Publications by authors named "Aditya H Gaur"

75 Publications

Correlates of High HIV Viral Load and Antiretroviral Therapy Adherence Among Viremic Youth in the United States Enrolled in an Adherence Improvement Intervention.

AIDS Patient Care STDS 2021 May;35(5):145-157

Department of Biostatistics, Gillings School of Public Health, Collaborative Studies Coordinating Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

A sizable portion of youth (ages 13-24) living with HIV in the United States have unsuppressed viral load. The AIDS Interventions (ATN) 152 study [evaluating the Triggered Escalating Real-Time Adherence (TERA) intervention] baseline data were examined to identify correlates of high viremia (>5000 copies/mL) and self-reported adherence, which can help in planning of differentiated services for viremic youth. Depression, HIV-stigma, and cannabis use were common in this sample of 87 youth. Almost half (48%) had high viremia, which associated with enacted stigma, moderate- to high-risk alcohol use, mental health diagnosis, and age ≥21. Self-reported adherence was related to viral load and associated with mental and physical health functioning, depression, social support, self-confident decision-making, total and internalized stigma, adherence motivation, and report of a missed a care visit in the past 6 months. Mental health emerged as a common correlate of viral load and adherence. Clinical Trial Registration number: NCT03292432.
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http://dx.doi.org/10.1089/apc.2021.0005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106249PMC
May 2021

Modeling Adherence Interventions Among Youth with HIV in the United States: Clinical and Economic Projections.

AIDS Behav 2021 Feb 6. Epub 2021 Feb 6.

Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.

The Adolescent Medicine Trials Network for HIV/AIDS Interventions is evaluating treatment adherence interventions (AI) to improve virologic suppression (VS) among youth with HIV (YWH). Using a microsimulation model, we compared two strategies: standard-of-care (SOC) and a hypothetical 12-month AI that increased cohort-level VS in YWH in care by an absolute ten percentage points and cost $100/month/person. Projected outcomes included primary HIV transmissions, deaths and life-expectancy, lifetime HIV-related costs, and incremental cost-effectiveness ratios (ICERs, $/quality-adjusted life-year [QALY]). Compared to SOC, AI would reduce HIV transmissions by 15% and deaths by 12% at 12 months. AI would improve discounted life expectancy/person by 8 months at an added lifetime cost/person of $5,300, resulting in an ICER of $7,900/QALY. AI would be cost-effective at $2,000/month/person or with efficacies as low as a 1 percentage point increase in VS. YWH-targeted adherence interventions with even modest efficacy could improve life expectancy, prevent onward HIV transmissions, and be cost-effective.
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http://dx.doi.org/10.1007/s10461-021-03169-0DOI Listing
February 2021

Rapid Start of Antiretroviral Therapy in Youth Diagnosed with HIV Infection.

Pediatr Infect Dis J 2021 Feb;40(2):147-150

From the Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Guidelines for the use of antiretroviral agents in adults and adolescents with HIV recommend that antiretroviral therapy (ART) be started as soon as possible. While rapid initiation of ART in adults with HIV has been well-described, there is relatively little information describing this approach for youth.

Methods: On April 1, 2018, St. Jude Children's Research Hospital began offering ART to youth with HIV infection at their first clinic visit. We report the results of a quality improvement initiative that compared patients who offered ART at their first visit to a historical cohort of patients who initiated ART at a subsequent visit. Demographic, HIV biomarker, and visit information were abstracted from medical records, described and compared using univariate statistical methods.

Results: There were 124 ART-naive youth (median age 19 years, 91% male, 94% black) first seen during the indicated time period. A total of 54 patients were in the baseline cohort and 70 patients were in the rapid start cohort. 90% of youth in the rapid start cohort started ART on their first clinic visit. Time from first clinic visit to undetectable viral load was significantly higher in the baseline cohort compared with the rapid start cohort (median 54 vs. 41 days; P = 0.01). Retention in care 12 months following the first clinic visit was comparable and overall high (>80%).

Conclusions: Starting ART-naïve youth with HIV infection on ART at their first clinic visit is feasible, has high acceptance, leads to faster viral load suppression, and is associated with high retention in care.
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http://dx.doi.org/10.1097/INF.0000000000002969DOI Listing
February 2021

Mucosal barrier injury-associated bloodstream infections in pediatric oncology patients.

Pediatr Blood Cancer 2020 08 9;67(8):e28234. Epub 2020 May 9.

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Single-center reports of central line-associated bloodstream infection (CLABSI) and the subcategory of mucosal barrier injury laboratory-confirmed bloodstream infection (MBI-LCBI) in pediatric hematology oncology transplant (PHO) patients have focused on the inpatient setting. Characterization of MBI-LCBI across PHO centers and management settings (inpatient and ambulatory) is urgently needed to inform surveillance and prevention strategies.

Methods: Prospectively collected data from August 1, 2013, to December 31, 2015, on CLABSI (including MBI-LCBI) from a US PHO multicenter quality improvement network database was analyzed. CDC National Healthcare Safety Network definitions were applied for inpatient events and adapted for ambulatory events.

Results: Thirty-five PHO centers reported 401 ambulatory and 416 inpatient MBI-LCBI events. Ambulatory and inpatient MBI-LCBI rates were 0.085 and 1.01 per 1000 line days, respectively. Fifty-three percent of inpatient CLABSIs were MBI-LCBIs versus 32% in the ambulatory setting (P  <  0.01). Neutropenia was the most common criterion defining MBI-LCBI in both settings, being present in ≥90% of events. The most common organisms isolated in MBI-LCBI events were Escherichia coli (in 28% of events), Klebsiella spp. (23%), and viridans streptococci (12%) in the ambulatory setting and viridans streptococci (in 29% of events), E. coli (14%), and Klebsiella spp. (14%) in the inpatient setting.

Conclusion: In this largest study of PHO MBI-LCBI inpatient events and the first such study in the ambulatory setting, the burden of MBI-LCBI across the continuum of care of PHO patients was substantial. These data should raise awareness of MBI-LCBI among healthcare providers for PHO patients, help benchmarking across centers, and help inform prevention and treatment strategies.
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http://dx.doi.org/10.1002/pbc.28234DOI Listing
August 2020

Liver Enzyme Elevations in Volunteer Infection Studies: Findings and Recommendations.

Am J Trop Med Hyg 2020 07 16;103(1):378-393. Epub 2020 Apr 16.

Medicines for Malaria Venture, Geneva, Switzerland.

Malaria volunteer infection studies (VISs) accelerate new drug and vaccine development. In the induced blood-stage malaria (IBSM) model, volunteers are inoculated with erythrocytes infected with . Observations of elevated liver enzymes in the IBSM model with new chemical entities (NCEs) promoted an analysis of available data. Data were reviewed from eight IBSM studies of seven different NCEs, plus two studies with the registered antimalarial piperaquine conducted between June 2013 and January 2017 at QIMR Berghofer, Brisbane, Australia. Alanine aminotransferase (ALT) was elevated (> 2.5 times the upper limit of normal [×ULN]) in 20/114 (17.5%) participants. Of these, 8.9% (10/114) had moderate increases (> 2.5-5 × ULN), noted in seven studies of six different NCEs ± piperaquine or piperaquine alone, and 8.9% (10/114) had severe elevations (> 5 × ULN), occurring in six studies of six different NCEs ± piperaquine. Aspartate aminotransferase (AST) was elevated (> 2.5 × ULN) in 11.4% (13/114) of participants, across six of the 10 studies. Bilirubin was > 2 × ULN in one participant. Published data from other VIS models, using sporozoite inoculation by systemic administration or mosquito feeding, also showed moderate/severe liver enzyme elevations. In conclusion, liver enzyme elevations in IBSM studies are most likely multifactorial and could be caused by the model conditions, that is, malaria infection/parasite density and/or effective parasite clearance, or by participant-specific risk factors, acetaminophen administration, or direct hepatotoxicity of the test drug. We make recommendations that may mitigate the risk of liver enzyme elevations in future VISs and propose measures to assist their interpretation, should they occur.
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http://dx.doi.org/10.4269/ajtmh.19-0846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356411PMC
July 2020

Safety, tolerability, pharmacokinetics, and antimalarial efficacy of a novel Plasmodium falciparum ATP4 inhibitor SJ733: a first-in-human and induced blood-stage malaria phase 1a/b trial.

