Background:  Capravirine (CPV) is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) that exhibits potent antiviral activity against wild type and NNRTI-resistant strains of HIV in vitro. In a phase II study evaluating CPV 700 or 1400 mg as add-on therapy to nelfinavir (NFV) + 2 NRTI in NNRTI-experienced, protease inhibitor (PI)-naïve patients, neither of the CPV-containing arms demonstrated a significant difference in efficacy versus background therapy.

Methods:  Study 1006 is a phase II, prospective, randomized (1:1:1:1), multi-center, double-blind, dose-ranging study of CPV (200, 400, or 700 mg) or placebo (PBO) + lopinavir/ritonavir (LPV/r) and ³2 PhenoSenseGT-selected NRTI. Patients must have previously failed >1 NNRTI, >2 NRTI, and 1 to 3 PI and demonstrate <40-fold change (FC) in susceptibility to LPV at baseline. Patients assigned to the PBO, CPV 200, or CPV 400 treatment groups received 400/100 mg LPV/r twice daily, while patients assigned to CPV 700 mg received 533/133 mg LPV/r twice daily to account for dose-dependent drug interaction.

Results:  Study arms were similar at baseline in overall mean age, gender, race, and percentage with ³1 NNRTI-resistance mutations:  44.6% and 69.6% of patients had <2.5-FC and <10-FC in CPV susceptibility at baseline, respectively; 73.7% and 86.4% of patients had <2.5-FC and <10-FC in LPV susceptibility at baseline, respectively.  Key data (intent to treat, non-completers = failures or *last observation carried forward) are presented in the following table:

The primary (time to virologic failure) and most secondary efficacy endpoints were statistically insignificant (p >0.05) for all active arms vs placebo. However, more patients receiving CPV 400 mg achieved <50 copies/mL at week 48 compared to placebo (p <0.05). The most frequently reported adverse events (>10% in any CPV arm) were diarrhea, nausea, headache, and influenza. Most adverse events were mild in severity. There were non-significant trends toward more gastrointestinal adverse events, more adverse events leading to treatment interruption or discontinuation, and more shifts in laboratory results of at least 2 toxicity grades with CPV 700 mg relative to the other treatments (p >0.05).

Conclusions:  Through 48 weeks of therapy, CPV was generally safe and well tolerated, but showed little or no added efficacy over LPV/r + 2 NRTI.