555    

Background:  Capravirine (CPV) is a next-generation NNRTI that exhibits potent in vitro activity against HIV-1 strains resistant to approved NNRTI. In serial passage studies, virus with high-level resistance to CPV is slow to emerge and contains multiple reverse transcriptase mutations, suggesting a high genetic barrier to resistance. Safety and tolerability has been demonstrated in phase 1/2 studies in more than 429 person years of therapy. Safety, tolerability and efficacy is being evaluated in treatment-experienced patients.

Methods:  Study 1002 is a phase 2, prospective, randomized (1:1:1), double-blind, multi-center, dose ranging study of CPV (700 mg [n = 60] or 1400 mg [n = 60]) or placebo (n = 59) added to a standard of care regimen (nelfinavir [NFV] + 2 PhenoSense^® GT selected NRTI) in NNRTI-experienced, PI-naïve patients. Each CPV arm was compared with the placebo arm using Fisher’s exact test.

Results:  Study arms were similar at baseline with an overall mean age (38.6 years), gender (66% male), race (40% white, 49% black) and ≥ 1 NNRTI-resistance mutation (84%). Discontinuation rates for adverse events were 8% (placebo), 12% (700 mg) and 7% (1400 mg), non-significant (ns, p = 0.56 and 0.99, respectively). At week 24, a positive trend was observed in a percentage of patients < 400 copies/mL (48%, 50%, and 60%) and < 50 copies/mL (39%, 40%, and 52%), for the placebo, 700-mg, and 1400-mg arms, respectively (ns). In a planned subgroup analysis of patients with baseline M184V with zidovudine (ZDV) resistance (M41L, D67N, K70R, L210W, T215Y/F, or K219E/N/Q), a trend favoring CPV was observed in a percentage of < 400 copies/mL, placebo (3 of 13, 23%) vs 1400 mg (14 of 24, 58%), p=0.08. All groups experienced a CD4 cell increase (68 to 100 cells/mm³ at week 24), with no significant differences between the CPV and placebo arms. The most frequently reported adverse events were diarrhea, loose stool, nausea, URI, headache, or vomiting. Most adverse events (≥ 10% in CPV-containing arm) were mild in severity and similar between placebo and CPV-containing arms (ns). Only 1 subject experienced a serious study drug-related adverse event, grade 4 AST/ALT in the 700-mg CPV arm.

Conclusions:  Through 24-week of therapy, CPV was safe and well tolerated as part of this 4-drug regimen with few discontinuations due to adverse events:  12 and 13% more patients in the 1400-mg CPV arm achieved < 400 and < 50 copies/mL compared with standard of care alone (placebo), a clinically, but statistically not significant difference. In patients with baseline lamivudine (3TC) and ZDV resistance, there was a strong trend towards more patients achieving < 400 copies/mL in the CPV 1400 arm compared with the placebo arm.

Keywords: Capravirine; NNRTI; Nelfinavir