CONTEXT: Emtricitabine is a new, once-daily nucleoside reverse transcriptase inhibitor (NRTI) with potent activity against human immunodeficiency virus (HIV). OBJECTIVE: To assess the efficacy and safety of emtricitabine as compared with stavudine when used with a background regimen of didanosine and efavirenz. DESIGN, SETTING, AND PATIENTS: Randomized, double-blind, double-dummy study conducted at 101 research clinics in North America, Latin America, and Europe. The first patient was enrolled on August 21, 2000; no investigator or patient was unblinded until the last patient randomized completed the week 48 visit on October 24, 2002. Analyses were based on data collected in a double-blind setting with a median follow-up of 60 weeks. Patients were 571 antiretroviral-naive, HIV-1-infected adults aged 18 years or older with viral load levels greater than or equal to 5000 copies/mL. INTERVENTIONS: Receipt of either 200 mg of emtricitabine once daily (plus stavudine placebo twice daily) (n = 286) or stavudine at standard doses twice daily (plus emtricitabine placebo once daily) (n = 285) plus open-label didanosine and efavirenz, once daily. MAIN OUTCOME MEASURE: Persistent virological response, defined as achieving and maintaining viral load at or below the limit of assay quantification (< or =400 or 50 copies/mL). RESULTS: At the interim analysis on June 14, 2002, when the last patient randomized completed 24 weeks of double-blind treatment (median follow-up time of 42 weeks), patients in the emtricitabine group had a higher probability of a persistent virological response < or =50 copies/mL vs the stavudine group (85% vs 76%, P =.005). This was associated with a higher mean CD4 cell count change from baseline for the emtricitabine group (156 cells/ microL vs 119 cells/microL, P =.01 [of note, there was no statistical difference at 48 weeks [P =.15], although a sensitivity analysis, using an intent-to-treat population with the last CD4 cell count observation carried forward to week 48 showed a difference [P =.02]]). The independent data and safety monitoring board recommended offering open-label emtricitabine based on the interim analysis. The probability of persistent virological response < or =50 copies/mL through week 60 was 76% for the emtricitabine group vs 54% for the stavudine group (P<.001). The probability of virological failure through week 60 was 4% in the emtricitabine group and 12% in the stavudine group (P<.001). Patients in the stavudine group had a greater probability of an adverse event that led to study drug discontinuation through week 60 than did those in the emtricitabine group (15% vs 7%, P =.005). CONCLUSION: Once-daily emtricitabine appeared to demonstrate greater virological efficacy, durability of response, and tolerability compared with twice-daily stavudine when used with once-daily didanosine and efavirenz.