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Vaginal Ring May Be More Effective than Gel for HIV Prevention

Intravaginal rings containing the experimental NNRTIs MIV-150 or MIV-160 produced high drug concentrations in genital fluid and tissue -- higher than levels seen with vaginal gel -- and protected monkeys from infection with an HIV-like simian virus, according to a pair of recent reports from researchers at the Population Council.Other ring candidates under study deliver tenofovir and the NNRTI dapivirine.

[Editor's note: This article was modified on 10/23/12 to include information about a new tenofovir intravaginal ring presented at the recent 2012 American Association of Pharmaceutical Scientists annual meeting.]

Treatment as prevention and pre-exposure prophylaxis studies have shown that antiretroviral drugs taken by HIV positive or HIV negative people can dramatically reduce the risk of HIV transmission or acquisition if used consistently. But for a variety of reasons, other administration methods besides daily pills may be more acceptable and convenient for specific populations.

Several studies have looked at antiretroviral microbicides, typically gels or films inserted into the vagina or rectum before or after sex to both provide a physical barrier against HIV and inhibit the virus with drugs. The CAPRISA 004 trial was the first to show that a 1% tenofovir vaginal gel was safe and reduced HIV infection in women by 39%.

Vaginal rings are yet another option. Intravaginal rings made of silicone or similar materials release antiretroviral drugs slowly over time. Rings potentially could be left in place -- perhaps for weeks or months -- to improve adherence and make them easier to use without a sexual partner's cooperation or even awareness. Ideally, rings could also protect against other sexually transmitted infections (STIs) and prevent pregnancy if desired. Combining more than 1 agent could allay concerns about drug resistance.

MV-150

Rachel Singer, Meropi Aravantinou, and Melissa Robbiani from the Population Council and colleagues tested intravaginal rings containing MIV-150 and MIV-160 in animal studies.MIV-150 was discovered by Sweden's Medivir AB and licensed to the Population Council for further development as a microbicide.

As described in the September 5, 2012, issue of Science Translational Medicine, the researchers tested the activity of MIV-150, administered via intravaginal rings made of silicone or ethylene vinyl acetate (EVA), in macaque monkeys

The team previously showed that a daily vaginal gel containing MIV-150 partially protected macaques from infection with SHIV-RT, a hybrid simian/human immunodeficiency virus, reducing the risk of viral acquisition by more than 50%. Adding zinc acetate, a broad-spectrum antiviral, to the gel increased its HIV activity and offered protection against other STIs.

In the present study, the researchers inserted intravaginal rings containing MIV-150 or placebo (without zinc acetate), either 24 hours or 2 weeks prior to SHIV-RT exposure, and removed them either immediately before or 2 weeks after exposure.

The rings produced detectable levels of MIV-150 in vaginal fluid and tissue within 30 minutes, indicating successful delivery. Furthermore, the EVA ring significantly protected the monkeys against infection; 2 out of17 macaques that received MIV-150 EVA rings became infected, compared with 11 of 16 that received inactive rings -- a risk reduction of 83%. Timing of insertion did not have an effect on infection risk, but removing the ring immediately prior to exposure reduced the protective effect to only 16%. Silicone rings reduced the risk of infection by 58%, but the decrease was not statistically significant.

"Our results demonstrate that MIV-150-containing intravaginal rings have the potential to prevent HIV infection and highlight the possible use of intravaginal rings for delivering drugs that block HIV and other STIs," the researchers concluded.

"This proof-of-concept study confirms that the investment in vaginal rings as a delivery system for HIV prevention is paying off," Population Council vice president Naomi Rutenberg stated in a press release. "Our findings show that rings can deliver an anti-HIV drug to prevent infection."

MV-160

In a second study, reported in the August 27, 2012, advance online edition of AIDS Research and Human Retroviruses, the Population Council team evaluated MIV-160, a NNRTI related to MIV-150 but with greater solubility. They tested unformulated MIV-160 in vitro, as well as in a carrageenan-based vaginal gel and an intravaginal ring. Rings were inserted 24 hours before and left in place for 2 weeks after exposure.

MIV-160 exhibited potent antiviral activity against SHIV-RT in macaque vaginal tissue samples in the laboratory. In living monkeys, the MIV-160/carrageenan gel offered no protection compared to carrageenan alone. However, the MIV-160 intravaginal ring significant reduced the risk of infection. Further analysis showed that hundreds of micrograms of MIV-160 were released daily from the ring, compared with undetectable amounts released from the gel.

"Our findings highlight the importance of testing different modalities of microbicide delivery to identify the optimal formulation for efficacy in vivo," the researchers emphasized.

Other Candidates

Further along in the pipeline, the National Institutes of Health this summer announced the launch of a Phase 3 trial testing an intravaginal ring containing another NNRTI, dapivirine (TMC120).

Finally, at the 2012 American Association of Pharmaceutical Scientists annual meeting this month in Chicago, researchers described a new intravaginal ring that delivers tenofovir, the drug with the most extensive data supporting its use for pre-exposure prophylaxis in both oral and vaginal gel forms.

Patrick Kiser and colleagues from the University of Utah, in collaboration with the reproductive health organization CONRAD, developed a new ring technology made with plastic tubing that absorbs water, as conventional rings do not work well for delivering water-soluble drugs like tenofovir.

The ring produced tenofovir vaginal concentrations in sheep similar to protective levels achieved with tenofovir gel in prior trials, and it is expected to remain effective for 90 days. Researchers are now working on a ring that will simultaneously deliver tenofovir plus the hormonal contraceptive levonorgestrel.

10/16/12 [modified 10/23/12]

References

R Singer, P Mawson, N Derby, et al. An Intravaginal Ring that Releases the NNRTI MIV-150 Reduces SHIV Transmission in Macaques. Science Translational Medicine 4(150):150ra123. September 5, 2012.

M Aravantinou, R Singer, N Derby, et al. The Nonnucleoside Reverse Transcription Inhibitor MIV-160 Delivered from an Intravaginal Ring, But Not from a Carrageenan Gel, Protects Against Simian/Human Immunodeficiency Virus-RT Infection. AIDS Research and Human Retroviruses. August 27, 2012 (Epub ahead of print).

Other Source

Population Council. Animal Study Finds Anti-HIV Vaginal Ring 
Can Prevent Virus Transmission. Press release. September 5, 2012.

American Association of Pharmaceutical Scientists. Novel Intravaginal Ring Shows Promise in HIV Prevention. Press release. October 16, 2012.