GUIDELINES ON LONG-ACTING INJECTABLE CABOTEGRAVIR FOR HIV PREVENTION WEB ANNEX B. SYSTEMATIC REVIEW, META-ANALYSIS AND GRADE EVIDENCE PROFILE ON SAFETY, EFFICACY, AND EFFECTIVENESS OF LONG-ACTING INJECTABLE CABOTEGRAVIR (CAB-LA) AS PRE-EXPOSURE PROPHYLAXIS (PREP) TO REDUCE THE RISK OF HIV ACQUISITION Virginia Fonner, Kathleen Ridgeway, Ariane van der Straten, Lara Lorenzetti, Nhi Dinh, Michelle Rodolph, Robin Schaefer and Rachel Baggaley Guidelines on long-acting injectable cabotegravir for HIV prevention. Web Annex B. Systematic review, meta-analysis and GRADE evidence profile on safety, efficacy, and effectiveness of long-acting injectable cabotegravir (CAB-LA) as pre-exposure prophylaxis (PrEP) to reduce the risk of HIV acquisition/ Virginia Fonner, Kathleen Ridgeway, Ariane van der Straten, Lara Lorenzetti, Nhi Dinh, Michelle Rodolph et al. ISBN 978-92-4-005412-7 (electronic version) © World Health Organization 2022 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial- ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization (http://www.wipo.int/amc/en/mediation/ rules/). Suggested citation. Fonner V, Ridgeway K, van der Straten A, Lorenzetti L, Dinh N, Rodolph M et al. Web Annex B. Systematic review, meta-analysis and GRADE evidence profile on safety, efficacy, and effectiveness of long-acting injectable cabotegravir (CAB-LA) as pre-exposure prophylaxis (PrEP) to reduce the risk of HIV acquisition. In: Guidelines on long-acting injectable cabotegravir for HIV prevention. Geneva: World Health Organization; 2022. Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris. Sales, rights and licensing. To purchase WHO publications, see http://apps.who.int/bookorders. To submit requests for commercial use and queries on rights and licensing, see https://www.who.int/ copyright. Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. The named authors alone are responsible for the views expressed in this publication. This publication forms part of the WHO guideline entitled Guidelines on long-acting injectable cabotegravir for HIV prevention. It is being made publicly available for transparency purposes and information, in accordance with the WHO handbook for guideline development, 2nd edition (2014). Design and layout by 400 Communications Limited. iiiWeb Annex B. Systematic review, meta-analysis and GRADE evidence profile on safety, efficacy, and effectiveness of long-acting injectable cabotegravir (CAB-LA) as pre-exposure prophylaxis (PrEP) to reduce the risk of HIV acquisition CONTENTS Abstract 1 GRADE evidence profile on systematic review on safety, efficacy, and effectiveness of longacting injectable cabotegravir (CAB-LA) as pre-exposure prophylaxis (PrEP) to reduce the risk of HIV acquisition 3 References 5 1Web Annex B. Systematic review, meta-analysis and GRADE evidence profile on safety, efficacy, and effectiveness of long-acting injectable cabotegravir (CAB-LA) as pre-exposure prophylaxis (PrEP) to reduce the risk of HIV acquisition Virginia Fonner1, Kathleen Ridgeway1, Ariane van der Straten2, Lara Lorenzetti1, Nhi Dinh1, Michelle Rodolph3, Robin Schaefer3, and Rachel Baggaley3 1 Global Health and Population Research, FHI 360, Durham, NC 2 ASTRA Consulting; University of California, San Francisco 3 World Health Organization, CAB-LA Guidelines Team Abstract Background: HIV remains a significant health threat, despite the increasing availability of effective HIV prevention tools, such as oral pre-exposure prophylaxis (PrEP). Long-acting injectable cabotegravir (CAB-LA) is one potential new PrEP option, and results from several efficacy studies on CAB-LA have recently become available. The purpose of this review was to synthesize the evidence to determine the overall effectiveness, cost–effectiveness, and safety of CAB-LA as PrEP to inform global guidelines about whether CAB-LA should be recommended as an additional prevention option for people at substantial risk of HIV infection. Methods: A comprehensive search