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WHO guidelines for the treatment of Chlamydia trachomatis

July 4, 2016 World Health Organization

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WHO GUIDELINES FOR THE

Treatment of Chlamydia trachomatis

WHO GUIDELINES FOR THE

Treatment of Chlamydia trachomatis

© World Health Organization 2016 All rights reserved. Publications of the World Health Organization are available on the WHO website (http://www.who.int) or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; email: bookorders@who.int). Requests for permission to reproduce or translate WHO publications – whether for sale or for non-commercial distribution– should be addressed to WHO Press through the WHO website (http://www.who.int/about/licensing/ copyright_form/index.html). 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 the World Health Organization 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 the World Health Organization 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 the World Health Organization 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 the World Health Organization be liable for damages arising from its use. Printed by the WHO Document Production Services, Geneva, Switzerland

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

CONTENTS

Acknowledgements iii Abbreviations and acronyms Executive summary iv 1

Overview of the guidelines for the prevention, treatment and management of STIs 6 STI epidemiology and burden 6 Why new guidelines for the prevention, treatment and management of STIs? 6 Approach to the revision of STI guidelines 8 References 9 WHO guidelines for the treatment of Chlamydia trachomatis 10 1. 1.1 1.2 1.3 1.4 1.5 2. 2.1 2.2 2.3 2.4 2.5 3. 3.1 3.2 3.3 4. 4.1 4.2 4.3 4.4 Introduction Epidemiology, burden and clinical considerations Clinical presentation Laboratory diagnosis Rationale for new recommendations Objectives Target audience Structure of the guidelines Methods Guideline Development Group (GDG) Questions and outcomes Reviews of the evidence Making recommendations Management of conflicts of interest 10 10 10 11 11 11 11 11 12 12 12 12 13 14

Dissemination, updating and implementation of the guidelines 15 Dissemination 15 Updating the STI guidelines and user feedback 15 Implementation of the WHO guidelines for the treatment of C. trachomatis 15 Adaptation, implementation and monitoring 15 Identifying and procuring STI drugs 16 Recommendations for treatment of chlamydial infections Uncomplicated genital chlamydia Recommendation 1 Anorectal chlamydial infection Recommendation 2 Chlamydial infection in pregnant women Recommendation 3a Recommendation 3b Recommendation 3c Lymphogranuloma venereum (LGV) Recommendation 4 17 17 17 18 18 19 19 19 19 20 20

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

CONTENTS (CONTINUED)

4.5

Ophthalmia neonatorum Recommendation 5 Recommendation 6 Recommendation 7

20 20 21 21

References 22 Annex A: STI guideline development teams Annex B: Detailed methods for guideline development Questions and outcomes Review of the evidence Applying the GRADE approach to making the recommendations Annex C: Lists of references for reviewed evidence Recommendation 1 Recommendation 2 Recommendation 3a, 3b, 3c Recommendation 4 Recommendation 5 Recommendations 6 and 7 23 32 32 35 38 39 39 40 41 42 43 43

Web annexes available at: www.who.int/reproductivehealth/publications/rtis/chlamydia-treatment-guidelines/en/ Web annex D: Evidence profiles and evidence-to-decision frameworks Web annex E: Systematic reviews for chlamydia guidelines Web annex F: Summary of conflicts of interest

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

iii

ACKNOWLEDGEMENTS

The Department of Reproductive Health and Research at the World Health Organization (WHO) would like to thank the members of the STI Guideline Development Group for their consistent availability and commitment to making these guidelines possible. The Department is also grateful to the STI External Review Group for peer reviewing these guidelines, and appreciates the contribution of the WHO Steering Committee. The names of the members of each group are listed below, with full details provided in Annex A. Special thanks to Dr Nancy Santesso, the guideline methodologist who also led the systematic review process, for her hard work and firm commitment of the guideline development process. We also thank the members of the Systematic Review Team from McMaster University. We appreciate the overall support of the WHO Guideline Review Committee Secretariat during the guideline development process, with grateful thanks to Dr Susan Norris. We thank Theresa Ryle for the administrative support and 400 Communications for assistance with the guideline design and layout. This guideline document was edited by Ms Jane Patten, of Green Ink, United Kingdom. Dr Teodora Wi led the guideline development process and Dr Nathalie Broutet co-led the process under the supervision of Dr James Kiarie and leadership of Dr Ian Askew. Lee Sharkey provided support during the guideline development process.

Members: Yaw (Sax) Adu-Sarkodie, Andrew Amato, Gail Bolan, John Changalucha, Xiang-Sheng Chen, Harrel Chesson, Craig Cohen, Francisco Garcia, Suzanne Garland, Sarah Hawkes, Mary Higgins, King Holmes, Jeffrey Klausner, David Lewis, Nicola Low, David Mabey, Angelica Espinosa Miranda, Nelly Mugo, Saiqa Mullick, Francis Ndowa, Joel Palefsky, Keith Radcliffe, Ulugbek Sabirov, Judith Stephenson, Richard Steen, Magnus Unemo, Bea Vuylsteke, Anna Wald, Thomas Wong and Kimberly A. Workowski STI GDG sub working group for chlamydia: Andrew Amato, Harrell Chesson, Craig Cohen, Patricia Garcia, Nicola Low, David Mabey, Angelica Miranda, Francis Ndowa, Keith Radcliffe, Judith Stephenson, Magnus Unemo, Bea Vuylsteke and Judith Wasserheit STI external reviewers: Laith Abu-Raddad, Adele Benaken-Schwartz, Mircea Betiu, Anupong Chitwarakorn, Anjana Das, Carolyn Deal, Margaret Gale-Rowe, William M. Geisler, Amina El Kettani, Mizan Kiros, Ahmed Latif, Philippe Mayaud, David McCartney, Ali M. Mir, Nuriye Ortayli, Khantanouvieng Sayabounthavong and Aman Kumar Singh WHO Steering Committee: WHO regional offices: Massimo Ghidinelli, Hamida Khattabi, Lali Khotenashvili, Ornella Lincetto Ying-Ru Lo, Frank Lule and Razia Pendse WHO headquarters: Moazzam Ali, Avni Amin, Rachel Baggaley, Venkatraman Chandra-Mouli, Jane Ferguson, Mario Festin, Mary Lyn Gaffield, Sami Gottlieb, Silvio Paolo Mariotti, Frances McConville, Lori Newman, Annette Mwansa Nkowane, Anita Sands, Igor Toskin and Marco Vitoria WHO STI Secretariat: Ian Askew, Teodora Elvira Wi (lead, development of the guidelines), Nathalie Broutet (co-lead, development of the guidelines), James Kiarie and Lee Sharkey Systematic Review Team: Nancy Santesso (lead), Housne Begum, Janna-Lina Kerth, Gian Paolo Morgano, Kristie Poole, Nicole Schwab, Matthew Ventresca, Yuan Zhang and Andrew Zikic (members) Methodologist: Nancy Santesso.

FUNDING The preparation and printing of the guidelines were funded exclusively by the UNDP/UNFPA/UNICEF/ WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP). No external source of funding was solicited or utilized.

CONTRIBUTORS TO WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS STI Guideline Development Group (GDG): Chairpersons: Judith Wasserheit, Holger Schünemann and Patricia Garcia

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

ABBREVIATIONS AND ACRONYMS

AIDS AMR DALY DFA DOI ELISA GDG GRADE GUD HIV HPV

acquired immune deficiency syndrome antimicrobial resistance disability-adjusted life year direct fluorescent antibody declaration of interests enzyme-linked immunosorbent assays Guideline Development Group Grading of Recommendations Assessment, Development and Evaluation genital ulcer disease human immunodeficiency virus human papillomavirus

HRP UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction HSV-2 LGV MSH MSM NAATs PICO POCT STI UNAIDS UNFPA UNICEF WHO herpes simplex virus type 2 lymphogranuloma venereum Management Sciences for Health men who have sex with men nucleic acid amplification tests (NAATs) population, intervention, comparator, outcome point-of-care test sexually transmitted infection Joint United Nations Programme on HIV/AIDS United Nations Population Fund United Nations Children’s Fund World Health Organization

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS EXECUTIVE SUMMARY

Sexually transmitted infections (STIs) are a major public health problem worldwide, affecting quality of life and causing serious morbidity and mortality. STIs have a direct impact on reproductive and child health through infertility, cancers and pregnancy complications, and they have an indirect impact through their role in facilitating sexual transmission of human immunodeficiency virus (HIV) and thus they also have an impact on national and individual economies. More than a million STIs are acquired every day. In 2012, an estimated 357 million new cases of curable STIs (gonorrhoea, chlamydia, syphilis and trichomoniasis) occurred among 15–49 year-olds worldwide, including 131 million cases of chlamydial infection.

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

Chlamydial infection, caused by Chlamydia trachomatis, is the most common bacterial STI and results in substantial morbidity and economic cost worldwide. Occurring most commonly among young sexually active adults, C. trachomatis causes cervicitis in women and urethritis in men, as well as extra-genital infections, including rectal and oropharyngeal infections. Asymptomatic infections are common in both men and women. Untreated chlamydial infection may cause severe complications in the upper reproductive tract, primarily in young women, including ectopic pregnancy, salpingitis and infertility. Lymphogranuloma venereum (LGV), caused by a more invasive serovar of C. trachomatis, is increasingly prevalent among men who have sex with men (MSM) in some settings. Maternal infection is associated with serious adverse outcomes in neonates, such as preterm birth, low birth weight, conjunctivitis, nasopharyngeal infection and pneumonia. C. trachomatis can be diagnosed by culture, direct immunofluorescence assays (DFAs) and enzymelinked immunosorbent assays (ELISAs), but nucleic acid amplification tests (NAATs) are preferred due to their superior performance characteristics.

OBJECTIVES The objectives of these guidelines are: • t o provide evidence-based guidance on treatment of infection with C. trachomatis; and • t o support countries to update their national guidelines for treatment of chlamydial infection.

METHODS These guidelines were developed following the methods outlined in the 2014 WHO handbook for guideline development. The Guideline Development Group (GDG) included international STI experts, clinicians, researchers and programme managers. The GDG prioritized questions and outcomes related to treatment of chlamydial infections to include in this update, and a methodologist and a team of systematic reviewers from McMaster University, the WHO Collaborating Centre for Evidence-Informed Policy, independently conducted systematic reviews of the effectiveness of different treatments for chlamydial infections. The evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach and presented to the GDG. Conflicts of interest were managed according to WHO guidelines and declared before the recommendations were discussed and finalized. Research implications were also developed by the GDG.

RATIONALE FOR THE GUIDELINES Since the publication of the World Health Organization (WHO) Guidelines for the management of sexually transmitted infections in 2003, changes in the epidemiology of STIs and advancements in prevention, diagnosis and treatment necessitate changes in STI management. These guidelines provide updated treatment recommendations for common infections caused by C. trachomatis based on the most recent evidence; they form one of several modules of guidelines for specific STIs. Other modules will focus on treatments for Neisseria gonorrhoeae (gonorrhoea), herpes simplex virus type 2 (HSV-2; genital herpes) and Treponema pallidum (syphilis). In addition, future work will provide guidance for syphilis screening and treatment of pregnant women, STI syndromic approach, clinical management, STI prevention, and treatments of other STIs. It is strongly recommended that countries take updated global guidance into account as they establish standardized national protocols, adapting this guidance to the local epidemiological situation and antimicrobial susceptibility data.

RECOMMENDATIONS The current guidelines provide nine treatment recommendations for genital infections and LGV caused by C. trachomatis. The recommendations summarized in Table 1 apply to adults, adolescents (10–19 years of age), people living with HIV and key populations, including sex workers, MSM and transgender persons. Specific recommendations have also been developed for genital chlamydial infection in pregnant women and for prophylaxis and treatment of ophthalmia neonatorum caused by C. trachomatis.

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

Table 1. Summary of recommendations for treatment of chlamydial infections Recommendations Strength of recommendation and quality of evidence Conditional recommendation, moderate quality evidence

Uncomplicated genital chlamydia Recommendation 1 The WHO STI guideline suggests treatment with one of the following options: • azithromycin 1 g orally as a single dose • doxycycline 100 mg orally twice a day for 7 days or one of these alternatives: • tetracycline 500 mg orally four times a day for 7 days • erythromycin 500 mg orally twice a day for 7 days • ofloxacin 200–400 mg orally twice a day for 7 days. Remarks: While good practice based on evidence of large net benefit dictates that patients should be treated for chlamydial infection, the choice of treatment may depend on the convenience of dosage, the cost and quality of the medicines in different settings, and equity considerations. When high value is placed on reducing costs, doxycycline in a standard dose may be the best choice; when high value is placed on convenience, azithromycin in a single dose may be the best choice. A delayed-release doxycycline formulation may be an alternative to twice daily dosing of doxycycline, but the high cost of the delayed-release formulation may prohibit its use. Note that doxycycline, tetracycline and ofloxacin are contraindicated in pregnant women (see recommendations 3a–3c). Anorectal chlamydial infection Recommendation 2 The WHO STI guideline suggests treatment with doxycycline 100 mg orally twice a day for 7 days over azithromycin 1 g orally as a single dose. Remarks: This recommendation applies to people with known anorectal infection and to people with suspected anorectal infections with genital co-infection. Clinicians should ask men, women and key populations (e.g. men who have sex with men, transgender persons and female sex workers) about anal sex and treat accordingly. Doxycycline should not be used in pregnant women because of adverse effects (see recommendations 3a–3c). Conditional recommendation, low quality evidence

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

Genital chlamydial infection in pregnant women Recommendation 3a The WHO STI guideline recommends treatment with azithromycin over erythromycin. Recommendation 3b The WHO STI guideline suggests treatment with azithromycin over amoxicillin. Recommendation 3c The WHO STI guideline suggests treatment with amoxicillin over erythromycin. Dosages: • azithromycin 1 g orally as a single dose • amoxicillin 500 mg orally three times a day for 7 days • erythromycin 500 mg orally twice a day for 7 days. Remarks: Azithromycin is the first choice of treatment but may not be available in some settings. Azithromycin is less expensive than erythromycin and since it is provided as a single dose, may result in better adherence and therefore better outcomes. Lymphogranuloma venereum (LGV) Recommendation 4 The WHO STI guideline suggests treatment with doxycycline 100 mg orally twice daily for 21 days over azithromycin 1 g orally, weekly for 3 weeks. Remarks: Good practice dictates effective treatment of LGV, in particular for men who have sex with men and for people living with HIV. When doxycycline is contraindicated, azithromycin should be provided. When neither treatment is available, erythromycin 500 mg orally four times a day for 21 days is an alternative. Doxycycline should not be used in pregnant women because of adverse effects (see recommendations 3a–3c). Ophthalmia neonatorum Recommendation 5 In neonates with chlamydial conjunctivitis, the WHO STI guideline recommends treatment with azithromycin 20 mg/kg/day orally, one dose daily for 3 days, over erythromycin 50 mg/kg/day orally, in four divided doses daily for 14 days. Remarks: This is a strong recommendation given the potential for the risk of pyloric stenosis with the use of erythromycin in neonates. In some settings, azithromycin suspension is not available and therefore erythromycin may be used. Side-effects should be monitored with the use of either medication. Strong recommendation, very low quality evidence Conditional recommendation, very low quality evidence Strong recommendation, moderate quality evidence Conditional recommendation, low quality evidence Conditional recommendation, low quality evidence

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

Recommendation 6 For all neonates, the WHO STI guideline recommends topical ocular prophylaxis for the prevention of gonococcal and chlamydial ophthalmia neonatorum. Recommendation 7 For ocular prophylaxis, the WHO STI guideline suggests one of the following options for topical application to both eyes immediately after birth: • tetracycline hydrochloride 1% eye ointment • erythromycin 0.5% eye ointment • povidone iodine 2.5% solution • silver nitrate 1% solution • chloramphenicol 1% eye ointment. Remarks: Recommendations 6 and 7 apply to the prevention of both chlamydial and gonococcal ophthalmia neonatorum. Cost and local resistance to erythromycin, tetracycline and chloramphenicol in gonococcal infection may determine the choice of medication. Caution should be taken to avoid touching eye tissue when applying the topical treatment and to provide a water-based solution of povidone iodine. DO NOT USE ALCOHOL-BASED POVIDONE IODINE SOLUTION.

Strong recommendation, low quality evidence

Conditional recommendation, low quality evidence

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

OVERVIEW OF THE GUIDELINES FOR THE PREVENTION, TREATMENT AND MANAGEMENT OF STIs STI EPIDEMIOLOGY AND BURDEN Sexually transmitted infections (STIs) are a major public health problem worldwide, affecting quality of life and causing serious morbidity and mortality. STIs have a direct impact on reproductive and child health through infertility, cancers and pregnancy complications, and they have an indirect impact through their role in facilitating sexual transmission of human immunodeficiency virus (HIV) and thus they also have an impact on national and individual economies. The prevention and control of STIs is an integral component of comprehensive sexual and reproductive health services that are needed to attain the related targets under Sustainable Development Goal (SDG) No. 3 (Ensure healthy lives and promote well-being for all at all ages), including: target 3.2 – to end preventable deaths of newborns and children under 5 years of age; target 3.3 – to end the epidemics of AIDS and other communicable diseases; target 3.4 – to reduce premature mortality from noncommunicable diseases and promote mental health and well-being; target 3.7 – to ensure universal access to sexual and reproductive health-care services; and target 3.8 – to achieve universal health coverage. Worldwide, more than a million curable STIs are acquired every day. In 2012, there were an estimated 357 million new cases of curable STIs among adults aged 15–49 years worldwide: 131 million cases of chlamydia, 78 million cases of gonorrhoea, 6 million cases of syphilis and 142 million cases of trichomoniasis (1). The prevalence of some viral STIs is similarly high, with an estimated 417 million people infected with herpes simplex virus type 2 (HSV-2) (2), and approximately 291 million women harbouring human papillomavirus (HPV) at any point in time (3). The burden of STIs varies by region and gender, and is greatest in resource-poor countries. When left undiagnosed and untreated, curable STIs can result in serious complications and sequelae, such as pelvic inflammatory disease, infertility, ectopic pregnancy, miscarriage, fetal loss and congenital infections. In 2012, an estimated 930 000 maternal syphilis infections resulted in 350 000 adverse pregnancy outcomes, including stillbirths, neonatal deaths, preterm births and infected infants (4). Curable STIs accounted for the loss of nearly 11 million disability-adjusted life years (DALYs) in 2010 (5). The psychological consequences of STIs include stigma, shame and loss of self-worth. STIs have also been associated with relationship disruption and gender-based violence (6). Both ulcerative and non-ulcerative STIs are associated with a several-fold increased risk of transmitting or acquiring HIV (7, 8). Infections causing genital ulcers are associated with the highest HIV transmission risk; in addition to curable ulcer-causing STIs (e.g. syphilis and chancroid), highly prevalent HSV-2 infections substantially increase that risk (9). Non-ulcerative STIs, such as gonorrhoea, chlamydia and trichomoniasis, have been shown to increase HIV transmission through genital shedding of HIV (10). Treating STIs with the right medicines at the right time is necessary to reduce HIV transmission and improve sexual and reproductive health (11). Efforts should therefore be taken to strengthen STI diagnosis and treatment.

WHY NEW GUIDELINES FOR THE PREVENTION, TREATMENT AND MANAGEMENT OF STIs? Since the publication of the World Health Organization (WHO) Guidelines for the management of sexually transmitted infections in 2003, changes in the epidemiology of STIs and advancements in prevention, diagnosis and treatment necessitate changes in STI management. Indeed, 88% of countries have updated their national STI guidelines or recommendations since 2006 (12). Updated global guidance reflecting the most recent evidence and expert opinion is therefore needed to assist countries to incorporate new developments into an effective national approach to the prevention and treatment of STIs. There is an urgent need to update global treatment recommendations to effectively respond to the changing antimicrobial resistance (AMR) patterns of STIs, especially for Neisseria gonorrhoeae. Effective treatment protocols that take into account global and local resistance patterns are essential to reduce the risk of further development of AMR. High-level gonococcal resistance to quinolones, a previously recommended first-line treatment, is widespread and decreased susceptibility to the extended-spectrum (third-generation) cephalosporins, another first-line treatment for gonorrhoea, is on the rise (13). Low-level resistance to Trichomonas vaginalis has also been reported for nitroimidazoles, the only available treatment. Resistance to azithromycin has been reported in some strains of Treponema pallidum and treatment failures have been reported for tetracyclines and macrolides in the treatment of Chlamydia trachomatis (14, 15).

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

A WHO STI expert consultation recommended updating the WHO 2003 guidelines for the first- and second-line treatments for C. trachomatis, increasing the dosage of ceftriaxone to 250 mg for treatment of N. gonorrhoeae with continued monitoring of antimicrobial susceptibility, and consideration of whether azithromycin (2 g, single dose) should be recommended in early syphilis (16). The epidemiology of STIs is changing, with viral pathogens becoming more prevalent than bacterial etiologies for some conditions; this means that updated information is required to inform locally appropriate prevention and treatment strategies. An increasing proportion of genital ulcers are now due to viral infections as previously common bacterial infections, such as chancroid, approach elimination in many countries (16, 17). As recommended during the STI expert consultation, treatment guidelines for genital ulcer disease (GUD) should be updated to include HSV-2 treatment and a longer treatment duration for HSV-2 should be explored. In addition, suppressive therapy for HSV-2 should be considered in areas with high HIV prevalence (16). The chronic, lifelong nature of viral infections also requires that renewed attention be paid to developing effective prevention strategies, including expanding accessibility to available vaccines for HPV and development of new vaccines for HSV-2. In the 2003 WHO guidelines, a syndromic approach was recommended for the management of STIs. The approach guides the diagnosis of STIs based on identification of consistent groups of symptoms and easily recognized signs and indicates treatment for the majority of organisms that may be responsible for producing the syndrome. The syndromic management algorithms need to be updated in response to the changing situation. In addition to changes to the GUD algorithm, other syndromes need to be re-evaluated, particularly vaginal discharge. The approach to syndromes for key populations also needs to be updated. For example, addition of a syndromic management algorithm for anorectal infections in men who have sex with men (MSM) and sex workers is urgently needed since a substantial number of these infections go unrecognized and untreated in the absence of guidelines (16).

New rapid, point-of-care diagnostic tests (POCTs) are changing STI management. Rapid syphilis diagnostic tests are now widely available, making syphilis screening more widely accessible and allowing for earlier initiation of treatment for those who test positive. Efforts are under way to develop POCTs for other STIs that will augment syndromic management of symptomatic cases and increase the ability to identify asymptomatic infections (12). Updated guidelines are needed that incorporate rapid tests into syndromic management of STIs and provide algorithms for testing and screening (16). Although recent technological advances in diagnostics, therapeutics, vaccines and barrier methods offer better opportunities for the prevention and care of STIs, access to these technologies is still limited, particularly in areas where the burden of infection is highest. For optimal effectiveness, global guidelines for the management of STIs need to include approaches for settings with limited access to modern technologies, as well as for settings in which these technologies are available. It is strongly recommended that countries take updated global guidance into account as they establish standardized national protocols, adapting this guidance to the local epidemiological situation and antimicrobial susceptibility data. Standardization ensures that all patients receive adequate treatment at every level of health-care services, optimizes the training and supervision of health-care providers and facilitates procurement of medicines. It is recommended that national guidelines for the effective management of STIs be developed in close consultation with local STI, public health and laboratory experts.

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

APPROACH TO THE REVISION OF STI GUIDELINES To ensure effective treatment for all STIs, WHO plans a phased approach to updating the STI guidelines to address a range of infections and issues. Four phases have been proposed by the WHO STI Secretariat and agreed upon by the STI Guideline Development Group (GDG) members (see Annex A for members of these groups). Table 2 summarizes the proposed phases and timeline. Table 2: Phases for development of the STI guidelines Phases Phase 1 Topics Treatment of specific STIs: Chlamydia trachomatis (chlamydia), Neisseria gonorrhoeae (gonorrhoea), HSV-2 (genital herpes) and Treponema pallidum (syphilis) Syphilis screening and treatment of pregnant women Timeframe November 2013 – April 2016

STI syndromic approach Clinical management package Phase 2 Phase 3 STI prevention: condoms, behaviour change communication, biomedical interventions and vaccines Treatment of specific STIs and reproductive tract infections (RTIs) not addressed in Phase 1: Trichomonas vaginalis (trichomoniasis), bacterial vaginosis, Candida albicans (candidiasis), Hemophilus ducreyi (chancroid), Klebsiella granulomatis (donovanosis), human papillomavirus (HPV; genital warts/cervical cancer), Sarcoptes scabiei (scabies) and Phthirus pubis (pubic lice) STI laboratory diagnosis and screening

May 2016 – December 2017 2017–2018 2017–2018

Phase 4

2017–2018

Phase 1 will focus on treatment recommendations for specific STIs as well as other important and urgent STI issues. Recommendations for the treatment of specific infections will be developed and published as independent modules: • Chlamydia trachomatis (chlamydia) • Neisseria gonorrhoeae (gonorrhoea) • HSV-2 (genital herpes) • Treponema pallidum (syphilis) • Syphilis screening and treatment of pregnant women.

In addition, guidelines for the STI syndromic approach and a clinical management package will be developed later in Phase 1. Phase 2 will focus on guidelines for STI prevention. The independent Phase 1 and 2 modules will later be consolidated into one document and published as comprehensive WHO guidelines on STI case management. Phase 3 will address treatment of additional infections, including Trichomonas vaginalis (trichomoniasis), bacterial vaginosis, Candida albicans (candidiasis), Hemophilus ducreyi (chancroid), Klebsiella granulomatis (donovanosis), HPV (genital warts/cervical cancer), Sarcoptes scabiei (scabies) and Phthirus pubis (pubic lice). Phase 4 will provide guidance on laboratory diagnosis and screening of STIs.

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

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1. Newman L, Rowley J, Vander Hoorn S, Wijesooriya NS, Unemo M, Low N et al. Global estimates of the prevalence and incidence of four curable sexually transmitted infections in 2012 based on systematic review and global reporting. PLoS One. 2015;10(12):e0143304. doi:10.1371/journal.pone.0143304. 2. Looker KJ, Magaret AS, Turner KME, Vickerman P, Gottlieb SL, Newman LM. Global estimates of prevalent and incident herpes simplex virus type 2 infections in 2012. PLoS One. 2015;10(1):e114989. doi:10.1371/journal.pone.0114989. 3. De Sanjosé S. Diaz M, Castellsagué X, Clifford G, Bruni L, Muñoz N, Bosch FX. Worldwide prevalence and genotype distribution of cervical human papillomavirus DNA in women with normal cytology: a meta-analysis. Lancet Infect Dis. 2007;7(7):453–9. 4. Wijesooriya NS, Rochat RW, Kamb ML, Turlapati P, Broutet N, Newman L. Declines in maternal and congenital syphilis from 2008 to 2012: progress towards elimination of mother-to-child transmission of syphilis. Lancet Global Health. 2016 (in press). 5. Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2197–223. doi:10.1016/S01406736(12)61689-4. 6. Gottlieb SL, Low N, Newman LM, Bolan G, Kamb M, Broutet N. Toward global prevention of sexually transmitted infections (STIs): the need for STI vaccines. Vaccine. 2014;32(14):1527–35. doi:10.1016/j. vaccine.2013.07.087. 7. Wasserheit JN. Epidemiological synergy: interrelationships between human immunodeficiency virus infections and other sexually transmitted diseases. Sex Transm Dis. 1992;19(2):61–77. 8. Sexton J, Garnett G, Røttingen J-A. Metaanalysis and metaregression in interpreting study variability in the impact of sexually transmitted diseases on susceptibility to HIV infection. Sex Transm Dis. 2005;32(6):351–7. 9. \Glynn JR, Biraro S, Weiss HA. Herpes simplex virus type 2: a key role in HIV incidence. AIDS. 2009;23(12):1595–8. doi:10.1097/QAD.0b013e32832e15e8. 10. Johnson LF, Lewis DA. The effect of genital tract infections on HIV-1 shedding in the genital tract: a systematic review and meta-analysis. Sex Transm Dis. 2008;35(11):946–59. doi:10.1097/ OLQ.0b013e3181812d15. 11. Cohen MS. Classical sexually transmitted diseases drive the spread of HIV-1: back to the future. J Infect Dis. 2012;206(1):1–2. doi:10.1093/infdis/jis303. 12. Progress report of the implementation of the global strategy for prevention and control of sexually transmitted infections: 2006–2015. Geneva: World Health Organization; 2015 (http://apps.who.int/ iris/bitstream/10665/183117/1/9789241508841_eng.pdf, accessed 24 May 2016). 13. Ndowa FJ, Ison CA, Lusti-Narasimhan M. Gonococcal antimicrobial resistance: the implications for public health control. Sex Transm Infect. 2013;89(Suppl 4):iv1–2. doi:10.1136/sextrans-2013-051394. 14. Gottlieb SL, Low N, Newman LM, Bolan G, Kamb M, Broutet N. Toward global prevention of sexually transmitted infections (STIs): the need for STI vaccines. Vaccine. 2014;32(14):1527–35. doi:10.1016/j. vaccine.2013.07.087. 15. Mabey D. Epidemiology of sexually transmitted infections: worldwide. Medicine. 2014;42(6):287–90. doi:10.1016/j.mpmed.2014.03.004. 16. Report of the expert consultation and review of the latest evidence to update guidelines for the management of sexually transmitted infections. Geneva: World Health Organization; 2011 (WHO/ RHR/11.37; http://apps.who.int/iris/bitstream/10665/75194/1/WHO_RHR_11.37_eng.pdf, accessed 24 May 2016). 17. Steen R. Eradicating chancroid. Bull World Health Organ. 2001;79(9):818–26.

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

01 INTRODUCTION 1.1 EPIDEMIOLOGY, BURDEN AND CLINICAL CONSIDERATIONS Chlamydial infection, caused by Chlamydia trachomatis, is the most common bacterial sexually transmitted infection (STI) and results in substantial morbidity and economic cost worldwide. The World Health Organization (WHO) estimates that in 2012, 131 million new cases of chlamydia occurred among adults and adolescents aged 15–49 years worldwide, with a global incidence rate of 38 per 1000 females and 33 per 1000 males. The estimated 128 million prevalent cases of chlamydia result in an overall prevalence of 4.2% for females and 2.7% for males, with the highest prevalence in the WHO Region of the Americas and the WHO Western Pacific Region (1). In many countries, the incidence of chlamydia is highest among adolescent girls aged 15–19 years, followed by young women aged 20–24 years. The three biovars of C. trachomatis, each consisting of several serovars or genotypes, cause genital infections, lymphogranuloma venereum (LGV: a genital ulcer disease [GUD] that affects lymphoid tissue), and trachoma (eye infection).

CLINICAL PRESENTATION Genital infections due to C. trachomatis are asymptomatic in approximately 70% of women and 50% of men (2). Symptoms of uncomplicated chlamydial infection in women include abnormal vaginal discharge, dysuria, and post-coital and intermenstrual bleeding. Common clinical signs on speculum examination include cervical friability and discharge. Symptomatic men usually present with urethral discharge and dysuria, sometimes accompanied by testicular pain. If left untreated, most genital infections will resolve spontaneously with no sequelae but they may result in severe complications, mainly in young women. Infection can ascend to the upper reproductive tract and can cause pelvic inflammatory disease, ectopic pregnancy, salpingitis and tubal factor infertility in women (3) and epididymitis in men (4). The risk of complications may increase with repeated infection. Infections at non-genital sites are common. Rectal infection may manifest as a rectal discharge, rectal pain or blood in the stools, but is asymptomatic in most cases. Oropharyngeal infections can manifest as pharyngitis and mild sore throat, but symptoms are rare. Chlamydial infection in pregnancy is associated with preterm birth and low birth weight. Infants of mothers with chlamydia can be infected at delivery, resulting in neonatal conjunctivitis and/or nasopharyngeal infection (3). Symptoms of ophthalmia include ocular discharge and swollen eyelids. In newborns, nasopharyngeal infection can lead to pneumonitis. LGV, caused by a more invasive serovar of C. trachomatis, affects the submucosal connective tissue and can spread to regional lymph nodes. It commonly presents as a unilateral, tender inguinal or femoral lymph node and a genital ulcer or papule (5). Anorectal exposure may result in proctitis, rectal discharge, pain, constipation or tenesmus. Left untreated, LGV can lead to rectal fistula or stricture.

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

LABORATORY DIAGNOSIS There have been major developments in the diagnosis of C. trachomatis in the last 10–20 years. Although C. trachomatis can be diagnosed by culture, direct immunofluorescence assays (DFAs), and laboratory-based and point-of-care enzymelinked immunosorbent assays (ELISAs), nucleic acid amplification tests (NAATs) are strongly recommended due to their superior performance characteristics. NAATs are highly sensitive and specific and can be used for a wide range of samples, including urine and vulvovaginal, cervical and urethral swabs. Several commercial NAATs using different technologies are available. The increased sensitivity of NAATs compared with other diagnostic tests, such as culture and antigen detection methods (DFA and ELISA), allows testing of non-invasive specimens, which can be collected conveniently at the primary level of care. Commercially available NAATs are not yet licensed for the diagnosis of extra-genital samples but have shown to be reliable for detection of chlamydial infection in rectal and pharyngeal swabs. Several commercially available tests for chlamydia are combined with tests for gonorrhoea. Further information is available in the WHO publication on laboratory diagnosis of STIs including HIV (6).

1.4 TARGET AUDIENCE These guidelines are primarily intended for health-care providers at all levels (primary, secondary and tertiary) of the health-care system involved in the treatment and management of people with STIs in low-, middleand high-income countries. They are also intended for individuals working in sexual and reproductive health programmes, such as HIV/AIDS, family planning, maternal and child health and adolescent health, to ensure appropriate STI diagnosis and management. The guidelines are also useful for policy-makers, managers, programme officers and other professionals in the health sector who are responsible for implementing STI management interventions at regional, national and subnational levels.

1.5 STRUCTURE OF THE GUIDELINES These guidelines provide evidence-based recommendations for the treatment of specific clinical conditions caused by C. trachomatis. These guidelines provide direction for countries as they develop national treatment recommendations; however, national guidelines should also take into account the local pattern of AMR, as well as health service capacity and resources. Updated treatment recommendations based on the most recent evidence are included for the most important common conditions caused by C. trachomatis. Recommendations were not updated for rare conditions and other conditions for which no new information has become available since the 2003 WHO STI guidelines were issued. Treatment recommendations for the following conditions caused by C. trachomatis are included in these guidelines: • uncomplicated genital infections • anorectal infections • uncomplicated genital infections in pregnant women • LGV • ophthalmia neonatorum (treatment and prophylaxis).

1.2 RATIONALE FOR NEW RECOMMENDATIONS The guidelines for treatment of chlamydial infections need to be updated to respond to the changes in epidemiology and antimicrobial susceptibility for chlamydia that have occurred since the previous WHO Guidelines for the management of sexually transmitted infections were published in 2003 (7). LGV is increasingly prevalent among men who have sex with men (MSM) in some settings, and treatment failure has been reported with tetracycline and macrolides in approximately 10% of cases (8). Moreover, the 2003 WHO STI guidelines are the only international guidelines that still recommend treating chlamydial infections with amoxicillin or tetracycline. As recommended by the WHO STI expert consultation in 2008, the first- and second-line treatment recommendations for C. trachomatis needed to be reviewed and revised based on the most recent available evidence.

1.3 OBJECTIVES The objectives of these guidelines are: • t o provide evidence-based guidance on treatment of infection with C. trachomatis; and • t o support countries to update their national guidelines for treatment of chlamydial infection.

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

02 METHODS These guidelines were developed following the methods outlined in the 2014 edition of the WHO handbook for guideline development (9) (see Annex B for a detailed description). 2.1 GUIDELINE DEVELOPMENT GROUP (GDG) To update the WHO guidelines for the prevention, treatment and management of STIs, a GDG was established, comprising 33 international STI experts, including clinicians, researchers and programme managers (Annex A). A core subgroup to focus on the guidelines related to chlamydia was created within the GDG, to provide more intensive feedback throughout the process (Annex A). The GDG participated in meetings and teleconferences to prioritize the questions to be addressed, discuss the evidence reviews and finalize the recommendations. The GDG reviewed and approved the final version of the guidelines.

2.2 QUESTIONS AND OUTCOMES In December 2013 the first GDG meeting was held to identify and agree on the key PICO (population, intervention, comparator, outcome) questions that formed the basis for the systematic reviews and the recommendations. Following this meeting, a survey of GDG members was conducted to prioritize the questions and outcomes according to clinical relevance and importance. Six PICO questions were identified for the update on the treatment of genital and anorectal chlamydial infections, treatment of LGV, and prevention and treatment of neonatal ophthalmia (see Annex B). These questions pertained to adults and other special populations, namely adolescents, pregnant women, people living with HIV, and populations at high risk of acquiring and transmitting STIs, such as men who have sex with men (MSM) and sex workers. Only outcomes that were ranked as critical or important to patients and decision-making were included: clinical and microbiological cure, and adverse effects (including maternal and fetal effects in pregnant women).

2.3 REVIEWS OF THE EVIDENCE The systematic reviews for each priority question were conducted by McMaster University, the WHO Collaborating Centre for Evidence-Informed Policy. Evidence for desirable and undesirable outcomes, patient values and preferences, resources, acceptability, equity and feasibility were reviewed from published and unpublished literature. Comprehensive searches for previously conducted systematic reviews, randomized controlled trials and non-randomized studies were performed from March to October 2015. Additional searches were conducted to identify studies on patient values and preferences (e.g. qualitative research designs) and resource implications (e.g. cost of interventions, cost–benefit and cost–effectiveness studies). Two members of the Systematic Review Team screened studies, extracted and analysed the data, and assessed the quality/certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.1

For more information, see: http://www.gradeworkinggroup.org/

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

The quality/certainty of the evidence was assessed at four levels: • H igh – We are very confident that the true effect lies close to that of the estimate of the effect. • M oderate – We are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. • L ow – Our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. • V ery low – We have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect. In addition, the direct costs of medicines were estimated using the 2014 Management Sciences for Health (MSH) International drug price indicator guide (10). References for all the reviewed evidence are listed in Annex C. All evidence was summarized in GRADE evidence profiles and in evidence-to-decision tables (see Web annexes D and E).

of the recommendations. Following the meeting, the recommendations were finalized via teleconference and final approval was obtained from all GDG members electronically. These guidelines were subsequently written up in full and then peer reviewed. The External Review Group approved the methods and agreed with the recommendations made by the GDG (members are listed in Annex A). According to the GRADE approach, the strength of each recommendation was rated as either strong or conditional. Strong recommendations are presented using the wording “The WHO STI guideline recommends…”, while conditional recommendations are worded as “The WHO STI guideline suggests…” throughout the guidelines. The implications of the differing strengths of recommendations for patients, clinicians and policy-makers are explained in detail in Table 3.

