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 > 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.
Flexner
Charles
C
Johns Hopkins University, Baltimore, Maryland, USA. flex@jhmi.edu
Tierney
Camlin
C
Gross
Robert
R
Andrade
Adriana
A
Lalama
Christina
C
Eshleman
Susan H
SH
Aberg
Judith
J
Sanne
Ian
I
Parsons
Teresa
T
Kashuba
Angela
A
Rosenkranz
Susan L
SL
Kmack
Anne
A
Ferguson
Elaine
E
Dehlinger
Marjorie
M
Mildvan
Donna
D
D044966:Anti-Retroviral Agents / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006678:HIV / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D061466:Lopinavir; D008297:Male; D016016:Proportional Hazards Models; D011744:Pyrimidinones / Q000008:administration & dosage*; D012367:RNA, Viral / Q000032:analysis; D019438:Ritonavir / Q000008:administration & dosage*; D016896:Treatment Outcome; D019562:Viral Load
D044966:Anti-Retroviral Agents; D011744:Pyrimidinones; D012367:RNA, Viral; D061466:Lopinavir; D019438:Ritonavir