Second-ever pre-exposure prophylaxis study reports no safety concerns and promising result

The last day of the Vienna International AIDS Conference featured the results of the second-ever completed randomised controlled trial of pre-exposure prophylaxis (PrEP) – giving antiretrovirals to HIV-negative people at high risk of HIV to prevent them becoming infected.

The trial, which randomised 400 gay men to take either a daily tenofovir (Viread) or a daily placebo pill, was too small to serve as an efficacy trial.

Lisa Grohskopf of the US Centers for Disease Control (CDC) told the conference that none of the seven men who became infected with HIV during the trial was taking tenofovir but, because of the size of the trial, this could possibly be a random effect – nothing could be read into it about the efficacy of once-daily tenofovir as a means of preventing HIV.

This is a similar situation to the only other previous PrEP trial, from Ghana, which a reported a non-significant reduction in HIV infections in women taking PrEP (see aidsmap report: First hint that PrEP might work in humans).

Inevitably, though, it will be taken as a promising signal in advance of the next trials to report – the CDC 4370 trial in Thai drug users (see aidsmap report: Early data from the Thai trial ) and the predominantly South Amercian iPrEX trial in gay men (see more on community consultation on aidsmap), which are due to report at the beginning of next year.

This trial, however, was intended as a safety trial, looking closely at side-effects of the tenofovir medication and especially at risks already associated or suspected of association with tenofovir, such as kidney failure and bone mineral loss.

The trial recruited gay men from San Francisco, Atlanta and Boston, and randomised them into four groups of 100. Two groups took either tenofovir or a dummy pill from the start, for two years. The other two waited for nine months before starting either tenofovir or placebo, and took them for the remaining 15 months. This was in order to have data from a control group that took no daily pills at all, in order to find out if taking a daily pill changed sexual and risk-taking behaviour.

In the end, 373 men started taking tenofovir or placebo and 323 completed the study, a retention rate of 86%.

The average age of the participants was 38.5 and there was a nearly significant difference in the racial balance of the trial, with 18% of those on placebo being African-American and 12% of those on tenofovir (p=0.07).

Participants had had, on average, four male partners in the last three months; 29% of those on tenofovir and 33% on placebo had had unprotected sex in the last three months (not a significant difference); and 12.5% of the participants had had risky sex, i.e. unprotected sex with someone who was or could have been HIV-positive.

There was virtually no difference in the rate of adverse events seen between patients on tenofovir and those on placebo. The only side-effect in which a significant difference was seen was back pain, suffered by 13% on tenofovir and 6% on placebo (p=0.04), and there were no differences in the rate of any serious side-effect.

In particular, there was no elevation whatsoever in creatinine levels (an indicator of kidney problems) and the rate of low blood phosphate, an indicator of possible bone mineral loss, was if anything higher in participants taking placebo, although not significantly so (p=0.12).

One person died during the trial, of an accidental overdose of opiate drugs with alcohol.

Seven participants tested HIV-positive during the trial. One of these was clearly someone recruited in the window period for HIV infection; he was HIV-negative when screened, but HIV-positive on the first day of enrolment, with a viral load of 1770 copies/ml.

Of the other six, three were on placebo when they contracted HIV and the other three were in one of the delayed-treatment arms and had not started taking either tenofovir or placebo. No tenofovir resistance was seen.

Sexual risk behaviour did not change significantly during the trial. At baseline, the proportion of men who said they had had unprotected anal sex during the last year was 60% in the immediate-treatment arm and 53% in the delayed-treatment arm (note that this was over a longer period than the baseline questionnaire, which asked about sexual behaviour in the last three months).

It went down from the beginning of the trial to the next quarterly visit, an effect often seen in trials, and went down more steeply in those randomised to immediately take a tenofovir or placebo pill, to 46% – suggesting that taking a daily pill may serve as a reminder to use condoms rather than a disincentive. It rose very slightly and non-significantly thereafter to about 55% in the immediate-treatment arm, but did not rise at all in the delayed-treatment arm.

Further analyses are continuing, which will look into risk behaviour more deeply, though as a member of the audience commented, it’s much less likely that people would take more sexual risks if they knew they might be taking an inactive placebo than if they were sure they were on tenofovir. Analyses will also look directly at bone mineral density and assess adherence.

Grohskopf L et al. Preliminary analysis of biomedical data from the phase II clinical safety trial of tenofovir disoproxil fumarate (TDF) for HIV-1 pre-exposure prophylaxis (PrEP) among U.S. men who have sex with men (MSM). Eighteenth International AIDS Conference, Vienna, abstract FRLBC102, 2010.

View abstract and slides from this session on the official conference website.