2.4 MAKING RECOMMENDATIONS Recommendations were developed during a second meeting of the GDG in October 2015, which was facilitated by two co-chairs, one with expertise in GRADE and the other with clinical STI expertise. The methodologist presented the GRADE evidence profiles and evidence-to-decision frameworks at the meeting. When formulating the recommendations, the GDG considered and discussed the desirable and undesirable effects of the interventions, the value placed on the outcomes, the associated costs and use of resources, the acceptability of the interventions to all stakeholders (including people affected by STIs), the impact on health equity and the feasibility of implementation. Treatments were judged according to the above criteria and final decisions and guideline recommendations were agreed. The discussion was facilitated by the co-chairs with the goal of reaching consensus across the GDG. Disagreements among the GDG members were noted in the evidence-to-decision framework for each judgement. In the case of failure to reach consensus for a recommendation, the planned procedure was for the GDG to take a vote and record the results. However, no votes were taken because the GDG reached consensus during discussion for all

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

Table 3. Implications of strong and conditional recommendations using the GRADE approach Implications Strong recommendation “The WHO STI guideline recommends…” For patients Most individuals in this situation would want the recommended course of action, and only a small proportion would not. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences. For clinicians Most individuals should receive the recommended course of action. Adherence to this recommendation according to the guidelines could be used as a quality criterion or performance indicator. Clinicians should recognize that different choices will be appropriate for each individual and that clinicians must help each individual arrive at a management decision consistent with the individual’s values and preferences. Decision aids may be useful to help individuals make decisions consistent with their values and preferences. For policymakers The recommendation can be adopted as policy in most situations. Policy-making will require substantial debate and involvement of various stakeholders. Conditional recommendation “The WHO STI guideline suggests…” The majority of individuals in this situation would want the suggested course of action, but many would not.

2.5 MANAGEMENT OF CONFLICTS OF INTEREST Management of conflicts of interest was a key priority throughout the process of guideline development. WHO guidelines for declaration of interests (DOI) for WHO experts were implemented (11). DOI statements were obtained from all GDG members prior to assuming their roles in the group. At the GDG meetings (December 2013 and October 2015), the members disclosed their interests, if any, at the beginning of the meeting. Their DOI statements are summarized in Web annex F. After analysing each DOI, the STI team concluded that no member had financial or commercial interests related to STI treatment. Other notified interests were minor; they were either not related to STI or were noncommercial grants or interests. The STI team concluded that there were no significant conflicts of interest that would exclude any member from participating fully in the guideline development process. Therefore, options for conditional participation, partial or total exclusion of any GDG member were not discussed.

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

03 3.1 DISSEMINATION

DISSEMINATION, UPDATING AND IMPLEMENTATION OF THE GUIDELINES

All levels of WHO (headquarters, regional offices and country offices) will work with regional and national partners – including the United Nations Population Fund (UNFPA), the United Nations Children’s Fund (UNICEF), the Joint United Programme on HIV/AIDS (UNAIDS), nongovernmental organizations (NGOs) and other agencies implementing sexual and reproductive health and STI services – to ensure that the new recommendations are integrated and implemented in sexual and reproductive health, family planning, and maternal, neonatal, child and adolescent health services. Reference to this document will be made within other relevant WHO guidelines. These guidelines will also be disseminated at major conferences related to STIs and HIV and the aforementioned programme areas.

3.2 UPDATING THE GUIDELINES AND USER FEEDBACK A system of monitoring relevant new evidence and updating the recommendations as new findings become available will be established within a year of implementing the guidelines. An electronic follow-up survey of key end-users of the STI guidelines will be conducted after the release of the guidelines. The results of the survey will be used to identify challenges and barriers to the uptake of the guidelines, to evaluate their usefulness for improving service delivery, and to identify topics or gaps in treatment that need to be addressed in future editions.

These guidelines will be made available as a printed publication, as a download on the website of the WHO Department of Reproductive Health and Research (where there will also be links to all supporting documentation)2, and in the WHO Reproductive Health Library (RHL)3. The recommendations will also be available in a guideline application (“app”) created with the GRADEpro GDT software. The guidelines will be announced in the next edition of the RHL newsletter and in the Reproductive Health and Research departmental newsletter, and other relevant organizations will be requested to copy the announcement in their respective newsletters. WHO headquarters will work with WHO’s regional offices and country offices to ensure that countries receive support in the adaptation, implementation and monitoring of these guidelines using the WHO Department of Reproductive Health and Research guidance on Introducing WHO’s reproductive health guidelines and tools into national programmes (12).

3.3 IMPLEMENTATION OF THE WHO GUIDELINES FOR THE TREATMENT OF C. TRACHOMATIS ADAPTATION, IMPLEMENTATION AND MONITORING These guidelines provide recommendations for treatment of chlamydial infection based on the best global evidence available at the time of compilation. However, the epidemiology and AMR of STIs vary by geographical location and are constantly changing, sometimes rapidly. It is recommended that countries conduct good quality studies to gather the information needed to adapt these guidelines to the local STI situation as they update their national guidelines. In areas lacking local data as a basis for adaptation, the recommendations in these guidelines can be adopted as presented.

2 These guidelines and all supporting documents will be available at: www.who.int/reproductivehealth/publications/rtis/chlamydia-treatment-guidelines/en/ 3 RHL is available at: http://apps.who.int/rhl/en/

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

For further guidance on adaptation, implementation and monitoring of national guidelines please refer to Introducing WHO’s reproductive health guidelines and tools into national programmes: principles and processes of adaptation and implementation (12). In adapting the guidelines for national use, recommended treatments should have an efficacy of at least 95%. The criteria to be considered for the selection of medicines are listed in Box 1. Recommended medicines should meet as many of the criteria as possible, taking into account local availability, efficacy, route and frequency of administration. BOX 1. CRITERIA FOR THE SELECTION OF MEDICINES FOR THE TREATMENT OF STIS • High efficacy (at least 95% cure rate) • High quality (potent active ingredient) • Low cost • Low toxicity levels • O rganism resistance unlikely to develop or likely to be delayed • Single dose • Oral administration • N ot contraindicated for pregnant or lactating women Appropriate medicines should be included in the national essential medicines lists. When selecting medicines, consideration should be given to the competencies and experience of health-care providers.

In order to estimate the quantity of medicines needed, it will be necessary to review the medicines that are recommended for treatment, their unit prices, the quantity required per treatment and the epidemiological information on the prevalence of infection. One can estimate medicine needs by multiplying the estimated number of cases by the total quantity of medicine specified for treatment of one case. These figures can be derived from health centres providing care but they must be verified to avoid wasteful over-ordering. Budgeting for medicines is critical. If the national ministry of health does not provide medicines for free and the patient cannot afford to buy the medicines, then there will essentially be no possibility of curtailing the spread of infection and the occurrence of complications. At the national level it is important that decision-makers, politicians and fiscal controllers understand the need to subsidize STI medicines. Low-cost STI medicines can be obtained through international vendors of generic products, nonprofit organizations with procurement schemes such as UNICEF, UNFPA and UNHCR, and through joint medicine procurement schemes. By way of such schemes, national programmes can join other national programmes to jointly procure medicines, thus reducing the overall costs by sharing the overhead costs and taking advantage of discounts for purchasing in bulk. Placing STI medicines on national lists of essential medicines increases the likelihood of achieving a supply of these medicines at low cost.

IDENTIFYING AND PROCURING STI DRUGS It is important not only to identify medicines that will be recommended as first-line treatment for STIs but also the estimated quantities of the medicines that will be required. Quantifying medication needs is important in order to estimate costs, to reconcile financial requirements with available budget, and to make orders in advance so that the unit and freight costs can be minimized.

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

RECOMMENDATIONS FOR TREATMENT OF CHLAMYDIAL INFECTIONS

Remarks: While good practice based on evidence of large net benefit dictates that patients should be treated for chlamydial infection, the choice of treatment may depend on the convenience of dosage, the cost and quality of the medicines in different settings, and equity considerations. When high value is placed on reducing costs, doxycycline in a standard dose may be the best choice; when high value is placed on convenience, azithromycin in a single dose may be the best choice. A delayed-release formulation of doxycycline may be an alternative to twice daily dosing of doxycycline, but the high cost of the delayed-release formulation may prohibit its use. Note that doxycycline, tetracycline and ofloxacin are contraindicated in pregnant women (see recommendations 3a–3c). Research implications: The potential for resistance to azithromycin, doxycycline and other treatment options should be investigated. Future research could compare these treatments and recommended dosages in randomized controlled trials measuring important outcomes such as clinical cure, microbiological cure, complications, side-effects (including allergy, toxicity, gastrointestinal effects), compliance, quality of life, HIV transmission and acquisition, and partner transmission of chlamydia. Studies are also needed that evaluate amoxicillin (500 mg three times a day for 7 days).

The following nine recommendations apply to adults, adolescents (10–19 years of age), people living with HIV, and key populations, including sex workers, men who have sex with men (MSM) and transgender persons. Specific recommendations have also been developed for ophthalmia neonatorum caused by C. trachomatis. 4.1 UNCOMPLICATED GENITAL CHLAMYDIA RECOMMENDATION 1 For people with uncomplicated genital chlamydia, the WHO STI guideline suggests one of the following options: • azithromycin 1 g orally as a single oral dose • doxycycline 100 mg orally twice a day for 7 days or one of these alternatives: • tetracycline 500 mg orally four times a day for 7 days • erythromycin 500 mg orally twice a day for 7 days • ofloxacin 200–400 mg orally twice a day for 7 days. Conditional recommendation, moderate quality evidence

SUMMARY OF THE EVIDENCE Evidence from a Cochrane systematic review was used. This review included 25 randomized studies comparing tetracycline, quinolones and macrolides. There are no data available for amoxicillin. Overall, there is moderate to low quality evidence for most comparisons of treatments. Moderate quality evidence shows trivial differences between azithromycin 1 g and doxycycline 100 mg orally twice a day for 7 days in the numbers of people microbiologically cured and experiencing adverse events. There were 10 fewer people per 1000 cured with azithromycin versus doxycycline, ranging from 38 fewer to 10 more (risk ratio [RR] 0.99; 95% confidence interval [CI] 0.96 to 1.10). In addition, there were 3 more adverse events per 1000 people with azithromycin versus doxycycline, ranging from 42 fewer to 64 more (RR 1.02; 95% CI 0.72 to 1.43). Similar results are shown in a recently published randomized study. Delayed-release doxycycline hyclate probably leads to little to no difference in the proportion of people microbiologically cured but probably has fewer sideeffects than standard dose doxycycline. Ofloxacin may result in fewer cures but also slightly fewer adverse events compared to doxycycline. When comparing multiple high doses of azithromycin (1 g weekly for 3 weeks) to a single dose, more people may be cured but

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

there are no data for adverse events related to very high doses. Higher doses of any tetracycline compared with lower doses may lead to more cures but will probably also lead to more adverse events. Tetracyclines compared with quinolones may lead to fewer cures but also slightly fewer adverse events. Erythromycin compared with quinolones may lead to fewer cures and more adverse events. There is no evidence relating to patient values and preferences but the Guideline Development Group (GDG) agreed that there is probably no variability in the values people place on the outcomes. Research related to other conditions indicates that adherence may be improved with simpler medication regimens. The GDG therefore agreed that azithromycin may be more acceptable to patients since it is a single dose regimen (a majority of the GDG members considered single-dose regimens to be preferable for patient compliance over multi-dose regimens). There is little to no evidence for equity issues and feasibility. Resistance in other infections (e.g. gonorrhoea and Mycoplasma genitalium) that often co-occur with chlamydia may restrict the use of some medicines, such as ofloxacin. For many of these medicines, costs may differ between countries; in places with high incidence of chlamydia, the cost differences between azithromycin and doxycycline may be large due to greater numbers of people requiring treatment. In summary, there was moderate quality evidence for trivial differences in benefits and harms between azithromycin and doxycycline, and although the cost of azithromycin is higher, the single dose may make it more convenient to use than doxycycline. While the differences are also trivial with the other medicines, the evidence is low quality and these are therefore provided as alternatives, with the exception of delayedrelease doxycycline, which is currently expensive. See Annex C for list of references of reviewed evidence, and Web annex D for details of the evidence reviewed, including evidence profiles and evidence-to-decision frameworks (pp. 3-22).

Conditional recommendation, low quality evidence Remarks: This recommendation applies to people with known anorectal infection and to people with suspected anorectal infections with genital coinfection. Clinicians should ask men, women and key populations (e.g. men who have sex with men [MSM], transgender persons and female sex workers) about anal sex and treat accordingly. Doxycycline should not be used in pregnant women because of adverse effects (see recommendations 3a–3c). Research implications: The global incidence of chlamydial anorectal infections should be determined. More research is necessary on the effects of treatments used for anorectal infections, particularly azithromycin, which is currently not on the WHO essential medicines list for anorectal chlamydial infections (13). Effects should be assessed in both men and women, and in key populations (e.g. MSM, transgender persons and female sex workers). SUMMARY OF THE EVIDENCE There is low quality evidence from eight nonrandomized studies (five direct comparisons and three single-arm studies) that evaluated doxycycline and azithromycin (see Web annexes D and E). There are no data for amoxicillin, erythromycin and quinolones. Evidence showed that there may be 200 fewer microbiological cures per 1000 people with azithromycin compared with doxycycline (RR 0.80; 95% CI 0.71 to 0.91). Evidence from studies of genital infections shows little to no difference in side-effects with these treatments (RR 1.02; 95% CI 0.72 to 1.43). Although there are fewer women than men in the studies, the evidence suggested little difference in effects between men and women. There is no evidence relating to patient values and preferences, but the GDG agreed that there are no known reasons to suspect values would vary for different people. There is little to no evidence for acceptability, but research in other conditions indicates that adherence may be improved with simpler medication regimens. There is also little to no evidence for equity issues and feasibility, but azithromycin is more expensive and typically the cost is transferred to consumers. The GDG agreed that equity may vary between the medicines depending on the population: in some populations, azithromycin may be more acceptable since it is a single-dose treatment, and some people may experience stigma related to visibility of a multi-dose regimen with doxycycline. Therefore, suggesting doxycycline over azithromycin could create inequity for people sensitive to stigma related to multi-dose regimens. Azithromycin is currently not listed as an essential medicine for anorectal chlamydial infection.

4.2 ANORECTAL CHLAMYDIAL INFECTION RECOMMENDATION 2 In people with anorectal chlamydial infection, the WHO STI guideline suggests using doxycycline 100 mg orally twice daily for 7 days over azithromycin 1 g orally single dose.

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

In summary, doxycycline may result in more cures, but although it is less expensive than azithromycin, azithromycin may be better accepted due to the single-dose treatment. See Annex C for list of references of reviewed evidence, and Web annex D for details of the evidence reviewed, including evidence profiles and evidence-to-decision frameworks (pp. 23-35).

SUMMARY OF THE EVIDENCE Overall, there is moderate to low quality evidence from 14 randomized controlled trials, two non-randomized comparative studies and two large cohort studies assessing the effects of azithromycin, erythromycin and amoxicillin in pregnant women with chlamydial infections. The differences in benefits between these different treatments are small, and wide confidence intervals included the possibility of greater or lesser benefits with azithromycin compared to other medicines. Moderate quality evidence found that there are probably 94 more people microbiologically cured per 1000 with azithromycin versus erythromycin (RR 1.11; 95% CI 0.94 to 1.30), and low-quality evidence found that there may be 72 more people cured per 1000 with azithromycin versus amoxicillin (RR 1.09, 95%CI 0.93 to 1.28). There are probably 40 fewer people microbiologically cured per 1000 with erythromycin versus amoxicillin (RR 0.95; 95% CI 0.88 to 1.02). There may be slightly fewer side-effects with azithromycin compared with erythromycin or amoxicillin (approximately 50/1000 fewer), but there may be substantially more side-effects with erythromycin versus amoxicillin (approximately 400/1000 more). Much of the evidence was uncertain for fetal outcomes as it came from indirect comparisons in large cohort studies. There were few events, and confidence intervals around the small differences included the potential for fewer or more events between comparisons. In summary, the GDG agreed that azithromycin is preferred over erythromycin because of greater effectiveness and lower cost, and preferred over amoxicillin due to greater effectiveness. Azithromycin may also be more acceptable due to single dosage; however, it may not be available in all settings due to misconceptions that it is costly. Amoxicillin is preferred over erythromycin as it is less costly and may result in greater benefits and fewer side-effects. See Annex C for list of references of reviewed evidence, and Web annex D for details of the evidence reviewed, including evidence profiles and evidence-to-decision frameworks (pp. 36-51).

4.3 CHLAMYDIAL INFECTION IN PREGNANT WOMEN RECOMMENDATION 3A In pregnant women with genital chlamydial infection, the WHO STI guideline recommends using azithromycin over erythromycin. Strong recommendation, moderate quality evidence RECOMMENDATION 3B In pregnant women with genital chlamydial infection, the WHO STI guideline suggests using azithromycin over amoxicillin. Conditional recommendation, low quality evidence RECOMMENDATION 3C In pregnant women with genital chlamydial infection, the WHO STI guideline suggests using amoxicillin over erythromycin. Conditional recommendation, low quality evidence Dosages: • azithromycin 1 g orally as a single dose • amoxicillin 500 mg orally three times a day for 7 days • erythromycin 500 mg orally twice a day for 7 days. Remarks: Azithromycin is the first choice of treatment but may not be available in some settings. Azithromycin is less expensive than erythromycin and since it is provided as a single dose, may result in better adherence and therefore better outcomes. Research implications: Research in pregnant women comparing these treatments and the recommended dosages should be conducted. Although these medicines are relatively safe in pregnancy, maternal and fetal complications (e.g. adverse pregnancy outcomes, fetal defects) with the use of these treatments for STIs and other infections should be monitored, collected and analysed to inform updated recommendations in the future. When conducting these studies, costs and acceptability of the treatments could be measured.

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

4.4 LYMPHOGRANULOMA VENEREUM (LGV) RECOMMENDATION 4 In adults and adolescents with LGV, the WHO STI guideline suggests using doxycycline 100 mg orally twice daily for 21 days over azithromycin 1 g orally, weekly for 3 weeks. Conditional recommendation, very low quality evidence Remarks: Good practice dictates treatment of LGV, in particular for men who have sex with men (MSM) and for people living with HIV. When doxycycline is contraindicated, azithromycin should be provided. When neither treatment is available, erythromycin 500 mg orally four times a day for 21 days is an alternative. Doxycycline should not be used in pregnant women because of adverse effects (see recommendations 3a–3c). Research implications: Additional research for each of the treatments and the dosages recommended is needed, in particular for erythromycin and azithromycin. Randomized controlled trials should be conducted, measuring critical and important outcomes, such as clinical cure, microbiological cure, complications, side-effects (including allergy, toxicity, gastrointestinal effects), quality of life, HIV transmission and acquisition, compliance and LGV transmission to partners. The effects of shorter courses of treatment should also be investigated. SUMMARY OF THE EVIDENCE There is very low quality evidence from 12 nonrandomized studies with no comparisons between treatments. These studies assessed treatment with azithromycin and doxycycline for 21 days, and erythromycin for 14 days. Evidence for doxycycline showed that there may be large benefits (clinical and microbiological cure rates greater than 90%) and trivial side-effects (e.g. persistent mucous membrane abnormalities, perirectal abscess and allergy). The effects of azithromycin and erythromycin were uncertain, with only 14 people receiving azithromycin and 31 people receiving erythromycin in the studies. Side-effects are likely trivial and similar to the sideeffects of these treatments in people with other chlamydial infections. There is no evidence relating to patient values and preferences, but the GDG agreed that there are no known reasons to suspect values would vary for different people. There is little to no evidence for acceptability, but research in other conditions indicates that adherence may be improved with simpler medication regimens. There is little evidence for equity issues and feasibility, but the GDG

agreed that these may be dependent on individuals and countries. Data for medicine prices and procurement indicate that doxycycline is cheaper than azithromycin and erythromycin, although the latter medicines are still inexpensive. In summary, there is very low quality evidence for all medicines for treatment of LGV. The evidence suggests large benefits with doxycycline over azithromycin, and the effects of erythromycin are unknown. In addition, doxycycline is the least expensive. See Annex C for list of references of reviewed evidence, and Web annex D for details of the evidence reviewed, including evidence profiles and evidence-to-decision frameworks (pp. 52-63).

4.5 OPHTHALMIA NEONATORUM RECOMMENDATION 5 In neonates with chlamydial conjunctivitis, the WHO STI guideline recommends using oral azithromycin 20 mg/kg/day orally, one dose daily for 3 days, over erythromycin 50 mg/kg/day orally, in four divided doses daily for 14 days. Strong recommendation, very low quality evidence Remarks: This is a strong recommendation given the potential for the risk of pyloric stenosis with the use of erythromycin in neonates. In some settings, azithromycin suspension is not available and therefore erythromycin may be used. Side-effects should be monitored with the use of either medication. Research implications: Additional research should be conducted to determine the effects of these medicines to treat ophthalmia neonatorum. The effects of other medications such as trimethoprim should also be investigated. Pyloric stenosis should be monitored or research conducted to evaluate this risk with the medicines suggested. SUMMARY OF THE EVIDENCE There is low quality evidence for a cure rate of 98% with erythromycin 50 mg/kg/day for 14 days, and uncertain effects on the cure rate for azithromycin given the small numbers of neonates receiving azithromycin in the study (see Web annexes D and E). There is very low quality evidence for 7 more instances of pyloric stenosis per 1000 with erythromycin. The GDG regarded the risk of pyloric stenosis as a serious adverse effect of erythromycin use in children. There are no data evaluating pyloric stenosis due to use of azithromycin. There are also no data assessing the effects of

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

trimethoprim. There is no evidence for variation in patient values and preferences, but compliance with treatments ranged from 77% to 89%. The costs for treatments are relatively low and similar, and most treatments are currently being used. In summary, azithromycin is preferred over erythromycin because of the potential risk of serious adverse events with erythromycin, and there are no data for trimethoprim. See Annex C for list of references of reviewed evidence, and Web annex D for details of the evidence reviewed, including evidence profiles and evidence-to-decision frameworks (pp. 64-74). RECOMMENDATION 6 For all neonates, the WHO STI guideline recommends topical ocular prophylaxis for the prevention of gonococcal and chlamydial ophthalmia neonatorum. Strong recommendation, low quality evidence RECOMMENDATION 7 For ocular prophylaxis, the WHO STI guideline suggests one of the following options for topical application to both eyes immediately after birth: • tetracycline hydrochloride 1% eye ointment • erythromycin 0.5% eye ointment • povidone iodine 2.5% solution (water-based) • silver nitrate 1% solution • chloramphenicol 1% eye ointment. Conditional recommendation, low quality evidence Remarks: Recommendations 6 and 7 apply to the prevention of both chlamydial and gonococcal ophthalmia neonatorum. Cost and local resistance to erythromycin, tetracycline and chloramphenicol in gonococcal infection may determine the choice of medication. Caution should be taken to avoid touching eye tissue when applying the topical treatment and to provide a water-based solution of povidone iodine. Alcohol-based povidone iodine solution must not be applied. The topical application should be administered immediately after birth. Research implications: The prevalence of gonococcal ophthalmia should be determined given the high prevalence of maternal gonorrhoea in some settings. The state of resistance to the medications should be explored and it should be established whether these organisms would be killed by ocular prophylaxis despite resistant strains being established in the organisms. More research comparing the benefits and harms of the different medications is needed, in particular comparisons with chloramphenicol.

SUMMARY OF THE EVIDENCE Overall, the quality of evidence is low to very low from 16 studies: 15 randomized studies and one non-randomized study with two comparison groups. There are few available data for the effects of chloramphenicol. Large benefits were reported for prophylaxis compared with no prophylaxis, in particular in babies born to women with known infection (approximately 70% reduction in conjunctivitis with prophylaxis using different medications). The benefits with different medications are similar; however, the low to very low quality evidence indicates that the benefits of tetracycline hydrochloride, erythromycin or povidone iodine may be slightly greater than for silver nitrate. Few data are available for the incidence of noninfectious conjunctivitis after prophylaxis or no prophylaxis. Low quality evidence shows a slight reduction or little difference and indicates that between 4 and 50 per 1000 infants have non-infectious conjunctivitis after application of different prophylactic medications. There is little evidence relating to patient values and preferences, but the GDG agreed that there would likely be little difference in the high value placed on avoiding long-term consequences of both gonococcal and chlamydial conjunctivitis. The GDG also agreed that there would be little effect on acceptability, equity and feasibility, as prophylaxis is currently used in many countries. The GDG reported that alcoholbased povidone iodine has erroneously been used as prophylaxis resulting in serious harm to babies. Silver nitrate is the most expensive prophylaxis option. In summary, there are large benefits for prophylaxis to prevent ophthalmia neonatorum, and these benefits outweigh the risk of non-infectious conjunctivitis due to prophyalaxis with any of the topical medications. Some topical medications may provide greater protection (tetracycline hydrochloride, erythromycin or povidone iodine), but all are feasible to provide. See Annex C for list of references of reviewed evidence, and Web annex D for details of the evidence reviewed, including evidence profiles and evidence-to-decision frameworks (pp. 75-96).

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

REFERENCES

1. Newman L, Rowley J, Vander Hoorn S, Wijesooriya NS, Unemo M, Low N et al. Global estimates of the prevalence and incidence of four curable sexually transmitted infections in 2012 based on systematic review and global reporting. PLoS One. 2015;10(12):e0143304. doi:10.1371/journal.pone.0143304. 2. Harryman L, Blee K, Horner P. Chlamydia trachomatis and non-gonococcal urethritis. Medicine. 2014;42(6):327–332. doi:10.1016/j.mpmed.2014.03.001. 3. Haggerty CL, Gottlieb SL, Taylor BD, Low N, Xu F, Ness RB. Risk of sequelae after Chlamydia trachomatis genital infection in women. J Infect Dis. 2010;201(Suppl 2):S134-55. doi:10.1086/652395. 4. Bébéar C, de Barbeyrac B. Genital Chlamydia trachomatis infections. Clin Microbiol Infect. 2009;15(1):4–10. doi:10.1111/j.1469-0691.2008.02647.x. 5. Herring A, Richens J. Lymphogranuloma venereum. Sex Transm Infect. 2006;82(Suppl 4):iv23–5. doi:10.1136/sti.2006.023143. 6. Laboratory diagnosis of sexually transmitted infections including human immunodeficiency virus. Geneva: World Health Organization; 2013 (http://apps.who.int/iris/ bitstream/10665/85343/1/9789241505840_eng.pdf, accessed 24 May 2016). 7. Guidelines for the management of sexually transmitted infections. Geneva: World Health Organization; 2003 (http://www.who.int/hiv/pub/sti/en/STIGuidelines2003.pdf, accessed 25 May 2016). 8. Manhart LE, Gillespie CW, Lowens MS, Khosropour CM, Colombara DV, Golden MR et al. Standard treatment regimens for nongonococcal urethritis have similar but declining cure rates: a randomized controlled trial. Clin Infect Dis. 2013;56(7):934–42. doi:10.1093/cid/cis1022. 9. WHO handbook for guideline development, 2nd edition. Geneva: World Health Organization; 2014 (http://www.who.int/kms/handbook_2nd_ed.pdf, accessed 25 May 2016). 10. Management Sciences for Health (MSH) and World Health Organization (WHO). International drug price indicator guide, 2013 edition (updated annually). Medford (MA): MSH; 2014 (http://apps.who.int/ medicinedocs/documents/s21497en/s21497en.pdf, accessed 24 May 2016). 11. WHO guidelines for declaration of interests (WHO experts). Geneva: World Health Organization; 2014. 12. Introducing WHO’s reproductive health guidelines and tools into national programmes: principles and processes of adaptation and implementation. Geneva: World Health Organization; 2007 (http:// whqlibdoc.who.int/hq/2007/WHO_RHR_07.9_eng.pdf, accessed 25 May 2016). 13. WHO essential medicines list, 19th edition. Geneva: World Health Organization; 2015 (http://www. who.int/selection_medicines/committees/expert/20/EML_2015_FINAL_amended_AUG2015.pdf, accessed 24 May 2016).

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

ANNEX A: STI GUIDELINE DEVELOPMENT TEAMS WHO STI Steering Committee WHO regional STI focal points 1. 2. 3. 4. 5. Massimo Ghidinelli Lali Khotenashvili Ying-Ru Lo Frank Lule Razia Pendse and Ornella Lincetto Hamida Khattabi and Gabriela Reidner Region Region of the Americas (AMR) Washington, DC – United States of America (USA) European Region (EUR) Copenhagen – Denmark Western Pacific Region (WPR) Manila – Philippines African Region (AFR) Brazzaville – Congo South-East Asia Region (SEAR) New Delhi – India WHO Country Representative, Bhutan Eastern Mediterranean Region (EMR) Cairo – Egypt Department and Team Department of Reproductive Health and Research Human Reproduction Team Department of Reproductive Health and Research Adolescents and at-Risk Populations Department of HIV/AIDS Key Populations and Innovative Prevention Department of Reproductive Health and Research Adolescents and at-Risk Populations Department of Maternal, Newborn, Child and Adolescent Health; Research and Development Department of Reproductive Health and Research Human Reproduction Team Department of Reproductive Health and Research Human Reproduction Team Department of Reproductive Health and Research Human Reproduction Team Department of Noncommunicable Disease and Mental Health Management of Noncommunicable Diseases, Disability, Violence and Injury Prevention Blindness Deafness Prevention, Disability and Rehabilitation Department of Maternal, Newborn, Child and Adolescent Health Department of Reproductive Health and Research Human Reproduction Team

WHO headquarters 7. 8. 9. 10. 11. 12. 13. 14. 15. Moazzam Ali Avni Amin Rachel Baggaley Venkatraman Chandra-Mouli Jane Ferguson Mario Festin Mary Lyn Gaffield Sami Gottlieb Silvo Paolo Mariotti

16. 17.

Frances McConville Lori Newman

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

18. 19. 20. 21.

Annette Mwansa Nkowane Anita Sands Igor Toskin Marco Vitoria

Department of Health Workforce Essential Medicines and Health Products, Prequalification Team Department of Reproductive Health and Research Human Reproduction Team Department of HIV/AIDS Treatment and Care Department and Team Department of Reproductive Health and Research Human Reproduction Team Department of Reproductive Health and Research Human Reproduction Team Department of Reproductive Health and Research Human Reproduction Team Department of Reproductive Health and Research Human Reproduction Team Department of Reproductive Health and Research Human Reproduction Team

WHO STI Secretariat 22. 23. 24. 25. 26. Ian Askew Nathalie Broutet (co-lead of the development process) James Kiarie Lee Sharkey Teodora Elvira Wi (lead of the development process)

METHODOLOGIST Nancy Santesso Area of expertise: Guideline development, systematic reviews, clinical epidemiology Address: Department of Clinical Epidemiology and Biostatistics McMaster University 1200 Main Street West Hamilton, Ontario L8N 3Z5 Canada

SYSTEMATIC REVIEW TEAM: MCMASTER UNIVERSITY Team lead: Nancy Santesso Team members: Housne Begum, Janna-Lina Kerth, Gian Paolo Morgano, Kristie Poole, Nicole Schwab, Matthew Ventresca, Yuan Zhang, Andrew Zikic

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

STI GUIDELINE DEVELOPMENT GROUP Chairpersons: Judith Wasserheit, Holger Schünemann, Patricia Garcia Name and address 1. Yaw (Sax) Adu-Sarkodie School of Medical Sciences Kwame Nkrumah University of Science and Technology (KNUST) PO Box 1934, Bantama Kumasi Ghana Andrew Amato European Centre for Disease Prevention and Control Tomtebodavägen 11a 171 83 Stockholm Sweden Gail Bolan Centers for Disease Control and Prevention 1600 Clifton Rd. Atlanta, GA 30333 USA John Changalucha National Institute for Medical Research Mwanza Medical Research Centre PO Box 1462 Mwanza Tanzania Xiang-Sheng Chen National Center for STD Control Chinese Academy of Medical Sciences and Peking Union Medical College 12 Jiangwangmiao Street Nanjing 210042 China Harrel Chesson Division of STI Prevention Centers for Disease Control and Prevention 1600 Clifton Rd. Atlanta, GA 30333 USA Craig Cohen University of California, San Francisco 50 Beale Street, Suite 1200 San Francisco, CA 94117 USA Francisco Garcia Pima County Health Department 3950 S. Country Club Road Suite 100 Tucson, AZ 85714 USA Region AFR Sex M

EUR

AMR

AFR

WPR

AMR

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

Patricia Garcia (Co-Chair) School of Public Health and Administration Universidad Peruana Cayetano Heredia Ave Honorio Delgado 430 31 AP, 4314 Lima Peru Suzanne Garland Royal Women’s Hospital, Level 1 Bldg 404, Bio 21 Institute 30 Flemington Road, Parkville Victoria Australia Sarah Hawkes University College London Institute for Global Health London United Kingdom Mary Higgins International Confederation of Midwives Laan van Meerdervoort 70 2517 AN The Hague The Netherlands King Holmes Department of Global Health and Department of Medicine University of Washington Harborview Medical Center 325 9th Ave., Box 359931 Seattle, WA 98104 USA Jeffrey Klausner Division of Infectious Diseases and Program in Global Health David Geffen School of Medicine and Fielding School of Public Health University of California, Los Angeles USA David Lewis Western Sydney Sexual Health Centre Marie Bashir Institute for Infectious Diseases and Biosecurity Sydney Medical School Westmead, University of Sydney Sydney Australia Nicola Low Epidemiology and Public Health University of Bern Institute of Social and Preventive Medicine Finkenhubelweg 11 3012 Bern Switzerland

AMR

10.

WPR

11.

EUR

12.

EUR

13.

AMR

14.

AMR

15.

WPR

16.

EUR

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

17.

David Mabey Communicable Diseases London School of Hygiene and Tropical Medicine (LSHTM) Keppel Street London WC1E 7HT United Kingdom Angelica Espinosa Miranda Núcleo de Doenças Infecciosas Universidade Federal do Espirito Santo Av. Marechal Campos 1468 Maruípe Vitória – ES CEP 29040-091 Brazil Nelly Mugo Kenya Medical Research Institute Mbagathi Rd. PO Box 54840 - 00200 Nairobi Kenya Saiqa Mullick Implementation Science University of the Witwatersrand Hillbrow Health Precinct Hillbrow, Johannesburg South Africa Francis Ndowa 6 Thames Road Vainona, Harare Zimbabwe Joel Palefsky Division of Infectious Diseases Box 0654 513 Parnassus Ave, Room S420 University of California, San Francisco San Francisco, CA 94143 USA Keith Radcliffe European STI Guidelines Project International Union against Sexually Transmitted Infections (IUSTI) Royal Society of Medicine 1 Wimpole Street London W1G 0AE United Kingdom Ulugbek Sabirov National STI Program Republican Center for Dermato-Venereology Tashkent Uzbekistan Holger Schünemann (Co-Chair) Department of Clinical Epidemiology and Biostatistics McMaster University 1200 Main Street West Hamilton, Ontario L8N 3Z5 Canada

EUR

18.

AMR

19.

AFR

20.

AFR

21.

AFR

22.

AMR

23.

EUR

24.

EUR

25.

AMR

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

26.

Richard Steen Localitá Cassaluvo Diano San Pietro Imperia 18013 Italy Judith Stephenson University College London Gower Street London United Kingdom Magnus Unemo Department of Laboratory Medicine Microbiology Örebro University Hospital SE-701 85 Örebro Sweden Bea Vuylsteke Institute of Tropical Medicine Nationalestraat 155 2000 Antwerp Belgium Anna Wald University of Washington Virology Research Clinic Harborview Medical Center 325 9th Ave, Box 359928 Seattle, WA 98104 USA Judith Wasserheit (Co-Chair) Department of Global Health Professor of Global Health and Medicine Adjunct Professor of Epidemiology University of Washington Harris Hydraulics Building, Room 309D 1705 NE Pacific Street Box 357965 Seattle, WA 98195-7965 USA Thomas Wong Division of Community Acquired Infections Centre for Communicable Diseases and Infection Control Public Health Agency of Canada Room 2391, 100 Eglantine Driveway Tunney’s Pasture, AL 0602C Ottawa, Ontario K1A 0L2 Canada Kimberly A. Workowski Centers for Disease Control and Prevention (CDC) Division of Infectious Diseases Emory University School of Medicine 1600 Clifton Rd. Atlanta, GA 30333 USA

EUR

27.

EUR

28.

EUR

29.

EUR

30.

AMR

31.

AMR

32.

AMR

33.

AMR

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

STI Guideline Development Group: Working group for chlamydia 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. Andrew Amato Harrell Chesson Craig Cohen Patricia Garcia Nicola Low David Mabey Angelica Miranda Francis Ndowa Keith Radcliffe Judith Stephenson Magnus Unemo Bea Vuylsteke Judith Wasserheit

STI External Review Group: Working group for chlamydia Name and address 1. Laith Abu-Raddad Biostatistics, Epidemiology and Biomathematics Research Core Infectious Disease Epidemiology Group Department of Public Health Weill Cornell Medical College Cornell University Qatar Foundation – Education City Qatar Adele Benaken-Schwartz Ministry of Health STI, AIDS and Viral Hepatitis Department SAF Sul Trecho 2, Ed. Premium Torre I, Térreo, Sala 12 70.070-600 – Brasília – DF Brazil Mircea Betiu Nicolae Testemițanu State University of Medicine and Pharmacy Republic of Moldova Anupong Chitwarakorn Department of Diseases Control Bureau of AIDS, TB and STIs Ministry of Public Health Nonthaburi Thailand Region EMR Sex M

AMR

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WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

Anjana Das FHI 360 New Delhi India Carolyn Deal National Institute of Allergy and Infectious Diseases (NIAID) United States Department of Health and Human Services National Institutes of Health Washington, DC USA Margaret Gale-Rowe Professional Guidelines and Public Health Practice Division Centre for Communicable Diseases and Infection Control Public Health Agency of Canada Ottawa, Ontario Canada William M. Geisler Medicine and Epidemiology University of Alabama at Birmingham Division of Infectious Diseases 703 19th Street South Zeigler Research Building, Room 242 Birmingham, AL 35294-0007 USA Amina El Kettani Direction de l’Epidémiologie Service des MST-sida Ministry of Health 71 Avenue Ibn Sinaa, Agdal Rabat Morocco Ahmed Latif Public Health Consultant Zimbabwe Mizan Kiros Disease Prevention and Control Directorate Federal Ministry of Health Ethiopia Philippe Mayaud Clinical Research Department Faculty of Infectious and Tropical Diseases London School of Hygiene and Tropical Medicine Keppel Street London WC1E 7HT United Kingdom

SEAR

AMR

EMR

10.

