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How Antiretroviral Breaks May Raise Heart Disease Risk
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Mark Mascolini
February 26, 2007
14th Conference on Retroviruses and Opportunistic Infections
Los Angeles
CD4 count-guided treatment breaks upped the risk of cardiovascular disease in the SMART trial, which found an overall higher risk of AIDS and non-AIDS disease progression in people who suspended therapy when their CD4s climbed above 350 cells [1]. At the 14th Conference on Retroviruses, SMART statistician Andrew Phillips (Royal Free and University College, London) offered data suggesting that overall positive effects on lipids with continuous antiretroviral therapy may explain the higher heart disease risk with interrupted treatment. But that may not be the only explanation.
Before the trial began, SMART researchers hypothesized that CD4-driven drug holidays would cut the odds of cardiovascular disease and other non-AIDS conditions that plague an aging antiretroviral-treated population. But the opposite proved true.
To figure out why, Phillips compared rates of fatal or nonfatal heart disease in people who never suspended therapy and in people who suspended treatment at a CD4 count above 350 and resumed below 250, as the SMART protocol stipulated. He counted 48 major cardiovascular complications in the treatment-break group and 31 in the control group. Those numbers meant people who suspended therapy had a 57% higher risk of heart trouble than people who did not (relative hazard [RH] 1.57, 95% confidence interval [CI] 1.00 to 2.46). The P value for that increased risk, 0.05, meant the higher risk with drug holidays has "borderline significance," according to Phillips.
Taking a nonnucleoside regimen that did not include a protease inhibitor (PI) approximately doubled the risk of major cardiovascular disease in the drug interruption group, as did taking a nucleoside-only regimen in that group. But these higher heart disease risks did not reach statistical significance. On the other hand, cumulative years on a nonnucleoside regimen slightly lowered the chance of heart disease in the drug-break group, though this finding also lacked statistical significance. Curiously, a higher CD4 count boosted the heart risk in the drug-holiday group 11%, but again that jump fell shy of statistical significance (P = 0.08).
To see whether the SMART definition of heart disease affected these findings, Phillips broadened that definition in two steps, first adding peripheral vascular disease, congestive heart failure, and coronary artery disease requiring a drug change, then adding death from any heart-related cause. Neither analysis changed the major finding that drug breaks raise the cardiovascular odds by about half.
Among people either on or off antiretrovirals when they enrolled in SMART, being in the drug-holiday group correlated with significantly lower triglycerides after 1 year of follow-up (P < 0.0001). The opposite proved true for "good" high-density lipoprotein (HDL) cholesterol, which rose significantly more after 1 year of follow-up in the steady-therapy group (P < 0.0001).
Looking for a tie-breaker to settle these divergent lipid outcomes, Phillips figured the 1-year change in total cholesterol-to-HDL cholesterol ratio in the drug-break and non-drug-break groups, again splitting the analysis between those on and off therapy when the trial began. In both analyses the ratio improved (fell) significantly more in the steady-therapy group (P < 0.0001 for those on treatment at baseline and P = 0.02 for those off treatment at baseline).
Phillips proposed that the better ratio with continuous therapy may explain the higher heart disease rate in the treatment-interruption group. Another possibility, proposed by Indiana University's Michael Dube in a question-and-answer session, is that antiretrovirals quell inflammation. Phillips said the SMART team is now evaluating that possibility.
References
1. The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355:2283-2296.
2. Phillips A, Carr A, Neuhaus J, et al. Interruption of ART and risk of cardiovascular
disease: findings from SMART. 14th Conference on Retroviruses and Opportunistic Infections. February 25-28, 2007. Los Angeles. Abstract 41.
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