Publications by authors named "Ronald Dallas"

23 Publications

  • Page 1 of 1

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

The Aerogen Solo Is an Alternative to the Small Particle Aerosol Generator (SPAG-2) for Administration of Inhaled Ribavirin.

Pharmaceutics 2020 Nov 29;12(12). Epub 2020 Nov 29.

Department of Infectious Diseases, St. Jude Children Research Hospital, Memphis, TN 38105, USA.

Respiratory syncytial virus (RSV) is associated with adverse outcomes among immunocompromised patients. Inhaled ribavirin has been shown to improve mortality rates. The Small-Particle Aerosol Generator delivery system (SPAG-2) is the only FDA-cleared device to deliver inhaled ribavirin. However, it is difficult to set up and maintain. We developed a method for delivery of this medication using the vibrating mesh nebulizer (Aerogen). We did not observe any adverse events with this method.
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http://dx.doi.org/10.3390/pharmaceutics12121163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760766PMC
November 2020

Infectious Norovirus Is Chronically Shed by Immunocompromised Pediatric Hosts.

Viruses 2020 06 5;12(6). Epub 2020 Jun 5.

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Noroviruses are a leading cause of gastroenteritis worldwide. Although infections in healthy individuals are self-resolving, immunocompromised individuals are at risk for chronic disease and severe complications. Chronic norovirus infections in immunocompromised hosts are often characterized by long-term virus shedding, but it is unclear whether this shed virus remains infectious. We investigated the prevalence, genetic heterogeneity, and temporal aspects of norovirus infections in 1140 patients treated during a 6-year period at a pediatric research hospital. Additionally, we identified 20 patients with chronic infections lasting 37 to >418 days. Using a new human norovirus in vitro assay, we confirmed the continuous shedding of infectious virus for the first time. Shedding lasted longer in male patients and those with diarrheal symptoms. Prolonged shedding of infectious norovirus in immunocompromised hosts can potentially increase the likelihood of transmission, highlighting the importance of isolation precautions to prevent nosocomial infections.
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http://dx.doi.org/10.3390/v12060619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354526PMC
June 2020

Rothia mucilaginosa Infections in Pediatric Cancer Patients.

J Pediatric Infect Dis Soc 2020 May 25. Epub 2020 May 25.

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

We performed a retrospective study to determine the epidemiology of Rothia mucilaginosa infections among pediatric cancer patients. Over 20 years, 37 cases were identified; 27% developed complications, but there was no infection-related mortality. All cases were successfully treated with vancomycin.
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http://dx.doi.org/10.1093/jpids/piaa047DOI Listing
May 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

A multicenter study to define the epidemiology and outcomes of Clostridioides difficile infection in pediatric hematopoietic cell and solid organ transplant recipients.

Am J Transplant 2020 08 10;20(8):2133-2142. Epub 2020 Mar 10.

Department of Pediatrics, Albert Einstein College of Medicine and Children's Hospital at Montefiore, Bronx, New York, USA.

Hematopoietic cell transplant (HCT) and solid organ transplant (SOT) recipients are at increased risk for Clostridioides difficile infection (CDI). We conducted a multicenter retrospective study to describe the incidence of CDI in children transplanted between January 2010 and June 2013. Nested case-control substudies, matched 1:1 by transplant type, institution, patient age, and time of year (quartile) of transplant, identified CDI risk factors. Cohorts included 1496 HCT and 1090 SOT recipients. Among HCT recipients, 355 CDI episodes were diagnosed in 265 recipients (18.2%). Nested case-control study identified prior history of CDI (odds ratio [OR] 2.6, 95% confidence interval [CI] 1.5-4.7), proton pump inhibitors (PPIs; OR 2.1, 95% CI 1.3-3.4), and exposure to third- (OR 2.4, 95% CI 1.4-4.2) or fourth-generation (OR 2.1, 95% CI 1.2-3.7) cephalosporins as risk factors. Notably, fluoroquinolone exposure appeared protective (OR 0.6, 95% CI 0.3-0.9). Ninety-two episodes of CDI were diagnosed among 79 SOT recipients (7.3%), and exposure to PPIs (OR 2.4, 95% CI 1.1-5.4) and third-generation cephalosporin therapy (OR 3.9, 95% CI 1.4-10.5) were identified as risk factors. Strategies to decrease PPI use and changes in the class of prophylactic antibiotics may impact CDI incidence and warrant further study.
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http://dx.doi.org/10.1111/ajt.15826DOI Listing
August 2020

Baseline Serum Vitamin A and D Levels Determine Benefit of Oral Vitamin A&D Supplements to Humoral Immune Responses Following Pediatric Influenza Vaccination.