AFR

11.

AFR

12.

EUR

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

13.

David McCartney Research and Technical Support International Planned Parenthood Federation (IPPF) 4 Newhams Row, London SE1 3UZ United Kingdom Ali M. Mir Population Council No. 7 Street 62, Sector F/6-3 Islamabad Pakistan Nuriye Ortayli United Nations Population Fund (UNFPA) 605 Third Avenue, 4rd floor New York, NY 10158 USA Khantanouvieng Sayabounthavong Ministry of Health Lao People’s Democratic Republic Aman Kumar Singh Department of AIDS Control (National AIDS Control Organization) Ministry of Health and Family Welfare Government of India Chandralok Building, 9th Floor, 36, Janpath New Delhi 110001 India

EUR

14.

SEAR

15.

AMR

16.

WPR

17.

SEAR

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

ANNEX B: DETAILED METHODS FOR GUIDELINE DEVELOPMENT QUESTIONS AND OUTCOMES To determine which recommendations to update, in December 2013 the World Health Organization (WHO) Department of Reproductive Health and Research reviewed current recommendations of key international guidelines: • S exually transmitted diseases treatment guidelines, 2010, Department of Health and Human Services, United States Centers for Disease Control and Prevention (CDC)4; • U nited Kingdom national guidelines for the management of sexually transmitted infections, British Association for Sexual Health and HIV (BASHH), 2006–2011;5 • C anadian guidelines on sexually transmitted infections, Public Health Agency of Canada, 2013–2014;6 • E uropean sexually transmitted infections guidelines, International Union of Sexually Transmitted Infections (IUSTI);7 • N ational management guidelines for sexually transmissible infections, Sexual Health Society of Victoria, Australia, 2008;8 • N ational guideline for the management and control of sexually transmitted infections (STIs), National Department of Health, South Africa, 2009;9 and • N ational guidelines on prevention, management and control of reproductive tract infections including sexually transmitted infections, Ministry of Health and Family Welfare, Government of India, August 2007.10 Based on the review, four proposed categories of sexually transmitted infection (STI) conditions were prioritized: a. STI conditions included in the 2003 WHO STI guidelines11 that were selected by the GDG to be reviewed and updated in the new WHO STI guidelines. These are important and common conditions. b. STI conditions not included in the 2003 WHO STI guidelines that were selected by the GDG to be reviewed and added in the new WHO STI guidelines. These are important and common conditions. c. STI conditions included in the 2003 WHO STI guidelines that were not updated but were selected by the GDG to be included in the new WHO STI guidelines. These STI conditions are rare and diagnosis is not often made in the majority of settings, or it is unlikely that there is new information available as a basis for making any changes to the 2003 WHO STI recommendations. d. STI conditions not included in the 2003 WHO STI guidelines that are part of other national guidelines, but were not selected by the GDG to be included in the new WHO STI guidelines. These conditions are rare and difficult to diagnose in the majority of settings, or it is unlikely that new research or information has become available; there are existing recommendations for these conditions that can be applied in other settings (e.g. reference hospitals that manage complicated conditions). A meeting was held in December 2013, at which the Guideline Development Group (GDG) discussed and decided on the initial list of population, intervention, comparator and outcome (PICO) questions identified by WHO. After the meeting, surveys pertaining to each of the four STI topic areas (i.e. gonorrhoea, chlamydia, syphilis and herpes simplex virus type 2 [HSV-2]) were administered among subgroups of the GDG members with expertise relating to the relevant STIs. The goal of the surveys was to rank the population, interventions and outcomes for each specific STI condition by importance. The surveys required the members of the STI subgroups to rank the population, interventions and outcomes on a scale of 1 to 9, from lowest to highest priority.

4 5 6 7

Available at: http://www.cdc.gov/std/treatment/2010/std-treatment-2010-rr5912.pdf Available at: http://www.bashh.org/BASHH/Guidelines/Guidelines/BASHH/Guidelines/Guidelines.aspx?hkey=072c83ed-0e9b-44b2-a989-7c84e4fbd9de Available at: http://www.phac-aspc.gc.ca/std-mts/sti-its/cgsti-ldcits/index-eng.php Available at: http://www.iusti.org/regions/europe/euroguidelines.htm

8 Melbourne Sexual Health Centre Treatment Guidelines, available at: http://mshc.org.au/HealthProfessional/MSHCTreatmentGuidelines/tabid/116/Default. aspx#.V06yFJMrKV4 9 Lewis DA, Maruma E. Revision of the national guideline for first-line comprehensive management and control of sexually transmitted infections: what’s new and why? South Afr J Epidemiol Infect. 2009;24(2):6-9 (http://apps.who.int/medicinedocs/documents/s18369en/s18369en.pdf, accessed 14 June 2016). 10 Available at: http://www.ilo.org/wcmsp5/groups/public/---ed_protect/---protrav/---ilo_aids/documents/legaldocument/wcms_117313.pdf 11 Guidelines for the management of sexually transmitted infections. Geneva: World Health Organization; 2003 (http://www.who.int/hiv/pub/sti/en/ STIGuidelines2003.pdf, accessed 30 May 2016).

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

Four different priority STI surveys were conducted, and each survey attained a 90–100% response rate from the STI subgroup members. The survey results for priority populations, interventions and outcomes were analysed. Populations, interventions and outcomes with an average rating of 7 to 9 were considered “critical”; those with an average rating of 4 to 6 were considered “important”; and those with an average rating of 1 to 3 were considered “not important” and were thus not covered in the guidelines. Some questions that scored less than 7 were kept for consistency. The number of comparisons in each question was also reduced; only “critical” interventions were compared with each other and with important interventions. Thus, “important” interventions were not compared to each other.

A revised list of questions was then compiled and all members of the full STI GDG were requested to review the priority questions. The priority questions were then revised based on this feedback. Six questions were identified for the update of the chlamydial infections guideline. Each question is framed using the PICO format (population, intervention, comparator and outcome). Each question corresponds to a recommendation.

1. Uncomplicated genital (cervix, urethra) chlamydial infections in adults and adolescents Population Adults and adolescents with uncomplicated genital (cervix, urethra) chlamydial infections Intervention Azithromycin 1 g orally x 1 dose Doxycycline 100 mg twice daily x 7 days Comparator Doxycycline extended release (ER) 200 mg daily x 7 days Erythromycin 500 mg orally, four times daily x 7 days Erythromycin ethylsuccinate (ES) 800 mg orally, four times daily x 7 days Erythromycin 500 mg orally, twice daily x 10–14 days Amoxicillin 500 mg orally, thrice daily x 7 days Quinolones Outcome Critical: Clinical cure, microbiological cure, STI complications, side-effects (including allergy, toxicity, gastro), compliance Important: Quality of life, HIV transmission and acquisition, partner transmission

2. Uncomplicated anorectal chlamydial infections in adults and adolescents, excluding lymphogranuloma venereum (LGV) Population Adults and adolescents with uncomplicated anorectal chlamydial infections (excluding LGV) Intervention Azithromycin 1 g orally x 1 dose Doxycycline 100 mg twice daily x 7 days Comparator Doxycycline (ER) 200 mg daily x 7 days Erythromycin 500 mg orally, four times daily x 7 days Erythromycin ES 800 mg orally, four times daily x 7 days Erythromycin 500 mg orally, twice daily x 10–14 days Amoxicillin 500 mg orally, thrice daily x 7 days Quinolones Outcome Critical: Clinical cure, microbiological cure, STI complications, side-effects (including allergy, toxicity, gastro), compliance Important: Quality of life, HIV transmission and acquisition, partner transmission

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

3a–c. Chlamydia in pregnancy Population Pregnant women with chlamydia Intervention Azithromycin 1 g orally x 1 dose Erythromycin 500 mg orally, four times daily x 7 days Comparator Amoxicillin 500 mg orally, thrice daily x 7 days Erythromycin 500 mg orally, twice daily x 14 days Erythromycin 250 mg orally, four times daily x 14 days Erythromycin ES 800 mg orally, four times daily x 7 days Erythromycin ES 400 mg orally, four times daily x 14 days Outcome Critical: Fetal outcomes (e.g. teratogenicity, toxicity), fetal loss, prematurity/low birth weight, chorioamnionitis, infant pneumonitis/neonatal ophthamia, postpartum endometritis, microbiological cure, side-effects (including allergy, toxicity, gastro), clinical cure (symptoms), compliance Important: HIV acquisition, quality of life, transmission to partner

4. Lymphogranuloma venereum (LGV) in all populations Population Adults and adolescents with LGV Intervention Doxycycline 100 mg twice daily x 21 days Azithromycin 1 g orally once a week x 1–3 weeks Comparator Doxycycline 100 mg twice daily x 14 days Erythromycin base 500 mg orally, four times daily x 21 days Outcome Critical: Clinical cure, microbiological cure Important: STI complications, side-effects (including allergy, toxicity, gastro), quality of life, HIV transmission and acquisition, compliance, LGV transmission to partner

5. Ophthalmia neonatorum treatment Population Neonates with neonatal conjunctivitis Intervention and comparator Erythromycin in 4 divided doses orally, daily x 14 days: 20 mg/kg/day, 30 mg/kg/day, or 50 mg/kg/day Azithromycin 20 mg/kg/day orally, daily x 3 days Trimethoprim 40 mg + sulfa 200 mg orally, twice daily x 14 days Outcome Critical: Clinical cure, microbiological cure, Complications, side-effects (including allergy, toxicity, gastro), antimicrobial resistance, compliance

6 and 7. Ophthalmia neonatorum prophylaxis Population Neonates at risk for ophthalmia neonatorum Intervention and comparator Ophthalmic ointment in each eye at the time of delivery: Erythromycin 0.5% Silver nitrate 1% Chloramphenicol Tetracycline 1% Povidone iodine 2.5% Outcome Critical: Absence of conjunctivitis, keratitis, complications, blindness, corneal scarring, antimicrobial resistance

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

REVIEWS OF THE EVIDENCE

SEARCH FOR EVIDENCE FOR EFFECTS OF INTERVENTIONS To avoid duplication of reviews that have been previously published, evidence was searched using a hierarchical approach. The team first searched for synthesized evidence then searched the primary studies for all the factors needed to complete the evidence-to-decision framework for each question (i.e. benefits and harms, patient values, acceptability, feasibility, equity and costs). The hierarchical approach consisted of identifying pre-existing synthesized evidence, including from previously published guidelines that included systematic reviews of the literature. When synthesized evidence about benefits and harms for an intervention was not available or the synthesized evidence was not up to date, a new systematic review of randomized controlled trials (RCTs) and non-randomized studies was conducted. The search strategies were developed by an information specialist trained in systematic reviews. The strategies included the use of keywords from the controlled vocabulary of the database and text words based on the PICO questions. There were no restrictions based on language, publication status or study design. RCTs were included for critical and important outcomes, and non-randomized studies for critical outcomes when no evidence was available from RCTs. Additional strategies included contacting Cochrane review groups and authors of study protocols. The Cochrane Library suite of databases (Cochrane Database of Systematic Reviews [CDSR], Database of Abstracts of Reviews of Effects [DARE], Health Technology Assessment [HTA] database and the American College of Physicians [ACP] Journal Club) was searched for published systematic reviews and protocols from 2004 to 2015. Search strategy: 1. chlamydia.mp. 2. trachomatis.mp. 3. ct infection*.tw. 4. or/1-3

Primary studies were searched for in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase databases. Search end dates for each PICO question varied between March and October 2015 (see list below). The strategies included searching for subject headings and text words that included chlamydia and specific interventions (e.g. medication names and classes). Additional strategies included checking reference lists and consulting with the GDG for any missed articles. We searched for RCTs for critical and important outcomes, and non-randomized studies for critical outcomes when no evidence was available from RCTs. Search end dates: • U ncomplicated genital (cervix, urethra) chlamydial infections in adults and adolescents: up to March 2015 • U ncomplicated anorectal chlamydial infections (excluding LGV) in adults and adolescents: up to June 2015 • C hlamydia in pregnancy: up to 1 June 2015; up to 1 December 2015 for non-randomized comparative studies • L ymphogranuloma venereum in all populations: up to June 2015 • Ophthalmia neonatorum treatment: up to May 2015 • O phthalmia neonatorum prevention: up to October 2015.

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

SCREENING STUDIES, DATA EXTRACTION AND ANALYSIS Two researchers independently screened titles and abstracts of systematic reviews identified through database searching to determine studies eligible for inclusion in the analysis. Disagreements were resolved by discussing study inclusion with a third member of the research team. Data were extracted using a pilottested form for patient characteristics (including the subgroups identified by the GDG), diagnosis, treatment (dose, schedule, etc.), setting, follow-up and outcomes. Two investigators independently abstracted data. Risk of bias of each study was also assessed using risk of bias tools appropriate for RCTs (http://handbook. cochrane.org/chapter_8/8_assessing_risk_of_bias_ in_included_studies.htm) and using the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I; previously called ACROBAT) tool to assess nonrandomized studies (www.riskofbias.info). To measure the treatment effect, the data were analysed using RevMan 5.2.12 For dichotomous outcomes, we calculated relative risks with 95% confidence intervals (e.g. risk ratios and odds ratios) by pooling results from RCTs and pooling results from non-randomized studies using the random effects model. Moderate to high heterogeneity (I2 > 50%) was explored. Effects were converted to absolute effects using the calculated relative effect and a representative baseline risk (agreed upon by the GDG). When nonrandomized studies with one group were included, a pooled proportion of an event (and confidence intervals) were calculated across the studies using the generic inverse variance. For continuous outcomes, a mean difference or a standardized mean difference (when studies used different scales to measure an outcome) was calculated. When possible, the forest plots of the meta-analyses were made available to the GDG. When data could not be pooled across studies, narrative synthesis methods were used (see http://methods. cochrane.org/sites/methods.cochrane.org/files/ Mckenzie.pdf). Results were presented in tables (e.g. median effects with interquartile ranges), or were narratively described by direction of the effect or by statistical significance as reported in the primary study.

PATIENT VALUES AND PREFERENCES, ACCEPTABILITY, EQUITY AND FEASIBILITY Studies on patient values and preferences, acceptability, equity and feasibility were searched for and screened using two methods. First, while screening studies for the effects of treatments and costs, two investigators identified studies of potential relevance in these areas. Secondly, a separate search was conducted in MEDLINE, Embase and PsycINFO from January 2000 to July 2015. Text words and keywords for the different STIs were used in combination with words such as “preference”, “adherence”, “satisfaction”, “attitudes”, “health utilities” and “value”, “equity” and “feasibility”. The results included 2563 unique references. Two investigators screened the studies, and 162 studies were identified for full text retrieval. Any study design was included that addressed equity or feasibility. In addition, when adherence was measured in RCTs or nonrandomized studies, the data were collected, synthesized and presented in the evidence profiles for each PICO question. The following study designs were included: a. Patient utilities and health status values studies: These studies examine how patients value alternative health states and their experiences with treatment. The measurement techniques used can include: standard gamble, time trade-off, visual analogue scale, or mapping results based on generic surveys (EuroQol five dimensions health questionnaire [EQ5D] or the 36-Item Short Form Health Survey [SF-36]) or specific measurement (e.g. St George Respiratory Questionnaire) of health-related quality of life. b. Studies of patients’ direct choices when presented with decision aids: These studies examine the choices patients make when presented with decision aids for management options (i.e. probabilistic trade-off techniques). c. Studies on non-utility measurement of health states: These studies quantitatively examine patients’ views, attitudes, satisfaction or preferences through questionnaires or scales; these are neither utility studies nor studies of patients’ responses to decision aids. Patients are asked about how desirable or aversive a particular outcome is for them. This category includes some studies that use questionnaires or scales. d. Qualitative studies: These studies explore patients’ views, attitudes, satisfactions or preferences related to different treatment options based on qualitative research methods including focus group discussions, interviews, etc.

12 RevMan (Computer Program). Copenhagen: The Nordic Cochrane Center, The Cochrane Collaboration; 2012.

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

From the search, we included 17 studies reporting information relating to different STIs. In many instances, data for all infections informed the evidence for chlamydia specifically.

RESOURCES We searched the published literature for evidence on use of resources and obtained data on direct costs of medicines. Based on the list of possible treatments identified by the GDG, an estimate of the cost associated with each alternative was calculated. This costing estimate refers only to the actual market price of the medication and does not include the costs of other resources that could be involved, such as syringes, injection time or needle disposal. Data were presented in a table and included: treatment, dose per day, treatment duration, days, medicine cost per dose, medicine cost per full course of treatment, and 25% of procurement costs (as defined in the 2014 MSH International drug price indicator guide)13. A final price for a full course of treatment for each medicine by dosage was calculated as the number of doses per day, multiplied by the number of days of the treatment, plus 25% of the procurement costs for the medicines used. The unit price of the medicine was obtained from the median prices provided in the 2014 MSH International drug price indicator guide and information available on the Internet. In order to determine a precise and reliable estimate, the price per unit (all expressed in US dollars) was provided only when the information available matched the dosage of interest (grams per pill or 1000 units per vial). No calculations were made based on assumptions about the cost per unit of hypothetical packaging not listed in the directory. The major medical databases were also searched (MEDLINE, Embase and the Cochrane Library for Economic Evaluation and Technology Assessment reports) from January 2005 to July 2015. Three studies addressed the cost-effectiveness of different treatment strategies for chlamydia. In addition, while screening studies for the effects of treatments, two investigators also identified studies of potential relevance for costs, and abstracted data regarding possible resources to be considered during the decision-making process.

13 International drug price indicator guide, 2014 edition (updated annually). Medford (MA): Management Science for Health; 2015 (http://erc.msh.org/ dmpguide/pdf/DrugPriceGuide_2014.pdf, accessed 3 June 2016).

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

APPLYING THE GRADE APPROACH TO MAKING THE RECOMMENDATIONS EVIDENCE PROFILES An evidence profile was made for each PICO question using the GRADEpro software (www.gradepro.org). Each profile included the critical and important outcomes, the relative and absolute effects, and the quality of evidence according to the GRADE domains (see the GRADE handbook)14. Briefly, the GRADE approach assesses the quality of evidence for treatment interventions using well-established criteria for the design, risk of bias, inconsistency, indirectness, imprecision, effect size, dose–response curve and other considerations that may affect the quality of the evidence. Two investigators used the GRADE approach to assess the quality and level of certainty of the evidence. The evidence profiles for each recommendation are available in Web annex D.

MAKING THE RECOMMENDATIONS In October 2015, the GDG met to make the recommendations. This meeting was facilitated by two co-chairs – one with expertise in GRADE and the other with clinical expertise of chlamydia. During the meeting, the evidence profiles and evidence-to-decision frameworks were presented by the methodologists. The GDG discussed each GRADE criterion and judged which intervention was favoured. Then a final decision and guideline recommendation was developed. The goal was to arrive at agreement across all members of the GDG and this was facilitated by the chairpersons through discussion. When there was disagreement for a criterion, it was noted in the evidence-to-decision framework for the relevant judgement. If there was disagreement for any of the final recommendations, the plan was for the GDG to vote and the numbers to be recorded. Because there was no disagreement for any of the final recommendations, however, votes were not taken or reported in these guidelines. The GDG made a strong or conditional recommendation for or against each intervention and described special circumstances in the remarks. Research implications were also developed and presented, based on the gaps identified in the evidence. Following the meeting, the recommendations were finalized via teleconference, and final approval was obtained from the GDG members electronically. All decisions and discussions from the GDG for each recommendation are available in the evidence-to-decision frameworks in Web annex D.

EVIDENCE-TO-DECISION FRAMEWORKS Evidence-to-decision frameworks were also developed using GRADEpro software (www.gradepro.org). Evidence-to-decision frameworks present the desirable and undesirable effects of the interventions, the value of the outcomes, the costs and resource use, the acceptability of the interventions to all stakeholders, the impact on health equity, and the feasibility of implementation (i.e. the GRADE criteria for making decisions). The evidence-to-decision frameworks are based on a population perspective for these recommendations. All GRADE criteria were considered from this perspective.

14 Schünemann H, Brożek J, Guyatt G, Oxman A, editors. GRADE handbook. Hamilton, Ontario: McMaster University and Evidence Prime Inc.; 2013 (http://gdt.guidelinedevelopment.org/central_prod/_design/client/ handbook/handbook.html, accessed 31 May 2016).

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

ANNEX C: LISTS OF REFERENCES FOR REVIEWED EVIDENCE RECOMMENDATION 1 Treatments for adults and adolescents with uncomplicated genital (cervix, urethra) chlamydial infections Systematic review 1. Páez-Canro C, Martinez-Martinez F, Alzate JP, Lethaby A, Gaitán HG. Antibiotics for treating genital Chlamydia trachomatis infection in men and non-pregnant women (protocol). Cochrane Database Syst Rev. 2013;(12):CD010871. Included studies 1. Bowie WR, Yu JS, Fawcett A, Jones HD. Tetracycline in nongonococcal urethritis. Comparison of 2 g and 1 g daily for seven days. Br J Vener Dis. 1980;56(5):332-6. 2. Campbell WF, Dodson MG. Clindamycin therapy for Chlamydia trachomatis in women. Am J Obstet Gynecol. 1990;162(2):343-7. 3. Cramers M, Kaspersen P, From E, Møller BR. Pivampicillin compared with erythromycin for treating women with genital Chlamydia trachomatis infection. Genitourin Med. 1988;64(4):247-8. 4. Csángó PA, Gundersen T, Anestad G. Doxycycline in the treatment of chlamydial urethritis: a therapeutic study. Pharmatherapeutica. 1980;2(5):341-5. 5. Fong IW, Linton W, Simbul M, Thorup R, McLaughlin B, Rahm V, et al. Treatment of nongonococcal urethritis with ciprofloxacin. Am J Med. 1987;82(4A):311-6. 6. Geisler WM, Koltun WD, Abdelsayed N, Burigo J, Mena L, Taylor SN, et al. Safety and efficacy of WC2031 versus vibramycin for the treatment of uncomplicated urogenital Chlamydia trachomatis infection: a randomized, double-blind, doubledummy active-controlled, multicenter trial. Clin Infect Dis. 2012;55(1):82-8. doi:10.1093/cid/cis291. 7. Guven MA, Gunyeli I, Dogan M, Ciragil P, Bakaris S, Gul M. The demographic and behavioural profile of women with cervicitis infected with Chlamydia trachomatis, Mycoplasma hominis and Ureaplasma urealyticum and the comparison of two medical regimens. Arch Gynecol Obstet. 2005;272:197-200. 8. Hammerschlag MR, Golden NH, Oh MK, Gelling M, Sturdevant M, Brown PR, et al. Single dose of azithromycin for the treatment of genital chlamydial infections in adolescents. J Pediatr. 1993;122(6):961-5. 9. Hawkins DA, Taylor-Robinson D, Evans RT, Furr PM, Harris JR. Unsuccessful treatment of non-gonococcal urethritis with rosoxacin provides information on the aetiology of the disease. Genitourin Med. 1985;61(1):51-5. 10. Hooton TM, Rogers ME, Medina TG, Kuwamura LE, Ewers C, Roberts PL, et al. Ciprofloxacin compared with doxycycline for nongonococcal urethritis. Ineffectiveness against Chlamydia trachomatis due to relapsing infection. JAMA. 1990;264(11):1418-21. 11. Ibsen HH, Møller BR, Halkier-Sørensen L, From E. Treatment of nongonococcal urethritis: comparison of ofloxacin and erythromycin. Sex Transm Dis. 1989;16(1):32-5. 12. Kitchen VS, Donegan C, Ward H, Thomas B, Harris JR, TaylorRobinson D. Comparison of ofloxacin with doxycycline in the treatment of non-gonococcal urethritis and cervical chlamydial infection. J Antimicrob Chemother. 1990;26(Suppl D):99-105. 13. Lauharanta J, Saarinen K, Mustonen MT, Happonen HP. Single-dose oral azithromycin versus seven-day doxycycline in the treatment of non-gonococcal urethritis in males. J Antimicrob Chemother. 1993;31(Suppl E):177-83. 14. Lister PJ, Balechandran T, Ridgway GL, Robinson AJ. Comparison of azithromycin and doxycycline in the treatment of non-gonococcal urethritis in men. J Antimicrob Chemother. 1993;31(Suppl E):185-92. 15. Manhart LE, Gillespie CW, Lowens MS, Khosropour CM, Colombara DV, Golden MR, et al. Standard treatment regimens for nongonococcal urethritis have similar but declining cure rates: a randomized controlled trial. Clin Infect Dis. 2013;56(7):934-42. 16. Martin DH, Mroczkowski TF, Dalu ZA, McCarty J, Jones RB, Hopkins SJ, et al. A controlled trial of a single dose of azithromycin for the treatment of chlamydial urethritis and cervicitis. The Azithromycin for Chlamydial Infections Study Group. N Engl J Med. 1992;327(13):921-5. 17. McCormack WM, Dalu ZA, Martin DH, Hook EW 3rd, Laisi R, Kell P, et al.; Trovafloxacin Chlamydial Urethritis/Cervicitis Study Group. Double-blind comparison of trovafloxacin and doxycycline in the treatment of uncomplicated Chlamydial urethritis and cervicitis. Sex Transm Dis. 1999;26(9):531-6. 18. McCormack WM, Martin DH, Hook EW 3rd, Jones RB. Daily oral grepafloxacin vs. twice daily oral doxycycline in the treatment of Chlamydia trachomatis endocervical infection. Infect Dis Obstet and Gynecol. 1998;6(3):109-15. 19. Nilsen A, Halsos A, Johansen A, Hansen E, Tørud E, Moseng D, et al. A double blind study of single dose azithromycin and doxycycline in the treatment of chlamydial urethritis in males. Genitourin Med. 1992;68(5):325-7. 20. Pereira CA, Montagnini SD. A prospective randomized trial of ofloxacin vs. doxycycline in the treatment of nongonococcal urethritis caused by Chlamydia trachomatis. Arquivos brasileiros de medicina. 1994;68(1):51-3. 21. Robson HG, Shah PP, Lalonde RG, Hayes L, Senikas VM. Comparison of rosaramicin and erythromycin stearate for treatment of cervical infection with Chlamydia trachomatis. Sex Trans Dis. 1983;10(3):130-4. 22. Stamm WE, Hicks CB, Martin DH, Leone P, Hook EW 3rd, Cooper RH, et al. Azithromycin for empirical treatment of the nongonococcal urethritis syndrome in men. A randomized double-blind study. JAMA. 1995;274(7):545-9. 23. Thambar IV, Simmons PD, Thin RN, Darougar S, Yearsley P. Double-blind comparison of two regimens in the treatment of nongonococcal urethritis. Seven-day vs 21-day course of triple tetracyclinc (Deteclo). Br J Vener Dis. 1979;55(4):284-8.

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

24. Topic A, Skerk V, Puntaric A, Milavec Puretic V, Beus A, Begovac J. Azithromycin: 1.0 or 3.0 gram dose in the treatment of patients with asymptomatic urogenital chlamydial infections. J Chemother. 2006;18(1):115-6. 25. van der Willigen AH, Polak-Vogelzang AA, Habbema L, Wagenvoort JH. Clinical efficacy of ciprofloxacin versus doxycycline in the treatment of non-gonococcal urethritis in males. Eur J Clin Microbiol Infect Dis. 1988;7(5):658-61. Patient values and preferences, acceptability and cost: specific to chlamydial infections 1. Dixon-Woods M, Stokes T, Young B, Phelps K, Windridge K, Shukla R. Choosing and using services for sexual health: a qualitative study of women's views. Sex Transm Infect. 2001;77(5):335-9. 2. International drug price indicator guide, 2014 edition (updated annually). Medford (MA): Management Sciences for Health; 2015 (http://erc.msh.org/dmpguide/pdf/DrugPriceGuide_2014.pdf, accessed 3 June 2016). 3. Sahin-Hodoglugil NN, Woods R, Pettifor A, Walsh J. A comparison of cost-effectiveness of three protocols for diagnosis and treatment of gonococcal and chlamydial infections in women in Africa. Sex Transm Dis. 2003;30:455-69. Patient values and preferences, acceptability and cost: other sexually transmitted infections and conditions 1. Kingston M, Carlin E. Treatment of sexually transmitted infections with single-dose therapy: a double-edged sword. Drugs. 2002;62(6):871-8. 2. Nagarkar A, Mhaskar P. A systematic review on the prevalence and utilization of health care services for reproductive tract infections/sexually transmitted infections: evidence from India. Indian J Sex Transm Dis. 2015;36(1):18-25. doi:10.4103/02537184.156690. 3. Ryan R, Santesso N, Lowe D, Hill S, Grimshaw J, Prictor M, et al. Interventions to improve safe and effective medicines use by consumers: an overview of systematic reviews. Cochrane Database Syst Rev. 2014;4:CD007768. Additional references 1. Amin A, Garcia Moreno C. Addressing gender-based violence to reduce risk of STI and HIV. Sex Transm Infect. 2013;89 (Suppl 1):A8. doi:10.1136/sextrans-2013-051184.0022. 2. Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386(9995):743-800. doi:10.1016/S0140-6736(15)60692-4. 3. Holmes K. Sexually transmitted diseases, 4th edition. New York (NY): McGraw Hill; 2008. 4. Newman L, Rowley J, Vander Hoorn S, Wijesooriya NS, Unemo M, Low N, et al. Global estimates of the prevalence and incidence of four curable sexually transmitted infections in 2012 based on systematic review and global reporting. PLoS One. 2015;10(12):e0143304. doi:10.1371/journal.pone.0143304.

RECOMMENDATION 2 Treatments in adults and adolescents with uncomplicated anorectal chlamydial infections (excluding lymphogranuloma venereum Systematic review 1. Kong FY, Tabrizi SN, Fairley CK, Vodstrcil LA, Huston WM, Chen M, et al. The efficacy of azithromycin and doxycycline for the treatment of rectal chlamydia infection: a systematic review and meta-analysis. J Antimicrob Chemother. 2015;70(5):1290-7. doi:10.1093/jac/dku574. Included studies 1. Ding A, Challenor R. Rectal chlamydia in heterosexual women: more questions than answers. Int J STD AIDS. 2014. 25(8):58792. doi:10.1177/0956462413515637. 2. Drummond F, Ryder N, Wand H, Guy R, Read P, McNulty AM, et al. Is azithromycin adequate treatment for asymptomatic rectal chlamydia? Int J STD AIDS. 2011;22(8):478-80. doi:10.1258/ ijsa.2011.010490. 3. Elgalib A, Alexander S, Tong CY, White JA. Seven days of doxycycline is an effective treatment for asymptomatic rectal Chlamydia trachomatis infection. Int J STD AIDS. 2011;22(8):4747. doi:10.1258/ijsa.2011.011134. 4. Hathorn E, Opie C, Goold P. What is the appropriate treatment for the management of rectal Chlamydia trachomatis in men and women? Sex Trans Infect. 2012;88(5):352-4. doi:10.1136/ sextrans-2011-050466. 5. Khosropour CM, Dombrowski JC, Barbee LA, Manhart LE, Golden MR. Comparing azithromycin and doxycycline for the treatment of rectal chlamydial infection: a retrospective cohort study. Sex Transm Dis. 2014;41(2):79-85. doi:10.1097/ OLQ.0000000000000088. 6. Khosropour CM, Duan R, Metsch LR, Feaster DJ, Golden MR. Persistent/recurrent chlamydial infection among STD clinic patients treated with CDC- recommended therapies. Abstracts of the STI and AIDS World Congress, Vienna, Austria. Sex Transm Infect. 2013;89(Suppl 1):A29. doi:10.1136/ sextrans-2013-051184.0092. 7. Steedman NM, McMillan A. Treatment of asymptomatic rectal Chlamydia trachomatis: is single-dose azithromycin effective? Int J STD AIDS. 2009;20(1):16-8. doi:10.1258/ijsa.2008.008211. 8. White JA. Manifestations and management of lymphogranuloma venereum. Curr Opin Infect Dis. 2009;22(1):57-66. doi:10.1097/ QCO.0b013e328320a8ae. Patient values and preferences, acceptability and cost: specific to chlamydial infections 1. Dixon-Woods M, Stokes T, Young B, Phelps K, Windridge K, Shukla R. Choosing and using services for sexual health: a qualitative study of women's views. Sex Transm Infect. 2001;77(5):335-9. 2. International drug price indicator guide, 2014 edition (updated annually). Medford (MA): Management Sciences for Health; 2015 (http://erc.msh.org/dmpguide/pdf/DrugPriceGuide_2014.pdf, accessed 3 June 2016).

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

Patient values and preferences, acceptability and cost: other sexually transmitted infections and conditions 1. Nagarkar A, Mhaskar P. A systematic review on the prevalence and utilization of health care services for reproductive tract infections/sexually transmitted infections: evidence from India. Indian J Sex Transm Dis. 2015;36(1):18-25. doi:10.4103/02537184.156690. 2. Ryan R, Santesso N, Lowe D, Hill S, Grimshaw J, Prictor M, et al. Interventions to improve safe and effective medicines use by consumers: an overview of systematic reviews. Cochrane Database Syst Rev. 2014;4:CD007768. Additional references 1. Amin A, Garcia Moreno C. Addressing gender-based violence to reduce risk of STI and HIV. Sex Transm Infect. 2013;89(Suppl 1):A8. 2. Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386(9995):743-800. doi:10.1016/S0140-6736(15)60692-4. 3. Holmes K. Sexually transmitted diseases, 4th edition. New York (NY): McGraw Hill; 2008. 4. Newman L, Rowley J, Vander Hoorn S, Wijesooriya NS, Unemo M, Low N, et al. Global estimates of the prevalence and incidence of four curable sexually transmitted infections in 2012 based on systematic review and global reporting. PLoS One. 2015;10(12):e0143304. doi:10.1371/journal.pone.0143304.

5. Bush MR, Rosa C. Azithromycin and erythromycin in the treatment of cervical chlamydial infection during pregnancy. Obstet Gynecol. 1994;84(1):61-3. 6. Crombleholme WR, Schachter J, Grossman M, Landers DV, Sweet RL. Amoxicillin therapy for Chlamydia trachomatis in pregnancy. Obstet Gynecol. 1990;75(5):752-6. 7. Edwards MS, Newman RB, Carter SG, Leboeuf FW, Menard MK, Rainwater KP. Randomized clinical trial of azithromycin for the treatment of Chlamydia cervicitis in pregnancy. Infect Dis Obstet Gynecol. 1996;4(6):333-7. 8. Jacobson GF, Autry AM, Kirby RS, Liverman EM, Motley RU. A randomized controlled trial comparing amoxicillin and azithromycin for the treatment of Chlamydia trachomatis in pregnancy. Am J Obstet Gynecol. 2001;184(7):1352-4 9. Kacmar J, Cheh E, Montagno A, Peipert JF. A randomized trial of azithromycin versus amoxicillin for the treatment of Chlamydia trachomatis in pregnancy. Infect Dis Obstet Gynecol. 2001;9(4):197-202. 10. Magat AH, Alger LS, Nagey DA, Hatch V, Lovchik JC. Doubleblind randomized study comparing amoxicillin and erythromycin for the treatment of Chlamydia trachomatis in pregnancy. Obstet Gynecol. 1993;81(5 Pt 1):745-9. 11. Martin DH, Eschenbach DA, Cotch MF, Nugent RP, Rao AV, Klebanoff MA, et al. Double-blind placebo-controlled treatment trial of Chlamydia trachomatis endocervical infections in pregnant women. Infect Dis Obstet Gynecol. 1997;5(1):10-7. 12. Nadafi M, Abdali KH, Parsanejad ME, Rajaee-Fard AR, Kaviani M. A comparison of amoxicillin and erythromycin for asymptomatic Chlamydia trachomatis infection in pregnancy. Int J Gynaecol Obstet. 2005;90(2):142-3. 13. Rahangdale L, Guerry S, Bauer HM, Packel L, Rhew M, Baxter R, et al. An observational cohort study of Chlamydia trachomatis treatment in pregnancy. Sex Transm Dis. 2006;33(2):106-10. 14. Rosenn M, Macones GA, Silverman N. A randomized trial of erythromycin and azithromycin for the treatment of chlamydia infection in pregnancy. Am J Obstet Gynecol. 1996;174:410. 15. Rosenn MF, Macones GA, Silverman NS. Randomized trial of erythromycin and azithromycin for treatment of chlamydial infection in pregnancy. Infect Dis Obstet Gynecol. 1995;3(6):241-4. 16. Silverman NS, Hochman M, Sullivan M, Womack M. A randomized prospective trial of amoxicillin versus erythromycin for the treatment of chlamydia in pregnancy. Am J Obstet Gynecol. 1993;168:420. 17. Silverman NS, Sullivan M, Hochman M, Womack M, Jungkind DL. A randomized, prospective trial comparing amoxicillin and erythromycin for the treatment of Chlamydia trachomatis in pregnancy. Am J Obstet Gynecol. 1994;170(3):829-32. 18. Turrentine MA, Troyer L, Gonik B. Randomized prospective study comparing erythromycin, amoxicillin and clindamycin for the treatment of Chlamydia trachomatis in pregnancy. Infect Dis Obstet Gynecol. 1995;2(5):205-9. 19. Wehbeh HA, Ruggeirio RM, Shahem S, Lopez G, Ali Y. Single-dose azithromycin for chlamydia in pregnant women. J Reprod Med. 1998 Jun;43(6):509-14.

RECOMMENDATIONS 3A, 3B, 3C Treatments in pregnant women with chlamydial infections Systematic review 1. Brocklehurst P, Gordon A, Heatley E, Milan SJ. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev. 2013;(1):CD000262. Included studies 1. Adair CD, Gunter M, Stovall TG, McElroy G, Veille JC, Ernest JM. Chlamydia in pregnancy: a randomized trial of azithromycin and erythromycin. Obstet Gynecol. 1998;91(2):165-8. 2. Alary M, Joly JR, Moutquin JM, Mondor M, Boucher M, Fortier A, et al. Randomised comparison of amoxicillin and erythromycin in treatment of genital chlamydial infection in pregnancy. Lancet. 1994;344(8935):1461-5. 3. Alger LS, Lovchik JC. Comparative efficacy of clindamycin versus erythromycin in eradication of antenatal Chlamydia trachomatis. Am J Obstet Gynecol. 1991;165(2):375-81. 4. Bell TA, Sandstrom IK, Eschenbach DA, Hummel D, Kuo C, Wang S, et al. Treatment of Chlamydia trachomatis in pregnancy with amoxicillin. In: Marsh PA editor(s). Chlamydial infections. Elsevier Biomedical Press; 1982:221-4.

