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Brown T.T.,Johns Hopkins University | Tassiopoulos K.,Center for Biostatistics in Research | Bosch R.J.,Center for Biostatistics in Research | Shikuma C.,University of Hawaii at Manoa
Diabetes Care | Year: 2010

OBJECTIVE - To determine whether systemic inflammation after initiation of HIV-antiretroviral therapy (ART) is associated with the development of diabetes. RESEARCH DESIGN AND METHODS - We conducted a nested case-control study, comparing 55 previously ART-naive individuals who developed diabetes 48 weeks after ART initiation (case subjects) with 55 individuals who did not develop diabetes during a comparable follow-up (control subjects), matched on baseline BMI and race/ethnicity. Stored plasma samples at treatment initiation (week 0) and 1 year later (week 48) were assayed for levels of high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and the soluble receptors of tumor necrosis factor-α (sTNFR1 and sTNFR2). RESULTS - Case subjects were older than control subjects (median age 41 vs. 37 years, P = 0.001), but the groups were otherwise comparable. Median levels for all markers, except hs-CRP, decreased from week 0 to week 48. Subjects with higher levels of hs-CRP, sTNFR1, and sTNFR2 at 48 weeks had an increased odds of subsequent diabetes, after adjustment for baseline marker level, age, BMI at week 48, CD4 count at week 48 (〈vs.〉 200 cells/mm3), and indinavir use (all P trend ≤ 0.05). After further adjustment for week 48 glucose, effects were attenuated and only sTNFR1 remained significant (odds ratio, highest quartile vs. lowest 23.2 [95% CI 1.28-423], P = 0.03). CONCLUSIONS - Inflammatory markers 48 weeks after ART initiation were associated with increased risk of diabetes. These findings suggest that systemic inflammation may contribute to diabetes pathogenesis among HIV-infected patients. © 2010 by the American Diabetes Association.

Bosch R.J.,Center for Biostatistics in Research | Zhang X.,Center for Biostatistics in Research | Sandler N.G.,National Institute of Allergy and Infectious Diseases
Current Opinion in HIV and AIDS | Year: 2013

Purpose of review: The dramatic increase in the number and type of immune biomarkers that can be measured, particularly those assessing immune activation, has led to numerous investigations in HIV-infected individuals to explore pathogenesis and to assess therapeutic interventions that aim to attenuate immune activation. An overview is provided on study designs and related statistical and operational issues relevant to these investigations. RECENT FINDINGS: Cohort studies and nested case-control studies within these cohorts have identified multiple biomarkers that are associated with an increased risk of disease. Early-stage clinical trials of therapies to address these risks in HIV-infected individuals with viral suppression on antiretroviral therapy are a substantial focus of current HIV research. SUMMARY: Appropriate study design is essential in biomarker research. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Madhi S.A.,University of Witwatersrand | Nachman S.,State University of New York at Stony Brook | Violari A.,University of Witwatersrand | Kim S.,Center for Biostatistics in Research | And 5 more authors.
New England Journal of Medicine | Year: 2011

BACKGROUND: The dual epidemic of human immunodeficiency virus (HIV) and tuberculosis is a major cause of sickness and death in sub-Saharan Africa. We conducted a double-blind, randomized, placebo-controlled trial of preexposure isoniazid prophylaxis against tuberculosis in HIV-infected children and uninfected children exposed to HIV during the perinatal period. METHODS: We randomly assigned 548 HIV-infected and 804 HIV-uninfected infants (91 to 120 days of age) to isoniazid (10 to 20 mg per kilogram of body weight per day) or matching placebo for 96 weeks. All patients received bacille Calmette-Guérin (BCG) vaccination against tuberculosis within 30 days after birth. HIV-infected children had access to antiretroviral therapy. The primary outcome measures were tuberculosis disease and death in HIV-infected children and latent tuberculosis infection, tuberculosis disease, and death in HIV-uninfected children within 96 to 108 weeks after randomization. RESULTS: Antiretroviral therapy was initiated in 98.9% of HIV-infected children during the study. Among HIV-infected children, protocol-defined tuberculosis or death occurred in 52 children (19.0%) in the isoniazid group and 53 (19.3%) in the placebo group (P = 0.93). Among HIV-uninfected children, there was no significant difference in the combined incidence of tuberculosis infection, tuberculosis disease, or death between the isoniazid group (39 children, 10%) and the placebo group (45 children, 11%; P = 0.44). The rate of tuberculosis was 121 cases per 1000 child-years (95% confidence interval [CI], 95 to 153) among HIV-infected children as compared with 41 per 1000 child-years (95% CI, 31 to 52) among HIV-uninfected children. There were no significant differences in clinical or severe laboratory toxic effects between treatment groups. CONCLUSIONS: Primary isoniazid prophylaxis did not improve tuberculosis-disease- free survival among HIV-infected children or tuberculosis-infection-free survival among HIV-uninfected children immunized with BCG vaccine. Despite access to antiretroviral therapy, the burden of tuberculosis remained high among HIV-infected children. (Funded by the National Institutes of Health and Secure the Future; number, NCT00080119.) Copyright © 2011 Massachusetts Medical Society.

