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Date Posted: 20:36:52 02/28/02 Thu
Author: Anonymous
Subject: Boosted protease inhibitors go head-to-head

Boosted protease inhibitors go head-to-head

Dr Sarah Cumbers
Remarkable progress has been made in the management of HIV and AIDS, with the development of antiretroviral therapy. However, clinicians are continually challenged to design drug regimens that secure minimal failure rates, while maintaining patient safety. Although the protease inhibitor (PI), ritonavir, has been found to have a profound effect as a boosting agent, when co-administered with a second PI, such as saquinavir, indinavir or amprenavir , clinical efficacy of each combination is unclear as clinical trials have not, as yet, sufficiently cross-matched patient populations. This feature outlines the results of an important trial co-ordinated by the Copenhagen HIV Programme, which evaluated the safety and efficacy of indinavir/ritonavir versus saquinavir/ritonavir in adult HIV-1 infected patients.

Summary

At the 8th European Conference on Clinical Aspects and Treatment of HIV Infection the interim results were presented from MaxCmin1 , the first clinical trial to compare two ritonavir-boosted protease inhibitors (PIs) in the treatment of HIV-1 infection. Designed to assess the efficacy and safety of Fortovase/r (saquinavir soft gel capsules 1000 mg plus 100 mg ritonavir, BID) and indinavir/r (800/100 mg BID), the 24-week data set demonstrated low virological failure rates, and similar levels of efficacy with both treatment arms. Fortovase/r was better tolerated, however, with relatively fewer adverse events reported and a lower number of adverse event-related discontinuations.
Background

Protease inhibitors have proven a valuable addition to drug regimens tackling the HIV-1 virus. Highly active antiretroviral therapy (HAART) can achieve clinically significant reductions in viral replication and prolong patient life, but side effects, pill burden and complex dosing constraints can present a significant barrier to adherence and the success of a regimen. Recent studies have found that sub-therapeutic doses of the protease inhibitor ritonavir (r) can have a profound effect on the pharmacokinetics of a co-administered second protease inhibitor. Consequent improved and sustained drug levels result in enhanced antiviral potency while allowing reduced pill burdens and simplified dosing schedules. The ritonavir-induced increase in peak concentration of a second protease inhibitor taken at the same time, and/or the length of time that it stays in the blood, is known as PI-boosting.

Figure 1. Demonstration of PI boosting by ritonavir
Comparing boosted protease inhibitors

Three protease inhibitors, saquinavir, indinavir and amprenavir (which were developed and tested in unboosted regimens) now offer the potential of efficacy at lower daily doses when co-administered with ritonavir. The latest PI to be developed, lopinavir, is available only as a boosted agent. Although clinicians have obtained encouraging results with boosted PIs no trials have been conducted with the specific aim of establishing their relative efficacy. Comparisons of these agents in the laboratory cannot be used to predict reliably which drugs will be most active in patients. If a boosted PI performs well in vitro this may not translate into clinical efficacy. The cross-comparison of results from different clinical trials where these drugs have been used is also flawed, because data gathered from unmatched patient populations are not transferable. For these reasons the MaxCmin set of clinical trials was designed to judge the relative efficacy of one boosted PI against another by head-to-head comparison in closely matched sets of patients. Direct clinical efficacy data will assist clinicians in identifying the most appropriate drug to choose.
Trial design

MaxCmin1 was designed as a Phase IV, open-label trial. Prior to randomization to one of the two boosted PIs, a regimen involving at least two nucleoside analogues, and/or non-nucleoside anti-HIV drugs was allocated to individual patients. This ensured that the HAART received was unbiased by background medication. Study participants were analysed at baseline and at weeks 4, 12 and 24 for interim analysis. Interim data were assessed under the Peto rule, whereby a significance level of P £ 0.001 between the two treatment arms would be grounds for early discontinuation of the trial by the data and safety monitoring board.
Patient populations

The trial recruited 317 patients from a broad European base, and sites in North and South America (Figure 2).



