Raising hopes and many questions

Vaccine trial sponsors’ new approaches to providing antiretrovirals for trial volunteers

By Emily Bass*

AIDS vaccine research has long been seen as having scant overlap with treatment for people infected with HIV. But in 2003 several major AIDS vaccine trial sponsors effectively redrew the boundaries between the fields of AIDS vaccines and treatment with announcements that they would work to ensure the availability of antiretrovirals (ARVs) for volunteers who become infected through high-risk contact, such as unprotected sex, during the course of an AIDS vaccine trial.

The new commitments address a hotly-debated question that has hovered over the field since its inception: Are vaccine trial sponsors responsible for treating people who become infected with HIV during the course of a trial?

The ARV issue looms largest for large-scale efficacy trials, where the most infections are likely to be found. Infections are rare in small Phase I studies which generally enroll low-risk volunteers; Phase II and III studies are larger and take place in populations with higher HIV incidence rates. For example, in the recently-completed Phase III trial of AIDSVAX in North America and Europe, there were just under 300 HIV infections at the end of a 3-year, 5,000 person trial. Volunteers in this study and the related Phase III trial that took place in Thailand were referred to government-subsidized ARV treatment programs.

But today several large-scale AIDS vaccine trials are planned for the developing world, in particular sub-Saharan Africa, where the vast majority of HIV-infected people do not yet have access to ARVs. In 2003 the process of planning for these trials helped fuel an intense re-examination of ‘the ARV question’—and ultimately resulted in the most explicit commitments to AIDS treatment that the vaccine field has ever made.

For the most part, these commitments are still in early development, with crucial details like funding sources, care providers and collaborating partners to be determined. The broad strokes, however, are clear: the US HIV Vaccine Trials Network (HVTN), the International AIDS Vaccine Initiative (IAVI) and the South African AIDS Vaccine Initiative (SAAVI) have all stated a commitment to ensure—either through direct funding or in collaboration with ARV programs—that volunteers have access to ARVs for a specified time (generally five to ten years) starting from whenever the volunteer becomes medically eligible for treatment. Merck is also taking this approach for its ongoing Phase I studies that are being conducted with the HVTN—although the company has not developed an overall policy. The US Military HIV Research Program has set its sights even higher, with ambitious plans to implement community-wide ARV treatment programs at all of its potential vaccine trial sites.

Revisiting a difficult dilemma

The new stance on treatment came into focus during a year of heated debates between researchers, funders, and advocates from the AIDS vaccine field and other areas of HIV prevention including microbicides, behavioral science and mother-to-child transmission. Over the course of these discussions—which culminated in a WHO-UNAIDS sponsored summit, Consultation on HIV Treatment for Participants in HIV Prevention Trials in July 2003—participants revisited the reasons why AIDS prevention trials have generally not included ARVs as part of their trial-related care.

One primary concern has been the gross inequity that would be created if a sponsor were to provide ARVs to trial participants but not to other community members. In this situation, volunteers might feel pressured to share their medication with family members, eliminating its benefit and possibly leading to drug resistance. The prospect of receiving ARVs should they become infected with HIV might also serve as an ‘undue inducement’ for volunteers to enroll in the trial. The alternative of providing ARVs for all community members would tax the financial and human resources of some research projects, and perhaps derail them altogether.

Other longstanding questions include how long sponsors should pay for ARVs that should, ideally, be taken for life; what to offer for would-be volunteers who are identified as being HIV infected during the trial screening process; and how to ensure continuity of care if the research project ends and the sponsor is no longer active in the community.

In all of the meetings, there was unanimity that, in an ideal world, volunteers and communities would have access to ARVs. But participants returned again and again to the realities of the resource-poor communities where AIDS prevention research is taking place. “As we take elegantly-designed studies into the field, that’s where reality hits,” said Quarraisha Abdool Karim, head of the Women and AIDS Programme at the Centre for the AIDS Programme of Research in South Africa, at a 2003 consultation on trial-sponsored health care convened by IAVI and the Global Campaign for Microbicides. “The existing standard of health care in most countries is minimal. If you are doing research in that setting…anything you offer is substantially more than what is already available.”