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

Reviews and studies for adverse outcomes 1. Morency AM, Bujold E. The effect of second-trimester antibiotic therapy on the rate of preterm birth. J Obstet Gynaecol Can. 2007;29(1):35-44. 2. Romøren M, Lindbæk M, Nordeng H. Pregnancy outcome after gestational exposure to erythromycin – a populationbased register study from Norway. Br J Clin Pharmacol. 2012;74(6):1053-62. doi:10.1111/j.1365-2125.2012.04286.x. 3. van den Broek NR, White SA, Goodall M, Ntonya C, Kayira E, Kafulafula G, Neilson JP. The APPLe study: a randomized, community-based, placebo-controlled trial of azithromycin for the prevention of preterm birth, with meta-analysis. PLoS Med. 2009;6(12):e1000191. doi:10.1371/journal.pmed.1000191. Patient values and preferences, acceptability and cost: specific to chlamydial infections 1. Dixon-Woods M, Stokes T, Young B, Phelps K, Windridge K, Shukla R. Choosing and using services for sexual health: a qualitative study of women's views. Sex Transm Infect. 2001;77(5):335-9. 2. International drug price indicator guide, 2014 edition (undated annually). Medford (MA): Management Science for Health; 2015 (http://erc.msh.org/dmpguide/pdf/DrugPriceGuide_2014.pdf, accessed 3 June 2016). 3. Pitsouni E, Iavazzo C, Athanasiou S, Falagas ME. Single-dose azithromycin versus erythromycin or amoxicillin for Chlamydia trachomatis infection during pregnancy: a meta-analysis of randomised controlled trials. Int J Antimicrob Agents. 2007;30(3):213-21. Patient values and preferences, acceptability and cost: other sexually transmitted infections and conditions 1. Nagarkar A, Mhaskar P. A systematic review on the prevalence and utilization of health care services for reproductive tract infections/sexually transmitted infections: evidence from India. Indian J Sex Transm Dis. 2015;36(1):18-25. doi:10.4103/0253-7184.156690. 2. Ryan R, Santesso N, Lowe D, Hill S, Grimshaw J, Prictor M, et al. Interventions to improve safe and effective medicines use by consumers: an overview of systematic reviews. Cochrane Database Syst Rev. 2014;4:CD007768. Additional references 1. Amin A, Garcia Moreno C. Addressing gender-based violence to reduce risk of STI and HIV. Sex Transm Infect. 2013;89(Suppl 1):A8. 2. Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386(9995):743-800. doi:10.1016/S0140-6736(15)60692-4.

RECOMMENDATION 4 Treatments for adults and adolescents with lymphogranuloma venereum Included studies 1. Ballard RC, Ye H, Matta A, Dangor Y, Radebe F. Treatment of chancroid with azithromycin. Int J STD AIDS. 1996;7(Suppl.1):9-12. 2. Collado CAM, Aguilar REB. Lymphogranuloma venereum. Clinical aspects, diagnostic methods and treatment of 120 patients. Dermatologia Revista Mexicana. 2003;47(1):5-12. 3. De Vries C, Smelov V, Middelburg JG, Pleijster J, Speksnijder AG, Morré SA. Delayed microbial cure of lymphogranuloma venereum proctitis with doxycycline treatment. Clin Infect Dis. 2009;48(5):e53-e56. doi:10.1086/597011. 4. Heras E, Llibre JM, Martró E, Casabona J, Martin R, Sirera G. [Lymphogranuloma venereum proctocolitis in men with HIV-1 infection] Enferm Infecc Microbiol Clin. 2011;29(2):124-6 (in Spanish). doi:10.1016/j.eimc.2010.07.011. [correction in Enferm Infecc Microbiol Clin. 2012 Jun;30(6):357]. 5. Hevia H, Honeyman J, De la Parra M. [Treatment of early syphilis and venereal lymphogranulomatosis with doxycycline]. Rev Med Chil. 1971;99(6):402-5 (in Spanish). 6. Hill SC, Hodson L, Smith A. An audit on the management of lymphogranuloma venereum in a sexual health clinic in London, UK. Int J STD AIDS. 2010;21(11):772-6. doi:10.1258/ ijsa.2010.010329. 7. Kamarashev J, Riess CE, Mosimann J, Läuchlf S. Lymphogranuloma venereum in Zurich, Switzerland: Chlamydia trachomatis serovar L2 proctitis among men who have sex with men. Swiss Med Wkly. 2010;140(13-14):209-12. doi:smw-12962. 8. Krishnamurthy VR, Johnson M, Rangasamy J, Murali RVK. Efficacy of streptomycin, chloramphenicol, co-trimoxazole and doxycycline in lymphogranuloma venereum. Indian J Sex Transm Dis. 1982;3(1):26-8. 9. Marangoni A, D'Antuono A, Filippini A, Bellavista S, Baraldi C, Foschi C, et al. Lymphogranuloma venereum cases identified in patients attending a STD outpatients clinic in Italy. Poster (P2.013] presented 16 July 2013 at the STI & AIDS World Congress 2013, 14–17 July, Vienna, Austria. 10. Oud EV, de Vrieze NH, de Meij A, de Vries HJ. Pitfalls in the diagnosis and management of inguinal lymphogranuloma venereum: important lessons from a case series. Sex Transm Infect. 2014;90(4):279-82. doi:10.1136/sextrans-2013-051427. 11. Rodríguez-Domínguez M, Puerta T, Menéndez B, González-Alba JM, Rodríguez C, Hellin T, et al. Clinical and epidemiological characterization of a lymphogranuloma venereum outbreak in Madrid, Spain: co-circulation of two variants. Clin Microbiol Infect. 2014;20(3), 219-25. doi:10.1111/1469-0691.12256. 12. Sethi G, Allason-Jones E, Richens J, Annan NT, Hawkins D, Ekbote A, et al. Lymphogranuloma venereum presenting as genital ulceration and inguinal syndrome in men who have sex with men in London, UK. Sex Transm Infect. 2009;85(3):165-70. doi:10.1136/sti.2008.034348. 13. Vas A, Leighton J, Saxon C, Lebari D, Stott C, Ahmad S, et al. Audit of the clinical management of lymphogranuloma venereum in three inner-city genitourinary medicine clinics. International Journal of STD and AIDS, Conference, 11th Spring Meeting of the British Association for Sexual Health and HIV (BASHH), 15–17 May 2013. Bristol, United Kingdom. Conference Publication.

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

Patient values and preferences, acceptability and cost: specific to chlamydial infections 1. International drug price indicator guide, 2014 edition (updated annually). Medford (MA): Management Sciences for Health; 2015 (http://erc.msh.org/dmpguide/pdf/DrugPriceGuide_2014.pdf, accessed 3 June 2016). 2. Sahin-Hodoglugil NN, Woods R, Pettifor A, Walsh J. A comparison of cost-effectiveness of three protocols for diagnosis and treatment of gonococcal and chlamydial infections in women in Africa. Sex Transm Dis. 2003:30:455-69. Patient values and preferences, acceptability and cost 1. Nagarkar A, Mhaskar P. A systematic review on the prevalence and utilization of health care services for reproductive tract infections/sexually transmitted infections: evidence from India. Indian J Sex Transm Dis. 2015;36(1):18-25. doi:10.4103/02537184.156690. 2. Ryan R, Santesso N, Lowe D, Hill S, Grimshaw J, Prictor M, et al. Interventions to improve safe and effective medicines use by consumers: an overview of systematic reviews. Cochrane Database Syst Rev. 2014;4:CD007768. Additional references 1. O'Farrell N, Morison L, Moodley P, Pillay K, Vanmali T, Quigley M, Sturm AW. Genital ulcers and concomitant complaints in men attending a sexually transmitted infections clinic: implications for sexually transmitted infections management. Sex Transm Dis. 2008;35:545-9. doi:10.1097/OLQ.0b013e31816a4f2e.

8. Sandström I. Treatment of neonatal conjunctivitis. Arch Ophthalmol. 1987;105(7):925-8. 9. Sandström I, Kallings I, Melen B. Neonatal chlamydial conjunctivitis. A long term follow-up study. Acta Paediatri Scand. 1988;77(2):207-13. 10. Stenberg K, Mårdh PA. Chlamydial conjunctivitis in neonates and adults. History, clinical findings and follow-up. Acta Ophthalmol. 1990;68(6):651-7. 11. Stenberg, K, Mårdh P. A. Treatment of chlamydial conjunctivitis in newborns and adults with erythromycin and roxithromycin. J Antimicrob Chemother. 1991;28(2):301-7. Patient values and preferences, acceptability and cost: specific to chlamydial infections 1. Deogan CL, Bocangel MK, Wamala SP, Månsdotter AM. A cost-effectiveness analysis of the Chlamydia Monday – a community-based intervention to decrease the prevalence of chlamydia in Sweden. Scand J Public Health. 2010;38(2):141-50. 2. International Drug Price Indicator Guide, 2014 Edition (updated annually). Medford (MA): Management Sciences for Health; 2015 (http://erc.msh.org/dmpguide/pdf/DrugPriceGuide_2014.pdf, accessed 3 June 2016). Additional references 1. Darling EK, McDonald H. A meta-analysis of the efficacy of ocular prophylactic agents used for the prevention of gonococcal and chlamydial ophthalmia neonatorum. J Midwifery Womens Health. 2010;55(4):319-27. doi:10.1016/j.jmwh.2009.09.003. 2. Kakar S, Bhalla P, Maria A, Rana M, Chawla R, Mathur NB. Chlamydia trachomatis causing neonatal conjunctivitis in a tertiary care center. Indian J Med Microbiol. 2010;28(1):45-7. doi:10.4103/0255-0857.58728.

RECOMMENDATION 5 Treatment of chlamydial ophthalmia neonatorum Included studies 1. Cooper WO, Griffin MR, Arbogast P, Hickson GB, Gautam S, Ray WA. Very early exposure to erythromycin and infantile hypertrophic pyloric stenosis. Arch Pediatr Adolesc Med. 2002;156(7):647-50. 2. Fransen L, Nsanze H, D'Costa L. Oral erythromycin estolate in nongonococcal neonatal conjunctivitis. Eur J Sex Transm Dis. 1986;3(2):85-9. 3. Heggie AD, Jaffe AC, Stuart LA, Thombre PS, Sorensen RU. Topical sulfacetamide vs oral erythromycin for neonatal chlamydial conjunctivitis. Am J Dis Child. 1985;139(6):564-6. 4. Hammerschlag MR, Chandler JW, Alexander ER, English M, Koutsky L. Longitudinal studies on chlamydial infections in the first year of life. Pediatr Infect Dis. 1982;1(6):395-401. 5. Hammerschlag,MR, Gelling M., Roblin PM, Kutlin A, Jule JE. Treatment of neonatal chlamydial conjunctivitis with azithromycin. Pediatr Infect Dis J. 1998;17(11):1049-50. 6. Patamasucon PR, Retting PJ, Faust KL, Kusmiesz HT, Nelson JD. Oral v topical erythromycin therapies for chlamydial conjunctivitis. Am J Dis Child. 1982;136(9):817-21. 7. Rosenman MB, Mahon BE, Downs SM, Kleiman MB. Oral erythromycin prophylaxis vs watchful waiting in caring for newborns exposed to Chlamydia trachomatis. Arch Pediatr Adolesc Med. 2003;157(6):565-71.

RECOMMENDATIONS 6 AND 7 Prevention of gonococcal and chlamydial ophthalmia neonatorum Systematic reviews 1. Darling EK, McDonald H. A meta-analysis of the efficacy of ocular prophylactic agents used for the prevention of gonococcal and chlamydial ophthalmia neonatorum. J Midwifery Womens Health. 2010;55(4):319-27. doi:10.1016/j.jmwh.2009.09.003. 2. Kapoor VS, Whyte R, LaRoche RR. Interventions for preventing ophthalmia neonatorum (intervention protocol). Cochrane Database Syst Rev. 2015;(12):CD001862. 3. Mabry-Hernandez IR, Koenig HC. Ocular prophylaxis for gonococcal ophthalmia neonatorum: evidence update for the U.S. Preventive Services Task Force Reaffirmation Recommendation Statement. AHRQ Publication No. 10-05146. Rockville (MD): Agency for Healthcare Research and Quality; 2010. 4. Zuppa AA, D’Andrea V, Catenazzi P, Scorrano A, Romagnoli C. Ophthalmia neonatorum: what kind of prophylaxis? J Matern Fetal Neonatal Med. 2011;24(6):769-73. doi:10.3109/147 67058.2010.531326.

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

Included studies 1. Ali Z, Khadije D, Elahe A, Mohammad M, Fateme Z, Narges Z. Prophylaxis of ophthalmia neonatorum comparison of betadine, erythromycin and no prophylaxis. J Trop Pediatr. 2007;53(6):388-92. 5. Brussieux J, Boisivon A, Théron HP, Faidherbe C, Machado N, Michelon B. [Prevention of neonatal conjunctivitis. A comparative clinical and bacteriologic study of 2 eyedrops: silver nitrate and oxytetracycline]. Ann Pediatr. 1991;36(9):63741 (in French). 6. Chen JY. Prophylaxis of ophthalmia neonatorum: comparison of silver nitrate, tetracycline, erythromycin and no prophylaxis. Pediatr Infect Dis J. 1992;11(12):1026-30. 7. David M, Rumelt S, Weintraub Z. Efficacy comparison between povidone iodine 2.5% and tetracycline 1% in prevention of ophthalmia neonatorum. Ophthalmology. 2011;118(7):1454-8. 8. Fischer PR, Reta BB. Prevention of neonatal conjunctivitis in Zaire. Ann Trop Paediatr. 1988;8(2):85-6. 9. Hammerschlag MR, Cummings C, Roblin PM, Williams TH, Delke I. Efficacy of neonatal ocular prophylaxis for the prevention of chlamydial and gonococcal conjunctivitis. N Engl J Med. 1989;320(12):769-72. 10. Hammerschlag MR, Chandler JW, Alexander ER, English M, Chiang WT, Koutsky L, et al. Erythromycin ointment for ocular prophylaxis of neonatal chlamydial infection. JAMA. 1980;244(20):2291-3. 11. Hammerschlag MR, Chandler JW, Alexander ER, English M, Koutsky L. Longitudinal studies on chlamydial infections in the first year of life. Pediatr Infect Dis. 1982;1(6):395-401. 12. Isenberg SJ, Apt L, Del Signore M, Gichuhi S, Berman NG. A double application approach to ophthalmia neonatorum prophylaxis. Br J Ophthalmol. 2003; 87(12):1449-52. 13. Isenberg SJ, Apt L, Wood M. A controlled trial of povidone-iodine as prophylaxis against ophthalmia neonatorum. N Engl J Med. 1995;332(9):562-6. 14. Laga M, Plummer FA, Plot P, Datta P, Namaara W, Neinya-Achola JO, et al. Prophylaxis of gonococcal and chlamydial ophthalmia neonatorum. A comparison of silver nitrate and tetracycline. N Engl J Med. 1988;318(11):653-7. 15. Matinzadeh ZK, Beiragdar F, Kavemanesh Z, Abolgasemi H, Amirsalari S. Efficacy of topical ophthalmic prophylaxis in prevention of ophthalmia neonatorum. Trop Doct. 2007;37(1):47-9. 16. Ozkan H, Abacioglu H, Duman N, Celikkol B, Ozkutuk A. A controlled trial of efficacy and safety of povidone- iodine as prophylaxis against ophthalmia neonatorum. Çocuk Sağliği ve Hastaliklari Dergisi [J of Child Health Dis]. 1999;42(4):459-67 (in Turkish). 17. Ramirez-Ortiz MA, Rodriguez-Almaraz M, Ochoa-Diazlopez H, Diaz-Prieto P, Rodriguez-Suárez RS. Randomised equivalency trial comparing 2.5% povidone-iodine eye drops and ophthalmic chloramphenicol for preventing neonatal conjunctivitis in a trachoma endemic area in southern Mexico. Br J Ophthalmology. 2007;91(11):1430-4. 18. Steigleder GK. [Efficacy of neonatal ocular prophylaxis for the prevention of chlamydial and gonococcal conjunctivitis]. Z Hautkr. 1989;64(5):347 (in German). 19. Zanoni D, Isenberg SJ, Apt L. A comparison of silver nitrate with erythromycin for prophylaxis against ophthalmia neonatorum. Clin Pediatr. 1992;31(5):295-8.

Resistance data 1. Hedberg K, Ristinen TL, Soler JT, White KE, Hedberg CW, Osterholm MT, MacDonald KL. Outbreak of erythromycin resistant staphylococcal conjunctivitis in a newborn nursery. Pediatr Infect Dis J. 1990;9:268-73. 2. Isenberg SJ, Apt L, Wood M. A controlled trial of povidone iodine as prophylaxis against ophthalmia neonatorum. N Engl J Med. 1995;332:562–6. 3. Ison CA, Terry P, Bendayna K, Gill MJ, Adams J, Woodford N. Tetracycline-resistant gonococci in UK. Lancet. 1988;1:651–2. 4. Knapp JS, Zenilman JM, Biddle JW, Perkins GH, DeWitt WE, Thomas ML, et al. Frequency and distribution in the United States of strains of Neisseria gonorrhoeae with plasmidmediated, high-level resistance to tetracycline. J Infect Dis. 1987;155:819-22. 5. Schwarcz SK, Zenilman JM, Schnell D, Knapp JS, Hook EW 3rd, Thompson S, et al. National surveillance of antimicrobial resistance in Neisseria gonorrhoeae. The Gonococcal Isolate Surveillance Project. JAMA. 1990;264:1413-7. References related to patient values and preferences, acceptability and cost 1. Deogan CL, Bocangel MK, Wamala SP, Månsdotter AM. A cost-effectiveness analysis of the Chlamydia Monday – a community-based intervention to decrease the prevalence of chlamydia in Sweden. Scand J Public Health. 2010;38(2):141-50. 2. Keenan JD, Eckert S, Rutar T. Cost analysis of povidone-iodine for ophthalmia neonatorum prophylaxis. Arch Ophthalmol. 2010;128(1):136-7. 3. International Drug Price Indicator Guide, 2014 Edition (updated annually). Medford (MA): Management Sciences for Health; 2015 (http://erc.msh.org/dmpguide/pdf/DrugPriceGuide_2014.pdf, accessed 3 June 2016). Additional references 1. Darling EK, McDonald H. A meta-analysis of the efficacy of ocular prophylactic agents used for the prevention of gonococcal and chlamydial ophthalmia neonatorum. J Midwifery Womens Health. 2010;55(4):319-27. doi:10.1016/j.jmwh.2009.09.003. 2. Kakar S, Bhalla P, Maria A, Rana M, Chawla R, Mathur NB. Chlamydia trachomatis causing neonatal conjunctivitis in a tertiary care center. Indian J Med Microbiol. 2010;28(1):45-7. doi:10.4103/0255-0857.58728.

WHO GUIDELINES FOR THE TREATMENT OF CHLAMYDIA TRACHOMATIS

For more information, contact: Department of Reproductive Health and Research World Health Organization Avenue Appia 20, CH-1211 Geneva 27 Switzerland Fax +41 22 791 4171 E-mail: reproductivehealth@who.int www.who.int/reproductive health

WHO GUIDELINES FOR THE

Treatment of Chlamydia trachomatis Web annex D: Evidence profiles and evidence-to-decision frameworks

The full guidelines are available at: www.who.int/reproductivehealth/publications/rtis/chlamydia-treatment-guidelines/en/

WHO GUIDELINES FOR THE

Treatment of Chlamydia trachomatis Web annex D: Evidence profiles and evidence-to-decision frameworks

CONTENTS

Recommendation 1 2 Assessment 3 Summary of judgments 7 Conclusions 8 Evidence profiles 10 References 17 Recommendation 2 19 Assessment 20 Summary of judgements 24 Conclusions 25 Evidence profile 27 References 29 Recommendations 3 30 Assessment 31 Summary of judgements 35 Conclusions 36 Evidence profile 38 Azithromycin versus erythromycin 38 Azithromycin versus amoxicillin 41 Erythromycin versus amoxicillin 43 References 46 Recommendation 4 48 Assessment 49 Summary of judgements 52 Conclusions 53 Evidence profile 54 References 55 Recommendation 5 56 Assessment 57 Summary of judgements 61 Conclusions 62 Evidence profile 63 References 65 Recommendations 6 and 7 66 Assessment 67 Summary of judgements 70 Conclusions 71 Evidence profiles 73 Treatments versus erythromycin 73 Treatments versus tetracycline 1% 77 Povidone iodine versus other treatments 79 One treatment versus no treatment 82 Resistance to prophylaxis 86 References 86

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

RECOMMENDATION 1 Treatments for adults and adolescents with uncomplicated genital (cervix, urethra) chlamydial infections? Population: Intervention: Comparison: Main outcomes: Adults and adolescents with uncomplicated genital (cervix, urethra) chlamydial infections Azithromycin or doxycycline Other antibiotics Critical: Clinical cure, microbiological cure, sexually transmitted infections (STIs), complications, side-effects (including allergy, toxicity, gastro), compliance Important: Quality of life, HIV transmission and acquisition, partner transmission Setting: Perspective: Background: Outpatient Population The global prevalence and incidence of chlamydia in adult women and men, like other STIs, remain high, with nearly one million new curable infections each day. This infection causes acute conditions such as cervicitis, urethritis and genital ulceration. The 2003 WHO guidelines recommend treatment of uncomplicated anogenital infections with either doxycycline 100 mg orally twice daily for 7 days, or azithromycin 1 g orally in a single dose. Alternatively, amoxicillin 500 mg orally thrice daily for 7 days; erythromycin 500 mg orally four times daily for 7 days; ofloxacin 300 mg orally twice daily for 7 days; or tetracycline 500 mg orally four times daily for 7 days. The Guideline Development Group (GDG) identified azithromycin and doxycycline for comparison to other treatments for review.

RECOMMENDATION 1

ASSESSMENT Judgement Is the problem a priority? Problem Desirable Effects Undesirable Effects Research evidence Research evidence: An estimated 131 million new cases of chlamydia (100–166 million) were reported (Newman, 2012) globally in 2012. According to 2013 Global Burden of Disease estimates, chlamydia was the 10th most common incident condition. Chlamydial infection can also lead to severe complications and long-term sequelae, including pelvic inflammatory disease, ectopic pregnancy, infertility, chronic pelvic pain, neurological and cardiovascular disease in adults, neonatal death, premature delivery and severe disability in infants (Holmes, 2008). Furthermore, STIs such as chlamydia frequently result in stigma, stereotyping, vulnerability and shame and have been associated with gender-based violence (Amin, 2013). There is also an associated risk of HIV transmission. Additional considerations: The GDG agreed that the global estimates of chlamydia are generally underestimated due to under-diagnosis. However, the global estimates made by Newman took this factor into consideration. It was also noted that considerations for sex workers and other key populations should be of importance. How substantial are the desirable anticipated effects? Research evidence: Evidence from a not yet published Cochrane systematic review was used (see Páez-Canro et al., 2013 – protocol for the review). This review included 25 randomized studies comparing tetracycline, quinolones and macrolides. We compared azithromycin to doxycycline, doxycycline to ofloxacin, high-dose azithromycin to low-dose azithromycin, high-dose tetracycline to low-dose tetracycline, extended release to standard-dose doxycycline, tetracyclines to quinolones, and erythromycin to other quinolones. There were no data for amoxicillin. See the evidence profiles for each of the comparisons. Additional considerations: • There were trivial differences in cure rates between azithromycin 1 g and doxycycline 100 mg twice daily for 7 days (8 or 10 fewer per 1000). • There may be more clinical cures with 3 g azithromycin (high dose) versus 1 g azithromycin (low dose) (94 more per 1000). How substantial are the undesirable anticipated effects?

• • • •

No Probably no Probably yes Yes

• Varies • Don’t know

• • • •

Trivial Small Moderate Large

• Varies • Don’t know

• Doxycycline hyclate delayed-release probably leads to slightly fewer cures than using the standard dose.

• • • •

Large Moderate Small Trivial

• Doxycycline compared to ofloxacin may yield fewer cures. • High dose any tetracycline compared to lower dose may lead to more clinical cures.

• Tetracyclines compared to quinolones may lead to fewer cures. • Erythromycin compared to other quinolones may lead to fewer cures. • There were trivial differences in adverse events between azithromycin 1 g and • • • • • doxycycline 100 mg twice daily for 7 days (3 more per 1000). This data did not include women. Doxycycline hyclate delayed-release probably leads to fewer adverse events than standard dose. Doxycycline compared to ofloxacin may have lead to slightly fewer adverse events. Any high-dose tetracycline compared to lower dose probably leads to fewer adverse events. Tetracyclines compared to quinolones may lead to slightly fewer adverse events. Erythromycin compared to other quinolones may lead to more adverse events.

• Varies • Don’t know

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

What is the overall certainty of the evidence of effects?

• • • • •

Very low Low Moderate High No included studies

Additional considerations: Moderate certainty for comparisons between azithromycin and doxycycline, but low certainty for some comparisons of other drugs. Lower certainty is primarily due to the studies including few events, and using confidence intervals that included the potential for benefit and harm.

Certainty of evidence Values Balance of effects

Is there important uncertainty about or variability in how much people value the main outcomes?

• I mportant uncertainty or variability • Possibly important uncertainty or variability • Probably no important uncertainty or variability • No important uncertainty or variability • N o known undesirable outcomes Does the balance between desirable and undesirable effects favour the intervention or the comparison?

Research evidence: None Additional considerations: Due to trivial differences, neither azithromycin nor doxycycline was favoured over the other. Due to little evidence, neither high dose nor low dose was favoured over the other. Doxycycline hyclate delayed-release is probably favoured over the standard dose. Neither doxycycline nor ofloxacin were favoured over the other. Other quinolones may be favoured over erythromycin.

• Favours the comparison • Probably favours the comparison

• Does not favour either the intervention or the comparison • Probably favours the intervention • Favours the intervention

• Varies • Don’t know

RECOMMENDATION 1

How large are the resource requirements (costs)?

Resources required Certainty of evidence of required resources Cost–effectiveness

• • • • •

Large costs Moderate costs Negligible costs and savings Moderate savings Large savings

A Azithromycin 1 g po Doxycycline 100 mg po Doxycycline (ER) 200 mg po Erythromycin ES 800 mg po Erythromycin 500 mg po Amoxicillin 500 mg po Quinolones po

B 1 2 1 4 2 3

C 1 7 7 7 10-14 7

D* $0.38 (500 mg) $0.0191 n.a. n.a. $0.0738 $0.032 n.a.

E $0.76 $0.2674 n.a. n.a. $1.476 – $2.06 $0.672 n.a.

F $0.95 $0.3342 n.a. n.a. $1.88 – $2.57 $0.84 n.a.

• Varies • Don’t know

Additional considerations: The GDG agreed that azithromycin is more expensive than doxycycline but less expensive than erythromycin. Globally, most STI drugs come from out-of-pocket payments, and this should be the primary consideration rather than how much governments or donors are willing to pay. For many of these drugs, costs may be different across countries, and in places with high incidence of chlamydia, the cost differences may be larger with a greater number of people treated. The GDG also indicated that co-treatment for gonorrhoea infection must be considered in determining cost of treatments.

What is the certainty of the evidence of resource requirements (costs)?

No studies exploring resource costs were found.

• • • •

Very low Low Moderate High

• No included studies Does the cost-effectiveness of the intervention favour the intervention or the comparison? Research evidence: Sahin-Hodoglugil et al. (2003) found that the “gold standard” protocol with diagnosis and treatment, using azithromycin for chlamydial infections, was found to be more cost-effective than using doxycycline. For both the gold standard and syndrome management protocols, the total cost of the program was most sensitive to the percentage of women seeking STI treatment and the prevalence of non-STI vaginal discharge. In contrast, the cost of mass treatment was almost exclusively determined by coverage rates. Additional considerations: The GDG agreed that azithromycin is more expensive than doxycycline but less expensive than erythromycin. Globally, most STI drugs come from out-of-pocket payments, and this should be the primary consideration rather than how much governments or donors are willing to pay. For many of these drugs costs may be different across countries, and in places with high incidence of chlamydia the cost differences may be larger with a greater number of people treated. The GDG also indicated that co-treatment for gonorrhoea infection must be considered in determining cost of treatments.

• Favours the comparison • Probably favours the comparison

• Does not favour either the intervention or the comparison • Probably favours the intervention • Favours the intervention

• Varies • No included studies

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

What would be the impact on health equity?

Research evidence: No research evidence Additional considerations: It was suggested that multi-dose regimens (like doxycycline) may reduce equity because of a stigma surrounding taking treatments, but this may vary across different populations, including men who have sex with men (MSM), transgender patients and young women at increased risk of anorectal infections. More research is needed. Therefore, azithromycin probably increases equity.

Equity Acceptability Feasibility

• • • • •

Reduced Probably reduced Probably no impact Probably increased Increased

• Varies • Don’t know Is the intervention acceptable to key stakeholders?

• • • •

No Probably no Probably yes Yes

• Varies • Don’t know

Research evidence: A systematic review (in India) of the literature for treatment utilization in STI reported that utilization ranged from 16% to 55% in community-based studies and was higher (approximately 70%) in research trials. Treatment may not be acceptable to patients due to the resources and availability of services, social factors and/or distance from a clinic. Non-utilization was also due to ignorance, illiteracy and lack of awareness. Women reported a lack of female doctors, being afraid of results, judgement from doctors, stigma, shyness and embarrassment. Cost of care and lack of faith in clinical care were also factors. A review of the literature for single versus multi-dosing found 2 studies specifically for treatment of chlamydia (Kingston, 2002) reporting 70% of men preferred the single dose regimen. Furthermore, overview of reviews of medication adherence (Ryan, 2014) reported that adherence may be improved with simpler drug regimens. Additional considerations: The GDG agreed that one dose of azithromycin would be more acceptable than a course of doxycycline twice daily for 7 days. The GDG also discussed the need for sexual abstinence during treatment. It was noted that for azithromycin therapy, sexual abstinence may be more important than with doxycycline treatment in avoiding reinfection, as the prolonged doxycycline concentration could maintain some protection throughout the course of the treatment. However, there is no clear evidence for these effects.

Is the intervention feasible to implement?

Research evidence: No research evidence Additional considerations: The GDG noted that important social considerations were needed for adolescent girls (and other populations), due to difficulties in bringing therapy home. The treatments were considered feasible, with distribution and compliance concerns taken into account.

• • • •

No Probably no Probably yes Yes

• Varies • Don’t know

RECOMMENDATION 1

SUMMARY OF JUDGEMENTS Judgement Problem Desirable Effects Undesirable Effects Certainty of evidence Values No Trivial Large Very low Important uncertainty or variability Favours the comparison Probably no Small Moderate Low Possibly important uncertainty or variability Probably favours the comparison Probably yes Moderate Small Moderate Probably no important uncertainty or variability Does not favour either the intervention or the comparison Negligible costs and savings Moderate Yes Large Trivial High No important uncertainty or variability Probably favours the intervention Favours the intervention Varies Varies Varies Varies Don’t know Don’t know Don’t know No included studies No known undesirable outcomes Don’t know

Balance of effects

Resources required Certainty of evidence of required resources Cost– effectiveness

Large costs

Moderate costs Low

Moderate savings High

Large savings

Varies

Don’t know

Very low

No included studies

Favours the comparison

Probably favours the comparison

Does not favour either the intervention or the comparison Probably no impact Probably yes Probably yes

Probably favours the intervention

Favours the intervention

Varies

No included studies

Equity Acceptability Feasibility

Reduced No No

Probably reduced Probably no Probably no

Probably increased Yes Yes

Increased

Varies Varies Varies

Don’t know Don’t know Don’t know

CONCLUSIONS

Treatments for uncomplicated genital (cervix, urethra) chlamydial infections Conditional recommendation against the intervention • • Conditional recommendation for either the intervention or the comparison Conditional recommendation for the intervention Strong recommendation for the intervention

Type of recommendation

Strong recommendation against the intervention

•

• •

Recommendation

For people with uncomplicated genital chlamydia, the WHO STI guideline suggests one of the following options:

• Azithromycin 1 g as a single oral dose • Doxycycline 100 mg twice a day for 7 days

Alternative options

• Tetracycline 500 mg four times a day for 7 days • Erythromycin 500 mg twice a day for 7 days • Ofloxacin 200–400 mg twice a day for 7 days

Conditional recommendation, moderate quality evidence

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Remarks: While good practice, resulting from large net benefit, dictates that patients should be treated for chlamydial infection, the choice of treatment may depend on the convenience of dosage, the cost and quality of the medicines in different resource settings and equity considerations. When high value is placed on reducing costs, doxycycline in a standard dose may be the best choice; however, when high value is placed on convenience, azithromycin in a single dose may be the best choice. Doxycycline extended release (ER) may be an alternative to twice daily dosing of doxycycline, but the high cost of the delayed release formulation may prohibit its use. Note that doxycycline, tetracycline and ofloxacin are contraindicated in pregnant women (see Recommendation 3).

Justification

Evidence from a not yet published Cochrane systematic review was used (Páez-Canro et al., 2013 – protocol for the review). This review included 25 randomized studies comparing tetracycline, quinolones and macrolides. There is no data for amoxicillin. Overall there is moderate to low quality evidence for most comparisons of treatments. Moderate quality evidence shows trivial differences between azithromycin 1 g and doxycycline 100 mg twice daily for 7 days in the number of people microbiologically cured and experiencing adverse events. There were 10 fewer per 1000 people cured with azithromycin versus doxycycline, ranging from 38 fewer to 10 more (risk ratio [RR] 0.99, 95% confidence interval [CI] 0.96 to 1.10). In addition, there were 3 more per 1000 adverse events with azithromycin versus doxycycline, ranging from 42 fewer to 64 more (RR 1.02, 95% CI 0.72 to 1.43). Similar results are shown in a recently published randomized study.

Doxycycline hyclate delayed release probably leads to little to no difference in number of people microbiologically cured, but probably has fewer side-effects than the standard dose. Ofloxacin may have fewer cures, but slightly fewer adverse events compared to doxycycline. When comparing high doses of azithromycin (1 g weekly for 3 weeks) to a single dose, there may be more people cured, but there is no data for adverse events related to very high doses. Higher doses of any tetracycline compared with lower doses may lead to more cures and probably lead to more adverse events. Tetracyclines compared with quinolones may lead to fewer cures but slightly fewer adverse events. Erythromycin compared with quinolones may lead to fewer cures and more adverse events.

There is no evidence for patient values and preferences, however, the GDG agreed that there are no known reasons to suspect values would vary between different people. Research in other conditions indicates that adherence may be improved with simpler drug regimens. The GDG, therefore, agreed that azithromycin may be perceived to be more acceptable since it is a single dose and a majority of the GDG members consider single-dose regimens as preferable for patient compliance over multi-dose regimens.

There is little-to-no evidence for equity issues and feasibility. Resistance in other infections (e.g. gonorrhoea and Mycoplasma genitalium) that co-occur with chlamydia may restrict the use of some medicines, such as ofloxacin. For many of these drugs, costs may differ between countries; for example, in places with high incidence of chlamydia, the minimal cost differences between azithromycin and doxycycline may be large due to greater numbers of people requiring treatment.

In summary, there was moderate quality evidence for trivial differences in benefits and harms between azithromycin and doxycycline; and although the cost of azithromycin is higher, the single dose may be more convenient than doxycycline. While the differences are also trivial with the other drugs, the evidence is low quality and is therefore provided as alternatives, with the exception of doxycycline-delayed release, which is currently expensive.

Subgroup considerations

Implementation considerations

Monitoring and evaluation

Research priorities

The potential for resistance to azithromycin, doxycycline and other treatment options should be investigated. Future research could compare these treatments and recommended dosages in randomized controlled trials measuring important outcomes such as clinical cure, microbiological cure, complications, side-effects (including allergy, toxicity, gastro-intestinal), compliance, quality of life, HIV transmission and acquisition, and partner transmission of chlamydia. Studies are also needed that evaluate amoxicillin (500 mg thrice a day for 7 days).

RECOMMENDATION 1 9

EVIDENCE PROFILES

Azithromycin 1 g compared to doxycycline 100 mg for uncomplicated genital (cervix, urethra) chlamydial infections in adults and adolescents Summary of findings Imprecision Study event rates (%) With doxycycline 100 mg Risk with doxycycline 100 mg With azithromycin 1 g Relative effect (95% CI) Publication bias Overall quality of evidence Anticipated absolute effects Risk difference with azithromycin 1 g

Quality assessment

No. of participants (studies) Follow-up

Risk of bias

Inconsistency

Indirectness

Microbiological cure1 not serious HIGH (0.96– 1.01) none 263/277 (94.9%) 310/328 (94.5%) RR 0.99 950 per 1000 10 fewer per 1000 (38 fewer to 10 more)

605 (8 RCTs)

not serious

Clinical cure – Men serious2 MODERATE none 188/226 (83.2%) 308/361 (85.3%) RR 0.99 (0.88– 1.12) 820 per 1000 8 fewer per 1000 (98 fewer to 98 more)

587 (4 RCTs)

not serious2

not serious

Adverse events serious2 MODERATE none 72/454 (15.9%) 98/572 (17.1%) RR 1.02 (0.72– 1.43) 150 per 1000 3 more per 1000 (42 fewer to 64 more)

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

1026 (5 RCTs)

not serious2

not serious

STI complications – not measured

Compliance – not measured

Quality of life – not measured

HIV transmission and acquisition – not measured

Partner transmission – not measured

CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio

1. The results were similar across men and women.

2. Some concern with no or unclear method of randomization, and results considered imprecise since 95% CI includes potential for more or fewer cures and adverse events.

Any dose doxycycline compared to ofloxacin for uncomplicated genital (cervix, urethra) chlamydial infections in adults and adolescents Summary of findings Imprecision With ofloxacin With doxycycline Risk with ofloxacin Publication bias Overall quality of evidence Study event rates (%) Relative effect (95% CI) Anticipated absolute effects Risk difference with any dose doxycycline

Quality assessment

No. of participants (studies) Follow-up

Risk of bias

Inconsistency

Indirectness

Microbiological cure serious1,3 MODERATE none 57/57 (100.0%) 55/59 (93.2%) RR 0.94 (0.83 to 1.08) 990 per 1000 59 fewer per 1000 (168 fewer to 79 more)

116 (2 RCTs)

not serious

Clinical cure serious1,3 LOW none 41/53 (77.4%) 32/43 (74.4%) RR 0.91 (0.73 to 1.13) 780 per 1000 70 fewer per 1000 (211 fewer to 101 more)

96 (2 RCTs)

serious

not serious

Adverse events serious4 LOW none 19/150 (12.7%) 11/147 (7.5%) RR 0.62 (0.31 to 1.24) 70 per 1000 27 fewer per 1000 (48 fewer to 17 more)

297 (2 RCTs)

serious2

not serious

STI complications – not measured

Compliance – not measured

Quality of life – not measured

HIV transmission and acquisition – not measured

Partner transmission – not measured

CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio

1. 95% CI includes potential for more or fewer cures

RECOMMENDATION 1

2. Some concern with no or unclear method of randomization

3. Few events across studies

4. 95% CI includes potential for more or fewer adverse events.

