centros dos EUA para o Controle e Prevenção das Doenças – Kathryn Curtis Universidade de Washington – Jared Baeten Instituto de Saúde Reprodutiva e HIV da Universidade de Witwatersrand – Helen Rees Observador Zandile Mnisi (Ministro da Saúde, Reino de Essuatíni) Grupo de Revisores Externos Florence Anam (Médicos sem Fronteiras, África do Sul), Winfred Apio (Fórum de Jovens e Adolescentes, Uganda), Lynn Bakamjian (consultor independente, Estados Unidos da América), Milena Brito (Universidade de São Paulo, Brasil), Roy Jacobstein (IntraHealth, Estados Unidos da América), Ernest Maya (Universidade do Gana, Gana), Mari Ngai (Centro Nacional para a Saúde e Medicina Global, Japão), Cristina Puig Borràs (Consórcio Europeu para a Contracepção de Emergência, Espanha), Nusrat Shah (Sociedade de Obstetrícia e Ginecologia, Paquistão), Bulbul Sood (Jphiego, Índia). Secretariado da OMS O Secretariado da OMS participou da reunião e vários funcionários da OMS fizeram apresentações de contextos anteriores (Rachel Baggaley, Mary Lyn Gaffield, James Kiarie, Nancy Kidula). O Secretariado da OMS estava presente para servir como um recurso de apoio, se solicitado pelo GDD. Os funcionários da OMS, do Programa Conjunto das Nações Unidas sobre HIV/AIDS (UNAIDS) e do Fundo de População das Nações Unidas (UNFPA) não participaram da tomada de decisão ou da formulação das recomendações, que eram de responsabilidade exclusiva do GDD. Vários funcionários da OMS contribuíram para as revisões sistemáticas (Mary Lyn Gaffield, James Kiarie, Petrus Steyn) e a redação da diretriz. Sede da OMS Departamento de Saúde Reprodutiva e Investigação da OMS – Ian Askew, Mary Lyn Gaffield, James Kiarie, Antonella Lavelanet, Manjulaa Narasimhan (impossibilitada de comparecer), Petrus Steyn Departamento de HIV da OMS – Rachel Baggaley, Virginia MacDonald, Michele Rodolph Departamento de Regulação de Medicamentos e outras Tecnologias da Saúde da OMS – Ray Corrin | Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz16 Escritórios Regionais da OMS Escritório Regional da OMS para a África– Nancy Kidula, Léopold Ouedraogo Programa Conjunto das Nações Unidas sobre HIV/ AIDS - UNAIDS Peter Godfrey-Fausett Fundo de População das Nações Unidas (UNFPA) Divisão Técnica – Gifty Addico, Mieko Yabuta (impossibilitado de comparecer) Coordenação geral Departamento de Saúde Reprodutiva e Investigação da OMS - Mary Lyn Gaffield, com apoio logístico de Jane Werunga- Ndanareh. Redação A diretriz foi redigida em nome da OMS por Caitlin Baumhart, Kathryn Curtis, Mary Lyn Gaffield, Philip Hannaford, Natasha Kaoma, Caitlin Kennedy e Maria Isabel Rodriguez. A revisão sistemática que examinou o uso de dispositivos intrauterinos contendo cobre e a aquisição do HIV foi da autoria conjunta de Tsungai Chipato, Kathryn Curtis, Philip Hannaford e Angeline Ti. A atualização da revisão sistemática de 2016, focada na contracepção hormonal e na aquisição do HIV, foi da autoria conjunta de Tsungai Chipato, Kathryn Curtis, Philip Hannaford, James Kiarie e Petrus Steyn. As tabelas GRADE e o conhecimento sobre a metodologia GRADE foram fornecidos por Maria Isabel Rodriguez. A preparação da tabela evidência para decisão e o conhecimento da literatura sobre valores e preferências foram fornecidos por Caitlin Kennedy. A edição foi realizada por Markus MacGill e Jane Patten, da Green Ink (www.greenink.co.uk) e o layout, por Lushomo (www.lushomo. net). Tradução A tradução técnica e adaptação para o português foi feita por Carolina Sales Vieira Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz | 17 ANEXO 2: DECLARAÇÕES DE CONFLITOS DE INTERESSE Seguindo as orientações emitidas em 24 de setembro de 2014 pelo Departamento de Conformidade, Gestão de Riscos e Ética (Compliance, Risk Management and Ethics - CRE) da OMS e antes da reunião de 29 a 31 de julho de 2019, foram publicados no site da OMS (https://www.who.int/reproductivehealth/ publications/contraceptives-methods-hiv), entre 27 de maio e 10 de junho de 2019, o nome e uma breve biografia de cada membro proposto para o Grupo de Desenvolvimento das Diretrizes (GDD). O público pode visualizar e enviar seus comentários ao Secretariado da OMS usando um endereço de e-mail geral (hrx_info@who.int) sobre quaisquer conflitos de interesse percepcionados ou reais dos membros propostos para o GDD. Além disso, antes do período do anúncio público, o Secretariado da OMS revisou o curriculum vitae de cada potencial participante e realizou buscas na Internet (Google Scholar, Open Payments, PubMed), para obter informações sobre possíveis conflitos de interesse financeiro e acadêmico relacionados ao assunto da reunião. Após o período de publicação e em consulta com o CRE, os convites oficiais para a participação no GDD foram realizados. Além disso, o Secretariado da OMS analisou potenciais conflitos de interesse financeiro e acadêmico relacionados ao assunto da reunião do Grupo proposto de Revisão Externa: nenhum conflito foi declarado entre este grupo de 11 membros. Dos 28 especialistas que participaram deste trabalho, seis declararam conflito de interesse relacionado à contracepção. O Secretariado da OMS, CRE e GDD