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PRIORITY PRESS - 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/46th Annual Meeting of the Infectious Diseases Society of America

Washington, D.C./ October 25-28, 2008

The ability to detect CXCR4-using minor variants of HIV in HIV-infected patients is paramount to identifying those patients with a low likelihood of responding to CCR5 co-receptor antagonists.

As the first approved agent in this class, maraviroc is indicated (in combination with other antiretroviral agents) for treatment-experienced patients infected solely with CCR5-tropic HIV detectable.

The CCR5 co-receptor antagonists prevent HIV from entering CD4+ cells by blocking its predominant entry route—the CCR5 co-receptor. This class of medicines is thus ineffective for the treatment of patients with mixed tropism (infected with a combination of R5, X4, and/or dual-tropic viruses), and inclusion of patients with dual-tropic or mixed tropism infection in clinical trials of CCR5 co-receptor antagonists would dilute the efficacy of this drug class in reducing viral load to undetectable levels.

Tropism testing therefore allows identification of HIV’s preferred point of entry to CD4+ cells and its results permit the selection of an optimal agent for viral entry inhibition. A new tropism assay that is 30 times more sensitive in detecting minority variants of HIV has replaced the original tropism assay and is the only assay used in clinical practice today. The enhanced sensitivity assay is able to detect dual/mixed or CXC4-tropic variants of HIV when present in <u>></u>0.3% of the total viral population.

Original Study MERIT Re-Analysis

The enhanced sensitivity tropism assay was used to reclassify patients who were enrolled into the MERIT (Maraviroc vs. Efavirenz Regimens as Initial Therapy) study, which was conducted before the enhanced tropism assay was developed.

In MERIT, the CCR5 co-receptor antagonist maraviroc was compared with efavirenz in treatment-naïve patients with R5 HIV. Patients were randomized to either agent over a background of zidovudine and lamivudine.

“We were asking whether maraviroc, when used up front in a naïve population worked as well as efavirenz, with an AZT/3TC backbone,” reported Dr. Michael Saag, Professor of Medicine and Director of the Center for AIDS Research, University of Alabama, Birmingham. “The original MERIT study used the original less sensitive tropism assay.” As such, the original analysis of MERIT could not show non-inferiority of maraviroc vs. efavirenz for achieving viral loads of <50 copies/mL at week 48.

A re-analysis of the MERIT study with the enhanced tropism assay (MERIT-ES) was therefore undertaken because the investigators believed that it would more precisely identify patients unlikely to respond to the novel agent on the basis of dual-tropic or mixed tropism infection and therefore, represent a truer picture of the efficacy of maraviroc in patients with R5 HIV.

Reclassification of MERIT Patients

“There were 721 patients who were enrolled in the original MERIT study on the basis of an R5 tropism using the original assay. It turns out that the original tropism assay missed a fair number of minor variant dual/mixed populations, in which case maraviroc wouldn’t work,” indicated Dr. Saag, lead investigator of MERIT-ES. “When you use the new assay, as in MERIT-ES, you lose 15% of patients in the original study…they fell out with the new assay because they really had dual/mixed tropism at baseline.”

The proportion of patients with discordant results between the original and enhanced tropism assay was similar between the two treatment arms.

In the original MERIT study, 69% of patients in the efavirenz arm and 64% in the maraviroc arm achieved HIV RNA <50 copies/mL.

“In the first MERIT analysis using the original tropism assay, maraviroc was 4.2% less effective than efavirenz in achieving HIV RNA to <50 copies/mL, but the lower end of the confidence interval was 10.9%,” Dr. Saag told the audience. “The U.S. Food and Drug Administration required that the lower confidence interval be 10% in order to claim non-inferiority.”

He continued, “With the new analysis, just by eliminating the patients who had dual/mixed tropism at baseline, the difference in suppressing the virus to undetectable levels narrows to 0.2% between the two treatments, and the lower end of the confidence interval is 7.4%.The take-home point is that if the better assay had been used at the beginning, maraviroc would have been judged to be noninferior” (Figure 1).

Figure 1.

In the enhanced tropism assay, 68% of patients in each treatment arm achieved HIV RNA <50 copies/mL. In addition, the total overall discontinuation on the CCR5 co-receptor decreased from 27% to 24%, and the number of discontinuations due to lack of efficacy decreased from 12% to 9%. The reanalysis did not affect the number of patients discontinuing on efavirenz.

In MERIT-ES, improved virologic responses were observed with maraviroc in patients with a high baseline viral load (<u>></u>10,000 copies/mL) as well as patients with a low baseline viral load (< 10,000 copies/mL).

The current analysis is critical to inform clinical practice because the original tropism assay is no longer available, Dr. Saag emphasized.

Greater CD4+ Increases

In MERIT, the novel agent was associated with persistently greater increases in CD4+ cell counts compared with efavirenz. The additional CD4+ cells it conferred were functional as determined by analysis of time to an AIDS-defining (Category C) event, according to Prof. Adriano Lazzarin and colleagues, San Raffaele Scientific Institute, Milan, Italy.

The post-hoc analysis revealed significantly greater and more rapid increases in CD4+ cell counts compared to the efavirenz arm. The median change from baseline in CD4+ cell count at week 48 was +151 cells/mm³ in patients assigned to maraviroc and +122 cells/mm³ in patients assigned to efavirenz (P=0.002). The difference in CD4+ cell counts between the two groups was apparent and significant as early as week 4, at which time patients in the maraviroc group had a median increase of 77 cells/mm³ from baseline compared to a median increase of 47 cells/mm³ from baseline in the efavirenz group (P=0.0001).

In MERIT-ES, the novel agent maintained its advantage over efavirenz in increasing CD4+ cell counts, noted Dr. Saag. In the patient population with true R5 tropism, it was associated with a mean increase in CD4+ cells of 174 cells/mm³, compared with a mean increase of 144 cells/mm3 associated with efavirenz.

On-treatment CD4+ cell count was a significant predictor of time to a Category C event occurrence, which supports the premise that the additional CD4+ cells conferred were functional, and that antagonism of the CCR5 co-receptor is not associated with deleterious effects as measured by Category C events, confirmed Prof. Lazzarin.

Achieving an HIV RNA <50 copies/mL also predicted fewer Category C events, as did a low baseline HIV RNA level.