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ObjectivesSeveral single-tablet regimens (STRs) are now available and are recommended for first-line antiretroviral therapy (ART); however, STR use for youth with HIV (YHIV) has not been systematically studied. We examined the characteristics associated with initiation of STRs versus multi-tablet regimens (MTRs) and the virological outcomes for youth with nonperinatally acquired HIV (nPHIV).MethodsA retrospective cohort study of nPHIV youth aged 13-24 years initiating ART between 2006 and 2014 at 18 US HIV clinical sites in the HIV Research Network was performed. The outcomes measured were initiation of STRs versus MTRs, virological suppression (VS) at 12 months, and time to VS. Demographic and clinical factors associated with initiation of STR versus MTR ART and VS ( 500 cells/μL (AOR 1.76; 95% CI 1.0-3.10). STR use was not associated with a shorter time to VS compared with MTR use [hazard ratio (HR) 1.07; 95% CI 0.90-1.28].ConclusionsUse of STR was associated with a greater likelihood of sustained VS 12 months after ART initiation in YHIV.

The antiretroviral protease inhibitor atazanavir inhibits hepatic uridine diphosphate glucuronosyltransferase (UGT) 1A1, thereby preventing the glucuronidation and elimination of bilirubin. Resultant indirect hyperbilirubinemia with jaundice can cause premature discontinuation of atazanavir. Risk for bilirubin-related discontinuation is highest among individuals who carry two UGT1A1 decreased function alleles ( UGT1A1*28 or *37). We summarize published literature that supports this association and provide recommendations for atazanavir prescribing when UGT1A1 genotype is known (updates at ). [ABSTRACT FROM AUTHOR]

PURPOSE: To obtain input from adolescents with human immunodeficiency virus-1 (HIV-1) infection to inform the design of a community-based modified directly observed therapy (MDOT) antiretroviral adherence intervention. METHODS: Pediatric AIDS Clinical Trials Group (PACTG) protocol 1036A conducted three focus groups with 17 adolescents aged 17-22 years (10 female, 65% African-American) from three geographically distinct US PACTG sites. Focus group sessions were scripted, audio-taped, and transcribed verbatim. A coding dictionary was developed and validated; Ethnograph version 5.08 was used to summarize coded data across and within the three sites. Prevalent themes were identified via frequencies and are reported as percentages. RESULTS: Adolescents provided the following specific input: the MDOT provider should be familiar with the participant and empathic; the MDOT location should be mutually agreed on, flexible, and private; and participant and provider communication should be bidirectional, preferably by phone. Ideally the MDOT program should be continued until adolescents independently demonstrate adherence and should include a weaning phase as a test of skill acquisition. The most commonly endorsed barrier to the proposed program was that MDOT would be an invasion of privacy. Initially, after introduction to the purpose of the focus group, all but one adolescent expressed the belief that MDOT could benefit persons other than themselves; however, at the conclusion of the focus group discussion, a significant shift in openness to the intervention occurred, in that 11 participants indicated they would consider participation in an MDOT program if such a program were offered. CONCLUSIONS: Focus group feedback clarified the feasibility, logistics, and patient concerns about the design and implementation of a proposed MDOT intervention for adolescents with HIV-1 infection who struggle with medication adherence. [ABSTRACT FROM AUTHOR]

BACKGROUND: The extent to which drug-resistant human immunodeficiency virus type 1 (HIV-1) acquired through mother-to-child transmission (MTCT) or failed chemoprophylaxis populates viral reservoirs and limits responses to antiretroviral treatment in infants is unknown. METHODS: We evaluated the presence, type, and persistence of drug-resistant HIV-1 in pretreatment plasma and resting CD4(+) T cells from US infants enrolled in a multicenter, open-label, phase 1/2 treatment trial of lopinavir/ritonavir (Pediatric AIDS Clinical Trials Group Protocol 1030) in young infants. RESULTS: Twenty-two consecutively enrolled infants initiating highly active antiretroviral therapy at a median age of 9.7 weeks and treated for up to 96 weeks were studied. Drug-resistant HIV-1 was present in 5 (23.8%) of 21 infants analyzed; 4 (80.0%) had nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV-1, only 1 of whom had a history of receiving nevirapine chemoprophylaxis. All 4 infants had NNRTI-resistant variants other than the K103N mutation. The fifth infant had the M184V mutation. Drug-resistant virus was archived in the resting CD4(+) T cell latent reservoir in all 5 infants. CONCLUSIONS: The high rate, types, and early archiving of drug-resistant HIV-1 suggests that resistance testing be considered for infants, especially when an NNRTI-based regimen is planned. Furthermore, drug-resistance outcomes in infants should be an important secondary end point in MTCT trials. Copyright © 2007 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

During the past century the excitement of discovering antibiotics as a treatment of infectious diseases has given way to a sense of complacency and acceptance that when faced with antimicrobial resistance there will always be new and better antimicrobial agents to use. Now, with clear indications of a decline in pharmaceutical company interest in anti-infective research, at the same time when multi-drug resistant micro-organisms continue to be reported, it is very important to review the prudent use of the available agents to fight these micro-organisms. Injudicious use of antibiotics is a global problem with some countries more affected than others. There is no dearth of interest in this subject with scores of scholarly articles written about it. While over the counter access to antibiotics is mentioned as an important contributor towards injudicious antibiotic use in developing nations, as shown in a number of studies, there are many provider, practice and patient characteristics which drive antibiotic overuse in developed nations such as the United States. Recognizing that a thorough review of this subject goes far and beyond the page limitations of a review article we provide a summary of some of the salient aspects of this global problem with a focus towards readers practicing in developing nations. [ABSTRACT FROM AUTHOR]