Lancet Infect Dis 2020 08 8;20(8):964-975. Epub 2020 Apr 8.

University of Kentucky College of Pharmacy, University of Kentucky, Lexington, KY, USA.

Background: (+)-SJ000557733 (SJ733) is a novel, orally bioavailable inhibitor of Plasmodium falciparum ATP4. In this first-in-human and induced blood-stage malaria phase 1a/b trial, we investigated the safety, tolerability, pharmacokinetics, and antimalarial activity of SJ733 in humans.

Methods: The phase 1a was a single-centre, dose-escalation, first-in-human study of SJ733 allowing modifications to dose increments and dose-cohort size on the basis of safety and pharmacokinetic results. The phase 1a took place at St Jude Children's Research Hospital and at the University of Tennessee Clinical Research Center (Memphis, TN, USA). Enrolment in more than one non-consecutive dose cohort was allowed with at least 14 days required between doses. Participants were fasted in seven dose cohorts and fed in one 600 mg dose cohort. Single ascending doses of SJ733 (75, 150, 300, 600, 900, or 1200 mg) were administered to participants, who were followed up for 14 days after SJ733 dosing. Phase 1a primary endpoints were safety, tolerability, and pharmacokinetics of SJ733, and identification of an SJ733 dose to test in the induced blood-stage malaria model. The phase 1b was a single-centre, open-label, volunteer infection study using the induced blood-stage malaria model in which fasted participants were intravenously infected with blood-stage P falciparum and subsequently treated with a single dose of SJ733. Phase 1b took place at Q-Pharm (Herston, QLD, Australia) and was initiated only after phase 1a showed that exposure exceeding the threshold minimum exposure could be safely achieved in humans. Participants were inoculated on day 0 with P falciparum-infected human erythrocytes (around 2800 parasites in the 150 mg dose cohort and around 2300 parasites in the 600 mg dose cohort), and parasitaemia was monitored before malaria inoculation, after inoculation, immediately before SJ733 dosing, and then post-dose. Participants were treated with SJ733 within 24 h of reaching 5000 parasites per mL or at a clinical score higher than 6. Phase 1b primary endpoints were calculation of a parasite reduction ratio (PRR) and parasite clearance half-life, and safety and tolerability of SJ733 (incidence, severity, and drug-relatedness of adverse events). In both phases of the trial, SJ733 hydrochloride salt was formulated as a powder blend in capsules containing 75 mg or 300 mg for oral administration. Healthy men and women (of non-childbearing potential) aged 18-55 years were eligible for both studies. Both studies are registered with ClinicalTrials.gov (NCT02661373 for the phase 1a and NCT02867059 for the phase 1b).

Findings: In the phase 1a, 23 healthy participants were enrolled and received one to three non-consecutive doses of SJ733 between March 14 and Dec 7, 2016. SJ733 was safe and well tolerated at all doses and in fasted and fed conditions. 119 adverse events were recorded: 54 (45%) were unrelated, 63 (53%) unlikely to be related, and two (2%) possibly related to SJ733. In the phase 1b, 17 malaria-naive, healthy participants were enrolled. Seven participants in the 150 mg dose cohort were inoculated and dosed with SJ733. Eight participants in the 600 mg dose cohort were inoculated, but two participants could not be dosed with SJ733. Two additional participants were subsequently inoculated and dosed with SJ733. SJ733 exposure increased proportional to the dose through to the 600 mg dose, then was saturable at higher doses. Fasted participants receiving 600 mg exceeded the target area under the concentration curve extrapolated to infinity (AUC) of 13 000 μg × h/L (median AUC 24 283 [IQR 16 135-31 311] μg × h/L, median terminal half-life 17·4 h [IQR 16·1-24·0], and median timepoint at which peak plasma concentration is reached 1·0 h [0·6-1·3]), and this dose was tested in the phase 1b. All 15 participants dosed with SJ733 had at least one adverse event. Of the 172 adverse events recorded, 128 (74%) were mild. The only adverse event attributed to SJ733 was mild bilateral foot paraesthesia that lasted 3·75 h and resolved spontaneously. The most common adverse events were related to malaria. Based on parasite clearance half-life, the derived logPRR and corresponding parasite clearance half-lives were 2·2 (95% CI 2·0-2·5) and 6·47 h (95% CI 5·88-7·18) for 150 mg, and 4·1 (3·7-4·4) and 3·56 h (3·29-3·88) for 600 mg.

Interpretation: The favourable pharmacokinetic, tolerability, and safety profile of SJ733, and rapid antiparasitic effect support its development as a fast-acting component of combination antimalarial therapy.

Funding: Global Health Innovative Technology Fund, Medicines for Malaria Venture, and the American Lebanese Syrian Associated Charities.
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http://dx.doi.org/10.1016/S1473-3099(19)30611-5DOI Listing
August 2020

Brief Report: Phase IIa Safety Study of a Vaginal Ring Containing Dapivirine in Adolescent Young Women.

J Acquir Immune Defic Syndr 2020 02;83(2):135-139

Merck Research Labs, Rahway, NJ; and.

Background: Young women aged 15-24 years are disproportionately affected by the HIV epidemic. Two phase III trials of a vaginal ring containing 25-mg dapivirine demonstrated HIV-1 risk reduction in adult women older than 21 years but not in those aged 18-21 years. Lack of protection was correlated with low adherence.

Methods: In this phase-IIa, randomized, double-blind, placebo-controlled, US, multicenter trial of the dapivirine ring in sexually active females, aged 15-17 years, participants were randomized 3:1 to a dapivirine or placebo ring to be inserted monthly for 6 months (NCT02028338). Primary safety end points included grade 2 product related adverse events and any grade 3 and higher adverse events. Adherence to ring use was assessed by plasma dapivirine concentrations, residual levels in used rings, and self-report. A plasma dapivirine concentration of >95 pg/mL was used to define short-term adherence; a residual ring level of <23.5 mg was used to define long-term adherence. Acceptability was assessed through computer-assisted self-interviews.

Results: Ninety-six participants were enrolled across 6 US sites. The median age was 16.0 years. There were no differences in safety outcomes between treatment arms. Adherence to the dapivirine ring was demonstrated by both plasma measurements (87%) and residual drug levels in rings (95%). Forty-two percent (95% confidence interval: 32 to 52) of participants reported that they never removed the ring. Participants noted no discomfort due to the ring at 87% of visits and "liking" the ring at 93% of visits.

Conclusion: The dapivirine vaginal ring, a promising topical microbicide, was well tolerated and acceptable in young US adolescents.
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http://dx.doi.org/10.1097/QAI.0000000000002244DOI Listing
February 2020

Outcomes after bloodstream infection in hospitalized pediatric hematology/oncology and stem cell transplant patients.

Pediatr Blood Cancer 2019 12 5;66(12):e27978. Epub 2019 Sep 5.

