Background:  In a 10-day monotherapy study, 6 of 6 patients, who were treated with once-daily GS-9137 50 mg/ritonavir 100 mg, had >1.5 log₁₀ copies/mL reductions in HIV RNA from baseline.

Methods:  This ongoing randomized, partially blinded, active-controlled, dose-ranging, 48-week, phase 2 study initially assessed the non-inferiority of GS-9137 to boosted comparator protease inhibitors (CPI/r) in HIV-1-infected, treatment-experienced subjects. Eligible patients had HIV RNA ≥1000 copies/mL, any CD4 cell count, and ≥1 protease resistance mutation. Subjects received nucleoside reverse transcriptase inhibitor (NRTI) ħT-20 and were randomized 1:1:1:1 (stratified by T-20 use) to receive CPI/r or once-daily GS-9137 20 mg, 50 mg, or 125 mg each given with 100 mg ritonavir. After week 8, the GS-9137 20-mg arm was closed because of a high rate of virologic failure, and the addition of darunavir or tipranavir to GS-9137 arms was permitted when new data showed a lack of drug-drug interactions. The primary endpoint is DAVG_24, but analyses were also performed on week-16 data to assess the non-inferiority of GS-9137 vs boosted protease inhibitors (PI), since only 4 patients receiving GS-9137 added a PI prior to week 16.

Results:  Baseline characteristics of the 278 patients were:  mean age of 45 years, 90% male, and 73% Caucasian. Baseline mean HIV RNA was 4.59 log₁₀ copies/mL and CD4 cells was 185 cells/mm³. T-20 was used by 22% of patients for the first time. Prior to week 16, the majority of GS-9137 patients received only 2 NRTI as background therapy; 26% of the GS-9137 50 mg and 125 mg patients added a PI by week 24. The mean DAVG₁₆ and DAVG₂₄ for the GS-9137 125 mg arm were statistically superior to those of the CPI/r arm (see the table). GS-9137 was well tolerated. No dose relationship was observed in treatment-emergent grade 3 or 4 adverse events or laboratory abnormalities, and fewer patients in the GS-9137 treatment arms discontinued study drug because of adverse events than in the CPI/r arm.

Conclusions:  Both DAVG₁₆ and DAVG₂₄ for GS-9137 125 mg were statistically superior to those for boosted PI. GS-9137 was well tolerated.  These data support the evaluation of GS-9137 in phase 3 studies.