Viruses 2019 09 30;11(10). Epub 2019 Sep 30.

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Maximizing vaccine efficacy is critical, but previous research has failed to provide a one-size-fits-all solution. Although vitamin A and vitamin D supplementation studies have been designed to improve vaccine efficacy, experimental results have been inconclusive. Information is urgently needed to explain study discrepancies and to provide guidance for the future use of vitamin supplements at the time of vaccination. We conducted a randomized, blinded, placebo-controlled study of influenza virus vaccination and vitamin supplementation among 2 to 8 (inclusive) year old children over three seasons, including 2015-2016 ( = 9), 2016-2017 ( = 44), and 2017-2018 ( = 26). Baseline measurements of vitamins A and D were obtained from all participants. Measurements were of serum retinol, retinol-binding protein (RBP, a surrogate for retinol), and 25-hydroxyvitamin D (25(OH)D). Participants were stratified into two groups based on high and low incoming levels of RBP. Children received two doses of the seasonal influenza virus vaccine on days 0 and 28, either with an oral vitamin supplement (termed A&D; 20,000 IU retinyl palmitate and 2000 IU cholecalciferol) or a matched placebo. Hemagglutination inhibition (HAI) antibody responses were evaluated toward all four components of the influenza virus vaccines on days 0, 28, and 56. Our primary data were from season 2016-2017, as enrollment was highest in this season and all children exhibited homogeneous and negative HAI responses toward the Phuket vaccine at study entry. Responses among children who entered the study with insufficient or deficient levels of RBP and 25(OH)D benefited from the A&D supplement ( < 0.001 for the day 28 Phuket response), whereas responses among children with replete levels of RBP and 25(OH)D at baseline were unaffected or weakened ( = 0.02 for the day 28 Phuket response). High baseline RBP levels associated with high HAI titers, particularly for children in the placebo group (baseline RBP correlated positively with Phuket HAI titers on day 28, = 0.6, = 0.003). In contrast, high baseline 25(OH)D levels associated with weak HAI titers, particularly for children in the A&D group (baseline 25(OH)D correlated negatively with Phuket HAI titers on day 28, = -0.5, = 0.02). Overall, our study demonstrates that vitamin A&D supplementation can improve immune responses to vaccines when children are vitamin A and D-insufficient at baseline. Results provide guidance for the appropriate use of vitamins A and D in future clinical vaccine studies.
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http://dx.doi.org/10.3390/v11100907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832482PMC
September 2019

The influence of religious beliefs and practices on health care decision-making among HIV positive adolescents.

AIDS Care 2020 07 19;32(7):896-900. Epub 2019 Sep 19.

Division of Adolescent and Young Adult Medicine, Children's National, Washington, DC, USA.

It is unknown if religiousness/spirituality influences end-of-life treatment preferences among adolescents. Investigators assessed whether religiousness/spirituality moderates the relationship between an advance care planning intervention and end-of-life treatment preferences among 85 primarily African-American adolescents living with HIV/AIDS in outpatient-hospital-based HIV-specialty clinics in the United States. Adolescents aged 14-21 years living with HIV/AIDS and their families were randomized to three-weekly-60-minute sessions either: advance care planning (survey, goals of care conversation, advance directive); or control (developmental history, safety tips, nutrition/exercise). At 3-months post-intervention the intervention effect ( the likelihood of choosing to continue treatments in ) was significantly moderated by religiousness/spirituality. Highly religious/spiritual adolescents were four times more likely to choose to continue treatments in . Thus, intensive treatments at end-of-life may represent health equity, rather than health disparity. The belief believed that HIV is a punishment from God at baseline (15%, 14/94) was not associated with end-of-life treatment preferences. Twelve percent (11/94) reported they had stopped taking HIV medications for more than 3 days because of the belief in a miracle. Religiousness moderates adolescent's medical decision-making. Adolescents who believe in miracles should receive chaplaincy referrals to help maintain medication adherence.
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http://dx.doi.org/10.1080/09540121.2019.1668523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080568PMC
July 2020

Clinical correlation of influenza and respiratory syncytial virus load measured by digital PCR.

