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Coadministration of Combination Tablet and Tenofovir Elucidates Route of Resistance in Abacavir-Zidovudine-Lamivudine Cocktail: Presented at ICAAC

By Paula Moyer

WASHINGTON, DC -- December 22, 2005 -- When HIV develops resistance to the combination antiretroviral drug Trizivir (zidovudine + lamivudine + abacavir) and tenofovir (Viread), the route of resistance appears to be thymidine analogue mutations (TAMS) instead of K65R mutation, according to investigators speaking here at the 45^th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).

The combination tablet Trizivir contains 300 mg of abacavir (Ziagen), 300 mg of zidovudine (Retrovir), and 150 mg of lamivudine (Epivir).

By taking the combination pill and tenofovir together, the hope is that patients can manage their disease with a total of 3 pills taken at a single dosing once daily, said principal investigator Richard A. Elion, MD, attending physician, George Washington University Hospital, Washington, DC.

To establish the route by which HIV develops resistance to the combination treatment, Dr. Elion and colleagues conducted an open-label, 48-week pilot study that evaluated a daily regimen consisting of Trizivir and tenofovir in patients who had not yet undergone antiretroviral therapy.

The investigators obtained patients' plasma HIV samples at baseline, at the time of virologic failure, and at week 48. Samples were analyzed by population genotype and phenotype. They defined virologic failure as confirmed HIV RNA (RNA) of at least 400 copies/mL at 24 weeks or longer. Resistance mutations were defined by previously established criteria.

Among the 123 subjects, baseline median RNA was 5.1 log₁₀ copies/mL. Through week 48, 11% of patients either met virologic criteria or changed therapy. These subjects had a median RNA of 5.4 log₁₀ at baseline and a median RNA of 4.0 log₁₀ at the time of virologic failure. At baseline, three of these subjects had genotypic mutations, consisting of V118I, K103N, Y188F/H/L/Y, M184V, and T215A/I/S.

At the last study visit while patients with virologic failure were on therapy, 5 subjects had wild-type genotype and the other 9 had the following mutations: thymidine analogue mutations (TAMs) in 3, TAMs + M184V in 3, M184V in 1, and K65R/K in 2.

The investigators obtained the phenotype for all but 1 patient with virologic failure. No patient had resistance to any of the study drugs at baseline. At the last visit while on therapy, 31% of the 13 with phenotype data had phenotypic resistance to study drugs as follows: none were resistant to tenofovir, abacavir resistance in 3, zidovudine resistance in 1, and lamivudine resistance in 4.

The resistance pattern in this study differs significantly from those of other tenofovir-containing triple nucleoside regimens, Elion reported during his presentation on December 17^th.

"These results show that TAMs selection is a preferred resistance route of this combination, with zidovudine modulating the resistance pathway," he said.

"The low incidence of K65R suggests that the counter selection by zidovudine towards TAMs may be lessened when administered once daily, and that use of once daily instead of twice-daily zidovudine should be explored in future trials," he added.

Trizivir is manufactured by GlaxoSmithKline, and Viread is manufactured by Gilead.


[Presentation title: Selection of HIV Reverse Transcriptase (RT) Thymidine Analogue Mutations (TAMS) Rather Than K65R is the Preferred Route of Resistance Seen in Patients With Virologic Failure (VF) on Once-Daily (QD) Trizivir (TZV) and Tenofovir (TDF). Abstract H-1068]

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