analisaram todas as declarações e não encontraram conflitos de interesse suficientes para impedir alguém de participar das deliberações ou do desenvolvimento de recomendações relevantes para a contracepção hormonal e o HIV. Consequentemente, os seis participantes que declararam conflito de interesses relacionados à contracepção, bem como os outros 22 participantes, participaram totalmente das deliberações, discussões e decisões finais da reunião. Embora nem todos os conflitos de interesses declarados estejam especificamente relacionados à contracepção e suscetibilidade ao HIV, eles estão resumidos e divulgados abaixo. Sharon Achilles recebeu US $ 4.225 em 10 de maio de 2016 para dar consultoria especializada sobre as mais recentes terapias contra o HIV durante uma reunião de um dia patrocinada pela Merck Sharp & Dohme. Sua unidade de pesquisa recebeu US $ 2.638.373 dos United States National Institutes of Health/ National Institute of Allergy and Infectious Diseases para conduzir um estudo intitulado “Quantification of immune cells in women using contraception”, durante 2012–2019. Para 2012–2019, sua unidade de pesquisa receberá US $ 4.999.999 da Fundação Bill & Melinda Gates para conduzir um estudo intitulado, “HIV-target cell response in women initiating contraception in high HIV- incidence areas”. Durante 2014–2016, a unidade de pesquisa da Dra. Achilles recebeu US $ 240.225 da Fundação Bill & Melinda Gates para conduzir um estudo que aborda o IFN-epsilon e a modulação da contracepção hormonal no risco de aquisição do HIV. Atualmente, para 2018-2020, a unidade de pesquisa da Dra. Achilles está recebendo US $ 535.958 da Food and Drug Administration (FDA) dos Estados Unidos para conduzir um estudo que apoia novas abordagens para melhorar a fabricação e a qualidade do produto, intitulado “Physiologically-based model of the female reproductive tract: vaginal and intrauterine delivery components”. Sharon Cameron trabalha em uma unidade de pesquisa que recebeu um financiamento de pesquisa da Pfizer, Reino Unido, de £ 99.000, o qual finalizou em 2016. O estudo foi implementado para determinar a viabilidade e aceitabilidade da administração farmacêutica da contracepção injetável subcutânea. Alison Edelman recebe um royalty anual de cerca de US $ 1.000 do site de informações da Internet, UpToDate, como autora do conteúdo. Entre maio de 2016 e maio de 2017, ela recebeu US $ 10.000 por ano da Agile Pharmaceuticals como consultora especializada sobre um adesivo contraceptivo hormonal que atualmente não é aprovado pela FDA. Esta consultoria já terminou. Desde janeiro de 2016, ela atuou como instrutora do Nexplanon, um mandato da FDA para a Merck Sharp & Dohme, mas não recebeu honorários por essas sessões e como consultora especializada, em janeiro de 2016, para esta empresa, recebendo US $ 1.500 por seus serviços. Sua unidade de pesquisa recebeu US $ 540.000 do Merck Women’s Health Investigator Initiated Studies Program para conduzir pesquisas focadas no tratamento de sangramento doloroso com o implante contraceptivo (2016–2019). De 2015 a 2017, sua unidade de pesquisa recebeu um financiamento de pesquisa de US $ 250.000 da Society for Family Planning para investigar o momento do uso de acetato de ulipristal e de contraceptivos orais. Desde 2002, a Dra. Edelman recebe cerca de US $ 3.000 por ano da Contemporary Forums como membro do corpo docente em suas conferências de educação médica continuada (o montante varia de acordo com o número de palestras que ela dá). De novembro de 2015 a junho de 2016, ela recebeu um honorário de US $ 3.000 da Oregon State University para aconselhamento especializado sobre o treinamento estatal obrigatório para permitir o fornecimento direto de contraceptivos por farmacêuticos. Desde julho de 2016, a Dra. Edelman recebe US $ 500 por ano como honorário por servir no painel de monitoramento de dados e segurança da FHI 360, que está desenvolvendo um novo contraceptivo injetável ainda não aprovado pela FDA. De abril a setembro de 2017, a Dra. Edelman foi consultora da HRA Pharma para um estudo que investigou uma pílula de progestagênio. Desde julho de 2017, ela tem sido consultora especializada da Sugar Palm Foundation; esse contrato foi canalizado através de sua instituição e encerrado em 2019. Desde junho de 2017, ela presta consultoria especializada ao Ipas para treinar profissionais de saúde em Bangladesh: este contrato agora é administrado por sua instituição. Desde 2016, a Dra. Edelman recebe um honorário da Universidade da | Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz18 Califórnia, em São Francisco, por palestras e auditorias do programa de bolsas para planejamento familiar. Durante o período de 2018 a janeiro de 2019, ela recebeu um honorário da Exeltis para fornecer uma revisão especializada sobre um método contraceptivo atualmente não aprovado pela FDA. Esta consultoria já terminou. Anna Glasier realiza regularmente ao fabricante (HRA Pharma) uma consultoria médica especializada sobre a pílula contraceptiva de emergência com acetato de ulipristal. O valor não foi divulgado. Ela trabalha com eles para tentar obter aprovação para o uso, sem