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McComsey G.A.,Case Western Reserve University | Walker U.A.,University of Basel | Budhathoki C.B.,Statistical and Data Analysis Center | Su Z.,Statistical and Data Analysis Center | And 6 more authors.
AIDS | Year: 2010

Background: Lipoatrophy is prevalent on thymidine nucleoside reverse transcriptase inhibitors (tNRTIs). A pilot trial showed that uridine (NucleomaxX) increased limb fat. Methods: A5229 was a multicenter trial in which HIV-infected individuals with lipoatrophy on tNRTI regimens were randomized to NucleomaxX or placebo. Primary endpoint was change in limb fat from baseline to week 48. The study was powered to detect 400-g difference between arms at week 48. A stratified Wilcoxon rank-sum test was used to assess between-arm differences. Results: The 165 participants were 91% men, 62% white;median age 49 years, CD4 cell count 506 cells/μl, and limb fat 3037g;81% had HIV-1 RNA 50copies/ml or less; 76% were on zidovudine (ZDV). Baseline characteristics were similar between groups. Only 59% completed 48 weeks of treatment;however, only three participants (one on uridine) discontinued due to toxicity (diarrhea). In intent to treat, there was no difference for changes in limb fat between treatments at week 24 or week 48. On as-treated analysis, uridine resulted in an increase in %limb fat vs. placebo (3.4 vs. -0.8%, P = 0.01) at week 24 but not at week 48 (1.8 vs. 3.8%, P = 0.93). Similar results were seen when limiting the analysis to patients with at least 80% adherence. The results were not related to severity of lipoatrophy or type of tNRTI. No changes were found in facial anthropometrics, fasting lipids, trunk fat, CD4 cell count, or HIV RNA. Conclusions: We found a modest transient improvement in limb fat after 24 weeks of uridine. The lack of sustained efficacy at week 48 was not due to changes in adherence or reduction in sample size. Uridine was well tolerated and did not impair virologic control. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Dawson R.,Frontier Science and Technology and Research Foundation | Lavori P.W.,Stanford University
Statistics in Medicine | Year: 2015

Nonadherence to assigned treatment jeopardizes the power and interpretability of intent-to-treat comparisons from clinical trial data and continues to be an issue for effectiveness studies, despite their pragmatic emphasis. We posit that new approaches to design need to complement developments in methods for causal inference to address nonadherence, in both experimental and practice settings. This paper considers the conventional study design for psychiatric research and other medical contexts, in which subjects are randomized to treatments that are fixed throughout the trial and presents an alternative that converts the fixed treatments into an adaptive intervention that reflects best practice. The key element is the introduction of an adaptive decision point midway into the study to address a patient's reluctance to remain on treatment before completing a full-length trial of medication. The clinical uncertainty about the appropriate adaptation prompts a second randomization at the new decision point to evaluate relevant options. Additionally, the standard 'all-or-none' principal stratification (PS) framework is applied to the first stage of the design to address treatment discontinuation that occurs too early for a midtrial adaptation. Drawing upon the adaptive intervention features, we develop assumptions to identify the PS causal estimand and to introduce restrictions on outcome distributions to simplify expectation-maximization calculations. We evaluate the performance of the PS setup, with particular attention to the role played by a binary covariate. The results emphasize the importance of collecting covariate data for use in design and analysis. We consider the generality of our approach beyond the setting of psychiatric research. © 2015 John Wiley & Sons, Ltd.

Brady M.T.,Nationwide Childrens Hospital | Brady M.T.,Ohio State University | Oleske J.M.,Rutgers University | Williams P.L.,Harvard University | And 4 more authors.
Journal of Acquired Immune Deficiency Syndromes | Year: 2010

CONTEXT: Introduction of highly active antiretroviral therapy has significantly decreased mortality in HIV-1-infected adults and children. Although an increase in non-HIV-related mortality has been noted in adults, data in children are limited. OBJECTIVES: To evaluate changes in causes and risk factors for death among HIV-1-infected children in Pediatric AIDS Clinical Trials Group 219/219C. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, prospective cohort study designed to evaluate long-term outcomes in HIV-1-exposed and infected US children. There were 3553 HIV-1-infected children enrolled and followed up between April 1993 and December 2006, with primary cause of mortality identified in the 298 observed deaths. MAIN OUTCOME MEASURES: Mortality rates per 100 child-years overall and by demographic factors; survival estimates by birth cohort; and hazard ratios for mortality by various demographic, health, and antiretroviral treatment factors were determined. RESULTS: Among 3553 HIV-1-infected children followed up for a median of 5.3 years, 298 deaths occurred. Death rates significantly decreased between 1994 and 2000, from 7.2 to 0.8 per 100 person-years, and remained relatively stable through 2006. After adjustment for other covariates, increased risk of death was identified for those with low CD4 and AIDS-defining illness at entry. Decreased risks of mortality were identified for later birth cohorts, and for time-dependent initiation of highly active antiretroviral therapy (hazard ratio 0.54, P < 0.001). The most common causes of death were "End-stage AIDS" (N = 48, 16%) and pneumonia (N = 41, 14%). The proportion of deaths due to opportunistic infections (OIs) declined from 37% in 1994-1996 to 24% after 2000. All OI mortality declined during the study period. However, a greater decline was noted for deaths due to Mycobacterium avium complex and cryptosporidium. Deaths from "End-stage AIDS," sepsis and renal failure increased. CONCLUSIONS: Overall death rates declined from 1993 to 2000 but have since stabilized at rates about 30 times higher than for the general US pediatric population. Deaths due to OIs have declined, but non-AIDS-defining infections and multiorgan failure remain major causes of mortality in HIV-1-infected children. Copyright © 2009 by Lippincott Williams & Wilkins.

