Search

In 2023, the US Centers for Disease Control and Prevention recommended universal screening for hepatitis B virus (HBV); however, the proportion of US adults screened before implementing this recommendation is unknown. We analysed nationally representative data from the National Health Interview Survey (2013-2017) on self-reported HBV testing among noninstitutionalized US adults ≥18 years. We employed Poisson logistic regression to identify factors associated with self-reported testing, using a conceptual framework that included four overarching factors: sociodemographic characteristics, healthcare access, health-seeking behaviours and experiences, and access to internet-based health information. Among 149,628 survey respondents, the self-reported HBV testing rate was 27.2% (95% CI 26.2-28.7) and increased by 1.7% from 2013 to 2017 (p = .006). In adjusted analysis, health-seeking behaviours and experiences had the strongest associations of self-reported testing including a history of hepatitis (AOR 2.68, 95% CI 1.92-3.73), receipt of hepatitis B vaccination (AOR 5.11, 95% CI 4.61-5.68) and prior testing for hepatitis C (AOR 9.14, 95% CI 7.97-10.48) and HIV (AOR 2.69, 95% CI 2.44-2.97). Other factors associated with testing included being male (AOR 1.14, 95% CI 1.03-1.26), ages 30-44 years (AOR 1.37, 95% CI 1.17-1.61), 45-60 years (AOR 1.55, 95% CI 1.30-1.80) and ≥60 years (AOR 1.53, 95% CI 1.28-1.84), residence in the Western US region (AOR 1.23, 95% CI 1.06-1.43), and access to internet-based health information (AOR 1.32, 95% CI 1.18-1.47). Being Hispanic was associated with lower odds of testing (AOR 0.80, 95% CI 0.66-0.97). These findings may help guide optimal HBV screening in the universal testing era., (© 2024 The Author(s). Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

Substance use is associated with decreased antiretroviral therapy (ART) adherence among people with HIV (PWH). Adherence plays a significant role in mediating the negative effects of substance use on HIV suppression and is a principal modifiable patient-level factor in improving HIV suppression and reducing ART drug resistance. Understanding substance use and ART adherence, particularly with rapidly changing substance use epidemiology and ART regimens, is vital to improving HIV care. Among 10,557 PWH (2010-2021) from 8 academic clinical sites nationally we examined longitudinal associations of substance use severity and number of substances used (measured using AUDIT-C and modified ASSIST) with patient-reported ART adherence (visual analog scale). Alcohol (68% any use, 18% unhealthy use [AUDIT-C > 4 men, > 3 women]), marijuana (33%), and methamphetamine (9%) use were most reported. Polysubstance use was common (32%). Both higher severity substance use and higher number of substances used were associated with lower ART adherence. Severity of methamphetamine use had the strongest dose-response association with ART adherence (low severity [ASSIST 1-3]: -3.05%, 95% CI: -4.23%, -1.87%; moderate [ASSIST 4-26]: -6.20%, 95% CI: -7.08%, -5.33%; high [ASSIST > 26]: -10.77%, 95% CI: -12.76%, -8.78%). Severe substance use, especially methamphetamine, and higher number of illicit drugs used were associated with declines in adherence at levels that were likely clinically meaningful in the modern era of ART. Findings support integrating substance use care with HIV care and potential benefits of harm reduction strategies for improving adherence such as encouraging lower levels of substance use and fewer number of substances used., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Since its global reemergence in 2022, monkeypox (mpox) has demonstrated increased incidence and severity among people with human immunodeficiency virus (HIV [PWH]). Predictors of mpox diagnosis, vaccination, and outcomes among PWH are limited., Methods: We included PWH with primary care visits after 1 January 2022 at 9 US sites participating in the Centers for AIDS Research Network of Integrated Clinic Systems Network. We identified mpox diagnosed between 1 June 2022 and 31 May 2023, through a combination of polymerase chain reaction result, diagnosis code, and/or tecovirimat receipt. We examined validated clinical diagnoses, laboratory results, vaccine data, and patient reported outcomes. We evaluated relative risks (RR) of mpox diagnosis, hospitalization, tecovirimat treatment, and vaccine receipt., Findings: Among 19 777 PWH in care, 413 mpox cases (all male sex at birth) occurred (2.2 cases/100 person-years). Age <40 years, geographic region, Hispanic/Latine ethnicity, lack of antiretroviral therapy, detectable HIV viral load, and recent bacterial sexually transmitted infection predicted mpox diagnosis. PWH with CD4 200-349 cells/mm3 were most likely to be hospitalized (adjusted RR, 3.20; 95% confidence interval: 1.44-7.09) compared to CD4 ≥500, but half as likely as those with CD4 <200 to receive tecovirimat. Overall, smallpox/mpox vaccine effectiveness of ≥1 vaccine was 71% (adjusted RR, 0.29; 95% confidence interval: .14-.47) at preventing mpox, and 86% or better with CD4 ≥350 or HIV viral suppression. Non-Hispanic Black PWH were less likely to be vaccinated than other racial/ethnic identities., Interpretation: PWH not on antiretroviral therapy or with unsuppressed HIV were more likely to be diagnosed with, and hospitalized for, mpox. Mpox/smallpox vaccine effectiveness was high, inclusive of those with low CD4 count and HIV viremia., Competing Interests: Potential conflicts of interest. A. E. S. received funding from Merck as a clinical trial investigator for unrelated work. K. A. C. has been a medical advisory board member for Gilead Sciences and a workshop participant for Janssen outside of this work. R. B. I. is on a Scientific Advisory Board for AbbVie and received research funding from Enanta Pharmaceutics and Ascentage Pharma through her institution, unrelated to this work. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© 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.)

