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Nevirapine, Zidovudine, and Didanosine Compared with Zidovudine and Didanosine in Patients with HIV-1 Infection: A Randomized, Double-Blind, Placebo-Controlled Trial

Richard T. D'Aquila, MD; Michael D. Hughes, PhD; Victoria A. Johnson, MD; Margaret A. Fischl, MD; Jean-Pierre Sommadossi, PharmD, PhD; Song-heng Liou, MA; Joseph Timpone, MD; Maureen Myers, PhD; Nesli Basgoz, MD; Manette Niu, MD; and Martin S. Hirsch, MD
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The National Institute of Allergy Infectious Diseases AIDS Clinical Trials Group Protocol 241 Investigators* For author affiliations and current author addresses, see end of text. *For a listing of additional members of the AIDS Clinical Trials Group Protocol 241 Investigators, see the Appendix. Acknowledgments: The authors thank the patients and staff who contributed to the study and thank Xiao-Jian Zhou, PhD (University of Alabama at Birmingham, Birmingham, Alabama) for the pharmacology analysis, Elaine Gebhardt (AIDS Clinical Trials Group Statistical and Data Analysis Center), the participating AIDS Clinical Trials Group Unit site virologists and virology laboratory staff, and the AIDS Clinical Trials Group Operations Office staff. Grant Support: In part by the AIDS Clinical Trials Group of NIAID. Zidovudine was provided by Glaxo Wellcome, Research Triangle Park, North Carolina; didanosine was provided by Bristol-Myers Squibb, Wallingford, Connecticut; and nevirapine was provided by Boehringer-Ingelheim Pharmaceuticals, Ridgefield, Connecticut. Requests for Reprints: Richard T. D'Aquila, MD, Infectious Disease Unit, Massachusetts General Hospital, 149 13th Street, Charlestown, MA 02129. Current Author Addresses: Dr. D'Aquila: Infectious Disease Unit, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Charlestown, MA 02129.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1996;124(12):1019-1030. doi:10.7326/0003-4819-124-12-199606150-00001
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Objective: To study the addition of a third human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitor, nevirapine, to the combination of zidovudine and didanosine.

Design: A 48-week, randomized, double-blind, placebo-controlled trial at 16 AIDS (acquired immunodeficiency syndrome) Clinical Trials Units.

Patients: 398 adults who had HIV-1 infection, had 350 or fewer CD4+ T lymphocytes/mm3, and had had more than 6 months of previous nucleoside therapy.

Intervention: 1) Either nevirapine or placebo [200 mg/d for 2 weeks, then 400 mg/d thereafter] and 2) open-label zidovudine (600 mg/d) and didanosine (400 mg/d for patients weighing more than equals to 60 kg).

Measurements: CD4+ T lymphocyte counts, time to first HIV-1 disease progression event or death, adverse events, and nevirapine levels in plasma samples taken at random were measured in all patients. Plasma levels of HIV-1 RNA; HIV-1 infectivity titer in peripheral blood mononuclear cells; serum p24 antigen levels; and plasma levels of zidovudine and didanosine were measured in patients enrolled at half the study sites.

Results: After 48 weeks of study treatment, the patients assigned to the triple-combination regimen (nevirapine, zidovudine, and didanosine) had an 18% higher mean absolute CD4 cell count (95% CI, 7% to 29%; P = 0.001), a 0.32 log10 lower mean infectious HIV-1 titer in peripheral blood mononuclear cells (CI, 0.05 to 0.59 log10 infectious units per million cells; P = 0.023), and a 0.25 log10 lower mean plasma HIV-1 RNA level (CI, 0.03 to 0.48 log10RNA copies/mL; P = 0.028) than did patients assigned to the double-combination regimen (zidovudine and didanosine). Severe rashes were more common among patients assigned to receive the triple combination (9% compared with 2%; P = 0.002). Risk for disease progression did not differ between the two groups (relative hazard of the triple-combination group, 1.24 [CI, 0.75 to 2.06]; P > 0.2), although the study had only moderate power to detect a major difference.

Conclusions: Adding nevirapine to zidovudine and didanosine improved the long-term immunologic and virologic effects of therapy and was associated with severe rash among the patients studied, who had had extensive previous therapy. These results support 1) the continuing development of combinations of more than two antiretroviral drugs to increase and prolong HIV-1 suppression and 2) the potential utility of nevirapine in combination regimens.


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Figure 1.
Median zidovudine and didanosine plasma concentrations after administration of the combination of zidovudine and didanosine with either nevirapine (black bars) or placebo (white bars). Top.Bottom.P

Plasma concentrations of zidovudine. Plasma concentrations of didanosine. Plasma samples were collected at visits during week 8 (between 0.25 to 0.5 hours and 1.0 to 1.5 hours after simultaneous administration of all drugs), week 24 (between 2.0 and 2.5 hours after simultaneous administration of all drugs), week 32 (between 3.5 and 4.0 hours after simultaneous administration of all drugs), and week 44 (between 7.0 and 8.0 hours after simultaneous administration of all drugs). The number of patients sampled is indicated within each bar, and the value (determined using the Wilcoxon test) for the difference between treatment groups at each time interval is indicated above each set of bars.

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Figure 2.
Mean changes from baseline, by treatment group. Top.Middle.10Bottom.10

Mean changes in CD4 cell counts as percentage of baseline count. Mean changes in peripheral blood mononuclear cell human immunodeficiency virus type 1 (HIV-1) infectivity titers in log infectious units per million cells (IUPM). Mean changes in plasma HIV-1 RNA levels in log plasma HIV-1 RNA copies/mL. Dashed lines indicate the triple-combination (nevirapine, zidovudine, and didanosine) treatment group; solid lines indicate the double-combination (zidovudine and didanosine) treatment group. Bars represent the SE. The numbers of patients tested at each time point are indicated above the x-axis.

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