Background: Coformulated bictegravir, emtricitabine, and tenofovir alafenamide is a single-tablet regimen and was efficacious and well tolerated in children and adolescents with HIV (aged 6 years to <18 years) in a 48-week phase 2/3 trial. In this study, we report data from children aged at least 2 years and weighing 14 kg to less than 25 kg., Methods: We conducted this open-label, multicentre, multicohort, single-arm study in South Africa, Thailand, Uganda, and the USA. Participants were virologically suppressed children with HIV, aged at least 2 years, weighing 14 kg to less than 25 kg. Participants received bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) once daily, switching to bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) upon attaining a bodyweight of at least 25 kg. The study included pharmacokinetic evaluation at week 2 to confirm the dose of coformulated bictegravir, emtricitabine, and tenofovir alafenamide for this weight band by comparing with previous adult data. Primary outcomes were bictegravir area under the curve over the dosing interval (AUC tau ) and concentration at the end of the dosing interval (C tau ) at week 2, and incidence of treatment-emergent adverse events and laboratory abnormalities until the end of week 24 in all participants who received at least one dose of bictegravir, emtricitabine, and tenofovir alafenamide. This study is registered with ClinicalTrials.gov, NCT02881320., Findings: Overall, 22 participants were screened (from Nov 14, 2018, to Jan 11, 2020), completed treatment with bictegravir, emtricitabine, and tenofovir alafenamide (until week 48), and entered an extension phase. The geometric least squares mean (GLSM) ratio for AUC tau for bictegravir was 7·6% higher than adults (GLSM ratio 107·6%, 90% CI 96·7-119·7); C tau was 34·6% lower than adults (65·4%, 49·1-87·2). Both parameters were within the target exposure range previously found in adults, children, or both". Grade 3-4 laboratory abnormalities occurred in four (18%) participants by the end week 24 and six (27%) by the end of week 48. Drug-related adverse events occurred in three participants (14%) by the end of week 24 and week 48; none were severe. No Grade 3-4 adverse events, serious adverse events, or adverse events leading to discontinuation occurred by the end of week 24 and week 48., Interpretation: Data support the use of single-tablet coformulated bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) for treatment of HIV in children aged at least 2 years and weighing 14 kg to less than 25 kg., Funding: Gilead Sciences., Competing Interests: Declaration of interests CAR received grant support to their institution from Gilead, GSK, and ViiV Healthcare during the study and outside the submitted work; and support for meeting travel from Gilead outside the submitted work. RS reports grant support to their institution from Gilead, GSK, Merck, and Penta outside the submitted work; and support for meeting travel from Gilead outside the submitted work. CKC and PK report grant support to their institution from Gilead for the conduct of this study. MK, RL, JTH, VAV, and KK are employed by Gilead and hold stocks in Gilead. MFC reports grant support to their institution from Gilead for the conduct of this study. AHG reports clinical trial agreement to their institution from Gilead for the conduct of this study; and is Chair of the Data Safety and Monitoring Board for a study sponsored by the National Institute of Dental and Craniofacial Research. All other authors declare no competing interests., (© 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Combined intramuscular long-acting cabotegravir and long-acting rilpivirine constitute the first long-acting combination antiretroviral therapy (ART) regimen approved for adults with HIV. The goal of the IMPAACT 2017 study (MOCHA [More Options for Children and Adolescents]) was to assess the safety and pharmacokinetics of these drugs in adolescents., Methods: In this phase 1/2, multicentre, open-label, non-comparative, dose-finding study, virologically suppressed adolescents (aged 12-17 years; weight ≥35 kg; BMI ≤31·5 kg/m 2 ) with HIV-1 on daily oral ART were enrolled at 15 centres in four countries (Botswana, South Africa, Thailand, and the USA). After 4-6 weeks of oral cabotegravir (cohort 1C) or rilpivirine (cohort 1R), participants received intramuscular long-acting cabotegravir or long-acting rilpivirine every 4 weeks or 8 weeks per the adult dosing regimens, while continuing pre-study ART. The primary outcomes were assessments of safety measures, including all adverse events, until week 4 for oral cabotegravir and until week 16 for long-acting cabotegravir and long-acting rilpivirine, and pharmacokinetic measures, including the area under the plasma concentration versus time curve during the dosing interval (AUC 0-tau ) and drug concentrations, at week 2 for oral dosing of cabotegravir and at week 16 for intramuscular dosing of cabotegravir and rilpivirine. Enrolment into cohort 1C or cohort 1R was based on the participant's pre-study ART, meaning that masking was not done. For pharmacokinetic analyses, blood samples were drawn at weeks 2-4 after oral dosing and weeks 4-16 after intramuscular dosing. Safety outcome measures were summarised using frequencies, percentages, and exact 95% CIs; pharmacokinetic parameters were summarised using descriptive statistics. This trial is registered at ClinicalTrials.gov, NCT03497676, and is closed to enrolment., Findings: Between March 19, 2019, and Nov 25, 2021, 55 participants were enrolled: 30 in cohort 1C and 25 in cohort 1R. At week 16, 28 (97%, 95% CI 82-100) of the 29 dose-evaluable participants in cohort 1C and 21 (91%; 72-99) of the 23 dose-evaluable participants in cohort 1R had reported at least one adverse event, with the most common being injection-site pain (nine [31%] in cohort 1C; nine [39%] in cohort 1R; none were severe). One (4%, 95% CI 0-22) participant in cohort 1R had an adverse event of grade 3 or higher, leading to treatment discontinuation, which was defined as acute rilpivirine-related allergic reaction (self-limiting generalised urticaria) after the first oral dose. No deaths or life-threatening events occurred. In cohort 1C, the week 2 median cabotegravir AUC 0-tau was 148·5 (range 37·2-433·1) μg·h/mL. The week 16 median concentrations for the every-4-weeks and every-8-weeks dosing was 3·11 μg/mL (range 1·22-6·19) and 1·15 μg/mL (<0·025-5·29) for cabotegravir and 52·9 ng/mL (31·9-148·0) and 39·1 ng/mL (27·2-81·3) for rilpivirine, respectively. These concentrations were similar to those in adults., Interpretation: Study data support using long-acting cabotegravir or long-acting rilpivirine, given every 4 weeks or 8 weeks, per the adult dosing regimens, in virologically suppressed adolescents aged 12 years and older and weighing at least 35 kg., Funding: The National Institutes of Health and ViiV Healthcare., Competing Interests: Declaration of interests BMB, KB, PS, AHG, MAM, KC, and PO received IMPAACT Network grant funding from the National Institutes of Health (NIH) to support work on this protocol. AHG and PO's institutions have Clinical Trials Agreements (CTAs) with ViiV Healthcare to support the IMPAACT 2017 study. AHG's institution has a CTA with Janssen to support COVID-19 research and AHG is part of the ViiV Healthcare Pediatric Advisory Board. BMB, KB, MAM, SW, and RM's institution receives funding from ViiV Healthcare. MAM is a consultant for Bio-rad and receives royalties from Elsevier; their institution receives funding from Gilead for industry-sponsored research and funding from the NIH for HIV prevention and microbicide-related research. BMB's institution receives grant funding from Janssen for the study. HC, RMVS-R, and KV are employees of Janssen and have stock and stock options with Johnson & Johnson. ALA received grants or contracts from Gilead, Merck, and ViiV; and is content development faculty for the Simply Speaking HIV Prevention Series, an expert witness, an unpaid Advocates for Youth Board Chair, and an unpaid HIVMA Vice Chair. AC-G is a ViiV Healthcare consultant. CM and CMH are employees at ViiV Healthcare. SLF and JH are employees at GSK. SLF and CM own GSK stock or stock options. EVC is a Data Safety and Management Board member for a paediatric antibacterial study with Melinta Pharmaceuticals. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Long-acting injectable cabotegravir and rilpivirine have demonstrated safety, acceptability, and efficacy in adults living with HIV-1. The IMPAACT 2017 study (MOCHA study) was the first to use these injectable formulations in adolescents (aged 12-17 years) living with HIV-1. Herein, we report acceptability and tolerability outcomes in cohort 1 of the study., Methods: In this a secondary analysis of a phase 1/2, multicentre, open-label, non-comparative dose-finding study, with continuation of pre-study oral combination antiretroviral treatment (ART), 55 adolescents living with HIV-1 were enrolled to receive sequential doses of either long-acting cabotegravir or rilpivirine and 52 received at least two injections. Participants had a body weight greater than 35 kg and BMI less than 31·5 kg/m 2 and had been on stable ART for at least 90 consecutive days with an HIV-1 viral load of less than 50 copies per mL at a participating IMPAACT study site. Participants had to be willing to continue their pre-study ART during cohort 1. The primary objectives of the study were to confirm doses for oral and injectable cabotegravir and for injectable rilpivirine in adolescents living with HIV. This analysis of participant-reported outcomes included a face scale assessment of pain at each injection and a Pediatric Quality of Life Inventory (PedsQL) at baseline and week 16 for participants in the USA, South Africa, Botswana, and Thailand. A subset of 11 adolescents and 11 parents or caregivers in the USA underwent in-depth interviews after receipt of one or two injections. This trial is registered at ClinicalTrials.gov, NCT03497676., Findings: Between March 19, 2019, and Nov 25, 2021, 55 participants were enrolled into cohort 1. Using the six-point face scale, 43 (83%) of participants at week 4 and 38 (73%) at week 8 reported that the injection caused "no hurt" or "hurts little bit", while only a single (2%) participant for each week rated the pain as one of the two highest pain levels. Quality of life was not diminished by the addition of one injectable antiretroviral. In-depth interviews revealed that parents and caregivers in the USA frequently had more hesitancy than adolescents about use of long-acting formulations, but parental acceptance was higher after their children received injections., Interpretation: High acceptability and tolerability of long-acting cabotegravir or rilpivirine injections suggests that these are likely to be favoured treatment options for some adolescents living with HIV., Funding: National Institutes of Health and ViiV Healthcare., Competing Interests: Declaration of interests KC, SB, and DEY received grant funding from the National Institutes of Health (NIH) to support work on this protocol. JC received support to travel and attend a meeting from the IMPAACT Network. AHG's institution has Clinical Trial agreements with ViiV to support work on this study and has a Clinical Trial agreement with Janssen to support other studies; and AHG received payment from ViiV Healthcare to attend a Pediatric Advisory Board meeting. KB, RM, and SW had funds paid to their institution by ViiV Healthcare related to their work on this manuscript. HC and RMVS-R are employees of Janssen and have stock and stock options with Johnson & Johnson. ALA is site principal investigator for multi-site Gilead and Merck studies, a Gilead expert advisory board attendee, a Merck consultant, expert advisory board attendee for ViiV, presenter at a workshop supported by ViiV, part of the Speaker's Bureau for the Simply Speaking HIV Prevention Series, an expert witness, an unpaid Advocates for Youth Board Chair, an unpaid member of the Well Project Board, and an unpaid HIVMA Vice Chair. AC-G is a ViiV Healthcare consultant and has received funds from Merck and Janssen. CCM, VC, and CH are employees at ViiV Healthcare. CCM and VC own GSK stock or stock options. DEY was previously an unpaid technical advisor for the following non-profit institutions: Cover the Globe and Maipelo Trust. JH is an employee at GSK. DEY is an employee of NIH. AA, AB, EDL, RO, CB-M, CS-A, BH, JK, and JDA declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Competing Interests: We declare no competing interests. The views in this Comment are those of the authors and do not necessarily reflect the view of the US President's Emergency Plan for AIDS Relief, the US Agency for International Development, or the US Government.

