A large study of pre-exposure prophylaxis (PrEP) in women is to close after investigators concluded that even if it carries on to its originally planned conclusion, the FEM-PrEP trial is highly unlikely to show a significant protective effect of Truvada (tenofovir and FTC) against HIV infection in this population.
Trial organiser Family Health International stressed in a statement on April 18 that it would be premature to conclude that PrEP did not work in this trial population, and that more analyses will be needed in order to determine what effect, if any, taking Truvada had on a woman’s risk of acquiring HIV during this study.
Pre-exposure prophylaxis is the daily use of antiretroviral drugs by HIV-negative people to prevent HIV infection. Several animal studies and one large randomised trial in men who have sex with men (see below) have shown that Truvada can reduce the risk of infection.
The FEM-PrEP study recruited 1951 HIV-negative women aged 18 to 35 at risk of HIV infection in South Africa, Kenya and Tanzania. Women were randomised to receive daily oral Truvada (tenofovir and FTC in one pill) or placebo. Family Health International says that around 90% of women enrolled were retained in the study, and took the study drug for approximately 12 months.
Among all trial participants the approximate annual rate of new HIV infections was 5% per year, and a total of 56 new infections had been recorded by February 18 2011. These were equally distributed between the Truvada and placebo groups.
Follow-up for each participant was due to last 52 weeks, and the trial was designed to recruit 3900 women.
The decision to halt recruitment at this point indicates that the Independent Data Monitoring Committee which scrutinises the trial has come to the conclusion that even if another 2000 women were to be enrolled onto the trial and followed for 52 weeks, it is highly unlikely that any protective effect of Truvada that might emerge in this group would be enough to demonstrate a statistically significant benefit overall.
This might be because the magnitude of effect seen in the first 1951 women was somewhat too small to be statistically significant, or because there was no substantial difference, and more analysis of the trial data will be needed.
In particular it is unclear whether the women in the two study arms had a similar total exposure to their assigned study medication: an equal number of infections at month 12 may not translate into an equal rate of infection, because women in one group may have a higher number of total months covered by study medication.
It is unclear if adherence might explain the apparent lack of effect in this study. Overall adherence was reported to be 95%, but at this stage FHI is unable to report any differences in adherence between study arms, differences in adherence over time or differences in adherence according to the adherence measures used.
The FEM-PrEP study employed regular reviews of participant adherence to identify any problems, and also measured participant blood levels of antiretrovirals to check on the correlation between self-reported adherence, pill counts and actual drug consumption.
Contrast to IPrEX study
The disappointing results of the FEM-PrEP study in high-risk women stand in contrast to the results of the IPREX study in men who have sex with men. This study showed that use of Truvada reduced the risk of HIV infection by 44%, but reduced the risk of infection among men who took it more than 90% of the time by 73%.
One possibility raised by the early closure of the FEM-PrEP study is that antiretroviral drugs may show different levels of effectiveness in preventing new infections according to the populations and locations in which they are studied. In other words, the prevention impact of antiretrovirals may be highly dependent on the context rather than on biological differences between the populations studied.
One critical question, which may be impossible to answer given the limited numbers enrolled, is whether there were differences between trial participants in South Africa and Kenya which might explain the apparent lack of effect, either in terms of sexual behaviour or adherence.
Two studies will continue to test the use of Truvada to prevent HIV infection in women.
The Partners study is testing the use of PrEP in 4700 male-female couples in Kenya and Uganda where one partner is HIV-positive and one partner is uninfected, and is expected to report results in 2013. This study is comparing oral tenofovir and oral Truvada.
The VOICE study is comparing the effectiveness of oral tenofovir or oral Truvada to a vaginal gel containing tenofovir in 5000 heterosexual women in South Africa, Uganda and Zimbabwe. This study is also expected to report results in 2013.
More pregnancies in Truvada recipients
One question that investigators will be keen to explore is why more women became pregnant in the Truvada arm of the study than in the placebo arm.
The trial protocol sought to minimise the exposure of unborn infants to tenofovir, because at the time the study was designed there was little information about the effects of foetal exposure to this drug on development.
Accordingly, women were required to be using a contraceptive method at the time of enrolment. Women who became pregnant during the study stopped taking study medication as soon as a pregnancy test confirmed a pregnancy. Women were tested every four weeks, and were also counselled about contraception and offered free contraception, in addition to receiving counselling about safer sex and being provided with free condoms.
Around one-third of women used oral contraception and two-thirds received an injectable hormonal contraceptive. Almost none used the intrauterine device (IUD) or a contraceptive implant.
Nevertheless nine per cent of women taking part in the study became pregnant, and more women in the Truvada group became pregnant than in the placebo group.
Possible explanations for this difference include:
- A possible, previously unknown drug interaction between tenofovir or FTC and hormonal contraception (no interactions have been reported previously).
- A difference in adherence to contraception
Family Health International information on FEM-PrEP can be viewed here.