Dataset Information

Stroke incidence is highest in women and non-Hispanic blacks living with HIV in the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials cohort.

ABSTRACT: OBJECTIVE:To investigate the incidence of first-ever stroke/transient ischemic attack (TIA) and associated risk factors in a cohort of persons living with HIV infection (PLWH). DESIGN:Observational cohort study METHODS:We determined incidence rates of first-ever stroke/TIA in PLWH after ART initiation from the AIDS Clinical Trials Group ALLRT cohort and its parent trials. Poisson regression models evaluated baseline and time-varying covariates as risk factors for stroke/TIA. RESULTS:The incidence rate of stroke/TIA was 1.69 per 1000 person-years. Incidence rates were highest in women (2.88?stroke/TIAs per 1000 person-years compared with 1.40 per 1000 person-years in men) and non-Hispanic Blacks (2.51?stroke/TIAs per 1000 person-years compared with 0.77 per 1000 person-years in Hispanic/other race/ethnicities and 1.56 per 1000 person-years in whites). In a multivariable model, we found a significant age-by-sex interaction (P?=?0.01). The higher risk of stroke/TIA in women was more pronounced at younger ages, whereas older age conferred a greater increase in stroke/TIA risk in men than women. Other risk factors for stroke/TIA included hypertension, higher LDL, and HIV RNA greater than 200?copies/ml. Overweight/obese BMI and higher CD4+:CD8+ ratio protected against stroke/TIA. CONCLUSION:Women and non-Hispanic Blacks living with HIV had the highest incidence rates of stroke/TIA. A concerted effort must be made to include PLWH from these at-risk groups in observational and interventional studies aimed at understanding stroke mechanisms and reducing stroke risk in HIV infection. Strategies to modify stroke risk in PLWH should employ a multipronged approach targeting vascular risk factors and engaging and retaining patients in HIV care.

SUBMITTER: Chow FC

PROVIDER: S-EPMC5955006 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Stroke incidence is highest in women and non-Hispanic blacks living with HIV in the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials cohort.

Chow Felicia C FC Wilson Michael R MR Wu Kunling K Ellis Ronald J RJ Bosch Ronald J RJ Linas Benjamin P BP

AIDS (London, England) 20180601 9

<h4>Objective</h4>To investigate the incidence of first-ever stroke/transient ischemic attack (TIA) and associated risk factors in a cohort of persons living with HIV infection (PLWH).<h4>Design</h4>Observational cohort study<h4>Methods</h4>We determined incidence rates of first-ever stroke/TIA in PLWH after ART initiation from the AIDS Clinical Trials Group ALLRT cohort and its parent trials. Poisson regression models evaluated baseline and time-varying covariates as risk factors for stroke/TIA ...[more]

PMID: 29746317

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Project description:Association studies have shown and continue to show a substantial amount of success in identifying links between multiple single nucleotide polymorphisms (SNPs) and phenotypes. These studies are also believed to provide insights toward identification of new drug targets and therapies. Albeit of all the success, challenges still remain for applying and prioritizing these associations based on available biological knowledge. Along with single variant association analysis, genetic interactions also play an important role in uncovering the etiology and progression of complex traits. For gene-gene interaction analysis, selection of the variants to test for associations still poses a challenge in identifying epistatic interactions among the large list of variants available in high-throughput, genome-wide datasets. Therefore in this study, we propose a pipeline to identify interactions among genetic variants that are associated with multiple phenotypes by prioritizing previously published results from main effect association analysis (genome-wide and phenome-wide association analysis) based on a-priori biological knowledge in AIDS Clinical Trials Group (ACTG) data. We approached the prioritization and filtration of variants by using the results of a previously published single variant PheWAS and then utilizing biological information from the Roadmap Epigenome project. We removed variants in low functional activity regions based on chromatin states annotation and then conducted an exhaustive pairwise interaction search using linear regression analysis. We performed this analysis in two independent pre-treatment clinical trial datasets from ACTG to allow for both discovery and replication. Using a regression framework, we observed 50,798 associations that replicate at p-value 0.01 for 26 phenotypes, among which 2,176 associations for 212 unique SNPs for fasting blood glucose phenotype reach Bonferroni significance and an additional 9,970 interactions for high-density lipoprotein (HDL) phenotype and fasting blood glucose (total of 12,146 associations) reach FDR significance. We conclude that this method of prioritizing variants to look for epistatic interactions can be used extensively for generating hypotheses for genomewide and phenome-wide interaction analyses. This original Phenome-wide Interaction study (PheWIS) can be applied further to patients enrolled in randomized clinical trials to establish the relationship between patient's response to a particular drug therapy and non-linear combination of variants that might be affecting the outcome.

