Population Council’s new microbicides protect against HIV for 24 hours in monkeys

Two microbicide gels each containing new agents that can prevent HIV infection protected female monkeys from vaginal infection with HIV for up to 24 hours after one application, US scientists report today in the journal PLoS One.

The research funded by the Population Council shows that a gel which combines zinc acetate and the non-nucleoside reverse transcriptase inhibitor MIV-150 protected rhesus macaques from HIV infection in every case if applied daily for two weeks, while application every other day for four weeks protected around three-quarters of the macaques from HIV infection.

Microbicides to prevent HIV infection are now a promising avenue of HIV prevention research following the results of the CAPRISA 004 trial, which showed that a microbicide gel containing the antiretroviral drug tenofovir reduced the risk of HIV infection for women by around 39%.

Antiretroviral agents from six antiretroviral drug classes are also under investigation for use in microbicides, including the non-nucleoside reverse transcriptase inhibitor dapivirine.

According to the study investigators, MIV-150 is less likely to lead to resistance than other agents of the NNRTI class, potentially making it suitable for use in a microbicide.

The investigators also tested zinc acetate, which has the potential to prevent HIV infection and also other sexually transmitted infections, such as HSV-2, the virus that causes genital herpes.

Both agents were tested individually and in combination with each other, and were delivered in a carageenan-based gel. Carrageenan is extracted from seaweed. The Population Council has previously tested a carageenan-based microbicide product, Carraguard, but found that although safe to use, it failed to protect women against HIV infection.

In this study researchers also looked at whether the products were effective when used a long time before HIV exposure. Most previous studies, in both animals and humans, have used products that were applied no more than a few hours before HIV exposure, so-called `coitally-dependent` application.

The need to apply a gel at the right time – no more than a few hours before intercourse takes place – may be one reason why almost all microbicide trials have shown that agents which look promising in the test tube or in animal studies tend not to protect against HIV infection when used by women in real-life conditions.

Good adherence – using a microbicide gel on the majority of occasion when vaginal intercourse takes place – was strongly associated with a lower risk of HIV acquisition in the CAPRISA 004 study, for example.

A `coitally independent` microbicide, which could be used each day, but at a time of the woman’s choosing rather than just before sexual intercourse, might be easier for women to use consistently.

One approach already being investigated is the use of a ring lodged at the cervix to dispense an antiviral agent in the vagina for up to a month, but approaches using a long-acting gel may also be useful, particularly if that product can protect against a range of sexually transmitted infections.

The study reported this week shows that the gel containing MIV-150 has a long-lasting effect if it is applied daily for at least two weeks, even when a very low dose of the drug is used. This may be a result of MIV-150’s tendency to accumulate in tissues, particularly in the cervical tissue.

The risk of infection appeared to be correlated with concentrations of the drug in the cervical tissue, the researchers reported. They also say that they have observed that cells exposed to MIV-150 remain resistant to HIV infection for up to five days, although these data remain unpublished.

The risk of drug resistance as a result of using antiretroviral microbicides is a concern shared by many researchers, particularly in relation to drugs in common use for antiretroviral treatment of HIV-infected people in developing countries.

No trace of MIV-150 could be found in the blood, and no drug resistance could be detected in macaques that became infected despite dosing with the microbicide containing MIV-150.

The researchers refer to unpublished data showing that resistance to MIV-150 is slow to develop in comparison to other NNRTIs, and active against viruses resistant to nevirapine, currently the most commonly used NNRTI in developing countries.

However viruses resistant to efavirenz, the other NNRTI now coming into greater use in developing countries, may have some resistance to MIV-150. This suggests that a small risk exists that the microbicide might not protect against efavirenz-resistant HIV, and further tests will be needed to investigate this question.

When used alone, MIV-150 protected 56% of macaques challenged with SHIV eight hours after the last gel application and 11% of macaques challenged 24 hours after the last gel application.

When combined with zinc acetate, the combination gel protected all 21 macaques challenged with SHIV 24 hours after the last gel application, following two weeks of daily gel application. When the gel was applied every other day for four weeks, and seven macaques were then challenged 24 hours after the last application, 67% were protected against HIV infection.

Zinc acetate was also tested for its anti-HIV effect alone, and showed a strong protective effect, protecting 11 of 14 macaques from infection. When data from daily or every-other-day dosing were pooled, the protective effect was statistically significant (70%, p<0.02).

The Population Council now plans to test both the combination product and zinc acetate as microbicides against HIV infection in phase 1 human trials which could begin in early 2012. MIV-150 was developed by the Swedish company Medivir and licensed to the Population Council in 2003.

Kenney J et al. An antiretroviral/zinc combination gel provides 24 hours of complete protection against vaginal SHIV infection in macaques. PLoS One 6 (1): e15835, 2011.