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Maraviroc in Treatment-Experienced and Treatment-Naive Patients

Data presented at the 4th IAS Conference confirm the value of maraviroc for treatment-experienced patients, but its role in treatment-naive patients remains uncertain.

Maraviroc is the first CCR5 inhibitor approved for HIV treatment. As previously reported, FDA approval was based primarily on 24-week results from the MOTIVATE studies, which involved more than 1000 highly treatment-experienced patients infected with CCR5-tropic virus (ACC Aug 10 2007). At the 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention, investigators reported subgroup analyses from the MOTIVATE studies and also provided data from the MERIT study about the use of maraviroc in treatment-naive patients.

More Data from MOTIVATE
In a pooled 24-week analysis of the two MOTIVATE studies, Gulick and colleagues confirmed results previously reported from the two individual studies: When combined with an optimized background regimen, maraviroc (300 mg once or twice daily) yielded significantly greater rates of HIV suppression than did placebo (Table 1) [Abstract WEPEB116LB]. Although the studies were not designed for a formal comparison of maraviroc dosing, investigators observed higher rates of virologic suppression with twice-daily maraviroc than with once-daily maraviroc in several subgroups, including patients who had no active drugs in their optimized background regimens, patients with viral loads 100,000 copies/mL at screening, and patients with baseline CD4 counts <50 cells/mm³. In this study, maraviroc was not associated with increased risk of malignancy or of other adverse events, including clinically significant hepatotoxicity among patients coinfected with hepatitis B or C virus.

In a second pooled analysis of the MOTIVATE data, van der Ryst and colleagues described the efficacy of maraviroc in combination with other active agents in the optimized background regimen [Abstract WEPEB115LB]. First-time use of T-20 and use of fully active lopinavir/ritonavir were each associated with an increased likelihood of virologic suppression. This finding is consistent with those of similar studies, in which the use of a second potent agent has been central to the success of the investigational compound.

Taken together, these two analyses help establish maraviroc as an important new option for managing treatment-experienced patients and reinforce the importance of using the drug with at least one other fully active agent.

The MERIT Study
Whether maraviroc has a role in the therapy of treatment-naive patients remains unclear, even with the data now available from the manufacturer-sponsored MERIT study [Abstract WESS104]. This trial, reported by Saag and colleagues, tested the hypothesis that maraviroc was not virologically inferior to efavirenz among treatment-naive patients who had CCR5-tropic virus, viral loads 2000 copies/mL, and no evidence of resistance to efavirenz, AZT, or 3TC. Patients were randomized to receive AZT/3TC plus either maraviroc (300 mg once or twice daily) or efavirenz. The primary endpoint was the proportion of patients who achieved viral loads <50 copies/mL through 48 weeks of follow-up.

At week 16, the Data Safety and Monitoring Board closed the once-daily maraviroc arm because of inadequate response rates, leaving only the twice-daily maraviroc and efavirenz arms for comparison (721 patients total). At baseline, the groups had similar median CD4 counts (241 and 254 cells/mm³, respectively) and mean viral loads (approximately 4.9 log copies/mL).

At 48 weeks, 65.3% of the twice-daily maraviroc group and 69.3% of the efavirenz group achieved viral loads <50 copies/mL (Table 2). Although the difference in response rates was relatively modest, it failed to meet the preselected criteria for noninferiority because the lower bound of the 97.5% confidence interval was greater than –10% (–10.9%). Interestingly, if <400 copies/mL had been used as the cutoff point for virologic response, noninferiority would have been established (lower bound, –9.5%).

Subgroup analyses revealed some intriguing differences. Among patients with baseline viral loads <100,000 copies, efavirenz and maraviroc had similar virologic efficacy. However, among those with baseline viral loads 100,000 copies, efavirenz was superior to maraviroc (proportion with viral loads <50 copies/mL, 66.6% vs. 59.6%). Differences in outcome based on geography were also noted. Efavirenz and maraviroc had comparable efficacy among patients who entered the trial from the Northern Hemisphere (North America or Europe), but efavirenz was superior among those who entered from the Southern Hemisphere (South Africa, Argentina, or Australia; proportion with viral loads <50 copies/mL, 71.0% for efavirenz vs. 62.1% for maraviroc). No clear reason for this difference was apparent.

Overall rates of study discontinuation were similar in the two treatment arms. However, patients who received efavirenz had higher rates of discontinuation due to adverse events (13.6%, compared with 4.2% in the maraviroc arm), whereas those who received maraviroc experienced higher rates of virologic failure (11.9%, vs. 4.2% in the efavirenz arm). At week 48, CD4-cell gains were significantly greater with maraviroc than with efavirenz (170 vs. 144 cells/mm³). Rates of lab abnormalities (including liver inflammation) and of new malignancies did not differ between the treatment arms.

— Charles B. Hicks, MD

Published in AIDS Clinical Care September 10, 2007