Protecting the Volunteer when the Vaccine Fails

by Emily Bass

Large-scale phase III trials of vaccine efficacy are likely to take place in poor countries that are hardest hit by the epidemic. These areas have the high-incidence populations best suited for testing new vaccine candidates. Where HIV infection rates are high, it takes a smaller study to determine whether or not a vaccine is effective. But the countries best suited for these trials are among the least able to provide HIV care for their citizens. What happens to vaccine trial participants who contract HIV in spite of the vaccine ? In potential host countries like Uganda, South Africa, Thailand and Trinidad, highly active antiretroviral therapy remains a rumor, an option reserved for a wealthy minority. Trial sponsors in these countries must decide what type of care, if any, to offer volunteers. Will it be the "best proven" care in the world or the "highest attainable" care -which may amount to very little at all ?

This question also comes up with any HIV treatment trial conducted out-side the narrow zone in which triple combination therapy is readily available . But the issue of an ethically acceptable standard of care is more volatile in the context of vaccine studies. Such trials, with their potential for fore ver altering the epidemic, place countries, cohorts and individuals in the global spotlight. Vaccine trial participants who become infected while in the trial are likely to find small comfort in their contribution to the advancement of science. Trial sponsors are not legally bound to provide treatment when the vaccine fails, but there is a powerful ethical argument that the sponsors or society as a whole owe some form of care to the volunteers whom the vaccine failed to protect.

Exactly what that treatment looks like remains to be seen. Absent a universally accepted standard of care, each country and research team must balance real and ideal treatment options and come up with its own package of services for those deemed vaccine failures. The old activist chestnut, "Think globally, act locally," has never been so difficult to apply.

Who Is Responsible ?

Since vaccine volunteers are uninfected at the start of the trial, it could be argued that trial sponsors’ responsibility begins and ends with state-of-the-art prevention care. This package would include extensive counseling, male and female condoms and treatment for STDs, which increase the risk of HIV trans-mission. According to the UNAIDS guidelines, it should also provide clean syringes for injection drug users "where available." A country’s laws regarding needle exchange determine whether or not needles are made available.

Following this line of reasoning, anything beyond prevention services should be provided by the public and private health systems in the trial’s host country. This, at least, is the governing logic in VAXGen’s AIDSVax trial, now in Phase III in the United States and Thailand. U.S. volunteers who test positive are referred to their local doctor or clinic where, presumably, they begin HAART if and when they choose. Thai participants in the same study are referred to Bangkok Metropolitan Authority, a public health service that provides dual nucleoside analog therapy for individuals whose CD4 cell count falls below 500 cells/mm3, as well as TB drugs and Bactrim.

The decision to offer substandard treatment to participants was a difficult one, according to Natth Bhamarapravati, a trial organizer, but in the end it was the only one that seemed possible. "Giving [triple therapy] within the trial would be an unethical approach to buy the willingness of volunteers," he said in an interview with the International AIDS Vaccine Initiative.

This arrangement ensures that local authorities remain accountable for the cost and quality of HIV care. It also leaves trial volunteers open to the vagaries of their country’s treatment program. If Thai public health policy changes, so will the care given to VAXGen’s volunteers. In the U.S., the quality of care will vary depending on where an individual lives and what type of insurance he or she has.

Uneven, substandard care is the reality for the majority of the world’s HIV-infected population, and trial sponsors may, arguably, be under no obligation to offer special protection to their volunteers. However, testing positive does not end a vaccine volunteer’s involvement in the study. Some of the most valuable data on vaccine efficacy could come from HIV-infected participants. Many preventive vaccines will be considered successful if they merely slow the progression of HIV disease. Even if the vaccine does not prevent infection, it could help the body control the virus. These properties will be evaluated by tracking viral load and immune markers in vaccinated "breakthrough" infections. In the AIDSVax trial, for example, HIV-positive participants have the option of rolling over into a secondary study arm where they are monitored for signs of vaccine-enhanced immune markers and viral control.

Researchers will follow the vaccine-altered course of disease. The clearest data on these effects will likely come from trials where participants do not have access to HAART. In studies that do not guarantee treatment, infected individuals with little or no treatment will continue to contribute data. It is an ethically dubious avenue that leads, in many minds, straight back to the Tuskegee experiments of the 1960s.

Recent observations from Harvard researcher Bruce Walker suggest that starting treatment soon after infection provides decisive help in creating effective immune responses against HIV. In vaccine volunteers, infection with HIV could actually serve as a second vaccine that boosts the original inoculation. Immediate treatment could provide these individuals with an even greater edge over the virus, in much the same way that it did for some of Walker’s patients. It would be difficult, once again, to isolate the effects of the vaccine itself. Should Walker’s results be borne out, it will become much more difficult to track the effects of trial vaccines on breakthrough infections. "If it turns out that the standard of care becomes immediate treatment, we may have a situation where the only way to do a trial is to go somewhere where HAART isn’t available," said Seth Berkley, head of the International AIDS Vaccine Initiative.