Background: Case investigations and contact tracing are essential disease control measures used by health departments. Early in the pandemic, they were seen as a key strategy to stop COVID-19 spread. The CDC urged rapid action to scale up and train a large workforce and collaborate across public and private agencies to halt COVID-19 transmission., Methods: We developed a program for case investigation and contact tracing that followed CDC and local health guidelines, compliant with the Occupational Safety and Health Administration (OSHA) regulations and tailored to the needs and resources of our institution. Program staff were trained and assessed for competency before joining the program., Results: From March 2020 to May 2021, we performed 838 COVID-19 case investigations, which led to 136 contacts. Most employees reported a known SARS-CoV-2 exposure from the community ( n  = 435) or household ( n  = 343). Only seven (5.1%) employees were determined as more likely than not to have SARS-CoV-2 infection related to workplace exposure, and when so, lapses in following the masking recommendations were identified. Between June 2021-February 2022, our program adjusted to the demand of the different waves, particularly omicron, by significantly reducing the amount of data collected. No transmission from employees to patients or caregivers was observed during this period., Conclusion: Prompt implementation of case investigation and contact tracing is possible, and it effectively reduces workplace exposures. This approach can be adapted to suit the specific needs and requirements of various healthcare settings, particularly those serving the most vulnerable patient populations., Competing Interests: RH has served on advisory boards for Abbott Diagnostics and T2 Diagnostics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hijano, Dennis, Hoffman, Tang, Hayden, St. Jude COVID-19 Case Investigation and Contact Tracing Team, Gaur and Hakim.)