receita médica, nos Estados Unidos da América, do contraceptivo de emergência com acetato de ulipristal e de uma pílula apenas de progestagênio e para obter a aprovação para o uso, sem receita médica, no Reino Unido da Grã-Bretanha e Irlanda do Norte e Europa, de uma pílula apenas de progestagênio. O processo está ainda em curso. Andy Gray é presidente do Names and Scheduling Advisory Committee of the South African Health Products Regulatory Authority e atua em seus Comitês Consultivos Jurídico e Regulador. Ele é membro do Comitê Nacional de Medicamentos Essenciais da África do Sul (South African National Essential Medicines List Committee), responsável pela seleção de medicamentos e pelo desenvolvimento de diretrizes de tratamento padrão para o setor público. Carolina Sales Vieira recebe um honorário (US $ 4.000/ano) por atuar no comitê consultivo médico da Merck Sharpe & Dohme e por dar palestras ad hoc para esta indústria farmacêutica. Esta consultoria está em andamento. A Dra. Sales Vieira recebe um honorário (US $ 3.000/ano) por servir no comitê consultivo médico da Bayer e dar palestras ad hoc para esta indústria farmacêutica. A Dra. Sales Vieira recebeu um honorário único (US $ 1.000) por atuar no comitê consultivo médico da Exeltis, em 2019. Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz | 19 ANEXO 3: PERFIS DE EVIDÊNCIAS GRADE Resultado Tipo e número de estudos (número de participantes) Limitações Inconsistências Imprecisão Uso de evidências indiretas Qualidade global Estimativa de efeito AMPD versus métodos contraceptivos não hormonais ou ausência de métodos contraceptivos Aquisição do HIV 1 estudo randomizado1 (7.829)a Poucas limitaçõesb Nenhuma inconsistência séria Nenhuma imprecisão séria Ausência de uso de evidências indiretas Alta HR ajustado 1,04 (0,82–1,33) para AMPD versus DIU-Cu Aquisição do HIV 10 estudos de coorte2-11 + 1 meta-análise de dados individuais de 7 estudos 12,c (40.506)a Algumas limitaçõesd Nenhuma inconsistência séria Nenhuma imprecisão séria Ausência de uso de evidências indiretas Baixa a moderadae HR ajustado entre 0,46– 2,04, 8 estudos com risco aumentado (variação do HR: 1,25-2,04), com efeitos estatisticamente significativos em 3 estudos; 2 estudos tenderam a redução de risco (HR 0,46 e 0,75 com intervalos de confiança amplos) HR agrupado ajustado 1,40 (1,24–1,58) NET-EN versus métodos contraceptivos não hormonais ou ausência de métodos contraceptivos Aquisição do HIV 6 estudos de coorte2,5,7,8,10,11 + 1 meta-análise de dados individuais de 7 estudos12,c (29.922)a Algumas limitaçõesd Nenhuma inconsistência séria Nenhuma imprecisão séria Ausência de uso de evidências indiretas Baixa HR ajustado entre 0,87-1,76. 5 estudos com risco aumentado (variação do HR de 1,20-1,76), nenhum estatisticamente significativo; 2 estudos sem efeito (HR ajustado entre 0,87–1,05) HR agrupado ajustado 1,14 (0,93–1,39) Uso de implantef use versus contraceptivos não-hormonais Aquisição do HIV 1 estudo randomizado1 (7.829)a Poucas limitaçõesb Nenhuma inconsistência séria Nenhuma imprecisão séria Ausência de uso de evidências indiretas Alta HR ajustado de 1,18 (0,91–1,53) para DIU-Cu versus implante de LNG Aquisição do HIV 3 estudos de coorte2–4,c (4.514)a Algumas limitaçõesd Nenhuma inconsistência séria Nenhuma imprecisão séria Ausência de uso de evidências indiretas Baixag HRs ajustados entre 0,46– 0,99 HR ajustados: 0,96 (0,29– 3,14), 0,99 (0,40–2,45), e 0,46 (0,13–1,70); nenhum estatisticamente significativo HR agrupado ajustado 0,82 (0,44–1,53) Uso de implantef versus NET-EN Aquisição do HIV 1 estudo de coorte2 (1.136)a Algumas limitaçõesd Nenhuma inconsistência séria Nenhuma imprecisão séria Ausência de uso de evidências indiretas Baixag HR ajustado 0,45 (0,13–1,53) para uso de implante versus NET-EN PERFIL DE EVIDÊNCIAS GRADE PARA USO DE CONTRACEPTIVOS HORMONAIS EM MULHERES HIV NEGATIVAS | Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz20 Resultado Tipo e número de estudos (número de participantes) Limitações Inconsistências Imprecisão Uso de evidências indiretas Qualidade global Estimativa de efeito Uso de contraceptivos hormonais orais versus métodos contraceptivos não hormonais ou ausência de métodos contraceptivos Aquisição do HIV 11 estudos de coorte3–6,8–14,c (43.482)a Algumas limitaçõesd Nenhuma inconsistência séria Nenhuma imprecisão séria Ausência de uso de evidências indiretas Baixa a moderadae HR ou IRR ajustados entre 0,66–1,80 3 estudos com aumento de risco (HR 1,39–1,80) Apenas 1 estudo relatou achado estatisticamente significativo (HR ajustado = 1,48 [1,05–2,09]) Os 8 estudos restantes relataram um risco diminuído (HR ajustado entre 0,66 a 0,99), nenhum dos quais foi estatisticamente significativo HR ajustado 1,02 (0,88–1,19) AMPD versus NET-EN Aquisição do HIV 2 estudos de coorte2,15 e 1 meta- análise de dados individuais de 17 estudos studies12,c (42.788)a Algumas limitaçõesd Nenhuma inconsistência séria Nenhuma imprecisão séria Ausência de uso de evidências indiretas Baixa a moderadae HRs ajustados de 1,32 (1,08–1,61) e 0,89 (0,55–1,44) em estudos de coorte e 1,41 (1,06–1,89) de uma me- ta-análise de dados individuais de 