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Charlottesville, Va—In the last few years, the success of highly active antiretroviral therapy (HAART) in suppressing HIV viral load levels has given people infected with HIV hope for survival. Yet while the potent multidrug regimens can prolong life for patients, they have many drawbacks. High costs, adverse effects, toxicity, and a complicated medication schedule often cause noncompliance with or abandonment of treatment. Evidence indicates that HAART cannot completely eliminate HIV from the body, as was once hoped.
But until a way of eradicating the virus is discovered, long-term control of HIV is the goal of therapy. This is why a number of researchers are exploring ways to improve HAART, to minimize its problems without compromising its effectiveness. One approach some are investigating involves prescribing antiretroviral therapy to be given in an intermittent rather than continuous fashion, a method that—if it proves successful—would reduce the amount of time a patient receives treatment.
Among those studying interrupted therapy is Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases. His team is currently enrolling HIV-infected patients on HAART in a randomized controlled study to compare continuous therapy with intermittent therapy administered on a 2-month-on, 1-month-off schedule.
Speaking at the Bayer Symposium on Infectious Diseases held here last month, Fauci explained that the concept of interrupted therapy is based on a number of recent observations of the behavior of HIV in the presence of HAART. It is quite clear, he said, that even when someone is successfully treated with HAART, the virus continues to replicate at a very low rate. This undetectable virus allows for the rebound of plasma viremia in virtually all patients when therapy is stopped or suspended.
Good news—and better?
It has been shown, said Fauci, that when HAART is resumed after temporary treatment disruption, patients' viral levels drop back down to undetectable amounts, and no deleterious effect involving reinitiated therapy is noted (AIDS. 1999;13:677-683). Furthermore, he said, evidence from a small number of patients shows that a structured on-again, off-again therapeutic approach can affect the virological set point—the baseline level to which the virus rises when therapy is stopped. This may happen in one of two ways, said Fauci: "Either the duration of time before the set point is reached may be prolonged, which would be good news, or the level of the set point might be decreased, which would be better news."
The first effect would be good news because it could reduce the amount of time a patient needs treatment—the main goal of this approach, and also the most likely outcome, according to Fauci. Although not as optimistic about the second possibility, he pointed out, "If we're lucky and the virological set point is substantially decreased, we may actually be creating a subset of long-term nonprogressors."
Fauci said his group also is trying to improve the HIV-specific immune response with intermittent therapy. Their hope is that they will see a gradual increase in the level of HIV-specific CD8+T cells at each cycle. "This is exactly what we see in the very small group of long-term nonprogressors who have barely detectable virus and a very good CD8+response," he said, adding, "even if we fail in truly resetting the immunological set point, if the only thing that comes out of this is that you can keep people off therapy for x number of months per year, that will have been a major accomplishment."
Still, because evidence for adopting a strategy of structured therapy interruption is thin as yet, experts suggest the need for caution and for further research.
Resistance not seen
One of the greatest concerns is whether the interrupted therapy approach will cause drug resistance to develop. Fauci said encouraging evidence that this does not occur, at least in the short term, was presented at the Seventh Annual Conference on Retroviruses and Opportunistic Infections in January. Three groups that looked at individuals undergoing structured therapy interruptions found no evidence of emergence of resistance mutations, he reported. However, he said long-term studies are needed.
"There's an awful lot to do in the next several years as we begin to manipulate therapeutic regimens," said Fauci. "I hope in the next few years we'll be in a situation where we can have people on regimens that are truly acceptable to them and not what we have now, which is that after a few years virtually everyone feels they can't take any more therapy."
As Merle A. Sande, MD, of the University of Utah School of Medicine pointed out, the cycling mechanism might not only improve care for HIV-infected patients in the United States, it may improve the feasibility of using HAART in places such as Africa, if costs of treatment are reduced by the regimen.
Friedrich MJ. HAART Stopping News: Experts Examine Structured Therapy Interruption for HIV. JAMA. 2000;283(22):2917–2918. doi:10.1001/jama.283.22.2917
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