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HIV enters cells by binding to the CD4 molecule and a coreceptor. One of the main viral coreceptors is CCR5. Maraviroc, the first CCR5 antagonist to be approved, underwent phase III testing in two large, industry-funded, multinational studies called MOTIVATE 1 and 2; the results of these two pivotal trials have just been published.
A total of 1049 adults with R5-tropic HIV only and resistance to or previous treatment with drugs from three antiretroviral classes were randomized to receive once- or twice-daily maraviroc or placebo along with optimized background therapy. Agents that were investigational when the study was launched — including the now-approved drugs darunavir, raltegravir, and etravirine — were not permitted.
At week 48, 46% of the twice-daily maraviroc group and 43% of the once-daily maraviroc group had viral loads (VLs) <50 copies/mL, compared with 17% of the placebo group. CD4-count increases were also greater with maraviroc than with placebo (mean, 124 cells/mm3 in the twice-daily maraviroc group vs. 61 cells/mm3 in the placebo group). The rate of drug discontinuation because of treatment-related adverse events was low (3%) in all three groups.
In subgroup analyses, maraviroc was superior to placebo in patients who had CD4 counts <50 cells/mm3 at baseline or VLs ≥100,000 copies/mL at screening. (In fact, the approved dosing is based, in part, on 24-week findings that more participants in these hard-to-treat groups and in the group with HIV resistant to all other agents achieved undetectable VLs when given maraviroc twice daily than when given maraviroc once daily, with no evidence of increased toxicity.) Although the proportion of patients with hepatitis C or B virus coinfection was low, maraviroc appeared to be safe in this population. Among patients who experienced virologic failure on maraviroc and underwent repeat tropism testing, 57% were found to have dual-mixed or X4-tropic HIV.
Gulick RM et al. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med 2008 Oct 2; 359:1429.
Fätkenheuer G et al. Subgroup analyses of maraviroc in previously treated R5 HIV-1 infection. N Engl J Med 2008 Oct 2; 359:1442.
Dolin R. A new class of anti-HIV therapy and new challenges. N Engl J Med 2008 Oct 2; 359:1509.
Comment
Unlike other antiretroviral medications, maraviroc binds to a host protein rather than to a viral target. To date, the drug appears to be safe and well tolerated, and it does not appear to have excess rates of hepatotoxicity or malignancy, which had been concerns with other CCR5 antagonists; nevertheless, long-term monitoring for unexpected adverse events is warranted. As anticipated, the rate of virologic suppression was highest when maraviroc was combined with other active agents; results should be even better than those seen in the MOTIVATE trials when maraviroc is given with active drugs, such as darunavir, etravirine, and raltegravir, that were not available during the study period.
Maraviroc should be restricted to patients who are infected with R5-tropic HIV only, which somewhat limits its use. For example, in studies of treatment-experienced patients, 38% to 50% were found to have non–R5-tropic HIV. The proportion may be even higher with use of a new, enhanced tropism assay that can detect minority viral populations better than did the first-generation assay employed in the MOTIVATE studies. Although testing with this new assay might exclude more patients from using maraviroc, treatment results may be even better among those who qualify, because in some cases virologic failure probably arises from selection of preexisting non–R5-tropic HIV that was missed by the original test.