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Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is common in people with HIV (PWH). The morphological spectrum of MASLD compared to matched controls and of the correlation between the NAFLD activity score (NAS) and fibrosis stage in PWH remains unknown., Methods: Overall, 107 liver biopsies from PWH with MASLD (MASLD-PWH) were matched to 107 biopsies from individuals with MASLD and without HIV (MASLD controls) on age at biopsy, race/ethnicity, sex, type 2 diabetes, body mass index (BMI) and alanine aminotransferase (ALT) level. Biopsies were scored using NAS., Results: Compared to MASLD-controls, MASLD-PWH had lower steatosis grade (OR: 0.65, 95% CI: (0.47-0.90), p = 0.01), lower lobular inflammation grade (OR: 0.55, 95% CI: (0.34-0.89), p = 0.02), less portal inflammation (OR: 0.42, 95% CI: (0.25-0.72), p = 0.002) and less ballooned hepatocytes (OR: 0.60, 95% CI: (0.41-0.88), p = 0.01). Thus, NAS was lower in MASLD-PWH (OR: 0.69, 95% CI: (0.56-0.85), p < 0.001) than in MASLD controls. There was a trend towards lower prevalence of steatohepatitis in MASLD-PWH (OR: 0.84, 95% CI: (0.68-1.03), p = 0.09). A multivariate analysis demonstrated that MASLD-PWH cases had significantly less steatosis (OR: 0.66, p = 0.03), portal inflammation (OR: 0.34, p = 0.001) and ballooned hepatocytes (OR: 0.55, p = 0.01), yet higher stage fibrosis (OR: 1.42, p = 0.03) compared to MASLD controls., Conclusion: The NAS and histological drivers of fibrosis (e.g. inflammation and hepatocyte ballooning) are less pronounced in MASLD-PWH, and yet fibrosis stage was generally higher when compared to matched controls with MASLD without HIV. This suggests HIV-specific factors beyond hepatic necroinflammation may contribute to fibrosis progression in MASLD-PWH., (© 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Lower respiratory tract infection (LRTI) is a common reason for hospitalization and antibacterial use globally. There is considerable overlap in the clinical presentation of bacterial and viral LRTIs. Low- or middle-income countries (LMICs) face the dual challenge of appropriately targeting antibacterials for bacterial LRTI while reducing inappropriate antibacterials for viral LRTI. We propose a framework by which an electronic clinical decision support tool (eCDST) for diagnosing LRTI and reducing unnecessary antibacterial use may be developed, validated, and prospectively evaluated in an LMIC. The developed tool would be data driven, low-cost, feasible in the local setting, adaptable based on resource availability, and updated in real time, with prospective assessment to identify its clinical impact. We draw upon our team's recent experience developing an eCDST for LRTI management in Sri Lanka. Publicly sharing such processes and data is valuable, such that we can collectively improve clinical care in LMICs and other settings.

A subset of patients with chronic hepatitis C virus (HCV) infection demonstrate liver enzyme elevation (LEE) after achieving sustained virologic response (SVR). Risk factors for LEE are not well characterised. We conducted a single-centre retrospective cohort study of adults with HCV infection in the Duke University Health System who received direct-acting antiviral therapy and achieved SVR. We performed multivariable logistic regression to assess the relationship between potential risk factors and LEE. We used generalised linear mixed-effects models to explore longitudinal relationships between HIV and LEE. Among 1356 patients, 556 (41.0%) had LEE after achieving SVR. Higher pretreatment alanine aminotransferase (ALT) (adjusted odds ratio [aOR] 1.08 per 10 IU/L increase; 95% confidence interval [CI] 1.05-1.11) and pretreatment cirrhosis (aOR 2.26, 95% CI 1.60-3.21) were associated with higher odds of LEE; male sex was associated with lower odds of LEE (aOR 0.28, 95% CI 0.21-0.38). There was insufficient evidence of an association between HIV and LEE (aOR 0.83, 95% CI 0.47-1.44). Pretreatment ALT, cirrhosis and female sex predicted LEE in this cohort of patients with HCV infection who achieved SVR. These findings can help to identify patients at greatest risk of post-SVR liver injury., (© 2024 John Wiley & Sons Ltd.)

Importance: The effect of montelukast in reducing symptom duration among outpatients with mild to moderate COVID-19 is uncertain., Objective: To assess the effectiveness of montelukast compared with placebo in treating outpatients with mild to moderate COVID-19., Design, Setting, and Participants: This randomized clinical trial (Accelerating COVID-19 Therapeutic Interventions and Vaccines [ACTIV]-6) was conducted from January 27 through June 23, 2023, during the circulation of Omicron subvariants. Participants aged 30 years or older with confirmed SARS-CoV-2 infection and 2 or more acute COVID-19 symptoms for less than 7 days were included across 104 US sites., Interventions: Participants were randomized 1:1 to receive montelukast, 10 mg once daily, or matched placebo for 14 days., Main Outcomes and Measures: The primary outcome was time to sustained recovery (defined as ≥3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of health care utilization events (hospitalization, urgent care clinic visit, emergency department visit, or death); COVID-19 clinical progression scale score; and difference in mean time unwell. A modified intention-to-treat approach was used for the analysis., Results: Among 1250 participants who were randomized and received the study drug or placebo, the median age was 53 years (IQR, 42-62 years), 753 (60.2%) were female, and 704 (56.3%) reported receiving 2 or more doses of a SARS-CoV-2 vaccine. Among 628 participants who received montelukast and 622 who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio [AHR], 1.02; 95% credible interval [CrI], 0.92-1.12; P = .63 for efficacy). Unadjusted median time to sustained recovery was 10 days (95% CI, 10-11 days) in both groups. No deaths occurred, and hospitalizations were reported for 2 participants (0.3%) in each group; the composite of health care utilization events was reported for 18 participants (2.9%) in the montelukast group and 18 (2.9%) in the placebo group (AHR, 1.01; 95% CrI, 0.45-1.84; P = .48 for efficacy). Five participants (0.4%) experienced serious adverse events (3 [0.5%] in the montelukast group and 2 [0.3%] in the placebo group)., Conclusions and Relevance: In this randomized clinical trial of outpatients with mild to moderate COVID-19, treatment with montelukast did not reduce duration of COVID-19 symptoms. These findings do not support the use of montelukast for the treatment of mild to moderate COVID-19., Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

This case-control study explored cumulative tenofovir exposure among patients with human immunodeficiency virus/hepatis B virus (HIV/HBV) coinfection with HIV viral suppression. Among patients taking tenofovir disoproxil fumarate, median TFV-DP levels in dried blood spots were ∼3-fold lower among patients with incomplete HBV viral suppression (n = 4) compared to those with complete suppression (n = 5) (516 vs 1456 fmol/punch)., Competing Interests: Potential conflicts of interest . S. N.: Research funding to institution from Gilead Sciences; Scientific Advisory Board for Vir Bio and stock options/vesting. P. L. A.: Research funding from Gilead Sciences paid to institution. J.J.K. was employed by the University of Colorado at the time this work was performed; she is now an employee of Merck. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: Steatotic liver disease is common in people with HIV (PWH). Identifying those with advanced fibrosis (AF, bridging fibrosis or cirrhosis), F3-4, is important. We aimed to examine the performance of FIB-4 and nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS) in PWH to identify those with AF assessed by liver stiffness measurement (LSM)., Methods: We prospectively collected data on adults participating in 2 National Institute of Health-sponsored HIV NAFLD networks. All had HIV on antiretroviral therapy (ART) ≥6 months with HIV RNA <200 copies/mL. Those with viral hepatitis, other liver disease, excessive alcohol use, or hepatic decompensation were excluded. Vibration-controlled transient elastrography for LSM was performed, and AF defined as ≥11 kPa was compared with FIB-4 and NFS at predefined thresholds (<1.3 and >2.67 for FIB-4 and <-1.455 and >0.675 for NFS)., Results: A total of 1,065 participants were analyzed: mean age 51.6 years, 74% male, 28% White, 46% Black, 22% Hispanic, with 34% overweight (body mass index 25-29 kg/m 2 ) and 43% obese (body mass index ≥30 kg/m 2 ). Features of the metabolic syndrome were common: hyperlipidemia 35%, type 2 diabetes 17%, and hypertension 48%. The median CD4 + T-cell count was 666 cells/mm 3 , 74% had undetectable HIV RNA, and duration of HIV-1 was 17 years with most taking a nucleoside reverse transcriptase inhibitor (92%) and an integrase inhibitor (83%). The mean LSM was 6.3 kPa, and 6.3% had AF. The area under the receiver characteristic curve for FIB-4 and NFS to identify AF were 0.70 and 0.75, respectively. While both had high negative predictive values (97%-98%), the sensitivity at low thresholds and specificity at high thresholds were 64% and 97% for FIB-4 and 80% and 96% for NFS, respectively. Neither FIB-4 nor NFS at either threshold had good positive predictive value to detect AF., Discussion: FIB-4 and NFS have excellent specificity and negative predictive value for detecting AF, and thus can be used as screening tools in PWH to exclude those with AF who do not need further testing (LSM) or referral to hepatologist., (Copyright © 2024 by The American College of Gastroenterology.)