People with HIV (PWH) experience endothelial dysfunction (ED) that is aggravated by chronic inflammation and microbial translocation across a damaged gut barrier. Although this paradigm is well-described, downstream pathways that terminate in endothelial dysfunction are only partially understood. This study found increased expression of granulocyte macrophage colony stimulating factor (GM-CSF), toll-like receptor-4 (TLR4), and myeloperoxidase in the aortic endothelium of PWH compared to those without HIV. Bacteria-derived lipopolysaccharide (LPS) heightened glucose uptake and induced GM-CSF expression in primary human endothelial cells. Exposure to sodium-glucose cotransporter-2 (SGLT2) inhibitors reduced glucose uptake, GM-CSF release, and ED in LPS-activated endothelial cells ex vivo , and PWH treated with SGLT2 inhibitors for diabetes had significantly lower plasma GM-CSF levels than non-diabetic PWH not on this medication. The findings suggest that microbial products trigger glucose uptake and GM-CSF expression in the endothelium, contributing to localized inflammation in PWH. Modifying this altered state could offer therapeutic benefits., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Background: People with HIV (PWH) have higher risk of COVID-19 mortality. SARS-CoV-2 vaccination is highly effective among PWH, although vaccine hesitancy could limit the population-level impact., Setting: From February 2021 to April 2022, PWH from 8 sites in the Centers for AIDS Research Network of Integrated Clinical Systems completed a vaccine hesitancy instrument as part of routine care., Methods: Participants were defined as vaccine hesitant if they had not received the SARS-CoV-2 vaccine and would probably/definitely not receive it. We assessed factors associated with SARS-CoV-2 vaccine hesitancy using logistic regression adjusted for demographics, unsuppressed viral load (VL > 200 copies/mL), month, and time on ART; using inverse probability weighting for survey nonresponse., Results: Overall, 3288 PWH with a median age of 55 were included; 18% were female and 94% were virally suppressed. At the time of survey, 27% reported they had not received the SARS-CoV-2 vaccine, and 9% (n = 279) reported vaccine hesitancy. Factors associated with vaccine hesitancy included female sex (adjusted odds ratio [AOR] = 2.3; 95% confidence interval (CI): 1.6-3.2), Black vs. White race (AOR 1.7; 95% CI: 1.2 to 2.4), younger age (AOR 1.4; 95% CI: 1.2 to 1.5), and unsuppressed VL (AOR 1.9; 95% CI: 1.3 to 3.0)., Conclusion: Overall, over one-quarter of PWH in this multisite cohort were unvaccinated for SARS-CoV-2 when interviewed February 21-April 22. Vaccine hesitancy was reported by approximately 9% of PWH and was higher among women, Black PWH, younger PWH, PWH with unsuppressed VL, and those in the South/Midwest. Renewed efforts are needed to address concerns of PWH about vaccinations against COVID-19 as the pandemic evolves, and vaccines in general, given the potential for future pandemics., Competing Interests: M.A.S., D.V.G., M.O.J., K.A.C., K.H.M., A.E.S., H.M.C. and M.G. report funding from the NIH during conduct of the study. M.A.S., E.R.C., and K.H.M. report investigator-initiated grant support from Gilead Sciences. H.M.C. reports investigator-initiated grant support from ViiV. K.A.C. and K.H.M. have been a medical advisory board member for Gilead Sciences. D.V.G. reports personal fees from Gilead Sciences outside the submitted work. The remaining authors report no conflicts of interest. This work was funded by NIH/NIAID R01AI158013 (M.A.S., M.G., M.O.J.), NIH/NIAID R24AI067039 (K.A.C., M.O.J.), NIH/NIAID P30AI027763 (M.G.), NIH/NIMH P30MH062246 (M.O.J.), NIH/NIDA U01DA036935 (R.D.M.) NIH/NIDA R01DA047045 (H.M.C.) and NIH/NIDA 1K01DA056306 (J.P.J.) and NIH/NIAID K24 AI167805 (K.A.C)., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

To date, an affordable, effective treatment for an HIV-1 cure remains only a concept with most "latency reversal" agents (LRAs) lacking specificity for the latent HIV-1 reservoir and failing in early clinical trials. We assessed HIV-1 latency reversal using a multivalent HIV-1-derived virus-like particle (HLP) to treat samples from 32 people living with HIV-1 (PLWH) in Uganda, US and Canada who initiated combined antiretroviral therapy (cART) during chronic infection. Even after 5-20 years on stable cART, HLP could target CD4 + T cells harbouring latent HIV-1 reservoir resulting in 100-fold more HIV-1 release into culture supernatant than by common recall antigens, and 1000-fold more than by chemotherapeutic LRAs. HLP induced release of a divergent and replication-competent HIV-1 population from PLWH on cART. These findings suggest HLP provides a targeted approach to reactivate the majority of latent HIV-1 proviruses among individuals infected with HIV-1.

Background: Rising overdose deaths globally and increased social isolation during the coronavirus disease 2019 (COVID-19) pandemic may have disproportionately impacted people with human immunodeficiency virus (PWH) with substance use disorders (SUD). We examined trends in SUD risk among PWH before and after the COVID-19 shelter-in-place (SIP) mandate., Methods: Data were collected between 2018 and 2022 among PWH enrolled across 8 US sites in the Centers for AIDS Research Network of Integrated Clinical Systems cohort. We evaluated changes in moderate/high SUD risk after SIP using interrupted time series analyses., Results: There were 7126 participants, including 21 741 SUD assessments. The median age was 51 (interquartile range, 39-58) years; 12% identified as Hispanic or Latino/Latina, 46% Black/African American, and 46% White. Moderate/high SUD risk increased continuously after the pandemic's onset, with 43% (95% confidence interval [CI], 40%-46%) endorsing moderate/high SUD risk post-SIP, compared to 24% (95% CI, 22%-26%) pre-SIP ( P < .001). There were increases in the use of heroin, methamphetamine, and fentanyl, and decreases in prescription opioids and sedatives post-SIP. Further, there was a decrease in reported substance use treatment post-SIP compared to pre-SIP ( P = .025)., Conclusions: The rising prevalence of SUD through late 2022 could be related to an increase in isolation and reduced access to substance use and HIV treatment caused by disruptions due to COVID-19. A renewed investment in integrated substance use treatment is vital to address the combined epidemics of substance use and HIV following the COVID-19 pandemic and to support resilience in the face of future disruptions., Competing Interests: Potential conflicts of interest. M. A. S., D. V. G., M. O. J., K. A. C., K. H. M., H. M. C., and M. G. report funding from the NIH during conduct of the study. M. A. S., E. R. C., and K. H. M. report investigator-initiated grant support from Gilead Sciences. H. M. C. reports investigator-initiated grant support from ViiV. K. A. C. and K. H. M. have been medical advisory board members for Gilead Sciences. D. V. G. reports personal fees from Gilead Sciences outside the submitted work. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objective: The primary objective of the study was to assess the immunogenicity of an HIV-1 Gag conserved element DNA vaccine (p24CE DNA) in people with HIV (PWH) receiving suppressive antiretroviral therapy (ART)., Design: AIDS Clinical Trials Group A5369 was a phase I/IIa, randomized, double-blind, placebo-controlled study of PWH receiving ART with plasma HIV-1 RNA less than 50 copies/ml, current CD4 + T-cell counts greater than 500 cells/μl, and nadir CD4 + T-cell counts greater than 350 cells/μl., Methods: The study enrolled 45 participants randomized 2 : 1 : 1 to receive p24CE DNA vaccine at weeks 0 and 4, followed by p24CE DNA admixed with full-length p55 Gag DNA vaccine at weeks 12 and 24 (arm A); full-length p55 Gag DNA vaccine at weeks 0, 4, 12, and 24 (arm B); or placebo at weeks 0, 4, 12, and 24 (arm C). The active and placebo vaccines were administered by intramuscular electroporation., Results: There was a modest, but significantly greater increase in the number of conserved elements recognized by CD4 + and/or CD8 + T cells in arm A compared with arm C ( P  = 0.014). The percentage of participants with an increased number of conserved elements recognized by T cells was also highest in arm A (8/18, 44.4%) vs. arm C (0/10, 0.0%) ( P  = 0.025). There were no significant differences between treatment groups in the change in magnitude of responses to total conserved elements., Conclusion: A DNA-delivered HIV-1 Gag conserved element vaccine boosted by a combination of this vaccine with a full-length p55 Gag DNA vaccine induced a new conserved element-directed cellular immune response in approximately half the treated PWH on ART., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Sonographic diagnosis of spondylodiscitis is described in a 21-month-old girl who presented with altered gait. Spondylodiscitis, also referred to as discitis-osteomyelitis, is an infection of the intervertebral disc and adjacent vertebrae. The imaging modality of choice is spinal magnetic resonance imaging. Our case is the first description in the English language of the sonographic diagnosis of spondylodiscitis. Pediatric radiologists and sonographers should be acquainted with its features, for both incidental and intentional diagnosis., (© 2024. The Author(s).)

Alcohol use was associated with elevated COVID-19 risk in the general population. People with HIV (PWH) have high prevalences of alcohol use. To evaluate the effect of alcohol use on COVID-19 risks among PWH, we estimated the risk of COVID-19 diagnosis and COVID-19-related hospitalization among PWH in routine care at 8 HIV primary care centers that contributed data to the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort according to their alcohol use just prior to the COVID-19 pandemic. The CNICS data repository includes demographic characteristics, clinical diagnoses, and laboratory test results from electronic medical records and other sources. Alcohol use, substance use, and mental health symptoms were self-reported on tablet-based standardized surveys. Alcohol use was categorized according to standard, sex-specific Alcohol Use Disorder Identification Test-Consumption instrument cut-offs. We followed 5,496 PWH (79% male, 48% Black race, median age = 53 years) from March 1, 2020 to December 31, 2020. Relative to PWH with no baseline alcohol use, the adjusted hazard ratio (aHR) of COVID-19 diagnosis was 1.09 (95% confidence interval [CI]: 0.78, 1.51) for lower-risk drinking and 1.19 (95%CI: 0.81, 1.73) for unhealthy drinking. The aHR of COVID-19-related hospitalization was 0.82 (95%CI: 0.33, 1.99) for lower-risk drinking and 1.25 (95%CI: 0.50, 3.09) for unhealthy drinking. Results were not modified by recent cocaine or non-prescribed opioid use, depressive symptoms, or diagnoses of alcohol use disorder. The study suggested a slightly increased, but not statistically significant risk of COVID-19 diagnosis and hospitalization associated with unhealthy alcohol use., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We examined changes in the proportion of people with human immunodeficiency virus (PWH) with virologic suppression (VS) in a multisite US cohort before and since the coronavirus disease 2019 (COVID-19) pandemic. Overall, prior gains in VS slowed during COVID-19, with disproportionate impacts on Black PWH and PWH who inject drugs., Competing Interests: Potential conflicts of interest. M. A. S., D. V. G., M. O. J., K. A. C., K. H. M., A. E. S., M. G., and G. B. report institutional funding from the NIH during conduct of the study. M. A. S. and K. H. M. report investigator-initiated grant support from Gilead Sciences. E. R. C. reports institutional grants or contracts from Gilead Science for unrelated research and consulting fees from Theratechnologies for 1-time advisory board participation. K. A. C. and K. H. M. report serving as medical advisory board members for Gilead Sciences. K. A. C. reports payment or honoraria for educational events as a workshop participant from Janssen. D. V. G. reports personal consulting fees from Gilead Sciences outside the submitted work. H. M. C. reports institutional grants from the Agency for Healthcare Research and Quality and ViiV; consulting fees on patient-reported outcomes from ViiV (not relevant to this work); previous participation on a Gilead advisory board; and a previous, unpaid position on the NIH’s Office of AIDS Research Advisory Council. A. E. S. reports institutional funding grants for coronavirus disease 2019 therapy clinical trials from Vir Biotechnology; travel support from the Infectious Diseases Society of America Foundation; and participation on a data and safety monitoring board for Datura Trial with French National Agency for Research on AIDS and Viral Hepatitis/European and Developing Countries Clinical Trials Partnership. M. A. S. reports royalties or licenses for a chapter on human immunodeficiency virus Current Medical Diagnosis and Treatment chapter from McGraw Hill and payment or honoraria for role as editor for the Johns Hopkins eHIV Review. 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) 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.)

