Didanosine Compared with Continued Zidovudine Therapy for HIV-Infected Patients with 200 to 500 CD4 Cells/mm3: A Double-Blind, Randomized, Controlled Trial

doi:10.1059/0003-4819-123-8-199510150-00001

Didanosine Compared with Continued Zidovudine Therapy for HIV-Infected Patients with 200 to 500 CD4 Cells/mm³: A Double-Blind, Randomized, Controlled Trial

Julio S.G. Montaner, MD;
Martin T. Schechter, MD, PhD;
Anita Rachlis, MD;
John Gill, MD;
Raymond Beaulieu, MD;
Chris Tsoukas, MD;
Janet Raboud, PhD;
Bill Cameron, MD;
Horacio Salomon, PhD;
Lisa Dunkle, MD;
Laurie Smaldone, MD;
Mark A. Wainberg, PhD; and
The Canadian HIV Trials Network Protocol 002 Study Group*

From the Canadian HIV Trials Network, Vancouver, British Columbia, Canada; and Bristol-Myers Squibb, Montreal, Quebec, Canada, and Wallingford, Connecticut. Acknowledgments: The authors thank Sylvie Trottier, MD, Helene Senay, MD, Marie-Claude Level, Nashreen Somani, and Patricia Fulton for their assistance; Deborah Hamann-Trou and Kelly Hsu for secretarial assistance; and the patients and their treating physicians for their cooperation and support. Grant Support: By Bristol-Myers Squibb, United States, and the Canadian HIV Trials Network, Canada. Drs. Schechter and Wainberg are National Health research scientists; Dr. Montaner is a National Health scholar from the National Health Research Program Canada; and Dr. Raboud is a postdoctoral research fellow of the National Health Research Program Canada. Requests for Reprints: Julio S.G. Montaner, MD, FRCPC, St. Paul's Hospital, University of British Columbia, 667-1081 Burrard Street, Vancouver, British Columbia, Canada V6Z 1Y6. Current Author Addresses: Drs. Montaner and Schechter: Centre for Excellence in HIV/AIDS, St. Paul's Hospital, University of British Columbia, 667-1081 Burrard Street, Vancouver V6Z 1Y6, British Columbia, Canada.

Abstract

Objective: To compare the safety and efficacy of didanosine with that of continued zidovudine therapy in persons with human immunodeficiency virus (HIV) infection who had received zidovudine for at least 6 months and had CD4 cell counts of 200 to 500 CD4 cells/mm³.

Design: Double-blind, randomized, controlled trial.

Setting: 10 Canadian university-affiliated specialty clinics.

Patients: 246 patients were assigned to receive standard doses of either zidovudine or didanosine.

Outcome Measures: The primary clinical end point was the occurrence of a new, previously undiagnosed acquired immunodeficiency syndrome (AIDS)-defining illness or death.

Results: 245 of 246 patients were eligible (118 receiving didanosine and 127 receiving zidovudine). Sixty-six percent were asymptomatic, 30% had AIDS-related complex, and 4% had AIDS. The median baseline CD4 count was 320 cells/mm³. The median previous duration of zidovudine therapy was 471 days. Nine new AIDS-defining illnesses developed during the study; all but one were in the zidovudine group (relative risk, 7.9 [95% CI, 1.0 to 63.3; P = 0.02]). A change to didanosine led to a statistically significant increase in CD4 counts by week 2 that persisted until the end of the study at week 48 (P < equals 0.01). Viral sensitivity studies (done in 102 patients) showed that 28% of the zidovudine group and 21% of the didanosine group had high-level in vitro resistance to zidovudine (50% inhibitory concentration greater than 0.8 µm) at baseline (P = 0.49). Only one patient in the didanosine group developed high-level resistance to zidovudine during the study. In the zidovudine group, the cumulative probability of developing high-level resistance to zidovudine was 59% at 1 year (P = 0.01). Abdominal pain, leukopenia, and neutropenia were more frequent in the zidovudine group, and hyperuricemia was more frequent in the didanosine group (P < 0.05).

Conclusion: In clinically stable patients with 200 to 500 CD4 cells/mm³ who had tolerated zidovudine for at least 6 months, a change to didanosine led to a decrease in the rate of disease progression, a sustained increase in CD4 counts, and a decrease in the chances of developing high-level resistance to zidovudine. Both drugs were generally well tolerated.

*For additional members of the Canadian HIV Trials Network Protocol 002 Study Group, see the Appendix.