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Efficacy of the Dapivirine Vaginal Ring Accounting for Imperfect Adherence

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Abstract

Product adherence is critical to obtaining objective estimates of efficacy of pre-exposure prophylactic interventions against HIV-1 infection. With imperfect adherence, intention-to-treat analyses assess the collective effects of complete, sub-optimal and non-adherence, providing a biased and attenuated estimate of the average causal effect of an intervention. Using data from the MTN-020/ASPIRE phase III trial evaluating HIV-1 efficacy of the dapivirine vaginal ring, we conducted per-protocol, and adherence-adjusted causal inference analyses using principal stratification and marginal structural models. We constructed two adherence cut offs of ≥ 0.9 mg (low cutoff) and > 4.0 mg (high cutoff) that represent drug released from the ring over a 28-day period. The HIV-1 efficacy estimate (95% CI) was 30.8% (3.6%, 50.3%) (P = 0.03) from the per-protocol analysis, and 53.6% (16.5%, 74.3%) (P = 0.01) among the highest predicted adherers from principal stratification analyses using the low cutoff. Marginal structural models produced efficacy estimates (95% CIs) ranging from 48.8 (21.8, 66.4) (P = 0.0019) to 56.5% (32.8%, 71.9%) (P = 0.0002). Application of adherence-adjusted causal inference methods are useful in interpreting HIV-1 efficacy in secondary analyses of PrEP clinical trials.

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References

  1. Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367:399–410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Choopanya K, Martin M, Suntharasamai P, et al. Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2013;381:2083–90.

    Article  PubMed  Google Scholar 

  3. Grant RM, Lama JR, Anderson PL, et al. Pre-exposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363:2587–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Marrazzo JM, Ramjee G, Richardson BA, et al. Tenofovir based pre-exposure prophylaxis for HIV infection among African women. N Engl J Med. 2015;372:509–18.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Van Damme L, Corneli A, Ahmed K, et al. Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012;367(5):411–22.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Delany-Moretlwe S, Lombard C, Baron D, Bekker LG, Nkala B, Ahmed K, Sebe M, Brumskine W, Nchabeleng M, Palanee-Philips T, Ntshangase J, Sibiya S, Smith E, Panchia R, Myer L, Schwartz JL, Marzinke M, Morris L, Brown ER, Doncel GF, Gray G, Rees H. Tenofovir 1% vaginal gel for prevention of HIV-1 infection in women in South Africa (FACTS-001): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2018;18(11):1241–50.

    Article  CAS  PubMed  Google Scholar 

  7. Baeten JM, Palanee-Phillips T, Brown ER, et al. Use of a vaginal ring containing dapivirine for HIV-1 prevention in women. N Engl J Med. 2016;375:2121–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hewitt CE, Torgerson DJ, Miles JN. Is there another way to take account of noncompliance in randomized controlled trials? Can Med Assoc J. 2006;175(4):347.

    Article  Google Scholar 

  9. Palanee-Phillips T, Schwartz K, Brown ER, et al. Characteristics of women enrolled into a randomized clinical trial of dapivirine vaginal ring for HIV-1 prevention. PLoS ONE. 2015;10(6): e0128857. https://doi.org/10.1371/journal.pone.0128857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Spence P, Nel A, van Niekerk N, et al. Post-use assay of vaginal rings (VRs) as a potential measure of clinical trial adherence. J Pharm Biomed Anal. 2016;125:94–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Nel A, Haazen W, Nuttall J, et al. A safety and pharmacokinetic trial assessing delivery of dapivirine from a vaginal ring in healthy women. AIDS. 2014;28(10):1479–87.

    Article  CAS  PubMed  Google Scholar 

  12. Nel AM, Haazen W, Nuttall J, Romano JP, Mesquita PM, Herold BC, Rosenberg ZF, Niekerk NV. Pharmacokinetics and safety assessment of anti-HIV dapivirine vaginal microbicide rings with multiple dosing. J AIDS Clin Res. 2014;5:355.

    Google Scholar 

  13. Nel A, Bekker LG, Bukusi E, et al. Safety, acceptability and adherence of dapivirine vaginal ring in a microbicide clinical trial conducted in multiple countries in sub-Saharan Africa. PLoS ONE. 2016;11: e0147743.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Brown ER, Hendrix CW, van der Straten A, et al. Greater dapivirine release from the dapivirine vaginal ring is correlated with lower risk of HIV-1 acquisition: a secondary analysis from a randomized, placebo-controlled trial. J Int AIDS Soc. 2020;23:11.