strategy reviewed multiple electronic databases and conference abstracts for relevant citations between January 2010 and September 2021, with additional information solicited from experts. Outcomes of interest included HIV infection, adverse events, drug resistance, pregnancy-related adverse events, and outcomes relevant to sexual behaviour. Pooled effect estimates were calculated using random-effects meta-analysis. When meta-analysis was infeasible, results were summarized narratively. Data were summarized and evaluated using the GRADE methodology, with attention to evidence certainty. Results: Four studies were included, comprising 9 articles and 3 conference abstracts, including two phase 2a safety studies and two phase 2b/3 efficacy studies. All studies were multi-site, double-blind randomized controlled trials. The efficacy studies, HPTN 083 and HPTN 084 compared participants assigned to CAB-LA to participants assigned to oral PrEP (tenofovir disoproxil fumarate–emtricitabine, TDF-FTC). The phase 2a studies, ECLAIR and HPTN 077, compared CAB-LA to placebo. Study populations included cisgender men, cisgender women, transgender women, and a small number of transgender men. Overall 8120 individuals were enrolled across the four trials, with 4114 individuals randomized to receive active CAB-LA. The pooled effect estimate in meta-analysis of HIV infections reported in the two efficacy studies yielded a relative risk of 0.21 (95% CI: 0.07–0.61) comparing CAB-LA to TDF-FTC, resulting in a 79% reduction in HIV risk. Rates of adverse events and serious adverse events were similar across arms, although injection site reactions occurred more frequently in the CAB-LA arms. Out of 20 HIV infections identified among the groups randomized to CAB-LA, seven 7 exhibited resistance to integrase inhibitors (INSTI), suggesting CAB-LA is associated with INSTI drug resistance, although very few cases were identified. Although data related to pregnancy-related adverse events were sparse, no drug-related concerns were identified. Regarding sexual behaviour, STI incidence was similar across arms. Conclusion: CAB-LA is an effective means of HIV prevention and appears to have few safety risks beyond injection site reactions. CAB-LA may lead to an increased risk of INSTI resistance among those who begin taking CAB-LA while acutely infected or who experience a breakthrough infection. No cases of drug resistance were found among those who seroconverted during the “tail phase.” However, results from this review primarily focus on several controlled studies; more research is needed to understand implementation of CAB-LA outside of research settings. Additionally, more data are needed regarding the safety of CAB-LA during pregnancy and among populations not included in the trials, such as people who inject drugs, adolescents, sex workers, and transgender men. Guidelines on long-acting injectable cabotegravir for HIV prevention2 GRADE evidence profile on systematic review on safety, efficacy, and effectiveness of long-acting injectable cabotegravir (CAB-LA) as pre-exposure prophylaxis (PrEP) to reduce the risk of HIV acquisition Author(s): V. Fonner and K. Ridgeway Question: CAB-LA compared to oral PrEP for be offered as an additional prevention choice for people at substantial risk of HIV infection as part of combination prevention approaches Setting: global Bibliography: See references below Certainty assessment No. of patients Effect Certainty ImportanceNo. of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations CAB-LA oral PrEP Relative (95% CI) Absolute (95% CI) HIV infection 21,2 randomized trials not serious not serious not seriousa not seriousb none 17/3835 (0.4%) 75/3833 (2.0%) RR 0.21 (0.07 to 0.61) 15 fewer per 1000 (from 18 fewer to 8 fewer) ⨁⨁⨁⨁ High CRITICAL Any adverse event (measured as any grade 2+ adverse event) 21,2 randomized trials not serious not serious not serious not serious none 3593/3894 (92.3%) 3602/3892 (92.5%) RR 