Background: Nonalcoholic fatty liver disease (NAFLD) and subsequent progression to fibrosis is increasingly prevalent in people with HIV (PWH). We used noninvasive methods to stratify risk and identify associated factors of advanced fibrosis in PWH with NAFLD., Methods: We conducted a retrospective study of PWH in our clinic from 2005 to 2022. We used liver imaging or biopsy reports to identify cases of hepatic steatosis after excluding specified etiologies. We used the Fibrosis-4 (FIB-4), NAFLD Fibrosis (NFS), and body mass index, aspartate transaminase/alanine transaminase ratio, and diabetes score scores to stratify fibrosis. We used logistic regression to identify factors associated with advanced fibrosis., Results: Among 3959 PWH in care, 1201 had available imaging or liver biopsies. After exclusions, 114 of 783 PWH had evidence of hepatic steatosis (14.6%). Most were male (71.1%), with a median age of 47 years, and median body mass index of 30.1 kg/m 2 . Approximately 24% had lean NAFLD (ie, body mass index < 25 kg/m 2 ). Based on the FIB-4 and NFS, 34 (29.8%) and 36 (31.6%) had advanced fibrosis, whereas 1 in 4 had low risk of fibrosis based on FIB-4, NFS, and BARD scores. In adjusted analysis using FIB-4, advanced fibrosis was associated with age > 45 years (adjusted odds ratio, 6.29; 95% confidence interval, 1.93-20.50) and hypoalbuminemia (adjusted odds ratio, 9.45; 95% confidence interval, 2.45-32.52) in addition to elevated transaminases and thrombocytopenia, whereas using the NFS did not identify associations with advanced fibrosis., Conclusions: We found 14.6% of PWH had NAFLD, with 1 in 3 having advanced fibrosis. Our study provides practical insights into fibrosis risk stratification in HIV primary care settings., Competing Interests: Potential conflicts of interest. No reported conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objective: Accurate estimation of kidney function is critical among persons with HIV (PWH) to avoid under-dosing of antiretroviral therapies and ensure timely referral for kidney transplantation. Existing estimation equations for kidney function include race, the appropriateness of which has been debated. Given advancements in understanding of race and the necessity of accuracy in kidney function estimation, this study aimed to examine whether race, or genetic factors, improved prediction of serum creatinine among PWH., Design: This cross-sectional study utilized data from the Center for AIDS Research Network of Integrated Clinical Systems cohort (2008-2018). The outcome was baseline serum creatinine., Methods: Ordinary least squares regression was used to examine whether inclusion of race or genetic factors [ apolipoprotein-L1 ( APOL1 ) variants and genetic African ancestry] improved serum creatinine prediction. A reduction in root mean squared error (RMSE) greater than 2% was a clinically relevant improvement in predictive ability., Results: There were 4183 PWH included. Among PWH whose serum creatinine was less than 1.7 mg/dl, race was significantly associated with serum creatinine ( β  = 0.06, SE = 0.01, P  < 0.001) but did not improve predictive ability. African ancestry and APOL1 variants similarly failed to improve predictive ability. Whereas, when serum creatinine was at least 1.7 mg/dl, inclusion of race reduced the RMSE by 2.1%, indicating improvement in predictive ability. APOL1 variants further improved predictive ability by reducing the RMSE by 2.9%., Conclusion: These data suggest that, among PWH, inclusion of race or genetic factors may only be warranted at higher serum creatinine levels. Work eliminating existing healthcare disparities while preserving the utility of estimating equations is needed., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The prevalence of substance use in people with HIV (PWH) in the United States is higher than in the general population and is an important driver of HIV-related outcomes. We sought to assess if previously identified genetic associations that contribute to substance use are also observed in a population of PWH., Methods: We performed genome-wide association studies (GWAS) of alcohol, smoking, and cannabis use phenotypes in a multi-ancestry population of 7,542 PWH from the Center for AIDS Research Network of Integrated Clinical Systems (CNICS). We conducted multi-ancestry GWAS for individuals of African (n = 3,748), Admixed American (n = 1,334), and European (n = 2,460) ancestry. Phenotype data were self-reported and collected using patient reported outcomes (PROs) and three questions from AUDIT-C, an alcohol screening tool. We analyzed nine phenotypes: 1) frequency of alcohol consumption, 2) typical number of drinks on a day when drinking alcohol, 3) frequency of five or more alcoholic drinks in a 30-day period, 4) smoking initiation, 5) smoking cessation, 6) cigarettes per day, 7) cannabis use initiation, 8) cannabis use cessation, 9) frequency of cannabis use during the previous 30 days. For each phenotype we considered a) variants previously identified as associated with a substance use trait and b) novel associations., Results: We observed evidence for effects of previously reported single nucleotide polymorphisms (SNPs) related to alcohol (rs1229984, p = 0.001), tobacco (rs11783093, p = 2.22E-4), and cannabis use (rs2875907, p = 0.005). We also report two novel loci (19p13.2, p = 1.3E-8; and 20p11.21, p = 2.1E-8) associated with cannabis use cessation., Conclusions: Our analyses contribute to understanding the genetic bases of substance use in a population with relatively higher rates of use compared to the general population., Competing Interests: KMJ was employed by Bristol-Myers Squibb during the drafting of this manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors report no conflicts of interest to disclose., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019 (COVID-19) that presents with varied clinical manifestations ranging from asymptomatic or mild infections and pneumonia to severe cases associated with cytokine storm, acute respiratory distress syndrome (ARDS), and even death. The underlying mechanisms contributing to these differences are unclear, although exacerbated inflammatory sequelae resulting from infection have been implicated. While advanced aging is a known risk factor, the precise immune parameters that determine the outcome of SARS-CoV-2 infection in elderly individuals are not understood. Here, we found aging-associated (age ≥61) intrinsic changes in T cell responses when compared to those from individuals aged ≤ 60, even among COVID-positive patients with mild symptoms. Specifically, when stimulated with SARS-CoV-2 peptides in vitro , peripheral blood mononuclear cell (PBMC) CD4 + and CD8 + T cells from individuals aged ≥61 showed a diminished capacity to produce IFN-γ and IL-1β. Although they did not have severe disease, aged individuals also showed a higher frequency of PD-1 + cells and significantly diminished IFN-γ/PD-1 ratios among T lymphocytes upon SARS-CoV-2 peptide stimulation. Impaired T cell IL-1β expression coincided with reduced NLRP3 levels in T lymphocytes. However, the expression of these molecules was not affected in the monocytes of individuals aged ≥61. Together, these data reveal SARS-CoV-2-specific CD4 + and CD8 + T-cell intrinsic cytokine alterations in the individuals older than 61 and may provide new insights into dysregulated COVID-directed immune responses in the elderly., Competing Interests: The 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 © 2023 Mahalingam, Jayaraman, Arunkumar, Dudley, Anthony, Shive, Jacobson and Pandiyan.)

