Trial of Maraviroc (UK-427,857) in Combination With Zidovudine/Lamivudine Versus Efavirenz in Combination With Zidovudine/Lamivudine (MERIT)

• To compare the time to loss of virological response through Weeks 48 and 96 for the UK-427,857 regimen versus the efavirenz regimen. [ Time Frame: week 48 and 96 ] [ Designated as safety issue: No ]
• To compare the reduction of plasma log10 HIV-1 RNA from baseline through Weeks 24, 48 and 96 for the UK-427,857 regimen versus the efavirenz regimen. [ Time Frame: week 24, 48 and 96 ] [ Designated as safety issue: No ]
• To compare the differences in the magnitude of changes in CD4 cell counts from baseline through Weeks 24, 48 and 96 for the UK-427,857 versus the efavirenz regimen [ Time Frame: week 24, 48 and 96 ] [ Designated as safety issue: No ]
• To compare the differences in the magnitude of changes in CD8 cell counts from baseline through Weeks 24, 48 and 96 for the UK-427,857 regimens versus the efavirenz regimen. [ Time Frame: week 24, 48 and 96 ] [ Designated as safety issue: No ]
• To compare the Time-Averaged Difference (TAD) in log10 HIV-1 RNA at Weeks 24, 48 and 96 for the UK-427,857 regimen versus the efavirenz regimen. [ Time Frame: week 24, 48 and 96 ] [ Designated as safety issue: No ]
• To assess HIV-1 genotype and phenotype at baseline and at the time of failure [ Time Frame: baseline and at the time of failure ] [ Designated as safety issue: No ]
• To assess HIV-1 tropism at baseline and at the time of failure [ Time Frame: baseline and at the time of failure ] [ Designated as safety issue: No ]
• To assess the association between baseline resistance and virological response. [ Time Frame: baseline resistance and virological response. ] [ Designated as safety issue: No ]
• To compare the safety and tolerability of the two UK-427,857 regimens versus the efavirenz regimen. [ Time Frame: duration of trial ] [ Designated as safety issue: Yes ]
• To assess whether the percentage of subjects with HIV 1 RNA less than 400 or 50 copies per mL at Weeks 24 and 96 for the UK 427,857 regimen is noninferior versus the efavirenz regimen each in combination with zidovudine/lamivudine. [ Time Frame: week 24 and 96 ] [ Designated as safety issue: No ]

• To compare the time to loss of virological response through Weeks 48 and 96 for the UK-427,857 regimen versus the efavirenz regimen. [ Time Frame: week 48 and 96 ] [ Designated as safety issue: No ]
• To compare the reduction of plasma log10 HIV-1 RNA from baseline through Weeks 24, 48 and 96 for the UK-427,857 regimen versus the efavirenz regimen. [ Time Frame: week 24, 48 and 96 ] [ Designated as safety issue: No ]
• To compare the differences in the magnitude of changes in CD4 cell counts from baseline through Weeks 24, 48 and 96 for the UK-427,857 versus the efavirenz regimen [ Time Frame: week 24, 48 and 96 ] [ Designated as safety issue: No ]
• To compare the differences in the magnitude of changes in CD8 cell counts from baseline through Weeks 24, 48 and 96 for the UK-427,857 regimens versus the efavirenz regimen. [ Time Frame: week 24, 48 and 96 ] [ Designated as safety issue: No ]
• To compare the Time-Averaged Difference (TAD) in log10 HIV-1 RNA at Weeks 24, 48 and 96 for the UK-427,857 regimen versus the efavirenz regimen. [ Time Frame: week 24, 48 and 96 ] [ Designated as safety issue: No ]
• To assess HIV-1 genotype and phenotype at baseline and at the time of failure [ Designated as safety issue: No ]
• To assess HIV-1 tropism at baseline and at the time of failure [ Designated as safety issue: No ]
• To assess the association between baseline resistance and virological response. [ Designated as safety issue: No ]
• To compare the safety and tolerability of the two UK-427,857 regimens versus the efavirenz regimen. [ Designated as safety issue: Yes ]
• To assess whether the percentage of subjects with HIV 1 RNA less than 400 or 50 copies per mL at Weeks 24 and 96 for the UK 427,857 regimen is noninferior versus the efavirenz regimen each in combination with zidovudine/lamivudine. [ Time Frame: week 24 and 96 ] [ Designated as safety issue: No ]