1.00 (0.98 to 1.01) 0 fewer per 1000 (from 19 fewer to 9 more) ⨁⨁⨁⨁ High CRITICAL Any grade 3 or 4 adverse event (measured as any serious adverse event) 21,2 randomized trials not serious not serious not serious not serious none 152/3894 (3.9%) 154/3892 (4.0%) RR 0.99 (0.79 to 1.23) 0 fewer per 1000 (from 8 fewer to 9 more) ⨁⨁⨁⨁ High IMPORTANT INSTI drug resistant infections 23,4 randomized trials not serious not serious not serious seriousc none 7/20 (35.0%) 0/75 (0.0%) RR 20.90 (2.19 to 199.74) 0 fewer per 1000 (from 0 fewer to 0 fewer) ⨁⨁⨁ Moderate CRITICAL Web Annex B. Systematic review, meta-analysis and GRADE evidence profile on safety, efficacy, and effectiveness of long-acting injectable cabotegravir (CAB-LA) as pre-exposure prophylaxis (PrEP) to reduce the risk of HIV acquisition 3 Certainty assessment No. of patients Effect Certainty ImportanceNo. of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations CAB-LA oral PrEP Relative (95% CI) Absolute (95% CI) Contraceptive effectiveness 11,5 randomized trials not serious not serious not serious not serious none Pregnancy incidence: 1.5 per 100 py (95% CI: 1.0–2.2) Pregnancy incidence: 1.0 per 100 py (95% CI: 0.6–1.6) not estimable ⨁⨁⨁⨁ High IMPORTANT Pregnancy-related adverse events 11,5 randomized trials not serious not serious seriousd seriouse none CAB-LA participants (n=6) experienced more pregnancy-related AE than TDF-FTC participants. None of these AE were considered product- related not estimable ⨁⨁ Low CRITICAL Incident STI infections 21,2 randomized trials not serious not serious not serious not serious none f f not estimable ⨁⨁⨁⨁ High IMPORTANT CI: confidence interval; HR: hazard ratio; RR: risk ratio; AE: adverse events; TDF-FTC: tenofovir disoproxil fumarate–emtricitabine Explanations a The evidence is directly related to many populations of interest, including cisgender women, men who have sex with men, and transgender women who have sex with men, but of note, some populations for whom exposure to HIV is of potential concern, such as youth aged <18 years, people who inject drugs, people who are pregnant or breastfeeding, and transgender men, were not included in the two trials. b Only 17 cases of HIV infection were identified among participants receiving CAB; however, the sample sizes of the two trials were deemed sufficiently large, thus the evidence was not downgraded for imprecision. Of note, one case in HPTN 083 and one case in HPTN 084 were initially classified as incident infections but later re-adjudicated as baseline infections. These cases have been included in the primary analyses reported in each trial, thus they are also reported here. However, the true number of incident infections seen among those in the CAB arms is 15. c Only seven cases of drug-resistant infections out of 15 incident cases among those randomized to CAB-LA were identified. Given the low absolute number of resistant infections, as well as the low number of incident infections within the arms randomized to CAB-LA, evidence was downgraded for imprecision. d Downgraded for indirectness because outcomes were measured among women who were only exposed to the study product for a brief period during early pregnancy (all participants were regularly screened for pregnancy and CAB-LA was discontinued once pregnancy was detected). Therefore, these results may be different if women had been exposed to the study product for the entire duration of their pregnancies. e Downgraded for imprecision due to the low numbers of pregnancies that occurred over the course of the trial (n=49) and authors only report on 6 adverse events among pregnant women in the CAB-LA arm. Although no relative effect was presented, hazard ratios by arm are reported for any grade 2+ adverse event comparing pregnant to non-pregnant women: 113/100 py (95% CI: 69.3–185.4/100 py) in the CAB-LA arm vs. 166/100 py (95% CI: 102.2–271.0/100 py) in the TDF/FTC arm (p=0.064). f HPTN 083 reported on incident rates of