PLoS One 2019 3;14(9):e0220908. Epub 2019 Sep 3.

Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, United States of America.

Acute respiratory tract infections are a major cause of respiratory morbidity and mortality in pediatric patients worldwide. However, accurate viral and immunologic markers to predict clinical outcomes of this patient population are still lacking. Droplet digital PCR assays for influenza and respiratory syncytial virus (RSV) were designed and performed in 64 respiratory samples from 23 patients with influenza virus infection and 73 samples from 19 patients with RSV infection. Samples of patients with hematologic malignancies, solid tumors, or sickle cell disease were included. Clinical information from institutional medical records was reviewed to assess disease severity. Samples from patients with fever or respiratory symptoms had a significantly higher viral loads than those from asymptomatic patients. Samples from patients with influenza virus and RSV infection collected at presentation had significantly higher viral loads than those collected from patients after completing a course of oseltamivir or ribavirin, respectively. RSV loads correlated positively with clinical symptoms in patients ≤5 years of age, whereas influenza viral loads were associated with clinical symptoms, irrespective of age. Patients receiving antivirals for influenza and RSV had a significant reduction in viral loads after completing therapy. Digital PCR offers an effective method to monitor the efficacy of antiviral treatment for respiratory tract infections in immunocompromised hosts.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0220908PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720028PMC
March 2020

Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis.

N Engl J Med 2019 06;380(24):2327-2340

From the Departments of Neurology (M.R.W., V.D., S.A.J., F.C.C., J.M.G.), Biochemistry and Biophysics (H.A.S., K.C.Z., J.L.D.), Laboratory Medicine (S.A., G.Y., S.F., D.S., B.B., B.H., S.M., C.Y.C.), and Epidemiology and Biostatistics (J.N.), the Department of Medicine, Division of Infectious Diseases (C.L., C.Y.C.), the Department of Medicine, Division of Hospital Medicine (A.B.), and Weill Institute for Neurosciences (M.R.W., V.D., S.A.J., F.C.C., J.M.G.), University of California, San Francisco (UCSF), UCSF-Abbott Viral Diagnostics and Discovery Center (S.A., G.Y., S.F., D.S., B.B., C.Y.C.), the Chan Zuckerberg Biohub (C.L., J.L.D.), and Zuckerberg San Francisco General Hospital (B.H.), San Francisco, the School of Public Health, University of California, Berkeley, Berkeley (B.D.F.), Children's Hospital Los Angeles (S.N.N., J.B., J.D.B.), the Department of Medicine, Division of Infectious Diseases (J.M., M.C., T.V., P.R.A., J.D.K.), and the Departments of Neurology (P.M.V.) and Pathology and Laboratory Medicine (S.C., R.M.H.), University of California, Los Angeles, Los Angeles, and the Departments of Pathology and Laboratory Medicine (C.D.G., F.M., N.A.O., C.R.P.) and Neurological Surgery (L.L.Z.) and the Department of Internal Medicine, Division of Infectious Diseases (S.H.C., C.R.P.), University of California, Davis, Davis - all in California; the Children's National Medical Center and George Washington University School of Medicine, Washington, DC (R.L.D.); St. Jude Children's Research Hospital, Memphis, TN (R.D., G.M., R.H.); and Children's Hospital Colorado, Aurora (K.M., S.R.D.).

Background: Metagenomic next-generation sequencing (NGS) of cerebrospinal fluid (CSF) has the potential to identify a broad range of pathogens in a single test.

Methods: In a 1-year, multicenter, prospective study, we investigated the usefulness of metagenomic NGS of CSF for the diagnosis of infectious meningitis and encephalitis in hospitalized patients. All positive tests for pathogens on metagenomic NGS were confirmed by orthogonal laboratory testing. Physician feedback was elicited by teleconferences with a clinical microbial sequencing board and by surveys. Clinical effect was evaluated by retrospective chart review.