Children's Hospital Association, Washington, District of Columbia.

Background: Pediatric hematology/oncology (PHO) patients receiving therapy or undergoing hematopoietic stem cell transplantation (HSCT) often require a central line and are at risk for bloodstream infections (BSI). There are limited data describing outcomes of BSI in PHO and HSCT patients.

Methods: This is a multicenter (n = 17) retrospective analysis of outcomes of patients who developed a BSI. Centers involved participated in a quality improvement collaborative referred to as the Childhood Cancer and Blood Disorder Network within the Children's Hospital Association. The main outcome measures were all-cause mortality at 3, 10, and 30 days after positive culture date; transfer to the intensive care unit (ICU) within 48 hours of positive culture; and central line removal within seven days of the positive blood culture.

Results: Nine hundred fifty-seven BSI were included in the analysis. Three hundred fifty-four BSI (37%) were associated with at least one adverse outcome. All-cause mortality was 1% (n = 9), 3% (n = 26), and 6% (n = 57) at 3, 10, and 30 days after BSI, respectively. In the 165 BSI (17%) associated with admission to the ICU, the median ICU stay was four days (IQR 2-10). Twenty-one percent of all infections (n = 203) were associated with central line removal within seven days of positive blood culture.

Conclusions: BSI in PHO and HSCT patients are associated with adverse outcomes. These data will assist in defining the impact of BSI in this population and demonstrate the need for quality improvement and research efforts to decrease them.
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http://dx.doi.org/10.1002/pbc.27978DOI Listing
December 2019

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2B6 and Efavirenz-Containing Antiretroviral Therapy.

Clin Pharmacol Ther 2019 10 5;106(4):726-733. Epub 2019 Jul 5.

Department of Internal Medicine, Meharry Medical College School of Medicine, Nashville, Tennessee, USA.

The HIV type-1 nonnucleoside reverse transcriptase inhibitor, efavirenz, is widely used to treat HIV type-1 infection. Efavirenz is predominantly metabolized into inactive metabolites by cytochrome P450 (CYP)2B6, and patients with certain CYP2B6 genetic variants may be at increased risk for adverse effects, particularly central nervous system toxicity and treatment discontinuation. We summarize the evidence from the literature and provide therapeutic recommendations for efavirenz prescribing based on CYP2B6 genotypes.
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http://dx.doi.org/10.1002/cpt.1477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739160PMC
October 2019

Model-Based Methods to Translate Adolescent Medicine Trials Network for HIV/AIDS Interventions Findings Into Policy Recommendations: Rationale and Protocol for a Modeling Core (ATN 161).

JMIR Res Protoc 2019 Apr 16;8(4):e9898. Epub 2019 Apr 16.

Medical Practice Evaluation Center, Massachusetts General Hospital, Boston, MA, United States.

Background: The United States Centers for Disease Control and Prevention estimates that approximately 60,000 US youth are living with HIV. US youth living with HIV (YLWH) have poorer outcomes compared with adults, including lower rates of diagnosis, engagement, retention, and virologic suppression. With Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) support, new trials of youth-centered interventions to improve retention in care and medication adherence among YLWH are underway.

Objective: This study aimed to use a computer simulation model, the Cost-Effectiveness of Preventing AIDS Complications (CEPAC)-Adolescent Model, to evaluate selected ongoing and forthcoming ATN interventions to improve viral load suppression among YLWH and to define the benchmarks for uptake, effectiveness, durability of effect, and cost that will make these interventions clinically beneficial and cost-effective.

Methods: This protocol, ATN 161, establishes the ATN Modeling Core. The Modeling Core leverages extensive data-already collected by successfully completed National Institutes of Health-supported studies-to develop novel approaches for modeling critical components of HIV disease and care in YLWH. As new data emerge from ongoing ATN trials during the award period about the effectiveness of novel interventions, the CEPAC-Adolescent simulation model will serve as a flexible tool to project their long-term clinical impact and cost-effectiveness. The Modeling Core will derive model input parameters and create a model structure that reflects key aspects of HIV acquisition, progression, and treatment in YLWH. The ATN Modeling Core Steering Committee, with guidance from ATN leadership and scientific experts, will select and prioritize specific model-based analyses as well as provide feedback on derivation of model input parameters and model assumptions. Project-specific teams will help frame research questions for model-based analyses as well as provide feedback regarding project-specific inputs, results, sensitivity analyses, and policy conclusions.

Results: This project was funded as of September 2017.

Conclusions: The ATN Modeling Core will provide critical information to guide the scale-up of ATN interventions and the translation of ATN data into policy recommendations for YLWH in the United States.
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http://dx.doi.org/10.2196/resprot.9898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488956PMC
April 2019

Pre-vaccination prevalence of anogenital and oral human papillomavirus in young HIV-infected men who have sex with men.

Papillomavirus Res 2019 06 15;7:52-61. Epub 2019 Jan 15.

Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Electronic address:

The aims of this study were to: 1) determine prevalence of anogenital and oral HPV, 2) determine concordance between HPV at anal, perianal, scrotal/penile, and oral sites; and 3) describe factors associated with anogenital HPV types targeted by the 9-valent vaccine. Data were collected from 2012 to 2015 among men who have sex with men 18-26 years of age enrolled in a vaccine trial (N = 145). Penile/scrotal, perianal, anal, and oral samples were tested for 61 HPV types. Logistic regression was used to identify factors associated with types in the 9-valent vaccine. Participants' mean age was 23.0 years, 55.2% were African-American, and 26.2% were Hispanic; 93% had anal, 40% penile, and 6% oral HPV. Among those with anogenital infection, 18% had HPV16. Concordance was low between anogenital and oral sites. Factors independently associated with a 9-valent vaccine-type HPV were: race (African-American vs. White, OR=2.67, 95% CI=1.11-6.42), current smoking (yes vs. no, OR=2.37, 95% CI=1.03-5.48), and number of recent receptive anal sex partners (2+ vs. 0, OR=3.47, 95% CI=1.16-10.4). Most MSM were not infected with HPV16 or HPV18, suggesting that they may still benefit from HPV vaccination, but anogenital HPV was very common, highlighting the importance of vaccinating men before sexual initiation. CLINICAL TRIAL NUMBER: NCT01209325.
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http://dx.doi.org/10.1016/j.pvr.2019.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356116PMC
June 2019

Interest of Youth Living With HIV in Long-Acting Antiretrovirals.

J Acquir Immune Defic Syndr 2019 02;80(2):190-197

Divisions of Adult and Pediatric Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD.

Objectives: This study's primary objective was to characterize attitudes to long-acting antiretrovirals (LAARV), among youth aged 13-24 years living with perinatally acquired HIV and nonperinatally acquired HIV. Secondary objectives included: assessing whether those with detectable HIV RNA PCR viral load had higher enthusiasm for LAARV compared to those with suppressed viral load, and examining characteristics associated with LAARV enthusiasm.

Methods: A cross-sectional survey of 303 youth living with HIV (YHIV) followed at 4 pediatric/adolescent HIV clinics in the United States was performed to determine interest in LAARV, using a modified survey instrument previously used in adults. Interest in LAARV across groups was compared. Poisson regression with robust variance was used to determine the impact of various characteristics on interest in LAARV.

Findings: Overall, 88% of YHIV reported probable or definite willingness to use LAARV. The enthusiasm level was similar between youth with perinatally acquired HIV and nonperinatally acquired HIV (P = 0.93). Youth with HIV viral load >1000 copies per milliliter had significantly higher interest than youth with suppressed viral load [prevalence ratio 1.12 (95% confidence interval: 1.03 to 1.20); P = 0.005]. Female youth participants who had had past experience with implantable contraceptive methods had a significantly higher interest in LAARV (100% vs. 85.5%; P = 0.002). Proportion of respondents endorsing definite willingness to use was significantly higher with decreased injection frequency compared with increased injection frequency.