Introduction: Youth living with HIV in the US have low rates of viral suppression, in part because of challenges with antiretroviral therapy adherence., Methods: Daily dosing in the Adolescent Medicine Trials Network for HIV/AIDS Interventions 152 study, a randomized controlled trial of a 12-week adherence intervention (triggered escalating real-time adherence intervention) for viremic youth, compared with standard of care (SOC), was measured by electronic dose monitoring (EDM) throughout 48 weeks of follow-up. EDM data collected over the first 24 weeks were used to characterize patterns of antiretroviral therapy adherence with group-based trajectory models., Results: Four trajectory groups were identified among the 85 participants included in the analysis during the intervention phase of the study: (Worst) no interaction with EDM, (Declining) initially moderate EDM-based adherence followed by steep declines, (Good) initially high EDM-based adherence with modest declines, and (Best) consistently high EDM-based adherence. Being in the SOC arm, not being in school, higher evasiveness and panic decision-making scores, and lower adherence motivation were associated with higher odds of being in a worse trajectory group ( P < 0.05). A general decline in dosing was observed in the 12 weeks postintervention, when all participants were managed using SOC., Conclusions: Use of group-based trajectory models allowed a more nuanced understanding of EDM-based adherence over time compared with collapsed summary measures. In addition to the study intervention, other factors influencing EDM-based adherence included being in school, decision-making styles, and adherence-related motivation. This information can be used to design better intervention services for youth living with HIV., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Youth living with HIV (YLWH) in the US have low rates of viral suppression (VS). In a prospective randomized clinical trial (ATN152) that enrolled 89 YLWH on antiretroviral therapy (ART) with detectable viral load, we evaluated a 12 week triggered escalating real-time adherence (TERA) intervention with remote coaching, electronic dose monitoring (EDM), and outreach for missed/delayed doses compared to standard of care (SOC). Median [Q1, Q3] percent days with EDM opening was higher in TERA (72% (47%, 89%)) versus SOC (41% (21%, 59%); p < 0.001) and incidence of numbers of 7 day gaps between openings were lower (TERA to SOC ratio: 0.40; 95% CI 0.30, 0.53; p < 0.001). There were no differences in VS at week 12 (TERA 35%; 95% CI 21%, 51% versus SOC 36%; 95% CI 22%, 51%; p > 0.99) or later time-points. The intervention improved adherence but not VS in heavily ART-experienced YLWH. Remote coaching more closely tailored to the unique dosing patterns and duration of need for youth struggling to reach VS warrants further investigation., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Although numerous studies have evaluated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using cycle threshold (Ct) values as a surrogate of viral ribonucleic acid (RNA) load, few studies have used standardized, quantitative methods. We validated a quantitative SARS-CoV-2 digital polymerase chain reaction assay normalized to World Health Organization International Units and correlated viral RNA load with symptoms and disease severity., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objective: The objective of this study is to assess the utility of a nucleic acid amplification test-based approach to shorten isolation of healthcare workers (HCWs) with COVID-19 in the setting of the highly transmissible omicron variant., Methods: Between December 24, 2021, and January 5, 2022, HCWs who tested positive for SARS-CoV-2 were retested with PCR at least 5 days since onset of symptoms., Results: Forty-six sequential fully COVID-19 vaccinated HCWs who had tested positive for SARS-CoV-2 underwent follow-up testing. All the samples were confirmed as omicron variants and only four (8.7%) were negative in the follow-up test performed at a median of 6 (range 5-12) since onset of symptoms., Conclusions: Implementation of a test-based strategy is logistically challenging, increases costs, and did not lead to shorter isolation in our institution., (© 2022 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Background: Following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or vaccination there is significant variability between individuals in protective antibody levels against SARS-CoV-2, and within individuals against different virus variants. However, host demographic or clinical characteristics that predict variability in cross-reactive antibody levels are not well-described. These data could inform clinicians, researchers, and policymakers on the populations most likely to require vaccine booster shots., Methods: In an institutional review board-approved prospective observational cohort study of staff at St. Jude Children's Research Hospital, we identified participants with plasma samples collected after SARS-CoV-2 infection, after mRNA vaccination, and after vaccination following infection, and quantitated immunoglobulin G (IgG) levels by enzyme-linked immunosorbent assay to the spike receptor binding domain (RBD) from 5 important SARS-CoV-2 variants (Wuhan Hu-1, B.1.1.7, B.1.351, P.1, and B.1.617.2). We used regression models to identify factors that contributed to cross-reactive IgG against 1 or multiple viral variants., Results: Following infection, a minority of the cohort generated cross-reactive antibodies, IgG antibodies that bound all tested variants. Those who did had increased disease severity, poor metabolic health, and were of a particular ancestry. Vaccination increased the levels of cross-reactive IgG levels in all populations, including immunocompromised, elderly, and persons with poor metabolic health. Younger people with a healthy weight mounted the highest responses., Conclusions: Our findings provide important new information on individual antibody responses to infection/vaccination that could inform clinicians on populations that may require follow-on immunization., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: COVID-19 has caused over 305 million infections and nearly 5.5 million deaths globally. With complete eradication unlikely, organizations will need to evaluate their risk and the benefits of mitigation strategies, including the effects of regular asymptomatic testing. We developed a web application and R package that provides estimates and visualizations to aid the assessment of organizational infection risk and testing benefits to facilitate decision-making, which combines internal and community information with malleable assumptions., Results: Our web application, covidscreen, presents estimated values of risk metrics in an intuitive graphical format. It shows the current expected number of active, primarily community-acquired infections among employees in an organization. It calculates and explains the absolute and relative risk reduction of an intervention, relative to the baseline scenario, and shows the value of testing vaccinated and unvaccinated employees. In addition, the web interface allows users to profile risk over a chosen range of input values. The performance and output are illustrated using simulations and a real-world example from the employee testing program of a pediatric oncology specialty hospital., Conclusions: As the COVID-19 pandemic continues to evolve, covidscreen can assist organizations in making informed decisions about whether to incorporate covid test based screening as part of their on-campus risk-mitigation strategy. The web application, R package, and source code are freely available online (see "Availability of data and materials")., (© 2022. The Author(s).)

