Monkey study strengthens the case for a microbicide combining several anti-HIV drugs

Gus Cairns
Published: 09 August 2008

A study using a microbicide gel containing the antiretroviral drugs in the combination pill Truvada – tenofovir and FTC (emtricitabine) – completely protected six pigtail macaque monkeys from infection with a type of HIV designed to be infectious to monkeys, the XVII International AIDS Conference heard on Thursday.

‘Completely protected’ means that six monkeys given twice-weekly vaginal inoculations with three millilitres of a gel containing 5% FTC and 1% tenofovir, and then challenged 30 minutes later with a dose of 760,000 viral units of a laboratory-devised exposure of HIV called SHIV-SF162p3 were not infected after 20 doses. The reason five times as much FTC as tenofovir was used was simply because FTC is more soluble in water.

This dose, which is ten times the amount that should be expected to infected 50% of animals per inoculation, is actually a lower dose than that used in many previous studies, and was designed to mimic more closely the effects of regular sexual exposure in humans. In contrast five out of six monkeys given the placebo gel (one each at weeks two, three, four, five and eleven) were infected. When asked why one monkey given placebo was not infected, presenter Walid Heneine said that such statistical outliers often happened, though the substance used to make the gel, hydroxyethylcellulose (HEC) has some antiviral effect too.

Two monkeys just given doses of the virus and no gel both became infected at weeks three and four.

Low levels of both FTC and tenofovir were consistently detected in the blood of all the treated macaques 30 minutes after vaginal application of the gel: 67 nanograms (billionths of a gram) of FTC per millilitre (ng/ml) of FTC and 23 ng/ml of tenofovir. This is something like 2000 times lower than the minimum dose of tenofovir required to inhibit 50% of HIV (its IC50). There have been considerable concerns that the absorption of microbicides into the blood might produce resistance in human subjects that were unwittingly HIV-positive or experiencing infection at the time; however Heneine commented that these drug levels were well below those necessary to create the selective pressure that results in drug resistance.

Heneine was asked whether the results of this study would put pressure on investigators conducting human trials of microbicides to start using combinations of drugs rather than single ones; at present all the ongoing and planned human trials are going to use single drugs, including one of tenofovir, CAPRISA, which started in May 2008.

Monkey studies of oral prophylaxis against HIV (pre-exposure prophylaxis: PrEP) have seen a similar pattern; a study showing that a single-drug regimen, also using tenofovir, produced partial protection (Subbarao) followed by a study showing that a tenofovir/FTC dual combination produced complete protection, albeit in this case against only 14 challenges with infectious virus. As a result of this, all but one of the current or planned efficacy studies of PrEP is using or has switched to drug combinations.

Heneine said that a decision would be taken on this question after an imminent study using tenofovir alone, under the same protocol of challenges and infectious dose, was completed by the CDC.