Maraviroc versus Efavirenz, Both in Combination with Zidovudine-Lamivudine, for the Treatment of Antiretroviral-Naive Subjects with CCR5-Tropic HIV-1 Infection

University of New South Wales, Sydney, Australia.
The Journal of Infectious Diseases (Impact Factor: 6). 02/2010; 201(6):803-13. DOI: 10.1086/650697
Source: PubMed


The MERIT (Maraviroc versus Efavirenz in Treatment-Naive Patients) study compared maraviroc and efavirenz, both with zidovudine-lamivudine, in antiretroviral-naive patients with R5 human immunodeficiency virus type 1 (HIV-1) infection.
Patients screened for R5 HIV-1 were randomized to receive efavirenz (600 mg once daily) or maraviroc (300 mg once or twice daily) with zidovudine-lamivudine. Coprimary end points were proportions of patients with a viral load <400 and <50 copies/mL at week 48; the noninferiority of maraviroc was assessed.
The once-daily maraviroc arm was discontinued for not meeting prespecified noninferiority criteria. In the primary 48-week analysis (n = 721), maraviroc was noninferior for <400 copies/mL (70.6% for maraviroc vs 73.1% for efavirenz) but not for <50 copies/mL (65.3% vs 69.3%) at a threshold of -10%. More maraviroc patients discontinued for lack of efficacy (11.9% vs 4.2%), but fewer discontinued for adverse events (4.2% vs 13.6%). In a post hoc reanalysis excluding 107 patients (15%) with non-R5 screening virus by the current, more sensitive tropism assay, the lower bound of the 1-sided 97.5% confidence interval for the difference between treatment groups was above -10% for each end point.
Twice-daily maraviroc was not noninferior to efavirenz at <50 copies/mL in the primary analysis. However, 15% of patients would have been ineligible for inclusion by a more sensitive screening assay. Their retrospective exclusion resulted in similar response rates in both arms Trial registration. identifier: (NCT00098293) .

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    • "Suboptimal CD4+ T cell recovery during potent antiretroviral therapy (ART) is a common clinical dilemma with an incidence as high as 40% (Dronda et al., 2002; Florence et al., 2003; Goicoechea et al., 2006; Kaufmann et al., 2003) that can have detrimental clinical consequences (Grabar et al., 2000), including an increased rate of HIV associated infections, malignancies, and cardiovascular morbidity and mortality. Among ART-naïve subjects treated with either efavirenz or MVC, those receiving MVC experienced significantly greater CD4+ T cell recovery (mean CD4+ T cell gain: 170 vs 144 cells/mm 3 ) (Cooper et al., 2010). In ART-experienced subjects with ongoing viral replication, administration of MVC for 24 weeks resulted in significantly greater CD4+ T cell recovery than background ART alone despite similar reductions in viral load (Saag et al., 2009). "
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    ABSTRACT: Addition of the CCR5 inhibitor Maraviroc (MVC) to ongoing antiretroviral therapy increases CD4+ T cell counts in some virologically suppressed patients with suboptimal CD4+ T cell recovery. To understand the mechanisms by which MVC elicits increases in CD4+ T cell counts, the present study was undertaken to identify host factors (i.e. genes) that are modulated and are correlated with CD4+ T cell recovery during the 24 weeks of MVC intensification in 32 subjects. Median changes of CD4+ T cell counts over 24 weeks of MVC compared to baseline were 38 cells/mm(3) (p<0.001). The median slope of CD4+ T cell recovery was 39 cells/mm(3) per year before initiation of MVC and 76 cells/mm(3) per year during MVC intensification, however, this increase was not statistically significant (p=0.33). Microarray analysis (N=31,426 genes) identified a single differentially expressed gene, tumor necrosis factor alpha (TNF), which was modestly (1.44-fold, p<0.001) downregulated by MVC at week 24 compared to baseline. TNF differential expression was evaluated using an independent method of droplet digital PCR, but the difference was not significant (p=0.6). Changes in gene expression did not correlate with CD4+ T cell recovery or any changes in the CD4+ T cell maturation, proliferation and activation phenotypes. In summary, our data suggest that modest improvements of CD4+ T cell counts during MVC intensification cannot be explained by changes in gene expression elicited by MVC. However, the modest changes in T cell composition, including reduction of the percentages of Tregs, proliferating CD4+ T cells and senescent CD8+ T cells, suggest immunologically favorable effects of MVC.
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    • "Clinical resistance to CCR5 inhibitors can evolve through two major pathways. Minority X4 populations present prior to the initiation of therapy can emerge under selective pressure (Westby et al., 2006; Gulick et al., 2007; Landovitz et al., 2008; Demarest et al., 2009; Kitrinos et al., 2009; Tsibris et al., 2009; Cooper et al., 2010; Roche et al., 2013). Alternately, resistant viruses can continue to use CCR5 despite the presence of the inhibitor. "
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    ABSTRACT: Adequate determination of HIV-1 tropism is important in clinical and research settings. Genotypic and phenotypic approaches to evaluate tropism have been described. Phenotypic assays are widely used to determine HIV-1 tropism because of their sensitivity to detect minor CXCR4-using variants (X4). However they cannot differentiate mixed quasi-species of R5 and X4 viruses from dual-tropic viruses. We describe a clonal-based HIV-1 tropism phenotypic assay. Env-pseudo-typed viruses were produced by co transfection of the env expression plasmid pcDNA3.1/V5HisTOPO and a backbone vector pNL4-3.Luc.E-R- that expresses the entire HIV-1 genome except for env and vpr in 293T cell cultures. Co-receptor use was tested by infecting U87-CD4-CCR5+ and U87-CD4-CXCR4+ cells in the presence and absence of co-receptor inhibitors, using 10 clones from each sample. The ability of the assay to detect minor variants in a viral population was assessed by mixing X4 and R5 clones using different ratios. Both R5 and X4 minority variants were detected when present at greater than 0.4% in a mixture of envelopes populations. This assay can be useful in both clinical and research laboratories.
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    • "Based on previous observations that Maraviroc (MVC), a CCR5 antagonist, promotes a gain of CD4þ T cells in viremic HIV-infected patients (Cooper et al., 2010; Wilkin et al., 2010), it was hypothesized that the immunomodulatory effects of this drug could decrease immune activation and improve CD4þ T cell counts in patients under suppressive cART with insufficient immunological restoration. As observed in RAL intensification trials, no impact in residual viremia or HIV reservoir was achieved. "
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