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Prevalence and Predictive Value of Intermittent Viremia With Combination HIV Therapy
Diane V. Havlir, MD;
Roland Bassett, MS;
Diane Levitan, MD;
Peter Gilbert, PhD;
Pablo Tebas, MD;
Ann C. Collier, MD;
Martin S. Hirsch, MD;
Caroline Ignacio, BA;
Jon Condra, PhD;
Huldrych F. Günthard, MD;
Douglas D. Richman, MD;
Joseph K. Wong, MD
JAMA. 2001;286:171-179.
Context In HIV-infected patients having virologic suppression (plasma HIV RNA <50 copies/mL) with antiretroviral therapy, intermittent episodes of low-level viremia have been correlated with slower decay rates of latently infected cells and increased levels of viral evolution, but the clinical significance of these episodes is unknown.
Objective To determine if HIV-infected patients with intermittent viremia have a higher risk of virologic failure (confirmed HIV RNA >200 copies/mL).
Design and Setting Retrospective analysis of subjects in well-characterized cohorts, the AIDS Clinical Trials Group (ACTG) 343 trial of induction-maintenance therapy (August 1997 to November 1998) and the Merck 035 trial (ongoing since March 1995).
Patients Two hundred forty-one ACTG 343 patients, of whom 101 received triple-drug therapy throughout the study, and a small group of 13 patients from Merck 035 having virologic suppression after 6 months of indinavir-zidovudine-lamivudine.
Main Outcome Measures Association of intermittent viremia (plasma HIV RNA >50 copies/mL with a subsequent measure <50 copies/mL) with virologic failure (2 consecutive plasma HIV RNA measures >200 copies/mL) in both study groups; evidence of drug resistance in 7 patients from the small (n = 13) study group with long-term follow-up.
Results Intermittent viremia occurred in 96 (40%) of the 241 ACTG 343 patients of whom 32 (13%) had 2 consecutive HIV RNA values >50 copies/mL during the median 84 weeks of observation (median duration of observation after first intermittent viremia episode was 46 weeks). Of the 101 individuals receiving triple-drug therapy throughout, 29% had intermittent viremia; the proportion of episodes occurring during the maintenance period was 64% for the entire cohort and 68% for the group not receiving triple-drug therapy throughout vs 55% for those who did (P = .25). Intermittent viremia did not predict virologic failure: 10 (10.4%) of 96 patients with and 20 (13.8%) of 145 patients without intermittent viremia had virologic failure (relative risk, 0.76; 95% confidence interval [CI], 0.29-1.72). In a Cox proportional hazards model, the risk for virologic failure was not significantly greater in the ACTG 343 patients with intermittent viremia (hazard ratio, 1.28; 95% CI, 0.59-2.79). Median viral load in 10 ACTG 343 patients assessed between 24 and 60 weeks of therapy using an ultrasensitive 2.5-copies/mL detection level assay was 23 copies/mL in those with intermittent viremia vs <2.5 copies/mL in those without (P = .15). Intermittent viremia occurred in 6 of 13 patients from the small study group assessed after 76 to 260 weeks of therapy (using the 2.5-copies/mL detection level assay) and was associated with a higher steady state of viral replication (P = .03), but not virologic failure over 4.5 years of observation. Viral DNA sequences from 7 patients did not show evolution of drug resistance.
Conclusions Intermittent viremia occurred frequently and was associated with higher levels of replication (Merck 035), but was not associated with virologic failure in patients receiving initial combination therapy of indinavir-zidovudine-lamivudine (ACTG 343 and Merck 035). In this population, treatment changes may not be necessary to maintain long-term virologic suppression with low-level or intermittent viremia.
Author Affiliations: Departments of Medicine (Drs Havlir, Levitan, Richman, and Wong) and Pathology (Dr Richman and Ms Ignacio), University of California, San Diego, and the San Diego VA Healthcare System; School of Public Health (Mr Bassett and Dr Gilbert) and Department of Medicine, Infectious Diseases Unit (Dr Hirsch), Harvard University, Boston, Mass; Department of Internal Medicine, Washington University, St Louis, Mo (Dr Tebas); Department of Allergy and Infectious Diseases, University of Washington School of Medicine, Seattle (Dr Collier); Merck Research Laboratory, West Point, Pa (Dr Condra); and Department of Medicine, Division of Infectious Diseases and Hospital Epidemiology, University of Zurich, Zurich, Switzerland (Dr Günthard).
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