To understand reinfection rates and correlates of protection for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we established eight different longitudinal cohorts in 2020 under the umbrella of the PARIS (Protection Associated with Rapid Immunity to SARS-CoV-2)/SPARTA (SARS SeroPrevalence And Respiratory Tract Assessment) studies. Here, we describe the PARIS/SPARTA cohorts, the harmonized assays and analysis that are performed across the cohorts, as well as case definitions for SARS-CoV-2 infection and reinfection that have been established by the team of PARIS/SPARTA investigators. IMPORTANCE Determining reinfection rates and correlates of protection against SARS-CoV-2 infection induced by both natural infection and vaccination is of high significance for the prevention and control of coronavirus disease 2019 (COVID-19). Furthermore, understanding reinfections or infection after vaccination and the role immune escape plays in these scenarios will inform the need for updates of the current SARS-CoV-2 vaccines and help update guidelines suitable for the postpandemic world.

Background: SJ733, a newly developed inhibitor of P. falciparum ATP4, has a favorable safety profile and rapid antiparasitic effect but insufficient duration to deliver a single-dose cure of malaria. We investigated the safety, tolerability, and pharmacokinetics of a multidose SJ733 regimen and a single-dose pharmacoboost approach using cobicistat to inhibit CYP3A4, thereby increasing exposure., Methods: Two multidose unboosted cohorts (n = 9) (SJ733, 300 mg and 600 mg daily for 3 days) followed by three single-dose boosted cohorts combining SJ733 (n = 18) (75-, 300-, or 600-mg single dose) with cobicistat (150-mg single dose) as a pharmacokinetic booster were evaluated in healthy volunteers (ClinicalTrials.gov: NCT02661373)., Findings: All participants tolerated SJ733 well, with no serious adverse events (AEs), dose-limiting toxicity, or clinically significant electrocardiogram or laboratory test findings. All reported AEs were Grade 1, clinically insignificant, and considered unlikely or unrelated to SJ733. Compared to unboosted cohorts, the SJ733/cobicistat-boosted cohorts showed a median increase in area under the curve and maximum concentration of 3·9 × and 2·6 ×, respectively, and a median decrease in the ratio of the major CYP3A-produced metabolite SJ506 to parent drug of 4·6 × . Incorporating these data in a model of parasite dynamics indicated that a 3-day regimen of SJ733/cobicistat (600 mg/150 mg daily) relative to a single 600-mg dose ± cobicistat would increase parasite clearance from 10 6 to 10 12 parasites/µL., Interpretation: The multidose and pharmacoboosted approaches to delivering SJ733 were well-tolerated and significantly increased drug exposure and prediction of cure. This study supports the further development of SJ733 and demonstrates an innovative pharmacoboost approach for an antimalarial., Funding: Global Health Innovative Technology Fund, Medicines for Malaria Venture, National Institutes of Health, and American Lebanese Syrian Associated Charities., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

