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

Abstract

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 > or = 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 > or =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. Clinical trial registration. ClinicalTrials.gov registration number: NCT00036452.

Figure 1

Subject randomization and disposition. Shown are numbers of subjects randomized, completing therapy, and included in the final analysis. LPV/r QD = lopinavir/ritonavir 800 mg/200mg once daily; LFU = lost to follow-up.

Figure 2

Time to virologic failure overall (A) and by screening plasma HIV-1 RNA level (B). Subjects whose final visit occurred after 48 weeks were included in the proportional hazards model analyses and are shown in the figure based on the actual time of last visit. The decline in the probability of not failing after 48 weeks is due to an event occurring after sharp decrease in the number of subjects at risk in this 48 week study. Only 10 subjects completed their final follow-up visit after 50 week and most subjects came in for their final visit by that time.

Figure 2

Time to virologic failure overall (A) and by screening plasma HIV-1 RNA level (B). Subjects whose final visit occurred after 48 weeks were included in the proportional hazards model analyses and are shown in the figure based on the actual time of last visit. The decline in the probability of not failing after 48 weeks is due to an event occurring after sharp decrease in the number of subjects at risk in this 48 week study. Only 10 subjects completed their final follow-up visit after 50 week and most subjects came in for their final visit by that time.

Figure 3

LPV trough concentrations as a function of regimen assignment. Shown are median and range (box 25^th-75^th percentiles and whiskers 5^th-95^th percentiles) for lopinavir trough (C_12hours) concentrations, expressed in micrograms/mL, obtained from study subjects at weeks 16 and 48 of treatment.