Even during its preclinical development, lopinavir/ritonavir (LPV/r, Kaletra) displayed pharmacokinetic properties that suggested it could be dosed once-daily rather than its currently approved twice-daily schedule. A small pilot study just published in the Journal of Infectious Diseases (The Journal of Infectious Diseases, 2004;189:265-272) further supports the safety of this approach. This larger clinical trial provides confirmatory data on once- versus twice-daily lopinavir/ritonavir using tenofovir (TDF, Viread) and emtricitabine (FTC, Emtriva) as the NRTI backbone.

One hundred ninety antiretroviral-naive patients with HIV RNA greater than 1,000 copies/mL, regardless of CD4 count, were enrolled in multiple sites in the U.S. and abroad. The study randomized them in a 2:3 ratio to receive either standard-dose lopinavir/ritonavir (three capsules twice a day) or a once-daily dose of lopinavir/ritonavir (six capsules once a day), along with the once-daily NRTIs tenofovir (300 mg daily) and emtricitabine (200 mg daily). Baseline characteristics included a median CD4 cell count of around 220 cells/mm³, with nearly half of the patients having counts less than 200 cells/mm³, and an HIV RNA of 4.7 log.

At the end of 48 weeks, 70% of the once-daily arm and 64% of the twice-daily arm had HIV RNA less than 50 copies/mL by intent-to-treat, NC=F analysis, a non-significant difference. In the as-treated analysis, these results were 90% and 85%, respectively. There was also no difference in CD4 response. Although discontinuation rates were similar for both treatment arms, diarrhea occurred significantly more commonly in the once-daily (16%) versus the twice-daily (5%) arm (p=.04). The major change in fasting lipid values was in triglycerides, which increased by 82 mg/dL in the once-daily group and 76% in the twice-daily group; of note, both of these values were lower than the observed increases in Study 863, which used stavudine (d4T, Zerit)/lamivudine (3TC, Epivir) as the NRTI backbone.

This is the largest comparative trial of once-daily lopinavir/ritonavir, and confirms that it is sufficiently active virologically in treatment-naive patients. The increased rate of diarrhea and the pill burden of taking six capsules of the drug simultaneously may dissuade patients and practitioners from adopting once-daily lopinavir/ritonavir, but it is reassuring that this is an option for those who must use the drug once-daily due to work or other scheduling issues. It is hoped that a new formulation of lopinavir/ritonavir -- which is under development -- will reduce both the pill burden and, potentially, the gastrointestinal side effects associated with this drug.

Reference

Abstract: Once-Daily vs. Twice-Daily Lopinavir/Ritonavir in Antiretroviral-Naive Patients: 48-Week Results (Poster 570)
Authored by: J. Gathe, D. Podzamczer, M. Johnson, R. Schwartz, V. Yeh, N. Travers, K. Luff, R. Tressler, S. Brun
Affiliations: Therapeutic Concepts, P.A., Houston, TX; Hosp. de Bellvitge, Barcelona, Spain; Royal Free Hosp., London, UK; Private Practice, Fort Myers, FL; AIDS Healthcare Fndn., Los Angeles, CA; Abbott Labs., Abbott Park, IL
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