Interpretation: YHIV at 4 urban US pediatric/adolescent HIV clinics had high levels of enthusiasm for LAARV. LAARV should be given high priority as a potentially viable treatment option to improve clinical outcomes in YHIV.
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http://dx.doi.org/10.1097/QAI.0000000000001896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331217PMC
February 2019

Effect of Levofloxacin Prophylaxis on Bacteremia in Children With Acute Leukemia or Undergoing Hematopoietic Stem Cell Transplantation: A Randomized Clinical Trial.

JAMA 2018 09;320(10):995-1004

The Hospital for Sick Children, Toronto, Ontario, Canada.

Importance: Bacteremia causes considerable morbidity among children with acute leukemia and those undergoing hematopoietic stem cell transplantation (HSCT). There are limited data on the effect of antibiotic prophylaxis in children.

Objective: To determine the efficacy and risks of levofloxacin prophylaxis in children receiving intensive chemotherapy for acute leukemia or undergoing HSCT.

Design, Setting, And Participants: In this multicenter, open-label, randomized trial, patients (6 months-21 years) receiving intensive chemotherapy were enrolled (September 2011-April 2016) in 2 separate groups-acute leukemia, consisting of acute myeloid leukemia or relapsed acute lymphoblastic leukemia, and HSCT recipients-at 76 centers in the United States and Canada, with follow-up completed September 2017.

Interventions: Patients with acute leukemia were randomized to receive levofloxacin prophylaxis for 2 consecutive cycles of chemotherapy (n = 100) or no prophylaxis (n = 100). Those undergoing HSCT were randomized to receive levofloxacin prophylaxis during 1 HSCT procedure (n = 210) or no prophylaxis (n = 214).

Main Outcomes And Measures: The primary outcome was the occurrence of bacteremia during 2 chemotherapy cycles (acute leukemia) or 1 transplant procedure (HSCT). Secondary outcomes included fever and neutropenia, severe infection, invasive fungal disease, Clostridium difficile-associated diarrhea, and musculoskeletal toxic effects.

Results: A total of 624 patients, 200 with acute leukemia (median [interquartile range {IQR}] age, 11 years [6-15 years]; 46% female) and 424 undergoing HSCT (median [IQR] age, 7 years [3-14]; 38% female), were enrolled. Among 195 patients with acute leukemia, the likelihood of bacteremia was significantly lower in the levofloxacin prophylaxis group than in the control group (21.9% vs 43.4%; risk difference, 21.6%; 95% CI, 8.8%-34.4%, P = .001), whereas among 418 patients undergoing HSCT, the risk of bacteremia was not significantly lower in the levofloxacin prophylaxis group (11.0% vs 17.3%; risk difference, 6.3%; 95% CI, 0.3%-13.0%; P = .06). Fever and neutropenia were less common in the levofloxacin group (71.2% vs 82.1%; risk difference, 10.8%; 95% CI, 4.2%-17.5%; P = .002). There were no significant differences in severe infection (3.6% vs 5.9%; risk difference, 2.3%; 95% CI, -1.1% to 5.6%; P = .20), invasive fungal disease (2.9% vs 2.0%; risk difference, -1.0%; 95% CI, -3.4% to 1.5%, P = .41), C difficile-associated diarrhea (2.3% vs 5.2%; risk difference, 2.9%; 95% CI, -0.1% to 5.9%; P = .07), or musculoskeletal toxic effects at 2 months (11.4% vs 16.3%; risk difference, 4.8%; 95% CI, -1.6% to 11.2%; P = .15) or at 12 months (10.1% vs 14.4%; risk difference, 4.3%; 95% CI, -3.4% to 12.0%; P = .28) between the levofloxacin and control groups.

Conclusions And Relevance: Among children with acute leukemia receiving intensive chemotherapy, receipt of levofloxacin prophylaxis compared with no prophylaxis resulted in a significant reduction in bacteremia. However, there was no significant reduction in bacteremia for levofloxacin prophylaxis among children undergoing HSCT.
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http://dx.doi.org/10.1001/jama.2018.12512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143098PMC
September 2018

Safety, efficacy, and pharmacokinetics of single-tablet elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in virologically suppressed, HIV-infected children: a single-arm, open-label trial.

Lancet Child Adolesc Health 2017 Sep 29;1(1):27-34. Epub 2017 Jun 29.

Gilead Sciences, Foster City, CA, USA. Electronic address:

Background: No once-daily single-tablet regimen is available for HIV-infected children under 12 years. The single-tablet, fixed-dose combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is a once-daily, integrase strand transfer inhibitor-based regimen approved in the USA and European Union for individuals aged 12 years or older. In this study, we aimed to assess the pharmacokinetics, safety, and efficacy of this regimen in virologically suppressed, HIV-infected children.

Methods: In this single-arm, open-label trial, we enrolled virologically suppressed, HIV-infected children from five hospital clinics in Uganda, the USA, and Thailand. Eligible participants were aged 6-11 years, weighed 25 kg or more, had virological suppression (<50 copies of HIV-1 RNA per mL) on a stable regimen for at least 6 months, CD4 count of more than 100 cells per μL, and no history of resistance to elvitegravir, emtricitabine, tenofovir alafenamide, or tenofovir. All participants received the available fixed-dose oral formulation of elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg once per day. Primary outcomes were the pharmacokinetic parameters area under the curve (AUC) concentration at the end of the dosing interval (AUC) for elvitegravir and the AUC from time zero to the last quantifiable concentration (AUC) of tenofovir alafenamide, treatment-emergent serious adverse events, and all treatment-emergent adverse events. Results from baseline to week 24 are reported, unless specified otherwise. Primary and safety analyses included all enrolled participants who received one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01854775.

Findings: Between July 27 and Sept 28, 2015, we screened 26 children, of whom 23 were enrolled and initiated treatment. Median age was 10 years (IQR 8-11), median weight was 30·5 kg (IQR 27·5-33·0), and all participants had virological suppression. The mean AUC of elvitegravir was 33 814 ng × h/mL (coefficient of variation 58%), and the mean AUC of tenofovir alafenamide was 333 ng × h/mL (45%). Exposures to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide were higher, but modestly so, than those previously reported in adults. All 23 participants tolerated the regimen well; there were no serious adverse events or adverse event-related discontinuations. All participants maintained virological suppression (HIV-1 RNA <50 copies per mL) at week 24. CD4 count decreased by a median of -130 cells per μL (range -472 to 266) with little change in CD4 cell percentage (-2·1%, range -8·4 to 5·9).

Interpretation: The fixed-dose combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide was efficacious and well tolerated in virologically suppressed, HIV-infected children. Although plasma exposure of all components was higher than has been reported in adults, there were no safety concerns and the overall bone and renal safety profile was favourable. These data support the use of this regimen in children at least 25 kg in weight.

Funding: Gilead Sciences.
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http://dx.doi.org/10.1016/S2352-4642(17)30009-3DOI Listing
September 2017

Treatment and secondary prophylaxis with ethanol lock therapy for central line-associated bloodstream infection in paediatric cancer: a randomised, double-blind, controlled trial.

Lancet Infect Dis 2018 08 5;18(8):854-863. Epub 2018 Jun 5.

Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA; Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA.