In many of the discussions, participants referred to existing guidelines for research in human subjects, such as theDeclaration of Helsinki and the Council for International Organizations of Medical Sciences (CIOMS) guidelines. These documents do not stipulate an ethical responsibility to provide ARVs for AIDS vaccine trial volunteers since they are healthy and uninfected with HIV at the time of enrollment, and since participation in the study does not cause or increase risk of HIV. The current CIOMS guidelines do state that provision of care for diseases contracted during vaccine trials is “morally praiseworthy” but does not mandate a specific level of care. The WHO UNAIDS guidelines Ethical Considerations for Preventive AIDS Vaccine Trials also leave room for interpretation, stating that HIV-infected volunteers should receive some form of treatment, with “the ideal being to provide the best proven therapy, and the minimum to provide the highest level of care attainable in the host country.”

In the absence of a clear directive, ethicists have offered varying perspectives, while trial sponsors have developed packages of trial-related benefits that generally did not include ARVs. Although these packages were often developed in consultation with the community and local groups, they have occasionally been subject to fierce criticism, particularly in studies of HIV-discordant couples or mother-to-child prevention interventions that did not provide ARVs for HIV-infected participants. Trial planners say the past few years have been an often-turbulent search for solutions that meet local and international expectations. “The ground has been moving under our feet for at least five years. It’s been like an earthquake on some of these issues,” says Kate MacQueen (Family Health International) who helped draft the HIV Prevention Trials Network ethics guidance document, and participated in several of the 2003 consultations.

New directions

In the recent meetings, sponsors once again took stock of the landscape—and agreed that major changes had taken place. One focus of the discussion was the surge of ARV treatment initiatives in the developing world. The year was marked by commitments from governments and global health organizations. In January 2003 US President George W Bush pledged billions of dollars for AIDS care and treatment in Africa and other developing countries; later in the year, the World Health Organization launched its “3 by 5” program that will support efforts to supply 3 million people with ARVs by 2005; the South African government took long awaited steps to implement a national ARV treatment plan; and former US President Bill Clinton announced an agreement with manufacturers that would slash the price of ARV combinations to less than US$150 per year. These and other activities have contributed to an atmosphere of optimism around expanding access to ARVs that, even among veterans of the AIDS epidemic, is positively heady.

“It sounds strange to say, but I haven’t been this excited since Kennedy announced that we would send a man to the moon,” says Colonel Debbi Birx, head of the US Military HIV Research Program.

These developments were a major influence on AIDS vaccine trial sponsors’ decisions to include ARVs in trial-related care. With ARVs becoming more available through other sources, this offering appears less likely to serve as an undue inducement to participate in trials. “The access movement has really changed our ability to have the conversation about ARVs for trial volunteers,” says IAVI CEO and President Seth Berkley. “Even a few years ago, there really would be a question of undue inducement if vaccine trial volunteers were offered ARVs.”

The four African countries with ongoing AIDS vaccine trials—Botswana, Kenya, South Africa and Uganda—all have national ARV treatment plans that are in various stages of planning and implementation. Thailand, which has just launched its second Phase III AIDS vaccine trial (see Vaccine Briefs), is also expanding its national program, which initially provided ARV treatment for 6,000 people.

“We can contemplate ARV treatment and that’s why we’re having this discussion,” says Paula Munderi, a Ugandan clinician who attended a November consultation on ethics and microbicides research. “The cost barrier has been diminished, it has repeatedly been demonstrated that ART is feasible in resource-limited settings and the numbers of patients who will require treatment in the context of prevention trials is really very small indeed.”

Further impetus for change came from within the vaccine field where the expanding scope of trials has led to an increased focus on a range of health care services, such as voluntary counseling and testing for HIV, family planning and treatment for TB and malaria, all of which should be in place before a large-scale trial can begin. As part of preparing for trials in rural sites, many sponsors are looking for ways to strengthen and develop these services, often in partnership with existing hospitals and NGOs. “For the vaccine agenda to move forward, the treatment agenda also needs to move forward,” says Nzeera Ketter, Director of Efficacy Trials at IAVI.

