Background:  Tenofovir (TFV) is a nucleotide analog metabolized intracellularly to TFV diphosphate, an inhibitor of HIV-1 reverse transcriptase. Tenofovir disoproxil fumarate (TDF), an oral prodrug of TFV, is widely used for treatment of HIV-1 infection. GS-7340 is a novel, lymphatic targeting prodrug of TFV that provides higher intracellular TFV diphosphate concentrations in peripheral blood mononuclear cells (PBMC) resulting in more potent in vitro activity than TDF at equivalent TFV doses. GS-7340 has the potential in patients to demonstrate superior clinical antiviral activity at much lower TFV plasma concentrations compared with TDF.

Methods:  A randomized, double-blind, active-controlled, dose-escalation study was conducted comparing GS-7340 (50 mg once daily and 150 mg once daily) and TDF (300 mg once daily) 14-day monotherapy in treatment-naïve, HIV-1-infected subjects with HIV-1 RNA ≥15,000 copies/mL and CD4 count ≥200 cells/mm³. The primary endpoint was time-weighted average change in plasma HIV-1 RNA from baseline through week 2 (DAVG₂). Pairwise comparisons for DAVG₂ among all 3 arms were conducted using the Wilcoxon rank sum test. Also assessed were CD4 counts, viral resistance, adverse events, clinical laboratory tests, GS-7340, TDF and TFV pharmacokinetics, and TFV PBMC concentrations.

Results:  We enrolled 30 subjects (90% male, 43% Caucasian, ages 23 to 54, mean HIV-1 RNA  4.82 log₁₀ copies/mL, mean CD4 424 cells/mm³) who completed the study (n = 10/group).  Plasma HIV-1 RNA DAVG₂ was greater for GS-7340 50 mg (–0.95±0.32 log₁₀ copies/mL, p = 0.0211) and GS-7340 150 mg (–1.07±0.14, p = 0.0002) than for TDF 300 mg (–0.54±0.32). The mean change from baseline in HIV-1 RNA at week 2 was greater for GS-7340 50 mg (–1.57±0.53 log₁₀ copies/mL, p = 0.0257) and GS-7340 150 mg (–1.71±0.24, p = 0.0010) than for TDF 300 mg (–0.94±0.49). No TFV resistance mutations were detected after monotherapy with GS-7340 or TDF. Compared to TDF, plasma TFV C_max and AUC_0-t were 94% and 88% lower, respectively, with GS-7340 50 mg; 80% and 58% lower with GS-7340 150 mg. TFV PBMC-associated exposures were variable, but ~30-fold greater with GS-7340 vs TDF, normalized for TFV dose. No subject discontinued study medication. There were no clinically significant laboratory abnormalities or serious adverse events in any treatment group.

Conclusions:  Monotherapy with GS-7340 at doses of 50 or 150 mg for 14 days in subjects with HIV-1 infection was associated with significantly greater decreases in plasma HIV-1 RNA levels at lower systemic TFV exposures.