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(AIDSmeds.com)—Results from one of the largest HIV clinical trials ever conducted conclude that a specific strategy of interrupting HIV treatment more than doubles the risk of disease progression or death and is actually associated with a higher risk of serious side effects. Final data from the Strategies for Management of Antiretroviral Therapy (SMART) study, initially reported at a conference in February and reviewed in AIDSmeds.com's treatment interruption lesson, were published in the November 30 issue of the New England Journal of Medicine.
Most people who take HIV drug treatment see their viral loads decrease and their CD4 (T-cell) counts increase, often to levels that are comparable to those seen in HIV-negative people. In turn, researchers have looked at the possibility of treating HIV like other chronic diseases: starting therapy when the immune system shows signs of damage or when somebody experiences symptoms of HIV disease, stopping it when their health improves, and restarting treatment when the CD4 count falls again.
Several clinical trials have been conducted to determine the safety of such treatment interruptions, in which the decision to stop and restart therapy is determined using CD4 counts. In the SMART study, approximately 5,500 people with CD4 cell counts above 350 were enrolled. They were randomized to one of two groups: a continuous treatment group that did not stop HIV treatment, or a treatment interruption group that stopped treatment when the CD4 count rose above 350, restarted when the CD4 count dropped below 250, stopped again when it rose above 350, and so on.
The SMART study was coordinated by four international centers: the Medical Research Council Clinical Trials Unit in London; the Copenhagen HIV Program in Denmark; the National Centre in HIV Epidemiology and Clinical Research at the University of New South Wales in Sydney, Australia; and the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) in Washington, DC.
The clinical trial was supposed to continue for approximately nine years, but was stopped after 16 months due to worrisome results. Early data indicated that patients in the treatment interruption group had an increased risk of HIV disease progression (defined as the development of an AIDS-related opportunistic infection) or death, compared to patients in the continuous treatment group. Specifically, 120 patients in the treatment interruption group, compared with 47 patients in the continuous treatment group, had experienced disease progression. The difference represented a 2.6-fold increased risk for those in the treatment interruption group.
The SMART researchers were hoping that patients in the treatment interruption group would experience fewer complications that can be caused by HIV treatment, such as cardiovascular problems, kidney problems, and liver damage. But they actually found more of these adverse effects in the treatment interruption group.
"Quite unexpectedly, our results show that interrupting therapy increases the risk of serious non-AIDS-related events," says Wafaa El-Sadr, MD, MPH, of the Harlem Hospital Center and Columbia University in New York City, one of the co-chairs of the trial.
It is important to note, however, that other studies evaluating treatment interruptions of this nature have reported more encouraging results. In the August 5 edition of The Lancet, for example, the STACCATO trial found that treatment interruptions reduced the risk of side effects compared to those on continuous treatment. The study, enrolling 430 HIV-positive patients, used a CD4 count of 350 to signal the restart of treatment, which differs significantly from SMART’s 250 CD4 cell count cutoff.
After approximately 21 months of follow up in STACCATO, there were more cases of diarrhea and peripheral neuropathy, as well as higher cholesterol levels, in the continuous therapy group compared to the treatment interruption group. There were, however, more cases of candidiasis in the treatment interruption group.
Because STACCATO was technically a small study, it didn’t have enough statistical power to compare HIV disease progression rates between the two groups. However, the data that were available allowed for the conclusion that treatment interruptions – using a higher CD4 count cutoff for restarting treatment – may hold some promise.
David Cooper, MD, DSc, of the National Centre in HIV Epidemiology and Clinical Research at the University of New South Wales, the Sydney international coordinating center director of SMART, notes, "The prospect of lifelong treatment is difficult for people with HIV. We are gratified that the SMART study has so clearly delineated the risk and benefits of these two strategies, and we are committed to continuing to try to find ways to improve treatment strategies for those with chronic HIV disease."
