January 31, 2001
The fundamental goals of STI research are varied, studied for immune augmentation, safety, and drug avoidance.
Patients who have received less cumulative drug can have successful outcomes with less resistance, less toxicity, better QOL, and -- possibly -- immune benefit. These are reasons to rapidly move ahead with larger, randomized trials. The outstanding question should be: "Is TI better, the same, or worse than continuous treatment?"
Other participants immediately pointed out the difficulties in designing the next wave of trials. "As far as immune response goes, I don't see a clear group of patients who benefit." The heterogeneity of results from the many small studies may call for stratifying the planned trials by age, nadir CD4+ count, pre-treatment viral load or any number of other factors. Such diverse populations will require multicenter cooperation to enroll.
Phase III trials of immune benefit for chronic infection can't be considered until some key parameters of STI are better defined: Which populations to treat; how to schedule interruptions; and which endpoints to use.
One researcher suggested that study endpoints should perhaps be a composite of immune, viral and QOL measures. Still, we lack objective data about QOL and newer immunological markers have not standardized.
"What do we do with the 70% who don't benefit from the STI? People with chronic infection don't generate consistent responses." "I'm stuck between the poor predictive power of the immune responses and the variable data on those parameters. Some patients have had striking improvements -- but we don't know why."
One researcher participating in a large trial believes only clinical outcomes will be meaningful as primary endpoints for phase III study. But this should not preclude nesting basic virology and immunology research within clinical endpoint studies, although new alliances need to be formed: ". . . we need to (collect samples and) get the large trials linked to scientists." It also should not rule out doing lab-based surrogate marker phase I-II studies, depending on hypothesis, to set the stage for phase III studies.
Another participant brought the discussion full circle by stressing the need for better treatment strategies and the lure of STI: "If you can get the same viral load or CD4 result with less drug exposure, that would be enough for any disease -- except for HIV. The safety of STI has been demonstrated, more or less, let's roll with randomized controlled trials."
Putting immune benefit aside, the period of interruption to be studied can vary depending on the goal. Toxicity reduction may call for a two to three month interruption if it is possible at all. Maintaining viral load and CD4 levels stable with less drug exposure may require more frequent on/off cycles. [Or this may vary by person.] The only large trial of STI to date (SSITT) found QOL gains reported only during the first interruption.
The economic benefits of interruption and intermittent therapy also need to be critically examined. "If people can't go to work because they're feeling lousy or going to the doctor all the time, these are costs." There may be hidden costs to TI, such as an increased number of clinical events and hospitalizations, or more frequent monitoring while off therapy. "So let's think about all these kinds of costs and assess them in our effectiveness studies."
Use of the term "interruption" supposes that continuous treatment is the natural order. Perhaps we now know enough to overturn this model and begin talking about periods of treatment administration that interrupt and modulate the natural history of this disease.
Toxicity and Quality of Life