Agreeing to Disagree

The debate over the standard of care to which vaccine trials would be held began in earnest in 1998, when UNAIDS sponsored three regional meetings in Asia, Africa and Latin America to discuss HIV vaccine research ethics. UNAIDS hoped to generate a consensus document from the meetings. After several rounds of heated discussion, though, participants were still dead-locked. As the final document, UNAIDS Ethical Considerations in HIV Preventive Vaccine Research, states, "At present, there is no universal consensus regarding level of care and treatment that should be provided."

Instead, there was a spectrum of viewpoints, split largely along regional lines. Latin American countries argued that the standard of care should be nothing less than HAART, the best proven treatment in the world today. At the workshop held in Brazil, participants agreed that antiretrovirals were subject to "the same ethical imperative" that enjoins vaccine trial sponsors to provide preventive risk behavior counseling. Brazil is one of the only developing countries that provides government-funded, triple combination therapy. African and Asian participants pointed out that providing HAART would not only tax existing resources, it would also create a dramatic gap in the care available to those inside and outside the trial setting -a gap so wide that it could constitute an undue incentive for trial participation.

"By providing the ultimate, say, ’Boston’ standard of care to experimental trial participants, are you making the standard of care way, way, way out of reach for nonparticipants ? If you’re doing that, it becomes very unethical," said Nelson Sewankambo, a Ugandan researcher from Makerere University who is helping lead the Rakai Project, a rural cohort now in the early stages of Phase III vaccine preparedness work.

Ultimately, UNAIDS generated a loosely worded document that leaves plenty of room for interpretation. One directive is that sponsors "seek at minimum to ensure access to a level of care and treatment that approaches best proven care and treatment attainable in the potential host country." The guidelines also state that host and funding countries should aim for "the ideal of best proven therapy for trial participants in the light of relevant conditions and concerns."

To complicate matters, vaccine trial participants do not appear to be protected by the recently revised Declaration of Helsinki. The Declaration calls for new methods to be tested against the "best current prophylactic, diagnostic and therapeutic methods." At the conclusion of a trial, participants are to be assured access to the "best proven" methods identified by the study. Since HIV vaccine volunteers are healthy and do not stand to benefit from the experiment, they are not included in this research subjects’ bill of rights.

What’s to Be Done ?

Delaying trials until it is possible to provide top-of-the-line care is a problematic position. "Armchair ethicists [in the States] have the luxury of being thoughtful in a very theoretical way," said Berkley. "When it comes down to it, [a trial] standard of care ought to be based on the local standard of care." In South Africa, Graham Lindegger, principal investigator of the HIV/AIDS Vaccine Ethics Group, agrees. "As an aspirational principle, the best available standard of care should certainly be pursued. But in practice, it is more difficult."

Today, most trial design takes place in this difficult territory, where one of the guiding principles is sustainability : ensuring that a given standard of care is accessible to the entire population, not merely the study participants. Last year, South Africa’s newly minted vaccine initiative asked Gary Maartens, an HIV specialist at Cape Town’s Groote Schuur Hospital, for his recommendations on this issue. Maartens practices medicine in one of the few South African provinces with its own clinical guidelines for HIV management. His verdict : A vaccine trial standard of care should "push the envelope" of available services, without losing sight of reality -in this case, South African reality, which puts antiretrovirals out of reach of all but a tiny portion of the population.

Maartens proposed a package of care that includes staff capable of clinically staging the disease ; objective staging through CD4 or total lymphocyte counts ; Pap smear screening ; and a formulary of drugs including cotrimoxaole, TB prophylaxis, and treatments for common morbid events. "I think people were relieved that I wasn’t suggesting triple combination therapy for everybody," Maartens recalls. To Maartens, such guidelines are useless unless they can be widely implemented. "If we can’t go to that level [for everyone], then we shouldn’t bother at all."

Beginning with a standard of care that could, feasibly, be implemented as a national policy is one way of addressing the needs of individuals who test positive at the time of enrollment. In the setting of a vaccine trial where tens of thousands of people will be screened to generate a pool of HIV-negative participants, an overambitious standard of care could result in "a financial burden [that] might threaten the viability of the trial itself," stated David Patterson, author of a Canadian HIV/AIDS Legal Network paper on vaccine trial ethics. A country that chooses the route of realistic envelope-pushing might then prevail on international agencies to help boost care throughout the country, not just for study participants. If the disparity between local and experimental standards of care grow too high, a study risks being flooded by positive would-be applicants.