Plasma vascular endothelial growth factor (VEGF) coreceptor neuropilin-1 (NRP-1) had the largest association with coronary plaque in the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) proteomics analysis. With little known about NRP-1 in people with human immunodeficiency virus (PWH), we explored its relation to other proteins in REPRIEVE and validated our findings through a Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) case-cohort study by assessing its relation to host factors and incident cardiovascular disease and cancer. Within REPRIEVE, NRP-1 was associated with proteins involved in angiogenesis, signal transduction, immunoregulation, and cell migration/adhesion. Within CNICS, NRP-1 was associated with key host factors, including older age and male sex. NRP-1 was associated with an increased hazard of multiple cancers but a decreased prostate cancer risk. Finally, NRP-1 was most strongly associated with mortality and type 2 myocardial infarction. These data suggest that NRP-1 is part of a clinically relevant immunoregulatory pathway related to multiple comorbidities in PWH. Clinical Trials Registration . NCT02344290., Competing Interests: Potential conflicts of interest. S. R. S. reports grant support through his institution from NIH/NIAID. M. V. Z. reports grant support through her institution from NIH/NIAID and Gilead Sciences, relevant to the conduct of the study, and grants from NIH/NIAID and NIH/NHLBI, outside the submitted work. M. T. reports grant support from NIH/NHLBI, American Heart Association, and Robert Wood Johnson Foundation, outside the submitted work. C. J. F. reports grant support through his institution from Gilead Sciences, ViiV Healthcare, GSK, Janssen, AbbVie, Merck, Amgen, and Cytodyn, outside the submitted work. J. J. E. reports grant support through his institution from Gilead Sciences, ViiV Healthcare, and Janssen and personal fees from ViiV Healthcare, Merck, and Gilead Sciences, outside the submitted work. J. M. J. reports grant support through his institution from NIH/NIAID. K. H. M. reports unrestricted research grants to his institution from Gilead Sciences, Merck, and ViiV Healthcare and has served on scientific advisory boards for Gilead and Merck, outside the submitted work. C. M. reports institutional research support by Lilly and honoraria from ViiV Healthcare and Gilead Sciences for advisory board membership, outside the submitted work. R. D. M. reports grant support to his institution from NIH/NIAID and NIH/National Institute on Drug Abuse (NIDA) relevant to the conduct of the study. T. U. reports grant support from NIH/NHLBI and Kowa Pharmaceuticals during the conduct of the study and grants from NIH/NIAID and NIH/National Institute on Aging (NIA), outside the submitted work. M. S. S. reports grant support from NIH/NIAID relevant to the conduct of the study. J. A. A. reports institutional research support for clinical trials from Emergent Biosolutions, Frontier Technologies, Gilead Sciences, GlaxoSmithKline, Janssen, Macrogenics, Merck, Pfizer, Regeneron, and ViiV Healthcare; personal fees for advisory boards from GlaxoSmithKline and Merck; and data and safety monitoring board membership for Kintor Pharmaceuticals, outside the submitted work. J. S. C. reports consulting fees from Merck and Co and Resvirlogix. J. A. C. D. reports through to his institution from NIH/NHLBI, outside the submitted work. H. J. R. reports grants from NIH/NIAID and NIH/NHLBI during the conduct of the study, as well as grants from NIH/NIAID, NIH/NHLBI, NIH/National Institute of Diabetes and Digestive and Kidney Diseases, and NIH/NIA, outside the submitted work. H. M. C. reports grants from NIH/NHLBI during the conduct of this study; grants through her institution from NIH/NIDA, the Agency for Healthcare Research and Quality, and ViiV Healthcare; and advisory board membership for Gilead, outside the submitted work. P. W. H. reports grant support through his institution from Gilead Sciences; drug donation for an NIH-sponsored clinical trial he is leading from Merck; and personal fees from ViiV Healthcare, Gilead Sciences, and Merck. S. K. G. reports grant support through his institution from Kowa Pharmaceuticals America, Gilead Sciences, and ViiV Healthcare for the conduct of the study; and grants from Theratechnologies and Navidea, personal fees from Theratechnologies and ViiV, and service on the scientific advisory board of Marathon Asset Management, all outside the submitted work. All other authors report no potential conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: HIV infection leads to endothelial activation, promoting platelet adhesion, and accelerating atherosclerosis. Our goal was to determine whether biomarkers of endothelial activation and hemostasis/thrombosis were elevated in people with treated HIV (PWH) before myocardial infarction (MI)., Methods: In a case-control study nested within the CFAR Network of Integrated Clinical Systems (CNICS) cohort, we compared 69 adjudicated cases with type 1 MI with 138 controls matched for antiretroviral therapy regimen. We measured angiopoietin-1, angiopoietin-2 (ANG-2), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), von Willebrand factor, C-reactive protein (CRP), interleukin-6 (IL-6), plasminogen activation inhibitor-1, P-selectin, serum amyloid-A, soluble CD14, and apolipoprotein A1 in stored plasma. Conditional logistic regression identified associations with subsequent MI, with and without adjustment for Atherosclerotic Cardiovascular Disease (ASCVD) and Veterans Aging Cohort Study (VACS) scores., Results: Higher IL-6 was associated with MI after adjustment for ASCVD score (adjusted odds ratio [AOR] 1.51, 95% confidence interval [95% CI]: 1.05 to 2.17 per standard-deviation-scaled log 2 increment). In a separate model adjusting for VACS score, higher ANG-2 (AOR 1.49, 95% CI: 1.04 to 2.14), higher CRP (AOR 1.45, 95% CI: 1.06 to 2.00), and higher IL-6 (AOR 1.68, 95% CI: 1.17 to 2.41) were associated with MI. In a sensitivity analysis excluding PWH with viral load ≥400 copies/mL, higher IL-6 remained associated with MI after adjustment for ASCVD score and after adjustment for VACS score., Conclusions: Among PWH, higher levels of plasma IL-6, CRP, and ANG-2 predict subsequent type 1 MI, independent of conventional risk scores. IL-6 had the most consistent associations with type 1 MI, regardless of viral load suppression., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: People with human immunodeficiency virus (PWH) are at increased risk for comorbidities, and plasma interleukin 6 (IL-6) levels are among the most robust predictors of these outcomes. Tocilizumab (TCZ) blocks the receptor for IL-6, inhibiting functions of this cytokine., Methods: This was a 40-week, placebo-controlled, crossover trial (NCT02049437) where PWH on stable antiretroviral therapy (ART) were randomized to receive 3 monthly doses of TCZ or matching placebo intravenously. Following a 10-week treatment period and a 12-week washout, participants were switched to the opposite treatment. The primary endpoints were safety and posttreatment levels of C-reactive protein (CRP) and CD4+ T-cell cycling. Secondary