A clinical trial has found that Pfizer's CCR5-blocking entry inhibitor, Celsentri (maraviroc), when used by patients starting HIV treatment for the first time, appears somewhat inferior to standard-of-care Sustiva (efavirenz). However, moderate CD4 count and side-effect benefits were found to be associated with the drug, compared to Sustiva.
Celsentri has already been shown to be safe and effective in clinical trials involving treatment-experienced patients. Pfizer's MERIT study, reported by Michael Saag, MD, of the University of Alabama, at the fourth IAS Conference on HIV Pathogenesis, Treatment and Prevention in Sydney, is the first to test the drug in patients beginning HIV therapy for the first time.
Patients were randomized to receive Sustiva or Celsentri, using a 300 mg dose taken once or twice a day. All patients combined their assigned drug with Combivir (zidovudine plus lamivudine).
Sixteen weeks into the study, the once-daily maraviroc arm was discontinued due to inferior viral load responses.
Upon entering the study, patients were required to have CCR5-tropic HIV—virus targeting CCR5 on the surface of CD4 cells, as opposed to CXCR4, which typically arises in patients in more advanced stages of infection—and to have a pretreatment viral load above 2,000.
Among the 721 patients treated in the study, the average viral load and CD4 count at entry was 4.87 log and 250 cells, respectively. The average age was 37 years; roughly 71 percent of the study participants were male.
Ninety-one of the 361 (25.2 percent) Sustiva-treated patients discontinued treatment before the end of the 48-weeks study. Among the 360 patients in the Celsentri group, 97 (26.9 percent) discontinued treatment at some point during the study.
Dr. Saag noted that 11.9 percent of patients taking Celsentri stopped due to treatment failure, compared to 4.2 percent in the Sustiva group. Conversely, patients were more likely to discontinue treatment due to side effects in the Sustiva group compared to the Celsentri group (13.6 vs. 4.2 percent, respectively).
As for viral load reductions, 73.1 percent of those in the Sustiva group, compared to 70.6 percent in the Celsentri group, had viral loads below 400 copies after 48 weeks. The closeness of these data, Dr. Saag explained, indicated that Celsentri was "non-inferior" to Sustiva when using the viral load cutoff of 400.
Viral loads below 50 copies were documented in 69.3 percent of patients receiving Sustiva for 48 weeks, compared to 65.3 percent of those taking Celsentri. Dr. Saag said this 4.2 percent difference was just large enough to suggest that Celsentri is inferior to Sustiva in terms of reducing viral load to undetectable by today's technological standards.
CD4 counts increased in both groups, with a 26-cell advantage in the Celsentri arm. After 48 weeks, CD4s increased by 144 in the Sustiva group and 170 in the Celsentri group.
Patients with low pretreatment viral loads (below 100,000 copies) did similarly well in both groups, with 71.6 percent of the Sustiva users and 69.6 percent of the Celsentri users keeping their levels below 50 copies for 48 weeks. As for those with high pretreatment viral loads (above 100,000 copies), levels remained undetectable in 71 percent of Sustiva users, compared to 62.1 percent of Celsentri users.
Interestingly, participants being treated at sites in the northern hemisphere performed equally well in both groups (67.8 and 68 percent had viral loads below 50 after 48 weeks in the Sustiva and Celsentri group, respectively). Among patients enrolled in the southern hemisphere—sites in South Africa, Argentina, and Australia—71 percent of Sustiva takers, compared to 62.1 percent of Celsentri takers, had viral loads below 50 copies after 48 weeks. While the reason for this discrepancy in't yet clear to the study investigators, Dr. Saag said during a question-and-answer period that followed his talk that it may be due to lab errors, differences in geographical subtype of HIV, or a higher rate of "undetected" CXCR4 virus.
Dr. Saag reported that fewer patients experienced moderate to severe ("grade 3 or 4") adverse events in the Celsentri group compared to the Sustiva group. Lipid abnormalities, including changes in total cholesterol, "bad" LDL cholesterol and triglycerides, were more common among those taking Sustiva. Neuropsychiatric problems, such as dizziness and abnormal dreams, were also more common in the Sustiva group.
Colds (nasopharyngitis) and bronchitis were more common side effects in the Celsentri group.
Dr. Saag also noted a difference in the number of new cancers diagnosed during the trials. Four cases of cancer (two Hodgkin's disease, one non-Hodgkin's lymphoma and one Kaposi's sarcoma) were documented in the Sustiva group, compared to one case (a non-Hodgkin's lymphoma) in the Celsentri group.
Pfizer announced on June 20 that it had received an "approvable letter" from the U.S. Food and Drug Administration (FDA) for Celsentri. While not an official approval, such a letter typically means that the FDA is poised to grant marketing clearance for a drug once outstanding issues between the agency and manufacturer are settled.
A decision from the agency is expected soon.
Source:
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 [ZDV]/lamivudine [3TC]), for the treatment of antiretroviral-naive patients infected with R5 HIV1: Week 48 results of the MERIT study [Abstract WESS104]. Fourth IAS Conference on HIV Pathogenesis, Treatment and Prevention, Sydney, 2007.
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