Efficacy and safety of emtricitabine vs stavudine in combination therapy in anti retroviral-naive patients - A randomized trial

Context Emtricitabine is anew, 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 anti retroviral-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 (less than or equal to400 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 less than or equal to50 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/muL vs 119 cells/muL, 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 less than or equal to50 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.