July 9, 2001
It is difficult to summarize your own presentation, among other reasons because you can not hear yourself when you talk. On behalf of several investigators from five different sites in the U.S., I presented data about what happens when patients discontinue antiretroviral therapy while having an undetectable viral load.
Why did we think this was important? As you know, the prevailing "dogma" about antiretroviral therapy has been the continuous use of multiple antiretroviral drugs in order to suppress plasma HIV RNA levels below the level of detection. This strategy has been associated with substantial decreases in the mortality associated with HIV infection, especially when used in patients with low CD4+ T cell counts. But it has its problems: it requires a high level of adherence, many patients develop resistance to the treatment and the treatment itself can produce long-term complications. This makes this strategy difficult to implement in the developing world, one of the themes of this conference.
The popularity of structured treatment interruptions has started to make holes in the whole paradigm of continuous therapy. The idea we wanted to evaluate goes one step further and asks if it would be possible to develop a strategy not based in viral load, but one based on CD4 count, that would start and stop therapy at certain safe thresholds -- for example starting therapy when the CD4 count is 300 and stopping it when it reaches 500 or 600. At this level of CD4 cells one should not expect clinical events, and probably it would allow for prolonged periods of time off therapy, maintaining (at least in theory) the clinical benefits.
We looked retrospectively at 72 patients in our clinics that have done just that: stopping therapy while they were undetectable. We wanted to know how fast they where losing cells and if there were any predictors of this decay of CD4 cells. On average, patients lost approximately 16 cells per month, and the only predictor in the multivariable analysis was the total amount of CD4 cells that you gained when you were on therapy. So, the more cells patients gained on therapy, the faster patients tended to lose them when they went off therapy.
It is important to emphasize that there are risks with this strategy, so it should only be tried in the setting of well-controlled clinical trials. There is the potential for clinical events and the development of resistance (although because the patients are off medications this is unlikely). There is also a risk of increased transmission, so if this strategy works it will have to be coupled with education programs about transmission, because the patients will be more infectious when they have a detectable viral load. In any case, we think alternative approaches deserve formal evaluation in the setting of well-designed trials. We will see what the answer will be.
Several prospective studies are evaluating this approach systematically. We are conducting one in the ACTG, the study A5102, and the CPCRA group is starting another one called SMART.
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