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HIVR4P 2014: Vaginal Rings Show Promise for HIV Prevention

A silicone intravaginal ring that releases the antiretroviral drugs dapivirine and darunavir was shown to reach levels expected to be effective in vaginal and cervical fluid and tissues in monkeys, researchers reported at the HIV Research for Prevention meeting last week in Cape Town. A related study found that a single ring can potentially serve multiple purposes, preventing HIV, genital herpes, HPV, and pregnancy.

Dapivirine + Darunavir

Diarmaid Murphy from Queen's University in Belfast reported pre-clinical data from the European CHAARM project, testing combinations of antiretroviral drugs that may be suitable for delivery in a vaginal ring for HIV prevention.

Combination vaginal rings containing 2 or more antiretrovirals targeting different steps in the HIV lifecycle may be more effective than single microbicides at preventing sexual transmission, the researchers noted as background. Several combination rings are already in development, most commonly dispensing the nucleotide reverse transcriptase inhibitor tenofovir -- approved, along with emtricitabine, for oral pre-exposure prophylaxis (PrEP) -- and the experimental NNRTI dapivirine (TMC120).

This analysis evaluated matrix type silicone elastomer rings that delivered dapivirine plus the protease inhibitor darunavir (marketed in oral form as Prezista). The rings were tested in vitro and in cynomolgus macaque monkeys.

A variety of rings were produced, containing 25 mg dapivirine, 100 mg dapivirine, 300 mg darunavir, and 100 mg dapivirine + 300 mg darunavir. The researchers tested release of the drugs in vitro and calculated the IC50, or concentration needed to inhibit viral replication by 50%, when vaginal fluid was exposed to HIV. They also measured concentrations of the drugs in macaques' blood serum, vaginal fluid, and vaginal, cervical, and other tissues over 28 days of using the rings.

In vitro release from the rings was dependent on drug loading, whether the rings contained 1 or 2 drugs, and the release medium. The melting temperature of dapivirine was reduced when combined with darunavir.

In monkeys, blood serum levels ranged from 20 to 300 pg/mL for both dapivirine and darunavir. Vaginal fluid levels ranged from 2000 to 200,000 ng/g for both drugs. Vaginal fluid levels were "well above" the IC50 for both dapivirine and darunavir

Looking at tissue concentrations, vaginal tissue drug levels ranged from 1000 to 5000 ng/g, while cervical tissue levels were 100 to 400 ng/g. Drug levels in uterus and rectal tissue, however, were substantially lower. This is an interesting contrast with other studies presented at the meeting showing that oral Truvada (tenofovir + emtricitabine) and injectable rilpivirine reach higher levels in rectal compared with vaginal tissue.

Based on these results -- and in light of progress in an ongoing clinical trial of a 25 mg dapivirine-only ring, the researchers concluded that a combination vaginal ring containing dapivirine plus darunavir "is a viable second-generation HIV microbicide candidate."

Multipurpose Combo Ring

In a related study, Thomas Zydowsky from the Population Council and colleagues tested an intravaginal ring containing MIV-150 (another experimental NNRTI), zinc acetate, carrageenan (a seaweed derivative), and the hormonal contraceptive levonorgestrel, in an effort to prevent HIV infection, herpes simplex type 2 (HSV-2), human papillomavirus (HPV) infection, and pregnancy with a single multipurpose ring.

Prior studies have already shown that "MZC" (MIV-150, zinc acetate, and carrageenan) gel reduced the risk of infection with HSV-2 and a human-monkey hybrid HIV-like virus (SHIV), while carrageenan gel reduced HPV infection in mice.

In this study macaque monkeys were fitted with rings containing MZC, levonorgestrel only, MZC plus levonorgestrel, or placebo. The researchers measured levels of MIV-150, carrageenan, and levonorgestrel in blood and vaginal swab samples over 28 days of using the 4-way combination rings. In an efficacy analysis, rings were exchanged every 21 days, and monkeys were exposed to SHIV and HSV-2 on days 7, 10, 14, and 17 after ring insertion.

MIV-150 was detected in blood plasma and vaginal swabs 1 hour after ring insertion, with levels peaking after 1-3 days, declining from day 7 through 28, and finally becoming undetectable within 24 hours after ring removal. Levonorgestrel was detected in blood serum within 4 hours after insertion, plateaued by day 7, and again became undetectable within 24 hours after ring removal. Carrageenan was detected in vaginal swabs of most monkeys from day 3 until the rings were removed.

Preliminary data showed that the 4-way MZC plus levonorgestrel rings protected all but 1 of 12 macaques against SHIV exposure, while all 4 monkeys with levonorgestrel-only rings and 2 of 4 with placebo rings became infected.

About 30% fewer monkeys became infected with HSV-2 when using MZC or MZC plus levonorgestrel rings, and among those who did become infected, HSV-2 shedding was reduced.

This multipurpose intravaginal ring "significantly reduces SHIV-RT infection and HSV-2 shedding in macaques," the researchers concluded.

11/4/14

References

M Malcolm, D Murphy, D Desjardins, et al. A Combination Vaginal Ring Releasing Dapivirine and Darunavir. HIV Research for Prevention (HIV R4P). Cape Town, South Africa, October 28-31, 2014. Abstract OA03.04.

TM Zydowsky, J Kenney, M Aravantinou, et al. A Novel Intravaginal Ring (IVR) Protects Macaques against SHIV-RT Infection and Reduces HSV-2 Shedding after Repeated SHIV-RT/HSV-2 Co-challenge. HIV Research for Prevention (HIV R4P). Cape Town, South Africa, October 28-31, 2014. Abstract OA03.05.