Meeting Summary: Advisory Panel Considers Complexities of HIV Prevention Trials
The Bill & Melinda Gates Foundation seeks advice on conducting HIV prevention trials from an advisory panel convened by the Institute of Medicine
By Kristen Jill Kresge
HIV prevention trials have been grabbing many headlines in recent months. Some heralded results from trials that showed adult male circumcision was around 60% effective at lowering a man's chance of acquiring HIV. These trials were terminated early because the evidence overwhelmingly showed circumcision's protective effect and the board that monitors the safety and ethics of the trial decided it would be unethical not to also offer the procedure to the men in the placebo arm (see And the winner is... HIV treatment and prevention).
Unfortunately some other HIV prevention trials have been stopped in recent months for other, potentially graver, reasons. In January researchers from a US public health organization called CONRAD—a collaboration between the US Agency for International Development (USAID) and Eastern Virginia Medical School—announced that it was halting its Phase III efficacy trial of a microbicide gel in women volunteers from India, Benin, Uganda, and South Africa because the safety committee monitoring the trials had found a higher number of HIV infections in women receiving the microbicide than in those receiving the placebo. Data from this trial is still being analyzed and for now the reasons for the discrepancy remain unclear, but news of the trial sent ripples through the HIV community.
Other trials of new prevention technologies, including microbicides and pre-exposure prophylaxis (PrEP; seeTreatment as prevention, IAVI Report 10, 3, 2006), were stopped prematurely in the past for a variety of reasons, including a lower than expected HIV incidence in the community that rendered the trial futile, pressure from community activists over trial design, and the controversy of providing lifelong access to antiretrovirals (ARVs) for volunteers who became incidentally infected during the study.
These events have provoked the Bill & Melinda Gates Foundation, which funds many trials evaluating the efficacy of new prevention technologies, to investigate some of the challenges of conducting this research. Recently they requested that the prestigious Institute of Medicine (IOM), part of the well-respected National Academies in the US, convene an independent committee on methodological challenges in HIV prevention trials. This advisory panel of outside experts held its first public meeting focusing on microbicide and PrEP trials from February 6-7 in Washington, DC, and the 15-person panel heard from many of the organizations that are involved in designing and conducting these trials. A second meeting will be held on April 19 in London and the final guidance from the committee on the methodology, design, and conduct of HIV prevention trials—with an emphasis on microbicide and PrEP studies in particular—will be issued in a report to be released in the fall of this year.
Renee Ridzon, a program officer at the Gates Foundation who oversees non-vaccine HIV prevention trials, opened the first meeting by addressing the committee and highlighting some of the main areas where they are seeking guidance. These included the impact of prevention trials on HIV incidence, the need to enroll and keep women in trials, and the future role of male circumcision in other prevention trials. Another important consideration for any funding agency is, of course, the price of running these complex trials. Ridzon said that many prevention trials actually cost more than double what was originally calculated. The Gates Foundation is hopeful that the committee's suggestions will increase the likelihood that HIV prevention trials will be successful and enable donors to invest their resources wisely. "Trials to look at different interventions are crucial," said Ridzon. "And it's obvious that one round of trials isn't going to provide all the answers that are needed."
A common thread discussed for many of the microbicide and PrEP trials was the difficulty in estimating HIV incidence in a population where a trial will be conducted. Accurate incidence estimates are necessary to determine the number of volunteers required to demonstrate efficacy of the intervention. But this has become a growing concern for organizations conducting or funding prevention trials since several trials have recently been stopped or scaled back because of lower-than-anticipated HIV incidence rates.
In the absence of cohort studies to determine incidence, researchers rely on other methods, including using a p24 antigen assay to estimate the number of new infections, the BED assay that estimates HIV incidence based on a measurement of the level of HIV-specific antibodies in a serum sample as a marker of recent infection, or data collected from past studies done in these communities. But according to Salim Abdool Karim, a principal investigator of both microbicide and PrEP trials in South Africa, all of these methods tend to overestimate HIV incidence.
Leigh Peterson of Family Health International (FHI), a public health organization based in North Carolina, reported on a Phase III efficacy trial with the candidate microbicide gel Savvy that was stopped prematurely at sites in Ghana due to lower than expected incidence. The Savvy microbicide trial in Ghana was designed with an HIV incidence estimate of 5% in the placebo group, the actual observed incidence turned out to be just under 2%. Trials with the same product at sites in Nigeria were also closed early, but this time because the data safety monitoring board (DSMB) concluded during an interim analysis that the product was unlikely to be effective.
Another Phase III microbicide trial conducted by CONRAD was also stopped because the actual HIV incidence in the study was 2%, less than half that anticipated. This was a companion trial to the one being run in India, Benin, Uganda, and South Africa where the DSMB found a higher number of infections among women receiving the cellulose sulfate gel than those receiving placebo, but this effect was not observed in Nigeria. Researchers initially planned to expand the number of women in the trial to compensate for the lower HIV incidence but, partly because of additional complications with working in the war-torn delta region of the country, the trial was closed instead.
