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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

INTRODUCTION: A vaginal ring containing 25 mg of the antiretroviral dapivirine has demonstrated efficacy in reducing women’s risk of sexually acquiring HIV‐1; however, imperfect ring use likely diluted efficacy estimates in clinical trials. The amount of dapivirine remaining in returned rings may re...

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Autores principales: Brown, Elizabeth R, Hendrix, Craig W, van der Straten, Ariane, Kiweewa, Flavia M, Mgodi, Nyaradzo M, Palanee‐Philips, Thesla, Marzinke, Mark A, Bekker, Linda‐Gail, Soto‐Torres, Lydia, Hillier, Sharon L, Baeten, Jared M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673220/
https://www.ncbi.nlm.nih.gov/pubmed/33206462
http://dx.doi.org/10.1002/jia2.25634
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author Brown, Elizabeth R
Hendrix, Craig W
van der Straten, Ariane
Kiweewa, Flavia M
Mgodi, Nyaradzo M
Palanee‐Philips, Thesla
Marzinke, Mark A
Bekker, Linda‐Gail
Soto‐Torres, Lydia
Hillier, Sharon L
Baeten, Jared M
author_facet Brown, Elizabeth R
Hendrix, Craig W
van der Straten, Ariane
Kiweewa, Flavia M
Mgodi, Nyaradzo M
Palanee‐Philips, Thesla
Marzinke, Mark A
Bekker, Linda‐Gail
Soto‐Torres, Lydia
Hillier, Sharon L
Baeten, Jared M
author_sort Brown, Elizabeth R
collection PubMed
description INTRODUCTION: A vaginal ring containing 25 mg of the antiretroviral dapivirine has demonstrated efficacy in reducing women’s risk of sexually acquiring HIV‐1; however, imperfect ring use likely diluted efficacy estimates in clinical trials. The amount of dapivirine remaining in returned rings may reflect the extent of product use, permitting estimation of HIV protection in the context of consistent use. METHODS: We measured the amount of dapivirine in returned rings from a placebo‐controlled trial of the dapivirine vaginal ring conducted between August 2012 and June 2015 among 2629 African women. Phase I/II studies established that greater than 4 mg of dapivirine on average is released from the ring when used consistently over 28 days and ≤0.9 mg released suggested non‐use. We assessed the relative risk reduction associated with levels of ring use using residual dapivirine in returned rings as a time‐dependent covariate for HIV‐1 infection in multivariable Cox models, including multiple exploratory analyses designed to estimate upper limits of efficacy given uncertainty in timing of HIV‐1 acquisition. All models were adjusted for baseline covariates associated with HIV risk and adherence. RESULTS: Residual dapivirine levels indicating at least some use (>0.9 mg released over a month) were associated with a 48% relative reduction in HIV‐1 acquisition risk (95% confidence interval (CI): 21% to 66%; p = 0.002) compared to the placebo. Exploratory analyses accounting for potential misclassification in timing of HIV‐1 acquisition estimated 75% to 91% HIV‐1 risk reduction with> 4 mg released when compared to placebo. Results limited to the subgroup of women <25 years of age, who tended to have lower adherence, were generally consistent to those overall. CONCLUSIONS: Residual dapivirine levels, an objective measure of adherence, were correlated with HIV‐1 protection in a secondary analysis of a randomized trial. Periods of ring use were associated with approximately 50% protection, with exploratory analyses suggesting higher protection with more consistent use. The dapivirine vaginal ring is the first method to fulfil the promise of a fully reversible, long‐acting, woman‐initiated approach for discreet HIV‐1 prevention.
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spelling pubmed-76732202020-11-24 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 Brown, Elizabeth R Hendrix, Craig W van der Straten, Ariane Kiweewa, Flavia M Mgodi, Nyaradzo M Palanee‐Philips, Thesla Marzinke, Mark A Bekker, Linda‐Gail Soto‐Torres, Lydia Hillier, Sharon L Baeten, Jared M J Int AIDS Soc Research Articles INTRODUCTION: A vaginal ring containing 25 mg of the antiretroviral dapivirine has demonstrated efficacy in reducing women’s risk of sexually acquiring HIV‐1; however, imperfect ring use likely diluted efficacy estimates in clinical trials. The amount of dapivirine remaining in returned rings may reflect the extent of product use, permitting estimation of HIV protection in the context of consistent use. METHODS: We measured the amount of dapivirine in returned rings from a placebo‐controlled trial of the dapivirine vaginal ring conducted between August 2012 and June 2015 among 2629 African women. Phase I/II studies established that greater than 4 mg of dapivirine on average is released from the ring when used consistently over 28 days and ≤0.9 mg released suggested non‐use. We assessed the relative risk reduction associated with levels of ring use using residual dapivirine in returned rings as a time‐dependent covariate for HIV‐1 infection in multivariable Cox models, including multiple exploratory analyses designed to estimate upper limits of efficacy given uncertainty in timing of HIV‐1 acquisition. All models were adjusted for baseline covariates associated with HIV risk and adherence. RESULTS: Residual dapivirine levels indicating at least some use (>0.9 mg released over a month) were associated with a 48% relative reduction in HIV‐1 acquisition risk (95% confidence interval (CI): 21% to 66%; p = 0.002) compared to the placebo. Exploratory analyses accounting for potential misclassification in timing of HIV‐1 acquisition estimated 75% to 91% HIV‐1 risk reduction with> 4 mg released when compared to placebo. Results limited to the subgroup of women <25 years of age, who tended to have lower adherence, were generally consistent to those overall. CONCLUSIONS: Residual dapivirine levels, an objective measure of adherence, were correlated with HIV‐1 protection in a secondary analysis of a randomized trial. Periods of ring use were associated with approximately 50% protection, with exploratory analyses suggesting higher protection with more consistent use. The dapivirine vaginal ring is the first method to fulfil the promise of a fully reversible, long‐acting, woman‐initiated approach for discreet HIV‐1 prevention. John Wiley and Sons Inc. 2020-11-18 /pmc/articles/PMC7673220/ /pubmed/33206462 http://dx.doi.org/10.1002/jia2.25634 Text en © 2020 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Brown, Elizabeth R
Hendrix, Craig W
van der Straten, Ariane
Kiweewa, Flavia M
Mgodi, Nyaradzo M
Palanee‐Philips, Thesla
Marzinke, Mark A
Bekker, Linda‐Gail
Soto‐Torres, Lydia
Hillier, Sharon L
Baeten, Jared M
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673220/
https://www.ncbi.nlm.nih.gov/pubmed/33206462
http://dx.doi.org/10.1002/jia2.25634
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