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12th International HIV Drug Resistance Workshop10–14 June 2003, Cabo del Sol, Los Cabos, Mexico |
BACKGROUND: While highly active antiretroviral therapy has significantly impacted the treatment of HIV infection, complexity of administration and toxicity issues can lead to suboptimal adherence and the development of resistance mutations. Emtricitabine (FTC) is a new once-daily nucleoside analogue reverse transcriptase inhibitor (NRTI) with potent activity against HIV. In study FTC-301 we evaluated the safety and antiviral activity of a simple, non-thymidine, once-daily regimen as first-line treatment for therapynaïve HIV-infected patients.
METHODS: 571 antiretroviral-naïve patients with plasma HIV-1 RNA (VL) >5000 copies/ml were randomized in a 1:1 ratio to receive 200 mg FTC once daily or stavudine (d4T) twice daily in combination with once-daily didanosine (ddI) and once-daily efavirenz (EFV). VL was measured at baseline and every 4 weeks to week 48. Virological failure (VF) was defined as never achieving <400 copies/ml or rebound >400 copies/ml on two consecutive measurements. The incidence of VF was compared between treatment arms using a two-sided exact test. Patients who experienced VF had sequence analysis performed on the HIV RNA isolated from plasma at baseline and at the time of VF.
RESULTS: Virological failure occurred in 6% (17) of patients in the FTC arm and 15% (41) of patients in the d4T arm (P=0.0014). Genotypic data were obtained for 57/58 VF (16/17 FTC, 41/41 d4T) at baseline and at time of VF. In these 57 patients experiencing VF, the incidence of mutations was 69% in the FTC arm and 85% in the d4T arm. Development of non-nucleoside reverse transcriptase inhibitors (NNRTI) mutations accounted for the majority of mutations in both subgroups of VF, 63% FTC and 85% d4T. Development of the M184V mutation occurred only in FTC failures, 31%, while development of thymidine analogue-associated mutations (TAMs) occurred only in d4T failures, 15%. One VF in the FTC arm (6%) and three VF in the d4T arm (7%) developed ddI-associated mutations. In these antiretroviral-naïve patients who failed therapy, the prevalence of mutations at baseline was relatively high; 38% FTC and 32% d4T. NNRTI-associated mutations (31% FTC, 22% d4T) and TAMS (19% FTC and 15% d4T) were the most prevalent baseline mutations in each group. No FTC (M184I/V) or ddI (L74V/K65R) mutations were present in either cohort at baseline. The incidence of VF remained statistically higher in the d4T arm after censoring patients with baseline TAMs (d4T arm), P=0.0132, or baseline K103N (FTC arm) and K103N/TAMS (d4T arm), P=0.0182.
CONCLUSIONS: These results demonstrate that a regimen containing once daily FTC was statistically superior to twice-daily d4T, in a background of oncedaily ddI plus EFV, with a significantly lower rate of VF with fewer mutations, even after adjusting for the prevalence of baseline mutations.
PRESENTING AUTHOR: K Borroto-Esoda
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2003-07-08
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