Twice-daily application of HIV microbicides alter the vaginal microbiota

Study information

Needs review

study design

case-control

Citation

PMID PubMed identifier for scientific articles.

23249810

DOI Digital object identifier for electronic documents.

10.1128/mBio.00370-12

URI Uniform resource identifier for web resources.

https://pubmed.ncbi.nlm.nih.gov/23249810/

Authors

Ravel J, Gajer P, Fu L, Mauck CK, Koenig SS, Sakamoto J, Motsinger-Reif AA, Doncel GF, Zeichner SL

Journal

mBio

Year

2012

UNLABELLED: 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.

Experiment 1

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Curated date: 2022/01/14

Curator: Joyessa

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Subjects

Location of subjects: United States of America

Host species Species from which microbiome was sampled (if applicable): Homo sapiens

Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology: Vagina Distal oviductal region,Distal portion of oviduct,Vaginae,Vagina

Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology: Human immunodeficiency virus AIDS virus,HIV,Human immunodeficiency virus

Group 0 name Corresponds to the control (unexposed) group for case-control studies: Healthy females who recieved universal placebo
Group 1 name Corresponds to the case (exposed) group for case-control studies: Healthy females who recieved two vaginal HIV microbicidal gels
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: Healthy females were treated with two gels twice daily over 13.5 days.
Group 0 sample size Number of subjects in the control (unexposed) group: 10
Group 1 sample size Number of subjects in the case (exposed) group: 25

Lab analysis

Sequencing type: 16S

16S variable region One or more hypervariable region(s) of the bacterial 16S gene: V5-V6

Signature 1

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Source: Figure 1

Description: Complete interconnection Five primary bacterial community state categories were discovered using hierarchical clustering approaches (CSTs). Different Lactobacillus species dominated three CSTs: L. crispatus (CST I), L. iners (CST III), and L. gasseri (CST IV) (CST II). Higher proportions and types of anaerobic bacteria such as Atopobium, Prevotella, Megaspherae, Sneathia, and Mobiluncus, as well as Gardnerella (the latter in proportions ranging from 0.2 percent to 9.9 percent) were found in vaginal bacterial communities from samples that clustered in CST IV-B, whereas CST IV-A Schematicoftheclinicalstudydesign. Green recommends using the gel items twice a day. Idealizedmensesareindicatedinred. At visits 2, 3, 4, 5, and 6, vaginal swabs were taken.

Abundance in Group 1: increased abundance in Healthy females who recieved two vaginal HIV microbicidal gels

NCBI	Links
Atopobium
Enterococcus
Escherichia
Gardnerella ⚠
Mobiluncus
Prevotella
Sneathia
Streptococcus
Megas- pheraeMegas- pherae

Revision editor(s): Joyessa