Results: We enrolled 204 pediatric and adult patients at eight hospitals. Patients were severely ill: 48.5% had been admitted to the intensive care unit, and the 30-day mortality among all study patients was 11.3%. A total of 58 infections of the nervous system were diagnosed in 57 patients (27.9%). Among these 58 infections, metagenomic NGS identified 13 (22%) that were not identified by clinical testing at the source hospital. Among the remaining 45 infections (78%), metagenomic NGS made concurrent diagnoses in 19. Of the 26 infections not identified by metagenomic NGS, 11 were diagnosed by serologic testing only, 7 were diagnosed from tissue samples other than CSF, and 8 were negative on metagenomic NGS owing to low titers of pathogens in CSF. A total of 8 of 13 diagnoses made solely by metagenomic NGS had a likely clinical effect, with 7 of 13 guiding treatment.

Conclusions: Routine microbiologic testing is often insufficient to detect all neuroinvasive pathogens. In this study, metagenomic NGS of CSF obtained from patients with meningitis or encephalitis improved diagnosis of neurologic infections and provided actionable information in some cases. (Funded by the National Institutes of Health and others; PDAID ClinicalTrials.gov number, NCT02910037.).
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http://dx.doi.org/10.1056/NEJMoa1803396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764751PMC
June 2019

Triggered Escalating Real-Time Adherence Intervention to Promote Rapid HIV Viral Suppression Among Youth Living With HIV Failing Antiretroviral Therapy: Protocol for a Triggered Escalating Real-Time Adherence Intervention.

JMIR Res Protoc 2019 Mar 18;8(3):e11416. Epub 2019 Mar 18.

St. Jude Children's Research Hospital, Department of Infectious Diseases, Memphis, TN, United States.

Background: Youth living with HIV (YLWH) are confronted with many self-care challenges that can be experienced as overwhelming in the context of normal developmental processes that characterize adolescence and young adulthood. A sizable minority of YLWH have unsuppressed viral loads in the United States attributable to antiretroviral therapy (ART) nonadherence. Interventions to promote sustained viral suppression in YLWH are needed.

Objective: The aim of this study is to evaluate the efficacy of the Triggered Escalating Real-Time Adherence (TERA) intervention in comparison with standard of care (SOC) in YLWH (aged 13-24 years) failing ART on (1) primary outcome measures-HIV viral suppression (VLS), defined as both <200 copies/ml and <50 copies/ml at 12 weeks, and (2) secondary outcome measures-VLS rates and rates of ART adherence at 24, 36, and 48 weeks as well as patterns of adherence over time as measured by an electronic dose monitoring (EDM) device.

Methods: The TERA study is a phase 2, multisite clinical trial conducted with 120 YLWH failing ART (randomized 1:1 to TERA or SOC) at participating clinical sites within the Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN). Participants are followed for a total of 48 weeks. For TERA arm participants, the first 12 weeks involve delivery of the intervention. For all participants, clinical outcomes are collected throughout follow-up, and adherence is assessed using EDM over the full 48 weeks. During the 12-week intervention period, TERA arm participants receive 3 remote coaching sessions delivered in clinic via videoconferencing timed to coincide with baseline and follow-up clinical visits, text message reminders when the EDM has not been opened at dose time (which escalate to 2-way theory-informed short message service coaching interactions in response to real-time nonadherence), and review of dosing graphs produced by EDM at follow-up visits.

Results: Launch dates for enrollment varied by site. Enrollment began in April 2018 and is expected to be completed by August 2019, with results presented by the second quarter of 2021.

Conclusions: Effective, generalizable, and scalable approaches to rapidly assist YLWH failing to achieve and sustain VLS may have a substantial impact on individual health and efforts to curb transmission. Coaching for a brief but intensive period from remote coaches and using communication channels common to youth may offer multiple unique advantages in promoting self-care.

Trial Registration: ClinicalTrials.gov NCT03292432; https://clinicaltrials.gov/ct2/show/NCT03292432 (Archived by WebCite at http://www.webcitation.org/768J8ijjp).

International Registered Report Identifier (irrid): DERR1-10.2196/11416.
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http://dx.doi.org/10.2196/11416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441855PMC
March 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

Advance Care Planning and HIV Symptoms in Adolescence.

Pediatrics 2018 11 19;142(5). Epub 2018 Oct 19.