17 estudos. HR ajustado 1,27 (1,05–1,55) AMPD versus contraceptivo oral combinado Aquisição do HIV 1 meta-análise de dados individuais de 8 estudos12,c (24.853)a Algumas limitaçõesd Nenhuma inconsistência séria Nenhuma imprecisão séria Ausência de uso de evidências indiretas Baixa a moderadae HR ajustado de 1,41 (1,23– 1,67) em meta-análise de dados individuais de 8 estudos NET-EN versus contraceptivo oral combinado Aquisição do HIV 1 meta-análise de dados individuais de 9 estudos 12,c (25.398)a Algumas limitaçõesd Nenhuma inconsistência séria Nenhuma imprecisão séria Ausência de uso de evidências indiretas Baixa HR ajustado 1,30 (0,99–1,17) PERFIL DE EVIDÊNCIAS GRADE PARA USO DE CONTRACEPTIVOS HORMONAIS EM MULHERES HIV NEGATIVAS DIU-Cu: dispositivo intrauterino de cobre; AMPD-IM: acetato de medroxiprogesterona de depósito intramuscular; ETG: etonogestrel; GRADE: Grading Recommendations, Assessment, Development and Evaluation (Sistema GRADE – graduação da qualidade das evidências e força das recomendações para tomada de decisões em saúde); HR: hazard ratio (razão de risco); IRR: incidence rate ratio (razão da taxa de incidência); LNG: levonorgestrel; NET-EN: enantato de noretisterona. Nota: O viés de publicação não foi formalmente avaliado; estudos observacionais não puderam ter a qualidade elevada para grandes efeitos; relação dose-resposta ou fatores de confusão passíveis de aumentar os efeitos observados. Estimativas baseadas em estimativas de risco ajustadas, resultados da análise do modelo de Cox usada, quando disponível. a Tamanho da amostra é para toda a população do estudo. b Poucas limitações observadas no estudo, mas não sérias o suficiente para diminuir o nível de evidência. Embora o estudo não tenha sido cego para os participantes e os profissionais de saúde, os dados foram analisados centralmente por técnicos de estatística, para quem os grupos foram ocultados. c Restrito a estudos classificados como “informativos, mas com limitações importantes”. d Algumas limitações ou imprecisões observadas em todo o corpo de evidências, mas não suficientemente graves para diminuir o nível das evidências. e As evidências foram classificadas de baixa a moderada devido a resultados consistentes e precisos de estudos observacionais bem conduzidos e à coerência entre os estudos de uso versus não uso e estudos head-to-head. f Nenhuma evidência direta para implantes de ETG foi identificada para as comparações de interesse. Para implantes ETG, as recomendações foram extrapoladas de estudos sobre outros implantes. g Atualizado a partir de evidências de qualidade muito baixa (avaliação de 2016). Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz | 21 Referências: 1. Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium. HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial. Lancet. 2019;394(10195):303–13. doi: 10.1016/S0140-6736(19)31288-7. 2. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619–22. doi: 10.1097/ QAD.0000000000002260. 3. Sabo MC, Richardson BA, Lavreys L, Martin HL, Jr, Jaoko W, Mandaliya K et al. Does bacterial vaginosis modify the effect of hormonal contraception on HIV seroconversion. AIDS. 2019;33(7):1225–30. doi: 10.1097/QAD.0000000000002167. 4. Wall KM, Kilembe W, Vwalika B, Htee Khu N, Brill I, Chomba E et al. Hormonal contraception does not increase women’s HIV acquisition risk in Zambian discordant couples, 1994–2012. Contraception. 2015;91(6):480–7. Doi: 10.1016/j. contraception.2015.02.004. 5. Crook AM, Ford D, Gafos M, Hayes R, Kamali A, Kapiga S et al. Injectable and oral contraceptives and risk of HIV acquisition in women: an analysis of data from the MDP301 trial. Hum Reprod. 2014;29(8):1810–7. doi: 10.1093/humrep/deu113. 6. Heffron R, Donnell D, Rees H, Celum C, Mugo N, Were E et al. Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study. Lancet Infect Dis. 2012;12(1):19–26. doi: 10.1016/S1473-3099(11)70247-X. 7. Kleinschmidt I, Rees H, Delany S, Smith D, Dinat N, Nkala B et al. Injectable progestin contraceptive use and risk of HIV infection in a South African family planning cohort. Contraception. 2007;75(6):461–7. doi: 10.1016/j.contraception.2007.02.002. 8. McCoy SI, Zheng W, Montgomery ET, Blanchard K, van der Straten A, de Bruyn G et al. Oral and injectable contraception use and risk of HIV acquisition among women in sub-Saharan Africa. AIDS. 2013;27(6):1001–9. doi: 10.1097/ QAD.0b013e32835da401. 9. Morrison CS, Richardson BA, Mmiro F, Chipato T, Celentano DD, Luoto J et al. Hormonal contraception and the risk of HIV acquisition. AIDS. 2007;21(1):85–95. doi: 10.1097/QAD.0b013e3280117c8b. 10. Morrison CS, Skoler-Karpoff S, Kwok C, Chen PL, van de Wijgert J, Gehret-Plagianos M et al. Hormonal contraception and the risk of HIV acquisition among women in South Africa. AIDS. 2012;26(4):497–504. doi: 10.1097/QAD.0b013e32834fa13d. 11. Myer L, Denny L, Wright TC, Kuhn L. Prospective study of hormonal contraception and women’s risk of HIV infection in South Africa. Int J Epidemiol. 2007;36(1):166–74. doi: 10.1093/ije/dyl251. 