Maraviroc (UK-427,857), a selective and reversible CCR5 coreceptor antagonist, has been shown to be active in vitro against a wide range of clinical isolates (including those resistant to existing classes). In HIV-1 infected patients, maraviroc (UK-427,857) given as monotherapy for 10 days reduced HIV-1 viral load by up to 1.6 log, consistent with currently available agents. Safety and toleration have been studied in over 400 subjects for up to 28 days at 300 mg twice daily. No significant effects were seen on the QTc interval. The goal of this study is to compare the safety and efficacy of maraviroc (UK-427,857) versus efavirenz, when each are combined with two other antiretroviral agents, in patients who are previously naive to antiretroviral therapy. This study will involve approximately 200 centers from around the world to achieve a total randomized subject population of 1071 subjects. Patients will be randomly assigned to one of three groups: maraviroc (UK-427,857) 300 mg once daily added to zidovudine/lamivudine (300 mg/150 mg twice daily), Maraviroc (UK-427,857) 300 mg twice daily added to zidovudine/lamivudine (300 mg/150 mg twice daily) or efavirenz (600 mg once daily) added to zidovudine/lamivudine (300 mg/150 mg twice daily). The study will enroll over approximately an 18 month period (5 months Phase 2b run-in, 13 months Phase 3) with 96 weeks of treatment. This may be extended for an additional 3 years depending on the results at 96 weeks. Physical examinations will be performed at study entry, weeks 4, 8, 12, 16, 20, 24, 32, 40, 48, 60, 72, 84 and 96. Blood samples will also be taken at study entry, weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, 60, 72, 84 and 96. Additionally, blood samples will be drawn twice, at least 30 minutes apart, at weeks 2 and 48 for maraviroc (UK-427,857) pharmacokinetic analysis. As part of this clinical study a blood sample will be taken for non-anonymized pharmacogenetic analysis. Patients will undergo a 12-lead electrocardiogram at study entry, weeks 24, 48 and 96. A computerized tomography (CT) scan will also be performed, at selected centers, at study entry and week 96. Patients will be asked to complete a symptom distress questionnaire at study entry, weeks 12, 24, 48 and 96.

• Drug: Maraviroc + Zidovudine/Lamivudine
  maraviroc (UK-427,857) 300 mg once daily added to zidovudine/lamivudine (300 mg/150 mg twice daily)
• Drug: Efavirenz + Zidovudine/Lamivudine
  efavirenz (600 mg once daily) added to zidovudine/lamivudine (300 mg/150 mg twice daily)
• Drug: Maraviroc (UK-427,857) + Zidovudine/Lamivudine
  maraviroc (UK-427,857) 300 mg twice daily added to zidovudine/lamivudine (300 mg/150 mg twice daily)

• Experimental: 1
  Intervention: Drug: Maraviroc + Zidovudine/Lamivudine
• Active Comparator: 3
  Intervention: Drug: Efavirenz + Zidovudine/Lamivudine
• Experimental: 2
  Following a review of the interim analysis data, the DSMB recommended to terminate the UK-427,857 300 mg QD arm based on pre-specified protocol non-inferiority criteria not being met for the QD arm versus efavirenz
  Intervention: Drug: Maraviroc (UK-427,857) + Zidovudine/Lamivudine

• MacInnes A, Lazzarin A, Di Perri G, Sierra-Madero JG, Aberg J, Heera J, Rajicic N, Goodrich J, Mayer H, Valdez H. Maraviroc can improve lipid profiles in dyslipidemic patients with HIV: results from the MERIT trial. HIV Clin Trials. 2011 Jan-Feb;12(1):24-36.
• Funderburg N, Kalinowska M, Eason J, Goodrich J, Heera J, Mayer H, Rajicic N, Valdez H, Lederman MM. Effects of maraviroc and efavirenz on markers of immune activation and inflammation and associations with CD4+ cell rises in HIV-infected patients. PLoS One. 2010 Oct 6;5(10):e13188.
• Cooper DA, Heera J, Goodrich J, Tawadrous M, Saag M, Dejesus E, Clumeck N, Walmsley S, Ting N, Coakley E, Reeves JD, Reyes-Teran G, Westby M, Van Der Ryst E, Ive P, Mohapi L, Mingrone H, Horban A, Hackman F, Sullivan J, Mayer H. Maraviroc versus Efavirenz, both in combination with zidovudine-lamivudine, for the treatment of antiretroviral-naive subjects with CCR5-tropic HIV-1 infection. J Infect Dis. 2010 Mar 15;201(6):803-13.

Inclusion Criteria:

• Men or women at least 16 years of age (or minimum age as determined by local regulatory authorities)
• HIV-1 RNA viral load of greater than or equal to 2, 000 copies/mL
• A negative urine pregnancy test at the baseline visit for Women of Child Bearing Potential (WOCBP)
• Effective barrier contraception for WOCBP and males

Exclusion Criteria:

• Suspected or documented active, untreated HIV-1 related opportunistic infection (OI) or other condition requiring acute therapy
• Treatment for an active opportunistic infection, or unexplained temperature >38.5 degrees Celsius for 7 consecutive days
• Prior treatment with efavirenz, zidovudine or lamivudine or with any other antiretroviral therapy for more than 14 days at any time
• Active alcohol or substance abuse sufficient, in the Investigator's judgment, to prevent adherence to study medication and/or follow up
• Lactating women, or planned pregnancy during the trial period
• Suspected primary (acute) HIV-1 infection
• Previous therapy with a potentially myelosuppressive, neurotoxic, hepatotoxic and/or cytotoxic agent within 30 days prior to randomization or the expected need for such therapy during the study period
• Documented or suspected acute hepatitis or pancreatitis within 30 days prior to randomization
• Significantly elevated liver enzymes or cirrhosis
• Significant neutropenia, anemia or thrombocytopenia
• Malabsorption or an inability to tolerate oral medications
• Symptomatic postural hypotension or severe cardiovascular or cerebrovascular disease
• Certain medications
• Genotypic or phenotypic resistance to efavirenz, zidovudine or lamivudine
• X4- or dual/mixed-tropic virus or repeated assay failure
• Any other clinical condition that, in the Investigator's judgement, would potentially compromise study compliance or the ability to evaluate safety/efficacy