chlamydia (rectal and urine), gonorrhea (rectal and urine), and syphilis. HPTN 084 reported on incident rates of chlamydia, syphilis, trichomoniasis, and gonorrhea. Data were not able to be synthesized based on differences in reported outcomes and metrics. Study investigators did not report any significant differences in incident STIs comparing study arms. 4 Guidelines on long-acting injectable cabotegravir for HIV prevention References 1. Delany-Moretlwe S, Hughes J, Bock P, Gurrion S, Hunidzarira P, Kalonji D, et al. Long acting injectable cabotegravir is safe and effective in preventing HIV infection in cisgender women: interim results from HPTN 084. HIV R4P Conference; 2021. https://programme.hivr4p.org/ Abstract/Abstract/1479 2. Landovitz RJ, Donnell D, Clement ME, Hanscom B, Cottle L, Coelho L, et al. Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women. N Engl J Med. 2021 Aug 12;385(7):595– 608. 3. Marzinke MA, Grinsztejn B, Fogel JM, Piwowar-Manning E, Li M, Weng L, et al. Characterization of Human Immunodeficiency Virus (HIV) Infection in Cisgender Men and Transgender Women Who Have Sex With Men Receiving Injectable Cabotegravir for HIV Prevention: HPTN 083. J Infect Dis. 2021 Nov 16;224(9):1581–1592. doi: 10.1093/infdis/jiab152. 4. Eshleman SH, Fogel JM, Piwowar-Manning E, Chau G, Cummings VM, Agyei Y, et al. Characterization of HIV infections in women who received injectable cabotegravir or tenofovir disoproxil fumarate/emtricitabine for HIV prevention: HPTN 084. J Infect Dis. 2022 May 16;225(10):1741–1749. doi: 10.1093/infdis/jiab576. 5. Delany-Moretlwe S, Hughes J, Guo X, Hanscom B, Hendrix CW, Farrior J, et al. Evaluation of CAB-LA Safety and PK in Pregnant Women in the Blinded Phase of HPTN 084. CROI Conference; 2022. ISBN 978-92-4-005412-7 For more information, contact: World Health Organization Department of Global HIV, Hepatitis and Sexually Transmitted Infections Programmes 20, avenue Appia 1211 Geneva 27 Switzerland Email: hiv-aids@who.int
GUIDELINES ON LONG-ACTING INJECTABLE CABOTEGRAVIR FOR HIV PREVENTION WEB ANNEX B. SYSTEMATIC REVIEW, META-ANALYSIS AND GRADE EVIDENCE PROFILE ON SAFETY, EFFICACY, AND EFFECTIVENESS OF LONG-ACTING INJECTABLE CABOTEGRAVIR (CAB-LA) AS PRE-EXPOSURE PROPHYLAXIS (PREP) TO REDUCE THE RISK OF HIV ACQUISITION Virginia Fonner, Kathleen Ridgeway, Ariane van der Straten, Lara Lorenzetti, Nhi Dinh, Michelle Rodolph, Robin Schaefer and Rachel Baggaley Guidelines on long-acting injectable cabotegravir for HIV prevention. Web Annex B. Systematic review, meta-analysis and GRADE evidence profile on safety, efficacy, and effectiveness of long-acting injectable cabotegravir (CAB-LA) as pre-exposure prophylaxis (PrEP) to reduce the risk of HIV acquisition/ Virginia Fonner, Kathleen Ridgeway, Ariane van der Straten, Lara Lorenzetti, Nhi Dinh, Michelle Rodolph et al. ISBN 978-92-4-005412-7 (electronic version) © World Health Organization 2022 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial- ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization (http://www.wipo.int/amc/en/mediation/ rules/). Suggested citation. Fonner V, Ridgeway K, van der Straten A, Lorenzetti L, Dinh N, Rodolph M et al. Web Annex B. Systematic review, meta-analysis and GRADE evidence profile on safety, efficacy, and effectiveness of long-acting injectable cabotegravir (CAB-LA) as pre-exposure prophylaxis (PrEP) to reduce the risk of HIV acquisition. In: Guidelines on long-acting injectable cabotegravir for HIV prevention. Geneva: World Health Organization; 2022. Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris. Sales, rights and licensing. To purchase WHO publications, see http://apps.who.int/bookorders. To submit requests for commercial use and queries on rights and licensing, see https://www.who.int/ copyright. Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. The named authors alone are responsible for the views expressed in this publication. This publication forms part of the WHO guideline entitled Guidelines on long-acting injectable cabotegravir for HIV prevention. It is being made publicly available for transparency purposes and information, in accordance with the WHO handbook for guideline development, 2nd edition (2014). Design and layout by 400 Communications Limited. iiiWeb Annex B. Systematic review, meta-analysis and GRADE evidence profile on safety, efficacy, and effectiveness of long-acting injectable cabotegravir (CAB-LA) as pre-exposure prophylaxis (PrEP) to reduce the risk of HIV acquisition CONTENTS Abstract 1 GRADE evidence profile on systematic review on safety, efficacy, and effectiveness of longacting injectable cabotegravir (CAB-LA) as pre-exposure prophylaxis (PrEP) to reduce the risk of HIV acquisition 3 References 5 1Web Annex B. Systematic review, meta-analysis and GRADE evidence profile on safety, efficacy, and effectiveness of long-acting injectable cabotegravir (CAB-LA) as pre-exposure prophylaxis (PrEP) to reduce the risk of HIV acquisition Virginia Fonner1, Kathleen Ridgeway1, Ariane van der Straten2, Lara Lorenzetti1, Nhi Dinh1, Michelle Rodolph3, Robin Schaefer3, and Rachel Baggaley3 1 Global Health and Population Research, FHI 360, Durham, NC 2 ASTRA Consulting; University of California, San Francisco 3 World Health Organization, CAB-LA Guidelines Team Abstract Background: HIV remains a significant health threat, despite the increasing availability of effective HIV prevention tools, such as oral pre-exposure prophylaxis (PrEP). Long-acting injectable cabotegravir (CAB-LA) is one potential new PrEP option, and results from several efficacy studies on CAB-LA have recently become available. The purpose of this review was to synthesize the evidence to determine the overall effectiveness, cost–effectiveness, and safety of CAB-LA as PrEP to inform global guidelines about whether CAB-LA should be recommended as an additional prevention option for people at substantial risk of HIV infection. Methods: A comprehensive search strategy reviewed multiple electronic databases and conference abstracts for relevant citations between January 2010 and September 2021, with additional information solicited from experts. Outcomes of interest included HIV infection, adverse events, drug resistance, pregnancy-related adverse events, and outcomes relevant to sexual behaviour. Pooled effect estimates were calculated using random-effects meta-analysis. When meta-analysis was infeasible, results were summarized narratively. Data were summarized and evaluated using the GRADE methodology, with attention to evidence certainty. Results: Four studies were included, comprising 9 articles and 3 conference abstracts, including two phase 2a safety studies and two phase 2b/3 efficacy studies. All studies were multi-site, double-blind randomized controlled trials. The efficacy studies, HPTN 083 and HPTN 084 compared participants assigned to CAB-LA to participants assigned to oral PrEP (tenofovir disoproxil fumarate–emtricitabine, TDF-FTC). The phase 2a studies, ECLAIR and HPTN 077, compared CAB-LA to placebo. Study populations included cisgender men, cisgender women, transgender women, and a small number of transgender men. Overall 8120 individuals were enrolled across the four trials, with 4114 individuals randomized to receive active CAB-LA. The pooled effect estimate in meta-analysis of HIV infections reported in the two efficacy studies yielded a relative risk of 0.21 (95% CI: 0.07–0.61) comparing CAB-LA to TDF-FTC, resulting in a 79% reduction in HIV risk. Rates of adverse events and serious adverse events were similar across arms, although injection site reactions occurred more frequently in the CAB-LA arms. Out of 20 HIV infections identified among the groups randomized to CAB-LA, seven 7 exhibited resistance to integrase inhibitors (INSTI), suggesting CAB-LA is associated with INSTI drug resistance, although very few cases were identified. Although data related to pregnancy-related adverse events were