In-depth: Trials and Tribulations of HIV Prevention Research

AFRICA: Design of effective HIV prevention trials the first hurdle

A volunteer receives a trial HIV vaccine

johannesburg, 16 October 2007 (PlusNews) - We've long known how to protect ourselves from HIV, but the options are limited and not available to everyone: women who are powerless to refuse sex or insist on condoms, and can only trust that their partner will be faithful, pay the heaviest price. In sub-Saharan Africa, those between the ages of 15 and 24 are four times more likely to become infected than men of the same age.

Science is unlikely to yield any silver bullet solutions to the global AIDS fight anytime soon, but new prevention technologies like vaccines and microbicides could provide some additional weapons.

Unfortunately, developing these is a long process, and depends on the participation of thousands of clinical trial volunteers and the goodwill of their partners, families and communities.

Preparing a research site for a large-scale human effectiveness trial can take several years, and the trials themselves are extremely costly; scientists cannot afford to squander limited resources and public trust by making mistakes in the design and conduct of these studies.

The early closure of a microbicide trial in South Africa in January 2007, when preliminary findings indicated that the product might increase the risk of HIV infection, and the bad publicity that followed, have further raised the stakes.

"When you're designing a trial you need to do the best trial you can do, because you might only get one chance," said Dr Claire Von Mollendorf, of the Reproductive Health and HIV Research Unit (RHRU) at the University of Witwatersrand, in Johannesburg, who has worked on several microbicide trials involving protective gels applied before sex.

Measuring the unknown

Designing an HIV prevention trial means having to factor in something scientists cannot control or predict: human behaviour. When it comes to products like microbicides, which the participants themselves apply, the unknowns are even greater.

Ensuring that a randomly assigned product or placebo is evenly distributed among participants helps reduce unpredictability, but trial staff are usually forced to take the word of participants that they have actually used it.

One of the biggest challenges in the field of HIV prevention trials, commented Dr Quarraisha Abdool Karim of the Centre for the AIDS Programme of Research in South Africa (CAPRISA), was the lack of "surrogate markers", which measure the effect of a treatment by correlation with the desired outcome.

In trials of new treatment interventions, HIV positive participants' viral loads (the amount of virus in their system) and CD4 cells (an indicator of immune strength) can be measured to determine how effective the drug is.

"The only [surrogate] marker we have for both safety and efficacy in HIV prevention trials is HIV infection; we don't have anything in between," Abdool Karim explained, adding that the lack of other indicators meant scientists were particularly dependent on reports made by trial volunteers.

Various techniques are used to monitor adherence and improve the reliability of self-reporting. A trial of a microbicide called Pro2000, currently being run by the RHRU in Johannesburg, uses social scientists to conduct in-depth interviews with participants, which are then compared with shorter interviews by clinic staff and "coital diaries" kept by the women.

"If there are discrepancies we ask them why, and that gives us an idea of how confident we can be about reported sexual behaviours," said Jonathan Stadler, a social scientist with the RHRU.

The in-depth interviews provide more detailed information about adherence, with the added advantage of giving greater insight into the women's experiences of being in the trial and using the gel.

"Even if Pro2000 isn't found to work, the lessons we've learned can still be applied," said Stadler, because researchers were constantly building on their experience of previous studies. "Trials are also evolving, not just the products."

"Directly monitored adherence", in which participants visit a clinic every day to apply the product, is the closest scientists can get to ensuring adherence, short of being in the bedroom with volunteers. But the concept is controversial and still being debated.

A directly observed trial requires fewer participants, because compliance is factored into the size of the trial; the trade-off, said Stadler, would be the loss of data relating to the real-life experience of using the product.

Abdool Karim agreed. "If you had sex and it was unplanned, and you didn't have time to do what you needed to do, that's life; and that's what we need to measure."

She also argued that the idea of daily monitoring displayed a lack of trust and respect for participants. "These volunteers are exposing their body to an unlicensed product for the sake of science so, if someone says they did 'X', I have no reason not to believe them."

Better prevention means bigger trials

HIV prevention trials must measure the additional effects of an intervention after making sure, for ethical reasons, that participants have access to proven HIV protection measures such as condoms, treatment of sexually transmitted infections (STIs), and HIV counselling and testing.

As a result, trial participants are likely to have a lower than average incidence of HIV, but Dr Glenda Gray, of the University of the Witwatersrand Perinatal HIV Research Unit (PHRU), in Soweto, pointed out that "we don't live in people's bedrooms, and we're not there to put on the condoms." Despite the counselling and prevention services, trial results depend on the fact that participants will not practice safe sex all of the time.

Future trials will have to take into account the availability of new prevention methods. Based on 2006 findings that male circumcision can significantly lower a man's chances of contracting HIV, the recently halted "Phambili" vaccine trial, in South Africa, was already offering the procedure to participants.

In its 2007 annual report, Resetting the Clock, the AIDS Vaccine Advocacy Coalition noted, "When incidence goes down, trial size goes up; when size increases, so do the cost and the length of the trial."

"It certainly pushes the cost of a trial up," said Abdool Karim, "but you have an ethical obligation, when you are dealing with populations at high risk of HIV infection, to inform them and offer them interventions that are already known to work. So ... I see it as ... how we do research."

Future hurdles

As the relatively slow adoption of medical male circumcision has shown, proving effectiveness through clinical trials is often just the first hurdle in implementing new prevention methods.

In the case of microbicides and vaccines, finding companies willing to manufacture them at a cost affordable to people in developing countries, where they are most needed, could prove difficult.

Von Mollendorf estimates that even a partially effective "first-generation" microbicide is still five years away from pharmacy shelves. The wait for a vaccine is likely to be even longer. "It's a long process, but do we have any other options?" she asked. "I don't think we do."

Such is the public health crisis generated by HIV and AIDS in southern Africa that Abdool Karim believes scientists "cannot wait for all the i's to be dotted" before acting on encouraging trial results. "Science is only one part of it," she told delegates at a national AIDS conference in South Africa's east-coast city of Durban recently, "it's what we do with the science [that will make the difference]."

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Trials and Tribulations of HIV Prevention Research

October 2007

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