Zidovudine in Persons with Asymptomatic HIV Infection and CD4+ Cell Counts Greater than 400 per Cubic Millimeter
David A. Cooper, Jose M. Gatell, Susanne Kroon, Nathan Clumeck, Judith Millard, Frank-D Goebel, Johan N. Bruun, Georg Stingl, Rex L. Melville, Juan Gonzalez-Lahoz, John W. Stevens, A. Paul Fiddian, for The European-Australian Collaborative Group
Background Zidovudine therapy is of benefit in the treatmentof symptomatic and asymptomatic human immunodeficiency virus(HIV) infection in persons with CD4+ cell counts of less than500 per cubic millimeter. The efficacy, safety, and durationof benefit of zidovudine in those with 500 or more CD4+ cellsper cubic millimeter are uncertain.
Methods In a double-blind, placebo-controlled trial, 993 patientswith asymptomatic HIV infection and CD4+ cell counts above 400per cubic millimeter were randomly assigned to receive zidovudine(500 mg twice daily) or placebo for three years. The primaryend point was progression of disease, as defined by the developmentof Centers for Disease Control and Prevention (CDC) group IVdisease (including recurrent oral candidiasis, hairy leukoplakia,or progressive diarrhea) or two CD4+ cell counts below 350 percubic millimeter. This outcome measure was changed from theoriginal end point of the acquired immunodeficiency syndrome(AIDS) or advanced AIDS-related complex to reflect changes inrecommendations for management. The study was terminated afterthe first interim analysis.
Results Disease progression was significantly less frequentin the zidovudine group (relative risk, 0.56; 95 percent confidenceinterval, 0.43 to 0.75; P<0.001 by the log-rank test). Theprobability of disease progression at two years was 0.19 withzidovudine, as compared with 0.34 with placebo (95 percent confidenceinterval for the difference, -0.21 to -0.08). Progression toCDC group IV disease was reduced by half in the zidovudine recipients(relative risk, 0.49; P = 0.049) and decline in CD4+ cell countsto below 350 per cubic millimeter was reduced by 40 percent(relative risk, 0.60; P<0.001). The inclusion of early HIVdisease events (oral candidiasis, oral hairy leukoplakia, andherpes zoster) as end points confirmed the effects of zidovudineon the progression of clinical disease (relative risk, 0.55;95 percent confidence interval, 0.37 to 0.84; P = 0.004). Themedian duration of treatment was 94 weeks. Severe hematologicor clinical side effects were rare.
Conclusions Treatment with zidovudine benefits HIV-infectedpersons with CD4+ cell counts above 400 per cubic millimeter.Despite the use of doses larger than those now generally prescribed,zidovudine was well tolerated for up to three years by mostof our patients.
Source Information
From the National Centre in HIV Epidemiology and Clinical Research, St. Vincent's Hospital, University of New South Wales, Sydney, Australia (D.A.C.); Hospital Clinic I Provincial de Barcelona, Barcelona, Spain (J.M.G.); Bispebjerg University Hospital, Copenhagen, Denmark (S.K.); St. Pierre University Hospital, Brussels, Belgium (N.C.); the Wellcome Research Laboratories, Beckenham, Kent, United Kingdom (J.M., J.W.S., A.P.F.); Medizinische Poliklinik der Universitat, Munich, Germany (F.-D.G.); Ulleval University Hospital, Oslo, Norway (J.N.B.); University of Vienna Medical School, Vienna, Austria (G.S.); the Albion Street Centre, Prince of Wales Hospital, Sydney, Australia (R.L.M.); and the Instituto de Salud Carlos III, Madrid (J.G.-L.). A list of the persons and institutions participating in the European-Australian Collaborative Group appears in the Appendix.
Address reprint requests to Dr. Cooper at the National Centre in HIV Epidemiology and Clinical Research, 2nd floor, 376 Victoria St., Sydney NSW 2010, Australia.
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