Antiviral Activity, Safety, and Pharmacokinetics/Pharmacodynamics of Tenofovir Alafenamide as 10-Day Monotherapy in HIV-1–Positive Adults

作者：Peter Ruane, Edwin DeJesus, Daniel Berger, Martin Markowitz, U. Fritz Bredeek, Christian Callebaut, Lijie Zhong, Srini Ramanathan, Martin S. Rhee, Marshall W. Fordyce, Kitty Yale · 发表于：JAIDS Journal of Acquired Immune Deficiency Syndromes · 年份：2013 · DOI：10.1097/qai.0b013e3182965d45 · 被引用次数：307 · 研究领域：HIV/AIDS drug development and treatment、HIV Research and Treatment、HIV-related health complications and treatments

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