Background & Aims: Food insecurity (FI) is a risk factor for nonalcoholic fatty liver disease (NAFLD) and advanced fibrosis in the general population, but its impact on liver disease in people with HIV (PWH) is unknown., Methods: We examined the association of FI with prevalence of NAFLD and fibrosis in a diverse cohort of PWH. PWH aged ≥ 18 years on antiretroviral therapy, HIV RNA <200 copies/mL, and without other known liver diseases were screened for NAFLD (controlled attenuated parameter ≥263 decibels/meter) and advanced fibrosis (liver stiffness measurement ≥11 kilopascals) by vibration controlled transient elastography at 8 U.S., Centers: Participants were categorized as food insecure using the Six-Item Short Form Household Food Security Survey. We used multivariable logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of NAFLD and advanced fibrosis by FI status., Results: Among 654 PWH, NAFLD was present in 348 (53%) and advanced fibrosis in 41 (6%). FI was present in 203 of participants (31%), including 97/348 with NAFLD (28%) and 18/41 with advanced fibrosis (44%). In multivariable analysis, FI was associated with lower odds of NAFLD (OR, 0.57; 95% CI, 0.37-0.88) and a greater, but nonsignificant, odds of advanced fibrosis (OR, 1.38; 95% CI, 0.65-2.90). We identified a significant interaction between FI and diabetes (P = .02) on fibrosis risk, with greater odds of fibrosis among food insecure PWH and diabetes (OR, 3.83; 95% CI, 1.15-12.73) but not among food insecure nondiabetics (OR, 1.12; 95% CI, 0.47-2.98)., Conclusions: FI is highly prevalent among PWH and associated with lower odds of NAFLD, and among PWH with diabetes, there is greater odds of advanced fibrosis. FI may contribute to hepatic fibrosis through mechanisms other than steatosis in PWH., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objectives: Vaccination reduces the risk of acute coronavirus disease 2019 (COVID-19) in children, but it is less clear whether it protects against long COVID. We estimated vaccine effectiveness (VE) against long COVID in children aged 5 to 17 years., Methods: This retrospective cohort study used data from 17 health systems in the RECOVER PCORnet electronic health record program for visits after vaccine availability. We examined both probable (symptom-based) and diagnosed long COVID after vaccination., Results: The vaccination rate was 67% in the cohort of 1 037 936 children. The incidence of probable long COVID was 4.5% among patients with COVID-19, whereas diagnosed long COVID was 0.8%. Adjusted vaccine effectiveness within 12 months was 35.4% (95 CI 24.5-44.7) against probable long COVID and 41.7% (15.0-60.0) against diagnosed long COVID. VE was higher for adolescents (50.3% [36.6-61.0]) than children aged 5 to 11 (23.8% [4.9-39.0]). VE was higher at 6 months (61.4% [51.0-69.6]) but decreased to 10.6% (-26.8% to 37.0%) at 18-months., Conclusions: This large retrospective study shows moderate protective effect of severe acute respiratory coronavirus 2 vaccination against long COVID. The effect is stronger in adolescents, who have higher risk of long COVID, and wanes over time. Understanding VE mechanism against long COVID requires more study, including electronic health record sources and prospective data., (Copyright © 2024 by the American Academy of Pediatrics.)

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) has recently been proposed as a replacement term for NAFLD., Aims: To assess the effects of this new nomenclature on the prevalence and distribution of different SLD categories in people with HIV (PWH) and identified factors associated with MASLD and clinically significant fibrosis (CSF)., Methods: PWH were prospectively enrolled from 9 US centres and underwent clinical evaluation and vibration-controlled transient elastography for controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). SLD was defined as CAP ≥ 263 dB/m, CSF as LSM of ≥8 kPa, and advanced fibrosis (AF) as LSM ≥ 12 kPa. The prevalence of SLD, MASLD, metabolic dysfunction and alcohol-associated liver disease (MetALD), ALD, cryptogenic (cSLD), CSF and AF were determined. Uni- and multivariate logistic regression models were used to assess factors associated with MASLD and CSF risk., Results: Of 1065 participants, 74% were male, mean (SD) age 51.6 ± 11.9 years, 46% non-Hispanic Black and 74% with undetectable HIV RNA. The prevalence of SLD was 52%, MASLD 39%, MetALD 10%, ALD 3%, CSF 15% and AF 4%. Only 0.6% had cSLD. Black race was protective whereas obesity, ALT and AST levels were associated with increased risk of MASLD and CSF in MASLD. HIV or antiretroviral therapy did not affect MASLD risk., Conclusions: MASLD and MetALD are the dominant causes of SLD in PWH, affecting almost half. Application of the new nomenclature resulted in minimal change in the proportion of patients with MASLD who would have been diagnosed previously with NAFLD., (© 2023 John Wiley & Sons Ltd.)

Importance: The effect of higher-dose fluvoxamine in reducing symptom duration among outpatients with mild to moderate COVID-19 remains uncertain., Objective: To assess the effectiveness of fluvoxamine, 100 mg twice daily, compared with placebo, for treating mild to moderate COVID-19., Design, Setting, and Participants: The ACTIV-6 platform randomized clinical trial aims to evaluate repurposed medications for mild to moderate COVID-19. Between August 25, 2022, and January 20, 2023, a total of 1175 participants were enrolled at 103 US sites for evaluating fluvoxamine; participants were 30 years or older with confirmed SARS-CoV-2 infection and at least 2 acute COVID-19 symptoms for 7 days or less., Interventions: Participants were randomized to receive fluvoxamine, 50 mg twice daily on day 1 followed by 100 mg twice daily for 12 additional days (n = 601), or placebo (n = 607)., Main Outcomes and Measures: The primary outcome was time to sustained recovery (defined as at least 3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of hospitalization, urgent care visit, emergency department visit, or death; COVID-19 clinical progression scale score; and difference in mean time unwell. Follow-up occurred through day 28., Results: Among 1208 participants who were randomized and received the study drug, the median (IQR) age was 50 (40-60) years, 65.8% were women, 45.5% identified as Hispanic/Latino, and 76.8% reported receiving at least 2 doses of a SARS-CoV-2 vaccine. Among 589 participants who received fluvoxamine and 586 who received placebo included in the primary analysis, differences in time to sustained recovery were not observed (adjusted hazard ratio [HR], 0.99 [95% credible interval, 0.89-1.09]; P for efficacy = .40]). Additionally, unadjusted median time to sustained recovery was 10 (95% CI, 10-11) days in both the intervention and placebo groups. No deaths were reported. Thirty-five participants reported health care use events (a priori defined as death, hospitalization, or emergency department/urgent care visit): 14 in the fluvoxamine group compared with 21 in the placebo group (HR, 0.69 [95% credible interval, 0.27-1.21]; P for efficacy = .86) There were 7 serious adverse events in 6 participants (2 with fluvoxamine and 4 with placebo) but no deaths., Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with fluvoxamine does not reduce duration of COVID-19 symptoms., Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

