November 16, 2006
We are beginning to see a rash of clinical trials comparing the effectiveness of different boosted protease inhibitors (PIs) as initial therapy. The majority of these studies are comparing alternative boosted PIs with lopinavir/ritonavir (LPV/r, Kaletra), the most widely recommended boosted PI in both U.S. and other treatment guidelines at the time these studies were initiated. The first of these studies, recently published in the Lancet, was the KLEAN (Kaletra BID vs Lexiva BID, both with Epivir and Abacavir QD, in ART-Naive Patients) study, which compared the efficacy of boosted fosamprenavir (FPV, 908, Lexiva, Telzir) with lopinavir/ritonavir.1 No differences were observed between the two approaches with regard to a wide range of efficacy and tolerability endpoints, including changes in lipids. In other ongoing studies, lopinavir/ritonavir twice daily is being compared with boosted saquinavir (SQV, Invirase) twice daily, several different TMC114 (darunavir, Prezista) dosing approaches, and boosted atazanavir (ATV, Reyataz) once daily. Additional ongoing studies are comparing once-daily fosamprenavir and once-daily saquinavir with boosted atazanavir.
Preliminary data from a planned interim analysis of a study known as GEMINI were reported during the Glasgow conference.2 This randomized, open-label, multi-center study used a once-daily backbone of tenofovir/emtricitabine (TDF/FTC, Truvada) combined with either twice-daily saquinavir + ritonavir or lopinavir/ritonavir. The formulation of lopinavir/ritonavir used in the study was the old gel capsule formulation. The study included 337 treatment-naive individuals with a CD4+ cell count at or below 350 cells/mm3 and a viral load above 10,000 copies/mL. The primary endpoint is the proportion of patients with an undetectable viral load (below 50 copies/mL) at week 48. The planned interim analysis evaluated preliminary outcomes among the first 150 patients completing 24 weeks of therapy.
Patients entering the study were well matched across all baseline characteristics, including a mean HIV RNA of 5.1 to 5.2 log10 copies/mL and a mean CD4+ cell count of 121 to 134 cells/mm3.
At week 24, the proportion of patients with a viral load below 400 copies/mL by intent-to-treat analysis was 83.6% in the lopinavir/ritonavir arm and 80.6% in the saquinavir + ritonavir arm (P = .637). The proportion of patients with a viral load below 50 copies/mL were 75.3% and 69.4% for the lopinavir/ritonavir and saquinavir + ritonavir groups, respectively (P = .427). Similarly, no significant differences were observed between the two groups by observed analysis.
|Viral Load Outcome at Week 24||LPV/r (%)||SQV + RTV (%)||P Value|
|< 400 copies/mL||83.6||80.6||.637|
|< 50 copies/mL||75.3||69.4||.427|
|< 400 copies/mL||95.3||92.1||.328|
|< 50 copies/mL||85.9||79.4||.492|
CD4+ cell counts rose by 157 cells/mm3 and 140 cells/mm3 in the lopinavir/ritonavir and saquinavir + ritonavir groups, respectively. Two individuals in the lopinavir/ritonavir arm and five individuals in the saquinavir + ritonavir arm met the criteria for virologic failure, defined as two consecutive HIV RNA measurements above 400 copies/mL at week 16 or thereafter. Interestingly, no treatment-emergent PI mutations were observed in any of these individuals.
Safety-related discontinuations were reported in four of 76 lopinavir/ritonavir patients and three of 74 saquinavir + ritonavir patients. Few differences in grade 2-4 adverse events were observed, although nausea was somewhat more common with lopinavir/ritonavir (10 of 73 patients) relative to saquinavir + ritonavir (six of 73 patients), as was diarrhea (seven of 73 patients on lopinavir/ritonavir versus two of 73 patients on saquinavir + ritonavir).
With regard to lipids, similar changes were observed in the lopinavir/ritonavir and saquinavir + ritonavir groups on all cholesterol parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. However, significant differences in triglycerides were observed, with an increase of 88 mg/dL with lopinavir/ritonavir relative to an increase of 29 mg/dL with saquinavir + ritonavir (P = .02).
These preliminary data reported from the GEMINI Study are of considerable interest, but the sample sizes are not sufficiently large, nor is the follow-up sufficiently long, to fully clarify whether these two boosted-PI approaches have similar efficacy. It will be particularly important to see whether the similarities and differences in lipid parameters are sustained over time.
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