Effects of Maraviroc and Efavirenz on Markers of Immune Activation and Inflammation and Associations with CD4+ Cell Rises in HIV-Infected Patients

Maraviroc treatment for HIV-1 infected patients results in larger CD4(+) T cell rises than are attributable to its antiviral activity alone. We investigated whether this is due to modulation of T cell activation and inflammation.Thirty maraviroc-treated patients from the Maraviroc versus Efavirenz Regimens as Initial Therapy (MERIT) study were randomly selected from among those who had CCR5-tropic (R5) HIV on screening and achieved undetectable HIV RNA (<50 copies/mL) by Week 48. Efavirenz-treated controls were matched for baseline characteristics to the maraviroc-treated patients selected for this substudy. Changes in immune activation and inflammation markers were examined for associations with CD4(+) T cell changes. Maraviroc treatment tended to result in more rapid decreases in CD38 expression on CD4(+) T cells and in plasma D-dimer concentrations than did treatment with efavirenz. The proportion of patients with high-sensitivity C-reactive protein >2 µg/mL increased from 45% to 66% in the efavirenz arm, but remained constant in the maraviroc arm (P = 0.033). Decreases in CD38 expression on CD8(+) T cells were correlated with CD4(+) T cell rises for maraviroc treatment (r = -0.4, P = 0.048), but not for treatment with efavirenz.Maraviroc-treated patients had earlier, modest decreases in certain markers of immune activation and inflammation, although in this small study, many of the differences were not statistically significant. Levels of high-sensitivity C-reactive protein remained constant in the maraviroc arm and increased in the efavirenz arm. Decreases in immune activation correlated with increased CD4(+) T cell gains.ClinicalTrials.gov NCT00098293

Identification and Interpretation of Longitudinal Gene Expression Changes in Trauma

The relationship between leukocyte gene expression and recovery of respiratory function after injury may provide information on the etiology of multiple organ dysfunction.To find a list of genes for which expression after injury predicts respiratory recovery, and to identify which networks and pathways characterize these genes.Blood was sampled at 12 hours and at 1, 4, 7, 21 and 28 days from 147 patients who had been admitted to the hospital after blunt trauma. Leukocyte gene expression was measured using Affymetrix oligonucleotide arrays. A linear model, fit to each probe-set expression value, was used to impute the gene expression trajectory over the entire follow-up period. The proportional hazards model score test was used to calculate the statistical significance of each probe-set trajectory in predicting respiratory recovery. A list of genes was determined such that the expected proportion of false positive results was less than 10%. These genes were compared to the Gene Ontology for 'response to stimulus' and, using Ingenuity software, were mapped into networks and pathways.The median time to respiratory recovery was 6 days. There were 170 probe-sets representing 135 genes that were found to be related to respiratory recovery. These genes could be mapped to nine networks. Two known pathways that were activated were antigen processing and presentation and JAK-signaling.The examination of the relationship of gene expression over time with a patient's clinical course can provide information which may be useful in determining the mechanism of recovery or lack of recovery after severe injury

Survival Analysis of Longitudinal Microarrays

Motivation: The development of methods for linking gene expressions to various clinical and phenotypic characteristics is an active area of genomic research. Scientists hope that such analysis may, for example, describe relationships between gene function and clinical events such as death or recovery. Methods are available for relating gene expression to measurements that are categorized or continuous, but there is less work in relating expressions to an observed event time such as time to death, response, or relapse. When gene expressions are measured over time, there are methods for differentiating temporal patterns. However, no methods have yet been proposed for the survival analysis of longitudinally collected microarrays. Results: We describe an approach for the survival analysis of longitudinal gene expression data. We construct a measure of association between the time to an event and gene expressions collected over time. The issue of high dimensionality and dependence when assessing statistical significance is addressed using permutations and control of the false discovery rate. Our proposed method is illustrated on a data set from a multi-center research study of inflammation and response to injury that aims to uncover the biological reasons why patients can have dramatically different outcomes after suffering a traumatic injury (www.gluegrant.org). Contact

Two-Year Safety and Virologic Efficacy of Maraviroc in Treatment-Experienced Patients With CCR5-Tropic HIV-1 Infection: 96-Week Combined Analysis of MOTIVATE 1 and 2

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CD4+ T-cell restoration after 48 weeks in the maraviroc treatment-experienced trials MOTIVATE 1 and 2

OBJECTIVES: To determine factors associated with CD4 responses to maraviroc (MVC)-containing regimens in treatment-experienced patients. METHODS: Forty-eight-week data from MOTIVATE 1 and 2 was used to assess MVC once or twice daily versus placebo (PBO), each with optimized background therapy (N = 1047). A repeated measures model evaluated longitudinal CD4 changes, multivariate linear regression evaluated predictors of week 48 increases, and Cox proportional hazard modeling evaluated time to category C events. RESULTS: Median CD4 increases were greater on MVC once or twice daily than PBO (92, 103, and 24 cells/mm3, respectively; P < 0.05), and the difference remained significant among patients achieving less than 50 HIV-1 RNA copies/mL (126, 125, and 96 cells/mm3; P < 0.05) or when adjusted for other predictors of CD4 increase including change in HIV-1 RNA. Time to a category C event was longer on MVC; in multivariate models, higher on-treatment CD4 count, but not MVC treatment, was protective against new events (hazard ratio 0.8 per +25 cells/mm3; 95% confidence interval 0.78-0.87). CONCLUSIONS: MOTIVATE patients receiving MVC had larger CD4+ T-cell increases than those receiving PBO, even after adjusting for the greater virologic potency of MVC-containing regimens. This additional CD4 response was associated with a longer time to the development of AIDS-defining events on MVC

Two-Year Safety and Virologic Efficacy of Maraviroc in Treatment-Experienced Patients With CCR5-Tropic HIV-1 Infection: 96-Week Combined Analysis of MOTIVATE 1 and 2

Background: Maraviroc, the first approved CCR5 antagonist, demonstrated 48-week safety and virologic efficacy in CCR5-tropic HIV-infected, treatment-experienced patients; however, critical longer-term safety and durability of responses are unknown. Methods: Two-year follow-up of 2 prospective, randomized, blinded studies of maraviroc once daily or twice daily, or placebo in treatment-experienced patients with R5-tropic HIV-1 receiving an optimized background regimen. Unblinding occurred after the week-48 visit of the last enrolled patient. Safety and virologic parameters were assessed through week 96. Results: One thousand forty-nine patients were randomized and received study drugs. HIV-1 RNA was <50 copies per milliliter at week 96 in 39% and 41% of patients receiving maraviroc every day or twice a day, respectively. Among patients with HIV-1 RNA,50 copies per milliliter at week 48, 81% and 87% of patients receiving maraviroc every day or twice a day, respectively, maintained this response at week 96. At week 96, median CD4+ T-cell counts increased from baseline by 89 and 113 cells per cubic millimeter with maraviroc every day and twice a day, respectively. Exposure-adjusted rates of adverse events were similar with maraviroc or placebo. No new or unexpected events were observed after week 48. Conclusions: Maraviroc-containing antiretroviral regimens maintained durable responses in treatment-experienced patients with R5 HIV-1 through 96 weeks of treatment with a safety profile similar to placebo