While the coronavirus disease 2019 (COVID-19) pandemic continues to present global challenges, sufficient time has passed to reflect on lessons learned and use those insights to inform policy and approaches to prepare for the next pandemic. In May 2022, the Duke Clinical Research Institute convened a think tank with thought leaders from academia, clinical practice, the pharmaceutical industry, patient advocacy, the National Institutes of Health, the US Food and Drug Administration, and the Centers for Disease Control and Prevention to share, firsthand, expert knowledge of the insights gained from the COVID-19 pandemic and how this acquired knowledge can help inform the next pandemic response. The think tank focused on pandemic preparedness, therapeutics, vaccines, and challenges related to clinical trial design and scale-up during the early phase of a pandemic. Based on the multi-faceted discussions, we outline 10 key steps to an improved and equitable pandemic response., Competing Interests: Potential conflicts of interest. A. F. H. reports contracts with Pfizer and Merck and consulting fees from Merck. B. L. is an employee of and owns stock in Moderna and reports support for travel to a meeting from Moderna. C. W. W. reports consulting fees from Arena Pharmaceuticals, BioFire, FHI Clinical, Giner, Karius, and SeLux Diagnostics; grants or contracts (paid to institution) from Defense Advanced Research Projects Agency, National Institutes of Health (NIH)-Antibacterial Resistance Leadership Group/National Institute of Allergy and Infectious Diseases/NIH Vaccine and Treatment Evaluation Units/National Institute of Mental Health/National Institute of General Medical Sciences, Sanofi, Najit, the Centers for Disease Control and Prevention (CDC), Patient-Centered Outcomes Research, United States Army Medical Research Acquisition Activity, Department of Defence, Abbott, and Pfizer; support for attending meetings and/or travel from the American Society for Microbiology (ASM); participation on a data and safety monitoring board (DSMB) or advisory board for IDbyDNA, Janssen, Regeneron, Roche Molecular Sciences; a leadership or fiduciary role for ASM and the American Society of Tropical Medicine and Hygiene; being employed by Duke University, Durham Veterans Affairs Hospital, Biomeme, and Equity/Founder of Predigen, Inc; and planned, issued, or pending patents for biomarkers for the molecular classification of bacterial infection, methods to diagnose and treat acute respiratory infections, gene expression signatures useful to predict or diagnose sepsis and methods of using the same, host-based molecular signatures of human infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 (coronavirus disease 2019 [COVID-19]), methods of identifying infectious disease and assays for identifying infectious disease, and nasopharyngeal protein biomarkers of acute respiratory virus infection and methods of using same. H. C. and S. C. B. are employees of and hold or may hold stock in AstraZeneca. J. W. reports being an employee of and owns stock/stock options in and received equipment, materials, drugs, medical writing, gifts, and other services from Johnson & Johnson and, as CMO, has been deposed in litigation; patents issued that do not relate to the current article (available on request); and a role on the Brooklyn College Cancer Center Advisory Board, a Brooklyn College Foundation Trustee, and on the Fellowships at Auschwitz for the Study of Professional Ethics, Academic Committee. J. R. D. is an employee and shareholder in Eli Lilly and Company. L. H. C. reports consulting fees from Regeneron for the NFL Players Association and grants or contracts from NIH for PCORI. L. S. reports stock/stock options in Novartis. L. R. is an employee of and owns stock/stock options in and received support for attending meetings and/or travel from Bayer AG. M. S. reports consulting fees from AbbVie, Assembly Bio, Antios, Arbutus, Gilead Sciences, Precision Bio, and GSK for scientific advisory boards and participation on a DSMB for Gilead Sciences and AbbVie and a role as editor of the Journal Viral Hepatitis. O. V. is an employee of Boehringer Ingelheim. P. P. has a patent pending for sotrovimab and is an employee and shareholder of Vir Biotechnology. S. N. reports consulting fees from Pardes Biosciences, Theratechnologies, and Silverback Therapeutics; stock/stock options in Vir Biotechnology; grants or contracts (paid to institution) from Gilead Sciences and AbbVie; participation on an advisory board for Vir Biotechnology, a DSMB for Personal Health Insights, Inc; and serving on an event adjudication committee for Bristol–Myers Squibb/PRA. M. A. M. reports consulting fees from Abcam; stock/stock options in Grid Therapeutics; a role as an advisory board member for GSK Belimumab Pregnancy Registry; and funding to Duke from NIAD (U01 AI151378): Centers for Research in Emerging Infectious Disease (CREID) Network Coordinating Center, HHS 75N93019C00050: Duke Collaborative Influenza Vaccine Innovation Centers (CIVICs) A: Vaccine Center, HHS 75N93019C00054: Duke CIVICs C: Clinical Core, U19 AI144177: A Global Syphilis Vaccine Targeting Outer Membrane Proteins Of Treponema pallidum, 2P01 AI089618: Structure-Function Analysis Of Infection- And Vaccine-Induced B Cell Repertoires. S. E. T. reports royalties from UptoDate; grants or contracts (paid to institution) from the CDC; payment or honoraria (to author) from the Infectious Disease Society of America (IDSA) and Emerson Hospital; support from DCRI to attend the meeting upon which this article was based. L. R. B. is involved in human immunodeficiency virus (HIV) and SARS-CoV-2 vaccine clinical trials conducted in collaboration with the NIH, HIV Vaccine Trials Network, COVID Vaccine Prevention Network, International AIDS Vaccine Initiative, Crucell/Janssen, Moderna, Military HIV Research Program, the Gates Foundation, and Harvard Medical School. reports participation on a DSMB for NIH and AMDAC Committee for the FDA (research funded by the NIH, Welcome Trust, and the Gates Foundation). R. T. G. reports a leadership or fiduciary role on the NIH COVID Treatment Guidelines Panel and IDSA COVID Treatment Guidelines Panel. R. G. reports grants (to institution) from NIH/NIAID, book chapter royalties from Elsevier, and section editor royalties from UpToDate. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Purpose of Review: The goal of this review is to summarize the recent literature linking HIV to metabolic dysfunction-associated steatotic liver disease (MASLD). This is a pressing issue due to the scale of the MASLD epidemic and the urgent need for preventive and therapeutic strategies for MASLD in PWH., Recent Findings: The prevalence of MASLD in PWH is higher than previously appreciated, approaching 50% depending on the population and definition of MASLD. MASLD in PWH is likely multifactorial due to risk factors present in the general population such as metabolic syndrome, and features unique to HIV including systemic inflammation and ART. Statin therapy results in a significant reduction in major adverse cardiovascular events in PWH. PWH are at high risk for MASLD. Screening PWH with metabolic syndrome features could enable earlier interventions to reduce morbidity and mortality associated with MASLD in PWH., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Veterans living with HIV have up to twice the risk of atherosclerotic cardiovascular disease (ASCVD) compared to those without HIV. Objective: Our study seeks to test a non-physician led virtual self-management implementation strategy to reduce ASCVD risk among people living with HIV (PWH). We aim to conduct a randomized control trial among PWH ( n  = 300) with a diagnosis of hypertension (HTN) who are enrolled in Veterans Health Administration (VHA) clinics, on suppressive antiretroviral therapy (ART), randomized 1:1 to intervention vs. education control for a 12-month duration. Methods: Using human centered design approach, we have adapted a previous 5-component telehealth focused, non-physician led intervention to a Veteran population. The education control arm receives enhanced education in addition to usual care. The primary outcome is 6 mmHg reduction in systolic BP over 12-month in the intervention arm compared to the control arm. The secondary outcome is a 12-month difference in non-HDL cholesterol. While each component of our intervention has an evidence base, they have not been tested together in an HIV context. Conclusion: The proposed multicomponent intervention has the potential to improve cardiovascular outcomes in PWH using novel virtual care methods in a patient centered care approach.