Figure 2. MaxCmin1 recruitment centres

Patients were randomized at a 1:1 ratio between the Fortovase/r and the indinavir/r arms. From this randomized intent-to-treat group, 306 patients initiated treatment with the designated protease inhibitor (IDV/r = 158; FTV/r = 148) and were assigned the ?exposed? intent-to-treat population (ITT/e).
Baseline characteristics

The patient population was both heterogeneous and moderately advanced, with a large proportion of MaxCmin1 participants having experienced previous PI failure or intolerance and/or having symptomatic AIDS. Therapy-naive patients represented only 25% of the study participants. Of the remainder, 61% had received at least one prior PI-containing therapy. Thirty-one percent of patients were classified as having progressed to AIDS (CDC category C). Although the baseline characteristics were well-balanced across the treatment arms (Figure 3), the Fortovase/r cohort contained 5% more patients in this category than the indinavir/r group. In terms of viral load, the Fortovase/r group was also slightly worse-off at baseline, as HIV-1 RNA levels were undetectable (below 400 copies/ml) in fewer patients (37%, compared with 42% beginning indinavir/r).

Figure 3. MaxCmin1 baseline characteristics
Treatment discontinuation

Seven percent of patients randomized to the Fortovase/r arm of MaxCmin1 failed to initiate the designated boosted PI, compared with less than one percent of patients in the indinavir/r cohort. In order to exclude this random bias from the interim analysis, the ITT/e population was used for further evaluation. Twenty-seven percent of the ITT/e population that initiated the indinavir/r-containing regimen had permanently discontinued therapy by the 24-week time point. Only 17% of patients withdrew from the Fortovase/r arm of the study. A breakdown of these figures shows that the primary reason for discontinuation in both arms was the development of clinical non-fatal adverse events, which occurred at a much higher frequency (20% vs. 8%) in the indinavir/r cohort. Gastrointestinal events were cited as the most common reason for discontinuation in both groups, with indinavir-associated renal events representing the major source of difference between treatments (Figure 4).

Figure 4. Occurrence of adverse events leading to treatment discontinuation

A higher rate of serious (grade 3 or 4) adverse events was seen in patients taking indinavir/r (75 events, versus 45 in those taking Fortovase/r; Figure 5). Again, the major source of this difference was indinavir-associated nephrotoxicity.

Figure 5. Occurrence of serious adverse events
Treatment efficacy

Only two patients in each treatment group discontinued their assigned PI combination because of virological failure. The MaxCmin1 protocol definition of failure was a rise in HIV-RNA to levels set according to the patients baseline status and adjusted according to the treatment period (Figure 6).

Figure 6. Definition of virological failure

Loss to follow up, death and withdrawn consent were also defined as virological failure. Figure 7 illustrates the low failure rates seen in both treatment arms of the trial. These findings are of key importance since, as described above, the population of patients recruited to the trial was relatively experienced to anti-retroviral therapy.

Figure 7. MaxCmin1 virological failure

The proportion of patients with undetectable viral loads (< 400 copies/ml) increased from baseline over the 24-week study period. Figure 8 shows the proportion of patients in both treatment arms with undetectable plasma viraemia at baseline and week 24 of follow-up, as assessed by a strict non-completion = failure (NC=F) analysis of the ITT/e population, in which discontinuation of the assigned study drug also counted as virological failure. A slightly higher response to treatment with Fortovase/r was observed by NC=F analysis, driven primarily by the higher discontinuation rate in the indinavir/r arm.

Figure 8. MaxCmin1 efficacy


Conclusions

The statistical significance of the difference between the two treatment arms did not surpass the P = 0.001 level defined by the Peto rule, and the data and safety monitoring board have therefore allowed the trial to continue to its full 48-week duration. The final results of the MaxCmin1 trial (for which significance will be assessed at the more usual P £ 0.05 level) are eagerly awaited, and are scheduled for presentation at the International AIDS Society conference in Barcelona, 2002. MaxCmin2, a second head-to-head trial comparing the safety and efficacy of Fortovase/r with lopinavir/r, is currently recruiting. Further information on these studies can be found at http://www.maxcmin.com . The positive interim findings of MaxCmin1 strengthen the anticipation that boosted protease inhibitors will achieve significant treatment effects with reduced side effects, and renew hope in the continuing battle against HIV.
Acknowledgement

This article is supported by an unrestricted educational grant from Roche Pharmaceuticals.

http://www.mediscover.net/boostedPI_feature.cfm

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