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CROI 2012: Studies Advance Development of Microbicides for HIV Prevention

A pair of studies presented in an oral session at the 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012) taking place this week in Seattle addressed the safety and acceptability of experimental microbicide preparations. Both studies found the microbicides to be well tolerated and acceptable.

Recently, the field of biomedical prevention has produced some important breakthroughs. PrEP or pre-exposure prophylaxis, treatment-as-prevention, and adult male circumcision have all demonstrated significant degrees of protection against HIV infection.

Another approach being studied is the use of microbicides -- topical products, typically gels -- that contain drugs or other compounds. While microbicides are intended to prevent microbial infection, one such product, nonoxynol-9 (N-9) was found to damage membranes and increase the risk of acquiring HIV.

Tenofovir Rectal Gel

Ian McGowan from the University of Pittsburgh School of Medicine presented results from a study examining a reformulated rectal gel containing 1% tenofovir. The study, called MTN-007, was a Phase 1 double-blind, placebo-controlled safety and acceptability study.

As reported at last year's CROI, trial RMP-02/MTN-006, a study of an earlier formulation of this gel with the same drug concentration but a higher level of glycerin, demonstrated good pharmacokinetics, but the gel was not well tolerated. Almost all of the participants in that study reported gastrointestinal side effects.

MTN-007 enrolled 65 volunteers -- 40 men and 25 women -- from 2 sites in the U.S. Participants were randomly assigned to use either the reformulated 1% tenofovir gel, 2% N-9 gel as a control, a placebo gel (HEC), or no treatment.

Results

• Grade 1 and 2 adverse events (AEs) were similar across arms, with a trend toward more AEs in the N-9 group;
• 56% of people in the tenofovir gel arm reported some gastrointestinal symptoms -- most commonly flatulence and abdominal pain
• While this AE rate is somewhat high, it is much lower than the frequency seen with the older gel formulation.
• 87% of people using the new tenofovir gel said they would continue using it, compared to 63% of those using the N-9 gel.
• There were no changes observed in rectal mucosal tissues.

Discussing these findings at a press conference, McGowan noted that a genetic analysis revealed changes in several hundred genes in people who used the tenofovir or N9 gels. "We don't know the biological significance of this," he said. "Tenofovir is very well-tolerated, but it is a DNA chain terminator, so it would be surprising if it didn’t turn some things on or off."

The results from this study are encouraging and will enable the product to move into Phase 2 studies, which will begin to look at efficacy as well as safety and acceptability in a larger population.

Dapivirine Vaginal Ring

Another approach being studied for to microbicide delivery is intravaginal rings. Such rings typically contain a month’s supply of a microbicide, designed to be released a little at a time.

Annalene Nel of the International Partnership for Microbicides in Silver Spring, MD, presented results from a study of monthly dapivirine-containing vaginal ring. Dapivirine (aka dapivarine), formerly known as TMC-120, is a non-nucleoside reverse transcriptase inhibitor.

This study enrolled 280 HIV negative women in South Africa, Kenya, Malawi, and Tanzania. Volunteers were given an intravaginal ring each month containing either dapivirine or placebo.

Results

• Large variability between study participants was observed in release of drug -- as much as 6-fold differences were seen.
• No treatment-related adverse events were reported.
• There were 3 new HIV infections during the study, all in the placebo group.
• 92% of participants reported good adherence, meaning the ring was never removed for longer than 1 day each month; the most common reason for removing the ring was for cleaning.
• The rings sometimes came out, most commonly during defecation, but this problem tended to decrease with longer use.
• 97% of women said they would be willing to continue using the ring.

These results are welcome news for microbicide advocates. The microbicide field has suffered some significant setbacks in recent years, with several once-promising approaches failing in larger clinical trials.

But this has begun to change. In 2010, the CAPRISA 004 study found that a 1% tenofovir vaginal gel reduced HIV infections by 39%-54%, depending on how often it was used. The results from CAPRISA 004 -- along with those presented here at CROI -- are giving added momentum to the effort to develop safe, effective, and acceptable microbicides to prevent HIV infection.

3/8/12

References

I McGowan, C Hoesley, P Andrew, et al. MTN-007: A Phase 1 Randomized, Double-blind, Placebo-controlled Rectal Safety and Acceptability Study of Tenofovir 1% Gel. 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012). Seattle, WA. March 5-8, 2012. Abstract 34LB.

A Nel, M Kamupira, C Woodsong, et al. Safety, Acceptability, and Adherence of Monthly Dapiravine Vaginal Microbicide Rings for HIV Prevention. 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012). Seattle, WA. March 5-8, 2012. Abstract 1089.