Background: The effectiveness of inhaled glucocorticoids in shortening the time to symptom resolution or preventing hospitalization or death among outpatients with mild-to-moderate coronavirus disease 2019 (Covid-19) is unclear., Methods: We conducted a decentralized, double-blind, randomized, placebo-controlled platform trial in the United States to assess the use of repurposed medications in outpatients with confirmed coronavirus disease 2019 (Covid-19). Nonhospitalized adults 30 years of age or older who had at least two symptoms of acute infection that had been present for no more than 7 days before enrollment were randomly assigned to receive inhaled fluticasone furoate at a dose of 200 μg once daily for 14 days or placebo. The primary outcome was the time to sustained recovery, defined as the third of 3 consecutive days without symptoms. Key secondary outcomes included hospitalization or death by day 28 and a composite outcome of the need for an urgent-care or emergency department visit or hospitalization or death through day 28., Results: Of the 1407 enrolled participants who underwent randomization, 715 were assigned to receive inhaled fluticasone furoate and 692 to receive placebo, and 656 and 621, respectively, were included in the analysis. There was no evidence that the use of fluticasone furoate resulted in a shorter time to recovery than placebo (hazard ratio, 1.01; 95% credible interval, 0.91 to 1.12; posterior probability of benefit [defined as a hazard ratio >1], 0.56). A total of 24 participants (3.7%) in the fluticasone furoate group had urgent-care or emergency department visits or were hospitalized, as compared with 13 participants (2.1%) in the placebo group (hazard ratio, 1.9; 95% credible interval, 0.8 to 3.5). Three participants in each group were hospitalized, and no deaths occurred. Adverse events were uncommon in both groups., Conclusions: Treatment with inhaled fluticasone furoate for 14 days did not result in a shorter time to recovery than placebo among outpatients with Covid-19 in the United States. (Funded by the National Center for Advancing Translational Sciences and others; ACTIV-6 ClinicalTrials.gov number, NCT04885530.)., (Copyright © 2023 Massachusetts Medical Society.)

Following the discovery of hepatitis C virus (HCV) in 1989, 3 decades of basic, translational, and clinical research culminated in the development of direct-acting antiviral (DAA) therapy-curative oral treatment for HCV infection. The availability of DAA therapy revolutionized HCV clinical management, including acute (duration of infection <6 mo) and recent (duration of infection <12 mo) infection. Several DAA regimens, including the contemporary pan-genotypic combinations of sofosbuvir-velpatasvir and glecaprevir-pibrentasvir, have been shown to be safe and effective among people with acute and recent HCV infection, highlighting their potential in an HCV controlled human infection model. This article describes the natural history and management of acute and recent HCV infection in the era of DAA therapy and outlines a strategy for use of DAA therapies in the setting of an HCV controlled human infection model., Competing Interests: Potential conflicts of interest. M. M. and G. V. M. are supported by the Australian National Health and Medical Research Council (NHMRC). M. M. reports salary support from the Australian NHMRC Early Career Fellowship. S. N. reports research funding from Gilead and AbbVie; consulting fees from Pardse Biosciences and Silverback; participation in a Data and Safety Monitoring Board (DSMB) with Vir Biotechnology; and stocks with Vir Biotechnology. J. K. R. reports consulting fees from Boehringer and speaker payments from Gilead, Janssen, Merck, and ViiV; DSMB participation with Abivax and Galapagos; and participation on the European AIDS Clinical Society (EACS) Governing Board. G. V. M. reports research funding, advisory board payments, and speaker payments from Gilead, Janssen, AstraZeneca, AbbVie, and ViiV, and research funding and speaker payments from Janssen. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Livers from donors with positive hepatitis B surface antigens (HBsAg+) have been used to expand the donor pool; however, outcome data are limited. We aim to evaluate survival following liver transplant (LT) from HBsAg+ donors. Using the United Network for Organ Sharing registry, we identified HBsAg+ donors used for LT from 2009 to 2020. We used Kaplan-Meier survival and Cox proportional hazards regression to compare post-LT survival in hepatitis B virus-negative recipients who utilized HBsAg+ donors to propensity-matched cohorts who utilized other types of donors. From 2009-2020, 70 patients received HBsAg+ livers, and 58 of them did not carry a diagnosis of chronic hepatitis B virus. The 1- and 3-year post-LT survival for hepatitis B virus-negative patients who received livers from HBsAg+ donors were 96.6% and 91.4%, respectively, with no statistical differences compared with patients who received livers from hepatitis C virus viremic donors (96.5%/93.0%, P = .961/.427), donation after cardiac death donors (93.0%/86.0%, P = .651/.598), average-risk donors (89.5%/86.0%, P = 0.264/0.617), and a combination of extended-criteria donors, including donation after cardiac death, donor age over 70, and graft with greater than 30% steatosis (93.0%/91.2%, P = .621/.785). Recipients of HBsAg+ livers have similar post-LT survival compared with those receiving other types of grafts. Increasing the utilization of HBsAg+ livers could safely expand the donor pool., (Copyright © 2023 American Society of Transplantation & American Society of Transplant Surgeons. All rights reserved.)

Importance: Despite aging-related comorbidities representing a growing threat to quality-of-life and mortality among persons with HIV (PWH), clinical guidance for comorbidity screening and prevention is lacking. Understanding comorbidity distribution and severity by sex and gender is essential to informing guidelines for promoting healthy aging in adults with HIV., Objective: To assess the association of human immunodeficiency virus on the burden of aging-related comorbidities among US adults in the modern treatment era., Design, Setting, and Participants: This cross-sectional analysis included data from US multisite observational cohort studies of women (Women's Interagency HIV Study) and men (Multicenter AIDS Cohort Study) with HIV and sociodemographically comparable HIV-seronegative individuals. Participants were prospectively followed from 2008 for men and 2009 for women (when more than 80% of participants with HIV reported antiretroviral therapy use) through last observation up until March 2019, at which point outcomes were assessed. Data were analyzed from July 2020 to April 2021., Exposures: HIV, age, sex., Main Outcomes and Measures: Comorbidity burden (the number of total comorbidities out of 10 assessed) per participant; secondary outcomes included individual comorbidity prevalence. Linear regression assessed the association of HIV status, age, and sex with comorbidity burden., Results: A total of 5929 individuals were included (median [IQR] age, 54 [46-61] years; 3238 women [55%]; 2787 Black [47%], 1153 Hispanic or other [19%], 1989 White [34%]). Overall, unadjusted mean comorbidity burden was higher among women vs men (3.4 [2.1] vs 3.2 [1.8]; P = .02). Comorbidity prevalence differed by sex for hypertension (2188 of 3238 women [68%] vs 2026 of 2691 men [75%]), psychiatric illness (1771 women [55%] vs 1565 men [58%]), dyslipidemia (1312 women [41%] vs 1728 men [64%]), liver (1093 women [34%] vs 1032 men [38%]), bone disease (1364 women [42%] vs 512 men [19%]), lung disease (1245 women [38%] vs 259 men [10%]), diabetes (763 women [24%] vs 470 men [17%]), cardiovascular (493 women [15%] vs 407 men [15%]), kidney (444 women [14%] vs 404 men [15%]) disease, and cancer (219 women [7%] vs 321 men [12%]). In an unadjusted model, the estimated mean difference in comorbidity burden among women vs men was significantly greater in every age strata among PWH: age under 40 years, 0.33 (95% CI, 0.03-0.63); ages 40 to 49 years, 0.37 (95% CI, 0.12-0.61); ages 50 to 59 years, 0.38 (95% CI, 0.20-0.56); ages 60 to 69 years, 0.66 (95% CI, 0.42-0.90); ages 70 years and older, 0.62 (95% CI, 0.07-1.17). However, the difference between sexes varied by age strata among persons without HIV: age under 40 years, 0.52 (95% CI, 0.13 to 0.92); ages 40 to 49 years, -0.07 (95% CI, -0.45 to 0.31); ages 50 to 59 years, 0.88 (95% CI, 0.62 to 1.14); ages 60 to 69 years, 1.39 (95% CI, 1.06 to 1.72); ages 70 years and older, 0.33 (95% CI, -0.53 to 1.19) (P for interaction = .001). In the covariate-adjusted model, findings were slightly attenuated but retained statistical significance., Conclusions and Relevance: In this cross-sectional study, the overall burden of aging-related comorbidities was higher in women vs men, particularly among PWH, and the distribution of comorbidity prevalence differed by sex. Comorbidity screening and prevention strategies tailored by HIV serostatus and sex or gender may be needed.

