An animal study has found that a single dose of a microbicide gel containing tenofovir and FTC completely protected six out of six monkeys given a twice-weekly vaginal challenge of a combined human/monkey virus called SHIV. No monkeys were infected after 20 challenges with the virus, whereas monkeys not given the microbicide were infected after an average of four challenges.
Unexpectedly, however, the study also found that a gel containing tenofovir alone was just as effective and also protected all the monkeys. This contrasts with previous studies, which have found lower rates of efficacy for single-drug microbicides.
To test the effectiveness of the 1% tenofovir intravaginal microbicide gel and a combination gel including 5% FTC and 1% tenofovir, the investigators designed a four-arm study involving a total of 21 pigtail macaques.
In order to simulate human sexual exposure more accurately than other studies, the investigators gave lower doses of SHIV than in previous studies, but gave them more frequently – twice rather than once a week. In addition, the monkeys were not treated with progesterone. Previous studies have dosed monkeys with this hormone because it stops the animals’ menstrual cycle, which is monthly like the human cycle, and keeps the vaginal wall thin, creating a state where the monkeys are permanently at their most vulnerable point of the cycle to infection. This study left the monkeys to menstruate and more accurately imitates women’s changes in vulnerability. Protection was measured over ten weeks, or two complete menstrual cycles.
The study used gels containing high doses of antiretrovirals. In particular, there was 30mg of tenofovir in each dose compared with 40mg in microbicide trials that are currently taking place in humans – weight for weight a much larger dose.
Presenter Charles Dobard of the Centers for Disease Control said that trials with lower doses were being contemplated, saying that “we wanted to aim high and scale back.”
There were eleven controls, nine of whom received a placebo gel and two no gel. The 1% tenofovir and 1% tenofovir/5% FTC arms contained six monkeys each. The gels were applied intravaginally 30 minutes before exposure to SHIV. Infection with SHIV was checked using both antibody and viral load tests. The investigators also measured drug absorption 30 minutes after administration.
Of the eleven macaques in the control arm, ten were infected with SHIV after a median of four exposures to the virus. Both of the animals that received no gel became infected.
After 20 exposures to SHIV, none of the macaques treated with either the tenofovir gel or the FTC/tenofovir gel were infected. The investigators comment that this demonstrates that “both tenofovir alone and when combined with FTC provided very significant protection (p
Drug-level monitoring demonstrated that low levels of FTC (median, 67ng/ml) or tenofovir (median, 22ng/ml) were consistently detected in blood after these drugs were administered. It was estimated that this represented just 0.029% of the total tenofovir dose and 0.026% of the FTC.
Dobard C et al. Complete protection against repeated vaginal seminal HIV exposures in macaques by a topical gel containing tenofovir alone or with emtricitabine. Sixteenth Conference on Retrovirus and Opportunistic Infections, Montreal, abstract 46, 2009.