As the UNAIDS guidelines suggest, it is difficult to fix the borders between what is attainable and what is, in fact, out of reach. Most Phase III trials are still a long way off, which means that trial sponsors who are developing cohorts also have plenty of time to invest in health-care infrastructure. Some facilities, like centers for voluntary testing and counseling, are likely to receive plenty of attention. But critics argue that it goes against basic public health principles to beef up the resources needed for vaccine testing without also caring for those infected.

Treatment may have the added benefit of lowering incidence. Research strongly suggests that reducing plasma viral load to below 2,500 copies/mL nearly eliminates the risk of transmission. Here, as with needle exchange, the question arises : For how long, and on what basis, can a known strategy -in this case treatment for preventive purposes-be overlooked simply because it is deemed unfeasible for a given setting ?

"I consider that if a HIVNET [vaccine preparedness] site hasn’t made itself superfluous in five years, it hasn’t done its job," said Carel IJsselmuiden, director of the School of Health Systems and Public Health at the University of Pretoria in South Africa. "The goal should be to lower incidence rates to the point where you can’t do the trial in a given community, and then move on."

Difficult Marriages

To find a solution to the ethical conundrums, both the funding and the host country must grapple with whose ethical parameters are given top priority - and with who will respond to criticism from different quarters. Like a marriage, this process involves uncomfortable compromises on both sides. "While protecting human subjects, it may become necessary to bend some of the rules," said Noah Kiwanuka, field director of the Ugandan Rakai Project. "Otherwise we will never do any research."

For Western partners, this may mean ceding the ethical high ground of a global standard of care and giving more weight to the opinions of local scientists. To get to this point, scientists on both sides of the world still have a lot to learn about what Graham Lindegger calls the ’dialogical process.’ "The whole issue of how to respect both partners’ principles and priorities is really in its infancy at present," he said.

Even when both parties are willing to sit down and talk things through, scarcity of resources will make it difficult for local researchers to stand on equal footing with international funders. As ethical watchdogs point out, it is unreasonable to ask an individual or a country with limited resources to make decisions based on the same criteria that would be used in the Western world. Who, they ask, will decide whether the bar is being set too low ? One solution is to follow the UNAIDS suggestion that trials be conducted in both the host and the funding countr y. To get around issues of subtype specificity -the as yet unproven concern that each HIV subtype will require its own vaccine - partners could create parallel arms testing different vaccine constructs.

Community input is another safeguard against charges of exploitation. Current vaccine preparedness efforts are devoting considerable energy to educating and soliciting input from communities where trials are likely to occur. For many issues, such as the best way to obtain informed consent, or compensate trial participants, this type of participation can be quite useful. But when it comes to deciding on medical care, communities may not be in the best position to anticipate, or set out, their needs. "We have to be careful about treating community opinion as inviolable," said Graham Lindegger. "We should not disrespect it, nor should it be treated as an absolute."

Precious Time

Many errors are made in haste. The history of the AIDS epidemic - and medical research as a whole - bears witness to missteps made in the name and service of urgency. The issues surrounding vaccine research are the latest version of the conundrum : How to do right without losing precious time. On the one hand, there is the time-consuming, "dialogic" decision-making process that will likely unearth the best solutions to tricky trial design problems. On the other, there is the need, felt by so many, to do something-anything - to slow the spread of AIDS. If this means altering the ethical guidelines laid out by those in the West, then so be it, say many in developing countries. In a recent Lancet editorial, members of the Gambian government wrote, "Stopping trials in Africa that are trying to improve the health of poor people so that those in affluent countries can have peace of mind seems a tortured form of ethical logic."

Nor, warns IJsselmuiden, should it be assumed that the gravity of the problem will result in equal access to vaccines further on down the line. "The problem may be urgent," he said. "But there is no precedent for speed in making [the solution] available afterwards." He points to recent breakthroughs, such as the hepatitis B vaccine, which has failed - more than a decade after its discovery -to spread throughout the developing world. As it stands, there is no guarantee that the trial participants in, say, Kenya or Brazil will be able to afford the vaccine that they are volunteering to test.

Vaccine trials in the developing world will be a proving ground for as yet untried compromises and solutions. A successful AIDS vaccine will make history, and so will the trials that lead to its discovery. As these trials get under way, previous shame and success weigh heavily on the debate over trial ethics. For every penicillin, there is a hepatitis B vaccine. And for every potential Tuskegee, there is the possibility of humane, ethically grounded research that improves the quality of the global community.

Source : http://ww2.aegis.org/pubs/amfar/2001/am010103.html