HTB

Important safety information: high rate of virologic failure in patients with HIV infection treated with a once-daily triple NRTI combination containing ddI, 3TC, and tenofovir DF

This is new information as compared to the message sent to you in July 2003 by GlaxoSmithKline, regarding a different triple nucleosides/nucleotide reverse transcriptase inhibitors combination containing Abacavir, Lamivudine and Tenofovir DF

20 October 2003

Dear Health Care Professional,

In agreement with the European Medicines Evaluation Agency’s scientific committee, the Committee for Proprietary Medicinal Products (CPMP) and the Irish Medicines Board (IMB), Gilead Sciences International Limited (Gilead) is writing to inform you of a high rate of early virologic failure and emergence of nucleoside/nucleotide reverse transcriptase inhibitor resistance associated mutations observed in a clinical study of HIV-infected treatment-naïve patients receiving a once-daily triple combination containing didanosine enteric coated beadlets (Videx“ EC, Bristol-Myers Squibb), lamivudine (Epivir“, GlaxoSmithKline), and tenofovir disoproxil fumarate (tenofovir DF, Viread“, Gilead). Based on these results:

Tenofovir DF in combination with didanosine and lamivudine should not be used when considering a new treatment regimen for therapy-naïve or treatment-experienced patients with HIV-infection, and particularly as a once a day regimen.

Any patient currently controlled on this triple combination should be closely monitored for signs of treatment failure and considered for treatment modification at the first sign of viral load increase.

In a 24-week, single-site, pilot study [(N=24) 20 males; 4 females; median age (39 years), range (28 – 57 years)] 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. Of 19 patients who had phenotyping results available, all samples showed susceptibility to TDF (<1.4X WT), while 5/10 patients with K65R showed reduced susceptibility to ddI (>1.7X WT). As a result of this high early failure rate, the study was stopped.

The precise nature of any interaction leading to non-response in this study is not known.

Similar recommendations have been made and were communicated by GlaxoSmithKline in July 2003 regarding a different triple combination containing abacavir/lamivudine/tenofovir DF as an investigational once-daily regimen, in antiretroviral-naïve HIV-1 infected adults (Farthing et al., 2003; Gallant JE et al., 2003).

Gilead is committed to providing you with current product information for the management of your patients with HIV infection. You can assist us in monitoring the safety of our products by reporting adverse reactions, which should be advised to the IMB or Gilead at the address overleaf or by phone on + 44 1223 897 500, fax + 44 1223 897 290 or email at csafety@gilead.com.For further information or a complete copy of the current Summary of Product Characteristics (SPC) for Viread, please contact me at the address overleaf.

For further information or a complete copy of the current Summary of Product Characteristics (SPC) for Viread, please contact me at the address overleaf.

Yours sincerely
Geoff Cotton
Medical Director

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.

Source: Gilead Sciences

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