High dose azithromycin compared to lower dose of azithromycin for uncomplicated genital (cervix, urethra) chlamydial infections in adults and adolescents Summary of findings Imprecision Anticipated absolute effects Risk with lower dose of azithromycin Risk difference with high dose azithromycin With lower dose of azithromycin With high dose azithromycin Publication bias Overall quality of evidence Study event rates (%) Relative effect (95% CI)

Quality assessment

No. of participants (studies) Follow-up

Risk of bias

Inconsistency

Indirectness

Microbiological cure serious2,3 LOW none 36/46 (78.3%) 48/54 (88.9%) RR 1.12 (0.90– 1.39) 780 per 1000 94 more per 1000 (78 fewer to 304 more)

100 (1 RCT)

serious1

not serious

Clinical cure – not measured

Adverse events – not measured

STI complications – not measured

Compliance – not measured

Quality of life – not measured

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

HIV transmission and acquisition – not measured

Partner transmission – not measured

CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio

1. Some concern with no or unclear method of randomization.

2. 95% CI includes potential for more or fewer cures.

3. Few events across studies.

High dose any tetracycline compared to lower dose any tetracycline for uncomplicated genital (cervix, urethra) chlamydial infections in adults and adolescents Summary of findings Imprecision With lower dose any tetracycline With high dose any tetracycline Risk with lower dose any tetracycline Publication bias Overall quality of evidence Study event rates (%) Relative effect (95% CI) Anticipated absolute effects Risk difference with high dose any tetracycline

Quality assessment

No. of participants (studies) Follow-up

Risk of bias

Inconsistency

Indirectness

Microbiological cure serious1 MODERATE none 204/221 (92.3%) 202/217 (93.1%) RR 1.00 (0.95– 1.05) 950 per 1000 0 fewer per 1000 (48 fewer to 48 more)

438 (3 RCTs)

not serious

Clinical cure – Men serious2 LOW none 97/147 (66.0%) 119/143 (83.2%) RR 1.25 (1.10– 1.42) 660 per 1000 165 more per 1000 (66 more to 277 more)

290 (2 RCTs)

serious3

not serious

Adverse events – Men serious2 MODERATE none 132/248 (53.2%) 99/246 (40.2%) RR 0.76 (0.62– 0.92) 530 per 1000 127 fewer per 1000 (201 fewer to 42 fewer)

494 (1 RCT)

not serious

STI complications – not measured

Compliance – not measured

Quality of life – not measured

HIV transmission and acquisition – not measured

Partner transmission – not measured

CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio

RECOMMENDATION 1

1. 95% CI includes potential for more or fewer cures

2. Few events across studies.

3. Some concern with no or unclear method of randomization.

High dose any tetracycline compared to lower dose any tetracycline for uncomplicated genital (cervix, urethra) chlamydial infections in adults and adolescents Summary of findings Imprecision Anticipated absolute effects Risk with vibramycin doxycycline Risk difference with doxycycline hyclate With vibramycin doxycycline With doxycycline hyclate Publication bias Overall quality of evidence Study event rates (%) Relative effect (95% CI)

Quality assessment

No. of participants (studies) Follow-up

Risk of bias

Inconsistency

Indirectness

Microbiological cure not serious MODERATE none 159/167 (95.2%) 146/156 (93.6%) RR 0.98 (0.93– 1.04) 950 per 1000 19 fewer per 1000 (66 fewer to 38 more)

323 (1 RCT)

not serious

Clinical cure – not measured

Adverse events serious1 MODERATE none 132/248 (53.2%) 99/246 (40.2%) RR 0.76 (0.62– 0.92) 530 per 1000 127 fewer per 1000 (201 fewer to 42 fewer)

494 (1 RCT)

not serious

STI complications – not measured

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Compliance – not measured

Quality of life – not measured

HIV transmission and acquisition – not measured

Partner transmission – not measured

CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio

1. Few events across studies.

Tetracyclines compared to quinolones for uncomplicated genital (cervix, urethra) chlamydial infections in adults and adolescents Summary of findings Imprecision With quinolones With tetracyclines Risk with quinolones Publication bias Overall quality of evidence Study event rates (%) Relative effect (95% CI) Anticipated absolute effects Risk difference with tetracyclines

Quality assessment

No. of participants (studies) Follow-up

Risk of bias

Inconsistency

Indirectness

Microbiological cure not serious MODERATE none 405/418 (96.9%) 447/480 (93.1%) RR 0.97 (0.93– 1.02) 980 per 1000 29 fewer per 1000 (69 fewer to 20 more)

898 (6 RCTs)

serious1

not serious

Clinical cure – Men serious2, 3 LOW none 122/183 (66.7%) 139/259 (53.7%) RR 0.79 (0.50– 1.23) 660 per 1000 139 fewer per 1000 (330 fewer to 152 more)

442 (3 RCTs)

serious1

not serious

Adverse events serious4 LOW none 159/474 (33.5%) 166/597 (27.8%) RR 0.88 (0.50– 1.56) 160 per 1000 19 fewer per 1000 (80 fewer to 90 more)

1071 (6 RCTs)

serious1

not serious

STI complications – not measured

Compliance – not measured

Quality of life – not measured

HIV transmission and acquisition – not measured

Partner transmission – not measured

CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio

1. Some concern with no or unclear method of randomization.

RECOMMENDATION 1

2. 95% CI includes potential for more or fewer cures.

Few events across studies.

95% CI includes potential for more or fewer adverse events.

Erythromycin compared to other quinolones for uncomplicated genital (cervix, urethra) chlamydial infections in adults and adolescents Summary of findings Imprecision Anticipated absolute effects Risk with other quinolones Risk difference with erythromycin With other quinolones With erythromycin Publication bias Overall quality of evidence Study event rates (%) Relative effect (95% CI)

Quality assessment

No. of participants (studies) Follow-up

Risk of bias

Inconsistency

Indirectness

Microbiological cure serious2, 3 LOW none 88/97 (90.7%) 63/96 (65.6%) RR 0.80 (0.44 to 1.43) 900 per 1000 180 fewer per 1000 (504 fewer to 387 more)

193 (3 RCTs)

serious1

not serious

Clinical cure serious2, 3 LOW none 87/102 (85.3%) 56/93 (60.2%) RR 0.73 (0.35 to 1.52) 850 per 1000 230 fewer per 1000 (553 fewer to 442 more)

195 (2 RCTs)

serious1

not serious

Adverse events serious3, 4 LOW none 32/191 (16.8%) 71/195 (36.4%) RR 2.11 (1.19 to 3.75) 180 per 1000 200 more per 1000 (34 more to 495 more)

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

386 (4 RCTs)

serious1

not serious

STI complications – not measured

Compliance – not measured

Quality of life – not measured

HIV transmission and acquisition – not measured

Partner transmission – not measured

CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio

1. Some concern with no or unclear method of randomization.

2. 95% CI includes potential for more or fewer cures.

Few events across studies.

95% CI includes potential for more or fewer adverse events.

RECOMMENDATION 1

REFERENCES

Systematic review 1. Páez-Canro C, Martinez-Martinez F, Alzate JP, Lethaby A, Gaitán HG. Antibiotics for treating genital chlamydia trachomatis infection in men and non-pregnant women (protocol). Cochrane Database Syst Rev. 2013;(12):CD010871. Included studies 1. Bowie WR, Yu JS, Fawcett A, Jones HD. Tetracycline in nongonococcal urethritis. Comparison of 2 g and 1 g daily for seven days. Br J Vener Dis. 1980;56(5):332-6. 2. Campbell WF, Dodson MG. Clindamycin therapy for Chlamydia trachomatis in women. Am J Obstet Gynecol. 1990;162(2):343-7. 3. Cramers M, Kaspersen P, From E, Møller BR. Pivampicillin compared with erythromycin for treating women with genital Chlamydia trachomatis infection. Genitourin Med. 1988;64(4):247-8. 4. Csángó PA, Gundersen T, Anestad G. Doxycycline in the treatment of chlamydial urethritis: a therapeutic study. Pharmatherapeutica. 1980;2(5):341-5. 5. Fong IW, Linton W, Simbul M, Thorup R, McLaughlin B, Rahm V, et al. Treatment of nongonococcal urethritis with ciprofloxacin. Am J Med. 1987;82(4A):311-6. 6. Geisler WM, Koltun WD, Abdelsayed N, Burigo J, Mena L, Taylor SN, et al. Safety and efficacy of WC2031 versus vibramycin for the treatment of uncomplicated urogenital Chlamydia trachomatis infection: a randomized, double-blind, doubledummy active-controlled, multicenter trial. Clin Infect Dis. 2012;55(1):82-8. doi:10.1093/cid/cis291. 7. Guven MA, Gunyeli I, Dogan M, Ciragil P, Bakaris S, Gul M. The demographic and behavioural profile of women with cervicitis infected with Chlamydia trachomatis, Mycoplasma hominis and Ureaplasma urealyticum and the comparison of two medical regimens. Arch Gynecol Obstet. 2005;272:197-200. 8. Hammerschlag MR, Golden NH, Oh MK, Gelling M, Sturdevant M, Brown PR, et al. Single dose of azithromycin for the treatment of genital chlamydial infections in adolescents. J Pediatr. 1993;122(6):961-5 9. Hawkins DA, Taylor-Robinson D, Evans RT, Furr PM, Harris JR. Unsuccessful treatment of non-gonococcal urethritis with rosoxacin provides information on the aetiology of the disease. Genitourin Med. 1985;61(1):51-5. 10. Hooton TM, Rogers ME, Medina TG, Kuwamura LE, Ewers C, Roberts PL, et al. Ciprofloxacin compared with doxycycline for nongonococcal urethritis. Ineffectiveness against Chlamydia trachomatis due to relapsing infection. JAMA. 1990;264(11):1418-21. 11. Ibsen HH, Møller BR, Halkier-Sørensen L, From E. Treatment of nongonococcal urethritis: comparison of ofloxacin and erythromycin. Sex Transm Dis. 1989;16(1):32-5. 12. Kitchen VS, Donegan C, Ward H, Thomas B, Harris JR, TaylorRobinson D. Comparison of ofloxacin with doxycycline in the treatment of non-gonococcal urethritis and cervical chlamydial infection. J Antimicrob Chemother. 1990;26(Suppl D):99-105. 13. Lauharanta J, Saarinen K, Mustonen MT, Happonen HP. Singledose oral azithromycin versus seven-day doxycycline in the treatment of non-gonococcal urethritis in males. J Antimicrob Chemother. 1993;31(Suppl E):177-83.

14. Lister PJ, Balechandran T, Ridgway GL, Robinson AJ. Comparison of azithromycin and doxycycline in the treatment of nongonococcal urethritis in men. J Antimicrob Chemother. 1993; 31(Suppl E): 185–92. 15. Manhart LE, Gillespie CW, Lowens MS, Khosropour CM, Colombara DV, Golden MR, et al. Standard treatment regimens for nongonococcal urethritis have similar but declining cure rates: a randomized controlled trial. Clin Infect Dis. 2013;56(7):934-42. 16. Martin DH, Mroczkowski TF, Dalu ZA, McCarty J, Jones RB, Hopkins SJ, et al. A controlled trial of a single dose of azithromycin for the treatment of chlamydial urethritis and cervicitis. The Azithromycin for Chlamydial Infections Study Group. N Engl J Med. 1992; 327(13):921–5. 17. McCormack WM, Dalu ZA, Martin DH, Hook EW 3rd, Laisi R, Kell P, et al.; Trovafloxacin Chlamydial Urethritis/Cervicitis Study Group. Double-blind comparison of trovafloxacin and doxycycline in the treatment of uncomplicated chlamydial urethritis and cervicitis. Sex Transm Dis. 1999;26(9):531-6. 18. McCormack WM, Martin DH, Hook EW 3rd, Jones RB. Daily oral grepafloxacin vs. twice daily oral doxycycline in the treatment of Chlamydia trachomatis endocervical infection. Infect Dis Obstet and Gynecol. 1998;6(3):109-15. 19. Nilsen A, Halsos A, Johansen A, Hansen E, Tørud E, Moseng D, et al. A double blind study of single dose azithromycin and doxycycline in the treatment of chlamydial urethritis in males. Genitourin Med. 1992; 68(5):325-7. 20. Pereira CA, Montagnini SD. A prospective randomized trial of ofloxacin vs. doxycycline in the treatment of nongonococcal urethritis caused by Chlamydia trachomatis. Arquivos brasileiros de medicina. 1994;68(1):51-3. 21. Robson HG, Shah PP, Lalonde RG, Hayes L, Senikas VM. Comparison of rosaramicin and erythromycin stearate for treatment of cervical infection with Chlamydia trachomatis. Sex Trans Dis. 1983;10(3):130-4. 22. Stamm WE, Hicks CB, Martin DH, Leone P, Hook EW 3rd, Cooper RH, et al. Azithromycin for empirical treatment of the nongonococcal urethritis syndrome in men. A randomized double-blind study. JAMA. 1995;274(7):545-9. 23. Thambar IV, Simmons PD, Thin RN, Darougar S, Yearsley P. Double-blind comparison of two regimens in the treatment of nongonococcal urethritis. Seven-day vs 21-day course of triple tetracyclinc (Deteclo). Br J Vener Dis. 1979;55(4):284-8. 24. Topic A, Skerk V, Puntaric A, Milavec Puretic V, Beus A, Begovac J. Azithromycin: 1.0 or 3.0 gram dose in the treatment of patients with asymptomatic urogenital chlamydial infections. J Chemother. 2006;18(1):115-6. 25. van der Willigen AH, Polak-Vogelzang AA, Habbema L, Wagenvoort JH. Clinical efficacy of ciprofloxacin versus doxycycline in the treatment of non- gonococcal urethritis in males. Eur J Clin Microbiol Infect Dis. 1988;7(5):658-61.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Patient values and preferences, acceptability and cost: specific to chlamydial infections 1. Dixon-Woods M, Stokes T, Young B, Phelps K, Windridge K, Shukla R. Choosing and using services for sexual health: a qualitative study of women's views. Sex Transm Infect. 2001;77(5):335-9. 2. International drug price indicator guide, 2014 edition (updated annually). Medford (MA): Management Sciences for Health; 2015 (http://erc.msh.org/dmpguide/pdf/DrugPriceGuide_2014.pdf, accessed 3 June 2016). 3. Sahin-Hodoglugil NN, Woods R, Pettifor A, Walsh J. A comparison of cost-effectiveness of three protocols for diagnosis and treatment of gonococcal and chlamydial infections in women in Africa. Sex Transm Dis. 2003;30:455-69. Patient values and preferences, acceptability and cost: other sexually transmitted infections and conditions 1. Kingston M, Carlin E. Treatment of sexually transmitted infections with single-dose therapy: a double-edged sword. Drugs. 2002;62(6):871-8. 2. Nagarkar A, Mhaskar P. A systematic review on the prevalence and utilization of health care services for reproductive tract infections/sexually transmitted infections: evidence from India. Indian J Sex Transm Dis. 2015;36(1):18-25. doi:10.4103/02537184.156690. 3. Ryan R, Santesso N, Lowe D, Hill S, Grimshaw J, Prictor M, et al. Interventions to improve safe and effective medicines use by consumers: an overview of systematic reviews. Cochrane Database Syst Rev. 2014;4:CD007768. Additional references 1. Amin A, Garcia Moreno C. Addressing gender-based violence to reduce risk of STI and HIV. Sex Transm Infect. 2013;89(Suppl 1):A8. doi:10.1136/sextrans-2013-051184.0022. 2. Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386(9995):743-800. doi:10.1016/S0140-6736(15)60692-4. 3. Holmes K. Sexually transmitted diseases, 4th edition. New York (NY): McGraw Hill; 2008. 4. Newman L, Rowley J, Vander Hoorn S, Wijesooriya NS, Unemo M, Low N, et al. Global estimates of the prevalence and incidence of four curable sexually transmitted infections in 2012 based on systematic review and global reporting. PLoS One. 2015;10(12):e0143304. doi:10.1371/journal.pone.0143304.

RECOMMENDATION 2

RECOMMENDATION 2 Treatments in adults and adolescents with uncomplicated anorectal chlamydial infections (excluding lymphogranuloma venereum Population: Intervention: Comparison: Main outcomes: Adults and adolescents with uncomplicated anorectal chlamydial infections Azithromycin or doxycycline Other antibiotics Critical: Clinical cure, microbiological cure, STI complications, side-effects (including allergy, toxicity, gastro), compliance Important: Quality of life, HIV transmission and acquisition, partner transmission Setting: Perspective: Background: Outpatient Population The global prevalence and incidence of chlamydia in adult women and men remain high, like other STIs, with nearly one million new curable infections each day. This infection causes acute conditions such as cervicitis, urethritis and genital ulceration. The 2003 WHO guidelines recommend treatment of uncomplicated anogenital infections with either doxycycline 100 mg orally twice daily for 7 days, or azithromycin 1 g orally, in a single dose. Alternatively, amoxicillin 500 mg orally thrice daily for 7 days; erythromycin 500 mg orally four times daily for 7 days; ofloxacin 300 mg orally twice daily for 7 days; or tetracycline 500 mg orally four times daily for 7 days. The Guideline Development Group (GDG) identified azithromycin and doxycycline for comparison to other treatments for review.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

ASSESSMENT Judgement Is the problem a priority? Problem Desirable Effects Undesirable Effects Certainty of evidence Research evidence Research evidence: There is no global prevalence data for anorectal chlamydial infections. Rectal infections are rarely tested for chlamydia and usually occur concurrently with genital infections. An estimated 131 million new cases of chlamydia (100–166 million) were reported (Newman, 2012) globally in 2012, and at any point in 2012, there were about 128 million cases of chlamydia among adults aged 15–49 years. Infection can lead to severe complications and long-term sequelae, including pelvic inflammatory disease, ectopic pregnancy, infertility, chronic pelvic pain, neurological and cardiovascular disease in adults, neonatal death, premature delivery and severe disability in infants (Holmes, 2008). Furthermore, STIs, including chlamydia, frequently result in stigma, stereotyping, vulnerability and shame and have been associated with gender-based violence (Amin, 2013). Additional considerations: The GDG agreed that treatment of anorectal infections will be related to treatment of genital infections as rectal infection may be unknown and usually occurs concurrently with genital infection. While the consequences of vaginal infection are worse, anorectal infection is still a priority due to the risk of vaginal reinfection (creating a pool of infection). Antimicrobial resistance data should be considered given the risks. However, there is little research in this area. Of particular interest to some in the group is the sensitivity of chlamydia to azithromycin. The GDG also noted that this infection preferentially affects certain populations and may consequently have effects on equity, feasibility and acceptability. How substantial are the desirable anticipated effects? Research evidence: We included 8 non-randomized studies (5 direct comparisons and 3 single arms studies). These studies evaluated doxycycline and azithromycin. Doses included were azithromycin 1 g orally x 1, and doxycycline 100 mg twice daily x 7 days. The studies included primarily men, but some data (from two studies) were available from women. Additional considerations: Evidence showed that there may be 200/1000 fewer cures with azithromycin compared to doxycycline, and little-to-no difference in side-effects. Although there were fewer women in the studies, the evidence suggested little difference in the effects between men and women. However, the GDG agreed that emphasis should be placed on treating women, since they might be tested for genital but not anal infection, despite the serious potential long-term consequences. The GDG also questioned the timing of testing, which may have been short as reinfection is common. Only one patient in one trial was noted to have diarrhoea with azithromycin. However, studies in people with genital infections using doxycycline or azithromycin found few and similar numbers of side-effects (approximately 15%). Therefore this difference was considered trivial. Additional considerations: Data for clinical cure was not available, and therefore microbiological cure was used to inform clinical cure.

• • • •

No Probably no Probably yes Yes

• Varies • Don’t know

• • • •

Trivial Small Moderate Large

• Varies • Don’t know How substantial are the undesirable anticipated effects?

• • • •

Large Moderate Small Trivial

• Varies • Don’t know What is the overall certainty of the evidence of effects?

• • • •

Very low Low Moderate High

• No included studies

RECOMMENDATION 2

Is there important uncertainty about or variability in how much people value the main outcomes?

• Important uncertainty or variability

Research evidence: Qualitative studies suggest that in making the decision to seek help, women act on a range of specific prompts, including lay ideas about the significance of symptoms, their own behaviour, their partner's symptoms or behaviour, contact tracing and health promotion. Psychosocial factors, such as embarrassment, are also important. Additional considerations: The GDG agreed that women who are tested positive for rectal chlamydia would want to be treated. There were no known reasons to believe that the values of outcomes would vary, and the group placed emphasis on the need to remove the infection from the community in general. The panel considered noting screening for anorectal infections in men who have sex with men (MSM), transgender women and other at-risk populations, but this was decided against due to the sensitivity required in many settings concerning these populations. Additional considerations: The GDG agreed that the greater benefits and little-to-no difference in side-effects with doxycycline, favoured doxycycline over azithromycin.

Values Balance of effects Resources required

• Possibly important uncertainty or variability • Probably no important uncertainty or variability • No important uncertainty or variability • No known undesirable outcomes

Does the balance between desirable and undesirable effects favour the intervention or the comparison?

• Favours the comparison • Probably favours the comparison

• Does not favour either the intervention or the comparison • Probably favours the intervention • Favours the intervention

• Varies • Don’t know How large are the resource requirements (costs)? A Azithromycin 1 g po Doxycycline 100 mg po Doxycycline (ER) 200 mg po Erythromycin ES 800 mg po Erythromycin 500 mg po Amoxicillin 500 mg po Quinolones po B 1 2 1 4 2 3 C 1 7 7 7 10-14 7 D* $0.38 (500 mg) $0.0191 n.a. n.a. $0.0738 $0.032 n.a. E $0.76 $0.2674 n.a. n.a. $1.476 – $2.06 $0.672 n.a. F $0.95 $0.3342 n.a. n.a. $1.88 – $2.57 $0.84 n.a.

• • • • •

Large costs Moderate costs Negligible costs and savings Moderate savings Large savings

• Varies • Don’t know

*Sources: International drug price indicator guide (MSH, 2015) and www.drugs.com A: treatment; B: dose per day; C: treatment duration; D: drug cost, per dose; E: drug per full-course treatment; F: 25% procurement

Additional considerations: The GDG agreed that azithromycin is more expensive than doxycycline, and since globally, most STI drugs come from out-of-pocket payments, this should be the primary consideration, rather than what governments or donors are willing to pay.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

What is the certainty of the evidence of resource requirements (costs)?

Research evidence: No studies of resource requirements were found. Additional considerations: None

Certainty of evidence of required resources Cost–effectiveness Equity

• • • •

Very low Low Moderate High

• No included studies Does the cost-effectiveness of the intervention favour the intervention or the comparison? Research evidence: No cost-effectiveness studies were found. Additional considerations: Similar to issues related to genital chlamydial infections, the GDG stated that cost was the main factor driving effectiveness, as it dictated how many patients could access treatment, and if a patient could afford a full course of treatment. In addition, there may be a greater number of cures with doxycycline, resulting in higher cost-effectiveness compared to azithromycin.

• Favours the comparison • Probably favours the comparison

• Does not favour either the intervention or the comparison • Probably favours the intervention • Favours the intervention

• Varies • No included studies What would be the impact on health equity? Research evidence: No studies assessed equity issues. Additional considerations: The GDG noted that azithromycin is not on the essential medicines list for rectal infections and is only regarded as essential for genital infections. However, it was mentioned that currently this is being reviewed. One barrier is that the essential medicines list requires evidence for particular uses, and as such, research was required for rectal infections. An opinion emerged that, by being unavailable for anorectal infections, azithromycin may be more expensive than it would otherwise be. It was suggested that multi-dose regimens (like doxycycline) may reduce equity because of a stigma surrounding taking treatments, but this may vary across different populations including MSM, transgender patients and young women at increased risk of anorectal infections. More research is needed.

• • • • •

Reduced Probably reduced Probably no impact Probably increased Increased

• Varies • Don’t know

RECOMMENDATION 2

Is the intervention acceptable to key stakeholders?

• • • •

No Probably no Probably yes Yes

• Varies • Don’t know

Research evidence: A systematic review (in India) of the literature for treatment utilization in STIs reported that utilization ranged from 16% to 55% in community-based studies, and was higher (approximately 70%) in research trials. Treatment may not be acceptable to patients due to the resources and availability of services, social factors, and distance from a clinic. Non-utilization was also due to ignorance, illiteracy and lack of awareness. Women reported a lack of female doctors, being afraid of results, judgement from doctors, stigma, shyness and embarrassment. Cost of care and lack of faith in clinical care were also factors. An overview of reviews of medication adherence (Ryan, 2014) reported that adherence may be improved with simpler drug regimens. Additional considerations: The GDG agreed that one dose of azithromycin would be more acceptable than a course of doxycycline twice daily for 7 days. The GDG also discussed the need for sexual abstinence during treatment. It was noted that for azithromycin therapy, sexual abstinence may be more important than with doxycycline treatment in avoiding reinfection, as the prolonged doxycycline concentration could maintain some protection throughout the course of the treatment. However, there is no clear evidence for these effects.

Acceptability Feasibility

Is the intervention feasible to implement?

Research evidence: We found no studies assessing feasibility issues. Additional considerations: The GDG noted that important social considerations were needed for adolescent girls (and other populations), due to difficulties in bringing therapy home. The importance of including the existing prevalence data for subpopulations in these considerations was indicated by the GDG, as it is rare to know if a person has anorectal as well as genital chlamydia. It was asserted that the recommendations should explicitly mention that treatment varies between settings where only presumptive treatment of anorectal infection is possible, and settings where anorectal infections can be tested.

• • • •

No Probably no Probably yes Yes

• Varies • Don’t know

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Balance of effects

Resources required Certainty of evidence of required resources Cost– effectiveness

Large costs

Moderate costs Low

Moderate savings High

Large savings

Varies

Don’t know

Very low

No included studies

Favours the comparison

Probably favours the comparison

Does not favour either the intervention or the comparison Probably no impact Probably yes Probably yes

Probably favours the intervention

Favours the intervention

Varies

No included studies

Equity Acceptability Feasibility

Reduced No No

Probably reduced Probably no Probably no

Probably increased Yes Yes

Increased

Varies Varies Varies

Don’t know Don’t know Don’t know

CONCLUSIONS

Treatments for uncomplicated anorectal chlamydial infections (excluding lymphogranuloma venereum)? Conditional recommendation against the intervention • • Conditional recommendation for either the intervention or the comparison Conditional recommendation for the intervention Strong recommendation for the intervention

Type of recommendation

Strong recommendation against the intervention

•

• •

Recommendation

In people with anorectal chlamydial infection, the WHO STI guideline suggests using doxycycline 100 mg twice daily for 7 days over azithromycin 1 g single dose. Conditional recommendation, very low quality evidence.

Remarks: This recommendation applies to people with known anorectal infection and to people with suspected anorectal infections with genital coinfection. Clinicians should ask men, women and key populations, such as MSM, transgender persons and female sex workers about anal sex and treat accordingly. Doxycycline should not be used in pregnant women because of adverse effects. (see Recommendation 3).

Justification

There is low quality evidence from 8 non-randomized studies (5 direct comparisons and 3 single arms studies) that evaluated doxycycline and azithromycin. There is no data for amoxicillin, erythromycin, or quinolones. Evidence showed that there may be 200/1000 fewer people with microbiological cure with azithromycin compared with doxycycline (RR 0.80, 95% CI: 0.71 to 0.91). Evidence in studies of genital infections shows little to no difference in side-effects with these treatments (RR 1.02, 95% CI: 0.72 to 1.43). Although there are fewer women in the studies, the evidence suggested little difference in effects between men and women.

There is no evidence for patient values and preferences, but the GDG agreed that there are no known reasons to suspect values would vary between different people. There is little-to-no evidence for acceptability, but research into other conditions indicates that adherence may be improved with simpler drug regimens. There is little-to-no evidence for equity issues and feasibility, but azithromycin is more expensive and typically the cost is paid by the consumers. The GDG agreed that equity may vary between the medicines depending on the population; in some populations, azithromycin may be more acceptable since it is a single-dose treatment, and some people may experience stigma related to visibility of a multi-dose regimen with doxycycline. Therefore, suggesting doxycycline over azithromycin could create inequity for people sensitive to stigma related to multi-doses. Azithromycin is currently not listed as an essential drug for anorectal chlamydial infection.

In summary, doxycycline may result in more cures, and although less expensive than azithromycin, azithromycin may be better accepted due to single dose treatment.

RECOMMENDATION 2 25

CONCLUSIONS

Type of recommendation

Strong recommendation against the intervention

•

• •

Subgroup considerations

Implementation considerations

Monitoring and evaluation

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Research priorities

The global incidence of chlamydial anorectal infections should be determined. More research is necessary on the effects of treatments used for anorectal infections, in particular azithromycin, as it is currently not on the WHO Essential Medicines list for anorectal chlamydial infections. Effects should be assessed in both men and women and in key populations (including MSM, transgender persons and female sex workers).

EVIDENCE PROFILE

Should azithromycin or doxycycline vs other antibiotics be used for anorectal chlamydial infections in adults and adolescents? Erythromycin 500 mg po bid x 10–14 days No study found No study found No study found No study found No study found Erythromycin ES 800 mg po qd x 7 days Erythromycin 500 mg po qd x 7 days Doxycycline (ER) 200 mg qd x 7 days Quinolones Amoxicillin 500 mg po tid x 7 days No study found

Outcomes

Azithromycin 1 g po x 1 dose

Doxycycline 100 mg bid x 7 days

Microbiological cure

RR 0.80 (95% CI: 0.71–0.91)

198 fewer cures (from 287 fewer to 89 fewer)

LOW

Quality of evidence

275/347

298/303

840 per 1000 (810–880)

990 per 10004 (980–1010)

372/461 (7 non-RCTs)

395/401 (5 non-RCTs)

VERY LOW 2, 3 No study found No study found No study found

Side-effects (including allergy, toxicity, gastrointestinal)

1 study reported one patient in the azithromycin cohort had diarrhoea

Not reported

Quality of evidence

LOW 3, 4

Risk of bias

RECOMMENDATION 2 27

Should azithromycin or doxycycline vs other antibiotics be used for anorectal chlamydial infections in adults and adolescents? Erythromycin 500 mg po bid x 10–14 days Erythromycin ES 800 mg po qd x 7 days Erythromycin 500 mg po qd x 7 days Doxycycline (ER) 200 mg qd x 7 days Quinolones Amoxicillin 500 mg po tid x 7 days

Outcomes

Azithromycin 1 g po x 1 dose

Doxycycline 100 mg bid x 7 days

Clinical cure – Not measured

STI complications – Not measured

Transmission to partners – Not measured

Compliance – Not measured

HIV transmission and acquisition – Not measured

Quality of life – Not measured

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

bid: twice daily; ER: extended release; ES: ethylsuccinate; po: by mouth (orally); qd: daily; RCT: randomized controlled trial; tid: thrice daily

1. Most studies with unclear risk of bias criteria due to poor reporting.

2. 1 arm of the study was considered, and authors did not mention any information related to the use of an appropriate analysis method that adjusted for all the critically important confounding domain.

Few participants.

Selectively reported outcome.

RECOMMENDATION 2

REFERENCES

Systematic review 1. Kong FY, Tabrizi SN, Fairley CK, Vodstrcil LA, Huston WM, Chen M, et al. The efficacy of azithromycin and doxycycline for the treatment of rectal chlamydia infection: a systematic review and meta-analysis. J Antimicrob Chemother. 2015;70(5):1290-7. doi:10.1093/jac/dku574. Included studies 1. Ding A, Challenor R. Rectal chlamydia in heterosexual women: more questions than answers. Int J STD AIDS. 2014. 25(8):58792. doi:10.1177/0956462413515637. 2. Drummond F, Ryder N, Wand H, Guy R, Read P, McNulty AM, et al. Is azithromycin adequate treatment for asymptomatic rectal chlamydia? Int J STD AIDS. 2011;22(8):478-80. doi:10.1258/ ijsa.2011.010490. 3. Elgalib A, Alexander S, Tong CY, White JA. Seven days of doxycycline is an effective treatment for asymptomatic rectal Chlamydia trachomatis infection. Int J STD AIDS. 2011;22(8): 474-7. doi:10.1258/ijsa.2011.011134. 4. Hathorn E, Opie C, Goold P. What is the appropriate treatment for the management of rectal Chlamydia trachomatis in men and women? Sex Trans Infect. 2012;88(5):352-4. doi:10.1136/ sextrans-2011-050466. 5. Khosropour CM, Dombrowski JC, Barbee LA, Manhart LE, Golden MR. Comparing azithromycin and doxycycline for the treatment of rectal chlamydial infection: a retrospective cohort study. Sex Transm Dis. 2014;41(2):79-85. doi:10.1097/ OLQ.0000000000000088. 6. Khosropour CM, Duan R, Metsch LR, Feaster DJ, Golden MR. Persistent/recurrent chlamydial infection among STD clinic patients treated with CDC-recommended therapies. Abstracts of the STI and AIDS World Congress, Vienna, Austria. Sex Transm Infect. 2013;89(suppl 1):A29. doi:10.1136/ sextrans-2013-051184.0092. 7. Steedman NM, McMillan A. Treatment of asymptomatic rectal Chlamydia trachomatis: is single-dose azithromycin effective? Int J STD AIDS. 2009;20(1):16-8. doi:10.1258/ijsa.2008.008211. 8. White JA. Manifestations and management of lymphogranuloma venereum. Curr Opin Infect Dis. 2009;22(1):57-66. doi:10.1097/ QCO.0b013e328320a8ae. Patient values and preferences, acceptability and cost: specific to chlamydial infections 1. Dixon-Woods M, Stokes T, Young B, Phelps K, Windridge K, Shukla R. Choosing and using services for sexual health: a qualitative study of women's views. Sex Transm Infect. 2001;77(5):335-9. 2. International drug price indicator guide, 2014 edition (updated annually). Medford (MA): Management Sciences for Health; 2015 (http://erc.msh.org/dmpguide/pdf/DrugPriceGuide_2014.pdf, accessed 3 June 2016).

Patient values and preferences, acceptability and cost: other sexually transmitted infections and conditions 1. Nagarkar A, Mhaskar P. A systematic review on the prevalence and utilization of health care services for reproductive tract infections/sexually transmitted infections: evidence from India. Indian J Sex Transm Dis. 2015;36(1):18-25. doi:10.4103/02537184.156690. 2. Ryan R, Santesso N, Lowe D, Hill S, Grimshaw J, Prictor M, et al. Interventions to improve safe and effective medicines use by consumers: an overview of systematic reviews. Cochrane Database Syst Rev. 2014;4:CD007768. Additional references 1. Amin A, Garcia Moreno C. Addressing gender-based violence to reduce risk of STI and HIV. Sex Transm Infect. 2013;89 (Suppl 1):A8. 2. Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386(9995):743-800. doi:10.1016/S0140-6736(15)60692-4. 3. Holmes K. Sexually transmitted diseases, 4th edition. New York (NY): McGraw Hill; 2008. 4. Newman L, Rowley J, Vander Hoorn S, Wijesooriya NS, Unemo M, Low N, et al. Global estimates of the prevalence and incidence of four curable sexually transmitted infections in 2012 based on systematic review and global reporting. PLoS One. 2015;10(12):e0143304. doi:10.1371/journal.pone.0143304.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

RECOMMENDATION 3 Treatments in pregnant women with chlamydial infections Population: Intervention: Comparison: Main outcomes: Chlamydial infections in pregnant women Azithromycin or erythromycin Other antibiotics Critical: Fetal outcomes (e.g. teratogenicity, toxicity), fetal loss,prematurity/low birth weight (LBW), chorioamnionitis, infant pneumonitis/ neonatal ophthalmia, postpartum endometritis, microbiological cure, side-effects (including allergy, toxicity, gastro), clinical cure (symptoms), compliance Important: HIV acquisition, quality of life, transmission to partner Setting: Perspective: Background: Out- or inpatient Population Chlamydia is a STI that can cause eye or lung infections in the newborn infant if the mother is infected during pregnancy or labour. Postpartum endometritis has also been associated with chlamydial infection. The 2003 WHO Guidelines recommend treatment of chlamydial infections during pregnancy with erythromycin 500 mg orally four times daily or 7 days or amoxicillin 500 mg orally thrice daily for 7 days. The Guideline Development Group (GDG) identified azithromycin and erythromycin for comparison to other treatments for review.

RECOMMENDATION 3

ASSESSMENT

Judgement Is the problem a priority? Problem Desirable Effects Undesirable Effects Certainty of evidence

Research evidence Research evidence: According to 2013 Global Burden of Disease estimates, chlamydia was the 10th most common incident condition. Mother-to-child transmission can occur at the time of delivery and may result in ophthalmia neonatorum or pneumonitis in the neonate. Estimates of the risk of transmission at the time of delivery vary. The risk of mother-to- child transmission resulting in moderate to severe conjunctivitis appears to be approximately 15% to 25% and for pneumonitis or infection of the lungs the risk is 5% to 15%. Mothers may also be at increased risk of infection of the uterus (Brocklehurst, 2013). Furthermore, STIs, including chlamydia, frequently result in stigma, stereotyping, vulnerability and shame, and have been associated with gender-based violence (Amin, 2013). Additional considerations: None

• • • •

No Probably no Probably yes Yes

• Varies • Don’t know

How substantial are the desirable anticipated effects?

• • • •

Trivial Small Moderate Large

Research evidence: We included a systematic review of 11 randomized controlled trials published up to January 1998 and found an additional 3 trials. There were two additional nonrandomized studies with over 100 pregnant women included. See the evidence profile below for the summary of the results. Additional considerations: The differences in benefits between the different treatments were small and confidence intervals used included the possibility of more benefit and less benefit. There are probably 95/1000 more microbiological cures with azithromycin versus erythromycin; and may be 72/1000 more microbiological cures with azithromycin versus amoxicillin. There are probably 40 fewer cures with erythromycin versus amoxicillin. There may be slightly fewer side-effects with azithromycin compared to erythromycin or amoxicillin (approximately 50/1000), but there may be more sideeffects with erythromycin versus amoxicillin. Much of the evidence was uncertain for fetal outcomes, as it came from indirect comparisons in large cohort studies. There were few events, and confidence intervals around the small differences included the potential for fewer or more events between comparisons. The GDG noted that adverse events may depend on the stage of pregnancy, but this was not investigated in studies. Additional considerations: There was moderate-to-low quality evidence for the desirable effects, but lowto-very-low quality evidence for the side-effects and fetal outcomes. However, the fetal outcomes with very low quality evidence did not change the direction of the recommendation and so the evidence was assessed as low quality.

