Tenofovir Disoproxil Fumarate in Nucleoside-Resistant HIV-1 Infection

Tenofovir Disoproxil Fumarate in Nucleoside-Resistant HIV-1 Infection

A Randomized Trial

Kathleen Squires, MD;
Anton L. Pozniak, MD;
Gerald Pierone, Jr., MD;
Corklin R. Steinhart, MD, PhD;
Daniel Berger, MD;
Nicholaos C. Bellos, MD;
Stephen L. Becker, MD;
Michael Wulfsohn, MD, PhD;
Michael D. Miller, PhD;
John J. Toole, MD, PhD;
Dion F. Coakley, PharmD;
Andrew Cheng, MD, PhD; and
for the Study 907 Team*

From Keck School of Medicine, University of Southern California, Los Angeles, California; Chelsea and Westminster Hospital, London, United Kingdom; Treasure Coast Infectious Disease, Vero Beach, and Florida/Caribbean AIDS Education Training Center, Miami, Florida; Northstar Medical Center, Chicago, Illinois; Southwest Infectious Disease, Dallas, Texas; and Pacific Horizon Medical Group, San Francisco, and Gilead Sciences, Foster City, California.

Abstract

Background: Resistance to antiretroviral agents remains a leading cause of treatment failure for patients infected with HIV-1.

Objective: To describe the efficacy and safety of tenofovir disoproxil fumarate (tenofovir DF) compared with placebo in patients with detectable viral replication despite current antiretroviral therapy.

Design: Randomized, double-blind, placebo-controlled study through 24 weeks. After 24 weeks, all patients received open-label tenofovir DF for the remainder of the 48-week study.

Setting: 75 North American, European, and Australian HIV clinics.

Patients: 552 HIV-1–infected adults who were receiving antiretroviral therapy and had stable HIV-1 RNA levels ranging from 400 to 10 000 copies/mL.

Measurements: Change in HIV-1 RNA level (time-weighted average from baseline through week 24); proportion of patients with grade 3 or 4 laboratory abnormalities and adverse events; and genotypic HIV-1 resistance testing in a separate substudy at baseline, week 24, and week 48.

Results: A statistically significant decrease in HIV-1 RNA level through week 24 (the primary end point) was observed in the tenofovir DF group versus the placebo group (−0.61 log₁₀ copies/mL vs. −0.03 log₁₀ copies/mL, respectively [P < 0.001]; difference, −0.58 log₁₀ copies/mL [95% CI, −0.68 to −0.49 log₁₀ copies/mL]). In a virologic substudy, 94% of 253 patients had plasma isolates expressing reverse transcriptase mutations associated with nucleoside resistance mutations at baseline. Through week 24, the incidence of clinical adverse events was similar between patients receiving placebo and those receiving tenofovir DF (14% vs. 13%). No evidence of tenofovir DF–related toxicity was seen through week 48.

Conclusion: In treatment-experienced patients with suboptimal viral suppression, tenofovir DF significantly reduced HIV-1 RNA level and had a safety profile similar to that of placebo.

*For members of the Study 907 Team, see the Appendix.

Article and Author Information

Presented in part at the 6th International Congress on AIDS in Asia and the Pacific, Melbourne, Australia, 5–10 October 2001; the 8th European Conference on Clinical Aspects and Treatment of HIV Infection, European AIDS Clinical Society, Athens, Greece, 28–31 October 2001; the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Chicago, Illinois, 16–19 December 2001; the 9th Conference on Retroviruses and Opportunistic Infections, Foundation for Retrovirology and Human Health, Seattle, Washington, 24–28 February 2002; and the 14th International AIDS Conference, International AIDS Society, Barcelona, Spain, 7–12 July 2002.
Acknowledgments: The authors gratefully acknowledge the contributions of all the study site personnel and patients who participated in this study.
Grant Support: By Gilead Sciences, Foster City, California.
Potential Financial Conflicts of Interest:Employment: M. Wulfsohn (Gilead Sciences), M.D. Miller (Gilead Sciences), J.J. Toole (Gilead Sciences), D.F. Coakley (Gilead Sciences), A. Cheng (Gilead Sciences); Consultancies: K. Squires (Gilead Sciences), G. Pierone, D. Berger (Gilead Sciences), S.L. Becker; Honoraria: K. Squires (Gilead Sciences), G. Pierone, D. Berger (Gilead Sciences), S.L. Becker; Stock ownership: D. Berger (Gilead Sciences), M. Wulfsohn (Gilead Sciences), M.D. Miller (Gilead Sciences), J.J. Toole, D.F. Coakley (Gilead Sciences), A. Cheng (Gilead Sciences); Grants received: K. Squires, G. Pierone, S.L. Becker; Grants pending: K. Squires; Other: A.L. Pozniak.
Requests for Single Reprints: Andrew Cheng, MD, PhD, 333 Lakeside Drive, Foster City, CA 94404.
Current Author Addresses: Dr. Squires: LAC + USC Medical Center, 1300 North Mission Road, Room 352, Los Angeles, CA 90033.
Dr. Pozniak: St. Stephen's Centre, Chelsea and Westminster Hospital, 369 Fulham Road, London SW109TH, United Kingdom.
Dr. Pierone: 3755 7th Terrace, Suite 302A, Vero Beach, FL 32960.
Dr. Steinhart: Mercy Professional Building, 3661 South Miami Avenue, Suite 806, Miami, FL 33133-4231.
Dr. Berger: 2835 North Sheffield Avenue, Suite 104, Chicago, IL 60657.
Dr. Bellos: 3801 Gaston Avenue, Suite 300, Dallas, TX 75246.
Dr. Becker: 2351 Clay Street, Suite 512, San Francisco, CA 94115.
Drs. Wulfsohn, Miller, Toole, Coakley, and Cheng: 333 Lakeside Drive, Foster City, CA 94404.
Author Contributions: Conception and design: M. Wulfsohn, M.D. Miller.
Analysis and interpretation of the data: K. Squires, M. Wulfsohn, M.D. Miller, J.J. Toole, D.F. Coakley, A. Cheng.
Drafting of the article: K. Squires, A.L. Pozniak, G. Pierone, M.D. Miller, D.F. Coakley, A. Cheng.
Critical revision of the article for important intellectual content: K. Squires, A.L. Pozniak, G. Pierone, C.R. Steinhart, D. Berger, N.C. Bellos, S.L. Becker, M. Wulfsohn, M.D. Miller, J.J. Toole, D.F. Coakley, A. Cheng.
Final approval of the article: K. Squires, A.L. Pozniak, G. Pierone, C.R. Steinhart, D. Berger, N.C. Bellos, S.L. Becker, M. Wulfsohn, M.D. Miller, J.J. Toole, D.F. Coakley, A. Cheng.
Provision of study materials or patients: K. Squires, A.L. Pozniak, G. Pierone, C.R. Steinhart, D. Berger, N.C. Bellos, S.L. Becker.
Statistical expertise: M. Wulfsohn.
Collection and assembly of data: G. Pierone, J.J. Toole.