Objective: We studied the safety and efficacy of hydroxychloroquine (HCQ) as pre-exposure prophylaxis for COVID-19 in healthcare workers (HCWs), using a meta-analysis of randomised controlled trials (RCTs)., Data Sources: PubMed and EMBASE databases were searched to identify randomised trials studying HCQ., Study Selection: Ten RCTs were identified (n=5079 participants)., Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used in this systematic review and meta-analysis between HCQ and placebo using a Bayesian random-effects model. A pre-hoc statistical analysis plan was written., Main Outcomes: The primary efficacy outcome was PCR-confirmed SARS-CoV-2 infection and the primary safety outcome was incidence of adverse events. The secondary outcome included clinically suspected SARS-CoV-2 infection., Results: Compared with placebo, HCWs randomised to HCQ had no significant difference in PCR-confirmed SARS-CoV-2 infection (OR 0.92, 95% credible interval (CI): 0.58, 1.37) or clinically suspected SARS-CoV-2 infection (OR 0.78, 95% CI: 0.57, 1.10), but significant difference in adverse events (OR 1.35, 95% CI: 1.03, 1.73)., Conclusions and Relevance: Our meta-analysis of 10 RCTs investigating the safety and efficacy of HCQ as pre-exposure prophylaxis in HCWs found that compared with placebo, HCQ does not significantly reduce the risk of confirmed or clinically suspected SARS-CoV-2 infection, while HCQ significantly increases adverse events., Prospero Registration Number: CRD42021285093., Competing Interests: Competing interests: All authors except BSA reported no financial relationship with commercial interest. BSA has received NIH funds for COVID-19-related research and holds equity in VOC Health, a start-up company that is developing novel COVID-19 testing., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To determine whether hydroxychloroquine (HCQ) is safe and effective at preventing COVID-19 infections among health care workers (HCWs)., Methods: In a 1: 1 randomized, placebo-controlled, double-blind, parallel-group, superiority trial at 34 US clinical centers, 1360 HCWs at risk for COVID-19 infection were enrolled between April and November 2020. Participants were randomized to HCQ or matched placebo. The HCQ dosing included a loading dose of HCQ 600 mg twice on day 1, followed by 400 mg daily for 29 days. The primary outcome was a composite of confirmed or suspected COVID-19 clinical infection by day 30, defined as new-onset fever, cough, or dyspnea and either a positive SARS-CoV-2 polymerase chain reaction test (confirmed) or a lack of confirmatory testing due to local restrictions (suspected)., Results: Study enrollment closed before full accrual due to recruitment challenges. The primary end point occurred in 41 (6.0%) participants receiving HCQ and 53 (7.8%) participants receiving placebo. No difference in the proportion of participants experiencing clinical infection (estimated difference of -1.8%, 95% confidence interval -4.6-0.9%, P = 0.20) was identified nor any significant safety issues., Conclusion: Oral HCQ taken as prescribed appeared safe among HCWs. No significant clinical benefits were observed. The study was not powered to detect a small but potentially important reduction in infection., Trial Registration: NCT04334148., Competing Interests: Declaration of competing interest All authors have completed the International Committee of Medical Journal Editors uniform disclosure form and declare: support from the Patient-Centered Outcomes Research Institute (PCORI) for the reported work; Vir Biotechnology (SC); AstraZeneca, GSK, Novartis, Pulmatric, Sanofi-Aventis, Genentech, Teva (MC); Vir Biotechnology (KA); Centers for Disease Control, Infection Control Education for Major Sports, LLC, UpToDate, AHRQ, NIAID (DA); NIH (KA); Pfizer (EO); Abbott (RR)., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Importance: It is unknown whether ivermectin, with a maximum targeted dose of 600 μg/kg, shortens symptom duration or prevents hospitalization among outpatients with mild to moderate COVID-19., Objective: To evaluate the effectiveness of ivermectin at a maximum targeted dose of 600 μg/kg daily for 6 days, compared with placebo, for the treatment of early mild to moderate COVID-19., Design, Setting, and Participants: The ongoing Accelerating COVID-19 Therapeutic Interventions and Vaccines 6 (ACTIV-6) platform randomized clinical trial was designed to evaluate repurposed therapies among outpatients with mild to moderate COVID-19. A total of 1206 participants older than 30 years with confirmed COVID-19 experiencing at least 2 symptoms of acute infection for less than or equal to 7 days were enrolled at 93 sites in the US from February 16, 2022, through July 22, 2022, with follow-up data through November 10, 2022., Interventions: Participants were randomly assigned to receive ivermectin, with a maximum targeted dose of 600 μg/kg (n = 602) daily, or placebo (n = 604) for 6 days., Main Outcomes and Measures: The primary outcome was time to sustained recovery, defined as at least 3 consecutive days without symptoms. The 7 secondary outcomes included a composite of hospitalization, death, or urgent/emergent care utilization by day 28., Results: Among 1206 randomized participants who received study medication or placebo, the median (IQR) age was 48 (38-58) years, 713 (59.1%) were women, and 1008 (83.5%) reported receiving at least 2 SARS-CoV-2 vaccine doses. The median (IQR) time to sustained recovery was 11 (11-12) days in the ivermectin group and 11 (11-12) days in the placebo group. The hazard ratio (posterior probability of benefit) for improvement in time to recovery was 1.02 (95% credible interval, 0.92-1.13; P = .68). Among those receiving ivermectin, 34 (5.7%) were hospitalized, died, or had urgent or emergency care visits compared with 36 (6.0%) receiving placebo (hazard ratio, 1.0 [95% credible interval, 0.6-1.5]; P = .53). In the ivermectin group, 1 participant died and 4 were hospitalized (0.8%); 2 participants (0.3%) were hospitalized in the placebo group and there were no deaths. Adverse events were uncommon in both groups., Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with ivermectin, with a maximum targeted dose of 600 μg/kg daily for 6 days, compared with placebo did not improve time to sustained recovery. These findings do not support the use of ivermectin in patients with mild to moderate COVID-19., Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

