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Dawson R.,Frontier Science and Technology and Research Foundation | Buckley P.,Georgia Regents University | Wallace A.E.,Texas A&M University | Herz M.,University of Miami | And 3 more authors.
Journal of Clinical Psychiatry | Year: 2015

Objective: Alcohol use disorders worsen the course of schizophrenia. Although the atypical antipsychotic clozapine appears to decrease alcohol use in schizophrenia, risperidone does not. We have proposed that risperidone's relatively potent dopamine D2 receptor blockade may partly underlie its lack of effect on alcohol use. Since long-acting injectable (LAI) risperidone both results in lower average steady-state plasma concentrations than oral risperidone (with lower D2 receptor occupancy) and encourages adherence, it may be more likely to decrease heavy alcohol use (days per week of drinking 5 or more drinks per day) than oral risperidone. Method: Ninety-five patients with DSM-IV-TR diagnoses of schizophrenia and alcohol use disorder were randomized to 6 months of oral or LAI risperidone between 2005 and 2008. Explanatory (efficacy) analyses were carried out to evaluate the potential benefits of LAI under suitably controlled conditions (in contrast to real-world settings), with intent-to-treat analyses being secondary. Results: Explanatory analyses showed that heavy drinking in the oral group worsened over time (P = .024) and that there was a statistical trend toward significance in the difference between the changes in heavy drinking days in the oral and LAI groups (P = .054). Furthermore, the 2 groups differed in the mean number of drinking days per week (P = .035). The intent-to-treat analyses showed no difference in heavy drinking but did show a difference in average drinking days per week similar to that obtained from the explanatory analyses (P = .018). Neither explanatory nor intent-to-treat analyses showed any between-group differences in alcohol use as measured by intensity or the Alcohol Use Scale. The plasma concentrations of the active metabolite 9-hydroxyrisperidone were significantly lower in patients taking LAI (P < .05), despite their significantly (overall) better treatment adherence (P < .005). Conclusion: For the population considered here, schizophrenia patients with alcohol use disorder appear to continue drinking some alcohol while taking either form of risperidone. Nonetheless, our data suggest that injectable risperidone may be a better choice than the oral form for these dual diagnosis patients. © Copyright 2015 Physicians Postgraduate Press, Inc.

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.

PubMed | Medical Center, University of Washington, Queen Elizabeth Control Hospital, U.S. National Institutes of Health and 6 more.
Type: Journal Article | Journal: Journal of AIDS & clinical research | Year: 2015

Intrapartum single-dose nevirapine (sdNVP) reduces HIV-1 perinatal transmission but selects NVP resistance among mothers and infants. We evaluated the frequency of antiretroviral resistance among infants with intrauterine HIV-1 infection exposed to sdNVP and maternal antenatal or breastfeeding antiretroviral therapy.This analysis included 429 infants from sub-Saharan Africa, India and Haiti whose 422 mothers received sdNVP plus maternal study treatment. At entry mothers had CD4>250/L and were ART-nave except for antenatal ZDV per local standard of care. Maternal study treatment started intrapartum and included ZDV/3TC, TDF/FTC or LPV/r for 7 or 21 days in a randomized factorial design. Infants received sdNVP study treatment and ZDV if local standard of care. Infant HIV RNA or DNA PCR and samples for genotype were obtained at birth and weeks 2, 4 and 12; infants who ever breast-fed were also tested at weeks 16, 24, 48 and 96. Samples from HIV-1-infected infants were tested for drug resistance by population genotype (ViroSeq). NVP or NRTI resistance mutations were assessed using the IAS-USA mutation list.Perinatal HIV-1 transmission occurred in 17 (4.0%) infants including 12 intrauterine infections. Resistance mutations were detected among 5 (42%) intrauterine-infected infants; of these, 3 had mutations conferring resistance to NVP alone, 1 had resistance to NRTI alone, and 1 had dual-class resistance mutations. Among the 2 infants with NRTI mutations, one (K70R) was likely maternally transmitted and one (K65R) occurred in the context of breastfeeding exposure to maternal antiretroviral therapy.Infants with intrauterine HIV infection are at risk of acquiring resistance mutations from exposure to maternal antiretroviral medications intrapartum and/or during breastfeeding. New approaches are needed to lower the risk of antiretroviral resistance in these infants.

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.

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.