Department of Pediatrics, School of Medicine and Health Sciences, George Washington University, Washington, District of Columbia.

Objectives: To determine the effect of family-centered pediatric advance care planning (FACE pACP) on HIV-specific symptoms.

Methods: In this single-blinded, randomized controlled trial conducted at 6 US hospital-based HIV clinics, 105 adolescent-family dyads, randomly assigned from July 2011 to June 2014, received 3 weekly sessions in either the FACE pACP arm ([1] pediatric advance care planning survey, [2] Respecting Choices interview, and [3] 5 Wishes directive) or the control arm ([1] developmental history, [2] safety tips, and [3] nutrition and exercise tips). The General Health Assessment for Children measured patient-reported HIV-specific symptoms. Latent class analyses clustered individual patients based on symptom patterns. Path analysis examined the mediating role of dyadic treatment congruence with respect to the intervention effect on symptom patterns.

Results: Patients were a mean age of 17.8 years old, 54% male, and 93% African American. Latent class analysis identified 2 latent HIV-symptom classes at 12 months: higher symptoms and suffering (27%) and lower symptoms and suffering (73%). FACE pACP had a positive effect on dyadic treatment congruence (β = .65; 95% CI: 0.04 to 1.28), and higher treatment congruence had a negative effect on symptoms and suffering (β = -1.14; 95% CI: -2.55 to -0.24). Therefore, FACE pACP decreased the likelihood of symptoms and suffering through better dyadic treatment congruence (β = -.69; 95% CI: -2.14 to -0.006). Higher religiousness (β = 2.19; 95% CI: 0.22 to 4.70) predicted symptoms and suffering.

Conclusions: FACE pACP increased and maintained agreement about goals of care longitudinally, which lowered adolescents' physical symptoms and suffering, suggesting that early pACP is worthwhile.
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http://dx.doi.org/10.1542/peds.2017-3869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317555PMC
November 2018

Gut Microbiome Composition Predicts Infection Risk During Chemotherapy in Children With Acute Lymphoblastic Leukemia.

Clin Infect Dis 2018 08;67(4):541-548

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

Background: Myelosuppression-related infections remain important causes of morbidity and mortality in children with acute lymphoblastic leukemia (ALL).

Methods: By analyzing fecal samples collected at diagnosis and after each of the initial 3 phases of chemotherapy, we evaluated the role of gut microbiota in predicting infections in 199 children with newly diagnosed ALL. The bacterial 16S rRNA gene was analyzed by high-depth sequencing to determine the diversity and composition of the microbiome.

Results: After the induction and reinduction I phases of chemotherapy, microbial diversity decreased significantly relative to the prechemotherapy value. After chemotherapy, the relative abundance of certain bacterial taxa (eg, Bacteroidetes) decreased significantly, whereas that of other taxa (eg, Clostridiaceae and Streptococcaceae) increased. A baseline gut microbiome characterized by Proteobacteria predicted febrile neutropenia. Adjusting for the chemotherapy phase and ALL risk level, Enterococcaceae dominance (relative abundance ≥30%) predicted significantly greater risk of subsequent febrile neutropenia and diarrheal illness, whereas Streptococcaceae dominance predicted significantly greater risk of subsequent diarrheal illness.

Conclusions: In children undergoing therapy for newly diagnosed ALL, the relative abundance of Proteobacteria before chemotherapy initiation predicts development of febrile neutropenia, and domination of the gut microbiota by Enterococcaceae or Streptococcaceae at any time during chemotherapy predicts infection in subsequent phases of chemotherapy.

Clinical Trial Registration: NCT00549848.
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http://dx.doi.org/10.1093/cid/ciy153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070042PMC
August 2018

Paediatric advance care planning survey: a cross-sectional examination of congruence and discordance between adolescents with HIV/AIDS and their families.

BMJ Support Palliat Care 2019 Mar 21;9(1):e22. Epub 2017 Sep 21.

Center for Translational Science/Children's Research Institute/Children's National Medical Center, Washington, District of Columbia, USA.

Objectives: To identify patient-reported paediatric advance care planning (pACP) needs of adolescents living with HIV and to examine the congruence with their family's perception of their needs.