endpoints included changes in inflammatory indices and lipid levels., Results: There were 9 treatment-related toxicities of grade 2 or greater during TCZ administration (mostly neutropenia) and 2 during placebo administration. Thirty-one of 34 participants completed the study and were included in a modified intent-to-treat analysis. TCZ reduced levels of CRP (median decrease, 1819.9 ng/mL, P < .0001; effect size, 0.87) and reduced inflammatory markers in PWH, including D-dimer, soluble CD14, and tumor necrosis factor receptors. T-cell cycling tended to decrease in all maturation subsets after TCZ administration, but was only significant among naive CD4 T cells. Lipid levels, including lipid classes that have been related to cardiovascular disease risk, increased during TCZ treatment., Conclusions: TCZ is safe and decreases inflammation in PWH; IL-6 is a key driver of the inflammatory environment that predicts morbidity and mortality in ART-treated PWH. The clinical significance of lipid elevations during TCZ treatment requires further study. Clinical Trials Registration. NCT02049437., Competing Interests: Potential conflicts of interest. N. T. F. reports grants or contracts from the NIH and Gilead, and has served as a consultant for Gilead. C. T. L. has received research grants from Gilead Sciences and Medtronic Foundation and has served on an advisory board for Esperion Therapeutics. A. L. has served as a consultant to Abbott. G. A. M. reports grants or contracts from Pfizer, Astellas, Roche, Genentech, Redhill, Cognivue, Vanda, and Tetraphase; served as scientific advisor and consultant for Gilead, Merck, Janssen, Theratechnologies, and GSK/ViiV; and received payment for expert testimony from Gilead. M. M. L. has received competitive grant funding from Gilead and has served as consultant for Merck. C. F. reports serving as a paid consultant for Gilead, Janssen, Merck, American Gene Technologies, Thera Technologies, Shinogi, and ViiV Healthcare; payment or honoraria for speaking engagements from International AIDS Society–USA and Virology Education; payment for expert testimony from Gilead Sciences; 3 issued or pending patents related to long-acting delivery of antiretroviral drugs; and participation on the scientific advisory board for Navigen Corporation and data and safety monitoring board (DSMB) or advisory board for Watermark, LLC. L. H. C. reports consulting fees from Sanofi Genzyme, Genetech, GSK, BMS, Galvani, and UCB; payment or honoraria for nonbranded speaking engagements from Sanofi and AstraZeneca. E. V. C. reports participation on a Melinta Pharmaceuticals data and safety monitoring board for a pediatric antibacterial study. D. D. A. reports a grant from the Department of Defense (grant number 12935153). C. L. S. reports a VA Merit Award and VA Career Development Award. B. R. has received payment or honoraria from Gilead Sciences, ViiV Healthcare, and Theratechnologies (paid to author). 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) 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.)

Background: Randomized controlled trials (RCTs) from low- and middle-income settings suggested that early initiation of antiretroviral therapy (ART) leads to higher mortality rates among people with HIV (PWH) who present with cryptococcal meningitis (CM). There is limited information about the impact of ART timing on mortality rates in similar people in high-income settings., Methods: Data on ART-naive PWH with CM diagnosed from 1994 to 2012 from Europe/North America were pooled from the COHERE, NA-ACCORD, and CNICS HIV cohort collaborations. Follow-up was considered to span from the date of CM diagnosis to earliest of the following: death, last follow-up, or 6 months. We used marginal structural models to mimic an RCT comparing the effects of early (within 14 days of CM) and late (14-56 days after CM) ART on all-cause mortality, adjusting for potential confounders., Results: Of 190 participants identified, 33 (17%) died within 6 months. At CM diagnosis, their median age (interquartile range) was 38 (33-44) years; the median CD4+ T-cell count, 19/μL (10-56/μL); and median HIV viral load, 5.3 (4.9-5.6) log10 copies/mL. Most participants (n = 157 [83%]) were male, and 145 (76%) started ART. Mimicking an RCT, with 190 people in each group, there were 13 deaths among participants with an early ART regimen and 20 deaths among those with a late ART regimen. The crude and adjusted hazard ratios comparing late with early ART were 1.28 (95% confidence interval, .64-2.56) and 1.40 (.66-2.95), respectively., Conclusions: We found little evidence that early ART was associated with higher mortality rates among PWH presenting with CM in high-income settings, although confidence intervals were wide., Competing Interests: Potential conflicts of interest. J. M. M. has received consulting honoraria and/or research grants from AbbVie, Angelini, Contrafect, Cubist, Genentech, Gilead Sciences, Jansen, Medtronic, MSD, Novartis, Pfizer, and ViiV Healthcare, outside the submitted work, as well as consulting fees from Lysovant. L. E. C. has stock or stock options and is an employee of AbbVie. C. Sabin reports payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing, or educational events from Gilead Sciences and ViiV Healthcare (payments to the author for preparation of educational materials); participation on a data and safety monitoring board (DSMB) or advisory board for Gilead Sciences and ViiV Healthcare (paid to the author); and service as vice chair of the British HIV Association. H. S. reports consulting fees from ViiV and MSD and payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing or educational events from MSD, ViiV, and Gilead. P. R., through his institution, has received independent scientific grant support from Gilead Sciences, Janssen Pharmaceuticals, Merck, and ViiV Healthcare and has served on scientific advisory boards for Gilead Sciences, ViiV Healthcare, and Merck, honoraria for which were all paid to his institution (all support outside the submitted work). V. B. reports support for attending meetings and/or travel from Gilead and Janssen and has stock or stock options in DWS Biotech LC Fond (private self-investment; no payments to author or institution received from any third party). F. V. received research or teaching grants from Gilead Sciences, ViiV Healthcare, and MSD, unrelated to the submitted work. N. O. reports grants or contracts from Simonsens Fond (paid to the institution). A. M. reports travel support, lecture fees, honorarium and consultancy fees from ViiV, Gilead, Eiland, and Bonnin, all outside the submitted work. L. W. reports grants or contracts from ANRS MIE. R. T. reports a research grant from Gilead Science; payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing, or educational events from Gilead Science (payment for lectures), Janssen (payment for lectures), and ViiV Healthcare (payment for lectures); support for travel from Gilead Science and Janssen; and participation on an advisory board for Gilead Science. A. D. M. reports consulting fees from ViiV, Gilead, and Janssen (paid to the author); payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing