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Important Drug Warning: Once-Daily Triple NRTI Regimen containing Didanosine, Lamivudine, and Tenofovir

10/14/2003

Gilead Sciences today issued a "Dear Health Care Professional" letter (below) describing high rates of vriologic failure in patients treated with a once-daily triple NRTI regimen containing Didanosine (ddI, Videx EC), Lamivudine (3TC, Epivir), and Tenofovir (Viread).

 

October 14, 2003

IMPORTANT DRUG WARNING

RE: High Rate of Virologic Failure in Patients with HIV Infection Treated With a Once-
Daily Triple NRTI Regimen containing Didanosine, Lamivudine, and Tenofovir

Dear Health Care Professional,

Gilead Sciences, Inc (Gilead) is writing to inform you of a high rate of early virologic failure and
emergence of nucleoside reverse transcriptase inhibitor (NRTI) resistance associated mutations
observed in a clinical study of HIV-infected treatment-naïve patients receiving a once-daily triple
NRTI regimen containing didanosine enteric coated beadlets (Videx EC, Bristol-Myers
Squibb), lamivudine (Epivir, GlaxoSmithKline), and tenofovir disoproxil fumarate (Viread,
Gilead).

These new data are consistent with the high rates of virologic failure observed in several recent
clinical studies that have evaluated the use of triple NRTI regimens. Based on these results:

· Tenofovir DF in combination with didanosine and lamivudine is not recommended when
considering a new treatment regimen for therapy-naïve or experienced patients with HIVinfection.
Patients currently on this regimen should be considered for treatment
modification.

In a 24-week, single-site, pilot study (N=24) designed to evaluate the safety and efficacy of a
triple NRTI once-daily regimen of didanosine EC (250 mg), lamivudine (300 mg) and tenofovir
DF (300 mg) in HIV-infected treatment-naïve patients, Jemsek et al. (Oral Communication,
September 2003) have identified a high frequency of virologic failure (91%), which was defined
as < 2 log10 reduction in plasma HIV RNA level by Week 12. Resistance testing was performed
on 21 patients; 20 patients (95%) had M184I/V and 10 of these patients (50%) had K65R in
addition to M184V. As a result of this high early failure rate, study enrollment was stopped.

Sub-optimal virologic response has also been reported with the use of the triple NRTI regimen
abacavir/lamivudine/zidovudine (Trizivir) (Gulick 2003) and abacavir/didanosine/stavudine
(Gerstoft 2003), and similarly early virologic failure and high rates of resistance mutations have
been reported with abacavir/lamivudine/tenofovir DF (Farthing 2003, Gallant 2003). Overall,
these studies demonstrate a lower response rate in patients on a triple NRTI regimen.
Furthermore, they indicate that patients who achieve viral suppression on a triple NRTI regimen
have a higher rate of virologic failure.
Reporting of Adverse Events

Please report all adverse events, following or coincident with the use of Viread, to Gilead Global
Drug Safety at 1-800-GILEAD-5, option 3, or to the FDA MedWatch Program by phone (1-800-
FDA-1088), by fax (1-800-FDA-0178), by mail (using postage-paid form to MedWatch, FDA,
5600 Fishers Lane, Rockville, MD 20852-9787) or via the internet (www.accessdata.fda.gov/scripts/medwatch/).

We hope this information will be helpful to you in caring for your patients. Please consult the
enclosed Prescribing Information for complete product information. If you have any additional
questions, please contact Gilead Medical Information toll free at 1-800-GILEAD-5, option 2.

Sincerely,

Jay Toole, MD, Ph.D.
Senior Vice President
Clinical Research

References: Farthing C, Khanlou H, Yeh V, et al. Early virologic failure in a pilot study evaluating the
efficacy of once daily abacavir (ABC), lamivudine (3TC), and tenofovir DF (TDF) in treatment naïve
HIV-infected patients (oral presentation). Presented at the 2nd International AIDS Society Meeting, Paris,
France, July 13-16, 2003. Gallant JE, Rodriguez A, Weinberg W, et al. Early non-response to tenofovir
DF (TDF) + abacavir (ABC) and lamivudine (3TC) in a randomized trial compared to efavirenz (EFV) +
ABC and 3TC: ESS30009 unplanned interim analysis (oral presentation # H-1722a). Presented at the 43rd
Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, September 14-17,
2003. Gerstoft J, Kirk O, Obel N, et al. Low efficacy and high frequency of adverse events in a
randomized trial of the triple nucleoside regimen abacavir, stavudine and didanosine. AIDS 2003,
17:2045-2052. Gulick RM, Ribaudo HJ, Shikuma CM, et al. ACTG 5095: a comparative study of 3
protease inhibitor-sparing antiretroviral regimens for the initial treatment of HIV infection. 2nd IAS
Conference on HIV Pathogenesis and Treatment. July 13-16, 2003. Paris. Abstract 41.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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