Vicriviroc plus optimized background therapy for treatment-experienced subjects with CCR5 HIV-1 infection: final results of two randomized phase III trials.

BACKGROUND Vicriviroc, a novel HIV CCR5 antagonist, demonstrated significant efficacy and favorable tolerability in phase II trials in treatment-experienced subjects, supporting further evaluation in phase III studies. METHODS Two identical double-blind, placebo (PBO)-controlled trials in CCR5-tropic HIV-infected subjects with documented resistance to two antiretroviral classes were conducted. Subjects were randomized to vicriviroc 30 mg QD (N = 571) or PBO (N = 286) with open-label optimized background therapy (OBT) containing ≥2 fully active antiretroviral drugs. The primary endpoint was percentage of subjects with <50 copies/mL HIV RNA at 48 weeks. It was analyzed in a logistic regression with treatment (vicriviroc + OBT/PBO + OBT), use of enfuvirtide in baseline OBT (yes/no), and baseline HIV RNA (≤100,000/>100,000 copies/mL) as covariates. In addition, a pre-planned analysis to examine other efficacy and safety endpoints was conducted. RESULTS Baseline characteristics of the pooled mITT population (vicriviroc, n = 486; PBO, n = 235) included mean HIV RNA of 4.6 log(10) copies/mL and mean CD4 count of 257 cells/μL. Approximately 60% of subjects received ≥3 active drugs in the OBT. The percentage of subjects with <50 copies/mL HIV RNA was not significantly different between vicriviroc and PBO at week 48 (64% vs 62%, p = 0.6). However, in subjects receiving ≤2 active drugs in their OBT, the proportion achieving <50 copies/mL HIV RNA was higher in those receiving vicriviroc compared with PBO (70% vs 55%, p = 0.02). CONCLUSIONS The studies failed to show significant efficacy gains when vicriviroc was added to OBT. However, given the efficacy results of earlier vicriviroc trials and other CCR5 antagonist, studies are needed to define the role of this class of drugs in the treatment of HIV. Clinical trial identifier: http://www.clinicaltrial.gov/: VICTOR-E3 (NCT00523211) and VICTOR-E4 (NCT00474370).

[1]  M. Hughes,et al.  Phase 2 study of the safety and efficacy of vicriviroc, a CCR5 inhibitor, in HIV-1-Infected, treatment-experienced patients: AIDS clinical trials group 5211. , 2007, The Journal of infectious diseases.

[2]  J. J. Henning,et al.  Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, January 28, 2000 , 1998, HIV clinical trials.

[3]  M. Hirsch,et al.  Discovery and Characterization of Vicriviroc (SCH 417690), a CCR5 Antagonist with Potent Activity against Human Immunodeficiency Virus Type 1 , 2005, Antimicrobial Agents and Chemotherapy.

[4]  E. Poveda,et al.  Prevalence of darunavir resistance mutations in HIV-1-infected patients failing other protease inhibitors. , 2007, The Journal of antimicrobial chemotherapy.

[5]  V. Miller,et al.  Novel clinical trial designs for the development of new antiretroviral agents , 2012, AIDS.

[6]  Bernard Hirschel,et al.  Subgroup analyses of maraviroc in previously treated R5 HIV-1 infection. , 2008, The New England journal of medicine.

[7]  Michael S Saag,et al.  Treatment for Adult HIV Infection 2006 Recommendations of the International AIDS Society–USA Panel , 2006 .

[8]  E. Coakley,et al.  Short communication prevalence of susceptibility to etravirine by genotype and phenotype in samples received for routine HIV type 1 resistance testing in the United States. , 2011, AIDS Research and Human Retroviruses.

[9]  R. Vilchez.  Novel clinical trial designs and HIV-1 RNA assessments with end-point and real-time PCR tests. , 2012, AIDS (London).

[10]  D. Hazuda,et al.  Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. , 2008, The New England journal of medicine.

[11]  C. Katlama,et al.  Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial , 2007, The Lancet.

[12]  S. Walmsley,et al.  Vicriviroc in combination therapy with an optimized regimen for treatment-experienced subjects: 48-week results of the VICTOR-E1 phase 2 trial. , 2010, The Journal of infectious diseases.

[13]  Michael S Saag,et al.  Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society--USA panel. , 2006, Topics in HIV medicine : a publication of the International AIDS Society, USA.

[14]  Anders Karlsson,et al.  Maraviroc for previously treated patients with R5 HIV-1 infection. , 2008, The New England journal of medicine.

[15]  Amalio Telenti,et al.  Antiretroviral Treatment of Adult HIV Infection2010 Recommendations of the International AIDS Society–USA Panel , 2010 .