Background: People with human immunodeficiency virus (HIV) with and without hepatitis C virus (HCV) coinfection had poor outcomes after liver transplant (LT). Integrase strand transfer inhibitors (INSTIs) and direct-acting antivirals (DAAs) have changed the treatment landscape for HIV and HCV, respectively, but their impact on LT outcomes remains unclear., Methods: This retrospective analysis of adults with HIV monoinfection (n = 246) and HIV/HCV coinfection (n = 286) who received LT compared mortality in patients with HIV who received LT before versus after approval of INSTIs and in patients with HIV/HCV coinfection who received LT before versus after approval of DAAs. In secondary analysis, we compared the outcomes in the different eras with those of propensity score-matched control cohorts of LT recipients without HIV or HCV infection., Results: LT recipients with HIV monoinfection did not experience a significant improvement in survival between the pre-INSTI and INSTI recipients with HIV (adjusted hazard ratio [aHR], 0.70 [95% confidence interval {CI}, .36-1.34]). However, recipients with HIV/HCV coinfection in the DAA era had a 47% reduction (aHR, 0.53 [95% CI, .31-9.2] in 1-year mortality compared with coinfected recipients in the pre-DAA era. Compared to recipients without HIV or HCV, HIV-monoinfected recipients had higher mortality during the pre-INSTI era, but survival was comparable between groups during the INSTI era. HIV/HCV-coinfected recipients also experienced comparable survival during the DAA era compared to recipients without HCV or HIV., Conclusions: Post-LT survival for people with HIV monoinfection and HIV/HCV coinfection has improved with the introduction of INSTI and DAA therapy, suggesting that LT has become safer in these populations., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: We sought to characterize in people with human immunodeficiency virus (PWH) the potential etiologies of elevated alanine aminotransferase (ALT) levels, which are common and often unexplained., Methods: Participants from the longitudinal observational AIDS Clinical Trials Group HAILO cohort without a history of hepatitis C virus (HCV) or hepatitis B virus (HBV) infection nor reported heavy alcohol use were included. Clinical and demographic characteristics, including medication use, the hepatic steatosis index (HSI), and metabolic syndrome (MetS) were compared between participants with and without ALT elevation., Results: Six hundred sixty-two participants were included; 444 (67%) had ≥1 and 229 (35%) ≥2 consecutive ALT elevations during a median of 4.0 years of follow-up. HSI and Hispanic or other (non-White or Black) race/ethnicity were consistently associated with higher odds of abnormal ALT (odds ratio [OR] 1.1 for HSI as a continuous variable, OR 1.9-2.8 for Hispanic/other race/ethnicity for ≥1 or ≥2 ALT elevations); older age and current smoking were associated with lower odds of abnormal ALT. Associations with metabolic disease, as well as with incident HBV and HCV infection, were strengthened by restricting outcomes to persistent and higher degrees of ALT elevation., Conclusions: ALT elevation was common in this cohort of PWH and associated with metabolic disease and hepatic steatosis markers. Nonalcoholic fatty liver disease is likely a common cause of liver inflammation in PWH receiving suppressive antiretrovirals, deserving targeted diagnosis and intervention., Competing Interests: Potential Conflicts of Interest. K. W. C. has received research funding to the institution from Merck Sharp & Dohme (grant) and Amgen (research contract), and served as a paid consultant for Pardes Biosciences, and reports payments and honoraria for CME presentations by a not-for-profit organization from International Antiviral Society-USA, and participation as Chair of a Safety Monitoring Committee for an investigator-initiated study where the sponsor is UCSF. F. J. P. has received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from ViiV, Janssen, Gilead, and Merck. S. N. has received research funding to the institution from Gilead Sciences and AbbVie Pharmaceuticals, served as a paid consultant for Pardes Biosciences, Theratechnologies, and Silverback Therapeutics, and served on an Advisory Board for Vir Biotechnology, a Data Safety Monitoring Board (DSMB) for Personal Health Insights, Inc, and an Event Adjudication Committee for Bristol-Myers Squibb/PRA, and reports stocks and stock options from Vir Biotechnology. E. T. O. has received research funding to the institution from Gilead Sciences and ViiV Healthcare, served as a consultant for ViiV Healthcare, Merck, and Theratechnologies, and reports stock or stock options from GSK, and since the completion of the analysis has become an employee of ViiV Healthcare. M. S. has served on a DSMB for Gilead and AbbVie, and on Advisory Boards for Abbvie, Arbutus, Assembly Bio, Antios, Gilead, GSK, Precision Bio, and Virion, and reports other financial or non-financial interests as the Editor, Journal of Viral Hepatitis, Wiley. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Menopause may impact the earlier onset of aging-related comorbidities among women with versus without human immunodeficiency virus (HIV). We found that menopausal status, age, and HIV were independently associated with higher comorbidity burden, and that HIV impacted burden most in the pre-/perimenopausal phases., Competing Interests: Potential conflicts of interest. A. A. A. reports funding for research provided to their institution from Merck and Gilead; consulting fees paid to the author from Merck and Gilead; a role as a member of the Infectious Diseases Society Board of Directors and as a member of International AIDS Society Governing Council. K. A. reports 3 grants from the National Institutes of Health (NIH) paid to their institution and unrelated to this work; support attending meetings and/or travel in the form of grants paid to their institution from the NIH. M.-C. K. reports support unrelated to this work from the NIH and paid to their institution. S. K. reports support unrelated to this work from the NIH and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Integritas Communications. M. A. F. reports support unrelated to this work from the NHLBI NIH. S. N. reports payments to their institution unrelated to this work from Gilead Sciences and AbbVie Pharmaceuticals; consulting fees paid to the author from Pardes Biosciences, Theratechnologies, and Silverback Therapeutics; participation on an Advisory Board for Vir Biotechnology, a Data Safety and Monitoring Board (DSMB) for Personal Health Insights, Inc, and an Event Adjudication Committee for Bristol-Myers Squibb/PRA; and 2866 stocks with options up to 5500 from Vir Biotechnology. I. O. reports grants or contracts from Merck unrelated to this work for Study 022 and Study 024 and a $4500 payment made to the author for consulting from Accordant (a CVS Caremark Company). F. J. P. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from ViiV, Gilead, Merck, and Janssen. P. C. T. reports grants or contracts unrelated to this work and paid to their institution from Merck. T. N. T. reports the following grants unrelated to this manuscript: Public Health Solutions (PHS) 21-BHO-364 Building Equity: Intervening Together for Health (BE InTo Health) for Black and/or Hispanic/Latino Older People with HIV (ages 50 and older) (project focuses on geriatric assessments in primary HIV care; sexual health is a minor focus; author is project director) and a PRIDE Special Research Project (SRP) award (R25HL105444-09; G. Jean-Louis, Principal Investigator [PI]) Adapting Cognitive Behavioral Therapy for Menopause-Associated Insomnia (CBT-MI) for Peri- and Post-menopausal Women with HIV (adapt and tailor CBT-MI for women with HIV with complex health needs and pilot test the feasibility of implementing this intervention within a primary HIV care setting; the author is PI). T. N. T. also reports consulting fees as a Qualitative Data Consultant for Dr. Anjali Sharma at Albert Einstein College of Medicine (project focuses on older adults with HIV and sexual health is a focus). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: The effectiveness of fluvoxamine to shorten symptom duration or prevent hospitalization among outpatients with mild to moderate symptomatic COVID-19 is unclear., Objective: To evaluate the efficacy of low-dose fluvoxamine (50 mg twice daily) for 10 days compared with placebo for the treatment of mild to moderate COVID-19 in the US., Design, Setting, and Participants: The ongoing Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-6) platform randomized clinical trial was designed to test repurposed medications in outpatients with mild to moderate COVID-19. A total of 1288 participants aged 30 years or older with test-confirmed SARS-CoV-2 infection and experiencing 2 or more symptoms of acute COVID-19 for 7 days or less were enrolled between August 6, 2021, and May 27, 2022, at 91 sites in the US., Interventions: Participants were randomized to receive 50 mg of fluvoxamine twice daily for 10 days or placebo., Main Outcomes and Measures: The primary outcome was time to sustained recovery (defined as the third day of 3 consecutive days without symptoms). There were 7 secondary outcomes, including a composite outcome of hospitalization, urgent care visit, emergency department visit, or death through day 28., Results: Among 1331 participants who were randomized (median age, 47 years [IQR, 38-57 years]; 57% were women; and 67% reported receiving ≥2 doses of a SARS-CoV-2 vaccine), 1288 completed the trial (674 in the fluvoxamine group and 614 in the placebo group). The median time to sustained recovery was 12 days (IQR, 11-14 days) in the fluvoxamine group and 13 days (IQR, 12-13 days) in the placebo group (hazard ratio [HR], 0.96 [95% credible interval, 0.86-1.06], posterior P = .21 for the probability of benefit [determined by an HR >1]). For the composite outcome, 26 participants (3.9%) in the fluvoxamine group were hospitalized, had an urgent care visit, had an emergency department visit, or died compared with 23 participants (3.8%) in the placebo group (HR, 1.1 [95% credible interval, 0.5-1.8], posterior P = .35 for the probability of benefit [determined by an HR <1]). One participant in the fluvoxamine group and 2 participants in the placebo group were hospitalized; no deaths occurred in either group. Adverse events were uncommon in both groups., Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with 50 mg of fluvoxamine twice daily for 10 days, compared with placebo, did not improve time to sustained recovery. These findings do not support the use of fluvoxamine at this dose and duration in patients with mild to moderate COVID-19., Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