Background: Central line-associated bloodstream infections (CLABSIs) affect about 25% of children with cancer, and treatment failure is common. Adjunctive ethanol lock therapy might prevent treatment failure but high-quality evidence is scarce. We evaluated ethanol lock therapy as treatment and secondary prophylaxis for CLABSI in children with cancer or haematological disorders.

Methods: This randomised, double-blind, placebo-controlled superiority trial, with two interim futility and efficacy analyses (done when the first 46 and 92 evaluable participants completed study requirements), was done at two paediatric hospitals in the USA and Australia. Patients aged 6 months to 24 years, inclusive, with cancer or a haematological disorder and new CLABSI were eligible. Participants were randomly assigned (1:1) to receive either ethanol lock therapy (70% ethanol) or placebo (heparinised saline) for 2-4 h per lumen daily for 5 days (treatment phase), then for up to 3 non-consecutive days per week for 24 weeks (prophylaxis phase). The primary composite outcome was treatment failure, consisting of attributable catheter removal or death, new or persistent (>72 h) infection, or additional lock therapy during the treatment phase, and recurrent CLABSI during the prophylaxis phase. This trial is registered with ClinicalTrials.gov, number NCT01472965.

Findings: 94 evaluable participants were enrolled between Dec 14, 2011, and Sept 12, 2016, of whom 48 received ethanol lock therapy and 46 received placebo. The study met futility criteria at the second interim analysis. Treatment failure was similar with ethanol lock therapy (21 [44%] of 48) and placebo (20 [43%] of 46; relative risk [RR] 1·0, 95% CI 0·6-1·6; p=0·98). Some adverse events, including infusion reactions and catheter occlusion, were more frequent in the ethanol lock therapy group than in the placebo group. Catheter occlusion requiring thrombolytic therapy was more common with ethanol lock therapy (28 [58%] of 48) than with placebo (15 [33%] of 46; RR 1·8, 95% CI 1·1-2·9; p=0·012). Discontinuation of lock therapy because of adverse effects or patient request occurred in a similar proportion of participants in the ethanol lock therapy (nine [19%] of 48) and placebo groups (ten [22%] of 46; p=0·72).

Interpretation: Ethanol lock therapy did not prevent CLABSI treatment failure and it increased catheter occlusion. Routine ethanol lock therapy for treatment or secondary prophylaxis is not recommended in this population.

Funding: American Lebanese Syrian Associated Charities to St Jude Children's Research Hospital and an Australian Government Research Training Scholarship.
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http://dx.doi.org/10.1016/S1473-3099(18)30224-XDOI Listing
August 2018

Adverse Effects of Intravenous Vancomycin-Based Prophylaxis during Therapy for Pediatric Acute Myeloid Leukemia.

Antimicrob Agents Chemother 2018 03 23;62(3). Epub 2018 Feb 23.

Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA

Children and adolescents with acute myeloid leukemia (AML) are at risk of life-threatening bacterial infections, especially with viridans group streptococci. Primary antibacterial prophylaxis with vancomycin-based regimens reduces this risk but might increase the risks of renal or liver toxicity or infection (CDI). A retrospective review of data for patients treated for newly diagnosed AML at St. Jude Children's Research Hospital between 2002 and 2008 was conducted. Nephrotoxicity was classified according to pediatric risk, injury, failure, loss, and end-stage renal disease (pRIFLE) criteria and hepatotoxicity according to Common Terminology Criteria for Adverse Events (CTCAE) criteria. The risks of nephrotoxicity, hepatotoxicity, and CDI were compared between patients receiving vancomycin-based prophylaxis, no intravenous prophylaxis, or other prophylaxis. Generalized linear mixed models were used to address potential confounding. A total of 392 chemotherapy courses (108 with no intravenous prophylaxis, 218 with vancomycin-based prophylaxis, and 66 with other prophylaxis) for 111 patients were included. Development of pRIFLE risk, injury, and failure occurred in 190, 44, and 2 courses, respectively. Increases of at least one, two, and three grades for hepatotoxicity occurred in 189, 52, and 19 courses, respectively. After adjustment for confounders, vancomycin-based prophylaxis was not associated with nephrotoxicity or hepatotoxicity and reduced the risk of CDI, compared to no intravenous prophylaxis (0.9% versus 6.5%; = 0.007) or other prophylactic regimens (0.9% versus 3.0%; = 0.23). Despite concerns about vancomycin toxicity, vancomycin-based prophylaxis in pediatric patients with AML did not increase the risk of nephrotoxicity or hepatotoxicity and reduced the risk of CDI. Caution is advised to avoid contributing to antibiotic resistance.
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http://dx.doi.org/10.1128/AAC.01838-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826122PMC
March 2018

A quality improvement initiative to increase Tdap (tetanus, diphtheria, acellular pertussis) vaccination coverage among direct health care providers at a children's hospital.

Vaccine 2018 01 6;36(2):214-219. Epub 2017 Dec 6.

Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA; Department of Pediatrics, University of Tennessee Health Sciences Center, 50 N. Dunlap, Memphis, TN 38103, USA. Electronic address:

Objectives: Health care providers (HCP) are at high risk of acquiring and transmitting pertussis to susceptible family members, co-workers, and patients. Public health authorities recommend administering a single dose of Tdap (tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis) vaccine to all adults, including HCP, to increase adult immunity to pertussis. We set a quality improvement goal to increase Tdap vaccination coverage among HCP who provided direct patient care at a children's hospital from 58% to 90% over 18 months.

Design: A multidisciplinary working group comprised of Occupational Health Program (OHP) staff and representatives of various medical services drew from a variety of qualitative methods and previous studies of vaccination programs in the healthcare system to understand barriers to Tdap vaccination within the institution and to develop interventions to increase vaccination rates.

Interventions: Interventions included changes to OHP processes, a general education campaign, improved access to vaccine, and personal engagement of HCP by task force members.

Results: Overall vaccination rates increased to 90% over 15 months, a rate that has been sustained by systematically assessing new employees' vaccination status and vaccinating those without documentation of previous Tdap vaccination.

Conclusions: Tdap vaccination coverage in our institution was significantly increased by an intensive, multipronged educational campaign, and by improving processes of screening and vaccination of HCP. The use of direct engagement of vaccine hesitant populations to increase vaccination rates warrants further study.
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http://dx.doi.org/10.1016/j.vaccine.2017.11.071DOI Listing
January 2018

Levofloxacin Prophylaxis During Induction Therapy for Pediatric Acute Lymphoblastic Leukemia.

Clin Infect Dis 2017 Nov;65(11):1790-1798

Oncology.

Background: Infection is the most important cause of treatment-related morbidity and mortality in pediatric patients treated for acute lymphoblastic leukemia (ALL). Although routine in adults with leukemia, antibacterial prophylaxis is controversial in pediatrics because of insufficient evidence for its efficacy or antibiotic choice and concerns about promoting antibiotic resistance and Clostridium difficile infection.

Methods: This was a single-center, observational cohort study of patients with newly diagnosed ALL, comparing prospectively collected infection-related outcomes in patients who received no prophylaxis, levofloxacin prophylaxis, or other prophylaxis during induction therapy on the total XVI study. A propensity score-weighted logistic regression model was used to adjust for confounders.

Results: Of 344 included patients, 173 received no prophylaxis, 69 received levofloxacin prophylaxis, and 102 received other prophylaxis regimens. Patients receiving prophylaxis had longer duration of neutropenia. Prophylaxis reduced the odds of febrile neutropenia, likely bacterial infection, and bloodstream infection by ≥70%. Levofloxacin prophylaxis alone reduced these infections, but it also reduced cephalosporin, aminoglycoside, and vancomycin exposure and reduced the odds of C. difficile infection by >95%. No increase in breakthrough infections with antibiotic-resistant organisms was seen, but this cannot be excluded.