Methods: A cross-sectional survey among six paediatric hospital-based outpatient HIV specialty clinics. Participants included 48 adolescent/family dyads (n=96 participants) within a larger study facilitating pACP. The main outcome measure was the Lyon Advance Care Planning Survey - Adolescent and Surrogate Versions-Revised.

Results: Adolescents' mean age was 18 years (range ≥14-<21); 54% male; 92% African-American; 27% with prior AIDS diagnosis. If dying, 92% ; 85% ;; 71% and 77% . Best timing for end-of-life (EOL) decisions was (38%), (17%), (4%), (8%), (4%) and (19%). Prevalence-adjusted bias-adjusted Kappa (PABAK) measured congruence in pACP needs within adolescent/family dyads. There was substantial congruence in that (PABAK=0.83), and (PABAK=0.92) were very important or important. There was discordance about (PABAK=0.08) and (PABAK=0.32).

Conclusions: Areas of discordance were associated with life-sustaining choices and when to have the EOL conversation. Targeted, adolescent/family-centred, evidence-based pACP interventions are needed to improve family understanding of youth's EOL wishes.

Trial Registration Number: NCT01289444; Results.
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http://dx.doi.org/10.1136/bmjspcare-2016-001224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862773PMC
March 2019

Rotavirus Infection in Pediatric Allogeneic Hematopoietic Cell Transplant Recipients: Clinical Course and Experience Using Nitazoxanide and Enterally Administered Immunoglobulins.

Pediatr Infect Dis J 2018 02;37(2):176-181

From the Department of Infectious Diseases, Department of Pathology, Department of Pharmaceutical Sciences, Department of Bone Marrow Transplantation and Cellular Therapy, and Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Rotaviruses may produce prolonged and severe disease in allogeneic hematopoietic cell transplant (HCT) recipients. Nitazoxanide and enterally administered human immunoglobulins are potential therapeutic options. This retrospective study describes the clinical course of rotavirus infection in pediatric allogeneic HCT recipients and a single-center experience with nitazoxanide and oral immunoglobulins as potential treatment options.

Methods: We identified 36 patients who had positive stool rotavirus antigen assays after allogeneic HCT from May 30, 2012, to July 31, 2015. Clinical, microbiologic and treatment data were collected and analyzed using descriptive statistics.

Results: Forty-nine discrete episodes of rotavirus infection were identified among these 36 patients for a cumulative incidence of 19.7%. For these 49 episodes, the median day to infection after HCT was day 82, and the median duration of diarrhea was 17.5 days (range 4-122). Nitazoxanide and enteral immunoglobulins were prescribed for 41 episodes. The median duration of clinical symptoms after initiation of nitazoxanide was 11 days (range 2-85), 23 days (range 10-107) after enteral immunoglobulins and 26 days (range 6-90) after a combination of nitazoxanide and enteral immunoglobulins (P = 0.1). No adverse effects of either treatment were documented, but efficacy could not be assessed in this patient population.

Conclusions: In pediatric HCT recipients, the clinical illness produced by rotaviruses is prolonged compared with otherwise healthy children. Nitazoxanide appears safe, but its efficacy for this indication requires further study.
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http://dx.doi.org/10.1097/INF.0000000000001740DOI Listing
February 2018

A randomized clinical trial of adolescents with HIV/AIDS: pediatric advance care planning.

AIDS Care 2017 10 30;29(10):1287-1296. Epub 2017 Mar 30.

h Division of Biostatistics and Study Methodology , Children's National, Children's Research Institute, Center for Translational Science , Washington , USA.

