HIV and Hepatitis.com Coverage of the
4th IAS Conference on HIV Pathogenesis, Treatment and Prevenion (IAS 2007)
  July 22-25, 2007, Sydney, Australia
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CCR5 Antagonist Maraviroc (Celsentri) Not Quite as Effective as Efavirenz but Better Tolerated in Treatment-naive Patients

By Liz Highleyman

Earlier this year, researchers reported that treatment-experienced patients taking the CCR5 co-receptor antagonist maraviroc (Celsentri) were about twice as likely to achieve undetectable HIV viral loads as those taking a placebo with an optimized background regimen.

Although the U.S. Food and Drug Administration issued an "approvable letter" for maraviroc, the agency declined to grant full marketing approval until manufacturer Pfizer provides additional information to address potential safety concerns.

At the 4th International AIDS Society Conference on HIV Treatment, Pathogenesis and Prevention this week in Sydney, Australia, researchers presented data from a Phase III trial of maraviroc in treatment-naive patients.

HIV-1 interacts with a cell-surface receptor, primarily CD4, and through conformational changes becomes more closely associated with the cell through interactions with other cell-surface molecules, such as the chemokine receptors CXCR4 and CCR5.

The MERIT study included 721 participants (29% women) receiving antiretroviral therapy for the first time. Nearly 400 were from the Northern hemisphere, while just over 300 were from the Southern hemisphere. Just over half were white and about 35% were black. The mean baseline viral load was about 700,000 copies/mL and the median baseline CD4 cell count was about 250 cells/mm3.

Subjects were pre-screened to ensure that they had exclusively CCR5-tropic HIV, that is, virus that uses the CCR5 co-receptor along with the CD4 receptor to enter human cells.

Participants were randomly assigned to receive either 300 mg maraviroc twice daily or 600 mg efavirenz (Sustiva) once daily, along with the Combivir (AZT/3TC) fixed-dose combination pill for 48 weeks. A once-daily maraviroc arm was previously halted after interim data showed a higher rate of virological failure.

Results
·         Overall, subjects taking maraviroc and efavirenz were about equally likely to achieve HIV RNA below 400 copies/mL (70.6% vs 73.1%, respectively).

·         However, patients taking maraviroc were slightly less likely than those on efavirenz to achieve viral loads below 50 copies/mL (65.3% vs 69.3%).

·         Among patients starting with lower baseline viral loads (< 100,000 copies/mL), those taking maraviroc and efavirenz had similar rates of virological suppression below 50 copies/mL (69.6% vs 71.6%).

·         Among those with higher baseline viral loads (100,000 copies/mL), however, fewer patients taking maraviroc achieved HIV RNA < 50 copies/mL compared with those taking efavirenz (59.6% vs 66.6%).

·         Maraviroc and efavirenz demonstrated similar efficacy among patients in the Northern hemisphere (68.0% vs 67.8% achieving < 50 copies/mL).

·       But maraviroc performed more poorly than efavirenz among participants in the South hemisphere (62.1% vs 71.0%).

·         Subjects taking maraviroc had a larger CD4 cell count increase than those taking efavirenz (170 vs 144 cells/mm3, respectively).

·         Overall, maraviroc was better tolerated than efavirenz.

·         A similar proportion of patients in the maraviroc and efavirenz arms stopped the study prematurely (26.9% and 25.2%, respectively), but did so for different reasons:

o        More patients in the maraviroc arm discontinued due to virological failure (11.9%, compared with 4.2% in the efavirenz arm);
o        More patients in the efavirenz arm discontinued due to adverse side effects (13.6%, compared with 4.2% in the maraviroc arm).

·         There were fewer malignancies reported in the maraviroc arm (1 case) than in the efavirenz arm (4 cases).

·         Severe liver toxicity was uncommon overall, and occurred with similar frequencies in both arms.

·         Patients in the efavirenz arm had larger increases in total cholesterol, low-density lipoprotein (LDL or “bad”) cholesterol, and triglycerides, but also a larger gain in high-density lipoprotein (HDL or “good”) cholesterol.

Conclusion

The researchers concluded that according to the pre-determined statistical cut-off, maraviroc was not shown to be "non-inferior" to efavirenz. However, presenter Michael Saag, MD, said that the data "fell just short" of showing that the drugs were comparably effective.

The findings regarding malignancies are reassuring, since several cases of cancer have been observed in studies of another investigational CCR5 antagonist, vicriviroc. The liver toxicity data are also promising, since development of a third candidate CCR5 blocker, aplaviroc, was discontinued for this reason.

The researchers are not sure why the study results differed in the Northern and Southern hemispheres, but Saag suggested this might be due to regional differences in HIV-1 clades, somewhat sicker patients in the Southern hemisphere, or differential accuracy of the test results. Further analysis of the data is currently underway.

University of Alabama at Birmingham, AL; University of the Witwatersrand, Johannesburg, South Africa; Orlando Immunology Center, Orlando, FL; Saint-Pierre University Hospital, Infectious Diseases, Brussels, Belgium; University of New South Wales, National Centre in HIV Epidemiology and Clinical Research, Sydney, Australia; Hospital of Infectious Diseases, Warsaw, Poland; Outpatient Care Unit, Muñiz Hospital, Buenos Aires City, Argentina; Istituto Nacional de Enfermedades Respiratorias, Center for Research in Infectious Diseases, Tlalpan, Mexico; University of Toronto, Ontario, Canada; Pfizer Global Research and Development, Sandwich, UK and New London, CT.

07/24/07

Reference

M Saag, P Ive, J Heera, and others. 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 naïve patients infected with R5 HIV-1: week 48 results of the MERIT study. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Sydney, Australia, July 22-25, 2007. Abstract WESS104.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 




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