Context: Plasma human immunodeficiency virus (HIV) RNA level predicts HIV disease progression, but the extent to which it explains the variability in rate of CD4 cell depletion is poorly characterized. Objective: To estimate the proportion of variability in rate of CD4 cell loss predicted by presenting plasma HIV RNA levels in untreated HIV-infected persons. Design: Repeated-measures analyses of 2 multicenter cohorts, comprising observations beginning on May 12, 1984, and ending on August 26, 2004. Analyses were conducted between August 2004 and March 2006. Setting: Two cohorts of HIV-infected persons: patients followed up at 4 US teaching medical institutions or participating in either the Research in Access to Care for the Homeless Cohort (REACH) or the San Francisco Men's Health Study (SFMHS) cohorts and participants in the Multicenter AIDS Cohort Study (MACS) cohort. Participants: Antiretroviral treatment-naive, chronically HIV-infected persons (n=1289 and n=1512 for each of the 2 cohorts) untreated during the observation period (≥6 months) and with at least 1 HIV RNA level and 2 CD4 cell counts available. Approximately 35% were nonwhite, and 35% had risk factors other than male-to-male sexual contact. Main Outcome Measures: The extent to which presenting plasma HIV RNA level could explain the rate of model-derived yearly CD4 cell loss, as estimated by the coefficient of determination (R2). Results: In both cohorts, higher presenting HIV RNA levels were associated with greater subsequent CD4 cell decline. In the study cohort, median model-estimated CD4 cell decrease among participants with HIVRNAlevels of 500 or less, 501 to 2000, 2001 to 10 000, 10 001 to 40 000, and more than 40 000 copies/mL were 20, 39, 48, 56, and 78 cells/μL, respectively. Despite this trend across broad categories of HIV RNA levels, only a small proportion of CD4 cell loss variability (4%-6%) could be explained by presenting plasma HIV RNA level. Analyses using multiple HIV RNA measurements or restricting to participants with high HIV RNA levels improved this correlation minimally (R2, 0.09), and measurement error was estimated to attenuate these associations only marginally (deattenuated R2 in the 2 cohorts, 0.05 and 0.08, respectively). Conclusions: Presenting HIV RNA level predicts the rate of CD4 cell decline only minimally in untreated persons. Other factors, as yet undefined, likely drive CD4 cell losses in HIV infection. These findings have implications for treatment decisions in HIV infection and for understanding the pathogenesis of progressive immune deficiency.
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