In for the Long Haul: Debate Paves Way for Long-Term Trials*
A small group of community advocates, a divided research community, huge sums of money, and urgent questions that threaten to break the mold of conventional trial designs -- all of these elements are at play in what may be one of the least publicized and most critical fields in HIV research today: long-term trial design. The National Institute of Allergy and Infectious Diseases (NIAID) has earmarked approximately $80 million for studies to answer such crucial questions as when to start and when to change HIV therapy. Some trials, particularly large, international collaborations, could cost even more.
Taking on long-term management questions has, once again, brought HIV to the frontier of existing medical expertise. In January 2000, a NIAID Division of AIDS (DAIDS) meeting brought together researchers, clinicians, community advocates, statisticians, and experts from cardiovascular and cancer research to discuss how best to answer long-term questions in the field of HIV disease management. The results were stimulating and daunting. "The word we got from people in cancer and heart disease was that this is at the cutting edge of clinical trials methodology in some ways," said DAIDS director Jack Killen. "There has been very little work in any field of clinical research that looks at very long-term outcomes over a very long period of time."
One of the major challenges is the sheer size of the trials. A study pool of many thousands of people is required to detect a meaningful reduction in the risk of "events" -- i.e. death, severe toxicities, or disease progression -- associated with long-term use of a particular treatment regimen or strategy. HIV treatment strategy trials of all kinds will, by necessity, enroll relatively healthy patients. It is medically and ethically indefensible not to treat those who are already sick or have CD4 counts below 200 cells/mm3. Starting with healthy individuals means it could be years before the effect of a strategy emerges. Large trials are a partial solution to this problem. The more participants there are, the more likely it is that a significant number of events will take place during the study period.
NIAID's largest, most expensive study to date, the ESPRIT trial, is enrolling 4000 people for 5 years to test the effects IL-2, an immune stimulator. That trial is costing $43 million, including the establishment of a new international network of sites that could be used for other long-term strategy trials, too. At the January meeting, statisticians estimated that a trial studying when to start antiretroviral therapy could require [several thousand] people and last a decade. Such a trial could cost [tens of millions of dollars], according to one projection from what large-scale cardiovascular trials cost. Not all trials will have to be so big or unwieldy. But even a 6000-person trial -- the target enrollment for the Strategies for the Management of Anti-Retroviral Therapy (SMART) study proposed by the Community Programs for Clinical Research on AIDS (CPCRA) -- handily outstrips ESPRIT in size.
Concerns about cost and feasibility have led some activists to question whether these trials should be conducted at all. They point out that big-budget "blockbuster" trials will siphon money, participants, and investigators away from other research projects. Any such trial will also bring the networks into uncharted waters in terms of enrollment targets, accrual rates, length and, potentially, large-scale international collaborations.
One of the chief obstacles for SMART is persuading patients and physicians to cede highly personal choices about treatment to random assignment in a trial. Current research suggests that there may be real benefit to beginning treatment during acute infection, but it is not clear whether there is any additional benefit to starting drugs at CD4 counts above 250 cells/mm3 during established infection. Short-term side effects and long-term toxicities of the drugs may prove detrimental to quality of life and survival time. As with cancer therapy, each doctor-patient pair must consider medical facts, open research questions, untested strategies, and personal factors like age, children, and likelihood of successful adherence.
For this reason, SMART could be difficult to enroll. Many physicians and patients think that how to treat is an important question to answer -- many fewer are willing to put it to the test themselves.
There are other issues, too. In order for a trial to take place, there has to be a clear, unanswered question. This elusive state of having no a priori opinion, or equipoise, is the foundation of clinical trial design. When it comes to SMART and equipoise, critics say it's there -- to a point. Cumulative data from observational cohort studies and other trials strongly suggest that it is safe to wait until falling below a CD4 count of 350 cells/mm3 to begin treatment. US treatment guidelines use this level as the threshold for starting therapy. A CD4 count of 250 cells/mm3 may be the lowest acceptable limit for starting therapy. This raises the question of whether significant time, energy, and money should be invested in paring down a zone of equipoise that spans just 100 CD4 cells/mm3.
A drop in CD4 T cell count of 100 cells/mm3 can take several years, and this is both a blessing and a curse. On the one hand, the wait boosts the relevance and importance of the SMART question. The interval lets people avoid the toxicities of HAART in the hope that less toxic drugs will be approved while they remain off treatment. By the same token, the advent of new drugs could sway individuals in the deferred arm to leave the trial and start treatment. For those who wait until the predetermined time to start therapy, improvements in drug efficacy and tolerability could obscure the effects of waiting.
Still, SMART could provide guidance for long-term treatment management questions: Must treatment be taken continuously to be effective, or can it be used as a time-limited, strategic intervention when CD4 cell counts begin to fall? What strategy maximizes the efficacy of antiretroviral therapy? For the trial to enroll and retain target numbers of participants, these questions must remain relevant for the duration of the study.
Losing track of participants is one of the major hazards of long-term trials. For strategy trials, planners must anticipate a situation in which new treatments and findings, or interim data from the study itself, cause a large number of participants to leave the trial or deviate from protocol. It is impossible to anticipate all the shifts and developments in HIV research that could occur over a 5- or 10-year period. Still, planners can make clear decisions from the outset about how interim data will be analyzed and presented to the public.
For long-term management trials to be feasible and useful to doctors and patients, they must also reflect, as much as possible, the real world conditions of treatment use. Short-term data from clinical and observational trials of HAART show that adherence and success rates of regimens are higher in clinical trials. Those involved in the long-term efforts stress that this highly controlled model will not provide the desired answers. "We need to make trials less restrictive, more open to a broader range of people, and to do them under, as close as we can, real world conditions. It's moving away from drug development-type trials," said Jim Neaton, a CPCRA biostatistician and principal investigator of the ESPRIT IL-2 trial.
As the debate continues, advocates and researchers agree that more education is needed to gain long-term commitment and public support for these trials. Many U.S. communities may have to be swayed from the belief that it is unsafe to wait to treat.
Five years of experience with HAART has proved insufficient to predict the long-term effects of these drugs on the heart, liver, and kidney -- or on HIV itself, which these regimens cannot completely suppress. As difficult as it is to conceive exactly how to bring off a long-term trial like SMART, it is even more difficult to imagine patients and physicians making a lifetime of treatment decisions based on educated guesses. "I'm hoping that what's done here is first in a generation of management trials that will incrementally improve how we take care of patients with HIV," said Jim Neaton.
* Complete article published in the amfAR Treatment Insider vol. 2, no. 1, February 2001. Reprinted with permission.
This article was provided by The Center for AIDS. It is a part of the publication Research Initiative/Treatment Action!. Visit CFA's website to find out more about their activities and publications.