Comparison of Once-Daily versus Twice-Daily Combination Antiretroviral Therapy in Treatment-Naive Patients: Results of AIDS Clinical Trials Group (ACTG) A5073, a 48-Week Randomized Controlled Trial

Background. Dosing frequency is an important determinant of regimen effectiveness. Methods. To compare efficacy of once-daily (QD) versus twice-daily (BID) antiretroviral therapy, we randomized human immunodeficiency virus (HIV)-positive, treatment-naive patients to lopinavir-ritonavir (LPV/r) administered at a dosage of 400 mg of lopinavir and 100 mg of ritonavir BID (n = 160) or 800 mg of lopinavir and 200 mg of ritonavir QD (n = 161), plus either emtricitabine 200 mg QD and extended-release stavudine at a dosage of 100 mg QD or tenofovir at a dosage of 300 mg QD. Randomization was stratified by screening HIV RNA level < 100,000 copies/mL versus >= 100,000 copies/mL. The primary efficacy end point was sustained virologic response (SVR; defined as reaching and maintaining an HIV RNA level < 200 copies/mL) through week 48. Results. Subjects were 78% male, 33% Hispanic, and 34% black. A total of 82% of subjects completed the study, and 71% continued to receive the initially assigned dosage schedule. The probability of SVR did not differ significantly for the BID versus QD comparison, with an absolute proportional difference of 0.03 (95% confidence interval [CI], -0.07 to 0.12). The comparison depended on the screening RNA stratum (P = .038); in the higher RNA stratum, the probability of SVR was significantly better in the BID arm than in the QD arm: 0.89 (95% CI, 0.79-0.94) versus 0.76 (95% CI, 0.64-0.84), a difference of 0.13 (95% CI, 0.01-0.25). Lopinavir trough plasma concentrations were higher with BID dosing. Adherence to prescribed doses of LPV/r was 90.6% in the QD arm versus 79.9% in the BID arm (P < .001). Conclusions. Although subjects assigned to QD regimens had better adherence, overall treatment outcomes were similar in the QD and BID arms. Subjects with HIV RNA levels >= 100,000 copies/mL had better SVR with BID regimens at 48 weeks, which suggests a possible advantage in this setting for more frequent dosing.