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

Ruane, Peter J. MB, MRCPI*; DeJesus, Edwin MD; Berger, Daniel MD; Markowitz, Martin MD§; Bredeek, U. Fritz MD; Callebaut, Christian PhD; Zhong, Lijie PhD; Ramanathan, Srini PhD; S. Rhee, Martin MD; Fordyce, Marshall W. MD; Yale, Kitty BS

JAIDS Journal of Acquired Immune Deficiency Syndromes: 1 August 2013 - Volume 63 - Issue 4 - p 449–455
doi: 10.1097/QAI.0b013e3182965d45
Clinical Science

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 levels, and lower plasma TFV exposures, at approximately 1/10th of the dose. This may translate into greater antiviral efficacy, a higher barrier to resistance, and an improved safety profile relative to TDF, supporting further investigation of TAF dosed once daily in HIV-infected patients.

*Peter J. Ruane MD Inc, Los Angeles, CA;

Orlando Immunology Center, Orlando, FL;

Northstar Healthcare, Chicago, IL;

§Aaron Diamond AIDS Research Center, The Rockefeller University, New York, NY;

Metropolis Medical, San Francisco, CA; and

Clinical Research, Gilead Sciences, Foster City, CA.

Correspondence to: Peter J. Ruane, MD, Peter J. Ruane MD Inc, 5901 W Olympic Blvd, Ste 401, Los Angeles, CA 90036 (e-mail: pjruane@lightsourcemedical.com).

Supported by Gilead Sciences Inc. All study investigators received research funding from Gilead to support their patients' participation in this trial. In addition, P.R., E.D., D.B., M.M., and U.B. have received honoraria from Gilead for their participation in meetings, advisory boards, and speakers’ bureau. P.R. and D.B. own Gilead stock.

Presented in part at the 29th Conference on Retroviruses and Opportunistic Infections, March 5–8, 2012, Seattle, WA.

C.C., L.Z., S.R., M.S.R, M.W.F, and K.Y. are Gilead employees and were the scientific, medical, and operational leaders responsible for this study's design, conduct, oversight, and analyses.

P.R. was the principal investigator with primary management responsibilities in the study and provided critical review of the data and contributed to the editing/writing of the manuscript. E.D.J., D.B., M.M., and U.B. were the investigators with primary management responsibilities in the study and provided critical review of the data and contributed to the editing/writing of the manuscript. C.C. was the virologist and contributed to study design, protocol development, data analysis (analyzed resistance data), and writing/editing of the manuscript. L.J. was the statistician and contributed to study design, protocol development, data analysis (developed statistical analysis plan), and writing/editing of the manuscript. S.R. was the clinical pharmacologist for the study, contributed to study design, protocol development, and data analysis, and was the author for the pharmacokinetic and pharmacokinetics/pharmacodynamics sections of the manuscript. M.R. was the medical monitor for the study, contributed to study design, protocol development, and data analysis, provided critical review of the data, and contributed to the editing/writing of the manuscript. M.F. was the primary author for the manuscript, with principal writing responsibilities. K.Y. was the clinical leader for the study and contributed to study design, protocol development, and data analysis.

Received January 08, 2013

Accepted April 09, 2013

© 2013 by Lippincott Williams & Wilkins