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What Explains Maraviroc Failures in the MERIT Trial of Naive Patients?
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15th Conference on Retroviruses and Opportunistic Infections
February 3-6, 2008
Boston
Mark Mascolini
When a maraviroc regimen failed in 43 previously untreated people, virus resistant to the CCR5 antagonist turned up in only 2 of them. So what explains the other failures? Emergence of DM/X4 virus between screening and treatment day 1, poor adherence, and resistance to lamivudine (3TC) surfaced as the prime culprits in an analysis by Pfizer's Mike Westby [1].
In the thorny parlance of clinical trials, maraviroc was "not noninferior" to efavirenz after 48 weeks in first-line regimens containing Combivir (AZT/3TC) [2], when presented at the Intl AIDS conference in Sydney this past summer; in plain English the MERIT study suggested that a standard efavirenz-based regimen is a better first-line choice than a combination including 300 mg of maraviroc twice daily: results reported from this study were that 69.3% of patients taking efavirenz +Combivir (AZT/3TC) and 65.3% of patients taking maraviroc +Combivir (AZT/3TC) had <50 copies/ml at week 48; the study findings did not meet the criteria that maraviroc was noninferior to efavirenz. While 43 people (11.9%) stopped maraviroc because of poor viral control, only 15 (4.2%) quit efavirenz for that reason. But 49 people (13.6%) stopped efavirenz because of side effects, compared with 15 (4.2%) for maraviroc.
At todayÕs CROI meeting new findings were reported in the oral session on new ARTs. Although all study participants had R5 virus when screened for MERIT, 25 (3.5%) had dual/mixed (D/M) virus (which can use either CCR5 or CXCR4) or X4 virus on the first day of treatment. After 48 weeks of treatment, just over two thirds of people who began treatment with R5 virus had a viral load under 50 copies, regardless of whether they took efavirenz (69.3%) or maraviroc (68.0%). Sub-50-copy rates were lower with either regimen in people who had DM/X4 virus on day 1, but much lower with maraviroc (7.1%) than efavirenz (54.6%). Viral load or CD4 count at screening did not correlate with a shift from R5 to DM/X4 virus between screening and day 1.
Among 32 people with R5 virus on day 1 and later maraviroc failure, 22 had R5 virus or virus whose coreceptor use could not be determined at failure. Eleven of those 22 (50%) had unmeasurable maraviroc levels at failure, a clear signal of poor adherence. Ten of the 32 people with R5 virus on day 1 and subsequent failure had X4 virus at failure, and only 1 of them had an undetectable maraviroc concentration.
Of the 22 people in whom maraviroc failed with R5 virus or virus of undetermined tropism, 10 (45%) had the 3TC-induced M184V mutation at that point, compared with all 19 people who had DM/X4 virus at failure. Five of 19 people (26%) with DM/X4 virus at failure had resistance to two nucleosides, compared with 2 of 22 (9%) with R5 virus at failure. Nine of 15 people (64%) in whom efavirenz failed (14 with R5 virus), had resistance to efavirenz at failure, 4 (29%) had M184V, and 1 (7%) had dual-nucleoside resistance.
Pfizer plans a retrospective analysis of failure samples with a more sensitive Monogram Biosciences assay to get a better fix on how many people in whom maraviroc failed actually had DM/X4-using virus on treatment day 1. In reality, a more sensitive assay is expected to identify more DM/X4 viruses so it is less likely that patients with R5 at screening who are really DM or X4 would not get identified as not R5. Monogram is developing this assay now.
References
1. Heera J, Saag M, P Ive P, et al. Virological correlates associated with treatment failure at week 48 in the phase 3 study of maraviroc in treatment-naive patients. 15th Conference on Retroviruses and Opportunistic Infections. February 3-6, 2008. Boston. Abstract 40LB.
2. Saag M, Ive P, Heera J, et al. A multicenter, randomized, double-blind, comparative trial of a novel CCR5 antagonist, maraviroc versus efavirenz, both in combination with Combivir (zidovudine/lamivudine), for the treatment of antiretroviral naive subjects infected with R5 HIV-1: week 48 results of the MERIT study. 4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention. July 22-25, 2007. Sydney. Abstract WESS104.
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