AIDS 2014：抗逆转录病毒药物疗法新近进展（MODERN试验）

ViiV Healthcare presents phase III data comparing once-daily maraviroc in combination with darunavir/ritonavir with emtricitabine/tenofovir plus darunavir/ritonavir in treatment-naïve adults with HIV-1

An investigational two drug-regimen of maraviroc dosed once daily, combined with darunavir/ritonavir (DRV/r) showed inferior efficacy compared to emtricitabine/tenofovir (FTC/TDF) with DRV/r.

ViiV Healthcare today presented, at the 20th International AIDS Congress in Melbourne, Australia, the analysis of the 48-week results from the phase III MODERN study comparing maraviroc (MVC; marketed as Celsentri® /Selzentry®) dosed once daily with darunavir/ritonavir (DRV/r) to emtricitabine/tenofovir (FTC /TDF) with DRV/r in antiretroviral-naïve subjects. The study did not meet the -10% non-inferiority endpoint. The proportion of study participants who were virologically suppressed (HIV-1 RNA <50 copies/mL) at week 48 was 77.3% for MVC+DRV/r compared to 86.8% for FTC /TDF +DRV/r (95% confidence interval -15.0% to -4.4%).

MODERN was designed as a double-blind, double dummy non-inferiority 96-week study, intended to determine if an investigational two-drug regimen of once-daily MVC (a CCR5 receptor antagonist) and DRV/r (a boosted protease inhibitor) could provide comparable antiviral activity when compared to a three-drug regimen consisting of two once-daily nucleosides (FTC /TDF) and DRV/r in antiretroviral-naïve subjects.  More MVC subjects discontinued due to lack of efficacy (8.3% for MVC+DRV/r vs 2.0% for FTC /TDF +DRV/r) and there were more protocol defined treatment failures in the maraviroc arm (10.1% for MVC and 3.2% for FTC /TDF).  There were no reports of viral resistance in subjects who failed in either arm of the study.

The secondary endpoints included safety and tolerability of maraviroc as well as the utility of genotypic and phenotypic testing and tropism change. There were no new or unique safety findings, and discontinuations due to adverse events were 4.8% for MVC+DRV/r and 4.5% for FTC /TDF +DRV/r. Category C events, grade 3/4 adverse events and laboratory abnormalities were similar between the two treatment arms.

The study was also designed to compare the performance of a genotypic tropism test with the phenotypic tropism test Trofile® (ESTA, Monogram Biosciences) to determine whether patients had R5-tropic HIV-1 virus and were therefore eligible for maraviroc treatment. This was the first trial to compare the treatment outcomes of patients prospectively randomized to either a genotypic or phenotypic tropism test. The proportion of subjects meeting the primary endpoint were comparable between the two arms in predicting a clinical response (for the MVC arm, difference was 6.86% in favour of genotyping, 95% confidence interval -1.28% to 15.0%; for FTC /TDF, difference was 0.3%, 95% confidence interval -6.4% to 6.9%).

“Although this investigational two-drug regimen was inferior to the three-drug regimen in this study, maraviroc remains a valuable antiretroviral therapy when used in combination with other antiretrovirals and dosed twice daily in adults with confirmed CCR5-tropic HIV.” said Dr. John Pottage, Chief Scientific and Medical Officer, ViiV Healthcare.

ViiV Healthcare decided to terminate the MODERN study in October 2013 following a preliminary review of the 48-week primary clinical efficacy data by the study’s external Independent Data Monitoring Committee (IDMC).  This decision was not based on any new or unique drug-related safety events. The results presented today are the first analysis of the 48-week primary endpoint of this study. Further analyses of the secondary objectives will be presented at future conferences.

 “ViiV Healthcare is committed to supporting innovative clinical programmes to better understand our therapies and the potential they could offer to people living with HIV.” said Dr. Dominique Limet, Chief Executive Officer, ViiV Healthcare. “The treatment of HIV has come a long way, but it is essential that we continue to pursue effective novel treatment strategies that minimise toxicity while maximising tolerability and convenience to meet our objective of delivering advances in care and treatment for all people living with HIV.”

About the MODERN study

‘Maraviroc Once daily with Darunavir Enhanced by Ritonavir in a Novel regimen’ (MODERN) was a Phase III, 96-week, multi-centre, randomised, double-blind, comparative study. The study started in 2011 and was carried out in 797 HIV-1 infected antiretroviral-naïve adults with HIV-1 RNA >1000 copies/mL (cpm) and without reported viral resistance from over 120 sites in the E.U., U.S., Australia and Canada. At baseline, the median age of subjects was 37 for MVC+DRV/r vs. 35 for FTC /TDF +DRV/r (9.1% vs. 8.5% were female respectively, and 81.3% in both arms were ethnically white).

Subjects with HIV-1 RNA >100 000cpm at baseline was 20.5% vs. 20.7% for MVC+DRV/r and FTC /TDF +DRV/r respectively.

As per the protocol, the primary endpoint for MODERN was the proportion of patients with HIV-1 RNA <50 copies/mL at week 48. Secondary objectives included the proportion of patients with HIV-1 RNA below the limits of assay detection at week 96; change in CD4+ cell counts through 48 and 96 weeks; assessment of the safety and tolerability of maraviroc including the effects on peripheral fat distribution and trunk to limb fat ratio; the effects on bone mineral density and tropism change and evolution of viral resistance.

MODERN was also the first large Phase III trial to prospectively compare the performance of a genotypic test with a phenotypic test to identify patients with CCR5 tropic virus to determine eligibility for maraviroc. Patients were randomised to undergo screening with either the genotypic or phenotypic test. Genotypic tropism testing in the MODERN study was provided by Siemens Healthcare Diagnostics and phenotypic testing (Trofile®) by Monogram Biosciences.

About maraviroc

Maraviroc is an oral CCR5 entry inhibitor. It is approved in the U.S, under the name Selzentry®, for both treatment-naïve and treatment-experienced adult patients with CCR5-tropic HIV-1 virus in combination with other anti-HIV medicines. Selzentry® is known as Celsentri® outside of the U.S. where it is indicated for appropriate treatment-experienced patients. Tropism testing with a highly sensitive tropism assay is required for the appropriate use of Selzentry®/Celsentri®.