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Nearly Everyone Agrees On the Need for ‘Strategy’ Type Clinical Studies — And That’s Where Consensus Ends

An intrepid Dr. Lange scales Mt. Sinai

First there was the CPCRA’s “Moving Target” protocol, which entailed half a decade of arduous, dog-chasing-its-tail conference calls and draft after draft after endless draft of protocol revisions, each one more complicated than the next. Then, there was the Ellen Cooper behemoth at AmFAR’s Community Based Clinical Trials Network (the CBCT), which boldly tempted fate with its characteristically arrogant acronym, “SMART.” Most recently, the ACTG HIV RAC has thrown its hat into the antiretroviral strategy protocol ring with Michael Saag’s “START” study.

Years later and countless two hour teleconferencing sessions since, “Moving Target” never budged; the sly “SMART” seems to have out-foxed even itself; and further development of “START” has been brought to a screeching halt. Why has it proven so difficult — even among clinical trials groups with seasoned expertise and abundant financial resources — to design a relatively long-term, but flexible, strategy-based antiretroviral study that many believe to be the only hope of obtaining answers to the thorny issues of long-term patient management? TAG’s Spencer Cox, community representative to the ACTG’s START protocol team, offers some insights.

This year’s clinical research buzzword is undoubtedly “strategy.” Almost everyone working in AIDS research agrees that strategy studies, which examine different ways of managing HIV-infected patients — rather than the effects of particular drugs, are desperately needed. However, amidst raging controversy over what strategies should be tested, the ACTG’s HIV Research Agenda Committee (RAC) has shot down proposals for ACTG 355 (the START protocol), the first major strategy trial to be proposed in the ACTG.

ACTG 355, which was being developed by a team of researchers led by the University of Alabama’s Dr. Michael Saag and Dr. William Powderly of Washington University, went through a number of incarnations with different primary questions. One draft would have tested “tight” control of viral load, in which patients attempted to maintain undetectable viral levels, versus “loose” control of viral load, in which patients with detectable virus levels below 5,000 copies/mL would have continued their current drug regimens. Another draft included a randomization between “immediate” and “deferred” protease inhibitors. In all drafts, patients and physicians would choose their therapies from a long list of available regimens.

In its review of the protocol, the HIV RAC noted that, “There is a critical need for a strategy protocol to prospectively validate observational studies on the clinical importance of viral RNA levels.” However, the RAC also noted disagreements about what question the study would answer. Informal discussion between members of the research team and of the RAC suggested that some RAC members simply thought that investigators had chosen the wrong question: of course undetectable viral levels are preferable to maintenance of low but detectable viral levels, and early protease inhibitor use is better than late protease inhibitor use. Other RAC members quarreled with the specifics of the protocol’s “decision tree” for which therapeutic regimens could be used. No one agreed on what the most important questions were: one investigator’s speculative assumption is another investigator’s career-making discovery.

Fundamentally, the problems faced by the ACTG 355 team are reflected in the current deliberations of two working groups, one established by the Public Health Service (PHS) and one assembled by the Office of AIDS Research (OAR) at the National Institutes of Health. These working groups are attempting to define guidelines for the treatment of HIV infection. While there is often surprising consensus on what specific recommendations to make, the PHS working group has spent hours discussing the caveats associated with their recommendations.

Aggressive treatment recommendations are sometimes being offered based on clinical interpretation of small, preliminary studies, rather than on larger, more reliable studies demonstrating improvement in clinical well-being. This raises questions about how to distinguish assumptions from demonstrated facts. For instance, no therapeutic regimen has been shown to be clinically superior to ddI monotherapy, however most knowledgeable investigators believe that the improved virologic response using AZT, 3TC and indinavir will necessarily improve outcome as compared to ddI.

Similarly, many investigators feel that the improved tolerance and virologic response using indinavir justifies its use as front-line therapy, however patient advocates and some clinicians worry that the tendency of indinavir to spawn multiple protease inhibitor cross-resistance may necessitate exploration of other alternatives.

What controversies need to be resolved by strategy studies? There is no consensus. In a presentation to the 4th Conference on Retroviruses and Opportunistic Infections, Dr. Joep Lange of the University of Amsterdam (who apparently was handed down the answers to these difficult questions on clay tablets) insisted that there are no major outstanding strategy questions: monitoring of viral load, tolerance and compliance will tell clinicians everything they need to know about the use of a particular regimen in a particular patient. According to Dr. Lange, the patient should start treatment “as soon as the patient is ready.” Otherwise, he added, “HIV infection seems to me a pretty good reason to begin treatment.”

This thorny situation came to a head in the PHS working group over the question of cross-resistance. All committee members agreed that clinicians need to know that current therapeutic choices will affect future options in the event of treatment failure. The committee also agreed that providing a wealth of information about genotypic resistance would not be terribly useful, as the data are confusing and their relationship to clinical response is not yet well characterized. However, without genotypic information, there is precious little evidence about how, in practice, sequencing of particular treatments may be important. Therefore the committee is asking clinicians to consider the future effects of current treatments without telling them specifically how to do so.

The ACTG 355 team hasn’t called it quits yet. Investigators are currently working within the ACTG to develop a process for prioritizing strategy questions, with the hope of developing a new study proposal. There is also talk of preparing a scientific article for publication regarding the development of strategy trials.

Still, all of this may be interpreted as a not-so-great omen for the newly-founded Forum for Collaborative Research, a group of researchers, industry representatives, community advocates and insurers, that was formed to stimulate studies that would answer the most pressing clinical questions. If there is no consensus on what questions need to be answered, then it will be difficult to advocate for research. Additionally, at an upcoming closed-door meeting of the FDA’s Antiviral Drugs Advisory Committee, pharmaceutical giant Glaxo-Wellcome is rumored to be developing a plan to minimize requirements for post-marketing research on their new drug, GW-1592U89. Without a strong FDA push for inclusion of strategy trials in post-marketing study plans, industry may not perceive a benefit to participation in these complex, long and expensive trials.

Ultimately, as usual, it is the patients who pay the price of this failure of will. It seems clear that clinical practice will be based on clinicians’ best clinical judgment for some time to come. And, if history is any judge, that means AZT monotherapy for most patients living with HIV.

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