At the recent Conference on Retroviruses and Opportunistic Infections (CROI), meeting in Boston (27th February – 2nd March) researchers reported results from two trials involving the use of antiretroviral drugs, currently used in therapy, for the prevention of HIV transmission. These trials (MTN 001 & RMP-02/MTN-006) are just two among a whole programme of HIV-related microbicide trials being currently undertaken by the Microbicide Trials Network (MTN) – an organisation established in 2006 by component institutions of the US National Institutes of Health (NIH) with a view to early licensing of products for widespread use. These trials are just a stage in the deployment of the wider MTN programme, but contribute important findings.
Recent years have seen increasing interest in the possibility of preventative regimes for individual use that could protect against HIV. A promising avenue currently very much under consideration is the prophylactic use of antiretroviral (ARV) drugs, either taken orally or applied topically to the vagina (or rectum in the case of homosexual transmission). Such an approach promises to place in the hands of women a means of protecting themselves against the virus, rather than having to rely on their male partners. This represents a considerable advantage, given the relative importance of heterosexual transmission in many places, and the greater vulnerability of women to acquiring HIV during sex (about double the probability).
The MTN trials take place in the wake of earlier path-breaking studies which have suggested the preventative potential of ARVs. CAPRISA-004 (2010), a South African study of 889 women who applied the tenofovir gel before and after sex, showed the product reduced the risk of HIV by 39%; while iPrEx (2010), another study involving 2,500 gay men, found 44% fewer HIV infections among those assigned to daily use of Truvada, as against the placebo group. A further stage in determining the prophylactic efficacy of ARV drugs will be marked by the conclusion (hopefully early in 2013) of phase IIb MTN study, MTN-003 – or VOICE (Vaginal and Oral Interventions to Control the Epidemic). The latter will enrol 5,000 sexually active HIV-negative women in Zimbabwe, Uganda and South Africa and will evaluate the relative efficacy of regimes involving daily use of Tenofovir and Truvada tablets, as well as Tenofovir gel.
Of the two trials, reported on at the Conference (CROI), and discussed below, MTN-001 was designed to complement the VOICE study; MTN-006 further explores the prophylactic effect of Tenofovir for transmission via anal sex.
This Phase II trial, the results of which have been reported at CROI, claims to be the first head-to-head comparison between tenofovir gel and oral tenofovir for HIV pre-exposure prophylaxis. The issue of the relative efficacy of these regimes remains to be resolved by the VOICE (MTN-003) study; MTN-001 is concerned with: 1. How much active drug is taken up by the body in each case (pharmacodynamics); 2. The participants’ preferences as regards gel and an orally administered medication. 168 women were enrolled: 72 in the US; the rest at sites in Uganda and South Africa.
Use of the tablet was associated with 20-times higher concentration of active drug in the blood; the gel regimen with a 100-times higher concentration in vaginal tissue. The significance will become clear when these findings are complemented by findings from the VOICE study. As regards the response of participants, both regimens were well tolerated, and both won the preference of certain participants. There was, however, an interesting divergence between US and African participants. US women tended to prefer the tablet (72% as against 14%), while 87% claimed they would be prepared to use the tablet, as against 64% the gel. African women marginally favoured the gel (42% as against 40%), while 100% claimed they would be willing to accept either regimen.
This study breaks new ground as the first to investigate the safety and efficacy of tenofovir gel applied to the rectum as a means to protect against HIV during anal intercourse. The phase I trial involved rectal tissue biopsies sampled from 18 HIV-negative participants who applied either tenofovir gel or a placebo gel daily for the course of one week. HIV infection was found to be “significantly inhibited” among those using the gel daily. Only 25% of participants using the tenofovir gel claimed to like it, though 75% reported a high likelihood of future use. 2 of the 12 participants using tenofovir reported severe gastrointestinal side effects.