COVID-19 remains a challenge worldwide, and testing of asymptomatic individuals remains critical to pandemic control measures. Starting March 2020, a total of 7497 hospital employees were tested at least weekly for SARS CoV-2; the cumulative incidence of asymptomatic infections was 5.64%. Consistently over a 14-month period half of COVID-19 infections (414 of 820, total) were detected through the asymptomatic screening program, a third of whom never developed any symptoms during follow-up. Prompt detection and isolation of these cases substantially reduced the risk of potential workplace and outside of workplace transmission. COVID-19 vaccinations of the workforce were initiated in December 2020. Twenty-one individuals tested positive after being fully vaccinated (3.9 per 1000 vaccinated). Most (61.9%) remained asymptomatic and in majority (75%) the virus could not be sequenced due to low template RNA levels in swab samples. Further routine testing of vaccinated asymptomatic employees was stopped and will be redeployed if needed; routine testing for those not vaccinated continues. Asymptomatic SARS-CoV-2 testing, as a part of enhanced screening, monitors local dynamics of the COVID-19 pandemic and can provide valuable data to assess the ongoing impact of COVID-19 vaccination and SARS-CoV-2 variants, inform risk mitigation, and guide adaptive, operational planning including titration of screening strategies over time, based on infection risk modifiers such as vaccination., Competing Interests: PGT is on the Scientific Advisory Board for Cytoagents Inc. RTH has served on advisory boards for Roche Molecular and Quidel Corporation. All other authors have no conflicts of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and has since caused a global pandemic resulting in millions of cases and deaths. Diagnostic tools and serological assays are critical for controlling the outbreak, especially assays designed to quantitate neutralizing antibody levels, considered the best correlate of protection. As vaccines become increasingly available, it is important to identify reliable methods for measuring neutralizing antibody responses that correlate with authentic virus neutralization but can be performed outside biosafety level 3 (BSL3) laboratories. While many neutralizing assays using pseudotyped virus have been developed, there have been few studies comparing the different assays to each other as surrogates for authentic virus neutralization. Here, we characterized three enzyme-linked immunosorbent assays (ELISAs) and three pseudotyped vesicular stomatitis virus (VSV) neutralization assays and assessed their concordance with authentic virus neutralization. The most accurate assays for predicting authentic virus neutralization were luciferase- and secreted embryonic alkaline phosphatase (SEAP)-expressing pseudotyped virus neutralizations, followed by green fluorescent protein (GFP)-expressing pseudotyped virus neutralization, and then the ELISAs. IMPORTANCE The ongoing COVID-19 pandemic is caused by infection with severe acute respiratory syndrome virus 2 (SARS-CoV-2). Prior infection or vaccination can be detected by the presence of antibodies in the blood. Antibodies in the blood are also considered to be protective against future infections from the same virus. The "gold standard" assay for detecting protective antibodies against SARS-CoV-2 is neutralization of authentic SARS-CoV-2 virus. However, this assay can only be performed under highly restrictive biocontainment conditions. We therefore characterized six antibody-detecting assays for their correlation with authentic virus neutralization. The significance of our research is in outlining the advantages and disadvantages of the different assays and identifying the optimal surrogate assay for authentic virus neutralization. This will allow for more accurate assessments of protective immunity against SARS-CoV-2 following infection and vaccination.