The objective of this study is to determine if pediatric advance care planning (pACP) increases adolescent/family congruence in end-of-life (EOL) treatment preferences longitudinally. Adolescents aged 14-21 years with HIV/AIDS and their families were randomized (N = 105 dyads) to three-60-minute sessions scheduled one week apart: either the pACP intervention (survey administered independently, facilitated conversation with adolescent and family present, completion of legal advance directive document with adolescent and family present) or an active control (developmental history, safety tips, nutrition and exercise education). This longitudinal, single-blinded, multi-site, randomized controlled trial was conducted in six pediatric hospital-based HIV-clinics, located in high HIV mortality cities. The Statement of Treatment Preferences measured adolescent/family congruence in EOL treatment preferences at immediately following the facilitated pACP conversation (Session 2), and at 3-month post-intervention. The mean age of adolescent participants was 18 years (range 14-21 years); 54% were male; and 93% were African-American. One-third had an AIDS diagnosis. Immediately post-intervention the Prevalence Adjusted Bias Adjusted Kappa showed substantial treatment preference agreement for pACP dyads compared to controls (High burden/low chance of survival, PABAK = 0.688 vs. 0.335; Functional impairment, PABAK = 0.687 vs. PABAK= 0.34; Mental impairment, PABKA = 0.717 vs. 0.341). Agreement to limit treatments was greater among intervention dyads than controls (High burden: 14.6% vs. 0%; Functional impairment = 22.9% vs. 4.4%; and Mental impairment: 12.5% vs. 4.4%). Overall treatment preference agreement among pACP dyads was high immediately post-intervention, but decreased over time. In contrast, treatment agreement among control dyads was low and remained low over time. As goals of care change over time with real experiences, additional pACP conversations are needed.
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http://dx.doi.org/10.1080/09540121.2017.1308463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846623PMC
October 2017

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

Acceptability of Family-Centered Advanced Care Planning for Adolescents With HIV.

Pediatrics 2016 12 1;138(6). Epub 2016 Nov 1.

Division of Adolescent and Young Adult Medicine, Center for Translational Science/Children's Research Institute, Children's National, Washington, District of Columbia.

Background And Objective: Small pilot studies support the appropriateness of engaging adolescents with chronic or life-limiting illnesses in pediatric advance care planning (pACP). We do not yet know if pACP is acceptable, feasible, and worthwhile, even if emotionally intense, in a fully powered randomized controlled trial.

Methods: We conducted a prospective 2-arm randomized controlled trial at 6 US urban hospitals. Adolescent/family member dyads were randomized to receive the 1-session-a-week 3-session FAmily-CEntered Advance Care Planning (FACE) pACP intervention (1, ACP Survey; 2, Goals of Care Conversation/Treatment Preferences; 3, Completion of Advance Directive) or active comparator (1, Developmental History; 2, Safety Tips; 3, Nutrition/Exercise). The Satisfaction Questionnaire was administered to participants independently after each session by a blinded research assistant.

Results: We enrolled 53% of eligible participants and intervened with 97 adolescent/family dyads. Adolescents ranged in age from 14 to 21 years; 54% were male individuals; 93% African American; and 73% perinatally infected. Attendance was 99% for all 3 sessions in each arm. At session 3, FACE adolescents and family dyad members, respectively, found the session useful (98%, 98%) and helpful (98%, 100%), despite feelings of sadness (25%, 17%). FACE adolescents' improvement in the total subscale A score (useful, helpful, like a load off my mind, satisfied, something I needed to do, courageous, worthwhile) was better than control adolescents at session 3 (β = 1.16, P = .02). There were no adverse events.

Conclusions: FACE enabled worthwhile conversations, while simultaneously eliciting intense emotions. No participants withdrew, 99% of those enrolled completed each session, and there were no adverse events, evidence of pACP's feasibility, acceptability, and safety.
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http://dx.doi.org/10.1542/peds.2016-1854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127070PMC
December 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

Acute respiratory infections in children and adolescents with acute lymphoblastic leukemia.

Cancer 2016 Mar 23;122(5):798-805. Epub 2015 Dec 23.

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

Background: Knowledge regarding the incidence, clinical course, and impact of respiratory viral infections in children with acute lymphoblastic leukemia (ALL) is limited.

Methods: A retrospective cohort of patients with newly diagnosed ALL who were treated on the Total Therapy XVI protocol at St Jude Children's Research Hospital between 2007 and 2011 was evaluated.

Results: Of 223 children, 95 (43%) developed 133 episodes of viral acute respiratory illness (ARI) (incidence, 1.1 per 1000 patient-days). ARI without viral etiology was identified in 65 patients (29%) and no ARI was detected in 63 patients (28%). There were no significant associations noted between race, sex, age, or ALL risk group and the development of ARI. Children receiving induction chemotherapy were found to be at the highest risk of viral ARI (incidence, 2.3 per 1000 patient-days). Influenza virus was the most common virus (38%) followed by respiratory syncytial virus (33%). Of 133 episodes of viral ARI, 61% of patients were hospitalized, 26% experienced a complicated course, 80% had their chemotherapy delayed, and 0.7% of patients died. Twenty-four patients (18%) developed viral lower respiratory tract infections (LRTI), 5 of whom (21%) had complications. Patients with viral LRTI had a significantly lower nadir absolute lymphocyte count; were sicker at the time of presentation; and were more likely to have respiratory syncytial virus, to be hospitalized, and to have their chemotherapy delayed for longer compared with those with viral upper respiratory tract infections.