Background: To evaluate the effect of cumulative human immunodeficiency virus (HIV)-1 viremia on aging-related multimorbidity among women with HIV (WWH), we analyzed data collected prospectively among women who achieved viral suppression after antiretroviral therapy (ART) initiation (1997-2019)., Methods: We included WWH with ≥2 plasma HIV-1 viral loads (VL) <200 copies/mL within a 2-year period (baseline) following self-reported ART use. Primary outcome was multimorbidity (≥2 nonacquired immune deficiency syndrome comorbidities [NACM] of 5 total assessed). The trapezoidal rule calculated viremia copy-years (VCY) as area-under-the-VL-curve. Cox proportional hazard models estimated the association of time-updated cumulative VCY with incident multimorbidity and with incidence of each NACM, adjusting for important covariates (eg, age, CD4 count, etc)., Results: Eight hundred six WWH contributed 6368 women-years, with median 12 (Q1-Q3, 7-23) VL per participant. At baseline, median age was 39 years, 56% were Black, and median CD4 was 534 cells/mm 3 . Median time-updated cumulative VCY was 5.4 (Q1-Q3, 4.7-6.9) log 10 copy-years/mL. Of 211 (26%) WWH who developed multimorbidity, 162 (77%) had incident hypertension, 133 (63%) had dyslipidemia, 60 (28%) had diabetes, 52 (25%) had cardiovascular disease, and 32 (15%) had kidney disease. Compared with WWH who had time-updated cumulative VCY <5 log 10 , the adjusted hazard ratio of multimorbidity was 1.99 (95% confidence interval [CI], 1.29-3.08) and 3.78 (95% CI, 2.17-6.58) for those with VCY 5-6.9 and ≥7 log 10 copy-years/mL, respectively ( P < .0001). Higher time-updated cumulative VCY increased the risk of each NACM., Conclusions: Among ART-treated WWH, greater cumulative viremia increased the risk of multimorbidity and of developing each NACM, and hence this may be a prognostically useful biomarker for NACM risk assessment in this population., Competing Interests: Potential conflicts of interest. M. A. F. reports support unrelated to this work from NIH/NHLBI. K. A. reports the following: funds from the NIH paid to institution supporting this and other work; and support attending meetings and/or travel in the form of grants paid to institution from the NIH. P. C. T. reports the following: funding from the NIH paid to institution supporting this work; grants or contracts unrelated to this work and paid to institution from Merck; and royalties or licenses paid to author from Up to Date. A. A. A. reports the following: funding for research provided to institution from Merck and Gilead; consulting fees paid to author from Merck and Gilead; a role as a member of Infectious Diseases Society of America Board of Directors, International AIDS Society Governing Council, and The Jackson Laboratory Board of Trustees; and participation on a Data Safety and Monitorig Board for ACTIV-6 and RECOVER-CT. F. J. P. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from ViiV, Gilead Sciences, and Janssen. S. K. reports the following: funds from the NIH paid to institution supporting this work; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Integritas Communications, LLC and Vindico Medical Education. S. N. reports the following: payments to institution unrelated to this work from Gilead Sciences and Abbvie Pharmaceuticals; consulting fees paid to author from Pardes Biosciences and Theratechnologies; serving as an advisor to Silverback Therapeutics without payment; participation on an Advisory Board for Vir Biotechnology, Data Safety and Monitoring Board for Personal Health Insights, Inc., and Event Adjudication Committee for Bristol-Meyers Squibb/PRA; and stocks and stock options from Vir Biotechnology. T. N. T. reports the following grants unrelated to this manuscript: Public Health Solutions 21-BHO-364 Building Equity: Intervening Together for Health (BE InTo Health) for “Black and/or Hispanic/Latino Older People with HIV (ages 50 and older) (project focuses on geriatric assessments in primary HIV care; sexual health is a minor focus; author is project director) and PRIDE Special Research Project Award (R25HL105444-09; G. Jean-Louis, Principal Investigator) Adapting Cognitive Behavioral Therapy for Menopause-Associated Insomnia (CBTMI) for Peri- and Post-menopausal Women with HIV (adapt and tailor CBTMI for women with HIV with complex health needs and pilot test the feasibility of implementing this intervention within a primary HIV care setting; author is PI). T. N. T. also reports consulting fees as Qualitative data Consultant for Dr. Anjali Sharma at Albert Einstein College of Medicine (project focuses on older adults with HIV and sexual health is a focus). I. O. reports grants or contracts from Merck supporting unrelated work., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

An older man from the mid-Southeastern USA presented with acute onset of fever, fatigue, and non-bloody diarrhoea. There was high suspicion for tick-borne illness given exposure history, clinical presentation and laboratory abnormalities. Despite prompt treatment with doxycycline, the patient clinically worsened. He was diagnosed with secondary hemophagocytic lymphohistiocytosis (HLH) due to Heartland virus (HRTV). This is the second documented case of secondary HLH due to HRTV, and the first in a relatively immunocompetent patient. Furthermore, though HRTV has been primarily concentrated in the Central USA, our case provides evidence of further geographic expansion of HRTV, mirroring the increased range of the Lone Star tick. Clinicians should consider HRTV when a patient with a clinical presentation consistent with tick-borne illness fails to respond to doxycycline. Furthermore, healthcare providers should be aware of the geographic expansion of HRTV and the potential of HRTV to lead to secondary HLH., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: The effectiveness of ivermectin to shorten symptom duration or prevent hospitalization among outpatients in the US with mild to moderate symptomatic COVID-19 is unknown., Objective: To evaluate the efficacy of ivermectin, 400 μg/kg, daily for 3 days compared with placebo for the treatment of early mild to moderate COVID-19., Design, Setting, and Participants: ACTIV-6, an ongoing, decentralized, double-blind, randomized, placebo-controlled platform trial, was designed to evaluate repurposed therapies in outpatients with mild to moderate COVID-19. A total of 1591 participants aged 30 years and older with confirmed COVID-19, experiencing 2 or more symptoms of acute infection for 7 days or less, were enrolled from June 23, 2021, through February 4, 2022, with follow-up data through May 31, 2022, at 93 sites in the US., Interventions: Participants were randomized to receive ivermectin, 400 μg/kg (n = 817), daily for 3 days or placebo (n = 774)., Main Outcomes and Measures: Time to sustained recovery, defined as at least 3 consecutive days without symptoms. There were 7 secondary outcomes, including a composite of hospitalization or death by day 28., Results: Among 1800 participants who were randomized (mean [SD] age, 48 [12] years; 932 women [58.6%]; 753 [47.3%] reported receiving at least 2 doses of a SARS-CoV-2 vaccine), 1591 completed the trial. The hazard ratio (HR) for improvement in time to recovery was 1.07 (95% credible interval [CrI], 0.96-1.17; posterior P value [HR >1] = .91). The median time to recovery was 12 days (IQR, 11-13) in the ivermectin group and 13 days (IQR, 12-14) in the placebo group. There were 10 hospitalizations or deaths in the ivermectin group and 9 in the placebo group (1.2% vs 1.2%; HR, 1.1 [95% CrI, 0.4-2.6]). The most common serious adverse events were COVID-19 pneumonia (ivermectin [n = 5]; placebo [n = 7]) and venous thromboembolism (ivermectin [n = 1]; placebo [n = 5])., Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with ivermectin, compared with placebo, did not significantly improve time to recovery. These findings do not support the use of ivermectin in patients with mild to moderate COVID-19., Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

Background: Adequate equitable recruitment of underrepresented groups in clinical research and trials is a national problem and remains a daunting challenge to translating research discoveries into effective healthcare practices. Engagement, recruitment, and retention (ER&R) training programs for Clinical Research Professionals (CRPs) often focus on policies and regulations. Although some training on the importance of diversity and inclusion in clinical research participation has recently been developed, there remains a need for training that couples critical equity, diversity, and inclusion (EDI) concepts with skill development in effective recruitment and retention strategies, regulations, and best practices., Approach and Methods: We developed the ER&R Certificate program as a holistic approach to provide Duke University CRPs the opportunity to build competency in gap areas and to increase comfort in championing equitable partnerships with clinical research participants. The thirteen core and elective courses include blended learning elements, such as e-learning and wiki journaling prompts, to facilitate meaningful discussions. Pre- and post-assessments administered to CRP program participants and their managers assessed program impact on CRP skills in ER&R tasks and comfort in equitable, diverse, and inclusive engagement of clinical research participants., Results and Discussion: Results from the first two cohorts indicate that CRPs perceived growth in their own comfort with program learning objectives, especially those centered on participant partnership and EDI principles, and most managers witnessed growth in competence and responsibility for ER&R-related tasks. Results suggest value in offering CRPs robust training programs that integrate EDI and ER&R training., (© The Author(s) 2022.)

