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Antimicrobial Agents and Chemotherapy, July 2006, p. 2471-2477, Vol. 50, No. 7
0066-4804/06/$08.00+0     doi:10.1128/AAC.00138-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Intracellular Metabolism and In Vitro Activity of Tenofovir against Hepatitis B Virus

William E. Delaney IV,* Adrian S. Ray, Huiling Yang, Xiaoping Qi, Shelly Xiong,{dagger} Yuao Zhu, and Michael D. Miller

Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, California 94404

Received 2 February 2006/ Returned for modification 15 March 2006/ Accepted 25 April 2006

Tenofovir is an acyclic nucleotide analog with activity against human immunodeficiency virus (HIV) and hepatitis B virus (HBV). Tenofovir disoproxil fumarate (tenofovir DF), a bis-alkoxyester prodrug of tenofovir, is approved for the treatment of HIV and is currently being developed to treat chronic hepatitis B. In this report, we further characterize the in vitro activity of tenofovir against HBV as well as its metabolism in hepatic cells. We show that tenofovir is efficiently phosphorylated to tenofovir diphosphate (TFV-DP) in both HepG2 cells and primary human hepatocytes. TFV-DP has a long intracellular half-life (95 h) and is a potent and competitive inhibitor of HBV polymerase (Ki = 0.18 µM). Tenofovir has a 50% effective concentration of 1.1 µM against HBV in cell-based assays, and potency is improved >50-fold by the addition of bis-isoproxil progroups. Tenofovir has previously demonstrated full activity against lamivudine-resistant HBV in vitro and clinically. Here we show that the major adefovir resistance mutation, rtN236T, confers three- to fourfold-reduced susceptibility to tenofovir in cell culture; the clinical significance of this susceptibility shift has not yet been determined. The rtA194T HBV polymerase mutation recently identified in tenofovir DF-treated HIV/HBV-coinfected patients did not confer in vitro resistance to tenofovir as a single mutation or in a lamivudine-resistant viral background. Overall, the antiviral and metabolic profile of tenofovir supports its development for the treatment of chronic hepatitis B.

* Corresponding author. Mailing address: Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA 94404. Phone: (650) 522-5598. Fax: (650) 522-5890. E-mail: william.delaney{at}gilead.com.

{dagger} Present address: Covance Inc., Rm. 503, 457 Wu Lu Mu Qi (N) Rd., Shanghai, China.

Antimicrobial Agents and Chemotherapy, July 2006, p. 2471-2477, Vol. 50, No. 7
0066-4804/06/$08.00+0     doi:10.1128/AAC.00138-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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