• Varies • Don’t know

How substantial are the undesirable anticipated effects?

• • • •

Large Moderate Small Trivial

• Varies • Don’t know What is the overall certainty of the evidence of effects?

• • • •

Very low Low Moderate High

• No included studies

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Is there important uncertainty about or variability in how much people value the main outcomes?

• Important uncertainty or variability

• Possibly important uncertainty or variability

• Probably no important uncertainty or variability

Research evidence: According to economic evaluation studies, the disutilities of different health states related to chlamydia (utility loss due to the health states), are as following: Pelvic inflammatory disease (outpatient): –0.37 Pelvic inflammatory disease (inpatient): –0.43 Ectopic pregnancy: –0.42 Chronic pelvic pain: –0.4 Neonatal conjunctivitis: –0.03 Neonatal pneumonia: –0.21 Qualitative studies suggest that in making the decision to seek help, women act on a range of specific prompts, including lay ideas about the significance of symptoms, their own behaviour, their partner's symptoms or behaviour, contact tracing and health promotion. Psychosocial factors, such as embarrassment, are also important. Additional considerations: The GDG was confident that pregnant women values would not vary.

Values Balance of effects Resources required

• No important uncertainty or variability

• No known undesirable outcomes

Does the balance between desirable and undesirable effects favour the intervention or the comparison?

Additional considerations: Azithromycin vs erythromycin: Favours azithromycin Azithromycin vs amoxicillin: Probably favours azithromycin Erythromycin vs amoxicillin: Probably favours amoxicillin

• F avours the comparison • Probably favours the comparison

• Does not favour either the intervention or the comparison • Probably favours the intervention • Favours the intervention

• Varies • Don’t know How large are the resource requirements (costs)? A Azithromycin 1 g po (orally) Erythromycin 500 mg po Amoxicillin 500 mg po Erythromycin 500 mg po Erythromycin 250 mg po Erythromycin ES 800 mg po Erythromycin ES 400 mg po B 1 4 3 2 4 4 4 C 1 7 7 14 14 7 14 D* $0.38 (500 mg) $0.0738 $0.032 $0.0738 $0.0428 n.a. n.a. E $0.76 $2.06 $0.672 $2.06 $2.39 n.a. n.a. F $0.95 $2.57 $0.84 $2.57 $2.98 n.a. n.a.

• • • • •

Large costs Moderate costs Negligible costs and savings Moderate savings Large savings

• Varies • Don’t know

* Sources: International drug price indicator guide (MSH, 2015) and www.drugs.com A: treatment; B: dose per day; C: treatment duration; D: drug cost, per dose; E: drug per full-course treatment; F: 25% procurement

In a systematic review (Pitsouni, 2007) of treatments for chlamydia in pregnant women, 3/7 studies measured costs. All three reported greater total costs of therapy with azithromycin versus amoxicillin or erythromycin. Additional considerations: Azithromycin vs erythromycin: Being cheaper than erythromycin, it was thought that azithromycin would have savings. Azithromycin vs amoxicillin: There is no large cost differential between azithromycin and amoxicillin. The GDG indicated that amoxicillin is slightly cheaper than azithromycin, easier to source, and could therefore have a smaller impact on resources.

RECOMMENDATION 3

What is the certainty of the evidence of resource requirements (costs)?

We found no studies assessing the resource use with these treatments

Certainty of evidence of required resources Cost–effectiveness Equity

• • • •

Very low Low Moderate High

• No included studies Does the cost-effectiveness of the intervention favour the intervention or the comparison? Research evidence: Although, there were many studies assessing costs of screening for chlamydia, there were no recent studies focused on cost of treatment. Resource factors in other models included index patient interview, record search, field visit, STD evaluation, treatment with dose of drug, expected late detection costs, investigation of the partner’s sexual partners, infection cost, disease intervention and specialist time/cost. Patient variability to consider: probability of care being sought, probability of consent to treatment, probability of adherence to referral, and probability of partner seeking care. Additional considerations: The GDG agreed that cost-effectiveness probably favours azithromycin over erythromycin, because it is more effective and it is cheaper. Cost-effectiveness also probably favours azithromycin over amoxicillin due to effectiveness. Amoxicillin may be more cost-effective than erythromycin because it costs less, is more effective and leads to fewer side-effects. Research evidence: We found no research evidence for equity issues. Additional considerations: The GDG identified that azithromycin may not be accessible in many settings and suggested that equity would decrease in these settings. In areas where azithromycin is unavailable, penicillin allergies pose equity problems, and erythromycin would therefore be the next best treatment.

• Favours the comparison • Probably favours the comparison

• Does not favour either the intervention or the comparison • Probably favours the intervention

• Favours the intervention • Varies • No included studies What would be the impact on health equity?

• • • • •

Reduced Probably reduced Probably no impact Probably increased Increased

• Varies • Don’t know

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Is the intervention acceptable to key stakeholders?

• • • •

No Probably no Probably yes Yes

• Varies • Don’t know

Research evidence: A systematic review of treatments for chlamydia in pregnant women analysed compliance across studies. Patients treated with azithromycin compared with erythromycin showed better compliance (374 patients, 6 RCTs): odds ratio (OR) 23.7 (95% CI: 9.34–60.14). Patients treated with azithromycin compared with erythromycin or amoxicillin showed better compliance (413 patients, 7 RCTs): OR = 21.96, 95% CI 9.05–53.3). An overview of reviews of medication adherence (Ryan, 2014) reported that adherence may be improved with simpler drug regimens. A systematic review (in India) of the literature for treatment utilization in STIs reported that utilization ranged from 16% to 55% in community-based studies and was higher (approximately 70%) in research trials. Treatment may not be acceptable to patients due to the resources and availability of services, social factors and distance from a clinic. Non-utilization was also due to ignorance, illiteracy and lack of awareness. Women reported a lack of female doctors, being afraid of results, judgement from doctors, stigma, shyness and embarrassment. Cost of care and lack of faith in clinical care were also factors. Additional considerations: The GDG noted that azithromycin may have better adherence, resulting in better effect in studies. The side-effects for erythromycin may make it a less acceptable treatment than amoxicillin, provided no allergies.

Acceptability Feasibility

Is the intervention feasible to implement?

Research evidence: We found no studies assessing feasibility. Additional considerations: The GDG believed that in countries where azithromycin is not being procured, it is generally due to a belief that it is more expensive, which is not true.

• • • •

No Probably no Probably yes Yes

• Varies • Don’t know

RECOMMENDATION 3

Balance of effects

Resources required Certainty of evidence of required resources Cost– effectiveness

Large costs

Moderate costs Low

Moderate savings High

Large savings

Varies

Don’t know

Very low

No included studies

Favours the comparison

Probably favours the comparison

Does not favour either the intervention or the comparison Probably no impact Probably yes Probably yes

Probably favours the intervention

Favours the intervention

Varies

No included studies

Equity Acceptability Feasibility

Reduced No No

Probably reduced Probably no Probably no

Probably increased Yes Yes

Increased

Varies Varies Varies

Don’t know Don’t know Don’t know

CONCLUSIONS

Treatments for adults and adolescents, and pregnant women with late syphilis Conditional recommendation against the intervention • • • Conditional recommendation for either the intervention or the comparison Conditional recommendation for the intervention Strong recommendation for the intervention

Type of recommendation

Strong recommendation against the intervention

•

Recommendation

Recommendation 3a

In pregnant women with genital chlamydial infection, the WHO STI guideline recommends using azithromycin over erythromycin. Strong recommendation, moderate quality evidence

Recommendation 3b In pregnant women with genital chlamydial infection, the WHO STI guideline suggests using azithromycin over amoxicillin. Conditional recommendation, low quality evidence

Recommendation 3c In pregnant women with genital chlamydial infection, the WHO STI guideline suggests using amoxicillin over erythromycin. Conditional recommendation, low quality evidence

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Dosages:

• Azithromycin 1 g as a single dose • Amoxicillin 500 mg 3 × a day × 7 days • Erythromycin 500 mg twice a day × 7 days

Remarks: Azithromycin is the first choice of treatment, but it may not be available in some settings. However, it is less expensive than erythromycin and since it is provided as a single dose this may result in better adherence and by extension better outcomes.

Type of recommendation Conditional recommendation against the intervention • • • Conditional recommendation for either the intervention or the comparison Conditional recommendation for the intervention Strong recommendation for the intervention

Strong recommendation against the intervention

•

Justification

Overall, there is moderate-to-low quality evidence from 14 RCTs, 2 non-randomized comparative studies and 2 large cohort studies assessing the effects of azithromycin, erythromycin and amoxicillin in pregnant women with chlamydial infections. The difference in benefits between these different treatments is small and wide confidence intervals included the possibility of greater or less benefit

with azithromycin compared to other drugs. Moderate quality evidence found that there are probably 94/1000 more people microbiologically cured with azithromycin versus erythromycin (RR 1.11; 95% CI: 0.94–1.30), and low-quality evidence found that there may be 72/1000 more people cured with azithromycin versus amoxicillin (RR 1.09, 95%CI: 0.93–1.28). There are probably 40 fewer people microbiologically cured with erythromycin versus amoxicillin (RR 0.95; 95% CI: 0.88–1.02).

There may be slightly fewer side-effects with azithromycin compared with erythromycin or amoxicillin (approximately 50/1000 fewer), but there may be more side-effects with erythromycin versus amoxicillin (approximately 400/1000 more).

Much of the evidence was uncertain for fetal outcomes as it came from indirect comparisons in large cohort studies. There were few events and confidence intervals around the small differences and included the potential for fewer or more events between comparisons.

In summary, the GDG agreed azithromycin would be preferred over erythromycin because of greater effectiveness and lower cost, and preferred over amoxicillin due to greater effectiveness. Azithromycin may also be more acceptable due to single dosage; however, it may not be available in all settings due to misconceptions that it is costly. Amoxicillin is preferred over erythromycin as it is less costly and may result in greater benefits and fewer side-effects.

The GDG judged the benefits of treatment with benzathine penicillin G versus no treatment as large, based on the historically successful treatment of syphilis over the past 70 years. It was also judged that the differences in benefits between medicines used for treatment are likely to be trivial. The differences in the undesirable anticipated effects (side-effects) were judged to be small. Because the benefits probably outweigh the harms, and because of the potential for resistance to azithromycin, greater cost and lack of historical data for azithromycin, benzathine penicillin G and procaine penicillin were suggested. The penicillins were suggested over doxycycline due to the lack of historical data in late syphilis and unknown side-effects and benefits of doxycycline. For pregnant women, the penicillins were also suggested over erythromycin since erythromycin does not cross the placental barrier. The GDG also judged administration of benzathine and procaine penicillins by injection as being acceptable to most people.

Subgroup considerations

Implementation considerations

Monitoring and evaluation

RECOMMENDATION 3

Research priorities

Research in pregnant women comparing these treatments and the recommended dosages should be conducted. Although these drugs are relatively safe in pregnancy, maternal and fetal complications (e.g. adverse pregnancy outcome, fetal defects) with the use of these treatments for STIs and other infections should be monitored, collected and analysed to inform these recommendations in the future. When conducting these studies, costs and acceptability of the treatments could be measured.

EVIDENCE PROFILE

Chlamydia in pregnant women

Azithromycin versus erythromycin Summary of findings Imprecision With erythromycin With azithromycin Risk with other erythromycin Publication bias Overall quality of evidence Study event rates (%) Relative effect (95% CI) Anticipated absolute effects Risk difference with azithromycin

Quality assessment

No. of participants (studies) Follow-up

Risk of bias

Inconsistency

Indirectness

Microbiological cure serious1, 2 MODERATE none 118/145 (81.4%) 134/145 (92.4%) RR 1.11 (0.94– 1.30) 850 per 1000 94 more per 1000 (51 fewer to 255 more) 850 per 1000 RR 1.51 (1.15– 1.99) 434 more per 1000 (127 more to 842 more) 137/141 (97.2%)

290 (4 RCTs)

not serious

169 (1 non-RCT) VERY LOW

serious3

not serious

serious1

none

18/28 (64.3%)

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Side-effects sufficient to stop treatment serious1, MODERATE none 13/80 (16.3%) 1/80 (1.3%) Low 50 per 1000 45 fewer per 1000 (49 fewer to 21 fewer) High 100 per 1000 89 fewer per 1000 (98 fewer to 41 fewer) RR 0.11 (0.02– 0.59)

160 (3 RCTs)

not serious

Azithromycin versus erythromycin (continued) Summary of findings Imprecision With erythromycin With azithromycin Risk with other erythromycin Publication bias Overall quality of evidence Study event rates (%) Relative effect (95% CI) Anticipated absolute effects Risk difference with azithromycin

Quality assessment

No. of participants (studies) Follow-up

Risk of bias

Inconsistency

Indirectness

Side-effects not sufficient to stop treatment serious1 MODERATE none 92/144 (63.9%) 21/145 (14.5%) RR 0.26 (0.16– 0.42) 400 per 1000 296 fewer per 1000 (336 fewer to 232 fewer)

289 (4 RCTs)

not serious

Fetal anomalies very serious1,5,6 VERY LOW none 1/65 (1.5%) 1/65 (1.5%) RR 1.00 (0.06– 15.65) 15 per 1000 0 fewer per 1000 (14 fewer to 186 more)

130 (1 RCT)

serious4

not serious

Delivery < 37 weeks very serious1,5,6 VERY LOW none 8/65 (12.3%) 6/65 (9.2%) RR 0.75 (0.28– 2.04) 110 per 1000 28 fewer per 1000 (79 fewer to 114 more) 8332/131967 (6.3%) 60 per 1000

130 (1 RCT)

serious4

not serious

serious3 not serious VERY LOW none

138 792 (2 observational studies)

not serious

530/6825 (7.8%)

RR 1.03 (0.94– 1.13)

2 more per 1000 (4 fewer to 8 more)

RECOMMENDATION 3 39

Azithromycin versus erythromycin (continued) Summary of findings Imprecision Anticipated absolute effects Risk with other erythromycin Risk difference with azithromycin With erythromycin With azithromycin Publication bias Overall quality of evidence Study event rates (%) Relative effect (95% CI)

Quality assessment

No. of participants (studies) Follow-up

Risk of bias

Inconsistency

Indirectness

Neonatal mortality/fetal loss very serious1,5 VERY LOW none VERY LOW 86/6780 (1.3%) 1186/131915 (0.9%) RR 1.19 (0.93– 1.52) not serious none 0/65 (1.5%) 0/65 (1.5%) 0 events , Not estimable 7 per 1000 1 more per 1000 (0 fewer to 4 more)

130 (1 RCT)

serious4

not serious

138 695 (2 observational studies)

serious3

not serious

Maternal postpartum endometritis and chorioamnionitis (non-RCT) serious1, 6 VERY LOW none 1/32 (3.1%) 3/178 (1.7%) RR 0.54 (0.06– 5.02) 31 per 1000 14 fewer per 1000 (29 fewer to 126 more)

210 (1 observational study)

serious3

not serious

Clinical cure – not measured

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Compliance – not measured

HIV acquisition – not measured

Quality of life – not measured

Transmission to partner – not measured

CI: confidence interval; OR: odds ratio; RR: risk ratio

Azithromycin versus amoxicillin Summary of findings Imprecision Study event rates (%) With erythromycin With azithromycin Risk with other erythromycin Relative effect (95% CI) Publication bias Overall quality of evidence Anticipated absolute effects Risk difference with azithromycin

Microbiological cure

No. of participants (studies) Follow-up

Risk of bias

Inconsistency

Indirectness

Neonatal mortality/fetal loss very serious1,2 LOW none 59/85 (69.4%) 62/83 (74.7%) RR 1.09 (0.93– 1.28) 800 per 1000 72 more per 1000 (56 fewer to 224 more) 800 per 1000

168 (2 RCTs)

not serious

162 (1 non-RCT) VERY LOW

serious3

not serious

serious2

none

20/21 (95.2%)

137/141 (97.2%)

RR 1.02 (0.92– 1.13)

16 more per 1000 (64 fewer to 104 more)

Side-effects sufficient to stop treatment very serious1,5, 6 LOW none 6/63 (9.5%) 3/66 (4.5%) RR 0.48 (0.12– 1.83) 100 per 1000 52 fewer per 1000 (88 fewer to 83 more)

129 (1 RCT)

not serious

Side-effects not sufficient to stop treatment very serious1,5, 6 LOW none 10/20 (50.0%) 5/19 (26.3%) RR 0.53 (0.22– 1.26) 500 per 1000 235 fewer per 1000 (390 fewer to 130 more)

39 (1 RCT)

not serious

Delivery < 37 weeks not serious none VERY LOW 634/6780 (6.3%) 8332/131,967 (6.3%) RR 0.96 (0.89– 1.04) 64 per 1000 3 fewer per 1000 (7 fewer to 3 more) RECOMMENDATION 3

138,792 (2 observational studies)

serious3

not serious

Azithromycin versus amoxicillin (continued) Summary of findings Imprecision Anticipated absolute effects Risk with other erythromycin Risk difference with azithromycin With erythromycin With azithromycin Publication bias Overall quality of evidence Study event rates (%) Relative effect (95% CI)

Quality assessment

No. of participants (studies) Follow-up

Risk of bias

Inconsistency

Indirectness

Neonatal mortality/fetal loss not serious VERY LOW none 86/6780 (1.3%) 1186/131,915 (0.9%) RR 1.19 (0.93– 1.52) 9 per 1000 2 more per 1000 (1 fewer to 5 more)

138,695 (2 observational studies)

serious3

not serious

Maternal postpartum endometritis and chorioamnionitis (non-RCT) serious1, 6 VERY LOW none 0/22 (0.0%) 3/178 (1.7%) RR 0.90 (0.05– 16.86)

210 (1 observational study)

serious3

not serious

Clinical cure – not measured

Compliance – not measured

HIV acquisition – not measured

Quality of life – not measured

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Transmission to partner – not measured

CI: confidence interval; OR: odds ratio; RR: risk ratio

Erythromycin versus amoxicillin Summary of findings Imprecision With erythromycin With azithromycin Risk with other erythromycin Publication bias Overall quality of evidence Study event rates (%) Relative effect (95% CI) Anticipated absolute effects Risk difference with azithromycin

Quality assessment

No. of participants (studies) Follow-up

Risk of bias

Inconsistency

Indirectness

Microbiological cure serious2 MODERATE none 182/199 (91.5%) 163/191 (85.3%) RR 0.95 (0.88 to 1.02) 800 per 1000 40 fewer per 1000 (96 fewer to 16 more)

390 (3 RCTs)

not serious

Microbiological cure serious1,2 VERY LOW none 83/85 (97.6%) 73/86 (84.9%) RR 0.82 (0.52 to 1.30) 800 per 1000 144 fewer per 1000 (384 fewer to 240 more)

171 (2 non-RCTs)

serious3

not serious

Side-effects sufficient to stop treatment very serious1,6 LOW none 10/285 (3.5%) 50/280 (17.9%) RR 5.11 (1.67 to 15.63) 13/58 (22.4%) 100 per 1000 411 more per 1000 (67 more to 1463 more) 100 per 1000 RR 7.17 (1.69 to 30.44) 2/64 (3.1%) 617 more per 1000 (69 more to 2944 more)

565 (5 RCTs)

not serious

122 (1 non-RCT) VERY LOW

serious4

not serious

serious1,6

none

RECOMMENDATION 3 43

Erythromycin versus amoxicillin (continued) Summary of findings Imprecision Anticipated absolute effects Risk with other erythromycin Risk difference with azithromycin With erythromycin With azithromycin Publication bias Overall quality of evidence Study event rates (%) Relative effect (95% CI)

Quality assessment

No. of participants (studies) Follow-up

Risk of bias

Inconsistency

Indirectness

Side-effects not sufficient to stop treatment very serious1,5,6 LOW none 10/154 (6.5%) 35/150 (23.3%) RR 3.35 (1.74 to 6.46) 500 per 1000 1175 more per 1000 (370 more to 2730 more) 500 per 1000 315 fewer per 1000 (460 fewer to 375 more)

304 (3 RCTs)

not serious

122 (1 non-RCT) VERY LOW

serious4

not serious

serious1,6

none

6/64 (12.5%)

2/58 (3.4%)

RR 0.37 (0.08 to 1.75)

Preterm delivery/ Delivery < 37 weeks serious1 VERY LOW none 450/8143 (5.5%) 346/5729 (6.0%) RR 1.09 (0.95 to 1.25) 55 per 1000 5 more per 1000 (3 fewer to 14 more)

13872 (1 observational study)

serious3

not serious

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Fetal death serious1,6 VERY LOW none 62/6824 (0.9%) 41/5729 (0.7%) RR 0.79 (0.53 to 1.17) 9 per 1000 2 fewer per 1000 (4 fewer to 2 more)

12553 (1 observational study)

serious3

not serious

Erythromycin versus amoxicillin (continued) Summary of findings Imprecision With erythromycin With azithromycin Risk with other erythromycin Publication bias Overall quality of evidence Study event rates (%) Relative effect (95% CI) Anticipated absolute effects Risk difference with azithromycin

Quality assessment

No. of participants (studies) Follow-up

Risk of bias

Inconsistency

Indirectness

Major malformations not serious VERY LOW none 36/1599 (2.3%) 51/1786 (2.9%) RR 1.27 (0.83 to 1.93) 23 per 1000 6 more per 1000 (4 fewer to 21 more)

3385 (1 observational study)

serious3

not serious

Maternal postpartum endometritis and chorioamnionitis serious1, 6 VERY LOW none 0/22 (0.0%) 1/32 ( 3.1%) RR 2.09 (0.09 to 49.09)

54 (1 non-RCT)

serious3

not serious

Clinical cure – not measured

Compliance – not measured

HIV acquisition – not measured

Quality of life – not measured

Transmission to partner – not measured

CI: confidence interval; OR: odds ratio; RR: risk ratio

1. Few events or participants.

2. 95% CI includes potential for more or fewer cures.

3. It was a non-RCT, and authors did not mention any information related to the use of an appropriate analysis method that adjusted for all the critically important confounding domains.

RECOMMENDATION 3

Selective reporting likely since few trials reported on this outcome.

5. Number of participants based on total pregnant women in study.

95% CI includes potential for more or fewer adverse events.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

REFERENCES

Systematic reviews 1. Brocklehurst P, Gordon A, Heatley E, Milan SJ. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev. 2013;(1):CD000262. Included studies 1. Adair CD, Gunter M, Stovall TG, McElroy G, Veille JC, Ernest JM. Chlamydia in pregnancy: a randomized trial of azithromycin and erythromycin. Obstet Gynecol. 1998;91(2):165-8. 2. Alary M, Joly JR, Moutquin JM, Mondor M, Boucher M, Fortier A, et al. Randomised comparison of amoxicillin and erythromycin in treatment of genital chlamydial infection in pregnancy. Lancet. 1994;344(8935):1461-5. 3. Alger LS, Lovchik JC. Comparative efficacy of clindamycin versus erythromycin in eradication of antenatal Chlamydia trachomatis. Am J Obstet Gynecol. 1991;165(2):375-81. 4. Bell TA, Sandstrom IK, Eschenbach DA, Hummel D, Kuo C, Wang S, et al. Treatment of Chlamydia trachomatis in pregnancy with amoxicillin. In: Marsh PA, editor. Chlamydial infections. Elsevier Biomedical Press; 1982:221-4. 5. Bush MR, Rosa C. Azithromycin and erythromycin in the treatment of cervical chlamydial infection during pregnancy. Obstet Gynecol. 1994;84(1):61-3. 6. Crombleholme WR, Schachter J, Grossman M, Landers DV, Sweet RL. Amoxicillin therapy for Chlamydia trachomatis in pregnancy. Obstet Gynecol. 1990;75(5):752-6. 7. Edwards MS, Newman RB, Carter SG, Leboeuf FW, Menard MK, Rainwater KP. Randomized clinical trial of azithromycin for the treatment of Chlamydia cervicitis in pregnancy. Infect Dis Obstet Gynecol. 1996;4(6):333-7. 8. Jacobson GF, Autry AM, Kirby RS, Liverman EM, Motley RU. A randomized controlled trial comparing amoxicillin and azithromycin for the treatment of Chlamydia trachomatis in pregnancy. Am J Obstet Gynecol. 2001;184(7):1352-4. 9. Kacmar J, Cheh E, Montagno A, Peipert JF. A randomized trial of azithromycin versus amoxicillin for the treatment of Chlamydia trachomatis in pregnancy. Infect Dis Obstet Gynecol. 2001;9(4):197-202. 10. Magat AH, Alger LS, Nagey DA, Hatch V, Lovchik JC. Doubleblind randomized study comparing amoxicillin and erythromycin for the treatment of Chlamydia trachomatis in pregnancy. Obstet Gynecol. 1993;81(5 Pt 1):745-9. 11. Martin DH, Eschenbach DA, Cotch MF, Nugent RP, Rao AV, Klebanoff MA, et al. Double-blind placebo-controlled treatment trial of Chlamydia trachomatis endocervical infections in pregnant women. Infect Dis Obstet Gynecol. 1997;5(1):10-7. 12. Nadafi M, Abdali KH, Parsanejad ME, Rajaee-Fard AR, Kaviani M. A comparison of amoxicillin and erythromycin for asymptomatic Chlamydia trachomatis infection in pregnancy. Int J Gynaecol Obstet. 2005;90(2):142-3. 13. 13. Rahangdale L, Guerry S, Bauer HM, Packel L, Rhew M, Baxter R, et al. An observational cohort study of Chlamydia trachomatis treatment in pregnancy. Sex Transm Dis. 2006;33(2):106-10.

14. Rosenn M, Macones GA, Silverman N. A randomized trial of erythromycin and azithromycin for the treatment of chlamydia infection in pregnancy. Am J Obstet Gynecol. 1996;174:410. 15. Rosenn MF, Macones GA, Silverman NS. Randomized trial of erythromycin and azithromycin for treatment of chlamydial infection in pregnancy. Infect Dis Obstet Gynecol. 1995;3(6): 241-4. 16. Silverman NS, Hochman M, Sullivan M, Womack M. A randomized prospective trial of amoxicillin versus erythromycin for the treatment of chlamydia in pregnancy. Am J Obstet Gynecol. 1993;168:420. 17. Silverman NS, Sullivan M, Hochman M, Womack M, Jungkind DL. A randomized, prospective trial comparing amoxicillin and erythromycin for the treatment of Chlamydia trachomatis in pregnancy. Am J Obstet Gynecol. 1994;170(3):829-32. 18. Turrentine MA, Troyer L, Gonik B. Randomized prospective study comparing erythromycin, amoxicillin and clindamycin for the treatment of Chlamydia trachomatis in pregnancy. Infect Dis Obstet Gynecol. 1995;2(5):205-9. 19. Wehbeh HA, Ruggeirio RM, Shahem S, Lopez G, Ali Y. Single-dose azithromycin for chlamydia in pregnant women. J Reprod Med. 1998;43(6):509-14. Reviews and studies for adverse outcomes 1. Morency AM, Bujold E. The effect of second-trimester antibiotic therapy on the rate of preterm birth. J Obstet Gynaecol Can. 2007;29(1):35-44. 2. Romøren M, Lindbæk M, Nordeng H. Pregnancy outcome after gestational exposure to erythromycin – a populationbased register study from Norway. Br J Clin Pharmacol. 2012;74(6):1053-62. doi:10.1111/j.1365-2125.2012.04286.x. 3. van den Broek NR, White SA, Goodall M, Ntonya C, Kayira E, Kafulafula G, Neilson JP. The APPLe study: a randomized, community-based, placebo-controlled trial of azithromycin for the prevention of preterm birth, with meta-analysis. PLoS Med. 2009;6(12):e1000191. doi:10.1371/journal.pmed.1000191. Patient values and preferences, acceptability and cost: specific to chlamydial infections 1. Dixon-Woods M, Stokes T, Young B, Phelps K, Windridge K, Shukla R. Choosing and using services for sexual health: a qualitative study of women's views. Sex Transm Infect. 2001;77(5):335-9. 2. International drug price indicator guide, 2014 edition (undated annually). Medford (MA): Management Science for Health; 2015 (http://erc.msh.org/dmpguide/pdf/DrugPriceGuide_2014.pdf, accessed 3 June 2016). 3. Pitsouni E, Iavazzo C, Athanasiou S, Falagas ME. Single-dose azithromycin versus erythromycin or amoxicillin for Chlamydia trachomatis infection during pregnancy: a meta-analysis of randomised controlled trials. Int J Antimicrob Agents. 2007;30(3):213-21.

RECOMMENDATION 3

Patient values and preferences, acceptability and cost: other sexually transmitted infections and conditions 1. Nagarkar A, Mhaskar P. A systematic review on the prevalence and utilization of health care services for reproductive tract infections/sexually transmitted infections: Evidence from India. Indian J Sex Transm Dis. 2015;36(1):18-25. doi:10.4103/02537184.156690. 2. Ryan R, Santesso N, Lowe D, Hill S, Grimshaw J, Prictor M, et al. Interventions to improve safe and effective medicines use by consumers: an overview of systematic reviews. Cochrane Database Syst Rev. 2014;4:CD007768. Additional references 1. Amin A, Garcia Moreno C. Addressing gender-based violence to reduce risk of STI and HIV. Sex Transm Infect. 2013;89 (Suppl 1):A8. 2. Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386(9995):743-800. doi:10.1016/S0140-6736(15)60692-4.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

RECOMMENDATION 4 Treatments for adults and adolescents with lymphogranuloma venereum Population: Intervention: Comparison: Main outcomes: Adults and adolescents with lymphogranuloma venereum (LGV) Doxycycline or azithromycin Other antibiotics Critical: Clinical cure, microbiological cure Important: STI complications, side-effects (including allergy, toxicity, gastro), quality of life, HIV transmission and acquisition, compliance, LGV transmission to partner Out- or inpatient Population Lymphogranuloma venereum (LGV) is a bacterial infection caused by variations of Chlamydia trachomatis. Diagnosis of LGV may be missed due to the lack of tests/tools to distinguish LGV from chlamydial infections. LGV has been reported in men who have sex with men (MSM) and is associated with HIV infection. LGV infection is curable using antibiotics. The 2003 WHO guidelines recommend treatment with doxycycline 100 mg orally twice daily for 14 days or erythromycin 500 mg orally four times daily for 14 days. An alternative regimen is also recommended: tetracycline 500 mg orally four times daily for 14 days. The Guideline Development Group (GDG) requested a review of evidence for doxycycline and erythromycin for a longer duration (21 days), as well as for azithromycin 1 g orally once a week x 1–3 weeks.

Setting: Perspective: Background:

RECOMMENDATION 4

ASSESSMENT Judgement Is the problem a priority? Problem Desireable effects Undesireable effects Certainty of evidence Research evidence Research evidence: Epidemiological research reports that LGV is endemic in parts of Africa, Asia, South America and the Caribbean. A report from 2008 found that of 162 men attending a STI clinic, 14% had LGV (O’Farrell, 2008). LGV is a more invasive form of chlamydia, lacks clinically convenient diagnostic tests for strains, and has historically required longer treatment than genital chlamydia. People infected with LGV can experience discharge, pain, bleeding, ulcers, tenesmus and cramping. Long-term consequences without treatment can include tissue damage, abscesses, chronic fissures or strictures. Additional considerations: The GDG also indicated the concern that the potential for HIV and hepatitis C transmission could be increased with LGV infection. How substantial are the desirable anticipated effects? Research evidence: We found no randomized controlled trials (RCTs) or comparative studies comparing doxycycline or azithromycin to other treatments. We found 12 non-randomized studies with no comparisons. None of these studies assessed the effects of the doses previously recommended in the 2003 WHO STI guidelines (i.e. 14-day regimens). See the evidence profile below for the summary of the results. Additional considerations: Low quality data show that doxycycline twice daily for 21 days may have high cure rates. The effects of azithromycin and erythromycin were uncertain with only 14 people receiving azithromycin and 31 people receiving erythromycin in studies. However, indirect evidence for azithromycin use in other chlamydial infections suggests it may have large effects. More research into the use of erythromycin and azithromycin in these infections is needed, specifically an RCT comparing doxycycline and azithromycin. There was no evidence in clinical studies to determine whether the type of LGV could impact the effectiveness of treatments. How substantial are the undesirable anticipated effects? There was very low quality evidence for trivial side-effects of doxycycline. However, there is moderate quality evidence for trivial side-effects of these treatments for other chlamydial infections.

• • • •

No Probably no Probably yes Yes

• Varies • Don’t know

• • • •

Trivial Small Moderate Large

• Varies • Don’t know

• • • •

Large Moderate Small Trivial

• Varies • Don’t know What is the overall certainty of the evidence of effects?

• • • •

Very low Low Moderate High

• No included studies

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Is there important uncertainty about or variability in how much people value the main outcomes?

Research evidence: No research evidence Additional considerations: The GDG agreed that there were no reasons to believe that values would vary between different people; however, it was noted that LGV proctitis is a more significant problem for HIV- and hepatitis C-infected patients and especially for MSM.

Values Balance of effects Resources required Certainty of evidence

• Important uncertainty or variability

• Possibly important uncertainty or variability

• Probably no important uncertainty or variability

• No important uncertainty or variability

• No known undesirable outcomes Does the balance between desirable and undesirable effects favour the intervention or the comparison? Research evidence: None Additional considerations: The GDG agreed that the balance of effects favoured doxycycline, probably favoured azithromycin, and was unsure of erythromycin.

• Favours the comparison • Probably favours the comparison

• Does not favour either the intervention or the comparison • Probably favours the intervention • Favours the intervention

• Varies • Don’t know How large are the resource requirements (costs)? A Azithromycin 1 g po × 3 Doxycycline 100 mg po Doxycycline (ER) 200 mg po Erythromycin ES 800 mg po Erythromycin 500 mg po x 21 days Amoxicillin 500 mg po Quinolones po B 1 2 1 4 2 3 C 1 7 7 7 10–14 7 D* $0.38 (500 mg) $0.0191 n.a. n.a. $0.0738 $0,032 n.a. E $ 0.76 $0.2674 n.a. n.a. 1.476– 2.06 $0.672 n.a. F $0.95 $0.3342 n.a. n.a. $1.88– $2.57 $0.84 n.a.

• • • • •

Large costs Moderate costs Negligible costs and savings Moderate savings Large savings

• Varies • Don’t know

*Sources: International drug price indicator guide (MSH, 2015) and www.drugs.com A: treatment; B: dose per day; C: treatment duration; drug cost, per dose; E: drug per full-course treatment; F: 25% procurement

Additional considerations: The GDG agreed that doxycycline was less expensive than the alternative antibiotics, but that these too were also inexpensive. What is the certainty of the evidence of resource requirements (costs)? Research evidence: No studies were found with details of resource use. Additional considerations: none

• • • •

Very low Low Moderate High

• No included studies

RECOMMENDATION 4

Does the cost-effectiveness of the intervention favour the intervention or the comparison?

• Favours the comparison • Probably favours the comparison

Research evidence: Sahin-Hodoglugil (2003) found that the “gold standard” protocol with diagnosis and treatment, using azithromycin for chlamydial infections, was found to be more cost-effective than using doxycycline. For both the gold standard and syndrome management protocols, the total cost of the program was most sensitive to the percentage of women seeking STI treatment and the prevalence of non-STI vaginal discharge. Although, there were many studies assessing costs of screening for chlamydia, there were no recent studies focused on cost of treatment. Resource factors in other models included index patient interview, record search, field visit, STD evaluation, treatment with dose of drug, expected late detection costs, investigation of the partner’s sex partners, infection cost, disease intervention and specialist time/cost. Patient variability to consider: probability of care being sought, probability of consent to treatment, probability of adherence to referral, and probability of partner seeking care. Additional considerations: Given the benefits and low cost, cost-effectiveness probably favours doxycycline or azithromycin, however cost-effectiveness is unknown for erythromycin due to its unknown effectiveness.

Cost-effectiveness Equity Acceptability Feasibilty

• Does not favour either the intervention or the comparison • Probably favours the intervention • Favours the intervention

• Varies • No included studies

What would be the impact on health equity?

Research evidence: No research evidence was found. Additional considerations: The GDG noted that LGV was a significant infection in MSM, and that there was evidence of its association with proctitis and hepatitis C infection. It was emphasized that this was not a trivial condition. If treatment is associated with a reduction in HIV transmission, it may help increase equity.

• • • • •

Reduced Probably reduced Probably no impact Probably increased Increased

• Varies • Don’t know Is the intervention acceptable to key stakeholders? Research evidence: A systematic review (in India) of the literature for treatment utilization in STIs reported that utilization ranged from 16% to 55% in the community-based studies, and was higher (approximately 70%) in research trials. Treatment may not be acceptable to patients due to the resources and availability of services, social factors, and distance from a clinic. Non-utilization was also due to ignorance, illiteracy and lack of awareness. Women reported a lack of female doctors, being afraid of results, judgement from doctors, stigma, shyness and embarrassment. Cost of care and lack of faith in clinical care were also factors. Additional considerations: The GDG agreed that the length of treatment may be an issue for compliance. However, if a patient does not take the course perfectly over 21 days, the course of treatment still appears to work. Is the intervention feasible to implement? Research evidence: None Additional considerations: The GDG considered the treatments as feasible, but distribution and compliance concerns should be taken into account.

• • • •

No Probably no Probably yes Yes

• Varies • Don’t know

• • • •

No Probably no Probably yes Yes

• Varies • Don’t know

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

SUMMARY OF JUDGEMENTS Judgement Problem Desirable effects Undesirable effects Certainty of evidence Values No Trivial Large Very low Important uncertainty or variability Favours the comparison Probably no Small Moderate Low Possibly important uncertainty or variability Probably favours the comparison Probably yes Moderate Small Moderate Probably no important uncertainty or variability Does not favour either the intervention or the comparison Negligible costs and savings Moderate Yes Large Trivial High No important uncertainty or variability Probably favours the intervention Favours the intervention Varies Varies Varies Varies Don’t know Don’t know Don’t know No included studies No known undesirable outcomes Don’t know

Balance of effects

Resources required Certainty of evidenceof required resources Costeffectiveness

Large costs

Moderate costs Low

Moderate savings High

Large savings

Varies

Don’t know

Very low

No included studies

Favours the comparison

Probably favours the comparison

Does not favour either the intervention or the comparison Probably no impact Probably yes Probably yes

Probably favours the intervention

Favours the intervention

Varies

No included studies

Equity Acceptability Feasibility

Reduced No No

Probably reduced Probably no Probably no

Probably increased Yes Yes

Increased

Varies Varies Varies

Don’t know Don’t know Don’t know

CONCLUSIONS

Treatments for lymphogranuloma venereum (LGV) Conditional recommendation against the intervention • • Conditional recommendation for either the intervention or the comparison Conditional recommendation for the intervention Strong recommendation for the intervention

Type of recommendation

Strong recommendation against the intervention

•

• •

Recommendation

In adults and adolescents with LGV, the WHO STI guideline suggests using doxycycline 100 mg twice daily for 21 days over azithromycin 1 gram weekly for 21 days. Conditional recommendation, very low quality evidence

Remarks: Good practice dictates treatment of LGV, in particular for MSM and for people living with HIV. When doxycycline is contraindicated, azithromycin should be provided. When neither treatment is available, erythromycin 500 mg orally four times daily for 21 days is an alternative. Doxycycline should not be used in pregnant women because of adverse effects (see Recommendation 3).