Siberry G.K.,U.S. National Institutes of Health | Jacobson D.L.,Center for Biostatistics in Research | Kalkwarf H.J.,Cincinnati Childrens Hospital Medical Center | Wu J.W.,Harvard University | And 13 more authors.
Clinical Infectious Diseases | Year: 2015

Background.Fetal bone effects of maternal tenofovir use have not been well studied. We sought to compare whole-body bone mineral content (BMC) of newborns exposed vs not exposed to tenofovir in utero. Methods.We enrolled participants from April 2011 to June 2013 at 14 US clinical sites. Singleton infants of women with human immunodeficiency virus (HIV) infection who took tenofovir in late pregnancy (tenofovir-exposed) or no tenofovir during pregnancy (tenofovir-unexposed) were enrolled during late pregnancy or within 72 hours of birth. Infants born before 36 weeks gestation or with confirmed HIV infection were excluded. Whole-body BMC was measured in the first month of life and compared with that of the tenofovir-exposed and tenofovir-unexposed newborns, unadjusted and adjusted for covariates. Results.Seventy-four tenofovir-exposed and 69 tenofovir-unexposed infants had evaluable BMC measurements. Tenofovir-exposed mothers were more likely to be married (31% vs 22%; P =. 04) and to use boosted protease inhibitors (84% vs 62%; P =. 004). Tenofovir-exposed newborns did not differ from unexposed newborns on mean gestational age (38.2 vs 38.1 weeks) or mean length (-0.41 vs-0.18) or weight (-0.71 vs-0.48) Z-scores. The mean (standard deviation) BMC of tenofovir-exposed infants was 12% lower than for unexposed infants (56.0 [11.8] vs 63.8 [16.6] g; P =. 002). The adjusted mean bone mineral content was 5.3 g lower (95% confidence interval,-9.5,-1.2; P =. 013) in the tenofovir-exposed infants. Conclusions.Maternal tenofovir use is associated with significantly lower neonatal BMC. The duration and clinical significance of this finding should be evaluated in longitudinal studies. © 2015 Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

Lipshultz S.E.,University of Miami | Williams P.L.,Center for Biostatistics in Research | Wilkinson J.D.,University of Miami | Leister E.C.,Center for Biostatistics in Research | And 10 more authors.
JAMA Pediatrics | Year: 2013

Importance: Prior to contemporary antiretroviral therapies (ARTs), children infected with human immunodeficiency virus (HIV) were more likely to have heart failure. This study suggests that highly active ART (HAART) does not appear to impair heart function. Objective: To determine the cardiac effects of prolonged exposure to HAART on HIV-infected children. Design: In the National Institutes of Health-funded Pediatric HIV/AIDS Cohort Study's Adolescent Master Protocol (AMP), we used linear regression models to compare echocardiographic measures. Setting: A total of 14 US pediatric HIV clinics. Participants: Perinatally HIV-infected children receiving HAART (n=325), HIV-exposed but uninfected children (n=189), and HIV-infected (mostly HAART-unexposed) historical pediatric controls from the National Institutes of Health-funded Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection (P 2C2-HIV) Study (n=70). Exposure: Long-term HAART. Main Outcomes and Measures: Echocardiographic measures of left ventricular (LV) function and structure. Results: The 325 AMP HIV-infected children had lower viral loads, higher CD4 counts, and longer durations of ART than did the 70 HIV-infected children from the P2C2-HIV Study (all P < .001). The z scores for LV fractional shortening (a measure of cardiac function) were significantly lower among HIV-infected children from the P 2C2-HIV Study than among the AMP HIV-infected group or the 189 AMP HIV-exposed but uninfected controls (P < .05). For HIV-infected children, a lower nadir CD4 percentage and a higher current viral load were associated with significantly lower cardiac function (LV contractility and LV fractional shortening z scores; all P =.001) and an increased LV end-systolic dimension z score (all P < .03). In an interaction analysis by HIV-infected cohort, the HIV-infected children from the P2C2-HIV Study with a longer ART exposure or a lower nadir CD4 percentage had lower mean LV fractional shortening z scores, whereas themean z scoreswere relatively constant among AMP HIV-infected children (P < .05 for all interactions). Conclusions and Relevance: Long-term HAART appears to be cardioprotective for HIV-infected children and adolescents. ©2013 American Medical Association. All rights reserved.

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