12. Morrison CS, Chen PL, Kwok C, Baeten JM, Brown J, Crook AM et al. Hormonal contraception and the risk of HIV acquisition: an individual participant data meta-analysis. PLoS Med. 2015;12(1):e1001778. doi: 10.1371/journal.pmed.1001778. 13. Balkus JE, Brown ER, Hillier SL, Coletti A, Ramjee G, Mgodi N et al. Oral and injectable contraceptive use and HIV acquisition risk among women in four African countries: a secondary analysis of data from a microbicide trial. Contraception. 2016;93(1):25–31. doi: 10.1016/j.contraception.2015.10.010. 14. Reid SE, Dai JY, Wang J, Sichalwe BN, Akpomiemie G, Cowan FM et al. Pregnancy, contraceptive use, and HIV acquisition in HPTN 039: relevance for HIV prevention trials among African women. J Acquir Immune Defic Syndr. 2010;53(5):606–13. doi: 10.1097/QAI.0b013e3181bc4869. 15. Noguchi LM, Richardson BA, Baeten JM, Hillier SL, Balkus JE, Chirenje ZM et al. Risk of HIV-1 acquisition among women who use different types of injectable progestin contraception in South Africa: a prospective cohort study. Lancet HIV. 2015;2(7):e279–87. doi: 10.1016/S2352-3018(15)00058-2. | Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz22 Resultado Tipo e número de estudos (número de participantes) Limitações Inconsistências Imprecisão Uso de evidências indiretas Qualidade global Estimativa de efeito DIUa versus ausência de método contraceptivo ou laqueadura tubária Aquisição do HIV 1 estudo prospec- tivo1,b (1.498)c Algumas limitaçõesd Nenhuma inconsistência séria Nenhuma imprecisão séria Ausência de uso de evidências indiretas Baixa HR ajustado 1,1 (0,4–3,0) para DIU-Cu versus ausência de contracepção ou laqueadura tubária DIUa versus implante,e AMPD, NET-EN Aquisição do HIV 1 estudo prospectivo2,b (1.136)c Algumas limitaçõesd Nenhuma inconsistência séria Nenhuma imprecisão séria Ausência de uso de evidências indiretas Baixa HR ajustado 0,90 (0,45–1,76) para AMPD, implantes, NET-EN versus DIU-Cu DIUa versus AMPD Aquisição do HIV 1 RCT3,b (7.829)c Poucas limitaçõesf Nenhuma inconsistência séria Nenhuma imprecisão séria Ausência de uso de evidências indiretas Alta HR ajustado 1,04 (0,82–1,33) para AMPD-IM versus DIU-Cu Aquisição do HIV 1 estudo prospectivo2,b (1.136)c Algumas limitaçõesd Nenhuma inconsistência séria Nenhuma imprecisão séria Ausência de uso de evidências indiretas Baixa HR ajustado 0,91 (0,44–1,87) para AMPD versus DIU-Cu DIUa versus NET-EN Aquisição do HIV 1 estudo prospectivo2,b (1.136)c Algumas limitaçõesd Nenhuma inconsistência séria Nenhuma imprecisão séria Ausência de uso de evidências indiretas Baixa HR ajustado 0,98 (0,47–2,03) para o DIU-Cu versus NET-EN DIUa versus implantee Aquisição do HIV 1 RCT3 (7.829)c Poucas limitaçõesf Nenhuma inconsistência séria Nenhuma imprecisão séria Ausência de uso de evidências indiretas Alta HR ajustado 1,18 (0,91–1,53) para DIU-Cu versus implante de LNG Aquisição do HIV 1 estudo prospectivo2,b (1.136)c Algumas limitaçõesd Nenhuma inconsistência séria Nenhuma imprecisão séria Ausência de uso de evidências indiretas Baixa HR ajustado 2,17 (0,59–7,69) para DIU-Cu versus implantes (LNG ou ETG) PERFIL DE EVIDÊNCIAS GRADE PARA USO DE DIU-CU EM MULHERES HIV NEGATIVAS DIU-Cu: dispositivo intrauterino de cobre; AMPD-IM: acetato de medroxiprogesterona de depósito intramuscular; ETG: etonogestrel; GRADE: Grading Recommendations, Assessment, Development and Evaluation (Sistema GRADE – graduação da qualidade das evidências e força das recomendações para tomada de decisões em saúde); HR: hazard ratio (razão de risco); IRR: incidence rate ratio (razão da taxa de incidência); LNG: levonorgestrel; NET-EN: enantato de noretisterona; RCT (randomized clinical trial: ensaio clínico randomizado); DIU: Dispositivo intrauterino Nota: O viés de publicação não foi formalmente avaliado; estudos observacionais não puderam ter a qualidade elevada para grandes efeitos; relação dose-resposta ou fatores de confusão passíveis de aumentar os efeitos observados. Estimativas baseadas em estimativas de risco ajustadas, resultados da análise do modelo de Cox usada, quando disponível. a Não foram identificadas evidências diretas do DIU-LNG para as comparações de interesse. Para os DIU de LNG, as recomendações foram extrapoladas das evidências sobre os DIU-Cu e outros produtos que contêm LNG. b Restrito a estudos classificados como “informativos, mas com limitações importantes”. c O tamanho da amostra é para toda a população do estudo. d Algumas limitações ou imprecisões foram observadas em todo o corpo de evidências, mas não suficientemente graves para diminuir o nível de evidência. e Não foram identificadas evidências diretas do implante de ETG para as comparações de interesse. Para implantes de ETG, as recomendações foram extrapoladas a partir das evidências sobre implantes de LNG. f Poucas limitações observadas no julgamento, mas não sérias o suficiente para diminuir o nível de evidência. Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz | 23 Referências: 1. Lavreys L, Baeten JM, Martin Jr HL, Overbaugh J, Mandaliya K, Ndinya-Achola J et al. Hormonal contraception and risk of HIV-1 acquisition: results of a 10-year prospective study. AIDS. 2004;18(4):695–7. 2. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619–22. doi: 10.1097/ QAD.0000000000002260. 3. Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium. HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial. Lancet. 2019;394(10195):303–13. doi: 10.1016/S0140-6736(19)31288-7. | Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz24 ANEXO 4: TABELA DE EVIDÊNCIAS PARA A TOMADA DE DECISÃO PARA MÉTODOS CONTRACEPTIVOS HORMONAIS E DISPOSITIVOS INTRAUTERINOS (DIU) Fator Explicações/evidências Julgamento Qualidade da evidência Contraceptivos contendo apenas progestagênio Para o resultado primário (aquisição do HIV), a evidência foi considerada de alta qualidade para o acetato de medroxiprogesterona de depósito intramuscular (AMPD- IM) e para os implantes de levonorgestrel (LNG). A evidência foi considerada de baixa qualidade para o enantato de noretisterona (NET-EN) e ausente para o AMPD subcutâneo (AMPD-SC), os dispositivos intrauterinos (DIU) de LNG e os implantes de etonogestrel (ETG). Para o NET-EN e o AMPD-SC, as recomendações foram extrapoladas a partir das evidências do uso do AMPD-IM. Para os implantes de ETG, as recomendações foram extrapoladas das evidências sobre os implantes de LNG. Alta, baixa ou ausente, dependendo do método contraceptivo DIU Para o resultado primário (aquisição do HIV), as evidências foram consideradas de alta qualidade para DIU contendo cobre (DIU-Cu). Não existiam evidências para os DIU de LNG. Para os DIU de LNG, as recomendações foram extrapoladas das evidências sobre os DIU de Cu e outros produtos que contêm LNG. Alta ou ausente, dependendo do método contraceptivo Contraceptivos hormonais combinados (CHC) A evidência foi considerada de qualidade baixa a moderada para os CHCs. Baixa-moderada Balanço entre benefícios e malefícios Contraceptivos contendo apenas progestagênio A contracepção é uma intervenção que salva vidas, com benefícios de saúde, sociais e econômicos bem reconhecidos. Todos os contraceptivos contendo apenas progestagênio são métodos reversíveis eficazes ou altamente eficazes. Evidências de alta qualidade de um ensaio clínico randomizado (ECR) não observaram diferenças estatisticamente significativas na aquisição do HIV entre: AMPD-IM versus DIU-Cu, AMPD-IM versus implante de LNG e DIU-Cu versus implante de LNG. Das evidências de qualidade baixa a moderada de 14 estudos observacionais, alguns estudos sugeriram um possível aumento do risco de contrair HIV com uso de contraceptivo injetável contendo apenas progestagênio, provavelmente devido a fatores de confusão não medidos. a, b Evidências de baixa qualidade de três estudos observacionais não sugeriram risco aumentado de infecção pelo HIV em usuárias de implantes. a, b Não foram identificados estudos de qualidade suficiente para as pílulas apenas de progestagênio. Embora nenhuma evidência direta estivesse disponível para AMPD-SC e implantes de ETG, foram usadas evidências indiretas do AMPD-IM e dos implantes de LNG, uma vez que não havia razão biológica ou clínica para acreditar que uma dose hormonal mais baixa, um mecanismo de administração diferente ou um progestagênio diferente modificaria o risco de adquirir o HIV. O balanço é a favor dos benefícios dos contraceptivos contendo apenas progestagênio DIU A contracepção é uma intervenção que salva vidas, com benefícios de saúde, sociais e econômicos bem reconhecidos. Todos os DIU são métodos reversíveis e altamente eficazes. Evidências de alta qualidade de um ECR, juntamente com evidências de baixa qual- idade de dois estudos observacionais, não sugeriram risco aumentado de aquisição do HIV com o uso de DIU-Cu. c-e Embora nenhuma evidência direta estivesse disponível para os DIU de LNG, as recomendações foram extrapoladas das evidências sobre os DIU de Cu e outros produtos que contêm LNG. O balanço é a favor dos benefícios dos DIU Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz | 25 Fator Explicações/evidências Julgamento Balanço entre benefícios e malefícios CHC A contracepção é uma intervenção que salva vidas, com benefícios de saúde, sociais e econômicos bem reconhecidos. Todos os contraceptivos hormonais combinados são métodos reversíveis e eficazes. Evidências de qualidade moderada e baixa de 11 estudos observacionais sugeriram não haver associação entre o uso de contraceptivo oral combinado (COC) e aquisição de HIV (presumiu-se que estudos que não especificassem o tipo de contraceptivo oral examinaram principalmente, se não exclusivamente, uso de COC). a, b Embora nenhuma evidência direta estivesse disponível para adesivos contraceptivos combinados, anel vaginal contraceptivo combinado ou contraceptivo injetável combinado, foram usadas evidências indiretas dos COCs, uma vez que não havia razões biológicas ou clínicas para acreditar que uma dose hormonal mais baixa, um mecanismo de administração diferente ou um progestagênio diferente modificaria o risco de aquisição do HIV. O balanço é a favor dos benefícios dos CHCs Valores e preferencias As mulheres têm o direito de tomar decisões informadas. As mulheres preferem ter escolha de métodos contraceptivos, informações completas sobre benefícios versus malefícios e tomar uma decisão final em conjunto com o profissional de saúde (tomada de