The findings of one study at the 16th International AIDS Conference in Toronto were in the media nearly a week before they were officially published, namely the first safety and efficacy data from a study of tenofovir pre-exposure prophylaxis (PrEP) in humans. Despite the conclusion of the authors that “the number of HIV infections was insufficient to conclude that tenofovir protected against HIV infection,” the statistical insignificance of the results did not prevent papers such as the Wall Street Journal publishing what they saw as the headline news, namely that three times more women on placebo (namely, six out of 368) had become infected with HIV than ones taking tenofovir (two out of 363, yielding a 65% reduced risk).
The study was the much-truncated one set up by Family Health International (FHI) in Ghana, Nigeria and Cameroon. The original intention had been to recruit 2000 HIV-negative women. Half of them could be given a daily dose of 300mg tenofovir and half a placebo. The study was originally planned to run from June 2004 to June 2005.
In two of the three trial sites the study did not proceed as planned. The Cameroon trial became caught up in the controversy about PrEP trials, especially over ensuring treatment for women who seroconverted during the trial, and recruitment was closed early in February 2005 – see this report on Aidsmap. The Nigerian trial was closed after it was found that the laboratory monitoring “failed to meet the necessary scientific standards”.
In the end 936 women were recruited up to March 2005, of which results for 731 were shown to the conference. While this was insufficient to prove that tenofovir PrEP was effective at stopping HIV infection, the results did suggest that giving tenofovir to HIV negative people did not raise any severe safety concerns, at least over the course of nine months.
The women were monitored for liver function and for two indications of kidney malfunction, creatinine and phosphate levels. Tenofovir has been in some studies associated with varying levels of renal toxicity, and because it is also active against hepatitis B, concerns have been expressed that its withdrawal or intermittent use could lead to liver inflammation ‘flares’ in people with chronic HBV that was previously untreated..
No woman on tenofovir had abnormal liver function results (compared with three on placebo); no woman on tenofovir had raised creatinine (compared with one on placebo); and two women on tenofovir and one on placebo had abnormally low phosphate levels.
There were no adverse events sufficient to compel withdrawal from the study and, though women taking tenofovir had a somewhat raised incidence of headache, this was not thought to be due to the drug.
Whether or not these results prove anything at all, they injected new energy into the research and policy agenda surrounding pre-exposure prophylaxis. Bill Gates pointedly referred to both microbicides and oral prophylaxis in his opening speech, and one session at the conference was devoted specifically to considering the implications for access and rollout if PrEP is shown to work.
Two large trials of PrEP are due to start this autumn, both of them hopefully better-prepared to forestall the controversy attending the earlier ones. In Botswana the US Centers for Disease Control will recruit 1200 HIV-negative adults aged 18-29 from the towns of Gaborone and Francistown – the latter being the urban area with possibly the highest HIV prevalence among the general population (46%) of any town on earth.
In Peru the US National Institutes of Health are co-sponsoring a trial of PrEP among 1400 men who have sex with men in the city of Lima and the two rain-forest provinces of Loreto and Ucayali.
Both of these trials have now switched their protocols to tenofovir/FTC (Truvada) after animal studies using this combination produced superior results.
Dawn Smith, principal investigator in the Botswana trial, told the conference that if studies showed that PrEP was effective, trial investigators would have obligations:
- To trial participants, to continue to provide open-label access to PreEP whilst national regulatory and programme decisions were made about how to make it available, and to continue to monitor clinical and behavioural safety;
- To trial communities, to disseminate the trial results in understandable language and with all relevant caveats (for instance if there turned out to be toxicity in one group and not another) and to help develop community HIV prevention advocacy;
- And to local partners, to give trial results to in-country regulators and policymakers as soon as possible, and to provide ancillary information to help them make decisions about implementing local plans, such as giving them advice on the frequency and likely cost of clinical monitoring.
She said that PrEP posed a number of new challenges to its providers owing to the fact that it was a prevention intervention, but a clinical one. Which clinics would provide it? Would HIV clinics be giving the same drugs to positive and negative people on a ‘Turn left if you’re negative, turn right if you’re positive’ basis? Would family planning clinics provide it, given that young men have a poor record of accessing such services? Or would new-style prevention clinics spring up?
She was equally clear, given the responsibilities that have sometimes been dumped at the doorstep of researchers, which responsibilities they did not have. These included deciding which populations got it and deciding exactly how it would be delivered to them.
The much-vexed question of assuring clinical care for seroconverters in a trial would hopefully become less problematic as countries moved towards providing full antiretroviral access. FHI Principal Investigator Leigh Peterson told Aidsmap that in the case of their trial they had negotiated a commitment to 15 years’ guaranteed care for seroconverters from local AIDS programmes.
Peterson said that several challenges remained when it came to devising further trials. The ethical obligation to provide condoms and effective safer-sex counselling meant that HIV incidence in the trials, as it has been in some microbicide trials, was lower than expected.
“We had expected 30 infections with an incidence of 5% a year, and we obtained half of that incidence,” she said. The annual incidence among placebo recipients in fact worked out at 2.48% a year and among tenofovir recipients 0.86%.
Another problem was the introduction of tenofovir and FTC (or, more usually its chemical cousin 3TC) in national treatment plans, raising the concern both that PrEP might be ineffective because of pre-existing tenofovir and FTC resistance in the population, and that the ‘seeding’ of resistance in the population by PrEP might jeopardise the success of treatment. In fact this was the reason why a further FHI PrEP trial among 500 men in Malawi was cancelled.
The introduction of other new prevention approaches could also be a problem. Former IAS President Dr Joep Lange told the conference that if male circumcision came to be introduced as a widespread prevention measure in countries, it could also make it difficult to prove the efficacy of PrEP (and, indeed, microbicides).
“Studies need to be coordinated – if you introduce circumcision as a standard practice for men you may need enormous studies if infection rates go down,” he said.
Some PrEP advocates continue to be convinced that doing trials in high-risk populations in developed countries – such as gay men – might provide quicker and ‘cleaner’ data.
The UK’s Dr Mike Youle said: “If what we want to do is to prove that PrEP works, we could do it quite quickly in a cohort of US or European gay men. There is no rush to simultaneously introduce it wholesale into developing-country populations when we have very limited data on long-term safety.”
Other advocates, Lange included, insisted that there was a rush, given the lack of other prevention alternatives for women in particular. He suggested that, given that we have much longer-term data of safety, 3TC might make a better PrEP candidate.
Finally, communities among whom PrEP trials take place still need to be carefully consulted. The Peruvian trial is a model in this respect; community consultation, involving activists in protocol design and focus groups with a number of different stakeholders, including several different populations of MSM, started in April 2004, two and a half years before the trial finally gets underway.
Even so, there is still room for misunderstanding. The only PrEP trial currently underway is the one among injecting drug users in Thailand. Thai activist Nimit Tien Udon said that counsellors had to design the consent-signing process so that it did not come across “as the researchers saying to volunteers ‘do that, do this’. I think it’s very important to have dialogue between the community and the researchers, and to emphasise that this is not some kind of ‘vaccine’: we must still emphasise condom use every time.”
Peterson L. et al. Findings from a double-blind, randomized, placebo-controlled trial of tenofovir disoproxil fumarate (TDF) for prevention of HIV infection in women. Sixteenth International AIDS Conference, Toronto. Abstract ThLb0103, 2006.