or educational events from Gilead and ViiV (paid to the author); and participation on a DSMB or advisory board for Janssen, Gilead, and ViiV (payment to the author). C. M. reports research grant from Gilead; payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing, or educational events from ViiV and Gilead; and participation on a DSMB or advisory board for Corimuno, Gilead, ViiV, Janssen, and MSD. H. F.’s institution received educational grants from AbbVie, ViiV, Gilead, MSD, Sandoz, and Pfizer, all outside the submitted work. M. S. S. reports research grants from Gilead Sciences and ViiV Healthcare (paid to the institution); payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing; or educational events from IAS-USA (not-for-profit organization); serving on the DSMB for the I-Spy COVID trial; and serving as board chair for IAS-USA. H. M. C. reports grants or contracts from the National Institutes of Health (NIH), the Agency for Healthcare Research and Quality, and ViiV (paid to institution); consulting fees from ViiV (pending); and participation on the Office of AIDS Research Scientific Advisory Board. J. J. E. reports grants or contracts from ViiV Healthcare, Gilead Sciences, and Janssen; consulting fees from Merck, ViiV Healthcare, Gilead Science, and Janssen; and leadership or fiduciary roles in other boards, societies, committees, or advocacy groups for the IAS-USA antiretroviral therapy guidelines committee. K. N. A. reports grants or contracts from the NIH (paid to institution), royalties or licenses from Coursera, consulting fees from the NIH (for the All of US Study), and payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing, or educational events for DC HIV Cohort (author served on the DC HIV Cohort’s external advisory board). M. J. G. reports consulting fees from Merck, Gilead, and ViiV (with occasional honoraria for ad hoc membership on human immunodeficiency virus advisory boards). H. C. B., in the 36 months before the submission of the current manuscript, has received grants, support for traveling, consultancy fees, and honoraria from Gilead, BMS, ViiV Healthcare, Roche, and Pfizer, unrelated to the current work. He served as the president of the Association Contre le HIV et Autres Infections Transmissibles until June 2022; in this function he received support for the Swiss HIV Cohort Study from ViiV Healthcare, Gilead, BMS, and MSD. 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) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Premature aging has been identified as a global risk factor for cancer. Causes of premature aging are multifactorial, including inflammation, infection, chronic stress, and lifestyle factors., Method: We evaluated whether premature aging in people living with HIV (PLWH) was associated with antiretroviral therapy (ART) or the diagnosis of cancer. We used well-established DNA methylation patterns to assess premature aging, using Horvath et al., in individuals with HIV located in Cleveland, Ohio and compared these to standardized datasets of US historical blood samples. Some of the PLWH developed cancer over time., Results: We found that DNA methylation analysis identified accelerated aging in PLWH whereas ART therapy mitigated the advancement of DNA methylation age. A variety of cancers were observed in this population, but a cancer diagnosis was not significantly associated with more advanced DNA methylation age., Conclusion: We find that the age acceleration detected in PLWH is mitigated by ART therapy and is not further accelerated by a diagnosis of cancer., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: HIV subtypes B and C together account for around 60% of HIV-1 cases worldwide. We evaluated the safety and immunogenicity of a subtype B DNA vaccine prime followed by a subtype C viral vector boost., Methods: Fourteen healthy adults received DNA plasmid encoding HIV-1 subtype B nef/tat/vif and env (n = 11) or placebo (n = 3) intramuscularly (IM) via electroporation (EP) at 0, 1, and 3 months, followed by IM injection of recombinant vesicular stomatitis virus encoding subtype C Env or placebo at 6 and 9 months. Participants were assessed for safety, tolerability of EP, and Env-specific T-cell and antibody responses., Results: EP was generally well tolerated, although some device-related adverse events did occur, and vaccine reactogenicity was mild to moderate. The vaccine stimulated Env-specific CD4 + T-cell responses in greater than 80% of recipients, and CD8 + T-cell responses in 30%. Subtype C Env-specific IgG binding antibodies (bAb) were elicited in all vaccine recipients, and antibody-dependent cell-mediated cytotoxicity (ADCC) responses to vaccine-matched subtype C targets in 80%. Negligible V1/V2 and neutralizing antibody (nAb) responses were detected., Conclusions: This prime/boost regimen was safe and tolerable, with some device-related events, and immunogenic. Although immunogenicity missed targets for an HIV vaccine, the DNA/rVSV platform may be useful for other applications., Clinicaltrials: gov: NCT02654080., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The following authors declare no conflicts of interest: MT, MDM, JE, DCM, JMJ, ME, DKC, GJW, GDT, GF, SK, ER, ME, TL, RX, SL. MA and MP are employed by NIAID but had no role in the funding decisions or grant oversight. DH is a full-time employee of Ichor Medical Systems, Inc. and receives a salary and equity for this work. SCDR reports funding from NIH, Bill & Melinda Gates Foundation for the work. IF gets research support from Moderna, Janssen, Pfizer and Sanofi, and is a consultant for Gilead, GlaxoSmithKline and Merck., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

HIV post-treatment controllers (PTCs) are rare individuals who maintain low levels of viremia after stopping antiretroviral therapy (ART). Understanding the mechanisms of HIV post-treatment control will inform development of strategies aiming at achieving HIV functional cure. In this study, we evaluated 22 PTCs from 8 AIDS Clinical Trials Group (ACTG) analytical treatment interruption (ATI) studies who maintained viral loads ≤400 copies/mL for ≥24 wk. There were no significant differences in demographics or frequency of protective and susceptible human leukocyte antigen (HLA) alleles between PTCs and post-treatment noncontrollers (NCs, n = 37). Unlike NCs, PTCs demonstrated a stable HIV reservoir measured by cell-associated RNA (CA-RNA) and intact proviral DNA assay (IPDA) during analytical treatment interruption (ATI). Immunologically, PTCs demonstrated significantly lower CD4 + and CD8 + T cell activation, lower CD4 + T cell exhaustion, and more robust Gag-specific CD4 + T cell responses and natural killer (NK) cell responses. Sparse partial least squares discriminant analysis (sPLS-DA) identified a set of features enriched in PTCs, including a higher CD4 + T cell% and CD4 + /CD8 + ratio, more functional NK cells, and a lower CD4 + T cell exhaustion level. These results provide insights into the key viral reservoir features and immunological profiles for HIV PTCs and have implications for future studies evaluating interventions to achieve an HIV functional cure.

