Subgroup analyses of maraviroc in previously treated R5 HIV-1 infection.

BACKGROUND We conducted subanalyses of the combined results of the Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) 1 and MOTIVATE 2 studies to better characterize the efficacy and safety of maraviroc in key subgroups of patients. METHODS We analyzed pooled data from week 48 from the two studies according to sex, race or ethnic group, clade, CC chemokine receptor 5 (CCR5) delta32 genotype, viral load at the time of screening, the use or nonuse of enfuvirtide in optimized background therapy (OBT), the baseline CD4 cell count, the number of active antiretroviral drugs coadministered, the first use of selected background agents, and tropism at baseline. Changes in viral tropism and the CD4 count at treatment failure were evaluated. Data on aminotransferase levels in patients coinfected with hepatitis B virus (HBV) or hepatitis C virus (HCV) were also analyzed. RESULTS A treatment benefit of maraviroc plus OBT over placebo plus OBT was shown in all subgroups, including patients with a low CD4 cell count at baseline, those with a high viral load at screening, and those who had not received active agents in OBT. Analyses of the virologic response according to the first use of selected background drugs showed the additional benefit of adding a potent new drug to maraviroc at the initiation of maraviroc therapy. More patients in whom maraviroc failed had a virus binding to the CXC chemokine receptor 4 (CXCR4) at failure, but there was no evidence of a decrease in the CD4 cell count at failure in such patients as compared with those in whom placebo failed. Subanalyses involving patients coinfected with HBV or HCV revealed no evidence of excess hepatotoxic effects as compared with baseline. CONCLUSIONS Subanalyses of pooled data from week 48 indicate that maraviroc provides a valuable treatment option for a wide spectrum of patients with R5 HIV-1 infection who have been treated previously. (ClinicalTrials.gov numbers, NCT00098306 and NCT00098722.)

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

[2]  R. Haubrich,et al.  Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials , 2007, The Lancet.

[3]  R. Haubrich,et al.  Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial , 2007, The Lancet.

[4]  Jonathan AC Sterne,et al.  Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies , 2002, The Lancet.

[5]  A. Mocroft,et al.  Hepatitis B and HIV: prevalence, AIDS progression, response to highly active antiretroviral therapy and increased mortality in the EuroSIDA cohort , 2005, AIDS.

[6]  A. Mocroft,et al.  Are Specific Antiretrovirals associated with an Increased Risk of Discontinuation due to Toxicities or Patient/Physician Choice in patients with Hepatitis C Virus Coinfection? , 2005, Antiviral therapy.

[7]  S. Hammer,et al.  Prognostic value of baseline human immunodeficiency virus type 1 DNA measurement for disease progression in patients receiving nucleoside therapy. , 2003, The Journal of infectious diseases.

[8]  M. Parmentier,et al.  CCR5 deficiency exacerbates T‐cell–mediated hepatitis in mice , 2005, Hepatology.

[9]  Eoin Coakley,et al.  HIV type 1 chemokine coreceptor use among antiretroviral-experienced patients screened for a clinical trial of a CCR5 inhibitor: AIDS Clinical Trial Group A5211. , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[10]  Mike Youle,et al.  Emergence of CXCR4-Using Human Immunodeficiency Virus Type 1 (HIV-1) Variants in a Minority of HIV-1-Infected Patients following Treatment with the CCR5 Antagonist Maraviroc Is from a Pretreatment CXCR4-Using Virus Reservoir , 2006, Journal of Virology.

[11]  J. Montaner,et al.  Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. , 2003, The New England journal of medicine.

[12]  G. Ahlenstiel,et al.  Frequency of the HIV-protective CC chemokine receptor 5-Δ32/Δ32 genotype is increased in hepatitis C , 2002 .

[13]  J. Crowe,et al.  The CCR5-Δ32 mutation: impact on disease outcome in individuals with hepatitis C infection from a single source , 2005, Gut.

[14]  Christos J. Petropoulos,et al.  Development and Characterization of a Novel Single-Cycle Recombinant-Virus Assay To Determine Human Immunodeficiency Virus Type 1 Coreceptor Tropism , 2006, Antimicrobial Agents and Chemotherapy.

[15]  Michael S Saag,et al.  Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1 , 2005, Nature Medicine.

[16]  J. Wheeler,et al.  Assessing Theoretical Risk and Benefit suggested by Genetic Association Studies of CCR5: Experience in a Drug Development Programme for Maraviroc , 2007, Antiviral therapy.

[17]  M. Westby.  Resistance to CCR5 antagonists , 2007, Current opinion in HIV and AIDS.

[18]  I. Keet,et al.  Prognostic Value of HIV-1 Syncytium-Inducing Phenotype for Rate of CD4+ Cell Depletion and Progression to AIDS , 1993, Annals of Internal Medicine.

[19]  Terri Wrin,et al.  Persistence of drug-resistant HIV-1 after a structured treatment interruption and its impact on treatment response , 2003, AIDS.

[20]  C. Hogaboam,et al.  CCR5 deficiency drives enhanced natural killer cell trafficking to and activation within the liver in murine T cell-mediated hepatitis. , 2007, The American journal of pathology.

[21]  G. Siame.  Hepatitis B and hepatitis C prevalence in HIV positive pregnant women , 2006, Retrovirology.

[22]  Stephen W Lagakos,et al.  Statistics in medicine--reporting of subgroup analyses in clinical trials. , 2007, The New England journal of medicine.

[23]  B. Clotet,et al.  Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial , 2007, The Lancet.

[24]  David A. Price,et al.  Maraviroc (UK-427,857), a Potent, Orally Bioavailable, and Selective Small-Molecule Inhibitor of Chemokine Receptor CCR5 with Broad-Spectrum Anti-Human Immunodeficiency Virus Type 1 Activity , 2005, Antimicrobial Agents and Chemotherapy.

[25]  B. Thiers.  Raltegravir with Optimized Background Therapy for Resistant HIV-1 Infection , 2009 .

[26]  G. Ahlenstiel,et al.  Frequency of the HIV-protective CC chemokine receptor 5-Delta32/Delta32 genotype is increased in hepatitis C. , 2002, Gastroenterology.

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

[28]  Christine Katlama,et al.  Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. , 2003, The New England journal of medicine.

[29]  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.