Dawson R.,Frontier Science and Technology and Research Foundation | Lavori P.W.,Stanford University
Biostatistics | Year: 2012

Clinical demand for individualized "adaptive" treatment policies in diverse fields has spawned development of clinical trial methodology for their experimental evaluation via multistage designs, building upon methods intended for the analysis of naturalistically observed strategies. Because often there is no need to parametrically smooth multistage trial data (in contrast to observational data for adaptive strategies), it is possible to establish direct connections among different methodological approaches. We show by algebraic proof that the maximum likelihood (ML) and optimal semiparametric (SP) estimators of the population mean of the outcome of a treatment policy and its standard error are equal under certain experimental conditions. This result is used to develop a unified and efficient approach to design and inference for multistage trials of policies that adapt treatment according to discrete responses. We derive a sample size formula expressed in terms of a parametric version of the optimal SP population variance. Nonparametric (sample-based) ML estimation performed well in simulation studies, in terms of achieved power, for scenarios most likely to occur in real studies, even though sample sizes were based on the parametric formula. ML outperformed the SP estimator; differences in achieved power predominately reflected differences in their estimates of the population mean (rather than estimated standard errors). Neither methodology could mitigate the potential for overestimated sample sizes when strong nonlinearity was purposely simulated for certain discrete outcomes; however, such departures from linearity may not be an issue for many clinical contexts that make evaluation of competitive treatment policies meaningful. © The Author 2011.

Difrancesco R.,Buffalo Center of Excellence | Rosenkranz S.L.,Frontier Science and Technology and Research Foundation | Taylor C.R.,Buffalo Center of Excellence | Pande P.G.,Rti International | And 3 more authors.
Therapeutic Drug Monitoring | Year: 2013

ABSTRACT:: Among National Institutes of Health HIV Research Networks conducting multicenter trials, samples from protocols that span several years are analyzed at multiple clinical pharmacology laboratories (CPLs) for multiple antiretrovirals. Drug assay data are, in turn, entered into study-specific data sets that are used for pharmacokinetic analyses, merged to conduct cross-protocol pharmacokinetic analysis, and integrated with pharmacogenomics research to investigate pharmacokinetic-pharmacogenetic associations. The CPLs participate in a semiannual proficiency testing (PT) program implemented by the Clinical Pharmacology Quality Assurance program. Using results from multiple PT rounds, longitudinal analyses of recovery are reflective of accuracy and precision within/across laboratories. The objectives of this longitudinal analysis of PT across multiple CPLs were to develop and test statistical models that longitudinally: (1) assess the precision and accuracy of concentrations reported by individual CPLs and (2) determine factors associated with round-specific and long-term assay accuracy, precision, and bias using a new regression model. A measure of absolute recovery is explored as a simultaneous measure of accuracy and precision. Overall, the analysis outcomes assured 97% accuracy (±20% of the final target concentration of all (21) drug concentration results reported for clinical trial samples by multiple CPLs). Using the Clinical Laboratory Improvement Act acceptance of meeting criteria for ≥2/3 consecutive rounds, all 10 laboratories that participated in 3 or more rounds per analyte maintained Clinical Laboratory Improvement Act proficiency. Significant associations were present between magnitude of error and CPL (Kruskal-Wallis P < 0.001) and antiretroviral (Kruskal-Wallis P < 0.001). Copyright © 2013 by Lippincott Williams and Wilkins.

PubMed | Center for Biostatistics in Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Frontier Science and Technology and Research Foundation, Harvard University and 3 more.
Type: Journal Article | Journal: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America | Year: 2015

Combination antiretroviral therapy (cART) has resulted in a dramatic decrease in human immunodeficiency virus (HIV)-related opportunistic infections and deaths in US youth, but both continue to occur.We estimated the incidence of complications and deaths in IMPAACT P1074, a long-term US-based prospective multicenter cohort study conducted from April 2008 to June 2014. Incidence rates of selected diagnoses and trends over time were compared with those from a previous observational cohort study, P219C (2004-2007). Causes of death and relevant demographic and clinical features were reviewed.Among 1201 HIV-infected youth in P1074 (87% perinatally infected; mean [standard deviation] age at last chart review, 20.9 [5.4] years), psychiatric and neurodevelopmental disorders, asthma, pneumonia, and genital tract infections were among the most common comorbid conditions. Compared with findings in P219C, conditions with significantly increased incidence included substance or alcohol abuse, latent tuberculosis, diabetes mellitus, atypical mycobacterial infections, vitamin D deficiency or metabolic bone disorders, anxiety disorders, and fractures; the incidence of pneumonia decreased significantly. Twenty-eight deaths occurred, yielding a standardized mortality rate 31.5 times that of the US population. Those who died were older, less likely to be receiving cART, and had lower CD4 cell counts and higher viral loads. Most deaths (86%) were due to HIV-related medical conditions.Opportunistic infections and deaths are less common among HIV-infected youth in the US in the cART era, but the mortality rate remains elevated. Deaths were associated with poor HIV control and older age. Emerging complications, such as psychiatric, inflammatory, metabolic, and genital tract diseases, need to be addressed.

PubMed | Child & Adolescent Center for Infectious Diseases and Virology, University of Indianapolis, University of Miami, University of Illinois at Chicago and 10 more.
Type: Journal Article | Journal: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America | Year: 2015

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.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.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.Maternal tenofovir use is associated with significantly lower neonatal BMC. The duration and clinical significance of this finding should be evaluated in longitudinal studies.ClinicalTrials.gov NCT01310023.

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