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. ClinicalTrials.gov identifier: (NCT00098293) .
"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). "
[Show abstract][Hide abstract] 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.
Antiviral research 04/2014; 107(1). DOI:10.1016/j.antiviral.2014.04.005 · 3.94 Impact Factor
"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. "
[Show abstract][Hide abstract] 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.
"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. "
[Show abstract][Hide abstract] ABSTRACT: Thirty years after the identification of HIV, a cure for HIV infection is still to be achieved. Advances of combined antiretroviral therapy (cART) in recent years have transformed HIV infection into a chronic disease when treatment is available. However, in spite of the favorable outcomes provided by the newer therapies, cART is not curative and patients are at risk of developing HIV-associated disorders. Moreover, universal access to antiretroviral treatment is restricted by financial obstacles. This review discusses the most recent strategies that have been developed in the search for an HIV cure and to improve life quality of people living with HIV.
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