Project description:AIDS Clinical Trial Group study A5202 (ClinicalTrials.gov identifier NCT00118898) was a phase 3b, randomized, partially blinded equivalence study of open-label atazanavir/ritonavir or efavirenz, plus either placebo-controlled tenofovir disoproxil fumarate/emtricitabine or abacavir/lamivudine, in treatment-naive adults living with HIV-1, evaluating efficacy, safety, and tolerability. We report an analysis of the contribution of participant characteristics to the disposition of tenofovir plasma concentrations. Tenofovir concentration data from a total of 817 individuals (88% of the total number of eligible patients randomly assigned to receive treatment in the TDF-containing arms of A5202) were available for analysis. Pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. One- and two-compartment models with first-order absorption and first-order elimination were evaluated. An exponential error model was used for examination of interindividual variability (IIV), and a proportional and mixed-error model was assessed for residual variability. The final structural model contained two compartments with first-order absorption and elimination. IIV was estimated for apparent clearance (CL/F) and the first-order absorption rate constant (ka ), and a proportional residual variability model was selected. The final mean parameter estimates were as follows: ka = 2.87 h-1, CL/F = 37.2 liters/h, apparent volumes of the central and peripheral compartments = 127 and 646 liters, respectively, and apparent intercompartmental clearance = 107 liters/h. In addition to race/ethnicity, creatinine clearance and assignment to atazanavir/ritonavir or efavirenz were significantly associated with CL/F (P < 0.001). In conclusion, race/ethnicity is associated with tenofovir oral CL in HIV-1 positive, treatment-naive adults. This covariate relationship raises questions about the possibility of differences in efficacy and risk of adverse events in different patient populations and suggests that examining preexposure prophylaxis regimens and tenofovir exposure in different race/ethnicity groups be considered.

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Project description:BackgroundNoninferiority trials are increasingly being performed. However, little is known about their methodological quality. We sought to characterize noninferiority cardiovascular trials published in the highest-impact journals, features that may bias results toward noninferiority, features related to reporting of noninferiority trials, and the time trends.MethodsWe identified cardiovascular noninferiority trials published in JAMA, Lancet, or New England Journal of Medicine from 1990 to 2016. Two independent reviewers extracted the data. Data elements included the noninferiority margin and the success of studies in achieving noninferiority. The proportion of trials showing major or minor features that may have affected the noninferiority inference was determined. Major factors included the lack of presenting the results in both intention-to-treat and per-protocol/as-treated cohorts, α>0.05, the new intervention not being compared with the best alternative, not justifying the noninferiority margin, and exclusion or loss of ≥10% of the cohort. Minor factors included suboptimal blinding, allocation concealment, and others.ResultsFrom 2544 screened studies, we identified 111 noninferiority cardiovascular trials. Noninferiority margins varied widely: risk differences of 0.4% to 25%, hazard ratios of 1.05 to 2.85, odds ratios of 1.1 to 2.0, and relative risks of 1.1 to 1.8. Eighty-six trials claimed noninferiority, of which 20 showed superiority, whereas 23 (21.1%) did not show noninferiority, of which 8 also demonstrated inferiority. Only 7 (6.3%) trials were considered low risk for all the major and minor biasing factors. Among common major factors for bias, 41 (37%) did not confirm the findings in both intention-to-treat and per-protocol/as-treated cohorts and 4 (3.6%) reported discrepant results between intention-to-treat and per-protocol analyses. Forty-three (38.7%) did not justify the noninferiority margin. Overall, 27 (24.3%) underenrolled or had >10% exclusions. Sixty trials (54.0%) were open label. Allocation concealment was not maintained or unclear in 11 (9.9%). Publication of noninferiority trials increased over time (P<0.001). Fifty-two (46.8%) were published after 2010 and had a lower risk of methodological or reporting limitations for major (P=0.03) and minor factors (P=0.002).ConclusionsNoninferiority trials in highest-impact journals commonly conclude noninferiority of the tested intervention, but vary markedly in the selected noninferiority margin, and frequently have limitations that may impact the inference related to noninferiority.

Dataset Information

Stroke incidence is highest in women and non-Hispanic blacks living with HIV in the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials cohort.

Publications

Stroke incidence is highest in women and non-Hispanic blacks living with HIV in the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials cohort.

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