Buchanan A.L.,Center for Biostatistics in Research | Montepiedra G.,Center for Biostatistics in Research | Sirois P.A.,Tulane University | Kammerer B.,Childrens Hospital Boston | And 3 more authors.
Pediatrics | Year: 2012

OBJECTIVE: Nonadherence to antiretroviral therapy among children/ youth with HIV often is associated with disease progression. This study examined the agreement between child and caregiver perceptions of barriers to adherence and factors associated with these barriers. METHODS: Children/youth with perinatally acquired HIV and their parents/caregivers (n = 120 dyads) completed a questionnaire about 19 potential barriers to adherence to the child's antiretroviral therapy regimen. Agreement between the 2 reports was measured via the kappa statistic. Factors associated with the barriers were assessed by using multiple logistic regression. RESULTS: Of the 120 children, 55% were African American, 54% were boys, and the average age was 12.8 years. The most frequently reported barrier by either the caregiver or youth was "forgot." There were varying degrees of agreement between child and caregiver on the following barriers: "forgot," "taste," "child was away from home,""child refused," and "child felt good." Children who knew their HIV status were more likely to report logistical barriers, such as scheduling issues. Children with a biological parent as their caregiver were more likely to report regimen or fear of disclosure as a barrier. CONCLUSIONS: Lack of agreement was observed for more than half of the studied barriers, indicating discrepancies between children's and caregivers' perceptions of factors that influence medication-taking. The findings suggest a need for interventions that involve both child and caregiver in the tasks of remembering when to administer the child's medications, sustaining adherence, and appropriately transitioning medication responsibility to the youth. Copyright © 2012 by the American Academy of Pediatrics.

Objectives: The extent to which highly active antiretroviral therapy (HAART) affects human papillomavirus (HPV) acquisition and clearance in HIV-infected women is not well understood. We sought to describe high-risk HPV detection and clearance rates over time since HAART initiation, based on time-varying HIV viral load (VL) and CD4 T-cell count, using novel statistical methods. Methods: We conducted a retrospective analysis of data from the completed AIDS Clinical Trials Group (ACTG) A5029 study using multi-state Markov models. Two sets of high-risk HPV types from 2003 and 2009 publications were considered. Results: There was some evidence that VL>400 HIV-1 RNA copies/mL was marginally associated with a higher rate of HPV detection [P=0.068; hazard ratio (HR)=4.67], using the older set of high-risk HPV types. Such an association was not identified using the latest set of HPV types (P=0.343; HR=2.64). CD4 count >350cells/μL was significantly associated with more rapid HPV clearance with both sets of HPV types (P=0.001, HR=3.93; P=0.018, HR=2.65). There was no evidence that HPV affects VL or CD4 cell count in any of the analyses. Conclusions: High-risk HPV types vary among studies and can affect the results of analyses. Use of HAART to improve CD4 cell count may have an impact on the control of HPV infection. The decrease in VL may also have an effect, although to a lesser degree. © 2012 British HIV Association.

Siberry G.K.,National Health Research Institute | Li H.,Rush University | Jacobson D.,Center for Biostatistics in Research
AIDS Research and Human Retroviruses | Year: 2012

The objective of this study was to examine the incidence of fractures in HIV-infected children and comparable HIV-exposed, uninfected (HEU) children in a multicenter, prospective cohort study (PACTG 219/219C) in the United States. The main outcome was first fracture during the risk period. Nine fractures occurred in 7 of 1326 HIV-infected and 2 of 649 HEU children, corresponding to incidence rates of 1.2 per 1000 person-years and 1.1 per 1000 person-years, respectively. The incidence rate ratio was 1.1 (95% CI 0.2, 5.5). There was no evidence of a substantially increased risk of fracture in HIV-infected compared to HEU children. © 2012, Mary Ann Liebert, Inc.

Li J.Z.,Harvard University | Gallien S.,Harvard University | Ribaudo H.,Center for Biostatistics in Research | Heisey A.,Harvard University | And 2 more authors.
AIDS | Year: 2014

Objectives:To evaluate the relationship between incomplete antiretroviral therapy (ART) adherence and levels of residual HIV-1 viremia. Design: Medication adherence and residual viremia less than 50 copies/ml were quantified in participants of a cohort of homeless and marginally housed individuals with HIV/AIDS. Methods: Participants had at least 6 months of virologic suppression of less than 50 copies/ml and were in the adherence monitoring cohort with monthly unannounced pill counts. Residual viremia was measured by the single-copy assay. Results: The median average ART adherence over the prior 1 and 2 months were 94% [interquartile range (IQR) 79-100%] and 93% (IQR 82-98%), respectively. Average ART adherence over the past 2 months was significantly associated with levels of residual HIV viremia (Spearman r=-0.25, P = 0.04). One-third of participants with 100% ART adherence over the past 2 months had detectable residual viremia. On multivariate regression analysis, ART adherence over the past 2 months, but not duration of virologic suppression, CD4 + T-cell count or or ART regimen, was significantly associated with levels of residual HIV viremia. Detectable residual viremia was associated with virologic failure (50 copies/ml) on univariate Cox proportional hazard analysis (hazard ratio 2.08, P = 0.02). However, on multivariate analysis, only ART adherence was associated with risk of virologic failure. Conclusion: Incomplete ART adherence is associated with higher levels of residual HIV-1 viremia, but detectable residual viremia can be present despite 100% measured ART adherence. © 2014 Wolters Kluwer Health.

