Inserts Containing Combination Therapy May Protect Women Against HIV

Vaginal inserts containing tenofovir alafenamide fumarate (TAF) in combination with elvitegravir (EVG) may help protect women against HIV infection.

Data compiled from a recent study showed that this therapy was highly effective in preventing simian/HIV (SHIV) infection in a macaque model mimicking vaginal transmission of HIV. ¹

Results of the study were presented last week at the Conference on Retroviruses and Opportunistic Infections in Seattle, Washington.

The data support the clinical development and first in-human testing of TAF/EVG inserts for on-demand topical prophylaxis against vaginally acquired HIV infection, according to study authors.¹

“On demand topical prophylaxis is targeted drug delivery, whereby antiretroviral drugs are delivered to the right place at the right time,” said Dr. Charles Dobard of the CDC, the study’s presenter. ²

On-demand topical pre-exposure prophylaxis (PrEP) for HIV prevention has several advantages over a daily oral PrEP regimen, including decreased risk of resistance, limited drug toxicity, potential to increase adherence, and reduced costs, according to the investigators.

The self-administered TAF/EVG inserts being studied are designed to rapidly dissolve, Dobard said.

These inserts are discreet, small, and offer minimal leakage, he said.

They are being developed by Conrad/EVMS for vaginal or rectal pericoital use.²

In the study, conducted by CDC investigators, normal cycling pigtail macaques (n=14) were exposed vaginally to SHIV162P3 once a week for up to 13 weeks. Six macaques received inserts containing a fixed-dose combination of TAF/EVG (20 mg/16 mg), and 8 received matching placebo inserts. Inserts were placed in the posterior vagina near the cervix 4 hours before each SHIV exposure. ¹

The study’s authors said that they recently found in a dose-ranging pharmacokinetic assessment in macaques that vaginal administration of inserts containing 16 and 20 of EVG and TAF, respectively, resulted in rapid accumulation of EVG and durable levels of tenofovir diphosphate in mucosal tissues at concentrations associated with in vivo protection.

Of the 8 macaques that received placebo inserts, 7 became SHIV infected, while 1 remained SHIV negative following 13 weekly challenges. The median number of challenges to infect macaques treated with placebo inserts was 3 (range 2-13). By contrast, 5 of 6 macaques that received TAF/EVG inserts remained protected after 13 challenges, resulting in an estimated efficacy of 92%. Survival analysis demonstrate at least a 9-fold reduction in risk of infection in macaques that received TAF/EVG compared with the placebo inserts (p=0.007; log-rank).¹

During the study, infection was monitored weekly by serology and RT-PCR amplification of SHIV RNA in plasma. A Kaplan-Meier survival analysis was used to compare the survival distribution between the 2.¹

The vaginal administration of TAF/EVG (20/16 mg) inserts within 4 hours prior to exposure protected macaques from vaginal SHIV infection, according to Dobard.

Studies are ongoing to assess the window of protection with inserts administered 24 hours before exposure, as PrEP, or 4 hours after exposure.²

Ongoing Phase 1 clinical studies for humans are evaluating the safety of TAF/EVG inserts.²

The study was conducted by the CDC in collaboration with Conrad and University of the Sciences. It was partially funded by an interagency agreement between the CDC and the US Agency for International Development with support from Gilead Sciences and the US President’s Emergency Plan for AIDS Relief.²

References

• Dobard C, Peet, M, Nishiura K, et al. Protection against vaginal SHIV infections with an insert containing TAF and EVG. In: Proceeding from the Conference on Retroviruses and Opportunistic Infections; March 4-7, 2019; Seattle, WA. Abstract 101.
• Dobard C. Protection against vaginal SHIV infections with an insert containing TAF and EVG. In: Presented at: Conference on Retroviruses and Opportunistic Infections; March 6, 2019; Seattle, WA. croiwebcasts.org/console/player/41207?mediaType=audio&. Accessed March 13, 2019.