Conclusions: This is the largest study to date of antibacterial prophylaxis during induction therapy for pediatric ALL and the first to include a broad-spectrum fluoroquinolone. Prophylaxis prevented febrile neutropenia and systemic infection. Levofloxacin prophylaxis also minimized the use of treatment antibiotics and drastically reduced C. difficile infection. Although long-term antibiotic-resistance monitoring is needed, these data support using targeted prophylaxis with levofloxacin in children undergoing induction chemotherapy for ALL.

Clinical Trials Registration: NCT00549848.
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http://dx.doi.org/10.1093/cid/cix644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850441PMC
November 2017

Guideline for the Management of Fever and Neutropenia in Children With Cancer and Hematopoietic Stem-Cell Transplantation Recipients: 2017 Update.

J Clin Oncol 2017 Jun 1;35(18):2082-2094. Epub 2017 May 1.

Thomas Lehrnbecher, Hospital for Children and Adolescents, Johann Wolfgang Goethe University, Frankfurt; Andreas H. Groll, University Children's Hospital, Muenster, Germany; Paula Robinson, Pediatric Oncology Group of Ontario; Sarah Alexander, L. Lee Dupuis, and Lillian Sung, The Hospital for Sick Children, Toronto, Ontario, Canada; Brian Fisher and Theo Zaoutis, Children's Hospital of Philadelphia, Philadelphia, PA; Roland A. Ammann, Bern University Hospital, University of Bern, Switzerland; Melissa Beauchemin, Columbia University/Herbert Irving Cancer Center, New York, NY; Fabianne Carlesse, Pediatric Oncology Institute, GRAACC/Federal University of Sao Paulo, Sao Paulo, Brazil; Gabrielle M. Haeusler, Peter MacCallum Cancer Centre, Melbourne; Monash Children's Hospital, Clayton, Victoria, Australia; Maria Santolaya, Hospital Luis Calvo Mackenna, Universidad de Chile, Santiago, Chile; William J. Steinbach, Duke University Medical Center, Durham, NC; Elio Castagnola, Istituto Giannina Gaslini, Genova, Italy; Bonnie L. Davis, High Tor Limited, Nassau, Bahamas; Aditya H. Gaur, St Jude Children's Research Hospital, Memphis, TN; Wim J.E. Tissing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; and Robert Phillips, Leeds Teaching Hospital, NHS Trust, Leeds; University of York, York, United Kingdom.

Purpose To update a clinical practice guideline (CPG) for the empirical management of fever and neutropenia (FN) in children with cancer and hematopoietic stem-cell transplantation recipients. Methods The International Pediatric Fever and Neutropenia Guideline Panel is a multidisciplinary and multinational group of experts in pediatric oncology and infectious diseases that includes a patient advocate. For questions of risk stratification and evaluation, we updated systematic reviews of observational studies. For questions of therapy, we conducted a systematic review of randomized trials of any intervention applied for the empirical management of pediatric FN. The Grading of Recommendation Assessment, Development and Evaluation approach was used to make strong or weak recommendations and to classify levels of evidence as high, moderate, low, or very low. Results Recommendations related to initial presentation, ongoing management, and empirical antifungal therapy of pediatric FN were reviewed; the most substantial changes were related to empirical antifungal therapy. Key differences from our 2012 FN CPG included the listing of a fourth-generation cephalosporin for empirical therapy in high-risk FN, refinement of risk stratification to define patients with high-risk invasive fungal disease (IFD), changes in recommended biomarkers and radiologic investigations for the evaluation of IFD in prolonged FN, and a weak recommendation to withhold empirical antifungal therapy in IFD low-risk patients with prolonged FN. Conclusion Changes to the updated FN CPG recommendations will likely influence the care of pediatric patients with cancer and those undergoing hematopoietic stem-cell transplantation. Future work should focus on closing research gaps and on identifying ways to facilitate implementation and adaptation.
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http://dx.doi.org/10.1200/JCO.2016.71.7017DOI Listing
June 2017

A Prospective, Holistic, Multicenter Approach to Tracking and Understanding Bloodstream Infections in Pediatric Hematology-Oncology Patients.

Infect Control Hosp Epidemiol 2017 06 12;38(6):690-696. Epub 2017 Apr 12.

7Dana-Farber/Boston Children's Cancer and Blood Disorders Center,Boston,Massachusetts.

OBJECTIVE To assess the burden of bloodstream infections (BSIs) among pediatric hematology-oncology (PHO) inpatients, to propose a comprehensive, all-BSI tracking approach, and to discuss how such an approach helps better inform within-center and across-center differences in CLABSI rate DESIGN Prospective cohort study SETTING US multicenter, quality-improvement, BSI prevention network PARTICIPANTS PHO centers across the United States who agreed to follow a standardized central-line-maintenance care bundle and track all BSI events and central-line days every month. METHODS Infections were categorized as CLABSI (stratified by mucosal barrier injury-related, laboratory-confirmed BSI [MBI-LCBI] versus non-MBI-LCBI) and secondary BSI, using National Healthcare Safety Network (NHSN) definitions. Single positive blood cultures (SPBCs) with NHSN defined common commensals were also tracked. RESULTS Between 2013 and 2015, 34 PHO centers reported 1,110 BSIs. Among them, 708 (63.8%) were CLABSIs, 170 (15.3%) were secondary BSIs, and 232 (20.9%) were SPBCs. Most SPBCs (75%) occurred in patients with profound neutropenia; 22% of SPBCs were viridans group streptococci. Among the CLABSIs, 51% were MBI-LCBI. Excluding SPBCs, CLABSI rates were higher (88% vs 77%) and secondary BSI rates were lower (12% vs 23%) after the NHSN updated the definition of secondary BSI (P<.001). Preliminary analyses showed across-center differences in CLABSI versus secondary BSI and between SPBC and CLABSI versus non-CLABSI rates. CONCLUSIONS Tracking all BSIs, not just CLABSIs in PHO patients, is a patient-centered, clinically relevant approach that could help better assess across-center and within-center differences in infection rates, including CLABSI. This approach enables informed decision making by healthcare providers, payors, and the public. Infect Control Hosp Epidemiol 2017;38:690-696.
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http://dx.doi.org/10.1017/ice.2017.57DOI Listing
June 2017

Use of Placebo Pills Before Treatment Initiation in Youth with HIV: Are They Ready?

J Int Assoc Provid AIDS Care 2017 Jul/Aug;16(4):412-417. Epub 2017 Apr 10.

3 Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA.

Highly active antiretroviral therapy (HAART) nonadherence is related to negative health outcomes and is well-documented in adolescents and young adults (AYAs) with behaviorally acquired HIV. Few studies describe methods to improve adherence in this population. This retrospective study describes placebo pill trial use (ie, pills with inert substance prescribed to practice taking HAART) in AYAs initiating HAART and its relation to disease outcomes. Sixty-two AYAs initiated HAART during the review period. Disease outcomes during the first year of standard clinical care were abstracted from medical records. In all, 72.6% of participants received ≥1 pill trial and 27.4% received ≥2 trials. Placebo trial use was not independently related to adherence post-HAART initiation. "Prescription" of a second trial was related to less optimal disease status over the first 6 months of treatment. Placebo trials have the potential to inform clinical care, aid in identifying AYAs at risk for nonadherence, and may provide a novel intervention strategy before/after HAART initiation.
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http://dx.doi.org/10.1177/2325957417702483DOI Listing
April 2018

Body Image and Risk Behaviors in Youth with HIV.