Noubary F.,Center for Biostatistics in Research
Journal of acquired immune deficiency syndromes (1999) | Year: 2012

To evaluate factors affecting antiretroviral therapy (ART) start time when triggered by a CD4 count <350 cells/μL while monitoring counts over time. Measurement frequency, requirement for confirmatory counts, and precision and accuracy of CD4 enumeration technology were considered. Using a model of CD4 count trajectories among seroconverters in the Multicenter AIDS Cohort Study, sequences of counts were simulated for a large hypothetical population monitored for 5 years from seroconversion. Time of first count <350 cells/μL was defined as ART start time. The simulation was adapted to evaluate the effect of the above factors on these times. ART initiation was considered "very late" among patients whose underlying trajectory declined less than 200 cells/μL during the period simulated if no previous observed count was <350 cells/μL. For 12-, 6-, 4-, and 3-monthly measurements, median start time was 48, 36, 32, and 30 months after seroconversion and proportion of patients starting ART very late was 11.5%, 1.6%, 0.2%, and 0.1%. For 6-monthly measurements, requiring confirmation increased the median to 49 months and proportion to 8.9%. Changes in standard deviation of short-term variability in counts of 25% and measurement bias for a novel technology of ±10% changed median time by ±6 months with modest change in the proportion very late (range, 0.5%-3.2%). : 6-monthly measurements appear adequate in achieving low rates of very late ART whereas confirmation affects rates adversely. Studies comparing new versus standard measurement technologies should focus on ruling out modest bias, particularly proximal to important thresholds for treatment management.

Hua L.,Center for Biostatistics in Research | Zhang Y.,University of Iowa
Biostatistics | Year: 2012

We propose to analyze panel count data using a spline-based semiparametric projected generalized estimating equation (GEE) method with the proportional mean model E((t)Z) = Λ0(t) eβ0TZ. The natural logarithm of the baseline mean function, logΛ0(t), is approximated by a monotone cubic B-spline function. The estimates of regression parameters and spline coefficients are obtained by projecting the GEE estimates into the feasible domain using a weighted isotonic regression (IR). The proposed method avoids assuming any parametric structure of the baseline mean function or any stochastic model for the underlying counting process. Selection of the working covariance matrix that accounts for overdispersion improves the estimation efficiency and leads to less biased variance estimations. Simulation studies are conducted using different working covariance matrices in the GEE to investigate finite sample performance of the proposed method, to compare the estimation efficiency, and to explore the performance of different variance estimates in presence of overdispersion. Finally, the proposed method is applied to a real data set from a bladder tumor clinical trial. The Author 2011. Published by Oxford University Press. All rights reserved.

Krishnan S.,Center for Biostatistics in Research
Journal of acquired immune deficiency syndromes (1999) | Year: 2012

Metabolic syndrome (MetS) is a cluster of risk factors for cardiovascular disease and diabetes, many of which are associated with HIV and antiretroviral therapy (ART). We examined prevalence and incidence of MetS and risk factors for MetS in ART-naive HIV-infected individuals starting ART. MetS, defined by the Adult Treatment Panel III criteria, was assessed at and after ART initiation in HIV-infected individuals who enrolled in selected AIDS Clinical Trials Group trials and were followed long-term after these trials as part of the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials cohort. Cox proportional hazards models were used to examine risk factors of incident MetS. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CI) are reported. At ART initiation, the prevalence of MetS was 20%. After ART initiation, the incidence of MetS was 8.5 per 100 person-years. After adjusting for demographics and body mass index, the risk of MetS was decreased for CD4+ T-cell counts >50 cells per cubic millimeter (aHR = 0.62, 95% CI = 0.43 to 0.90 for CD4 >500), and the risk was increased for HIV-1 RNA >400 copies per milliliter (aHR = 1.55 (95% CI = 1.25 to 1.92) and use of a protease-inhibitor (PI)-based regimen [relative to no PI use, aHR = 1.25 (95% CI = 1.04 to 1.51) for any PI use]. In HIV-infected individuals on ART, virologic suppression and maintenance of high CD4+ T-cell counts may be potentially modifiable factors that can reduce the risk of MetS. The effect of MetS on the risk of cardiovascular disease and diabetes needs to be evaluated.

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