Background: Men who have sex with men (MSM) are at high risk for human papillomavirus (HPV)-related anal cancer. Little is known about the prevalence of low-grade squamous intraepithelial lesions (LSILs) and the anal cancer precursor, high-grade squamous intraepithelial lesions (HSILs), among young MSM with HIV (MSMLWH). HPV vaccination is recommended in this group, but its safety, immunogenicity, and protection against vaccine-type HPV infection and associated LSILs/HSILs have not been studied., Methods: Two hundred and sixty MSMLWH aged 18-26 years were screened at 17 US sites for a clinical trial of the quadrivalent (HPV6,11,16,18) HPV (qHPV) vaccine. Those without HSILs were vaccinated at 0, 2, and 6 months. Cytology, high-resolution anoscopy with biopsies of lesions, serology, and HPV testing of the mouth/penis/scrotum/anus/perianus were performed at screening/month 0 and months 7, 12, and 24., Results: Among 260 MSMLWH screened, the most common reason for exclusion was detection of HSILs in 88/260 (34%). 144 MSMLWH were enrolled. 47% of enrollees were previously exposed to HPV16. No incident qHPV type-associated anal LSILs/HSILs were detected among men naive to that type, compared with 11.1, 2.2, 4.5, and 2.8 cases/100 person-years for HPV6,11,16,18-associated LSILs/HSILs, respectively, among those previously exposed to that type. qHPV was immunogenic and safe with no vaccine-associated serious adverse events., Conclusions: 18-26-year-old MSMLWH naive to qHPV vaccine types were protected against incident qHPV type-associated LSILs/HSILs. Given their high prevalence of HSILs, there is an urgent need to vaccinate young MSMLWH before exposure to vaccine HPV types, before initiating sexual activity, and to perform catch-up vaccination., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Purpose: The objective of this study was to evaluate the feasibility and acceptability of a dynamic, behavioral intervention to optimize medication adherence of adolescents and young adults (AYAs) with HIV newly initiating highly active antiretroviral therapy (HAART) and explore its efficacy on adherence and disease outcomes., Methods: The two-arm randomized controlled trial piloted a brief, individualized intervention designed for direct integration into standard clinical care. In total, 32 AYAs with a confirmed HIV diagnosis, reportedly horizontally acquired, and recommended to initiate HAART completed a two-week placebo trial before HAART initiation and were subsequently randomized to standard of care or the individualized intervention. Adherence and disease outcomes were measured over the first six months of HAART., Results: Results supported the primary study aim regarding feasibility (recruitment = 89%, attendance = 81%-100%, intervention exercise completion = 100%) and acceptability (average favorable response = 89%). Data also supported the positive effect of the intervention on select HAART adherence measures and disease outcomes. Adherence (by pharmacy refill) declined in both groups; however, adherence declined more slowly in the intervention group versus standard of care (p < .001). In addition, 100% of participants receiving the intervention obtained an undetectable viral load by 3 months and maintained an undetectable viral load at 6 months (vs. 68.8% standard of care)., Conclusions: This is one of the first interventions to target adherence for AYAs with HIV newly initiating HAART and designed for delivery in existing clinical care settings. Future research will help confirm efficacy and the potential utility of the intervention in promoting HAART adherence from medication initiation and preventing the decrease in adherence often observed over time., (Copyright © 2021 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Bictegravir is a potent integrase strand-transfer inhibitor (INSTI) with a high genetic barrier to resistance. Bictegravir, coformulated with emtricitabine and tenofovir alafenamide, is recommended by key European and US HIV treatment guidelines as the preferred single-tablet regimen for adults and adolescents. The aim of this study was to assess the pharmacokinetics, safety, and efficacy of switching to this regimen in virologically suppressed children and adolescents with HIV., Methods: In this single-arm, open-label trial, we enrolled virologically suppressed children and adolescents (aged 6 to <18 years) with HIV at 22 hospital clinics in South Africa, Thailand, Uganda, and the USA. Eligible participants had a bodyweight of at least 25 kg, were virologically suppressed (HIV-1 RNA <50 copies per mL) on a stable ART regimen for at least 6 months before screening, had a CD4 count of at least 200 cells per μL, and an estimated glomerular filtration rate of at least 90 mL/min per 1·73 m 2 by the Schwartz formula at screening. All participants received the fixed-dose regimen of coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg once daily. Pharmacokinetic analysis was used for dosing confirmation, and results compared with adult values. The primary outcomes were area under the curve at the end of the dosing interval (AUC tau ) and concentration at the end of the dosing interval (C tau ) of bictegravir, and incidence of treatment-emergent adverse events and laboratory abnormalities at week 24. Efficacy and safety analyses included all participants who received at least one dose of study drug. We report the 48-week results. This study is registered with ClinicalTrials.gov, NCT02881320., Findings: Between Sept 29, 2016 and Feb 16, 2018, we enrolled 102 participants. 100 participants received bictegravir, emtricitabine, and tenofovir alafenamide (cohort 1 [adolescents aged 12 to <18 years], n=50; cohort 2 [children aged 6 to <12 years], n=50). The mean bictegravir AUC tau was 89 100 ng × h/mL (coefficient of variation 31·0%) in adolescents (cohort 1) and 128 000 ng × h/mL (27·8%) in children (cohort 2). Compared with adults, bictegravir C tau was 35% lower in adolescents and 11% lower in children. The 90% CIs of both parameters were within the predefined pharmacokinetic equivalence boundary and within overall range of exposures observed in adults and deemed to be safe and efficacious (geometric least-squares mean ratio [GLSM] 86·3% [90% CI 80·0-93·0] for AUC tau and 65·4% [58·3-73·3] for C tau in adolescents; GLSM 125% [90% CI 117-134] for AUC tau and 88·9% [80·6-98·0] for C tau for children). Bictegravir, emtricitabine, and tenofovir alafenamide was well tolerated; most adverse events were grade 2 or less in severity and no study drug-related serious adverse events were reported. One participant discontinued study drug due to adverse events (grade 2 insomnia and anxiety). Virological suppression (HIV-1 RNA <50 copies per mL) was maintained by all 100 participants at week 24 and by 98 (98%) of 100 at week 48; no participants had treatment-emergent resistance., Interpretation: In adolescents and children with HIV, the bictegravir, emtricitabine, and tenofovir alafenamide single-tablet regimen was well tolerated and maintained virological suppression. Our data support the treatment of HIV in adolescents and children with this single-tablet regimen. At present, the single-tablet regimen is recommended as first-line treatment in the USA for adolescents and as an alternative regimen in children and has the potential to represent an important regimen in the paediatric population., Funding: Gilead Sciences., Competing Interests: Declaration of interests AHG reports that his institution holds a Clinical Trials Agreement with Gilead to support the clinical trials sponsored by Gilead, including those that contributed to data shared in this manuscript; no direct payment was made to AHG. CAR has received research grant support and payment for attending scientific meetings from Gilead. KC reports research support from Gilead. HMax, PW, DP, SM, MSY, HG, HMar, DMB, and CP are or were employees of Gilead at the time of this analysis and report and hold stock interest in the company. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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., (© 2021. The Author(s).)

