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Zidovudine Resistance and HIV-1 Disease Progression during Antiretroviral Therapy

Richard T. D'Aquila, MD; Victoria A. Johnson, MD; Seth L. Welles, PhD, ScD; Anthony J. Japour, MD; Daniel R. Kuritzkes, MD; Victor DeGruttola, PhD; Patricia S. Reichelderfer, PhD; Robert W. Coombs, MD, PhD; Clyde S. Crumpacker, MD; James O. Kahn, MD; and Douglas D. Richman, MD
[+] Article, Author, and Disclosure Information

From Massachusetts General Hospital, Beth Israel Hospital, Harvard Medical School, and Harvard School of Public Health, Boston, Massachusetts. University of Alabama at Birmingham School of Medicine and Birmingham Veterans Affairs Medical Center, Birmingham, Alabama. University of Colorado Health Sciences Center and Denver Veterans Affairs Medical Center, Denver, Colorado. National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland. University of California, San Francisco, and the San Francisco General Hospital AIDS Program, San Francisco, California. University of California, San Diego, and San Diego Veterans Affairs Medical Center, La Jolla, California. For The AIDS Clinical Trials Group Protocol 116B/117 Team and The Virology Committee Resistance Working Group. Requests for Reprints: Richard D'Aquila, MD, Infectious Disease Unit, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Charlestown, MA 02129. Acknowledgments: The authors thank Kimberly DeVore, Donna An, Lawrence Bechtel, Anu Savara (Massachusetts General Hospital, Boston, Massachusetts); D. Adam Plier, Mary Jane Burton (University of Alabama at Birmingham); Steven Kim, Linda Ecto (Beth Israel Hospital, New York, New York); Scott Bell, Russell Young, Piper Prach (University of Colorado Health Sciences Center, Denver, Colorado); Sara Albanil, Mary Ann del Fiorentino, Pat Ley (University of California, San Diego, La Jolla, California) for doing the laboratory studies; Elaine Gebhardt (ACTG Statistical and Data Analysis Center, Harvard School of Public Health, Boston, Massachusetts) for providing valuable logistical support; N.A. Roberts and Ian B. Duncan (Roche Products, Ltd., United Kingdom) for providing the saquinivir; and the work of investigators, clinicians, and virologists at each of the clinical sites participating in ACTG protocol 116B/117. Grant Support: National Institutes of Health (AI 27659, AI 29193, AI 32775, AI 32770, AI 29173, AI 01101, AI 27670, AI 29164, AI 30457, and AI27664), the Research Center for AIDS and HIV Infection of the San Diego Veterans Affairs Medical Center, and Bristol-Myers Squibb Company. Dr. Johnson acknowledges core research facilities of the University of Alabama, Birmingham, Center for AIDS Research, and the Birmingham Veterans Administration Medical Center.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1995;122(6):401-408. doi:10.7326/0003-4819-122-6-199503150-00001
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Objective: To evaluate the association between resistance of human immunodeficiency virus type 1 (HIV-1) to zidovudine and clinical progression.

Design: Retrospective analysis of specimens from patients in the AIDS Clinical Trials Group (ACTG) protocol 116B/117, a randomized comparison of didanosine with continued zidovudine therapy in patients with advanced HIV-1 disease who had received 16 weeks or more of previous zidovudine therapy.

Setting: Participating ACTG virology laboratories.

Patients: 187 patients with baseline HIV-1 isolates.

Measurements: Zidovudine susceptibility testing and assays for syncytium-inducing phenotype were done on baseline HIV-1 isolates. Relative hazards for clinical progression or death associated with baseline clinical, virologic, and immunologic factors were determined from Cox proportional-hazards regression models.

Results: Compared with other patients, 15% (26 of 170) with isolates showing high-level zidovudine resistance (50% inhibitory zidovudine concentration ≥ 1.0 µM) had 1.74 times the risk for progressing to a new AIDS-defining event or death (95% CI, 1.00 to 3.03) and 2.78 times the risk for death (CI, 1.21 to 6.39) in analyses that controlled for baseline CD4+ T-lymphocyte count, syncytium-inducing HIV-1 phenotype, disease stage, and randomized treatment assignment. The clinical benefit of didanosine was not limited to patients with highly zidovudine-resistant baseline HIV-1 isolates.

Conclusions: High-level resistance of HIV-1 to zidovudine predicted more rapid clinical progression and death when adjusted for other factors. However, patients with advanced HIV-1 disease may benefit from a change in monotherapy from zidovudine to didanosine whether high-level HIV-1 resistance to zidovudine is present or absent, and laboratory assessment of zidovudine resistance is not necessary for deciding when to switch monotherapy from zidovudine to didanosine.





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