Phase I/II study of the pharmacokinetics, safety and antiretroviral activity of tenofovir alafenamide, a new prodrug of the HIV reverse transcriptase inhibitor tenofovir, in HIV-infected adults.

BACKGROUND: Tenofovir alafenamide (formerly GS-7340) is a new oral prodrug of tenofovir, a nucleotide analogue that inhibits HIV-1 reverse transcription. Unlike the currently marketed tenofovir prodrug, tenofovir disoproxil fumarate, tenofovir alafenamide is stable in plasma and then rapidly converted into tenofovir once inside cells. METHODS: The pharmacokinetics, safety and antiviral activity of 40 or 120 mg of tenofovir alafenamide compared with 300 mg of tenofovir disoproxil fumarate when administered as monotherapy once daily for 14 days in HIV-1-infected, treatment-naive subjects was studied. RESULTS: Administration of 40 mg of tenofovir alafenamide for 14 days resulted in lower tenofovir Cmax (13 versus 207 ng/mL) and lower systemic exposures (AUC0-t, 383 versus 1810 ng ·â€Šh/mL) compared with subjects who received tenofovir disoproxil fumarate. There were higher intracellular tenofovir concentrations within peripheral blood mononuclear cells with both 40 mg of tenofovir alafenamide (8.2 µM) and 120 mg of tenofovir alafenamide (16.9 µM) compared with 300 mg of tenofovir disoproxil fumarate (0.9 µM). The most commonly observed adverse events were headache, nausea and flatulence, which occurred similarly across the three groups. After 14 days, the mean changes in HIV-1 RNA were -0.94 log10copies/mL for the tenofovir disoproxil fumarate group, -1.57 log10 copies/mL for the 40 mg of tenofovir alafenamide group and -1.71 log10 copies/mL for the 120 mg of tenofovir alafenamide group. The mean first-phase HIV-1 RNA decay slopes were -0.36, -0.63 and -0.64 for the tenofovir disoproxil fumarate group, the 40 mg of tenofovir alafenamide group and the 120 mg of tenofovir alafenamide group, respectively. No resistance mutations to either tenofovir alafenamide or tenofovir disoproxil fumarate were detected. CONCLUSIONS: Tenofovir alafenamide, a new once-daily oral prodrug of tenofovir, showed more potent anti-HIV-1 activity and higher intracellular tenofovir levels compared with tenofovir disoproxil fumarate, while maintaining lower plasma tenofovir exposure at 40 mg with good tolerability over 14 days of monotherapy.