Vaginal Microbiota May Affect Tenofovir Applied Intravaginally

SEATTLE – The vaginal microbiota may have an impact on the uptake of tenofovir when applied intravaginally, according to a new study presented at CROI 2017. Investigators report that the mechanisms associated with reduced tenofovir uptake warrant further research.¹

“We are only beginning to understand the impact of the vaginal microbiome on human health, but it is clear that the microbiome can impact drug delivery,” said Sharon Hillier, PhD, professor and vice chair for faculty affairs, and director of reproductive infectious disease research, department of obstetrics, gynecology and reproductive sciences, University of Pittsburgh School of Medicine in Pennsylvania.

Tenofovir is a nucleotide reverse transcriptase inhibitor (NRTI) widely used in the treatment of HIV, and the topical microbicide form of tenofovir is an investigational drug that has been shown to be safe. Currently, it is being studied to prevent sexual transmission of HIV and herpes simplex virus type 2 (HSV-2).

“The product was not shown to be effective for HIV prevention in 2 of 3 studies, while 1 study did show a 39% decrease in HIV. While it is generally accepted that nonadherence to the study product was one reason why tenofovir gel had a low level of efficacy, the data from our study suggest that the vaginal microbiome may also modify tenofovir delivery to the vagina,” Dr Hillier told Infectious Disease Advisor.

Currently, several forms of tenofovir-based microbicide products are being evaluated: a rectal gel, a vaginal ring, a vaginal tablet, and a vaginal film. CAPRISA 004 was a phase 2b, double-blind, randomized placebo-controlled study that assessed the effectiveness and safety of a vaginal gel containing 1% tenofovir for the prevention of HIV infection in South African women.² The study showed no differences in the rate of new HIV infections occurring in the tenofovir gel arm compared with the placebo arm. Following that trial, a secondary analysis of the CAPRISA 004 data was conducted and revealed some interesting discoveries. According to Dr Hillier, the secondary analysis suggested that women with a Lactobacillus-dominant vaginal microbiota had higher detection of tenofovir in cervicovaginal lavage fluid than women with non-Lactobacillus-dominant microbiota.

Dr Hillier and her team conducted a study with 41 healthy, HIV-negative women to evaluate the impact of vaginal microbiota on tenofovir concentrations in the genital tract and plasma. The mean age of the cohort was 28 and 71% were white. Each woman received either tenofovir 1% gel (40 mg) or film (40 mg and 10 mg) for 6 days.

The volunteers completed 6 self-administered doses, and cervicovaginal fluid was collected on day 7 prior to the final dose. For this investigation, the volunteers inserted the final dose at the clinic to confirm that the product was placed correctly. The investigators 2 hours later obtained cervical biopsies to assess for tissue tenofovir diphosphate and also collected plasma and cervicovaginal lavage for tenofovir quantification.

Prior to the treatment, vaginal swabs for the diagnosis of bacterial vaginosis and quantitative polymerase chain reaction (PCR) detection of Gardnerella vaginalis and Atopobium vaginae were collected. The researchers found that after 6 days of vaginal tenofovir use, trough tenofovir concentrations were lower in the cervicovaginal fluid and plasma in women with higher levels of G vaginalis. They also found that 2 hours after the final tenofovir dose, higher G vaginalis concentrations were significantly associated with lower levels of tenofovir diphosphate in cervical tissues and lower tenofovir concentrations in plasma.

The study also demonstrated a linear association between increasing concentrations of A vaginae and decreased tenofovir diphosphate in cervical tissue and plasma concentrations of tenofovir. “We were surprised that vaginal bacteria associated with bacterial vaginosis, a common vaginal syndrome in women, reduced the amount of drug getting into the genital tissues and blood,” said Dr Hillier. 

References

1. Hillier SL, Meyn LA, Bunge K, et al. Impact of vaginal microbiota on genital tissue and plasma concentrations of tenofovir. Presented at: CROI 2017. Seattle, WA; February 13-16, 2017. Abstract 86LB.
2. Clinical Trials: Antiretrovirals as Microbicides: Tenofovir (TFV). CONRAD Leaders in Reproductive Health and HIV Prevention website. www.conrad.org/microbicides-trials.html. Accessed February 15, 2017.