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CD4 Count-Guided Therapy May Increase Risk of HIV Disease Progression
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Mary Beth Nierengarten
Feb. 8, 2006 (Denver; www.medscape.org) - With increasing concern over treatment-related morbidities in HIV-infected patients receiving long-term antiretroviral therapy (ART), different strategies to reduce morbidities while maintaining treatment efficacy continue to be investigated. New results from a large trial that looked at one of these strategies - interrupting and initiating treatment based on CD4 cell counts - show just how difficult and complex a problem this balancing act is, and how much more work needs to be done.
Presenting the latest data from the Strategies for Management of Anti-Retroviral Therapy (SMART) trial, Wafaa El-Sadr, MD, MPH, MPA, from the Harlem Hospital Center and Columbia University in New York City, highlighted that what one may expect may not be born out by the evidence. He discussed the findings here at the 13th Conference on Retroviruses and Opportunistic Infections.
"We thought that those [patients] using less drugs would have fewer complications," Dr. El-Sadr said in a press briefing, "but the surprising thing in SMART is that patients treated on the interruption arm still did have more side effects."
In the SMART trials, patients with a CD4 count higher than 350 cells/mm3 were randomized to continuous ART aimed at viral suppression (VS) or to an experimental group of CD4 count–guided drug conservation (DC). For patients in the DC group, treatment was only initiated when CD4 count decreased to less than 250 cells/mm3 and stopped when the count rose above 350 cells/mm3.
Patient characteristics were comparable between the 2 groups, with a median age of 46 years, 27% were women, and 30% were black. The primary end point of the study was HIV disease progression or death, with secondary end points of death and severe treatment-related complications.
Although the trial was designed to enroll 6000 participants, it was stopped on January 11, 2006, after a review by the trial's data and safety monitoring board found that patients in the DC arm had twice the risk of disease progression or death than the VS arm (3.7/100 person-years vs 1.5/100 person-years), with a relative risk (RR) of 2.5 (P < .0001). The DC group was also associated with a significantly increased risk of serious AIDS-related events (0.5/100 person-years vs 0.1/100 person-years; RR, 82; P = .01), kidney, liver, and cardiovascular disease (2.0/100 person-years vs 1.2/100 person-years; RR, 1.62; P = .02) as well as death (1.5/100 person-years vs 0.9/100 person-years; RR, 1.63; P = .04). At the time it was stopped, the study had enrolled 5472 patients from 318 sites in 33 countries.
Of the patients who died, "most of the deaths were not AIDS-related," said Dr. El-Sadr, "so something else is going on.... It is more complicated than we thought."
According to Dr. El-Sadr, a key take-home message of the trial is that a lot has yet to be learned about strategies based on starting and stopping ART and that large trials are needed for accurate assessment of the outcomes. "There have been smaller studies that show these strategies were safe," she said. "This highlights the importance of conducting larger studies."
Calvin Cohen, MD, a clinical instructor at Harvard Medical School and research director of the Community Research Initiative of New England, both in Boston, Massachusetts, agreed that more studies are needed to evaluate treatment interruption strategies, such as "ongoing small studies testing approaches of 'short-cycle' treatment interruptions that allow a few days off before restarting in order to avoid what may be the consequences of viremia in people with successful viral suppression."
For Dr. Cohen, the practical application of these results is that "we can now say that if someone wants to stop treatment, we can explain that there is a real risk of serious complications that is greater than what we saw in those who stayed on meds."
But, he emphasized, patients may decide that the risk of complications is worth stopping treatment. "It is not at all a surprise that some will still choose to take this risk to gain some perceived or anticipated benefit - people still smoke, for example. But if someone is asking for guidance, these data suggest that current treatment is safer than stopping. I think now that we understand the risk versus benefit equation is now better informed," he said.
13th CROI: Abstract 106LB. Presented February 6, 2006.
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