Conclusions: Despite the low incidence of viral ARI in children with ALL, the associated morbidity, mortality, and delay in chemotherapy remain clinically significant. Viral LRTI was especially associated with high morbidity requiring intensive care-level support. Cancer 2016;122:798-805. © 2015 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.29833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764417PMC
March 2016

Pediatric palliative care for youth with HIV/AIDS: systematic review of the literature.

HIV AIDS (Auckl) 2013 29;5:165-79. Epub 2013 Jul 29.

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

Improvement in treatment has led to decreased death in youth with human immunodeficiency virus (HIV) in developed countries. Despite this, youth with HIV are still at risk for increased mortality and morbidity compared with their uninfected counterparts. In developing countries, high numbers of youth die from acquired immune deficiency syndrome (AIDS)-related illnesses due to lack of access to consistent antiretroviral treatment. As a result, pediatric palliative care is a relevant topic for those providing care to youth with HIV. A systematic review was conducted to gather information regarding the status of the literature related to pediatric palliative care and medical decision-making for youth with HIV. The relevant literature published between January 2002 and June 2012 was identified through searches conducted using PubMed, CINAHL, Scopus, and PSYCInfo databases and a series of key words. Articles were reviewed by thematic analysis using the pillars of palliative care set out by the National Consensus Project. Twenty-one articles were retained after review and are summarized by theme. In general, few empirically based studies evaluating palliative care and medical decision-making in youth with HIV were identified. Articles identified focused primarily on physical aspects of care, with less attention paid to psychological, social, ethical, and cultural aspects of care. We recommend that future research focuses on broadening the evaluation of pediatric palliative care among youth with HIV by directly evaluating the psychological, social, ethical, and cultural aspects of care and investigating the needs of all involved stakeholders.
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http://dx.doi.org/10.2147/HIV.S44275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733874PMC
August 2013

Longitudinal Pediatric Palliative Care: Quality of Life & Spiritual Struggle (FACE): design and methods.

Contemp Clin Trials 2012 Sep 1;33(5):1033-43. Epub 2012 Jun 1.

St. Jude Children's Research Hospital, Department of Infectious Diseases, Memphis, TN 38105, USA.

As life expectancy increases for adolescents ever diagnosed with AIDS due to treatment advances, the optimum timing of advance care planning is unclear. Left unprepared for end-of-life (EOL) decisions, families may encounter miscommunication and disagreements, resulting in families being charged with neglect, court battles and even legislative intervention. Advanced care planning (ACP) is a valuable tool rarely used with adolescents. The Longitudinal Pediatric Palliative Care: Quality of Life & Spiritual Struggle study is a two-arm, randomized controlled trial assessing the effectiveness of a disease specific FAmily CEntered (FACE) advanced care planning intervention model among adolescents diagnosed with AIDS, aimed at relieving psychological, spiritual, and physical suffering, while maximizing quality of life through facilitated conversations about ACP. Participants will include 130 eligible dyads (adolescent and family decision-maker) from four urban cities in the United States, randomized to either the FACE intervention or a Healthy Living Control. Three 60-minute sessions will be conducted at weekly intervals. The dyads will be assessed at baseline as well as 3-, 6-, 12-, and 18-month post-intervention. The primary outcome measures will be in congruence with EOL treatment preferences, decisional conflict, and quality of communication. The mediating and moderating effects of threat appraisal, HAART adherence, and spiritual struggle on the relationships among FACE and quality of life and hospitalization/dialysis use will also be assessed. This study will be the first longitudinal study of an AIDS-specific model of ACP with adolescents. If successful, this intervention could quickly translate into clinical practice.
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http://dx.doi.org/10.1016/j.cct.2012.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408828PMC
September 2012