Background: Emtricitabine (FTC) is a new Once-Daily (QD) NRTI in development with potent activity against HBV and HIV. Stavudine (d4T) is a thymidine analog frequently used for the treatment of HIV infection. Thymidine analog mutations (TAMs) have been associated with virologic failure (VF) of HAART regimens. 

Methods: Antiretroviral naïve patients with screening plasma HIV-1 RNA (VL) > 5,000 c/mL were randomized in a 1:1 ratio to receive 200 mg FTC QD or d4T BID in combination with QD didanosine (ddI), QD efavirenz (EFV) and double-dummy placebo. VL was measured at Baseline (BL), and every 4 wks to W48. VF was defined as never achieving < 400 cp/mL or rebound >400 cp/mL on two consecutive visits after reaching < 400 cp/mL. To determine if antiviral drug resistance was associated with failure, patients who experienced VF had DNA sequence analysis performed on the HIV polymerase gene isolated from plasma at the time of VF. The incidence of VF through W48, the frequency of genotypic mutations at time of failure and the CD4⁺ change from BL was compared between treatment arms using a 95% CI.

Results: A total of 571 (285 d4T, 286 FTC) patients were enrolled. The median BL VL was 4.9 log₁₀ and the mean BL CD4⁺ was 318 cells/mm³. The majority of patients (pts) were male (85%) and Caucasian (52%). BL characteristics were comparable between the 2 arms. The proportion of patients having VF through W48 was 5.3% in the FTC arm and 12.7% in the d4T arm (p < 0.05). The mean increase from BL to W48 in CD4⁺ was significantly greater in the FTC arm (153 cells/mm³) than the d4T arm (120 cells/mm³) (p < 0.05). Genotypic analysis was performed on 46 of the 49 confirmed VFs. Of the 33 genotypic evaluable pts failing d4T, 32 (97%) had mutations in the HIV polymerase gene as compared to 69% (9/13) from the FTC genotypic evaluable subgroup (p < 0.05). The M184V mutation was observed only in the FTC subset, 46% (6/13) while TAMs were observed in 8% (1/13) of FTC subset and 21% (7/33) of the d4T subset. Interestingly both the ddI associated mutations and the NNRTI mutations were less prevalent in the FTC subset, 0% and 69% (9/13) as compared to the d4T subset, 12% (4/33) and 88% (29/33) although these differences did not reach statistical significance.

Conclusions: These results demonstrate that once daily FTC was statistically superior to twice daily d4T and had a significantly lower rate of VF with fewer mutations when used within a background of once daily ddI plus EFV.