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MaxCmin2 Study: Kaletra vs saquinavir/ritonavir; final 48-week results
Reported by Jules Levin
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At the IAS Conference, final 48-week study viral response results were reported. This report includes excerpts from the poster.
Brief summary: Patients assigned in this study to Kaletra (LPV/r) or saquinavir/ritonavir (1000/100 mg twice daily) had similar baseline characteristics. About 27% of patients in the study were treatment-naive. The rest of the patients were treatment-experienced. About 32% of the patients were PI-failures. About 29% were PI-naive. After 48 weeks on the assigned treatment patients on Kaletra had 60% <50 copies/ml vs 53% for the patients taking saquinavir/r. The risk of protocol-defined virologic failure was higher in the SAQ/r arm compared to the LPV/r arm in the ITT/e (p=0.0009) analyses, but not in the on-treatment-analysis. The rates of failure appear to be driven by higher rates for switching regimens due to non-fatal adverse events in the saquinavir/r arm (13/167, 7.8% vs 20/172, 11.6%), and by patient choice/non-compliance (5/167, 3.0% vs 14/172, 8%). An analysis of changes in lipids (cholesterol, triglycerides) was not presented. Roche is reformulating saquinavir into 500mg tablets rather than the currently used 200mg capsules. It is my understanding that Invirase will be used rather than the Fortovase formulation. The Fortovase formulation has been associated with more GI side effects than the Invirase formulation. The results of a pilot bioequivalence study comparing the examining the new 500mg capsule was reported at the IAS Conference. Positive results were found in this pilot study, and Roche is proceeding with a pivotol bioequivalence study for FDA approval.
The MaxCmin1 trial found equivalent efficacy of indinavir/ritonavir (IDV/r) 800/100 mg bid and saquinavir/ritonavir (SAQ/r) 1000/100 mg bid but more discontinuations due to toxicity in the IDV/r arm. The Maxcmin2 study reports the final week 48 analysis of a phase IV, randomized, open-label, multicenter trial to evaluate safety and efficacy of lopinavir/ritonavir (400/100 mg bid) versus saquinavir/ritonavir (1000/100 mg bid) in adults with HIV. Mike Youle, MD, Royal Free Hospital (London, UK) reported the study results for the study team.
The primary population for the analysis was the intention-to-treat/exposed (ITT/e) including all randomized patients that had taken at least one dose of the assigned treatment. ITT/e/discontinuation=failure analysis were also performed as were analysis including only patients that remained on the assigned treatment (on-treatment, OT, analysis).
This is an equivalence trial with 80% chance that the 95% CI for the difference in failure rates will exclude a difference greater than 15% in either direction if sample size of 150 per group and underlying failure rates are 20% in both groups at week 48. Definition of viral failure: viral load at baseline <200 copies/ml: HIV-RNA >200 copies/ml; if viral at baseline is >200 copies/ml: any rise in HIV-RNA ³0.5 log and/orÑat week 4: ²0.5 log reduction; at week 12: ²1.0 log reduction; at week 24: HIV-RNA ³200 c/ml. All cases of suspected viral failure were confirmed by a new viral load determination.
Baseline characteristics. 34/163 and 31/161 in the LPV/r and SAQ/r arms, respectively, were ART naive at start of the study. 48/163 and 48/161 of patients in LPV/r and SAQ/r arms, respectively, were PI-naive. 33% and 31% were PI-failure (³400 copies/ml) in the LPV/r and SAQ/r arms, respectively. 19% and 21% in the LPV/r and SAQ/r arms, respectively, were PI-intolerant (<400 copies/ml). 31-32% of patients were CDC cat. C. HIV-RNA was 4.4 to 4.6 log (25,000 to 40,000 copies/ml). 21-22% had <400 copies/ml. CD4 count was 239-241. CD4 nadir was 100-101. Prior use of NRTIs: 65% (LPV/r) and 69% (SAQ/r). Prior use of NNRTIs: 29% (LPV/r) and 35% (SAQ/r). Prior use of PI: 52% and 52%.
RESULTS
The assigned treatment was initiated in 324/339 (96%) patients from whom complete follow-up data is available in 304 (94%). No difference was observed between the two arms in baseline characteristics.
Discontinuation of the assigned treatment occurred in 69/324 (21%) patients; 13% in the LPV/r versus 29% in the SAQ/r arm (p=0.001) for non-fatal adverse events. In 48% of cases discontinuation was due to a non-fatal adverse event. Patient choice/non-compliance was reason for switch (discontinuation of assigned treatment) in 5% vs 14% of patients in LPV/r and SAQ/r arms, respectively.
Pill count. For patients taking saquinavir regimen, there were 6 capsules taken twice per day; 5 saquinavir capsules plus 1 ritonavir capsule. Patients taking lopinavir/r took 3 capsules twice per day.
Formulation of saquinavir. Fortovase was used in this study, this formulation is generally considered to have more GI side effects than invirase (hard-gel formulation of saquinavir). Equivalency studies show that when boosted by ritonavir invirase is equivalent to Fortovase. Roche is reformulating saquinavir as a hard-gel capsule (500mg tablets). At IAS Roche presented a poster reporting the results of a study conducted in healthy volunteers to determine the bioavailability of the new SQV 500 mg tablet formulation relative to invirase 200mg tablets, following single-dose administration of 1000mg with 100mg ritonavir bid after a high fat breakfast. The Roche study investigators reported that the new formulation exhibits similar bioavailability to invirase. The mean exposure ratio was 1.05 (90% CI, 0.94-1.17) for AUC and 1.13 (1.00-1.26) for Cmax. Large inter-subject variability was observed in AUC and Cmax, which is well known for saquinavir and related to the effect of CYP3A4 and P-gp on its absorption. Contrary to previous observations, however, intra-subject variability was moderate with an estimated CV of about 25%. Based on the promising results of this pilot study, a pivotol bioequivalence study will be performed comparing Invirase/r with SAQ-tablet/r. The new saquinavir 500mg tablet could replace both the existing Invirase and Fortovase 200mg capsules.
The risk of protocol-defined virologic failure was higher in the SAQ/r arm compared to the LPV/r arm in the ITT/e (p=0.0009, log rank test) and the ITT/e/d (p=0.002); not shown) analyses, but not in the OT (p=0.14) analysis.
At week 48, 65% vs 57% (ITT/e), 60% vs 53% (ITT/e/s), and 70% vs 75% (OT) in the LPV/r and SAQ/r arm, respectively, had a HIV-RNA <50 copies/ml (p>0.05 for all comparisons).
No difference was seen in immunologic response between the two arms.
23 patients experienced a CDC cat. B or C disease, or death, 6 in the LPV/r arm and 17 in the SAQ/r arm (p=0.03). These were 2 vs 5 cat. B; 4 vs 7 cat. C; and 0 vs 5 deaths. 8/11 patients experiencing a CDC cat. C were at that stage at baseline, 6 SAQ/r vs 2 LPV/r. The 5 deaths were due to a CDC cat.C disease (3), lactic acidosis (1), and plane crash (1).
No difference in risk of grade 3 and/or 4 adverse events were seen between the two arms.
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