Background Despite declines in morbidity and mortality withthe use of combination antiretroviral therapy, its effectivenessis limited by adverse events, problems with adherence, and resistanceof the human immunodeficiency virus (HIV).
Methods We randomly assigned persons infected with HIV who hada CD4+ cell count of more than 350 per cubic millimeter to thecontinuous use of antiretroviral therapy (the viral suppressiongroup) or the episodic use of antiretroviral therapy (the drugconservation group). Episodic use involved the deferral of therapyuntil the CD4+ count decreased to less than 250 per cubic millimeterand then the use of therapy until the CD4+ count increased tomore than 350 per cubic millimeter. The primary end point wasthe development of an opportunistic disease or death from anycause. An important secondary end point was major cardiovascular,renal, or hepatic disease.
Results A total of 5472 participants (2720 assigned to drugconservation and 2752 to viral suppression) were followed foran average of 16 months before the protocol was modified forthe drug conservation group. At baseline, the median and nadirCD4+ counts were 597 per cubic millimeter and 250 per cubicmillimeter, respectively, and 71.7% of participants had plasmaHIV RNA levels of 400 copies or less per milliliter. Opportunisticdisease or death from any cause occurred in 120 participants(3.3 events per 100 person-years) in the drug conservation groupand 47 participants (1.3 per 100 person-years) in the viralsuppression group (hazard ratio for the drug conservation groupvs. the viral suppression group, 2.6; 95% confidence interval[CI], 1.9 to 3.7; P<0.001). Hazard ratios for death fromany cause and for major cardiovascular, renal, and hepatic diseasewere 1.8 (95% CI, 1.2 to 2.9; P=0.007) and 1.7 (95% CI, 1.1to 2.5; P=0.009), respectively. Adjustment for the latest CD4+count and HIV RNA level (as time-updated covariates) reducedthe hazard ratio for the primary end point from 2.6 to 1.5 (95%CI, 1.0 to 2.1).
Conclusions Episodic antiretroviral therapy guided by the CD4+count, as used in our study, significantly increased the riskof opportunistic disease or death from any cause, as comparedwith continuous antiretroviral therapy, largely as a consequenceof lowering the CD4+ cell count and increasing the viral load.Episodic antiretroviral therapy does not reduce the risk ofadverse events that have been associated with antiretroviraltherapy. (ClinicalTrials.gov number, NCT00027352
[ClinicalTrials.gov]
.)
Source Information
The members of the writing group (W.M. El-Sadr [cochair], Harlem Hospital Center and Columbia University, New York; J.D. Lundgren [cochair], Hvidovre University Hospital, Denmark; J.D. Neaton [cochair], University of Minnesota, Minneapolis; F. Gordin, Washington Veterans Affairs Medical Center, Washington, DC; D. Abrams, University of California, San Francisco; R.C. Arduino, University of Texas Medical School, Houston; A. Babiker, Medical Research Council, London; W. Burman, Denver Public Health Department; N. Clumeck, Centre Hospitalier Universitaire Saint-Pierre, Brussels; C.J. Cohen, Community Research Initiative of New England, Boston; D. Cohn, Denver Public Health Department; D. Cooper, National Centre in HIV Epidemiology and Clinical Research, Sydney; J. Darbyshire, Medical Research Council, London; S. Emery, National Centre in HIV Epidemiology and Clinical Research, Sydney; G. Fätkenheuer, University Hospital, Cologne; B. Gazzard, Medical Research Council, London; B. Grund, University of Minnesota, Minneapolis; J. Hoy, National Centre in HIV Epidemiology and Clinical Research, Melbourne; K. Klingman, National Institute of Allergy and Infectious Diseases, Bethesda, MD; M. Losso, Hospital General de Agudos J.M. Ramos Mejia, Buenos Aires; N. Markowitz, Henry Ford Hospital, Detroit; J. Neuhaus, University of Minnesota, Minneapolis; A. Phillips, Royal Free Hospital School of Medicine, London; and C. Rappoport, University of California, San Francisco) of the SMART study assume responsibility for the overall content and integrity of the article.
Address reprint requests to Dr. El-Sadr at Harlem Hospital Center, Division of Infectious Diseases, Rm. 3107, 506 Lenox Ave., New York, NY 10037, or at wme1{at}columbia.edu.
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