    Article  Google Scholar 

  15. Van der Weele TJ. Principal stratification—uses and limitations. Int J Biostat. 2011;7(1):28.

    Google Scholar 

  16. Frangakis CE, Rubin DB. Principal stratification in causal inference. Biometrics. 2002;58(1):21–9.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Shtatland E, Kleinman K, Cain E. Stepwise Methods in Using SAS PROC LOGISTIC and SAS Enterprise Miner for Prediction. In: SUGI'28 Proceedings; 2003.

  18. Follmann DA. On the effect of treatment among treatment compliers: an analysis of the Multiple Risk Factor Intervention Trial. J Am Stat Assoc. 2000;95(452):1101–9.

    Article  Google Scholar 

  19. Cole SR, Hernán MA. Constructing inverse probability weights for marginal structural models. Am J Epidemiol. 2008;168(6):656–64.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Robins JM, Hernán MA, Brumback B. Marginal structural models and causal inference in epidemiology. Epidemiology. 2000;11(5):550–60.

    Article  CAS  PubMed  Google Scholar 

  21. Robins JM, Finkelstein DM. Correcting for noncompliance and dependent censoring in an AIDS Clinical Trial with inverse probability of censoring weighted (IPCW) log-rank tests. Biometrics. 2000;56(3):779–88.

    Article  CAS  PubMed  Google Scholar 

  22. Hernán MA, Robins JM. Estimating causal effects from epidemiological data. J Epidemiol Community Health. 2006;60(7):578–86.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Cole SR, Hernán M. Adjusted survival curves with inverse probability weights. Comput Methods Programs Biomed. 2004;75(1):45–9.

    Article  PubMed  Google Scholar 

  24. Rubin DB. Estimating causal effects of treatments in randomized and nonrandomized studies. J Educ Psychol. 1974;56:688–701.

    Article  Google Scholar 

  25. Greenland S, Robins JM. Identifiability, exchangeability, and epidemiological confounding. Int J Epidemiol. 1986;15(3):413–9.

    Article  CAS  PubMed  Google Scholar 

  26. Husnik MJ, Brown ER, Marzinke M, et al. Implementation of a novel adherence monitoring strategy in a phase III, blinded, placebo-controlled, HIV-1 prevention clinical trial. J Acquir Immune Defic Syndr. 2017;76:330–7.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Cole SR, Frangakis CE. The consistency statement in causal inference: a definition or an assumption? Epidemiology. 2009;20(1):3–5.

    Article  PubMed  Google Scholar 

  28. Montgomery ET, van der Straten A, Chitukuta M, et al. Acceptability and use of a dapivirine vaginal ring in a phase III trial. AIDS. 2017;31(8):1159–67.

    Article  CAS  PubMed  Google Scholar 

  29. Montgomery ET, van der Straten A, Cheng H, Wegner L, Masenga G, von Mollendorf C, et al. Vaginal ring adherence in sub-Saharan Africa: expulsion, removal, and perfect use. AIDS Behav. 2012;7:1787–98.

    Article  Google Scholar 

  30. van der Straten A, Montgomery E, Cheng H, Wegner L, Masenga G, von Mollendorf C, et al. High acceptability of a vaginal ring intended as a microbicide delivery method for HIV prevention in African women. AIDS Behav. 2012;16:1775–86.

    Article  PubMed  Google Scholar 

  31. Griffin JB, Ridgeway K, Montgomery E, Torjesen K, Clark R, Peterson J, et al. Vaginal ring acceptability and related preferences among women in low- and middle-income countries: a systematic review and narrative synthesis. PLoS ONE. 2019;14(11): e0224898.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We wish to thank the MTN-020/ASPIRE study team, MTN leadership and MTN Laboratory Center staff, as well as the dedication of all study participants for making this research possible.