Sponsors also attribute their new stance on ARVs to shifting goal posts for the current generation of AIDS vaccine candidates, which induce primarily cell-mediated immune responses. One possibility is that such candidates will not prevent infection with HIV, but will instead provide some protection against HIV-related disease progression in vaccinated individuals. To test this hypothesis, vaccine trials will ask HIV-infected trial participants to return for multiple study visits over an extended time period to monitor the viral load, CD4+ cell counts and clinical course of HIV disease—data which could provide clues about vaccine effects on HIV disease progression.

A vaccine candidate that improved health and slowed disease progression in HIV infected people would function as a form of treatment. (Almost all current trials are looking for such an effect in people who are healthy and uninfected with HIV when they receive the vaccine). Studies of ‘therapeutic vaccines’ that might be used in already HIV-infected people are still in early stages.

HVTN head Larry Corey says that this change in expectations for first generation candidates was “the tipping point” for the HVTN in its deliberations about whether or not to provide ARVs for its trial volunteers who become infected through high-risk behavior. “As we started developing vaccines that would be ameliorating disease rather than preventing infection, it became very clear to the HVTN that the distinction between prevention and treatment had been lost,” says Corey.

Treatment funds for future needs

Having assembled compelling rationales—from feasibility to medical necessity—for providing ARVs, sponsors have set about devising strategies to meet trial participants’ treatment needs. IAVI, SAAVI and the HVTN have all proposed treatment funds, which would be established for each trial, with the precise amount to be determined by the incidence rate, the current cost of ARVs, and the duration of the sponsors’ commitment to funding ARVs. For example, the HVTN currently plans to set aside $1,500 per person per year to cover five to ten years of treatment.

There are practical reasons for making this distinction: volunteers are not likely to need treatment until several years after the trial has ended (most people infected with HIV do not develop AIDS-related symptoms until five to seven years after infection), and may even move away from the trial site. In South Africa, volunteers will receive an identification card that can be presented to an insurance company, which will pay for care at the clinic of their choice.

Sponsors have varying views on who will provide the care. The HVTN has said that it will use the infrastructure at its vaccine trial sites for ARV provision, although the treatment fund could also subsidize care at a non-trial-related facility. IAVI hopes to fund treatment at independent programs. “The worst case scenario is if IAVI or another trial sponsor has to implement the care policies itself,” says Seth Berkley. “We don’t know whether we will be operating in countries five or ten years hence. What we would like is a system that is sustainable and locally-administered.”

The treatment funds crystallize sponsors’ commitments to volunteers at a time when international leaders, and individual nations, are pledging to implement sweeping treatment programs. And opinion is divided as to whether volunteer-specific commitments are a bold step—or a wrong move—for sponsors working in these changing times.

Solly Benatar, Professor of Medicine and Director of the Bioethics Centre, University of Cape Town, South Africa, says that the SAAVI policy will stand even though South Africa has recently taken steps to implement a national treatment program. “The fact that [state-funded] clinics are running means that there will be a back-up for the trust [treatment fund]. But we will insist that the trust continue. Treatment for volunteers shouldn’t be solely the responsibility of a government that doesn’t even have infrastructure set up yet. Sponsors’ contributions will show a level of commitment to volunteers,” says Benatar.

But there are also those who say that sponsors’ volunteer-specific commitments are unnecessary, and that sponsors should work with local governments to supply the ARV benefit, rather than earmarking funds to pay for treatment themselves. One proponent of this view is the French research agency ANRS, which plans to conduct AIDS vaccine trials in West Africa, where it says host country governments will assume responsibility for post-trial care for participants, including ARVs.

“I know of no country in the developing world that has the infrastructure, medical staff and organizational ability needed to host a Phase I or II trial that is not a recipient of a grant from the Global Fund to Fight AIDS Tuberculosis and Malaria (GFATM) or of the World Bank and that is developing a national treatment program,” says Michel Kazatchkine, head of the ANRS and one of the most vociferous critics of the proposed treatment funds. “Countries like Kenya, Cameroon and Côte d’Ivoire all have funds to put several thousand people on treatment. Most countries that have applied to the GFATM list participants to research programs as priorities for treatment when demand for ARV exceeds by far the available number of treatments. I am sure they can save funds for the tens or hundreds who will become infected in a Phase I or II trial. I don’t see why someone external should take responsibility for care. Clinical trials in the developing world should be conducted as partnership between the North and the South, where benefits and burdens are shared by partners.”