decisão informada). A contracepção é única entre os medicamentos, porque as necessidades e preferências de uma mulher em relação às características dos métodos contraceptivos variam tanto entre mulheres individuais quanto na vida útil de uma única pessoa. Os temas comuns nas preferências contraceptivas incluem ser discretos, ter efeitos colaterais mínimos e ser de longa ação, reversíveis e fáceis de usar. As mulheres que usam injetáveis contendo apenas progestagênio geralmente gostam deste método por esses motivos descritos e se sentem confortáveis em usá-los após o aconselhamento. As preferências das mulheres por métodos são limitadas pelo conhecimento que elas possuem sobre o método, pela disponibilidade do método e por outros fatores que promovem ou limitam o acesso. Oferecer às mulheres a escolha de uma variedade de métodos é importante tanto da perspectiva da saúde quanto dos direitos. Suporte para otimizar a escolha informada do contraceptivo e a disponibilidade de uma ampla variedade de opções contraceptivas. Prioridade do problema O HIV é uma doença grave e uma grande epidemia global. A gravidez não planejada é um problema muito comum em todo o mundo e os riscos a ela associados são mais altos nos locais nos quais a mortalidade materna e a morbidade grave também são comuns. Ambos são prioridades para a saúde pública. Contracepção eficaz e prevenção do HIV são prioridades de saúde pública Equidade e direitos humanos Os princípios e padrões de direitos humanos das diretrizes existentes da Organização Mundial da Saúde (OMS) sobre direitos humanos e contracepção foram seguidos pelo Grupo de Desenvolvimento das Diretrizes (GDD) em suas deliberações. Isso inclui não discriminação, disponibilidade, acessibilidade, aceitabilidade, qualidade, tomada de decisão informada, privacidade e confidencialidade, participação e responsabilidade. Durante suas deliberações, o GDD considerou os possíveis efeitos positivos e negativos de suas considerações. Por exemplo, considerou e enfatizou a necessidade contínua de serviços integrados de planejamento familiar e HIV em locais com alta incidência de HIV. Também enfatizou a necessidade de expandir e otimizar as opções contraceptivas. As recomendações da diretriz da OMS sobre direitos humanos para contracepção são princípios fundamentais para a tomada de decisões sobre esse tópico Viabilidade A importância de uma comunicação clara da OMS sobre esse tópico foi enfatizada. Isso foi reforçado por estudos recentes que sugeriram que as mensagens baseadas nas orientações de 2017 da OMS eram difíceis de explicar e podem não ter sido totalmente compreendidas pelos pacientes ou profission- ais de saúde. Orientações claras e uma abordagem centrada na mulher são essenciais para uma implementação bem-sucedida | Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz26 Referências: a. Polis CB, Curtis KM, Hannaford PC, Phillips SJ, Chipato T, Kiarie JN et al. An updated systematic review of epidemiological evidence on hormonal contraceptive methods and HIV acquisition in women. AIDS. 2016;30(17):2665–83. doi: 10.1097/ QAD.0000000000001228. b. Sabo MC, Richardson BA, Lavreys L, Martin HL, Jr, Jaoko W, Mandaliya K et al. Does bacterial vaginosis modify the effect of hormonal contraception on HIV seroconversion. AIDS. 2019;33(7):1225–30. doi: 10.1097/QAD.0000000000002167. c. Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium. HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial. Lancet. 2019;394(10195):303–13. doi: 10.1016/S0140-6736(19)31288-7. d. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619–22. doi: 10.1097/ QAD.0000000000002260. e. Lavreys L, Baeten JM, Martin Jr HL, Overbaugh J, Mandaliya K, Ndinya-Achola J et al. Hormonal contraception and risk of HIV-1 acquisition: results of a 10-year prospective study. AIDS. 2004;18(4):695–7. Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz | 27 ANEXO 5: REVISÕES SISTEMÁTICAS Três revisões sistemáticas foram conduzidas como parte do desenvolvimento desta diretriz. Os detalhes dos métodos e estratégias de pesquisa estão incluídos nas revisões. As revisões publicadas em periódicos revisados por pares estão disponíveis através de acesso aberto. Este apêndice será atualizado periodicamente, à medida que as revisões forem publicadas. O acesso a revisões não publicadas pode ser solicitado enviando um e-mail para hrx-info@who.int. 1. Uso de método contraceptivo hormonal e aquisição do HIV em mulheres Existe uma revisão publicada anteriormente sobre o uso de contraceptivos hormonais e a aquisição do HIV. As estratégias de pesquisa dessa revisão foram usadas para procurar novas evidências desde então. As quatro novas publicações, a seguir, foram identificadas e atendiam aos critérios de inclusão. REVISÃO PREVIAMENTE PUBLICADA 1. Polis CB, Curtis KM, Hannaford PC, Phillips SJ, Chipato T, Kiarie JN et al. An updated systematic review of epidemiological evidence on hormonal contraceptive methods and HIV acquisition in women. AIDS. 2016;30(17):2665–83. doi: 10.1097/ QAD.0000000000001228. REVISÃO PUBLICADA 1. Curtis KM, Hannaford PC, Rodriguez MI, Chipato T, Steyn PS, Kiarie JN. Hormonal contraceptive method use and HIV acquisition in women: an updated systematic review. BMJ Sex Reprod Health. 