Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of tenofovir alafenamide as 10-day monotherapy in HIV-1-positive adults.

摘要: OBJECTIVE: To evaluate the antiviral activity, safety, pharmacokinetics, and pharmacokinetics/pharmacodynamics of short-term monotherapy with tenofovir alafenamide (TAF), a next-generation (TFV) prodrug. DESIGN: A phase 1b, randomized, partially blinded, active- placebo-controlled, dose-ranging study. METHODS: Treatment-naive experienced HIV-1-positive adults currently off antiretroviral therapy were randomized to receive 8, 25, or 40 mg TAF, 300 disoproxil fumarate (TDF), placebo, each once daily for 10 days. RESULTS: Thirty-eight subjects enrolled. Baseline characteristics similar across dose groups. Significant reductions in plasma HIV-1 RNA from baseline day 11 observed all TAF groups compared placebo (P < 0.01), median decrease 1.08-1.73 log10 copies per milliliter, including dose-response relationship viral load up 25 mg. At steady state, yielded mean TFV exposures [area under concentration-time curve (AUCtau)] 97%, 86%, 79% lower, respectively, as TDF. For intracellular peripheral blood mononuclear cell diphosphate AUCtau was ∼7-fold ∼25-fold higher, relative CONCLUSIONS: Compared TDF, demonstrated more potent higher levels, lower exposures, at approximately 1/10th dose. This may translate into greater efficacy, barrier resistance, an improved safety profile supporting further investigation dosed HIV-infected patients.