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Background:  The presence of mutations to nucleoside reverse transcriptase inhibitors (NRTI) or non-nucleoside reverse transcriptase inhibitors (NNRTI) among newly infected, antiretroviral (ART) naïve HIV-1⁺ patients may compromise viral response to regimens containing these agents.

Methods:  Study FTC-301A compared 200 mg of emtricitabine (FTC) once daily with stavudine (d4T) twice daily in combination with once daily didanosine (ddI) and efavirenz (EFV) in 571 ART-naïve patients from North America, Latin America, and Europe. Virologic failure was defined as never achieving a viral load <400 copies/mL by week 12 or rebound to >400copies/mL, confirmed. Genotypic analysis was performed on baseline HIV-1 RNA for all available samples; 546/571 (95.6%), 276 d4T, and 270 FTC. Baseline mutations were evaluated as predictors of virologic failure using logistic regression. Virologic failure rates were compared between subgroups using a 2-sided exact test. 

Results:  Overall, 16% (90/546) of patients entered the study with mutations at positions associated with resistance to NNRTI (A98/K101/K103/V106/V108/Y181C/P225H) or NRTI (M41/D67/K70/V75/L210/T215/K219).  There were no differences in the prevalence or type of mutations between arms. For subjects with wild type genotype at baseline, there was a significant difference in the incidence of virologic failure in the d4T arm (12%) compared to the FTC arm (5%); p = 0.012. Likewise, for patients with mutant genotype at baseline there was a higher incidence of virologic failure in the d4T arm (32%) compared with the FTC arm (13%); p = 0.039. NNRTI-associated mutations occurred in 10% (56/546) of patients and NRTI-associated mutations occurred in 8% (42/546) of patients at baseline. The presence of NNRTI-associated mutations at baseline was predictive of virologic failure in both the d4T and the FTC arms (p = 0.009 d4T, p = 0.016 FTC). The K103N was the only individual NNRTI mutation predictive of virologic failure in both arms (p = 0.001 d4T, p = 0.002 FTC). The K103N mutation was observed in 3% (14/546) of patients at baseline and occurred more frequently in samples from patients in North America than Europe or Latin America; p = 0.013. By contrast, the presence of NRTI-associated mutations was predictive of failure in the d4T arm (p = 0.026) but not in the FTC arm (p = 0.218).

Conclusions:  In this study, FTC demonstrated superior efficacy to d4T regardless of baseline genotype. The prevalence of baseline mutations, in particular NNRTI mutations, and the subsequent impact on virologic response in these ART-naïve patients demonstrates the importance of obtaining genotypic information prior to initiating anti-retroviral therapy.

Keywords: emtricitabine; stavudine; resistance