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The Duration of Zidovudine Benefit in Persons With Asymptomatic HIV InfectionProlonged Evaluation of Protocol 019 of the AIDS Clinical Trials Group
Paul A. Volberding, MD;
Stephen W. Lagakos, PhD;
Janet M. Grimes, MS;
Daniel S. Stein, MD;
Henry H. Balfour, Jr, MD;
Richard C. Reichman, MD;
John A. Bartlett, MD;
Martin S. Hirsch, MD;
John P. Phair, MD;
Ronald T. Mitsuyasu, MD;
Margaret A. Fischl, MD;
Ruy Soeiro, MD;
the AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases;
Carla B. Pettinelli, MD, PhD;
Ana I. Martinez, RPh;
Song-Heng Liou;
Keith Henry, MD;
Margaret Simpson, MD;
Ann DePaolis-Jones, RN;
Ross G. Hewitt, MD;
Donald C. Blair, MD;
Mark V. Packard, RN;
Carol Fowler, RRA;
Clyde S. Crumpacker, MD;
J. Davis Allan, MD;
Helen F. Fitch, RN, BSN;
Kathy Dybeck, RN;
Rebecca Coleman, PharmD;
Mark Jacobson, MD;
John P. Phair, MD;
Robert Murphy, MD;
Constance Benson, MD;
W. David Hardy, MD;
Suzette A. Chafey, RN, NP;
Sally Kruger, MS;
Janie Reese, RN, BSN;
Elisa Dale;
Carol Harris, MD;
Neal Steigbigel, MD;
Rebecca L. Becker, PA-C;
Vivian E. Rexroad, RPh;
Judith E. Feinberg, MD;
Stephen A. Spector, MD;
Douglas D. Richman, MD;
Ron Snyder, RN;
Thomas C. Merigan, Jr, MD;
Jeffrey Fessel, MD;
David Katzenstein, MD;
James A. Zachary, MD;
David M. Mushatt, MD;
Newton E. Hyslop, Jr, MD;
Ann C. Collier, MD;
Lawrence Corey, MD;
Robert W. Coombs, MD;
Michael F. Para, MD;
Robert J. Fass, MD;
Caroline Whitacre, PhD;
Henry S. Sacks, PhD, MD;
Donna Mildvan, MD;
Hilda Mendoza, RN;
Kenneth Fife, MD, PhD;
William G. Powderly, MD;
Lawrence D. Gelb, MD;
Michael Klebert, RN-P;
John M. Leedom, MD;
Maxine Liggins, MD;
Novella Quesada, RN;
Brian Wong, MD;
Jill Brinkdopke, LPN;
Maria Hoelle, RN;
David J. Gocke, MD;
Vincent J. McAuliffe, MD;
Fred T. Valentine, MD;
Jane Dowling, RN;
Mariel Wallace, RN;
Vera PaulJarrett, RN;
Victoria Cargill, MD;
George F. McKinley, MD;
Michael H. Grieco, MD;
Bruce Polsky, MD;
Delia C. Brown, RN;
Charles van der Horst, MD;
Susan Fiscus, PhD;
David Ragan, RN;
Sarah H. Cheeseman, MD;
Patrick G. Fairchild, MD;
Kwan Kew Lai, MD;
Monto Ho, MD;
Deborah McMahon, MD;
John A. Armstrong, ScD;
M. Elaine Eyster, MD;
W. Christopher Ehmann, MD;
David Irwin, MD;
Roy T. Steigbigel, MD;
Jack Fuhrer, MD;
Ruth Tenzler, RN;
Laura Ponticello, RN;
Michael F. Giordano, MD;
Henry W. Murray, MD
JAMA. 1994;272(6):437-442.
Abstract
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Objective.
—To determine the durability of zidovudine-induced delay in clinical progression of asymptomatic human immunodeficiency virus (HIV) disease and to assess the relationship between this effect and the entry CD4+ cell count.
Design and Interventions.
