Maraviroc trial results reanalysed using more sensitive CCR5 tropism test
26 December 2008. Related: Conference reports.
Simon Collins, HIV i-Base
Because the registrational trials for the CCR5 inhibitor maraviroc failed to show non-inferiority compared to efavirenz at reducing viral load to <50 copies/mL in treatment-naive patients [1], US and European approval was only granted for use treatment experienced patients. [2, 3]
This has limited use of what was initially hoped to be an important new drug with a wider indication.
One of the reasons for higher treatment failure in patients using maraviroc in these studies was later identified as dual or mixed CXCR4/CCR5 tropism in some patients that was not detected at baseline.
This year, the earlier tropism test (Trofile) was replaced by Trofile ES which has increased sensitivity for identifying patients who are likely to respond to maraviroc. This is likely to improve the relative efficacy compared to efavirenz in clinical practicecompared to the results seen in earlier trials.
A presentation from Michael Saag from the University of Alabama and colleagues reanalysed the Phase 3 MERIT results using the more sensitive test.
In the original analysis 65% of patients receiving maraviroc + Combivir achieved an <50 copies/mL compared to 69% for efavirenz + Combivir. More patients discontinued from the maraviroc arm for lack of efficacy (11.9% vs 4.2%), with 19/43 having dual or mixed tropism at failure, but fewer patients discontinued due to adverse events (4.2% vs 13.6%).
The enhanced Trofile assay reclassified approximately 15% of patients (106/721) who were originally R5-tropic as non R5-tropic and identified approximately half of the patients who were dual/mixed tropism at baseline or on study with the less sensitive test.
On reanalysis with enhanced Trofile, the total overall discontinuations on maraviroc decreased from 97 (27%) to 76 (24%) patients, while the number of discontinuations due to lack of efficacy decreased from 43 (12%) to 29 (9%) patients. The reanalysis had little effect on numbers of patients discontinuing in the efavirenz arm. Efficacy results meant that 68% of patients in each arm now suppressed to <50 copies/mL, with a difference between arms given as -2.5 (lower bound -9.8).
Discontinuations due to adverse events remained higher in the efavirenz arm.
COMMENT
Improved results for maraviroc from using Trofile ES were reported earlier this year at the Resistance Workshop in Sitges. [5]
Although in the MERIT analysis the lower bound of the one-sided 97.5% CI for the 48-week treatment difference between maraviroc and efavirenz, for both the <400 and <50 copies/mL endpoints, was brought to within the predefined -10% margin for non-inferiority, the presentation confusingly stated that “as this is a retrospective analysis, the confidence intervals presented in this poster are for descriptive purposes only”.
It is not clear wehther this was related to patients that would be excluded by the new assay, but knowing the actual confidence intervals based on these results appears a key point.
It is important to now know how the regulatory agencies will assess these data in any review of the current licensing indications.
References:
- Maraviroc fails to show “non-inferiority” to efavirenz in treatment-naive patients: 48 week result. HIV Treatment Bulletin July/August 2007.
http://www.i-base.info/htb/v8/htb8-8-9/Maraviroc.html - HIV Treatment Bulletin July/August 2007.
http://www.i-base.info/htb/v8/htb8-8-9/approved.html - HIV Treatment Bulletin October 2007.
http://www.i-base.info/htb/v8/htb8-10/maraviroc.html - Saag M et al. Reanalysis of the MERIT Study with the Enhanced Trofile Assay. Abstract H-1232a. 48th ICAAC, 25-28 October 2008. Washington.
- Detecting viral tropism: impact of a more sensitive Trofile (ES) assay. HIV Treatment Bulletin July/August 2008.
http://www.i-base.info/htb/v9/htb9-7-8/Detecting.html