sparse, no drug-related concerns were identified. Regarding sexual behaviour, STI incidence was similar across arms. Conclusion: CAB-LA is an effective means of HIV prevention and appears to have few safety risks beyond injection site reactions. CAB-LA may lead to an increased risk of INSTI resistance among those who begin taking CAB-LA while acutely infected or who experience a breakthrough infection. No cases of drug resistance were found among those who seroconverted during the “tail phase.” However, results from this review primarily focus on several controlled studies; more research is needed to understand implementation of CAB-LA outside of research settings. Additionally, more data are needed regarding the safety of CAB-LA during pregnancy and among populations not included in the trials, such as people who inject drugs, adolescents, sex workers, and transgender men. Guidelines on long-acting injectable cabotegravir for HIV prevention2 GRADE evidence profile on systematic review on safety, efficacy, and effectiveness of long-acting injectable cabotegravir (CAB-LA) as pre-exposure prophylaxis (PrEP) to reduce the risk of HIV acquisition Author(s): V. Fonner and K. Ridgeway Question: CAB-LA compared to oral PrEP for be offered as an additional prevention choice for people at substantial risk of HIV infection as part of combination prevention approaches Setting: global Bibliography: See references below Certainty assessment No. of patients Effect Certainty ImportanceNo. of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations CAB-LA oral PrEP Relative (95% CI) Absolute (95% CI) HIV infection 21,2 randomized trials not serious not serious not seriousa not seriousb none 17/3835 (0.4%) 75/3833 (2.0%) RR 0.21 (0.07 to 0.61) 15 fewer per 1000 (from 18 fewer to 8 fewer) ⨁⨁⨁⨁ High CRITICAL Any adverse event (measured as any grade 2+ adverse event) 21,2 randomized trials not serious not serious not serious not serious none 3593/3894 (92.3%) 3602/3892 (92.5%) RR 1.00 (0.98 to 1.01) 0 fewer per 1000 (from 19 fewer to 9 more) ⨁⨁⨁⨁ High CRITICAL Any grade 3 or 4 adverse event (measured as any serious adverse event) 21,2 randomized trials not serious not serious not serious not serious none 152/3894 (3.9%) 154/3892 (4.0%) RR 0.99 (0.79 to 1.23) 0 fewer per 1000 (from 8 fewer to 9 more) ⨁⨁⨁⨁ High IMPORTANT INSTI drug resistant infections 23,4 randomized trials not serious not serious not serious seriousc none 7/20 (35.0%) 0/75 (0.0%) RR 20.90 (2.19 to 199.74) 0 fewer per 1000 (from 0 fewer to 0 fewer) ⨁⨁⨁ Moderate CRITICAL Web Annex B. Systematic review, meta-analysis and GRADE evidence profile on safety, efficacy, and effectiveness of long-acting injectable cabotegravir (CAB-LA) as pre-exposure prophylaxis (PrEP) to reduce the risk of HIV acquisition 3 Certainty assessment No. of patients Effect Certainty ImportanceNo. of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations CAB-LA oral PrEP Relative (95% CI) Absolute (95% CI) Contraceptive effectiveness 11,5 randomized trials not serious not serious not serious not serious none Pregnancy incidence: 1.5 per 100 py (95% CI: 1.0–2.2) Pregnancy incidence: 1.0 per 100 py (95% CI: 0.6–1.6) not estimable ⨁⨁⨁⨁ High IMPORTANT Pregnancy-related adverse events 11,5 randomized trials not serious not serious seriousd seriouse none CAB-LA participants (n=6) experienced more pregnancy-related AE than TDF-FTC participants. None of these AE were considered product- related not estimable ⨁⨁ Low CRITICAL Incident STI infections 21,2 randomized trials not serious not serious not serious not serious none f f not estimable ⨁⨁⨁⨁ High IMPORTANT CI: confidence interval; HR: hazard ratio; RR: risk ratio; AE: adverse events; TDF-FTC: tenofovir disoproxil fumarate–emtricitabine Explanations a The evidence is directly related to many populations of interest, including cisgender women, men who have sex with men, and transgender women who have sex with men, but of note, some populations for whom