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Didanosine Compared with Continuation of Zidovudine in HIV-infected Patients with Signs of Clinical Deterioration While Receiving Zidovudine: A Randomized, Double-Blind Clinical Trial

Spotswood L. Spruance, MD; Andrew T. Pavia, MD; Dolores Peterson, MD; Allison Berry, MD; Richard Pollard, MD; Thomas F. Patterson, MD; Ian Frank, MD; Scot C. Remick, MD; Melanie Thompson, MD; Rodger D. MacArthur, MD; G. E. Morey, MD; Carlos H. Ramirez-Ronda, MD; Barry M. Bernstein, MD; Donna E. Sweet, MD; Lawrence Crane, MD; Eskild A. Peterson, MD; Constance T. Pachucki, MD; Stephen L. Green, MD; Jerry Brand, MD, MPH; Adan Rios, MD; Lisa M. Dunkle, MD; Anne Cross, PhD; Michael J. Brown, PhD; Peter Ingraham, PhD; Ronald Gugliotti, MPH; Andrew H. Schindzielorz, MD; and Laurie Smaldone, MD
[+] Article and Author Information

From Holy Cross Hospital and the University of Utah Health Sciences AIDS Center, Salt Lake City, Utah; the University of Texas Southwestern Medical Center at Dallas, Dallas, Texas; the University of Arizona Health Sciences Center, Tucson, Arizona; the Audie Murphy Veterans Administration Hospital, San Antonio, Texas; the University of Texas, Galveston, Texas; Yale University School of Medicine, New Haven, Connecticut; the University of Pennsylvania Immunodeficiency Program, Philadelphia, Pennsylvania; the Albany Medical Center, Albany, New York; the AIDS Research Consortium of Atlanta, Atlanta, Georgia; the Medical College of Ohio, Toledo, Ohio; the San Juan Veterans Affairs Medical Center and the University of Puerto Rico School of Medicine and Affiliated Hospital, San Juan, Puerto Rico; the Medical College of Wisconsin, Milwaukee, Wisconsin; the University of Kansas School of Medicine, Wichita, Kansas; the Harper Hospital, Detroit, Michigan; the University of Arizona, Tucson, Arizona; the Edward Hines Veterans Affairs Hospital, Hines, Illinois; the Home Health Care Services Research Institute, Orlando, Florida; the Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut. Presented in part at the 9th International Conference on AIDS, Berlin, Germany, 6 to 11 June 1993 and the State-of-the-Art Conference on Antiretroviral Therapy for Adult HIV-infected Patients, National Institutes of Health, Bethesda, Maryland, 23 to 25 June 1993. For the Bristol-Myers Squibb AI454-010 Study Group. Requests for Reprints: S. L. Spruance, MD, University of Utah Health Sciences AIDS Center, MC 4B322, 50 North Medical Drive, Salt Lake City, UT 84132. Grant Support: This study was funded in part by grants from Bristol-Myers Squibb, and its employees participated as coinvestigators in the design, analysis, and presentation of the study.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1994;120(5):360-368. doi:10.7326/0003-4819-120-5-199403010-00002
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Objective: To determine the benefits of switching to didanosine compared with continuing zidovudine among patients infected with human immunodeficiency virus (HIV) who have previously used zidovudine and have signs of clinical deterioration.

Design: Randomized, double-blind, two-armed, parallel, comparative clinical trial with a blinded, compassionate crossover provision at 12 weeks.

Setting: Outpatient clinics at 19 tertiary care medical centers.

Patients: 312 patients infected with HIV who had received zidovudine for 6 months or more, had CD4 cell counts of 300/mm3 or less, and had signs of clinical deterioration within 12 weeks before study entry.

Intervention: Peroral didanosine tablets (600 mg/d adjusted for weight, “high dose”) or zidovudine capsules (600 mg/d).

Measurements: Primary study end points were death, a new acquired immunodeficiency syndrome (AIDS)-defining event, or the combination of two new or recurrent HIV-related diagnoses with a 50% decrease in CD4 cells.

Results: Switching to didanosine was associated with fewer end points than continuing zidovudine (relative risk [RR] for zidovudine:didanosine = 1.5; 95% CI, 1.1 to 2.0). This benefit was consistent across subgroups of patients with either AIDS-related complex or AIDS and was most apparent among those with a CD4 count at entry of 100/mm3 or more (RR = 2.2; CI, 1.1 to 4.4).

Conclusions: This study shows a positive treatment effect for switching from zidovudine to didanosine among patients with either AIDS-related complex or AIDS and validates the common practice of using clinical signs or a decrease in the CD4 count as an indication for changing therapy.

*For members of the Study Group, see the appendix.

Figures

Grahic Jump Location
Figure 1.
Kaplan-Meier distributions of time to primary study end points by treatment group. Top.PBottom.3P

All patients (RR for zidovudine: didanosine =1.5; = 0.02). Patients with pretreatment CD4 cell counts 100 cells/mm or more (RR for zidovudine:didanosine = 2.2; = 0.03). The numbers within the figure are the patients remaining in the study at different points in time. DDI = didanosine; ZDV = zidovudine.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Median change in the CD4 cell count from pretreatment values by treatment group and time in study. Top.Bottom.3

All patients. Patients with pretreatment CD4 cell counts of 100 cells/mm or more. The numbers within the figure are the patients remaining in the study at different points in time. DDI = didanosine; ZDV = zidovudine.

Grahic Jump Location

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