—Extended follow-up data from subjects participating in protocol 019 of the AIDS [acquired immunodeficiency syndrome] Clinical Trials Group were examined. Subjects were offered a total daily dose of 500 mg of open-label zidovudine after the unblinding of the original randomized trial in 1989. Original treatment groups included placebo, 500 mg of zidovudine, or 1500 mg of zidovudine daily in divided doses. Three distinct analyses were conducted to assess the duration of zidovudine's effect on progression to AIDS or death: (1) analysis of all follow-up information from all subjects, (2) analysis of all subjects but with follow-up of original placebo-assigned subjects censored at the time open-label zidovudine was initiated, and (3) analysis of the effect of initiating zidovudine in subjects initially assigned to receive placebo.
Setting.
—University-based and university-affiliated AIDS research clinics participating in AIDS Clinical Trials Group protocol 019.
Patients.
—A total of 1565 asymptomatic HIV-infected subjects with entry CD4+ cell counts less than 0.50x109/L (500/µL).
Main Outcome Measure.
—Time to progression to AIDS or death.
Results.
—During follow-up of up to 4.5 years (mean, 2.6 years), 232 subjects progressed to AIDS or died. In each of the three analyses described herein, zidovudine was associated with a significant (P=.008.004.007) decrease in the risk of such progression. However, each of these analyses also indicated a decreasing placebo:zidovudine relative risk with duration of use (P=.002.08.04), suggesting a nonpermanent effect. The duration of benefit appeared to be related to entry CD4+ cell count, with greater benefit in those with higher counts at entry. No significant differences in survival were found between those originally randomized to zidovudine or placebo.
Conclusions.
—Zidovudine at 500 mg/d caused a significant delay in progression to AIDS or death, but its earlier use in asymptomatic disease was not associated with an additional prolongation of survival compared with delayed initiation. The delay in progression diminished over time especially in subjects with entry CD4+ cell counts less than 0.30x109/L (300/µL). Treatment strategies that alter drug regimens before the loss of zidovudine benefit should be explored.
(JAMA. 1994;272:437-442)
Author Affiliations
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Statistical and Data Analysis Center, Harvard School of Public Health; University of Minnesota; University of Rochester Medical Center; Duke University Medical Center; Harvard Medical School; University of California—San Francisco; Northwestern University Medical School; University of California—Los Angeles; University of Miami School of Medicine; Albert Einstein College of Medicine; Johns Hopkins University School of Medicine; University of California—San Diego; Stanford University School of Medicine; Tulane University School of Medicine; University of Washington, Seattle; Mount Sinai Medical Center; Indiana University; Washington University School of Medicine; George Washington University Medical Center; University of Southern California; University of Cincinnati Medical Center; University of New Jersey (Robert Wood Johnson); New York University Medical Center; Case Western Reserve University; St Luke's/ Roosevelt Hospital Center; Memorial SloanKettering Cancer Center; University of North Carolina; University of Massachusetts; University of Pittsburgh; The Milton S. Hershey Medical Center; State University of New York at Stony Brook; Cornell University Medical College
From the University of California-San Francisco and the San Francisco (Calif) General Hospital (Dr Volberding); the Harvard School of Public Health, Boston, Mass (Dr Lagakos and Ms Grimes); the National Institute of Allergy and Infectious Diseases, Bethesda, Md (Dr Stein); the University of Minnesota, Minneapolis (Dr Balfour); the University of Rochester (NY) School of Medicine and Dentistry (Dr Reichman); Duke University Medical Center, Durham, NC (Dr Bartlett); Harvard Medical School and Massachusetts General Hospital, Boston, Mass (Dr Hirsch); Northwestern University, Chicago, Ill (Dr Phair); University of California-Los Angeles (Dr Mitsuyasu); the University of Miami (Fla) School of Medicine (Dr Fischl); Albert Einstein/ Montefiore Medical Center, New York, NY (Dr Soeiro).
Footnotes
A partial list of persons and institutions participating in the AIDS Clinical Trials Group appears at the end of this article.
Reprint requests to the AIDS Program, San Francisco General Hospital, Ward 84,995 Potrero Ave, San Francisco, CA 94110 (Dr Volberding).
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