AIDS Patient Care STDS 2017 Apr 23;31(4):176-181. Epub 2017 Mar 23.

1 Department of Infectious Diseases, St. Jude Children's Research Hospital , Memphis, Tennessee.

Body image concerns are common among people living with HIV. Among adults with HIV, body image concerns have been shown to be related to risky sexual behaviors; little research has been conducted among youth living with HIV (YLWH). The current study examined the predictors, including body image, of sexual risk behaviors among YLWH. Adolescents from a single clinic (n = 143; age range, 16-24 years; 69% male; 95% African American) completed a computerized self-report survey to assess demographic, behavioral, and body image domains. Demographic and clinical data were abstracted from the medical record. Logistic regression analyses assessed associations between risk factors and risky sexual behaviors. Results indicated that YLWH who reported less favorable body image perceptions (p = 0.04) and more sexual partners (p = 0.05) were less likely to use condoms during their last sexual encounter. YLWH with six or more sexual partners were more likely to use drugs or alcohol during their last sexual encounter (p = 0.03). A belief that their HIV medications changed their body physically (p = 0.05), history of HIV-related complications (p = 0.03), an undetectable viral load at their most recent clinical laboratory draw (p = 0.01), and having a high school diploma or equivalent (p = 0.001) were independently associated with disclosure of participant's HIV status to a romantic/sexual partner. Findings suggest that body image perceptions may influence risky sexual behavior in YLWH. Further study is warranted to understand and intervene upon this relationship to improve individual and public health outcomes.
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http://dx.doi.org/10.1089/apc.2016.0259DOI Listing
April 2017

The impact of the UGT1A1*60 allele on bilirubin serum concentrations.

Pharmacogenomics 2017 Jan 14;18(1):5-16. Epub 2016 Dec 14.

Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.

Aim: Identify the functional status of the uridine-diphosphate glucuronyl transferase 1A1 (UGT1A1) -3279T>G (*60) variant.

Materials & Methods: Retrospective review of clinically obtained serum bilirubin concentrations in pediatric patients to evaluate the association of the UGT1A1 -3279T>G (*60) variant with bilirubin concentrations and assessed linkage disequilibrium of the UGT1A1 -3279T>G (*60) and A(TA)7TAA (*28) variants.

Results: Total bilirubin concentration did not differ between patients who had a UGT1A1*1/*1 diplotype and patients homozygous for the UGT1A1 -3279T>G (*60/*60) variant. Total bilirubin concentration was lower in patients homozygous for the UGT1A1 -3279T>G (*60/*60) variant than in patients homozygous for the UGT1A1 A(TA)7TAA (*28/*28) variant (p < 0.01). The -3279T>G (*60) and A(TA)7TAA (*28) variants were in strong incomplete linkage disequilibrium in both black and white patients.

Conclusion: The presence of the UGT1A1 -3279T>G (*60) variant is not associated with increased bilirubin concentrations.
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http://dx.doi.org/10.2217/pgs-2016-0135DOI Listing
January 2017

Safety, efficacy, and pharmacokinetics of a single-tablet regimen containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in treatment-naive, HIV-infected adolescents: a single-arm, open-label trial.

Lancet HIV 2016 12 17;3(12):e561-e568. Epub 2016 Oct 17.

Gilead Sciences Inc, Foster City, CA, USA. Electronic address:

Background: The prodrug tenofovir alafenamide is associated with improved renal and bone safety compared with tenofovir disoproxil fumarate. We aimed to assess safety, pharmacokinetics, and efficacy of this single-tablet, fixed-dose combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in HIV-infected, treatment-naive adolescents.

Methods: We did a 48 week, single-arm, open-label trial in treatment-naive adolescents with HIV from ten hospital clinics in South Africa, Thailand, Uganda, and the USA. Eligible participants were aged 12-18 years, with plasma HIV-1 RNA of at least 1000 copies per mL, a CD4 count of at least 100 cells per μL, and estimated glomerular filtration rate of at least 90 mL/min per 1·73 m by the Schwartz formula, bodyweight of at least 35 kg, and an HIV-1 genotype with sensitivity to elvitegravir, emtricitabine, and tenofovir. Participants received a single-tablet regimen once per day with food (administered by their parent or carer) containing 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, and 10 mg tenofovir alafenamide. Study visits to the clinic occurred at weeks 1, 2, 4, 8, 12, 16, 24, 32, 40, and 48. The coprimary endpoints were the pharmacokinetic parameters of area under the curve (AUC) concentration at the end of the dosing interval (AUC) for elvitegravir and the AUC from time zero to the last quantifiable concentration (AUC) for tenofovir alafenamide, incidence of treatment-emergent serious adverse events, and all adverse events that emerged after treatment started (including data for bone mineral density). All participants who received one dose of study drug were included in the primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT01854775.

Findings: Between May 22, 2013, and July 22, 2014, we enrolled 50 participants, and all 50 received the assigned treatment; 24 participated in the intensive pharmacokinetic assessment. 48 patients completed the 48 weeks of treatment; two discontinued (one withdrew consent at week 8, one was lost to follow-up at week 12). The regimen was well tolerated and no discontinuations related to adverse events occurred. The mean AUC for elvitegravir was 23 840 ng × h per mL (coefficient of variation [CV] 25·5%), and the mean AUC for tenofovir alafenamide was 189 ng × h per mL (CV 55·8%). Four participants (8%) had a serious adverse event, one of which (intermediate uveitis) was deemed related to the study regimen but resolved without treatment interruption. The most common study drug-related adverse events were nausea (in ten participants), abdominal pain (in six), and vomiting (in five). Exposures to the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide regimen were similar to those previously noted in adults.

Interpretation: The elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide regimen was well tolerated and achieved component plasma pharmacokinetic exposures similar to those in adults. Although non-comparative with a small sample size, these data support the use of this regimen in HIV-infected adolescents and its timely assessment in younger children.

Funding: Gilead Sciences.
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http://dx.doi.org/10.1016/S2352-3018(16)30121-7DOI Listing
December 2016

Central Line Associated Blood Stream Infections in Pediatric Hematology/Oncology Patients With Different Types of Central Lines.

Pediatr Blood Cancer 2016 09 16;63(9):1603-7. Epub 2016 May 16.

St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Central line associated bloodstream infections (CLABSIs) are a significant cause of morbidity and mortality in pediatric hematology/oncology (PHO) patients. Understanding the differences in CLABSI rates by central line (CL) type is important to inform clinical decisions.

Procedure: CLABSI, using similar definitions, noted with three commonly used CL types (totally implanted catheter [port], tunneled externalized catheter [TEC], peripherally inserted central catheter [PICC]) and CL-specific line days were prospectively tracked across 15 US PHO centers from May 2012 until April 2015 and CLABSI rates (CLABSI per 1,000 CL-specific line days) were calculated. Host and organism characterstics associated with the CLABSI events were analyzed.

Results: Over the course of 2.8 million line days, 1,113 CLABSI events (397 in inpatients and 716 in ambulatory patients) were noted. The inpatient CLABSI rate was higher than the ambulatory CLABSI rate for each of the CL types: 1.48 versus 0.16 for ports, 3.51 versus 1.38 for TECs, and 3.07 versus 1.16 for PICCs, respectively. TECs and PICCs were associated with higher CLABSI rates than ports, inpatient and ambulatory.