exposure to HIV is of potential concern, such as youth aged <18 years, people who inject drugs, people who are pregnant or breastfeeding, and transgender men, were not included in the two trials. b Only 17 cases of HIV infection were identified among participants receiving CAB; however, the sample sizes of the two trials were deemed sufficiently large, thus the evidence was not downgraded for imprecision. Of note, one case in HPTN 083 and one case in HPTN 084 were initially classified as incident infections but later re-adjudicated as baseline infections. These cases have been included in the primary analyses reported in each trial, thus they are also reported here. However, the true number of incident infections seen among those in the CAB arms is 15. c Only seven cases of drug-resistant infections out of 15 incident cases among those randomized to CAB-LA were identified. Given the low absolute number of resistant infections, as well as the low number of incident infections within the arms randomized to CAB-LA, evidence was downgraded for imprecision. d Downgraded for indirectness because outcomes were measured among women who were only exposed to the study product for a brief period during early pregnancy (all participants were regularly screened for pregnancy and CAB-LA was discontinued once pregnancy was detected). Therefore, these results may be different if women had been exposed to the study product for the entire duration of their pregnancies. e Downgraded for imprecision due to the low numbers of pregnancies that occurred over the course of the trial (n=49) and authors only report on 6 adverse events among pregnant women in the CAB-LA arm. Although no relative effect was presented, hazard ratios by arm are reported for any grade 2+ adverse event comparing pregnant to non-pregnant women: 113/100 py (95% CI: 69.3–185.4/100 py) in the CAB-LA arm vs. 166/100 py (95% CI: 102.2–271.0/100 py) in the TDF/FTC arm (p=0.064). f HPTN 083 reported on incident rates of chlamydia (rectal and urine), gonorrhea (rectal and urine), and syphilis. HPTN 084 reported on incident rates of chlamydia, syphilis, trichomoniasis, and gonorrhea. Data were not able to be synthesized based on differences in reported outcomes and metrics. Study investigators did not report any significant differences in incident STIs comparing study arms. 4 Guidelines on long-acting injectable cabotegravir for HIV prevention References 1. Delany-Moretlwe S, Hughes J, Bock P, Gurrion S, Hunidzarira P, Kalonji D, et al. Long acting injectable cabotegravir is safe and effective in preventing HIV infection in cisgender women: interim results from HPTN 084. HIV R4P Conference; 2021. https://programme.hivr4p.org/ Abstract/Abstract/1479 2. Landovitz RJ, Donnell D, Clement ME, Hanscom B, Cottle L, Coelho L, et al. Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women. N Engl J Med. 2021 Aug 12;385(7):595– 608. 3. Marzinke MA, Grinsztejn B, Fogel JM, Piwowar-Manning E, Li M, Weng L, et al. Characterization of Human Immunodeficiency Virus (HIV) Infection in Cisgender Men and Transgender Women Who Have Sex With Men Receiving Injectable Cabotegravir for HIV Prevention: HPTN 083. J Infect Dis. 2021 Nov 16;224(9):1581–1592. doi: 10.1093/infdis/jiab152. 4. Eshleman SH, Fogel JM, Piwowar-Manning E, Chau G, Cummings VM, Agyei Y, et al. Characterization of HIV infections in women who received injectable cabotegravir or tenofovir disoproxil fumarate/emtricitabine for HIV prevention: HPTN 084. J Infect Dis. 2022 May 16;225(10):1741–1749. doi: 10.1093/infdis/jiab576. 5. Delany-Moretlwe S, Hughes J, Guo X, Hanscom B, Hendrix CW, Farrior J, et al. Evaluation of CAB-LA Safety and PK in Pregnant Women in the Blinded Phase of HPTN 084. CROI Conference; 2022. ISBN 978-92-4-005412-7 For more information, contact: World Health Organization Department of Global HIV, Hepatitis and Sexually Transmitted Infections Programmes 20, avenue Appia 1211 Geneva 27 Switzerland Email: hiv-aids@who.int