2020;46(1):8-16. doi: 10.1136/ bmjsrh-2019-200509. NOVOS ARTIGOS 1. Haddad LB, Wall KM, Kilembe W, Vwalika B, Khu NH, Brill I et al. Bacterial vaginosis modifies the association between hormonal contraception and HIV acquisition. AIDS. 2018;32(5):595–604. doi: 10.1097/ QAD.0000000000001741. 2. Hofmeyr GJ, Singata-Madliki M, Lawrie TA, Bergel E, Temmerman M. Effects of injectable progestogen contraception versus the copper intrauterine device on HIV acquisition: sub-study of a pragmatic randomised controlled trial. J Fam Plann Reprod Health Care. 2017;43(3):175–80. doi: 10.1136/jfprhc-2016-101607. 3. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619– 22. doi: 10.1097/QAD.0000000000002260. 4. Sabo MC, Richardson BA, Lavreys L, Martin HL, Jr., Jaoko W, Mandaliya K et al. Does bacterial vaginosis modify the effect of hormonal contraception on HIV seroconversion. AIDS. 2019;33(7):1225-30. doi: 10.1097/ QAD.0000000000002167. 2. Uso de dispositivo intrauterino de cobre (DIU-Cu) e aquisição de HIV em mulheres Uma revisão sistemática foi realizada sobre o uso de DIU-Cu e aquisição de HIV em mulheres. Os seis artigos a seguir preencheram os critérios de inclusão. REVISÃO PUBLICADA 1. Hannaford PC, Ti A, Chipato T, Curtis KM. Copper intrauterine device use and HIV acquisition in women: an updated systematic review. BMJ Sex Reprod Health. 2020 ;46(1):17-25. doi: 10.1136/bmjsrh-2019-200512. NOVOS ARTIGOS 1. Hofmeyr GJ, Singata-Madliki M, Lawrie TA, Bergel E, Temmerman M. Effects of injectable progestogen contraception versus the copper intrauterine device on HIV acquisition: sub-study of a pragmatic randomised controlled trial. J Fam Plann Reprod Health Care. 2017;43(3):175–80. doi: 10.1136/jfprhc-2016-101607. 2. Kapiga SH, Lyamuya EF, Lwihula GK, Hunter DJ. The incidence of HIV infection among women using family planning methods in Dar es Salaam, Tanzania. AIDS. 1998;12(1):75–84. doi: 10.1097/00002030-199801000- 00009. 3. Lavreys L, Baeten JM, Martin Jr HL, Overbaugh J, Mandaliya K, Ndinya-Achola J et al. Hormonal contraception and risk of HIV-1 acquisition: results of a 10-year prospective study. AIDS. 2004;18(4):695–7. 4. Palanee-Phillips T, Brown ER, Szydlo D, Matovu Kiweewa F, Pather A, Harkoo I et al. Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study. AIDS. 2019;33(10):1619– 22. doi: 10.1097/QAD.0000000000002260. 5. Saracco A, Musicco M, Nicolosi A, Angarano G, Arici C, Gavazzeni G et al. Man-to-woman sexual transmission of HIV: longitudinal study of 343 steady partners of infected men. J Acquir Immune Defic Syndr. 1993;6(5):497-502. 6. Sinei SK, Fortney JA, Kigondu CS, Feldblum PJ, Kuyoh M, Allen MY et al. Contraceptive use and HIV infection in Kenyan family planning clinic attenders. Int J STD AIDS. 1996;7(1):65–70. doi: 10.1258/0956462961917104. | Elegibilidade dos contraceptivos para mulheres com alto risco de infecção pelo HIV: diretriz28 3. Valores e preferências em relação aos contraceptivos Uma revisão sistemática foi realizada sobre valores e preferências em relação aos contraceptivos. O protocolo e os métodos estão publicados e o manuscrito que apresenta os principais resultados da revisão está em revisão para publicação. Como esta revisão não identificou informações específicas para populações-chave em risco de infeção pelo HIV, foram realizados estudos consultivos na primavera de 2019, incluindo uma pesquisa online global com profissionais do sexo e discussões de grupos focais com participação de mulheres profissionais do sexo no Zimbábue (através do “Sisters with a Voice programme”). As apresentações que mostraram os achados desses trabalhos estão listadas abaixo e disponíveis mediante solicitação. Uma apresentação compartilhada pelas partes interessadas representando as populações afetadas para destacar suas perspectivas sobre o tema fazia parte das discussões do Grupo de Desenvolvimento das Diretrizes e está disponível mediante solicitação. 1. Kennedy CE, Yeh PT, Gaffield ME. Contraception values and preferences: protocol and methods for a global systematic review. Contraception. 2019 (in press). doi: 10.1016/j. contraception.2018.05.006Get. 2. Yeh PT, Kennedy CE, Gaffield ME. Contraception values and preferences: a global systematic review. Contraception. 2019; (accepted pending revisions). 3. Shapiro A. Female sex workers’ contraceptive practices, values and preferences. contraception and risk of HIV infection: a WHO Guideline Development Group review of the current evidence. 29 July 2019, Geneva, World Health Organization. 4. Sibanda E. Views on contraceptive methods among female sex workers in Harare, Zimbabwe: a participatory qualitative study. 29 July 2019, Geneva, World Health Organization. 5. Mworeko L. What do recommendations on contraceptives and HIV risk mean to women?, 29 July 2019, Geneva, World Health Organization.

Para mais informações, favor contatar: Department of Reproductive Health and Research, World Health Organization, Avenue Appia 20, CH-1211 Geneva 27, Switzerland. E-mail: reproductivehealth@who.int www.who.int/reproductivehealth