Conclusions: We found that CLABSI rates were significantly higher for inpatients compared to ambulatory PHO patients for all CL types. Among ambulatory patients, TECs had the highest CLABSI rate and ports the lowest. Among inpatients, TECs and PICCs had higher CLABSI rates than ports but were not statistically different from one another. Cognizant that host and underlying disease attributes may contribute to these differences, these results can still inform CL choice in clinical practice.
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http://dx.doi.org/10.1002/pbc.26053DOI Listing
September 2016

The Impact of Youth-Friendly Structures of Care on Retention Among HIV-Infected Youth.

AIDS Patient Care STDS 2016 Apr 16;30(4):170-7. Epub 2016 Mar 16.

5 Divisions of Infectious Diseases, Johns Hopkins School of Medicine , Baltimore, Maryland.

Limited data exist on how structures of care impact retention among youth living with HIV (YLHIV). We describe the availability of youth-friendly structures of care within HIV Research Network (HIVRN) clinics and examine their association with retention in HIV care. Data from 680 15- to 24-year-old YLHIV receiving care at 7 adult and 5 pediatric clinics in 2011 were included in the analysis. The primary outcome was retention in care, defined as completing ≥2 primary HIV care visits ≥90 days apart in a 12-month period. Sites were surveyed to assess the availability of clinic structures defined a priori as 'youth-friendly'. Univariate and multivariable logistic regression models assessed structures associated with retention in care. Among 680 YLHIV, 85% were retained. Nearly half (48%) of the 680 YLHIV attended clinics with youth-friendly waiting areas, 36% attended clinics with evening hours, 73% attended clinics with adolescent health-trained providers, 87% could email or text message providers, and 73% could schedule a routine appointment within 2 weeks. Adjusting for demographic and clinical factors, YLHIV were more likely to be retained in care at clinics with a youth-friendly waiting area (AOR 2.47, 95% CI [1.11-5.52]), evening clinic hours (AOR 1.94; 95% CI [1.13-3.33]), and providers with adolescent health training (AOR 1.98; 95% CI [1.01-3.86]). Youth-friendly structures of care impact retention in care among YLHIV. Further investigations are needed to determine how to effectively implement youth-friendly strategies across clinical settings where YLHIV receive care.
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http://dx.doi.org/10.1089/apc.2015.0263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827281PMC
April 2016

Characterizing Body Image in Youth with HIV.

AIDS Behav 2016 08;20(8):1585-90

Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mailstop 600, Memphis, TN, 38105, USA.

Emerging research in adults with HIV suggests negative body image may be found at a higher rate in this group. To date, few studies have examined body image in adolescents living with HIV. This exploratory study aimed to characterize body image perceptions among youth living with HIV. Adolescents (n = 143; age range 16-24 years; 69 % male) completed an Audio Computer Assisted Self-Interview Questionnaire that assessed body image, psychosocial, medical and sociodemographic information. Medical history and physical functioning information were abstracted from medical records. Results showed normative global body image on the Multidimensional Body Self-Relations Questionnaire-Appearance Scales. Some subscale elevations were observed; including decreased interest in self-care and appearance, as well as concerns with individual body areas. Overall, youth reported preference for own body shape on the Figure Rating Scale; however, 41 % of youth classified as "overweight" per CDC body mass index reported contentment with current body size. Further, 47 % of youth classified as "normal" weight desired to have larger body size. Youth identified as men who have sex with men most often reported desiring larger body size. Implications for clinical care are discussed.
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http://dx.doi.org/10.1007/s10461-015-1271-zDOI Listing
August 2016

The Impact of Vaccine Concerns on Racial/Ethnic Disparities in Influenza Vaccine Uptake Among Health Care Workers.

Am J Public Health 2015 Sep 16;105(9):e35-41. Epub 2015 Jul 16.

Rohit P. Ojha and Sericea Stallings-Smith are with the Department of Epidemiology and Cancer Control, and Patricia M. Flynn, Elisabeth E. Adderson, and Aditya H. Gaur are with the Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN. Tabatha N. Offutt-Powell is with the Data and Informatics Section, Division of Public Health, Delaware State Health Services, Dover.

Objectives: We explored whether collective concerns about the safety, effectiveness, and necessity of influenza vaccines mediate racial/ethnic disparities in vaccine uptake among health care workers (HCWs).

Methods: We used a self-administered Web-based survey to assess race/ethnicity (exposure), concerns about influenza vaccination (mediator; categorized through latent class analysis), and influenza vaccine uptake (outcome) for the 2012 to 2013 influenza season among HCWs at St. Jude Children's Research Hospital in Memphis, Tennessee. We used mediation analysis to estimate prevalence ratios (PRs) and 95% confidence intervals (CIs) for the total, direct, and indirect effects of race/ethnicity on influenza vaccine uptake.

Results: Non-Hispanic Blacks had lower influenza vaccine uptake than non-Hispanic Whites (total effect: PR = 0.87; 95% CI = 0.75, 0.99), largely mediated by high concern about influenza vaccines (natural indirect effect: PR = 0.89; 95% CI = 0.84, 0.94; controlled direct effect: PR = 0.98; 95% CI = 0.85, 1.1). Hispanic and Asian HCWs had modestly lower uptake than non-Hispanic Whites, also mediated by high concern about influenza vaccines.

Conclusions: Racial/ethnic disparities among HCWs could be attenuated if concerns about the safety, effectiveness, and necessity of influenza vaccines were reduced.
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http://dx.doi.org/10.2105/AJPH.2015.302736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4539840PMC
September 2015

The HIV Care Continuum: Changes over Time in Retention in Care and Viral Suppression.

PLoS One 2015 18;10(6):e0129376. Epub 2015 Jun 18.

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.

Background: The HIV care continuum (diagnosis, linkage to care, retention in care, receipt of antiretroviral therapy (ART), viral suppression) has been used to identify opportunities for improving the delivery of HIV care. Continuum steps are typically calculated in a conditional manner, with the number of persons completing the prior step serving as the base population for the next step. This approach may underestimate the prevalence of viral suppression by excluding patients who are suppressed but do not meet standard definitions of retention in care. Understanding how retention in care and viral suppression interact and change over time may improve our ability to intervene on these steps in the continuum.

Methods: We followed 17,140 patients at 11 U.S. HIV clinics between 2010-2012. For each calendar year, patients were classified into one of five categories: (1) retained/suppressed, (2) retained/not-suppressed, (3) not-retained/suppressed, (4) not-retained/not-suppressed, and (5) lost to follow-up (for calendar years 2011 and 2012 only). Retained individuals were those completing ≥ 2 HIV medical visits separated by ≥ 90 days in the year. Persons not retained completed ≥ 1 HIV medical visit during the year, but did not meet the retention definition. Persons lost to follow-up had no HIV medical visits in the year. HIV viral suppression was defined as HIV-1 RNA ≤ 200 copies/mL at the last measure in the year. Multinomial logistic regression was used to determine the probability of patients' transitioning between retention/suppression categories from 2010 to 2011 and 2010 to 2012, adjusting for age, sex, race/ethnicity, HIV risk factor, insurance status, CD4 count, and use of ART.

Results: Overall, 65.8% of patients were retained/suppressed, 17.4% retained/not-suppressed, 10.0% not-retained/suppressed, and 6.8% not-retained/not-suppressed in 2010. 59.5% of patients maintained the same status in 2011 (kappa=0.458) and 53.3% maintained the same status in 2012 (kappa=0.437).

Conclusions: Not counting patients not-retained/suppressed as virally suppressed, as is commonly done in the HIV care continuum, underestimated the proportion suppressed by 13%. Applying the care continuum in a longitudinal manner will enhance its utility.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0129376PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4473034PMC
April 2016