Background: Safe and effective long-acting injectable agents for preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection are needed to increase the options for preventing HIV infection., Methods: We conducted a randomized, double-blind, double-dummy, noninferiority trial to compare long-acting injectable cabotegravir (CAB-LA, an integrase strand-transfer inhibitor [INSTI]) at a dose of 600 mg, given intramuscularly every 8 weeks, with daily oral tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) for the prevention of HIV infection in at-risk cisgender men who have sex with men (MSM) and in at-risk transgender women who have sex with men. Participants were randomly assigned (1:1) to receive one of the two regimens and were followed for 153 weeks. HIV testing and safety evaluations were performed. The primary end point was incident HIV infection., Results: The intention-to-treat population included 4566 participants who underwent randomization; 570 (12.5%) identified as transgender women, and the median age was 26 years (interquartile range, 22 to 32). The trial was stopped early for efficacy on review of the results of the first preplanned interim end-point analysis. Among 1698 participants from the United States, 845 (49.8%) identified as Black. Incident HIV infection occurred in 52 participants: 13 in the cabotegravir group (incidence, 0.41 per 100 person-years) and 39 in the TDF-FTC group (incidence, 1.22 per 100 person-years) (hazard ratio, 0.34; 95% confidence interval, 0.18 to 0.62). The effect was consistent across prespecified subgroups. Injection-site reactions were reported in 81.4% of the participants in the cabotegravir group and in 31.3% of those in the TDF-FTC group. In the participants in whom HIV infection was diagnosed after exposure to CAB-LA, INSTI resistance and delays in the detection of HIV infection were noted. No safety concerns were identified., Conclusions: CAB-LA was superior to daily oral TDF-FTC in preventing HIV infection among MSM and transgender women. Strategies are needed to prevent INSTI resistance in cases of CAB-LA PrEP failure. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 083 ClinicalTrials.gov number, NCT02720094.)., (Copyright © 2021 Massachusetts Medical Society.)

The efficacy of coronavirus disease 2019 (COVID-19) vaccines administered after COVID-19-specific monoclonal antibody is unknown, and "antibody interference" might hinder immune responses leading to vaccine failure. In an institutional review board-approved prospective study, we found that an individual who received mRNA COVID-19 vaccination <40 days after COVID-19-specific monoclonal antibody therapy for symptomatic COVID-19 had similar postvaccine antibody responses to SARS-CoV-2 receptor binding domain (RBD) for 4 important SARS-CoV-2 variants (B.1, B.1.1.7, B.1.351, and P.1) as other participants who were also vaccinated following COVID-19. Vaccination against COVID-19 shortly after COVID-19-specific monoclonal antibody can boost and expand antibody protection, questioning the need to delay vaccination in this setting., Trial Registration: The St. Jude Tracking of Viral and Host Factors Associated with COVID-19 study; NCT04362995; https://clinicaltrials.gov/ct2/show/NCT04362995., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

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.

Evidence-based linkage to care interventions (LTCs) help recently diagnosed HIV+ individuals engage in care in a timely manner yet are heavily impacted by the systems in which they are embedded. We developed a prototype agent-based model informed by data from an established LTC program targeting youth and young adults aged 13-24 in Memphis, Tennessee. We then tested two interventions to improve LTC in a simulated environment: expanding testing sites versus using current testing sites but improving direct referral to LTC staff from organizations providing testing, to understand the impact on timely linkage to care. Improving direct referral to the LTC program decreased days to successful linkage from an average of 30 to 23 days but expanding testing sites increased average days to 31 days unless those sites also made direct referrals. We demonstrated how LTC is impacted by the system and interventions for shortening days to linkage to care.

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., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

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., (© 2020 Wiley Periodicals, Inc.)

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 48 ) 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 0-∞ ) of 13 000 μg × h/L (median AUC 0-∞ 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 log 10 PRR 48 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., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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 Plasmodium falciparum . 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.

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.

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., (© 2019 Wiley Periodicals, Inc.)

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., (© 2019 The Authors Clinical Pharmacology & Therapeutics  © 2019 American Society for Clinical Pharmacology and Therapeutics.)

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., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (©Anne M Neilan, Kunjal Patel, Allison L Agwu, Ingrid V Bassett, K Rivet Amico, Catherine M Crespi, Aditya H Gaur, Keith J Horvath, Kimberly A Powers, H Jonathon Rendina, Lisa B Hightow-Weidman, Xiaoming Li, Sylvie Naar, Sharon Nachman, Jeffrey T Parsons, Kit N Simpson, Bonita F Stanton, Kenneth A Freedberg, Audrey C Bangs, Michael G Hudgens, Andrea L Ciaranello. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 16.04.2019.)

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.

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.

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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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 Clostridium difficile 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%; P = 0.007) or other prophylactic regimens (0.9% versus 3.0%; P = 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., (Copyright © 2018 American Society for Microbiology.)

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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)