Other trial sponsors have also had to choose between drastically increasing the number of volunteers—which substantially increases the logistic complexity and cost of these trials—or scaling planned Phase III trials back to smaller, Phase IIb test-of-concept trials, which are most likely not sufficient to support licensure.
Even if researchers have accurate incidence estimates in a community at the start of a trial, the HIV incidence observed in clinical trial participants is often lower since trial volunteers receive regular risk-reduction counseling and have steady access to other prevention methods, like condoms. But Doug Taylor of FHI warned the IOM committee against concluding that behavior change is responsible for the lower-than-expected incidence in the cellulose sulfate trial. Other factors like the increasing number of HIV-infected people who are on ARV therapy may also be contributing to lower HIV incidence rates, especially in Nigeria and other countries where the US President's Emergency Plan for AIDS Relief (PEPFAR) is operating. While the proliferation of ARV programs in developing countries is a great success, it may also make it more difficult for organizations to conduct HIV prevention research in these same communities.
Another confounding factor raised is the difficulty of enrolling and retaining women in HIV prevention trials. Almost unanimously, presenters reported surprisingly high pregnancy rates in these trials. In the cellulose sulfate microbicide trial in Nigeria, 7% of women were found to be pregnant in the trial screening process and so could not participate. During the trial, 30% of the 2160 women became pregnant. This was particularly surprising since the candidate microbicide showed efficacy as a contraceptive in previous trials, and 60% of women claimed they were regularly using condoms.
In a PrEP trial run by FHI in Cameroon, Nigeria, and Ghana the pooled pregnancy rate for all sites was an astounding 56%. Peterson said such high pregnancy rates are predictable when women are having more than three sexual acts a week, as was the case in this trial. Due to potential safety concerns women have to suspend use of the microbicide while they are pregnant. In the Savvy trial in Ghana, women spent 10% of their overall time in the trial not using the microbicide, making it difficult to interpret the data.
Based on these results many presenters urged the IOM panel to consider recommending that women in these trials be allowed to continue using the microbicide candidate during pregnancy. Sharon Hillier, a professor of obstetrics, gynecology, and reproductive sciences at the University of Pittsburgh, said that the places where microbicides are needed most also have some of the highest fertility rates, and since women are unlikely to suspend use of a microbicide—if it is eventually approved and available—during pregnancy, researchers should keep these women actively involved in the study. She also reminded the committee members of the evidence that pregnant women are at an enhanced risk of contracting HIV.
During all of these HIV prevention trials women are offered free hormonal contraception, but many choose not to use it. The US Centers for Disease Control and Prevention is now making the use of hormonal contraception a requirement for enrollment in a PrEP study they are conducting in Botswana; however even this does not guarantee that women will actually take the contraception during the course of the trial.
Some of the other Gates-funded trials that garnered widespread attention when they were closed early were the PrEP studies in Cameroon, Nigeria, and Ghana (see Treatment as Prevention, IAVI Report 10, 3, 2006), and Peterson shared some of the sobering lessons from these trials with the IOM committee.
Before being shut down in 2006, the PrEP trial in Cameroon was suspended for several months while FHI satisfied study design questions at the behest of the government. During this time researchers continued to follow the women in the study, although they couldn't give them pills (either the ARV tenofovir or placebo). Despite the fact that women were receiving absolutely no intervention, researchers still retained 80% of the women through this seven-month period. Peterson said this was one of the most troubling aspects of all since it demonstrated the intense motivation these women had to participate in the trial.
Eventually questions over this trial became a "big scandal" in Cameroon, said Peterson. Cartoons in the local newspaper inaccurately depicted FHI staff members purposely injecting volunteers with HIV. Several of the IOM panelists peppered Peterson with questions on the activities FHI engaged in to prepare the community in advance of the trial. She said FHI thought there was a sufficient level of transparency about the design of the study, but obviously learned some valuable lessons. In Nigeria, Peterson reported that the trial was stopped because of inaccuracies in the laboratory data from this site, and not because of community or government pressure.
If all this makes it sound difficult to conduct HIV prevention research, it is only likely to get harder. Now that three studies have confirmed the protective effect of male circumcision, organizations sponsoring and funding trials are facing the possibility that this procedure will have to be offered to volunteers in other HIV prevention studies, making them even more complicated and expensive. This will be one of the topics the IOM advisory panel will discuss at the April meeting. Sten Vermund, director of the Institute for Global Health at Vanderbilt University, told the committee that researchers need to start thinking about testing prevention interventions in combination, much like drugs are used to treat HIV infection.