By Liz Highleyman

The first CCR5 antagonist, maraviroc (Selzentry), was approved in August 2007 for treatment-experienced HIV patients with drug-resistant virus. Agents in this class interfere with CCR5, one of the 2 coreceptors HIV uses to enter cells.

HIV tropism -- or which coreceptor the virus uses -- is determined by a tropism test such as Monogram Biosciences' Trofile assay. Only patients with exclusively CCR5-tropic virus, rather than CXCR4-tropic or dual/mixed strains, are considered eligible to use maraviroc.

As previously reported, the Phase III MERIT study failed to show that maraviroc was non-inferior to efavirenz (Sustiva) in treatment-naive individuals, especially those with a high baseline viral load. However, nearly half the patients who experienced virological failure while taking maraviroc were found to have CXCR4-tropic HIV that might have been present but undetected at screening.

In a late-breaking poster at the 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008), taking place this week in Washington, DC, researchers presented a retrospective reanalysis of the data -- dubbed MERIT ES -- utilizing a new, more sensitive version of the Trofile assay.

Briefly, MERIT included 721 participants starting antiretroviral therapy for the first time. About 70% were men, just over half were white, and about 35% were black; nearly 400 were from the Northern hemisphere and slightly more than 300 were from the Southern hemisphere. At baseline, the median CD4 cell count was about 250 cells/mm3 and the mean viral load was about 700,000 copies/mL. Participants were randomly assigned to receive either 300 mg twice-daily maraviroc or 600 mg once-daily efavirenz, both in combination with zidovudine/lamivudine (Combivir coformulation) for 48 weeks.

In MERIT ES, stored samples from study participants were retested using the recently introduced enhanced Trofile assay, which is better able to detect CXCR4-tropic virus. The enhanced Trofile test -- the only version currently available -- can detect CXCR4-tropic or dual/mixed HIV variants that make up as little as 0.3% of an individual's total virus population, a 30-fold improvement in sensitivity. Key 48-week study endpoints were reanalyzed after excluding patients found to have non-CCR5-tropic virus using the new test.

Results

• 106 of 721 patients (14.7%) across both treatment arms initially classified as having exclusively CCR5-tropic HIV were found to have dual/mixed virus using the new test, leaving 311 remaining in the maraviroc arm and 303 in the efavirenz arm (1 person was initially misclassified).

• Reanalysis using the enhanced test identified 52% of patients who displayed dual/mixed HIV at baseline or on study, and 12% who displayed CCR5 tropism at baseline or on study.

• Baseline characteristics were similar for the original and revised patient populations.

• At 48 weeks, 68% of patients in both the maraviroc and efavirenz arms achieved HIV RNA < 50 copies/mL (compared with 64% and 69%, respectively, in the original analysis).

• Among patients with baseline viral load ? 100,000 copies/mL, 64% of those taking maraviroc and 63% taking efavirenz achieved HIV RNA < 50 copies/mL (versus 60% and 66%, respectively, in the earlier analysis).

• For HIV RNA < 400 copies/mL, the new percentages were 73% in the maraviroc arm and 72% in the efavirenz arm (compared with 70% and 73%, respectively, in the original analysis).

• CD4 counts increased by 174 and 144 cells/mm3, respectively, in the maraviroc and efavirenz arms (similar to the initial analysis).

• 9% of patients in the maraviroc arm and 4% in the efavirenz arm discontinued therapy due to lack of efficacy (compared with 12% and 4%, respectively, in the earlier analysis).

• 4% of patients in the maraviroc arm and 14% in the efavirenz arm discontinued due to adverse events (similar to the original analysis).

Based on these findings, the investigators concluded, "The enhanced Trofile assay reclassified approximately 15% of patients as [having] non-R5 HIV and identified approximately 52% of patients who had [dual/mixed] virus at baseline or on study."

"Excluding these [patients] improved the efficacy of maraviroc relative to efavirenz compared with results using the original assay," they added. "Reclassification with the enhanced Trofile assay resulted in fewer overall discontinuations and discontinuations due to lack of efficacy in the maraviroc arm, but had little impact on these outcomes in the efavirenz arm."

"The results of MERIT ES are exciting as they show that with an enhanced sensitivity tropism assay the efficacy rate of Selzentry shown in MERIT with the original Trofile assay is improved further," presenter Michael Saag stated in a press release issued by maraviroc manufacturer Pfizer. "These findings are important for patients and physicians and offer guidance for clinical practice with the only version of Trofile currently available."

A similar reanalysis of data from the ACTG 5211 trial of Schering-Plough's investigational CCR5 antagonist vicriviroc also showed improved efficacy when patients were reclassified based on the enhanced Trofile assay.

Univ. of Alabama at Birmingham, Birmingham, AL; Orlando Immunology Ctr., Orlando, FL; Saint-Pierre Univ. Hosp., Brussels, Belgium; Univ. of New South Wales, Sydney, Australia; Univ. of Toronto, Toronto, Canada; Monogram BioSciences, South San Francisco, CA; Pfizer Global R&D, New London, CT; Pfizer Global R&D, Sandwich, UK.

10/28/08

Reference
M Saag, J Heera, J Goodrich, and others. Reanalysis of the MERIT study with the enhanced Trofile assay. 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008). Washington, DC. October 25-28, 2008. Abstract H-1232a.

Other source
Pfizer. Pfizer's Novel HIV/AIDS Treatment Selzentry (Maraviroc) Demonstrates Increased Efficacy Rate in Treatment-Naive HIV Patients. Press release. October 26, 2008.