Twice-Daily Application of HIV Microbicides Alters the Vaginal Microbiota

ABSTRACT Vaginal HIV microbicides offer great promise in preventing HIV transmission, but failures of phase 3 clinical trials, in which microbicide-treated subjects had an increased risk of HIV transmission, raised concerns about endpoints used to evaluate microbicide safety. A possible explanation...

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Autores principales:	Jacques Ravel, Pawel Gajer, Li Fu, Christine K. Mauck, Sara S. K. Koenig, Joyce Sakamoto, Alison A. Motsinger-Reif, Gustavo F. Doncel, Steven L. Zeichner
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2012
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/a7718b81e5254717a9f4623129494649
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spelling	oai:doaj.org-article:a7718b81e5254717a9f46231294946492021-11-15T15:39:11ZTwice-Daily Application of HIV Microbicides Alters the Vaginal Microbiota10.1128/mBio.00370-122150-7511https://doaj.org/article/a7718b81e5254717a9f46231294946492012-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00370-12https://doaj.org/toc/2150-7511ABSTRACT Vaginal HIV microbicides offer great promise in preventing HIV transmission, but failures of phase 3 clinical trials, in which microbicide-treated subjects had an increased risk of HIV transmission, raised concerns about endpoints used to evaluate microbicide safety. A possible explanation for the increased transmission risk is that the agents shifted the vaginal bacterial community, resulting in loss of natural protection and enhanced HIV transmission susceptibility. We characterized vaginal microbiota, using pyrosequencing of bar-coded 16S rRNA gene fragments, in samples from 35 healthy, sexually abstinent female volunteer subjects (ages 18 to 50 years) with regular menses in a repeat phase 1 study of twice-daily application over 13.5 days of 1 of 3 gel products: a hydroxyethylcellulose (HEC)-based “universal” placebo (10 subjects), 6% cellulose sulfate (CS; 13 subjects), and 4% nonoxynol-9 (N-9; 12 subjects). We used mixed effects models inferred using Bayesian Markov chain Monte Carlo methods, which showed that treatment with active agents shifted the microbiota toward a community type lacking significant numbers of Lactobacillus spp. and dominated by strict anaerobes. This state of the vaginal microbiota was associated with a low or intermediate Nugent score and was not identical to bacterial vaginosis, an HIV transmission risk factor. The placebo arm contained a higher proportion of communities dominated by Lactobacillus spp., particularly L. crispatus, throughout treatment. The data suggest that molecular evaluation of microbicide effects on vaginal microbiota may be a critical endpoint that should be incorporated in early clinical assessment of microbicide candidates. IMPORTANCE Despite large prevention efforts, HIV transmission and acquisition rates remain unacceptably high. In developing countries, transmission mainly occurs through heterosexual intercourse, where women are significantly more vulnerable to infection than men. Vaginal microbicides are considered to be one of the most promising female-controlled products, in that women themselves insert the microbicides into the vagina to prevent HIV transmission during sexual intercourse. The failure of several microbicides in clinical trials has raised questions concerning the low in vivo efficacy of such anti-HIV molecules. This study was designed to gain insights into the failures of two microbicides by testing the hypothesis that the microbicides negatively affect a critical line of defense against HIV, the vaginal microbiota. The results suggest that in the early assessment of candidate microbicides, culture-independent evaluation of their effect on the vaginal microbiota should be considered and may constitute a critical endpoint.Jacques RavelPawel GajerLi FuChristine K. MauckSara S. K. KoenigJoyce SakamotoAlison A. Motsinger-ReifGustavo F. DoncelSteven L. ZeichnerAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 3, Iss 6 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Jacques Ravel Pawel Gajer Li Fu Christine K. Mauck Sara S. K. Koenig Joyce Sakamoto Alison A. Motsinger-Reif Gustavo F. Doncel Steven L. Zeichner Twice-Daily Application of HIV Microbicides Alters the Vaginal Microbiota
description	ABSTRACT Vaginal HIV microbicides offer great promise in preventing HIV transmission, but failures of phase 3 clinical trials, in which microbicide-treated subjects had an increased risk of HIV transmission, raised concerns about endpoints used to evaluate microbicide safety. A possible explanation for the increased transmission risk is that the agents shifted the vaginal bacterial community, resulting in loss of natural protection and enhanced HIV transmission susceptibility. We characterized vaginal microbiota, using pyrosequencing of bar-coded 16S rRNA gene fragments, in samples from 35 healthy, sexually abstinent female volunteer subjects (ages 18 to 50 years) with regular menses in a repeat phase 1 study of twice-daily application over 13.5 days of 1 of 3 gel products: a hydroxyethylcellulose (HEC)-based “universal” placebo (10 subjects), 6% cellulose sulfate (CS; 13 subjects), and 4% nonoxynol-9 (N-9; 12 subjects). We used mixed effects models inferred using Bayesian Markov chain Monte Carlo methods, which showed that treatment with active agents shifted the microbiota toward a community type lacking significant numbers of Lactobacillus spp. and dominated by strict anaerobes. This state of the vaginal microbiota was associated with a low or intermediate Nugent score and was not identical to bacterial vaginosis, an HIV transmission risk factor. The placebo arm contained a higher proportion of communities dominated by Lactobacillus spp., particularly L. crispatus, throughout treatment. The data suggest that molecular evaluation of microbicide effects on vaginal microbiota may be a critical endpoint that should be incorporated in early clinical assessment of microbicide candidates. IMPORTANCE Despite large prevention efforts, HIV transmission and acquisition rates remain unacceptably high. In developing countries, transmission mainly occurs through heterosexual intercourse, where women are significantly more vulnerable to infection than men. Vaginal microbicides are considered to be one of the most promising female-controlled products, in that women themselves insert the microbicides into the vagina to prevent HIV transmission during sexual intercourse. The failure of several microbicides in clinical trials has raised questions concerning the low in vivo efficacy of such anti-HIV molecules. This study was designed to gain insights into the failures of two microbicides by testing the hypothesis that the microbicides negatively affect a critical line of defense against HIV, the vaginal microbiota. The results suggest that in the early assessment of candidate microbicides, culture-independent evaluation of their effect on the vaginal microbiota should be considered and may constitute a critical endpoint.
format	article
author	Jacques Ravel Pawel Gajer Li Fu Christine K. Mauck Sara S. K. Koenig Joyce Sakamoto Alison A. Motsinger-Reif Gustavo F. Doncel Steven L. Zeichner
author_facet	Jacques Ravel Pawel Gajer Li Fu Christine K. Mauck Sara S. K. Koenig Joyce Sakamoto Alison A. Motsinger-Reif Gustavo F. Doncel Steven L. Zeichner
author_sort	Jacques Ravel
title	Twice-Daily Application of HIV Microbicides Alters the Vaginal Microbiota
title_short	Twice-Daily Application of HIV Microbicides Alters the Vaginal Microbiota
title_full	Twice-Daily Application of HIV Microbicides Alters the Vaginal Microbiota
title_fullStr	Twice-Daily Application of HIV Microbicides Alters the Vaginal Microbiota
title_full_unstemmed	Twice-Daily Application of HIV Microbicides Alters the Vaginal Microbiota
title_sort	twice-daily application of hiv microbicides alters the vaginal microbiota
publisher	American Society for Microbiology
publishDate	2012
url	https://doaj.org/article/a7718b81e5254717a9f4623129494649
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Twice-Daily Application of HIV Microbicides Alters the Vaginal Microbiota

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