Effect of HIV-microbicide applications on the vaginal microbiota

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 barcoded 16S rRNA genes, in samples from 60 healthy, abstinent female volunteer subjects (age 18-50) with regular menses in a phase 1 study of twice-daily application over 13.5 days of 1 of 3 gel products: hydroxyethylcellulose (HEC)-based “universal” placebo, 6% cellulose sulfate (CS), and 4% nonoxynol-9 (N9). We used mixed effects models inferred using Bayesian Markov Chain Monte Carlo methods, which showed that treatment with active agents shifted the microbiota towards a community type lacking significant numbers of Lactobacillus sp and dominated by strict anaerobes. This state of the vaginal microbiota was associated with 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 sp, 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.