Ritonavir-boosted Saquinavir Shows Equivalent Efficacy and More Favorable Toxicity Profile Compared to Ritonavir-boosted Indinavir: The MaxCmin-1 Trial

By Ronald Baker, PhD

HIV clinicians and researchers increasingly are exploring the potential efficacy, durability and safety benefits of boosted protease inhibitor regimens. In this context, “boosted” means enhanced by low dose ritonavir.

Thus far there are scant data on the outcomes of these ritonavir-boosted PI combination regimens.

Recently, two studies (MaxCmin 1 and MaxCmin 2) presented at the 2^nd IAS Conference in Paris (July 14-16, 2003), yielded interesting results. The studies  compared boosted saquinavir (Fortovase) to boosted indinavir (Crixivan) and to boosted lopinavir (Kaletra).

Ritonavir-boosted Saquinavir vs Ritonavir-boosted Indinavir: Comparison of Hepatotoxicity (MaxCmin 1)

The stated objective of this phase IV, randomized, international (13 countries) trial was to determine a difference in the prevalence and/or severity of hepatotoxicity for the indinavir/ritonavir (IDV/r) arm compared to the saquinavir/ritonavir (SAQ/r) arm after 48 weeks of treatment.

A secondary objective was to investigate the influence of baseline-reported hepatitis on hepatotoxicity.

All patients were seen at baseline, week 4 and every 12 weeks thereafter through 48 weeks. Prior to randomization, the treating physician selected the components of concomitant use of 2 NRTIs / NNRTIs.

The administered doses of IDV/r and SAQ/r were 800/100 mg BID and 1000/100 mg BID, respectively. While the 800/100 BID dosing of IDV/r has been used in a number of earlier studies (and in clinical settings, even though not FDA-approved), the SAQ/r 1000/100 mg BID dose represents a radical departure from the initial FDA-approved dose of SAQ/r 400/400 mg BID.

Study Results

The investigators employed both an intent-to-treat/ exposed (ITT/e) analysis (discontinuation=failure) and an on treatment (OT) analysis (includes all patients who remained on the assigned regimen).

This trial found no significant difference in the rate of virologic failure between the IDV/r and the SAQ/r arms in the ITT/e and OT analyses.

However, the investigators did find more discontinuations in the IDV/r arm, which led to a higher rate of failure in the ITT/e/switch = failure analysis. Discontinuations were due primarily to mild to moderate adverse events.

Chronic hepatitis was reported at baseline among 24 patients (8%) starting ritonavir treatment, 13 in the IDV/r and 11 in the SAQ/r arm.

As expected, median bilirubin levels rose in the IDV/r arm and remained stable in the SAQ/r arm both in the total study population and in hepatitis patients. Median AST and ALT levels remained stable in both study arms (ITT/e and OT).

The proportion of patients with bilirubin, AST or ALT levels above the upper level of normal (ULN) at baseline was low and remained low through 48 weeks. In the patients with hepatitis, a higher proportion had values above ULN that also remained stable through 48 weeks.

Te use of Fortovase rather than Invirase (the initial FDA-approved formulation of saquinavir) in this study may explain the higher than expected discontinuation rate because Invirase is better tolerated than Fortovase.

Conclusions

Hepatitis prevalence in this patient population was relatively low (8%). The investigators determined the following:

- Elevated bilirubin was noted in the IDV/r arm; and

- No clinically significant hepatotoxicity was found in hepatitis patients compared to the overall study population in either arm.

Commentary

In terms of application to clinical practice, two primary outcomes in this study warrant discussion. First, the principal objective of evaluating and comparing hepatotoxic effects of the two drugs was achieved. Both PI regimens, in particular the SAQ/r arm, exhibited relatively benign toxicity profiles. The saquinavir-based arm showed a very favorable hepatic profile.

Secondly, the new and fortuitous dosing of SAQ/r at 1000/100 BID had to be largely responsible for producing the outcome of “equivalent efficacy” of the two regimens. Had the investigators used the FDA-approved dose of 400/400 mg BID for SAQ/r, the indinavir –based regimen would certainly be expected to outperform SAQ/r in all efficacy parameters. In addition, a 400 mg BID dose of ritonavir in the SAQ arm would likely have resulted in considerable dyslipidemia due to the higher ritonavir dose.

On the basis of these favorable results, by early 2004 Roche is expected to gain approval for a new, more convenient SAQ 500 mg tablet formulation and for the new SAQ/r 1000/100 dose (two 500 mg tablets twice daily SAQ)

8/20/03

Reference
JD Lundgen and others. Hepatotoxicity of ritonavir-boosted indinavir (800/100mg twice daily) and saquinavir (1000/100 mg twice daily, in a phase IV, randomized, open-label and multicentre trial in adult HIV-1 infection: the MaxCmin1 trial   Abstract 126. 5^th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV. July 9-11, 2003. Paris, France.