Justification

There is very low quality evidence from 12 non-randomized studies with no comparisons between treatments. These studies assessed azithromycin and doxycycline for 21 days, and erythromycin for 14 days. Evidence for doxycycline showed that there may be large benefits (number of people clinically and microbiologically cured was greater than 90%) and trivial side-effects (such as persistent mucous membrane abnormalities, perirectal abscess and allergy). The effects of azithromycin and erythromycin were uncertain, with only 14 people receiving azithromycin and 31 people receiving erythromycin in studies. Side-effects are likely trivial and similar to the side-effects of these treatments in people with other chlamydial infections.

There is no evidence for variation of patient values and preferences, but the GDG agreed that there are no known reasons to suspect values would vary between different people. There is little to no evidence for acceptability, but research in other conditions indicates that adherence may be improved with simpler drug regimens. There is little evidence for equity issues and feasibility, but the GDG agreed that these may be dependent on individuals and countries. Data for drug prices and procurement indicate that doxycycline is cheaper than azithromycin and erythromycin, although the latter drugs are still inexpensive. In summary, there is very low quality evidence for all drugs for treatment of LGV. The evidence suggests large benefits with doxycycline over azithromycin, and the effects of erythromycin are unknown. In addition, doxycycline is also the least expensive.

In summary, there is very low quality evidence for all drugs for treatment of LGV. The evidence suggests large benefits with doxycycline over azithromycin, and the effects of erythromycin are unknown. In addition, doxycycline is also the least expensive.

Subgroup considerations

Implementation considerations

Monitoring and evaluation

RECOMMENDATION 4

Research priorities

Additional research for each of the treatments and the dosages recommended is needed, in particular for erythromycin and azithromycin. Randomized controlled trials should be conducted and measure critical and important outcomes, such as clinical cure, microbiological cure, complications, sideeffects (including allergy, toxicity, gastrointestinal effects), quality of life, HIV transmission and acquisition, compliance and LGV transmission to partners. The effects of shorter courses of treatment should also be investigated.

EVIDENCE PROFILE Azithromycin 1 g single dose Azithromycin 500 mg x 3–5 daysb 1.00 (0.60–1.40) 1/1 1.00 (0.76–1.24) 4/4 0.00 (–0.33 – 0.33) 0/2 1.00 (0.60–1.40) 1/1 1.00 (0.94–1.06) 30/30 Azithromycin 1 g single dose x 12 days 0.00 (–0.40 – 0.40) 0/1 1.00 (0.80–1.20) 6/6 Azithromycin 1 g single dose x 3 weeks Erythromycin 500 mg bid x 21 days

Outcomes

Quality of evidence

Doxycycline 100 mg bid x 21 daysa

Clinical cure

Very low

0.92 (0.75–1.09) 11/12

Microbiological cure

Very low

0.98 (0.95–1.00) 181/186

Persistent mucous membrane abnormalities

Very low

0.38 (0.16–0.59) 6/16

Perirectal abscess

Very low

0.17 (–0.10 – 0.43) 1/6

Side-effects (doxycycline allergy)

Very lowc

0.02 (–0.03 – 0.06) 1/60

STI complications

Not measured

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Quality of life

Not measured

HIV transmission and acquisition

Not measured

Compliance

Not measured

LGV transmission to partner

Not measured

bid: twice daily Note: Data are presented as pooled proportions (95% CI) and study event rates n/N (%) (n=number of events, N = total number of patients followed-up).

a Two studies (Krishnamurthy, 1982; Hevia, 1971) not included: one study provided doxycycline 200 mg once daily × 10 days (6/8 patients had complete ulcer healing after treatment; 2 were resistant and retreated with spectinomycin; authors reported no side-effects); the other study provided 100 mg twice daily × 3 days, then 100 mg once daily × 12 days (10/10 had microbiological and clinical cure within 15 days; authors reported 4/36 had vomiting or nausea early in treatment).

Clinical cure data is based on patient treated for 5 days (Sethi, 2009) where as microbiological cure data is based on a study reported after 3 days of treatment (Kamarashev, 2010).

Quality of evidence very low due to high risk of bias in studies and imprecision.

RECOMMENDATION 4

REFERENCES

Included studies 1. Ballard RC, Ye H, Matta A, Dangor Y, Radebe F. Treatment of chancroid with azithromycin. Int J STD AIDS. 1996;7(Suppl 1):912. 2. Collado CAM, Aguilar REB. Lymphogranuloma venereum. Clinical aspects, diagnostic methods and treatment of 120 patients. Dermatologia Revista Mexicana. 2003;47(1):5-12. 3. De Vries C, Smelov V, Middelburg JG, Pleijster J, Speksnijder AG, Morré SA. Delayed microbial cure of lymphogranuloma venereum proctitis with doxycycline treatment. Clin Infect Dis. 2009;48(5):e53-e56. doi:10.1086/597011. 4. Heras E, Llibre JM, Martró E, Casabona J, Martin R, Sirera G. [Lymphogranuloma venereum proctocolitis in men with HIV-1 infection] Enferm Infecc Microbiol Clin. 2011;29(2):124-6 (in Spanish). doi:10.1016/j.eimc.2010.07.011. [correction in Enferm Infecc Microbiol Clin. 2012 Jun;30(6):357]. 5. Hevia H, Honeyman J, De la Parra M. [Treatment of early syphilis and venereal lymphogranulomatosis with doxycycline]. Rev Med Chil. 1971;99(6):402-5 (in Spanish). 6. Hill SC, Hodson L, Smith A. An audit on the management of lymphogranuloma venereum in a sexual health clinic in London, UK. Int J STD AIDS. 2010; 21(11):772-6. doi:10.1258/ ijsa.2010.010329. 7. Kamarashev J, Riess CE, Mosimann J, Läuchlf S. Lymphogranuloma venereum in Zurich, Switzerland: Chlamydia trachomatis serovar L2 proctitis among men who have sex with men. Swiss Med Wkly. 2010;140(13-14):209-12. doi:smw-12962. 8. Krishnamurthy VR, Johnson M, Rangasamy J, Murali RVK. Efficacy of streptomycin, chloramphenicol, co-trimoxazole and doxycycline in lymphogranuloma venereum. Indian J Sex Transm Dis. 1982;3(1):26-8. 9. Marangoni A, D'Antuono A, Filippini A, Bellavista S, Baraldi C, Foschi C, et al. Lymphogranuloma venereum cases identified in patients attending a STD outpatients clinic in Italy. Poster (P2.013] presented 16 July 2013 at the STI & AIDS World Congress 2013, 14–17 July, Vienna, Austria. 10. Oud EV, de Vrieze NH, de Meij A, de Vries HJ. Pitfalls in the diagnosis and management of inguinal lymphogranuloma venereum: important lessons from a case series. Sex Transm Infect. 2014;90(4):279-82. doi:10.1136/sextrans-2013-051427. 11. Rodríguez-Domínguez M, Puerta T, Menéndez B, González-Alba JM, Rodríguez C, Hellin T, et al. Clinical and epidemiological characterization of a lymphogranuloma venereum outbreak in Madrid, Spain: co-circulation of two variants. Clin Microbiol Infect. 2014;20(3), 219-25. doi:10.1111/1469-0691.12256. 12. Sethi G, Allason-Jones E, Richens J, Annan NT, Hawkins D, Ekbote A, et al. Lymphogranuloma venereum presenting as genital ulceration and inguinal syndrome in men who have sex with men in London, UK. Sex Transm Infect. 2009;85(3):165-70. doi:10.1136/sti.2008.034348. 13. Vas A, Leighton J, Saxon C, Lebari D, Stott C, Ahmad S, et al. Audit of the clinical management of lymphogranuloma venereum in three inner-city genitourinary medicine clinics. International Journal of STD and AIDS, Conference, 11th Spring Meeting of the British Association for Sexual Health and HIV (BASHH), 15–17 May 2013. Bristol, United Kingdom. Conference Publication.

Patient values and preferences, acceptability and cost: specific to chlamydial infections 1. International drug price indicator guide, 2014 edition (updated annually). Medford (MA): Management Sciences for Health; 2015 (http://erc.msh.org/dmpguide/pdf/DrugPriceGuide_2014.pdf, accessed 3 June 2016). 2. Sahin-Hodoglugil NN, Woods R, Pettifor A, Walsh J. A comparison of cost-effectiveness of three protocols for diagnosis and treatment of gonococcal and chlamydial infections in women in Africa. Sex Transm Dis. 2003:30:455-69. Patient values and preferences, acceptability and cost 1. Nagarkar A, Mhaskar P. A systematic review on the prevalence and utilization of health care services for reproductive tract infections/sexually transmitted infections: evidence from India. Indian J Sex Transm Dis. 2015;36(1):18-25. doi:10.4103/02537184.156690. 2. Ryan R, Santesso N, Lowe D, Hill S, Grimshaw J, Prictor M, et al. Interventions to improve safe and effective medicines use by consumers: an overview of systematic reviews. Cochrane Database Syst Rev. 2014;4:CD007768. Additional references 1. O’Farrell N, Morison L, Moodley P, Pillay K, Vanmali T, Quigley M, Sturm AW. Genital ulcers and concomitant complaints in men attending a sexually transmitted infections clinic: implications for sexually transmitted infections management. Sex Transm Dis. 2008;35:545-9. doi:10.1097/OLQ.0b013e31816a4f2e.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

RECOMMENDATION 5 Treatment of chlamydial ophthalmia neonatorum Population: Intervention: Comparison: Main outcomes: Setting: Perspective: Background: Neonatal conjunctivitis Erythromycin Erythromycin, azithromycin, or trimethoprim Critical: Clinical cure, microbiological cure, complications, side-effects (including allergy, toxicity, gastro), antimicrobial resistance, compliance Out- or inpatient Population Chlamydia trachomatis can be transmitted from the mother to the newborn infant during labour, causing neonatal conjunctivitis (ophthalmia neonatorum). Today, Chlamydia trachomatis appears to be the most common cause, but other pathogens include Neisseria gonorrhoeae, Staphylococcus spp., Streptococcus sp., Haemophilus influenza and Enterobacteriaceae can also cause neonatal conjunctivitis. Different strategies are available for prophylaxis, although many high-income countries do not utilize them. The 2003 WHO Guidelines recommend treatment of neonatal chlamydial conjunctivitis with erythromycin syrup 50 mg/kg daily orally given in 4 divided doses for 14 days. An alternative regimen of trimethoprim 40 mg with sulfamethoxazole 200 mg orally twice daily for 14 days is also recommended. The Guideline Development Group (GDG) identified erythromycin, azithromycin and trimethoprim for review.

RECOMMENDATION 5

ASSESSMENT Judgement Is the problem a priority? Problem Research evidence Research evidence: Recent research reports the risk of developing neonatal chlamydial conjunctivitis from mothers with Chlamydia trachomatis is 18–50% (Kakar, 2010). In addition, a review of the literature showed similar incidence in mothers exposed, and 1–10% in mothers not exposed or with unknown exposure (Darling, 2010). Long-term consequences of ophthalmia neonatorum may include blindness, and this is particularly prevalent in areas with poor access to health care. Additional considerations: The reviewers stated that there were no RCTs making direct comparisons of these treatments. There was one direct NRS comparison, and the remaining data were extracted from single arms of RCTs or non-randomized studies, hence the recommendation was made largely on indirect data. No data for trimethoprim was included. This was put down to the rarity of neonatal conjunctivitis in developed countries, where the panel said azithromycin was probably being used. Trimethoprim was included in the question because it forms part of the erstwhile WHO recommendation for this infection and while it is cheaper, one panel member emphasized that it is not used and should not be considered in this recommendation. Another issue raised was that diagnosis of specifically chlamydial conjunctivitis is rare. Most treatment of neonatal conjunctivitis would therefore be syndromic, and some panel members expressed concern that the recommendation should reflect this need to treat other infectious agents. WHO: A subgroup of the GDG discussed this question and others some weeks later, bringing in ophthalmic expertise. The outcomes of this teleconference are included where appropriate. WHO: The GDG automatically treated the problem as a priority, In the teleconference that followed, the team decided to look at whether treatment was recommended over no treatment and it was decided that treatment was recommended given the minimal adverse effects and large benefit of treatment. This is fully delineated in the question concerning gonococcal neonatal conjunctivitis.

• • • •

No Probably no Probably yes Yes

• Varies • Don’t know

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

How substantial are the desirable anticipated effects?

• • • •

Trivial Small Moderate Large

Research evidence: We found no randomized controlled trials (RCTs) comparing erythromycin, azithromycin, or trimethoprim. We found 9 studies (1 comparative, 6 non-randomized studies with a single arm, 2 randomized trials of which a single arm was used). We also found a review including 2 comparative studies for risk of pyloric stenosis with erythromycin for ophthalmia neonatorum, and a non-randomized study for risk of pyloric stenosis with erythromycin or other oral antibiotics for any indication. See the evidence profile below for the summary of the results. Additional considerations: The GDG agreed that the effects were uncertain given the small number of neonates in the studies: 12 provided data for cure rates with azithromycin. Additionally, it was noted that trimethoprim was included in the old guidelines, but more research is needed for its efficacy after some concern that there may not be in vitro data supporting its use. The GDG regarded pyloric stenosis as a widely known adverse effect of erythromycin use in children, to the extent that many paediatricians routinely opt for alternative antibiotics as standard practice. However, there is no data suggesting that azithromycin does not cause pyloric stenosis. The GDG also noted that a number of the negative outcomes (such as pneumonia, coughing, conjunctivitis, etc.) were complications of chlamydia and not sideeffects of the intervention itself.

Desireable effects Undsireable effects Certainty of evidence Values

• Varies • Don’t know How substantial are the undesirable anticipated effects?

• • • •

Large Moderate Small Trivial

• Varies • Don’t know

What is the overall certainty of the evidence of effects?

Research evidence: None Additional considerations: None

• • • •

Very low Low Moderate High

• No included studies Is there important uncertainty about or variability in how much people value the main outcomes? Research evidence: The GDG identified the following outcomes as critical: Clinical cure, microbiological cure, complications, side-effects (including allergy, toxicity, gastro), antimicrobial resistance, compliance. Economic evaluation studies found the disutilities of different health states related to chlamydia (utility loss due to the health states as: Neonatal conjunctivitis: –0.03; Neonatal pneumonia: –0.21 Additional considerations: None

• Important uncertainty or variability • Possibly important uncertainty or variability • Probably no important uncertainty or variability • No important uncertainty or variability

• No known undesirable outcomes

RECOMMENDATION 5

Does the balance between desirable and undesirable effects favour the intervention or the comparison?

Additional considerations: The GDG agreed that, on the basis of negligible favourability for efficacy of erythromycin in addition with concern for its correlation with pyloric stenosis in children, azithromycin was favoured over erythromycin.

Balance of effects Resources required Certainty of evidence of required resources

• Favours the comparison • Probably favours the comparison

• Does not favour either the intervention or the comparison • Probably favours the intervention • Favours the intervention

• Varies • Don’t know How large are the resource requirements (costs)? A Azithromycin 500 mg po Erythromycin base 500 mg po Trimethoprim B n.a. n.a. n.a. C n.a. n.a. n.a. D $0.38 $0.0738 n.a. E n.a n.a. n.a. F n.a n.a n.a.

• Large costs • Moderate costs • Negligible costs and savings • Moderate savings • Large savings

• Varies • Don’t know

Additional considerations: The GDG agreed that the treatments are relatively inexpensive. What is the certainty of the evidence of resource requirements (costs)? Research evidence: No studies were found that measured resource use. Additional considerations: None

• • • •

Very low Low Moderate High

• No included studies

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Does the cost- effectiveness of the intervention favour the intervention or the comparison?

Research evidence We found no studies assessing cost-effectiveness. Additional considerations: None

Cost-effectiveness Equity Acceptability Feasibility

• Favours the comparison • Probably favours the comparison

• Does not favour either the intervention or the comparison • Probably favours the intervention

• Favours the intervention • Varies • No included studies What would be the impact on health equity? Research evidence: We found no studies assessing equity. Additional considerations: The GDG noted that many countries were already using erythromycin; however, it was agreed that this would not affect equity.

• • • • •

Reduced Probably reduced Probably no impact Probably increased Increased

• Varies • Don’t know Is the intervention acceptable to key stakeholders? Research evidence: Non-compliance was reported in 2 studies (31 babies/mothers) at 11% and 23%. Additional considerations: Treatment options are already being used.

• • • •

No Probably no Probably yes Yes

• Varies • Don’t know Is the intervention feasible to implement? Research evidence: We found no studies assessing feasibility. Additional considerations: The GDG indicated that erythromycin is already used to treat a variety of paediatric infections, and a recommendation to shift towards azithromycin use might result in a procurement gap: a time during which there might not be suitable drugs available to treat infections. Therefore, certain drugs should be used according to availability.

• • • •

No Probably no Probably yes Yes

• Varies • Don’t know

RECOMMENDATION 5

Balance of effects

Resources required Certainty of evidence of required resources Costeffectiveness

Large costs

Moderate costs Low

Moderate savings High

Large savings

Varies

Don’t know

Very low

No included studies

Favours the comparison

Probably favours the comparison

Does not favour either the intervention or the comparison Probably no impact Probably yes Probably yes

Probably favours the intervention

Favours the intervention

Varies

No included studies

Equity Acceptability Feasibility

Reduced No No

Probably reduced Probably no Probably no

Probably increased Yes Yes

Increased

Varies Varies Varies

Don’t know Don’t know Don’t know

CONCLUSIONS

Treatment of neonatal ophthalmia neonatorum Conditional recommendation against the intervention • • • Conditional recommendation for either the intervention or the comparison Conditional recommendation for the intervention Strong recommendation for the intervention

Type of recommendation

Strong recommendation against the intervention

•

Recommendation

In neonates with chlamydial conjunctivitis, the WHO STI guideline recommends using oral azithromycin 20 mg/kg for 3 days over erythromycin 50 mg/ kg/day for 14 days. Strong recommendation, very low quality evidence

Remarks: This is a strong recommendation given the potential risk of pyloric stenosis with the use of erythromycin in neonates. In some settings, azithromycin suspension is not available and therefore erythromycin may be used. Side-effects should be monitored with the use of either medication.

Justification

There is low-quality evidence for a cure rate of 98% with erythromycin 50 mg/kg/day for 14 days and uncertain effects on cures given the small number of neonates receiving azithromycin in the study. There was very low-quality evidence for 7 more instances of pyloric stenosis per 1000 with erythromycin. The GDG regarded the risk of pyloric stenosis as a serious adverse effect of erythromycin use in children. There is no data evaluating pyloric stenosis due to azithromycin. There is also no data assessing the effects of trimethoprim. There is no evidence for variation in patient values and preferences, but compliance with treatments ranged from 77% to 89%. The costs for treatments are relatively low and similar, and most treatments are currently being used. In summary, azithromycin is preferred over erythromycin because of the risk of serious adverse events with erythromycin, and a lack of data for trimethoprim.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

In summary, azithromycin is preferred over erythromycin because of the potential risk of serious adverse events with erythromycin, and there is no data for trimethoprim.

Subgroup considerations

Implementation considerations

Azithromycin suspension should be made widely available.

Monitoring and evaluation

Research priorities

Additional research should be conducted to determine the effects of these drugs to treat ophthalmia neonatorum. The effects of other medications, such as trimethoprim, should also be investigated. Pyloric stenosis should be monitored or research conducted to evaluate this risk with the drugs suggested.

EVIDENCE PROFILE

Data are presented as pooled proportions (95% CI) and study event rates n/N (n=number of events, N = total number of patients followed-up). Superscript numbers link to the alphabetized list of references on the next page. Erythromycin 50 mg/kg/day × 10 days Azithromycin 20 mg/kg single dose 0.60 [0.27–0.93] 3/55 0.78 [0.60–0.96] 14/182 0.07 [–0.08–0.22] 1/142 1.04 [0.98–1.09] 3/584,10 0.23 [0.06–0.39] 5/222 0.53 [0.31–0.76] 8/154 0.06 [–0.01 – 0.13] 5/484,9 0.03 [–0.04 – 0.10] 1/339 0.06 [–0.00 – 0.13] 4/629,10 0.57 [0.51–0.63] 98/1703,4,5,8,9,10 0.27 [0.10–0.45] 6/226 0.50 [0.25–0.75] 6/125 0.50 0.25–0.75] 6/125 0.12 [0.01–0.23] 4/339 0.14 [–0.01 – 0.28] 3/22 6 0.98 [0.96–1.01] 126/1303,4,5,8,9,10 1.00 [0.93–1.07] 22/226 Erythromycin 50 mg/kg/day × 14 days Erythromycin < 50 mg/kg/day × 21 days Azithromycin 20 mg/kg/day x 3 days 0.86 [0.61–1.10] 6/75

Outcomes

Overall quality of evidence

Erythromycin 200 mg/day × 10 days

Clinical and microbiological cure

Lowa,b,c

0.93 [0.78–1.08] 10/14d, 11

Treatment relapses

Not assessed

Pneumonia

Very low

a,b

Nasopharyngeal co-infection

Very low

a,b

0.31 [0.16–0.48] 9/2811

Upper respiratory tract infections

Very low

a,b

Otitis media

Very low

a,b

Vaginal infection

Very lowa,b

Conjunctival scarring

Very lowa,b 0.04 [–0.06 – 0.15] 1/22 2 0.07 [0.01–0.13] 6/852

Coughing

RECOMMENDATION 5

Very lowa,b

Side-effects: gastrointestinale

Very lowa,b

0.43 [0.20–0.66] 6/149

0.12 [0.05–0.20] 10/717,10

0.18 [0.03–0.34] 4/226

Outcomes Erythromycin 50 mg/kg/day × 10 days Azithromycin 20 mg/kg/day x 3 days Erythromycin 50 mg/kg/day × 14 days Erythromycin < 50 mg/kg/day × 21 days Azithromycin 20 mg/kg single dose

Overall quality of evidence

Erythromycin 200 mg/day × 10 days

Pyloric stenosis 0.11 [–0.10 – 0.32] 1/93 0.23 [0.06–0.39] 5/226

See additional table

Very low

Non-compliance

Antimicrobial resistance- not measured

Note: Nasopharyngeal co-infections also included oropharyngeal co-infections from one study (Fransen, 1986).

a Non-randomized studies were at risk of bias due to unclear losses of follow-up, assessment of cure using inaccurate cultures, short-term follow-up for complications, outcome assessment and attrition bias.

Imprecision due to small sample sizes and few events.

Upgraded due to large effect, dose response and no plausible confounding.

This event rate represents microbiological cure only. The clinical cure at that follow-up time was 13/14 (92.9%).

All gastrointestinal-related issues were grouped under this outcome including diarrhoea, watery stools, nausea, vomiting and abdominal pain.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Few events and confidence intervals around absolute event rates include little to no effect and important harm.

RISK OF PYLORIC STENOSIS WITH ERYTHROMYCIN VERSUS OTHER ORAL ANTIBIOTIC (ESTIMATES PER 1000) Risk with other oral antibiotics (per 1000) 8.9 9.8 17.3 7.6 17.2 30.3 13.3 15.6 Risk with erythromycin (per 1000) Risk difference (per 1000) 6.7 more (1 fewer to 23 more) 115 more (2 more to ∞) 3 fewer (15 fewer to 94 more) 5 more (3 fewer to 22 more) Quality of evidence

Age

Risk ratio of erythromycin vs other

All ages (1 to 90 days)

1.75 (0.85–3.60)

Very low1 Very low1 Very low1 Very low1

3–13 days

12.75 (1.23–132.61)

14–27 days

0.83 (0.11–6.42)

28–90 days

1.60 (0.66–3.84)

1 Very few events and confidence intervals around absolute event rates typically include little to no effect and important harm

RECOMMENDATION 5

REFERENCES

1. Cooper WO, Griffin MR, Arbogast P, Hickson GB, Gautam S, Ray WA. Very early exposure to erythromycin and infantile hypertrophic pyloric stenosis. Arch Pediatr Adolesc Med. 2002;156(7):647-50. 2. Fransen L, Nsanze H, D'Costa L. Oral erythromycin estolate in nongonococcal neonatal conjunctivitis. Eur J Sex Transm Dis. 1986;3(2):85-9. 3. Heggie AD, Jaffe AC, Stuart LA, Thombre PS, Sorensen RU. Topical sulfacetamide vs oral erythromycin for neonatal chlamydial conjunctivitis. Am J Dis Child. 1985;139(6):564-6. 4. Hammerschlag MR, Chandler JW, Alexander ER, English M, Koutsky L. Longitudinal studies on chlamydial infections in the first year of life. Pediatr Infect Dis. 1982;1(6):395-401. 5. Hammerschlag MR, Gelling M, Roblin PM, Kutlin A, Jule JE. Treatment of neonatal chlamydial conjunctivitis with azithromycin. Pediatr Infect Dis J. 1998;17(11):1049-50. 6. Patamasucon PR, Retting PJ, Faust KL, Kusmiesz HT, Nelson JD. Oral v topical erythromycin therapies for chlamydial conjunctivitis. Am J Dis Child. 1982;136(9):817-21. 7. Rosenman MB, Mahon BE, Downs SM, Kleiman MB. Oral erythromycin prophylaxis vs watchful waiting in caring for newborns exposed to Chlamydia trachomatis. Arch Pediatr Adolesc Med. 2003;157(6):565-71. 8. Sandström I. Treatment of neonatal conjunctivitis. Arch Ophthalmol. 1987;105(7):925-8. 9. Sandström I, Kallings I, Melen B. Neonatal chlamydial conjunctivitis. A long term follow-up study. Acta Paediatri Scand. 1988;77(2):207-13. 10. Stenberg K, Mårdh PA. Chlamydial conjunctivitis in neonates and adults. History, clinical findings and follow-up. Acta Ophthalmol. 1990;68(6):651-7. 11. Stenberg, K, Mårdh P. A. Treatment of chlamydial conjunctivitis in newborns and adults with erythromycin and roxithromycin. J Antimicrob Chemother. 1991;28(2):301-7.

Patient values and preferences, acceptability and cost: specific to chlamydial infections 1. Deogan CL, Bocangel MK, Wamala SP, Månsdotter AM. A costeffectiveness analysis of the Chlamydia Monday – a communitybased intervention to decrease the prevalence of chlamydia in Sweden. Scand J Public Health. 2010;38(2):141-50. 2. International Drug Price Indicator Guide, 2014 Edition (updated annually). Medford (MA): Management Sciences for Health; 2015 (http://erc.msh.org/dmpguide/pdf/DrugPriceGuide_2014.pdf, accessed 3 June 2016). Additional references 1. Darling EK, McDonald H. A meta-analysis of the efficacy of ocular prophylactic agents used for the prevention of gonococcal and chlamydial ophthalmia neonatorum. J Midwifery Womens Health. 2010;55(4):319-27. doi:10.1016/j.jmwh.2009.09.003. 2. Kakar S, Bhalla P, Maria A, Rana M, Chawla R, Mathur NB. Chlamydia trachomatis causing neonatal conjunctivitis in a tertiary care center. Indian J Med Microbiol. 2010;28(1):45-7. doi:10.4103/0255-0857.58728.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

RECOMMENDATIONS 6 AND 7 Prevention of gonococcal and chlamydial ophthalmia neonatorum Population: Intervention: Comparison: Main outcomes: Setting: Perspective: Background: Neonates One treatment Another treatment Absence of conjunctivitis, keratitis, complications, blindness, corneal scarring, antimicrobial resistance Out- and in-patient care Population Ophthalmia neonatorum is a form of conjunctivitis occurring within the neonatal period. It is the most common cause of acute ophthalmic disease in newborns and is generally acquired during vaginal delivery from an infected mother. There are numerous causes of conjunctivitis, which can be either infectious or chemical in origin. The most frequent infectious agents involved in ophthalmia neonatorum are Chlamydia trachomatis and Neisseria gonorrhoeae; other agents include Escherichia coli, Haemophilus and Enterococcus. There is no guidance in the 2003 WHO Guidelines specific to prevention of ophthalmia neonatorum. The Guideline Development Group (GDG) identified preventative medications for ophthalmia neonatorum due to N. gonorrhoeae (i.e. gonorrhoea) (ophthalmic ointment including erythromycin 0.5%; silver nitrate 1%; chloramphenicol; tetracycline 1%; povidone iodine 2.5%).

RECOMMENDATIONS 6 AND 7

ASSESSMENT Judgement Is the problem a priority? Problem Desirable Effects Undesirable Effects Certainty of evidence Values Research evidence Research evidence: Recent research reports that the risk of developing neonatal chlamydial conjunctivitis from mothers with Chlamydia trachomatis is 18–50% (Kakar, 2010). In addition, a review of the literature showed similar incidence in mothers exposed, and 1–10% in mothers not exposed or with unknown exposure (Darling, 2010). Infection can lead to serious conjunctivitis and severe swelling of the eyelids. Long-term consequences of ophthalmia neonatorum (from any cause) may include blindness, and this is particularly prevalent in areas with poor access to health care. Additional considerations: The GDG panel noted that these numbers may be underestimating incidence, as the mothers’ status may be unknown and screening may not be done. How substantial are the desirable anticipated effects? Research evidence: We included 16 studies: 15 randomized studies and 1 non-randomized study with 2 comparison groups. See summary of the evidence in the evidence tables. Additional considerations: There were large benefits of prophylaxis when compared to no prophylaxis, particularly in babies born to women with known infection (approximately 70% reduction in conjunctivitis with various treatments). There were smaller differences in benefits between treatments.

• • • •

No Probably no Probably yes Yes

• Varies • Don’t know

• • • •

Trivial Small Moderate Large

• Varies • Don’t know How substantial are the undesirable anticipated effects?

• • • •

Large Moderate Small Trivial

Side-effects were often not reported. Non-infectious conjunctivitis was measured when comparing prophylaxis to no prophylaxis, but there were few infants and few events included in the studies. It is uncertain, and data showed reductions or little difference. When comparing prophylaxis, low-quality evidence showed differences between 4 and 50 per 1000 infants of - infectious conjunctivitis. The GDG noted that there have been incidences of using alcohol povidone iodine instead of water based, which have resulted in serious consequences. Therefore, warning should be included in this recommendation. Research evidence: None Additional considerations: Overall, evidence is typically low quality between comparisons.

• Varies • Don’t know What is the overall certainty of the evidence of effects?

• • • •

Very low Low Moderate High

• No included studies Is there important uncertainty about or variability in how much people value the main outcomes? Research evidence: The GDG identified the following outcomes as critical: Clinical cure, microbiological cure, complications, side-effects (including allergy, toxicity, gastro), antimicrobial resistance, compliance. Economic evaluation studies found the disutilities of different health states related to chlamydia (utility loss due to the health states) as: Neonatal conjunctivitis: –0.03 Neonatal pneumonia: –0.21 Additional considerations: The GDG felt that there would likely be little difference in value placed on avoiding long-term consequences.

• Important uncertainty or variability • Possibly important uncertainty or variability • Probably no important uncertainty or variability • No important uncertainty or variability

• No known undesirable outcomes

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Does the balance between desirable and undesirable effects favour the intervention or the comparison?

Research evidence: None Additional considerations: None

Balance of effects Resources required Certainty of evidence of required resources

• Favours the comparison • Probably favours the comparison

• Does not favour either the intervention or the comparison • Probably favours the intervention • Favours the intervention

• Varies • Don’t know How large are the resource requirements (costs)? Ophthalmic ointment Erythromycin 0.5% Silver nitrate 1% Chloramphenicol Tetracycline Povidone iodine Drug cost* $0.74 $7.30 $0.2956 $0.069 $0.01

• Large costs • Moderate costs • Negligible costs and savings • Moderate savings • Large savings

• Varies • Don’t know

*Based on the International drug price indicator guide (MSH, 2015)

Additional considerations: The GDG agreed that silver nitrate was most expensive and a high cost relative to other prophylaxis. What is the certainty of the evidence of resource requirements (costs)? Research evidence: No research studies assessing other resource issues were found. Additional considerations: None

• • • •

Very low Low Moderate High

• No included studies

RECOMMENDATIONS 6 AND 7

Does the cost-effectiveness of the intervention favour the intervention or the comparison?

• Favours the comparison • Probably favours the comparison

• Does not favour either the intervention or the comparison • Probably favours the intervention • Favours the intervention

Research evidence: A cost analysis published in 2010 estimated costs of prophylaxis with povidone iodine, 2.5%, erythromycin 0.5%, or azithromycin 1% in the United States of America (USA). Costs were considered in the USA and included preparation of the medications, but outcomes of prophylaxis were not calculated. The analysis was based on 354 000 births per month. The average monthly estimated cost of universal prophylaxis was $2.8 million for povidone iodine (assuming costs of $7.77 per infant), $0.7 million for erythromycin (assuming $1.94 per infant), and $25.5 million for topical azithromycin (assuming $72.12 per infant). Authors reported that there was initial concern that the detergent formulation of povidone iodine could mistakenly be applied to infants’ eyes, but that preparation and delivery would be distinguishable. Additional considerations: Cost-effectiveness may not consider the long-term consequences of prophylaxis. Costs favour the use of prophylaxis to prevent long-term consequences. Research evidence: No studies assessed equity issues. Additional considerations: Tetracycline is more available and more procured than erythromycin. Prophylaxis is currently provided in most settings; therefore, there is probably no impact on equity.

Cost-effectiveness Equity Acceptability Feasibility

• Varies • No included studies What would be the impact on health equity?

• • • • •

Reduced Probably reduced Probably no impact Probably increased Increased

• Varies • Don’t know Is the intervention acceptable to key stakeholders? Research evidence: No studies assessed acceptability. Additional considerations: Prophylaxis is currently being provided in most settings and acceptable to a majority of stakeholders.

• • • •

No Probably no Probably yes Yes

• Varies • Don’t know Is the intervention feasible to implement? Research evidence: No studies assessed feasibility. Additional considerations: Prophylaxis is currently being provided in most settings.

• • • •

No Probably no Probably yes Yes

• Varies • Don’t know

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

SUMMARY OF JUDGEMENTS

Judgement Problem Desirable effects Undesirable effects Certainty of evidence Values No Trivial Large Very low Important uncertainty or variability Favours the comparison Probably no Small Moderate Low Possibly important uncertainty or variability Probably favours the comparison Probably yes Moderate Small Moderate Probably no important uncertainty or variability Does not favour either the intervention or the comparison Negligible costs and savings Moderate Yes Large Trivial High No important uncertainty or variability Probably favours the intervention Favours the intervention Varies Varies Varies Varies Don’t know Don’t know Don’t know No included studies No known undesirable outcomes Don’t know

Balance of effects

Resources required Certainty of evidence of required resources Costeffectiveness

Large costs

Moderate costs Low

Moderate savings High

Large savings

Varies

Don’t know

Very low

No included studies

Favours the comparison

Probably favours the comparison

Does not favour either the intervention or the comparison Probably no impact Probably yes Probably yes

Probably favours the intervention

Favours the intervention

Varies

No included studies

Equity Acceptability Feasibility

Reduced No No

Probably reduced Probably no Probably no

Probably increased Yes Yes

Increased

Varies Varies Varies

Don’t know Don’t know Don’t know

CONCLUSIONS

Prevention of gonococcal and chlamydial ophthalmia neonatorum in neonates?

Type of recommendation

Strong recommendation against the intervention

Conditional recommendation against the intervention • • •

Conditional recommendation for either the intervention or the comparison

Conditional recommendation for the intervention

Strong recommendation for the intervention

•

Recommendation

For all neonates, the WHO STI guideline recommends topical ocular prophylaxis for the prevention of gonococcal and chlamydial ophthalmia neonatorum. Strong recommendation, low quality evidence

For ocular prophylaxis, the WHO STI guideline suggests one of the following options for topical application to both eyes immediately after birth:

• • • • •

Tetracycline hydrochloride 1% eye ointment Erythromycin 0.5% eye ointment Povidone iodine 2.5% solution (water-based) Silver nitrate 1% solution Chloramphenicol 1% eye ointment Conditional recommendation, low quality evidence

Remarks: This recommendation applies to the prevention of both chlamydial and gonococcal ophthalmia neonatorum. Cost and local resistance to erythromycin, tetracycline and chloramphenicol in gonococcal infection may determine the choice of drug. Caution should be taken to avoid touching eye tissue when applying the topical treatment and to provide a water-based solution of povidone iodine. DO NOT USE ALCOHOL-BASED POVIDONE IODINE SOLUTION.

Justification

Overall, the quality evidence from 16 studies is low to very low: 15 randomized and 1 non-randomized study with 2 comparison groups. There is little data for the effects of chloramphenicol. There were large benefits of prophylaxis compared with no prophylaxis, particularly in babies born to women with known infection (approximate 70% reduction in conjunctivitis with prophylaxis using different drugs). The benefits with different drugs are similar, however, the low- to very-low-quality evidence shows that benefits of tetracycline hydrochloride, erythromycin, or povidone iodine may be slightly greater than silver nitrate. Little data is available for the incidence of non-infectious conjunctivitis after prophylaxis or no prophylaxis. Low-quality evidence shows a reduction or little difference. Low-quality evidence shows between 4 and 50 per 1000 infants have non-infectious conjunctivitis after application of different prophylaxis.

RECOMMENDATIONS 6 AND 7

There is little evidence for patient values and preferences, but the GDG agreed that there would likely be little difference in the high value placed on avoiding long-term consequences of both gonococcal or chlamydial conjunctivitis. The GDG also agreed that there would be little effect on acceptability, equity and feasibility, as prophylaxis is currently used in many countries. The GDG reported that alcohol-based povidone iodine has erroneously been used as prophylaxis resulting in serious harm to babies. Silver nitrate is the most expensive prophylaxis option. In summary, there are large benefits for prophylaxis to prevent ophthalmia neonatorum, which are greater than the risk of non-infectious conjunctivitis due to prophylaxis with any of the topical drugs. Some topical drugs may provide greater protection (tetracycline hydrochloride, erythromycin, or povidone iodine), but all are feasible to provide.

Type of recommendation

Strong recommendation against the intervention

Conditional recommendation against the intervention • • •

Conditional recommendation for either the intervention or the comparison

Conditional recommendation for the intervention

Strong recommendation for the intervention

•

Justification

In summary, there are large benefits for prophylaxis to prevent ophthalmia neonatorum, which are greater than the risk of non-infectious conjunctivitis due to prophylaxis with any of the topical drugs. Some topical drugs may provide greater protection (tetracycline hydrochloride, erythromycin, or povidone-iodine), but all are feasible to provide.