Toward a broader vision

One reason that this debate has become so heated is that it is still too soon to tell when and how country-led ARV initiatives will develop. For the moment ARV programs are on the horizon in many countries and on the ground in very few. “In 2003 there were rhetorical and philosophical changes, but we won’t know until 2004, or later, whether these shifts will translate into change on the ground,” says Mitchell Warren, Senior Director for Vaccine Preparedness at IAVI. In this state of uncertainty, sponsors must decide whether it is more important for them to make volunteer-specific commitments, or to provide immediate support to programs that, if successful, will render treatment funds unnecessary.

For many sponsors, the answer is: Both. In addition to making volunteer-specific commitments, AIDS vaccine trial sponsors are, individually and collectively, embarking on a range of activities designed to support and accelerate scale up of ARV programs and related activities.

The US Military HIV Research Program has put forward the most ambitious plan. Colonel Debbi Birx and her colleagues hope to implement comprehensive health care packages, including ARVs, for all of the people living in the environs of a trial site, and have submitted multi-million dollar proposals to the Bush Presidential Emergency Plan for AIDS Relief (PEPFAR) to meet these goals. (Unlike the GFATM and the World Bank Multicountry HIV/AIDS Program (MAP) funding streams, the presidential AIDS initiative accepts applications from research entities.) Birx says that the Army proposals were developed with extensive local input and are designed to complement planned and existing national ARV initiatives.

“We’re banking on this money. It’s the only way to move forward,” Birx says. “We need the infrastructure [associated with providing ARVs] to test vaccines. Providing treatment and care heightens awareness of our project and our staff in the community.” And, if ARV treatment is widely available, it will likely improve community attitudes to voluntary counseling and testing in general; since there'll be treatment options available to those who are found to be HIV-infected there will be some incentive to come forward to be tested. Consequently, vaccine trial sponsors will likely find that enrollment will be an easier task in an atmosphere where testing is more widely accepted.

Bill Snow, one of the founders of the AIDS Vaccine Advocacy Coalition, hopes that more US trial sponsors will take steps to link research projects and efforts to improve global health infrastructure. “Researchers are in a parallel but separate universe from scale up activities; they should all get together and apply for money,” Snow says. “Right now, they are not looking at how to harness global activity and make it work for them.”

So far, the US Military HIV Research Program is the only vaccine trial sponsor that is currently making a direct application to a global funding source. But other trial sponsors, including IAVI, hope that communities where research takes place can be prioritized to receive funds from the GFATM and other sources. MAP and GFATM grants require countries to state which groups—such as activists or research volunteers—will be prioritized for receiving ARV treatment; initially, most countries will not be able to provide ARVs to all those who are medically eligible.

In December IAVI and its Ugandan research partner the Uganda Virus Research Institute met with government leaders and the architects of the Ugandan national ARV plan to discuss ways that the government and IAVI could share responsibility for treating volunteers. Dr. Elizabeth Madraa, head of the Ugandan ARV program, said that trial volunteers and research communities would be prioritized in the allocation of resources for ARV programs.

These efforts are key first steps according to Snow, who says that alliances between research projects and public health funders are not simple. Snow has spent the past few months attempting to build support among AIDS vaccine and prevention trial sponsors for an inter-agency collaboration around fundraising for treatment and care. Snow has proposed that the networks submit joint proposals for funds which could be used to strengthen local treatment and care services at and near research sites. He says that many of the major networks have responded positively to the suggestion, but that there are still hurdles on both sides. “There’s the skepticism among funders about funneling money through researchers,” he says. “And researchers can be uncomfortable about simply applying for grants instead of proposing treatment protocols.”

Snow sees these collaborations as a key way for the AIDS vaccine field to effect immediate change in access to prevention and care services—while pursuing its long term goal of a preventive vaccine. Many trial sponsors agree, and say that the outcome of these efforts will have an impact that far exceeds that of any single trial-related policy. “I am sure that when Kennedy said we were going to the moon, it seemed a lot more outlandish than getting care and treatment to Africa,” says Debbi Birx. “But it is going to take the same level of commitment—and a lot of work. I don’t know where we’re going to end up—but isn’t that the responsibility of us all?”

*Emily Bass is senior writer of the IAVI Report