Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection. A randomized, double-blind, placebo-controlled trial. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group Protocol 241 Investigators.

Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.

Ann Intern Med. 1996 Jun 15;124(12):1019-30. Unique Identifier : AIDSLINE MED/96233410
D'Aquila RT; Hughes MD; Johnson VA; Fischl MA; Sommadossi JP; Liou SH; Timpone J; Myers M; Basgoz N; Niu M; Hirsch MS; Infectious Disease Unit, Massachusetts General Hospital,; Charlestown 02129, USA.

Abstract: 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 > or = 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% Cl, 7% to 29%; P = 0.001), a 0.32 log10 lower mean infectious HIV-1 titer in peripheral blood mononuclear cells (Cl, 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 (Cl, 0.03 to 0.48 log10 RNA 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 [Cl, 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.

Keywords: Adult Comparative Study CD4 Lymphocyte Count Didanosine/ADVERSE EFFECTS/BLOOD/*THERAPEUTIC USE Disease Progression Double-Blind Method Drug Therapy, Combination Erythema/CHEMICALLY INDUCED Female Human HIV Infections/*DRUG THERAPY/IMMUNOLOGY/VIROLOGY *HIV-1 Male Prospective Studies Pyridines/ADVERSE EFFECTS/BLOOD/*THERAPEUTIC USE Reverse Transcriptase Inhibitors/ADVERSE EFFECTS/BLOOD/ *THERAPEUTIC USE RNA, Viral/BLOOD Support, U.S. Gov't, P.H.S. Zidovudine/ADVERSE EFFECTS/BLOOD/*THERAPEUTIC USE CLINICAL TRIAL CLINICAL TRIAL, PHASE II JOURNAL ARTICLE MULTICENTER STUDY RANDOMIZED CONTROLLED TRIAL
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M9690859

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