Subgroup considerations

Implementation considerations

Monitoring and evaluation

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Research priorities

The prevalence of gonococcal ophthalmia should be determined, given the high prevalence of maternal gonorrhoea in some settings. The state of resistance to the medications should be explored, and it should be established whether these organisms would be killed by ocular prophylaxis despite resistant strains being established in the organisms. More research comparing the benefits and harms of the different drugs is needed, in particular comparisons with chloramphenicol.

EVIDENCE PROFILES

For prevention of gonococcal and chlamydial ophthalmia neonatorum in neonates, what are the effects of different interventions?

Treatments versus erythromycin

Silver nitrate 1% vs erythromycin 0.5% Relative effect (95% CI) Risk with erythromycin 0.5% Risk difference with silver nitrate Anticipated absolute effects

Outcomes

No. of participants (studies) Follow-up

Quality of the evidence (GRADE)

Incidence of conjunctivitis among Infants exposed to chlamydia during delivery RR 3.59 (0.25 to 50.99) 70 per 1000 181 more per 1000 (53 fewer to 3499 more)

228 (2 RCTs)

VERY LOW1,3

Incidence of gonococcal conjunctivitis RR 0.39 (0.14 to 1.08) 3 per 1000 3 per 1000 RR 3.27 (0.18 to 60.82) 2 fewer per 1000 (3 fewer to 0 fewer) 7 more per 1000 (2 fewer to 179 more)

12808 (4 RCTs)

LOW1,3

47424 (1 Non-RCTs )

VERY LOW3,4

Incidence of chlamydial conjunctivitis 28 per 1000 28 per 1000 11 more per 1000 (0 fewer to 26 more) 21 fewer per 1000 (26 fewer to 4 fewer) RR 1.38 (0.99 to 1.92) RR 0.24 (0.07 to 0.86)

5324 (3 RCTs)

LOW

1,3

47424 (1 Non-RCT)

VERY LOW4

Incidence of infectious conjunctivitis 78 per 1000 78 per 1000 12 more per 1000 (4 fewer to 32 more) 47 fewer per 1000 (59 fewer to 29 fewer) RR 1.15 (0.95 to 1.41) RR 0.39 (0.24 to 0.63)

2041 (1 RCT)

LOW

1,3

RECOMMENDATIONS 6 AND 7

47424 (1 Non-RCT)

LOW4

Silver nitrate 1% vs erythromycin 0.5% Relative effect (95% CI) Risk with erythromycin 0.5% Risk difference with silver nitrate Anticipated absolute effects

Outcomes

No. of participants (studies) Follow-up

Quality of the evidence (GRADE)

Incidence of conjunctivitis among Infants exposed to chlamydia during delivery

Incidence of non-infectious conjunctivitis 70 per 1000 70 per 1000 33 fewer per 1000 (53 fewer to 10 more) 3 more per 1000 (11 fewer to 21 more) RR 1.04 (0.84 to 1.30) RR 0.53 (0.25 to 1.14)

2041 (1 RCT)

LOW

1,3

47424 (1 Non-RCT)

VERY LOW3,4

Side-effects – not measured

Keratitis – not measured

Complications – not measured

Blindness – not measured

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Corneal scarring – not measured

Tetracycline 1% vs erythromycin 0.5% Relative effect (95% CI) Risk with erythromycin 0.5% Risk difference with tetracycline 1% Anticipated absolute effects

Outcomes

No. of participants (studies) Follow-up

Quality of the evidence (GRADE)

Incidence of conjunctivitis among Infants exposed to chlamydia during delivery RR 0.80 (0.34 to 1.89) 70 per 1000 14 fewer per 1000 (46 fewer to 62 more)

154 (1 RCT)

VERY LOW1,3

Incidence of gonococcal conjunctivitis RR 0.70 (0.16 to 3.12) 3 per 1000 1 fewer per 1000 (3 fewer to 6 more)

10,946 (2 RCTs)

VERY LOW1,3

Incidence of chlamydial conjunctivitis 28 per 1000 3 fewer per 1000 (13 fewer to 16 more) 1,3

2744 (1 RCT)

VERY LOW

RR 0.90 (0.52 to 1.57)

Incidence of infectious conjunctivitis – not measured

Incidence of non-infectious conjunctivitis – not measured

Side-effects – not measured

Keratitis – not measured

Complications – not measured

Blindness – not measured

Corneal scarring – not measured

RECOMMENDATIONS 6 AND 7 75

Povidone iodine 2.5% vs erythromycin 0.5% Relative effect (95% CI) Risk with erythromycin 0.5% Risk difference with povidone iodine 2.5% Anticipated absolute effects

Outcomes

No. of participants (studies) Follow-up

Quality of the evidence (GRADE)

Incidence of gonococcal conjunctivitis RR 0.85 (0.35 to 2.03) 3 per 1000 0 fewer per 1000 (2 fewer to 3 more)

2391 (2 RCTs)

LOW1,3

Incidence of chlamydial conjunctivitis RR 0.76 (0.55 to 1.05) 28 per 1000 7 fewer per 1000 (13 fewer to 1 more)

2391 (2 RCTs)

LOW1,3

Incidence of infectious conjunctivitis 78 per 1000 10 fewer per 1000 (22 fewer to 5 more) RR 0.87 (0.71 to 1.07)

2391 (2 RCTs)

LOW

1,3

Incidence of non-infectious conjunctivitis 70 per 1000 34 fewer per 1000 (55 fewer to 20 more) RR 0.52 (0.21 to 1.28)

2391 (2 RCTs)

LOW

1,3

Side-effects – not measured

Keratitis – not measured

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Complications – not measured

Blindness – not measured

Corneal scarring – not measured

Treatments versus tetracycline 1%

Silver nitrate 1% vs tetracycline 1% Relative effect (95% CI) Risk with tetracycline 1% Risk difference with silver nitrate 1% Anticipated absolute effects

Outcomes

No. of participants (studies) Follow-up

Quality of the evidence (GRADE)

Conjunctivitis among Infants exposed to gonorrhoea during delivery RR 2.32 0.47 to 11.57) 30 per 1000 40 more per 1000 (16 fewer to 317 more)

137 (1 RCT)

VERY LOW1,2,3

Incidence of conjunctivitis among infants exposed to chlamydia during delivery RR 1.58 (0.86 to 2.90) 90 per 1000 52 more per 1000 (13 fewer to 171 more)

348 (2 RCTs)

VERY LOW1,2,3

Incidence of gonococcal conjunctivitis 1 per 1000 0 fewer per 1000 (0 fewer to 6 more) RR 1.39 (0.16 to 12.13)

14501 (5 RCTs)

LOW

1,3

Incidence of chlamydial conjunctivitis 7 per 1000 2 more per 1000 (2 fewer to 9 more) RR 1.31 (0.76 to 2.25)

5870 (3 RCTs)

LOW

1,3

Incidence of infectious conjunctivitis RR 1.40 (1.09 to 1.79) 52 per 1000 21 more per 1000 (5 more to 41 more)

3991 (3 RCTs)

LOW1,3

Incidence of non-infectious conjunctivitis RR 1.25 (0.80 to 1.97) 18 per 1000 4 more per 1000 (3 fewer to 17 more)

1259 (2 RCTs)

LOW1,3

Side-effects – not measured

Keratitis – not measured

Complications – not measured

RECOMMENDATIONS 6 AND 7

Blindness – not measured

Povidone iodine 2.5% vs tetracycline 1% Relative effect (95% CI) Risk with tetracycline 1% Risk difference with povidone iodine 2.5% Anticipated absolute effects

Outcomes

No. of participants (studies) Follow-up

Quality of the evidence (GRADE)

Incidence of gonococcal conjunctivitis not estimable – no events occurred

394 (1 RCT)

VERY LOW1,2

Incidence of chlamydial conjunctivitis not estimable – no events occurred

394 (1 RCT)

VERY LOW1,2

Incidence of infectious conjunctivitis 52 per 1000 53 more per 1000 (2 fewer to 164 more) 1,2,3

394 (1 RCT)

VERY LOW

RR 2.02 (0.97 to 4.17)

Incidence of non-infectious conjunctivitis 18 per 1000 345 more per 1000 (from 3 more to 1000 more) 1,2

394 (1 RCT)

VERY LOW

RR 20.17 (1.19 to 341.82)

Side-effects and complications not estimable – no events occurred

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

394 (1 RCT)

VERY LOW1,2

Keratitis – not measured

Complications – not measured

Blindness – not measured

Corneal scarring – not measured

Povidone iodine versus other treatments

Povidone iodine 2.5% vs silver nitrate 1% Relative effect (95% CI) Risk with silver nitrate Risk difference with povidone iodine 2.5% Anticipated absolute effects

Outcomes

No. of participants (studies) Follow-up

Quality of the evidence (GRADE)

Incidence of gonococcal conjunctivitis RR 1.94 (0.60 to 6.29) 4 per 1000 4 more per 1000 (2 fewer to 23 more)

2005 (1 RCT)

VERY LOW1,2,3

Incidence of chlamydial conjunctivitis RR 0.52 (0.38 to 0.71) 110 per 1000 53 fewer per 1000 (68 fewer to 32 fewer)

2005 (1 RCT)

LOW1

Incidence of infectious conjunctivitis RR 0.75 (0.61 to 0.92) 176 per 1000 44 fewer per 1000 (68 fewer to 14 fewer)

2005 (1 RCT)

LOW1

Incidence of non-infectious conjunctivitis 139 per 1000 42 fewer per 1000 (63 fewer to 15 fewer) RR 0.70 (0.55 to 0.89)

2005 (1 RCT)

LOW

Side-effects - not measured

Keratitis – not measured

Complications – not measured

Blindness – not measured RECOMMENDATIONS 6 AND 7

Corneal scarring – not measured

Povidone iodine 2.5% vs chloramphenicol eye drops Relative effect (95% CI) Risk with chloramphenicol eye drops Risk difference with povidone iodine 2.5% Anticipated absolute effects

Outcomes

No. of participants (studies) Follow-up

Quality of the evidence (GRADE)

Incidence of gonococcal conjunctivitis not estimable – no events occurred

2004 (1 RCT)

LOW1

Incidence of chlamydial conjunctivitis RR 1.77 (0.97 to 3.22) 20 per 1000 15 more per 1000 (1 fewer to 44 more)

2004 (1 RCT)

LOW3

Incidence of infectious conjunctivitis 79 per 1000 29 more per 1000 (2 more to 63 more) RR 1.36 (1.03 to 1.79)

2004 (1 RCT)

LOW

1,3

Incidence of non-infectious conjunctivitis 4 per 1000 4 fewer per 1000 (4 fewer to 4 more) 1,3

2004 (1 RCT)

VERY LOW

RR 0.10 (0.01 to 1.94)

Side-effects Author reports, ocular side-effects were rare and self-limiting in both groups (P = 0.223).

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

2004 (1 non-RCT)

VERY LOW1,4

Keratitis – not measured

Complications – not measured

Blindness – not measured

Corneal scarring – not measured

Povidone iodine 2 drops and povidone iodine 1 drop Quality of the evidence (GRADE) Risk with povidone iodine 1 drop Risk difference with povidone iodine 2 drops Relative effect (95% CI) Anticipated absolute effects

Outcomes

No. of participants (studies) Follow-up

Incidence of gonococcal conjunctivitis VERY LOW 1,2

719 (1 RCT)

not estimable – no events occurred

Povidone iodine 2 drops and povidone iodine 1 drop Relative effect (95% CI) Risk with povidone iodine 1 drop Anticipated absolute effects Risk difference with povidone iodine 2 drops

Outcomes

No. of participants (studies) Follow-up

Quality of the evidence (GRADE)

Incidence of chlamydial conjunctivitis RR 1.27 (0.26 to 6.24) 8 per 1000 2 more per 1000 (6 fewer to 39 more)

719 (1 RCT)

VERY LOW1,2

Incidence of infectious conjunctivitis 22 per 1000 12 more per 1000 (8 fewer to 60 more) 1,2

719 (1 RCT)

VERY LOW

RR 1.55 (0.65 to 3.69)

Incidence of non-infectious conjunctivitis 169 per 1000 49 more per 1000 (8 fewer to 125 more) 1,2

719 (1 RCT)

VERY LOW

RR 1.29 (0.95 to 1.74)

Side-effects – not measured

Inflammation (conjunctival redness, swelling and discharge) Authors report no differences between the two groups. However, eyelid oedema was significantly greater in the double-dose group than the single (scores 1.4 [67] vs 1.2 [73], P =0.0002).

719 (1 RCT)

VERY LOW1,2

Keratitis – not measured

Complications – not measured

RECOMMENDATIONS 6 AND 7

Blindness – not measured

Corneal scarring – not measured

One treatment versus no treatment

Silver nitrate 1% vs no treatment Relative effect (95% CI) Risk with no treatment Risk difference with silver nitrate 1% Anticipated absolute effects

Outcomes

No. of participants (studies) Follow-up

Quality of the evidence (GRADE)

Conjunctivitis among Infants exposed to gonorrhoea during delivery RR 0.17 (0.07 to 0.41) 418 per 1000 347 fewer per 1000 (389 fewer to 247 fewer)

138 (1 RCT)

LOW1,2

Incidence of conjunctivitis among Infants exposed to chlamydia during delivery 313 per 1000 213 fewer per 1000 (260 fewer to 125 fewer) RR 0.32 (0.17 to 0.60)

300 (1 RCT)

LOW

1,2

Incidence of gonococcal conjunctivitis 20 per 1000 17 fewer per 1000 (19 fewer to 14 fewer) RR 0.14 (0.06 to 0.31)

4804 (3 RCTs)

LOW

1,2

Incidence of chlamydial conjunctivitis 37 per 1000 24 fewer per 1000 (36 fewer to 78 more) 1,3

4477 (2 RCTs)

VERY LOW

RR 0.36 (0.04 to 3.12)

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Incidence of infectious conjunctivitis RR 0.27 (0.05 to 1.37) 75 per 1000 54 fewer per 1000 (71 fewer to 28 more)

2579 (2 RCTs)

MODERATE3

Incidence of non-infectious conjunctivitis – not measured

Side-effects – not measured

Keratitis – not measured

Complications – not measured

Blindness – not measured

Corneal scarring – not measured

Tetracycline 1% vs no treatment Relative effect (95% CI) Risk with no treatment Risk difference with tetracycline 1% Anticipated absolute effects

Outcomes

No. of participants (studies) Follow-up

Quality of the evidence (GRADE)

Incidence of conjunctivitis among Infants exposed to gonorrhoea during delivery 420 per 1000 391 fewer per 1000 (412 fewer to 298 fewer) 1,2

133 (1 RCT)

VERY LOW

RR 0.07 (0.02 to 0.29)

Incidence of conjunctivitis among infants exposed to chlamydia during delivery 310 per 1000 239 fewer per 1000 (from 167 fewer to 276 fewer) 1,2

312 (1 RCT)

VERY LOW

RR 0.23 (0.11 to 0.46)

Incidence of gonococcal conjunctivitis RR 0.05 (0.01 to 0.17) 20 per 1000 19 fewer per 1000 (20 fewer to 17 fewer)

5031 (3 RCTs)

LOW1

Incidence of chlamydial conjunctivitis RR 0.26 (0.02 to 2.69) 37 per 1000 27 fewer per 1000 (36 fewer to 63 more)

4817 (2 RCTs)

LOW3

Incidence of infectious conjunctivitis 75 per 1000 53 fewer per 100 0 (58 fewer to 47 fewer) 1

2732 (2 RCTs)

MODERATE

RR 0.29 (0.22 to 0.37)

Incidence of non-infectious conjunctivitis – not measured

Side-effects – not measured

Keratitis – not measured

Complications – not measured

Blindness – not measured

RECOMMENDATIONS 6 AND 7

Corneal scarring – not measured

Erythromycin 0.5% vs no treatment Relative effect (95% CI) Risk with no treatment Risk difference with erythromycin 0.5% Anticipated absolute effects

Outcomes

No. of participants (studies) Follow-up

Quality of the evidence (GRADE)

Incidence of gonococcal conjunctivitis not estimable – no events occurred

3170 (3 RCTs)

LOW1

Incidence of chlamydial conjunctivitis RR 0.92 (0.55 to 1.56) 37 per 1000 3 fewer per 1000 (17 fewer to 21 more)

4048 (2 RCTs)

LOW1,3

Incidence of infectious conjunctivitis 75 per 1000 13 fewer per 1000 (57 fewer to 150 more) 1,2,3

210 (1 RCT)

VERY LOW

RR 0.83 (0.23 to 3.01)

Incidence of non-infectious conjunctivitis 153 per 1000 28 fewer per 1000 (86 fewer to 81 more) 1,2,3

210 (1 RCT)

VERY LOW

RR 0.82 (0.44 to 1.53)

Incidence of non-infectious conjunctivitis Author reports no significant differences between groups - clinical or culture were observed. In drug-free group, 53 (38.4%) cases were observed, and in normal saline group, 44 cases (31.9%). Cultures were performed for 111 newborns (11.1%), 91 cases (9.1%) were positive and 20 newborns (2%) were negative. Greatest number of negative cultures were in the normal saline group and erythromycin group stood second.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

210 (1 RCT)

VERY LOW1,2

Side-effects – not measured

Keratitis – not measured

Complications – not measured

Blindness – not measured

Corneal scarring – not measured

Povidone iodine 2.5% vs no treatment Relative effect (95% CI) Risk with no treatment Risk difference with povidone iodine 2.5% Anticipated absolute effects

Outcomes

No. of participants (studies) Follow-up

Quality of the evidence (GRADE)

Incidence of gonococcal conjunctivitis not estimable – no events occurred

706 (2 RCTs)

VERY LOW1,2

Incidence of chlamydial conjunctivitis RR 2.14 (0.20 to 23.24) 37 per 1000 42 more per 1000 (30 fewer to 823 more)

706 (2 RCTs)

VERY LOW1,2,3

Incidence of infectious conjunctivitis 75 per 1000 3 more per 1000 (36 fewer to 80 more) 1,2,3

706 (2 RCTs)

VERY LOW

RR 1.04 (0.52 to 2.08)

Incidence of non-infectious conjunctivitis 153 per 1000 73 fewer per 1000 (136 fewer to 228 more) 1,2,3

706 (2 RCTs)

VERY LOW

RR 0.52 (0.11 to 2.49)

Side-effects – not measured

Keratitis – not measured

Complications – not measured

Blindness – not measured

Corneal scarring – not measured

Few events across studies.

RECOMMENDATIONS 6 AND 7

Sample size does not meet optimum minimum sample size criteria.

95% CI includes potential for more or fewer events.

4. Non-RCT, and authors did not mention any information related to the use of an appropriate analysis method that adjusted for all the critically important confounding domains.

WHO GUIDELINES FOR THE TREATMENT OF TREPONEMA PALLIDUM (SYPHILIS)

Resistance to prophylaxis Tetracycline may prove inconvenient as it may select resistant strains (Ison, 1988). Erythromycin 0.5% also selects resistant bacterial strains (Schwarcz, 1990; Hedberg, 1990). Povidone iodine 2.5% does not select resistant strains (Isenberg, 1995). Moreover Knapp et al. (1987) reported tetracycline resistant N. gonorrhoeae (TRNG) in the USA. Isolates of TRNG have been confirmed from 17 states. In addition, unconfirmed reports based on disk-diffusion testing in local laboratories have been reported from Alabama and the District of Columbia.

Included studies 1. Ali Z, Khadije D, Elahe A, Mohammad M, Fateme Z, Narges Z. Prophylaxis of ophthalmia neonatorum comparison of betadine, erythromycin and no prophylaxis. J Trop Pediatr. 2007;53(6):38892. 2. Brussieux J, Boisivon A, Théron HP, Faidherbe C, Machado N, Michelon B. [Prevention of neonatal conjunctivitis. A comparative clinical and bacteriologic study of 2 eyedrops: silver nitrate and oxytetracycline]. Ann Pediatr. 1991;36(9):637-41 (in French). 3. Chen JY. Prophylaxis of ophthalmia neonatorum: comparison of silver nitrate, tetracycline, erythromycin and no prophylaxis. Pediatr Infect Dis J.1992;11(12):1026-30. 4. David M, Rumelt S, Weintraub Z. Efficacy comparison between povidone iodine 2.5% and tetracycline 1% in prevention of ophthalmia neonatorum. Ophthalmology. 2011;118(7):1454-8. 5. Fischer PR, Reta BB. Prevention of neonatal conjunctivitis in Zaire. Ann Trop Paediatr. 1988;8(2):85-6. 6. Hammerschlag MR, Cummings C, Roblin PM, Williams TH, Delke I. Efficacy of neonatal ocular prophylaxis for the prevention of chlamydial and gonococcal conjunctivitis. N Engl J Med. 1989;320(12):769-72. 7. Hammerschlag MR, Chandler JW, Alexander ER, English M, Chiang WT, Koutsky L, et al. Erythromycin ointment for ocular prophylaxis of neonatal chlamydial infection. JAMA. 1980;244(20):2291-3. 8. Hammerschlag MR, Chandler JW, Alexander ER, English M, Koutsky L. Longitudinal studies on chlamydial infections in the first year of life. Pediatr Infect Dis. 1982;1(6):395-401. 9. Isenberg SJ, Apt L, Del Signore M, Gichuhi S, Berman NG. A double application approach to ophthalmia neonatorum prophylaxis. Br J Ophthalmol. 2003; 87(12):1449-52. 10. Isenberg SJ, Apt L, Wood M. A controlled trial of povidone-iodine as prophylaxis against ophthalmia neonatorum. N Engl J Med. 1995;332(9):562-6. 11. Laga M, Plummer FA, Plot P, Datta P, Namaara W, Neinya-Achola JO, et al. Prophylaxis of gonococcal and chlamydial ophthalmia neonatorum. A comparison of silver nitrate and tetracycline. N Engl J Med. 1988;318(11):653-7. 12. Matinzadeh ZK, Beiragdar F, Kavemanesh Z, Abolgasemi H, Amirsalari S. Efficacy of topical ophthalmic prophylaxis in prevention of ophthalmia neonatorum. Trop Doct. 2007;37(1):479. 13. Ozkan H, Abacioglu H, Duman N, Celikkol B, Ozkutuk A. A controlled trial of efficacy and safety of povidone- iodine as prophylaxis against ophthalmia neonatorum. Çocuk Sağliği ve Hastaliklari Dergisi [J of Child Health Dis]. 1999;42(4):459-67 (in Turkish). 14. Ramirez-Ortiz MA, Rodriguez-Almaraz M, Ochoa-Diazlopez H, Diaz-Prieto P, Rodriguez-Suárez RS. Randomised equivalency trial comparing 2.5% povidone-iodine eye drops and ophthalmic chloramphenicol for preventing neonatal conjunctivitis in a trachoma endemic area in southern Mexico. Br J Ophthalmology. 2007;91(11):1430-4 15. Steigleder GK. [Efficacy of neonatal ocular prophylaxis for the prevention of chlamydial and gonococcal conjunctivitis]. Z Hautkr. 1989;64(5):347 (in German). 16. Zanoni D, Isenberg SJ, Apt L. A comparison of silver nitrate with erythromycin for prophylaxis against ophthalmia neonatorum. Clin Pediatr. 1992;31(5):295-8.

REFERENCES References for the resistance data 1. Hedberg K, Ristinen TL, Soler JT, White KE, Hedberg CW, Osterholm MT, et al. Outbreak of erythromycin resistant staphylococcal conjunctivitis in a newborn nursery. Pediatr Infect Dis J 1990;9(4):268-73. 2. Isenberg SJ, Apt L, Wood M. A controlled trial of povidone-iodine as prophylaxis against ophthalmia neonatorum. N Engl J Med. 1995;332(9):562-6. 3. Ison CA, Terry P, Bendayna K, Gill MJ, Adams J, Woodford N. Tetracycline-resistant gonococci in UK. Lancet. 1988; 1(8586):651-2. 4. Knapp JS, Zenilman JM, Biddle JW, Perkins GH, DeWitt WE, Thomas ML, et al. Frequency and distribution in the United States of strains of Neisseria gonorrhoeae with plasmidmediated, high-level resistance to tetracycline. J Infect Dis. 1987;155(4):819-22. 5. Schwarcz SK, Zenilman JM, Schnell D, Knapp JS, Hook EW 3rd, Thompson S, et al. National surveillance of antimicrobial resistance in Neisseria gonorrhoeae. The Gonococcal Isolate Surveillance Project. JAMA. 1990;264:1413–7. Systematic reviews 1. Darling EK, McDonald H. A meta-analysis of the efficacy of ocular prophylactic agents used for the prevention of gonococcal and chlamydial ophthalmia neonatorum. J Midwifery Womens Health. 2010;55(4):319-27. doi:10.1016/j.jmwh.2009.09.003. 2. Kapoor VS, Whyte R, LaRoche RR. Interventions for preventing ophthalmia neonatorum (protocol). Cochrane Database Syst Rev. 2015;(12):CD001862. 3. Mabry-Hernandez IR, Koenig HC. Ocular prophylaxis for gonococcal ophthalmia neonatorum: evidence update for the U.S. Preventive Services Task Force Reaffirmation Recommendation Statement. AHRQ Publication No. 10-05146. Rockville (MD): Agency for Healthcare Research and Quality; 2010. 4. Zuppa AA, D’Andrea V, Catenazzi P, Scorrano A, Romagnoli C. Ophthalmia neonatorum: what kind of prophylaxis? J Matern Fetal Neonatal Med. 2011;24(6):769–73. doi:10.3109/14767058.2 010.531326.

RECOMMENDATIONS 6 AND 7

References related to patient values and preferences, acceptability and cost 1. Deogan CL, Bocangel MK, Wamala SP, Månsdotter AM. A costeffectiveness analysis of the Chlamydia Monday – a communitybased intervention to decrease the prevalence of chlamydia in Sweden. Scand J Public Health. 2010;38(2):141-50. 2. Keenan JD, Eckert S, Rutar T. Cost analysis of povidone-iodine for ophthalmia neonatorum prophylaxis. Arch Ophthalmol. 2010;128(1):136-7. 3. International Drug Price Indicator Guide, 2014 Edition (updated annually). Medford (MA): Management Sciences for Health; 2015 (http://erc.msh.org/dmpguide/pdf/DrugPriceGuide_2014.pdf, accessed 3 June 2016). Additional references 1. Darling EK, McDonald H. A meta-analysis of the efficacy of ocular prophylactic agents used for the prevention of gonococcal and chlamydial ophthalmia neonatorum. J Midwifery Womens Health. 2010;55(4):319-27. doi:10.1016/j.jmwh.2009.09.003. 2. Kakar S, Bhalla P, Maria A, Rana M, Chawla R, Mathur NB. Chlamydia trachomatis causing neonatal conjunctivitis in a tertiary care center. Indian J Med Microbiol. 2010;28(1):45-7. doi:10.4103/0255-0857.58728.

For more information, contact: Department of Reproductive Health and Research World Health Organization Avenue Appia 20, CH-1211 Geneva 27 Switzerland Phone +41 22 791 3264 Fax +41 22 791 4171 E-mail: reproductivehealth@who.int www.who.int/reproductive health

WHO GUIDELINES FOR THE

Treatment of Chlamydia trachomatis Web annex F: Summary of conflicts of interest

The full guidelines are available at: www.who.int/reproductivehealth/publications/rtis/chlamydia-treatment-guidelines/en/

Web annex F – Summary of conflict of interest

WHO Library Cataloguing-in-Publication Data WHO guidelines for the treatment of Chlamydia trachomatis. Contents: Web annex D: Evidence profiles and evidence-to-decision framework -- Web annex E: Systematic reviews -- Web annex F: Summary of conflicts of interest 1.Chlamydia trachomatis. 2.Chlamydia Infections - drug therapy. 3.Sexually Transmitted Diseases. 4.Guideline. I.World Health Organization. ISBN 978 92 4 154971 4 © World Health Organization 2016 All rights reserved. Publications of the World Health Organization are available on the WHO website (http://www.who.int) or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; email: bookorders@who.int). Requests for permission to reproduce or translate WHO publications –whether for sale or for non-commercial distribution– should be addressed to WHO Press through the WHO website (http://www.who.int/about/licensing/copyright_form/index.html).

(NLM classification: WC 600)

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 the World Health Organization 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 the World Health Organization 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 the World Health Organization 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 the World Health Organization be liable for damages arising from its use. Printed by the WHO Document Production Services, Geneva, Switzerland

Web annex F – Summary of conflict of interest

Members of the STI Guideline Development Group (GDG) Name Region Country Institution

Adu-Sarkodie, Yaw (Sax)

AFR

Ghana

Amato, Andrew

EUR

Sweden

Bolan, Gail Changalucha, John

AMR AFR

USA United Republic of Tanzania

School of Medical Sciences, Kwame Nkrumah University of Science and Technology (KNUST) European Centre for Disease Prevention and Control Centers for Disease Control and Prevention (CDC) National Institute for Medical Research, Mwanza Medical Research Centre

Meeting restriction Declared related non-commercial interest or grants No No

No No

No Yes: GSK – research support to evaluate the safety and immunogenicit y of the GSK HPV vaccines (ended 2011); HPV not part of STI guidelines No

No No

Chen, Xiang-

WPR

China

National Center for

WHO guidelines for the treatment of Chlamydia trachomatis

Name

Region

Country

Institution

Meeting restriction Declared related non-commercial interest or grants

Sheng

Chesson, Harrel

AMR

USA

Cohen, Craig

AMR

USA

STD Control, Chinese Academy of Medical Sciences and Peking Union Medical College Division of STI No Prevention, Centers for Disease Control and Prevention (CDC) University of No California, San Francisco

Yes: Consulted in the development of new drugs for bacterial vaginosis – Symbiomix Inc. (US$ 8000) No No

Garcia, Francisco Garcia, Patricia

AMR AMR

USA Peru

Pima County Health No Department School of Public No Health and Administration, Universidad Peruana Cayetano Heredia

No No

Yes: Grants not No related to STI studies (National Institutes of Health [NIH], CDC and the Bill & Melinda Gates Foundation) No No No No

Web annex F – Summary of conflict of interest

Name

Region

Country

Institution

Garland, Suzanne

WPR

Australia

Royal Women’s Hospital

Declarations of conflicts of interest (i.e. related to the topic of the meeting/guideline) Involved Declared Declared any in related any related indirectly academic commercial related work financial commercial interest financial interest No No Yes: Merck – award for HPV (US $5,500) Japan Ministry of Health – surveillance of recurrent respiratory papillomatosis (US$ 50 382); speaker at HPV symposiums GSK – vaccine trial (US$ 98 000)

Meeting restriction Declared related non-commercial interest or grants Yes: IARC – support work in HPV vaccine trials No

Hawkes, Sarah Higgins, Mary

EUR EUR

United Kingdom Netherlands

University College London International

No No

CSLbio – cervical cancer genotypes (US$ 210 000) No No No No

No No

WHO guidelines for the treatment of Chlamydia trachomatis

Name

Region

Country

Institution

Meeting restriction Declared related non-commercial interest or grants

Holmes, King

AMR

USA

Klausner, Jeffrey

AMR

USA

Confederation of Midwives Department of Global Health and Department of Medicine, University of Washington, Harborview Medical Center Division of Infectious Diseases and Program in Global Health, David Geffen School of Medicine and Fielding School of Public Health, University of California, Los Angeles

Yes: Standard Diagnostic – syphilis test provided, travel support (US$ 2000)

Yes: Hologic, Cepheid, Standard Diagnostics, ALere, MedMira, Chembio – free STI tests provided, not related to STI treatment (US$ 5000) Flora Bioscience – candidiasis

No (grant related to STI diagnostics)

Web annex F – Summary of conflict of interest

Name

Region

Country

Institution

Lewis, David

AFR

South Africa

Low, Nicola

EUR

Switzerland

Mabey, David

EUR

United Kingdom Brazil

Miranda, Angelica Espinosa

AMR

Mugo, Nelly Mullick, Saiqa

AFR AFR

Kenya South Africa

Western Sydney Sexual Health Centre, Marie Bashir Institute for Infectious Diseases and Biosecurity, Sydney Medical School Epidemiology and Public Health, University of Bern, Institute of Social and Preventive Medicine London School of Hygiene and Tropical Medicine (LSHTM) Núcleo de Doenças Infecciosas, Universidade Federal do Espirito Santo Kenya Medical Research Institute University of the

Meeting restriction Declared related non-commercial interest or grants No No

No No

WHO guidelines for the treatment of Chlamydia trachomatis

Name

Region

Country

Institution

Meeting restriction Declared related non-commercial interest or grants

Ndowa, Francis Palefsky, Joel

AFR AMR

Zimbabwe USA

Radcliffe, Keith

EUR

United Kingdom

Sabirov, Ulugbek

EUR

Uzbekistan

Schünemann, Holger

AMR

Canada

Witwatersrand, Hillbrow Health Precinct Private practice Division of Infectious Diseases, University of California, San Francisco European STI Guidelines Project, International Union against Sexually Transmitted Infections (IUSTI), Royal Society of Medicine National STI Program, Republican Center for DermatoVenereology Department of Clinical Epidemiology and Biostatistics,

No Yes

No No

Web annex F – Summary of conflict of interest

Name

Region

Country

Institution

Meeting restriction Declared related non-commercial interest or grants

Steen, Richard Stephenson, Judith Unemo, Magnus

EUR EUR EUR

Italy United Kingdom Sweden

Vuylsteke, Bea Wald, Anna

EUR AMR

Belgium USA

McMaster University Erasmus University University College London Department of Laboratory Medicine, Microbiology, Örebro University Hospital Institute of Tropical Medicine University of Washington, Virology Research Clinic, Harborview Medical Center Department of Global Health and Medicine, University of Washington Division of Community

No No No

No No

No Yes: Involved in the development of herpes simplex virus (HSV) vaccination No

No No

Wasserheit, Judith

AMR

USA

Wong, Thomas

AMR

Canada

WHO guidelines for the treatment of Chlamydia trachomatis

Name

Region

Country

Institution

Meeting restriction Declared related non-commercial interest or grants

Workowski, Kimberly A.

AMR

USA

Acquired Infections, Centre for Communicable Diseases and Infection Control, Public Health Agency of Canada Centers for Disease Control and Prevention, Division of Infectious Diseases, Emory University School of Medicine

WHO regions: AFR: African Region; AMR: Region of the Americas; EMR: Eastern Mediterranean Region; EUR: European Region; SEAR: South-East Asia Region; WPR: Western Pacific Region

Web annex F – Summary of conflict of interest

Methodologist Name

Region

Country

Institution

Santesso, Nancy

AMR

Canada

Department of Clinical Epidemiology and Biostatistics, McMaster University

Declarations of conflicts of interest (i.e. related to the topic of the meeting/guideline) Involved in Declared any Declared any related related indirectly academic work commercial related financial commercial interest financial interest No No No

Meeting restriction Declared related noncommercial interest or grants No No

AMR: WHO Region of the Americas

WHO guidelines for the treatment of Chlamydia trachomatis

Members of the External Review Group Name Region Country Institution Declarations of conflicts of interest (i.e. related to the topic of the meeting/guideline) Involved Declared Declared any in related any related indirectly academic work commercial related financial commercial interest financial interest No No No Meeting restriction Declared related noncommercial interest or grants No No

Abu-Raddad, Laith

EMR

Qatar

Akolo, Chris BenakenSchwartz, Adele Betie, Mircea

AMR AMR

USA Brazil

EUR

Republic of Moldova

Chitwarakorn, Anupong

SEAR

Thailand

Department of Public Health, Weill Cornell Medical College, Cornell University, Qatar Foundation – Education City FHI 360 STI, AIDS and Viral Hepatitis Department, Ministry of Health Nicolae Testemițanu State University of Medicine and Pharmacy Department of Diseases Control, Bureau of AIDS, TB and STIs, Ministry of Public Health

No No

Web annex F – Summary of conflict of interest

Name

Region

Country

Institution

Das, Anjana Deal, Carolyn

SEAR AMR

India USA

Gale-Row, Margaret

AMR

Canada

Geisler, William

AMR

USA

FHI 360 National Institute of Allergy and Infectious Diseases (NIAID), United States Department of Health and Human Services, National Institutes of Health Professional Guidelines and Public Health Practice Division, Centre for Communicable Diseases and Infection Control, Public Health Agency of Canada University of Alabama at Birmingham

Meeting restriction Declared related noncommercial interest or grants No No No No

Yes: Activbiotics Pharma, LLC –

Yes: Rifalazil was not included in the

WHO guidelines for the treatment of Chlamydia trachomatis

Name

Region

Country

Institution

Declarations of conflicts of interest (i.e. related to the topic of the meeting/guideline) Involved Declared Declared any in related any related indirectly academic work commercial related financial commercial interest financial interest involved in protocol development of phase 2 clinical trial of rifalazil for chlamydia treatment (US$ 4987) Warner Chilcott LLC – review efficacy data for clinical trial of a chlamydia drug – FDA discussion (US$ 10 640) No

Meeting restriction Declared related noncommercial interest or grants treatment recommendation being discussed for C. trachomatis Served as external reviewer only Participated in the technical discussions

Kettani, Amina

EMR

Morocco

Direction de l’Epidemiologie, Service des MSTsida, Ministry of Health

Web annex F – Summary of conflict of interest

Name

Region

Country

Institution

Kiros, Mizan

AFR

Ethiopia

Latif, Ahmed Philippe Mayaud

AFR EUR

Zimbabwe United Kingdom

McCartney, David

EUR

United Kingdom

Mir, Ali M.

EMR

Pakistan

Disease Prevention and Control Directorate Federal Ministry of Health Public Health Consultant Clinical Research Department, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine Research and Technical Support, International Planned Parenthood Federation Population Council

Meeting restriction Declared related noncommercial interest or grants No No

No No

WHO guidelines for the treatment of Chlamydia trachomatis

Name

Region

Country

Institution

Ortayli, Nuriya Sayabounthavon g, Khantanouvieng Singh, Aman Kumar

EMR WPR

Turkey Lao People’s Democratic Republic India

SEAR

United Nations Population Fund (UNFPA) Center for HIV/AIDS and STIs, Ministry of Health National AIDS Control Organization, Ministry of Health and Family Welfare

Meeting restriction Declared related noncommercial interest or grants No No No No

WHO regions: AFR: African Region; AMR: Region of the Americas; EMR: Eastern Mediterranean Region; EUR: European Region; SEAR: South-East Asia Region; WPR: Western Pacific Region

Key facts

Organisation World Health Organization (WHO)

Document type Publications

Adoption date July 4, 2016

Source World Health Organization