MTN-020/ASPIRE STUDY TEAM Study Team Leadership: Jared Baeten, University of Washington (Protocol Chair); Thesla Palanee-Phillips, Wits Reproductive Health and HIV Institute (Protocol Co-chair); Elizabeth Brown, Fred Hutchinson Cancer Research Center (Protocol Statistician); Lydia Soto-Torres, US National Institute of Allergy and Infectious Diseases (Medical Officer); Katie Schwartz, FHI 360 (Clinical Research Manager). Study sites and site Investigators of Record: Malawi, Blantyre site (Johns Hopkins University, Queen Elizabeth Hospital): Bonus Makanani; Malawi, Lilongwe site (University of North Carolina, Chapel Hill): Francis Martinson South Africa, Cape Town site (University of Cape Town): Linda-Gail Bekker; South Africa, Durban – Botha’s Hill, Chatsworth, Isipingo, Tongaat, Umkomaas, Verulam sites (South African Medical Research Council): Vaneshree Govender, Samantha Siva, Zakir Gaffoor, Logashvari Naidoo, Arendevi Pather, and Nitesha Jeenarain; South Africa, Durban, eThekwini site (Center for the AIDS Programme for Research in South Africa): Gonasagrie Nair South Africa, Johannesburg site (Wits RHI): Thesla Palanee-Phillips Uganda, Kampala site (John Hopkins University, Makerere University): Flavia Matovu Kiweewa Zimbabwe, Chitungwiza, Seke South and Zengeza sites (University of Zimbabwe, University of California San Francisco): Nyaradzo Mgodi Zimbabwe, Harare, Spilhaus site (University of Zimbabwe, University of California San Francisco): Felix Mhlanga. Data management was provided by The Statistical Center for HIV/AIDS Research & Prevention (Fred Hutchinson Cancer Research Center, Seattle, WA) and site laboratory oversight was provided by the Microbicide Trials Network Laboratory Center (Pittsburgh, PA).

Funding

The MTN-020/ASPIRE study was designed and implemented by the Microbicide Trials Network (MTN). The MTN was funded by the National Institute of Allergy and Infectious Diseases (UM1AI068633, UM1AI068615, UM1AI106707), with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The vaginal rings used in this study were supplied by the International Partnership for Microbicides (IPM).

Author information

Authors and Affiliations

  1. Department of Epidemiology, University of Washington, Seattle, WA, USA

    Marla J. Husnik, Renee Heffron & Jared M. Baeten

  2. Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Marla J. Husnik

  3. Department of Global Health, University of Washington, Seattle, WA, USA

    Renee Heffron & Jared M. Baeten

  4. Department of Biostatistics, University of Washington, Seattle, WA, USA

    James P. Hughes & Barbra Richardson

  5. Department of Medicine, The Center for AIDS Prevention Studies, University of California San Francisco, San Francisco, CA, USA

    Ariane van der Straten

  6. Faculty of Health Sciences, Wits Reproductive Health and HIV Institute, University of the Witwatersrand, Johannesburg, South Africa

    Thesla Palanee-Phillips

  7. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

    Lydia Soto-Torres

  8. University of Pittsburgh, Pittsburgh, PA, USA

    Devika Singh

  9. Makerere University John Hopkins University Research Collaboration (MU-JHU), Kampala, Uganda

    Brenda Gati Mirembe & Flavia Matovu Kiweewa

  10. Magee-Womens Research Institute, Pittsburgh, PA, USA

    Devika Singh & Edward Livant

  11. HIV Prevention Research Unit, South African Medical Research Council, Cape Town, South Africa

    Zakir Gaffoor & Samantha S. Siva

  12. Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa

    Leila E. Mansoor

  13. Johns Hopkins Bloomberg School of Public Health, Blantyre, Malawi

    Sufia Dadabhai

  14. ASTRA Consulting, Kensington, CA, USA

    Ariane van der Straten

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  1. Marla J. Husnik
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for the MTN-020/ASPIRE Study Team

Contributions

Marla J. Husnik was the lead author and statistical analyst, and Renee Heffron, James P. Hughes, Barbra Richardson, and Ariane van der Straten reviewed, and provided valuable insights into the epidemiological methods used for analysis of the MTN-020/ASPIRE study data. Thesla Palanee-Phillips, Lydia Soto-Torres, Devika Singh, Brenda Gati Mirembe, Edward Livant, Zakir Gaffoor, Leila E. Mansoor, Samantha S. Siva, Sufia Dadabhai, and Flavia Matovu Kiweewa were all involved in the implementation of the MTN-020/ASPIRE study and provided valuable comments/review of the manuscript over several iterations. Finally, Jared M. Baeten was the principal investigator for the MTN-020/ASPIRE study providing leadership to the study team and guidance to the lead author for the writing and analysis of this manuscript.

Corresponding author

Correspondence to Jared M. Baeten.

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JMB is an employee of Gilead Sciences outside of the present work.

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Husnik, M.J., Heffron, R., Hughes, J.P. et al. Efficacy of the Dapivirine Vaginal Ring Accounting for Imperfect Adherence. AIDS Behav (2024). https://doi.org/10.1007/s10461-024-04463-3

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