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CROI 2014: Dapivirine Vaginal Ring Appears Safe and Effective in Tissue Study

Vaginal rings containing the experimental NNRTI dapivirine were well-tolerated and blocked HIV infection of cervical tissue samples, but rings containing maraviroc did not produce adequate drug concentrations, researchers reported at the 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014) this month in Boston.

The area of biomedical prevention -- using antiretroviral drugs or other medical rather than behavioral approaches to prevent HIV transmission -- has produced some of the major gains in the HIV field in recent years. Studies have demonstrated the effectiveness of treatment-as-prevention and oral pre-exposure prophylaxis (PrEP), but researchers are also looking at other methods including long-acting injectables and microbicide gels and rings. Vaginal rings release drugs slowly over time, which could help with adherence.

Beatrice Chen from the University of Pittsburgh presented findings from a Phase 1 clinical trial (MTN-013/IPM 026) evaluating the safety and pharmacokinetics and pharmacodynamics of vaginal rings containing the investigational non-nucleoside reverse transcriptase inhibitor dapivirine (formerly TMC120)alone, the CCR5 co-receptor blocker maraviroc (Selzentry)alone, both drugs in 1 ring, or a placebo ring.

Thedapivirine-only ring is currently in Phase 3 trials. The combination ring -- being tested for the first time in a human trial -- contained 25 mg dapivirine plus 100 mg maraviroc. All rings are made of a silicone elastomer measuring 56 mm (about 2.25 inches) in diameter and 7.7 mm (about .25 inch) thick.

This double-blind, randomized, placebo-controlled trial included 48 HIV negative sexually abstinent women in Pittsburgh, Boston, and Birmingham, AL. Half the women were white, about 40% were black, and the average age was approximately 30 years.

The researchers measured dapivirine and maraviroc levels in blood plasma and vaginal fluid and collected information about adverse events. Adherence was assessed by self-report and residual drug levels in returned rings. After wearing the rings for 28 days, participants underwent cervical biopsies to collect tissue samples which were then exposed to HIV in the laboratory (known as an ex vivo challenge).

Results

• Almost all participants (98%) completed the study.
• More than 90% reported full adherence, which was confirmed by residual drug levels in used rings.
• Most women wore the ring continuously for 28 days, though nearly 1 in 5 said they would prefer not to do so during menstruation.
• Vaginal rings were generally safe and well-tolerated.
• Participants reported a total of 167 adverse events, most of which were mild (88%) or moderate (10%), and a majority of which (71%) were deemed unrelated to the study products.
• There were no significant differences in frequency of genitourinary side effects or moderate or worse adverse events across the treatment and placebo arms.
• Maximum plasma concentrations (Cmax) of dapivirine were similar in women using the dapivirine-only and combination rings (272 vs 294 pg/mL, respectively).
• Plasma concentrations of maraviroc, however, were below limits of quantification (further analysis using more sensitive tests is ongoing).
• At day 28, mean dapivirine levels in vaginal fluid were 14.9 and 10.0 mcg/mL, respectively, in women who used the dapivirine-only and combination rings.
• The mean maraviroc level in vaginal fluid reached 6.7 mcg/mL with the maraviroc-only ring, but only 1.1 mcg/mL with the combination ring.
• Levels of dapivirine in cervical tissue samples were 0.6 and 1.6 mcg/mL, respectively, with the dapivirine-only and combination rings.
• Only 4 of the 24 women who used the maraviroc-only or combination rings had cervical tissue levels above the limit of quantification.
• Cervical tissue samples from women using dapivirine and combination rings showed a significant inverse linear relationship between HIV replication and tissue dapivirine levels -- that is, higher levels were associated with reduced viral replication.

"Dapivirine but not maraviroc delivered by a vaginal ring for 28 days blocked HIV-1 infection in cervical tissue," the researchers concluded. "There was a linear correlation between dapivirine levels in tissue and protective effect. These data suggest that delivery of NNRTIs via vaginal rings is a viable approach for HIV prevention."

"It's encouraging that both drugs were safe, and that most women didn't mind wearing the ring," Chen said in a press release issued by the Microbicide Trials Network. "However, we found maraviroc wasn't getting absorbed in tissue like dapivirine was and it didn't work as well as dapivirine in our laboratory studies looking at activity against HIV."

Zeda Rosenberg from the Partnership for Microbicides said that the non-profit organization is doing additional development work to try to increase the amount of maraviroc that gets into cervical tissue and is planning a second safety study for 2015.

As described in the March 5, 2014 issue of PLoS ONE, researchers are also working on a combination polyurethane vaginal ring that features 2 separate compartments containing tenofovir (Viread) -- the most widely used antiretroviral for oral PrEP -- and the contraceptive levonorgestrel. This ring was previously presented at the American Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Exposition this past November.

"Products only work when they are used," study co-author David Friend of CONRAD, which develops reproductive health technologies for low-income countries, said in a Northwestern University press release. "By having a ring that can remain in the body for up to 90 days, our hope is that this ring will offer a solution to increase adherence, and therefore provide greater protection against HIV while also preventing pregnancy."

3/18/14

References

BA Chen, L Panther, C Hoesley, et al. Safety and Pharmacokinetics/Pharmacodynamics of Dapivirine and Maraviroc Vaginal Rings. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6. Abstract 41.

KE Bunge, CS Dezzutti, I Macio, et al. FAME-02: A Phase I Trial To Assess Safety, PK, and PD of Gel and Film Formulations of Dapivirine. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6. Abstract 42LB.

JT Clark, MR Clark, NB Shelke, P Kiser, et al. Engineering a Segmented Dual-Reservoir Polyurethane Intravaginal Ring for Simultaneous Prevention of HIV Transmission and Unwanted Pregnancy. PLoS ONE 9(3): e88509. March 5, 2014.

Other Sources

Microbicide Trials Network. First Trial of Combination ARV Vaginal Ring for HIV Prevention Finds Ring Safe but One ARV Carrying the Weight. Press release. March 4, 2014.

Northwestern University. Long-Lasting Device Protects Against HIV and Pregnancy. Press release. March 5, 2014.