Objectives: The coronavirus disease 2019 (COVID-19) pandemic has disproportionately afflicted vulnerable populations. Older adults, particularly residents of nursing facilities, represent a small percentage of the population but account for 40% of mortality from COVID-19 in the United States. Racial and ethnic minority individuals, particularly Black, Hispanic, and Indigenous Americans have experienced higher rates of infection and death than the White population. Although there has been an unprecedented explosion of clinical trials to examine potential therapies, participation by members of these vulnerable communities is crucial to obtaining data generalizable to those communities., Methods: We undertook an open-label, factorial randomized clinical trial examining hydroxychloroquine and/or azithromycin for hospitalized patients., Results: Of 53 screened patients, 11 (21%) were enrolled. Ten percent (3/31) of Black patients were enrolled, 33% (7/21) of White patients, and 50% (6/12) of Hispanic patients. Forty-seven percent (25/53) of patients declined participation despite eligibility; 58%(18/31) of Black patients declined participation. Forty percent (21/53) of screened patients were from a nursing facility and 10% (2/21) were enrolled. Enrolled patients had fewer comorbidities than nonenrolled patients: median modified Charlson comorbidity score 2.0 (interquartile range 0-2.5), versus 4.0 (interquartile range 2-6) for nonenrolled patients ( P = 0.006). The limitations of the study were the low participation rate and the multiple treatment trials concurrently recruiting at our institution., Conclusions: The high rate of nonparticipation in our trial of nursing facility residents and Black people emphasizes the concern that clinical trials for therapeutics may not target key populations with high mortality rates.

Background: Despite widespread availability of direct-acting antivirals including generic formulations, limited progress has been made in the global adoption of hepatitis C virus (HCV) treatment. Barriers to treatment scale-up include availability and access to diagnostic and monitoring tests, health-care infrastructure, and requirement for frequent visits during treatment., Methods: ACTG A5360 was a phase 4, open-label, single-arm trial across 38 sites in Brazil, South Africa, Thailand, Uganda, and the USA. Key inclusion criteria were age of 18 years or older, evidence of active HCV infection (HCV RNA >1000 IU/mL) and HCV treatment-naive; patients with compensated cirrhosis and HIV/HCV co-infection were included but their enrolment was capped. All participants received a fixed dose combination of oral sofosbuvir (400 mg) and velpatasvir (100 mg) once daily for 12 weeks. The minimal monitoring (MINMON) approach consisted of four components: (1) there was no pre-treatment genotyping; (2) the entire treatment course (84 tablets) was dispensed at entry; (3) there were no scheduled visits or laboratory monitoring; and (4) there were two points of remote contact, at week 4 for adherence and week 22, to schedule outcome assessment at week 24 (-2 weeks to +4 weeks). Participants who missed the week 24 window could return for a visit to assess treatment response any time before week 72. Unplanned visits for any reason were permissible before the week 24 visit. The primary efficacy outcome was sustained virological response (SVR), defined as HCV RNA less than the lower limit of quantification measured at least 22 weeks post-treatment initiation; the primary safety outcome was serious adverse events. The primary efficacy analysis included all participants who initiated treatment, using a missing=failure approach. The primary safety analysis included all participants who initiated treatment and had at least one post-treatment assessment. This trial is registered at ClinicalTrials.gov, NCT03512210., Findings: Between Oct 22, 2018, and July 19, 2019, 400 participants were enrolled across all 38 sites; 399 initiated treatment. At the SVR assessment visit, 355 (89%) of 397 participants reported taking 100% of the trial medication during the 12-week treatment period; two patients did not have any follow-up visits after the entry visit and were excluded from the safety analyses. Overall, 379 of the 399 who initiated treatment had an SVR (95·0%, 95% CI 92·4-96·7). 14 (4%) of 397 participants reported serious adverse events between treatment initiation and week 28; none were treatment related or led to treatment discontinuation or death. 15 (4%) of 399 participants had unplanned visits; none were related to treatment., Interpretation: In this diverse global population of people with HCV, the MINMON approach with sofosbuvir-velpatasvir treatment was safe and achieved SVR comparable to standard monitoring observed in real-world data. Coupled with innovative case finding strategies, this strategy could be crucial to the global HCV elimination agenda., Funding: US National Institutes of Health and Gilead Sciences., Competing Interests: Declaration of interests SSS declares grants and study products to the institution from Gilead Sciences related to the submitted work as well as grants and study product to the institution from Gilead Sciences and Abbott Laboratories not related to the submitted work, and honoraria from Gilead Sciences. GKR declares grants to his institution from Gilead Sciences, Citius Pharmaceuticals, Pfizer, Emergent Biosolutions, and Leonard Meron Bioscience, outside of the submitted work, and consulting fees from Teradyne Inc, Massachusetts Executive Office of Energy and Environmental Affairs, and Massachusetts Interscholastic Athletic Association. AS and NC are employees of Gilead Sciences and hold stock in the company. EPN declares honoraria from Gilead and AbbVie. DK declares honoraria and support to attend conferences from Gilead Sciences. JS declares speaker and advisory board honoraria from ViiV, Merck, Gilead, and AbbVie. PT declares consulting fees from ViiV and Merck. CB declares grants from Gilead Sciences paid to her institution, outside of the submitted work, and served as the chair of a data safety and monitoring board (DSMB) for GlaxoSmithKline. SN declares grants from Gilead Sciences and AbbVie to her institution, outside of the submitted work, personal consulting fees from BioMarin and Theratechnologies, support to attend meetings from Gilead Sciences, and has participated on DSMB for Bristol Myers Squibb, FHI 360, and Personal Health Insights Inc, and holds stock options in Vir Bio. DW declares grants to his institution from Gilead Sciences outside of the submitted work and discloses royalties/licenses from UpToDate. MS declares grants to his institution from Gilead Sciences, AbbVie, Janssen, and Assembly Biosciences outside of the submitted work, personal consulting fees from AbbVie, Gilead Sciences, Assembly Biosciences, Arbutus, Virion, Antios, and GlaxoSmithKline, has received honoraria from Practice Point Communication, DKB, and Clinical Care Options, and served on DSMBs and holds stock in Gilead Sciences and AbbVie. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) affects 25% of adults in the general population and is a disease spectrum ranging from steatosis to nonalcoholic steatohepatitis (NASH) to end-stage liver disease. NAFLD is an independent risk factor for cardiovascular disease, diabetes mellitus, and all-cause mortality, and NASH cirrhosis is a frequent indication for liver transplantation. In persons with human immunodeficiency virus (PWH), chronic liver disease is the second leading cause of non-human immunodeficiency virus-related mortality. Between 20% and 63% of PWH have NASH, and 14% to 63% have NASH with fibrosis. However, little is known about the optimal diagnostic strategies, risk factors for, and treatment of NAFLD in PWH. Here, we review current data on and identify knowledge gaps in the epidemiology, pathophysiology, diagnosis, and management of NAFLD in PWH and highlight priorities for research., (Copyright © 2022 AGA Institute. All rights reserved.)