Chronic hepatitis C can lead to cirrhosis and hepatocellular carcinoma. We studied the safety and immunogenicity of a novel therapeutic hepatitis C virus (HCV) genotype 1a/1b consensus DNA vaccine, INO-8000, encoding HCV NS3, NS4A, NS4B, and NS5A proteins alone or co-administered with DNA-encoding IL12 (INO-9012), a human cytokine that stimulates cellular immune function, in individuals with chronic hepatitis C. This was a phase I, multisite dose-escalation trial with an expansion cohort evaluating doses of 0, 0.3, 1.0, and 3.0 mg of INO-9012 (IL12 DNA) as an addition to 6.0 mg of (INO-8000; HCV DNA vaccine). Vaccines were administered by intramuscular injection followed by electroporation at study entry and at weeks 4, 12, and 24. HCV-specific CD4+ and CD8+ T-cell immune responses were measured by IFNγ ELISpot and flow cytometry-based assays. Transient, mild-to-moderate injection site reactions unrelated to IL12 DNA dose were common. Increases in HCV-specific IFNγ production occurred in 15/20 (75%) participants. Increases in the frequency of HCV-specific CD4+ and CD8+ T cells occurred at all dose levels, with the greatest increases seen at 1.0 mg of INO-9012. HCV-specific CD8+ and CD4+ T-cell activities increased in 16/18 (89%) and 14/17 (82%) participants with available data, respectively. The vaccine regimen was safe and induced HCV-specific CD4+ and CD8+ cellular immune responses of modest magnitude in most HCV-infected participants. The addition of 1.0 mg of IL12 DNA provided the best enhancement of immune responses. The vaccine regimen had little effect on controlling HCV viremia., Prevention Relevance: The administration of IL12 DNA along with a hepatitis C viral antigen DNA vaccine enhanced the HCV-specific immune responses induced by the vaccine in individuals with chronic hepatitis C, an important cause of hepatocellular carcinoma. IL12 could be an effective adjuvant in vaccines targeting HCV and other oncogenic viruses., (©2022 American Association for Cancer Research.)

Background: Vaporized nicotine (VN) use is increasing among people with HIV (PWH). We examined demographics, patterns of use, depression, and panic symptoms associated with VN and combustible cigarette (CC) use among PWH., Methods: We analyzed VN use among PWH in care at 7 US sites. PWH completed a set of patient-reported outcomes, including substance use and mental health. We categorized VN use as never vs. ever with the frequency of use (days/month) and CC use as never, former, or current. We used relative risk regression to associate VN and CC use, depression, and panic symptoms. Linear regression estimated each relationship with VN frequency. Models were adjusted for demographics., Results: Among 7431 PWH, 812 (11%) reported ever-using VN, and 264 (4%) reported daily use. Half (51%) of VN users concurrently used CC. VN users were more likely than those without use to be younger, to be White, and to report ever-using CC. PWH reporting former CC use reported ≥8.5 more days per month of VN use compared with never CC use [95% confidence interval (95% CI): 5.5 to 11.5 days/month] or current CC use (95% CI: 6.6 to 10.5 days/month). Depression (relative risk: 1.20 [95% CI: 1.02 to 1.42]) and panic disorder (1.71 [95% CI: 1.43 to 2.05]) were more common among PWH ever-using VN. Depression was common among PWH using VN (27%) and CC (22%), as was panic disorder (21% for VN and 16% for CC)., Conclusion: Our study elucidated demographic associations with VN use among PWH, revealed the overlap of VN and CC use, and associations with depression/panic symptoms, suggesting roles of VN in self-medication and CC substitution, warranting further longitudinal/qualitative research., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background : The high soft-tissue contrast of magnetic resonance imaging (MRI) makes it useful for evaluation of hand injuries, but its limitations include cost, imaging artifacts, and patient claustrophobia. Ultrasound is readily available, fast, noninvasive, and radiation free, but its utility for the evaluation of hand soft-tissue injury and pathology is less well known. Purpose : We sought to examine the accuracy of ultrasound for the evaluation of hand injury at a single institution. Methods : We queried a radiology information system for ultrasound cases between 2014 and 2020 at a tertiary care institution using the keyword "hand" and injury terms. We performed a retrospective chart review of cases found according to the type of injury detected on ultrasound. To evaluate the diagnostic accuracy of ultrasound in hand injury and pathology, we recorded postimaging clinical diagnoses and surgical findings. Results : We found 154 patients who underwent ultrasound for hand injuries and had confirmed surgical diagnosis and/or robust clinical follow-up. Tendon injury was the most commonly diagnosed condition on ultrasound (70/154); others detected were retained foreign body (31), mass (21), ligamentous injury (9), pulley injury (8), nerve injury (11), and traumatic arthropathy (4). Ultrasound correctly characterized hand injury in 150/154 cases (97.4%) based on surgical and/or clinical follow-up. Ultrasound failed to diagnose 3 cases of partial tendon tear and 1 case of digital nerve injury. Conclusion : In this retrospective, single-institution review, ultrasound was found to be highly accurate in the detection of soft tissue hand injury and pathology, demonstrating a high concordance rate with surgical and clinical findings. Further study is warranted., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Posttreatment controllers (PTCs) are rare HIV-infected individuals who can limit viral rebound after antiretroviral therapy interruption (ATI), but the mechanisms of this remain unclear. To investigate these mechanisms, we quantified various HIV RNA transcripts (via reverse transcription droplet digital PCR [RT-ddPCR]) and cellular transcriptomes (via RNA-seq) in blood cells from PTCs and noncontrollers (NCs) before and two time points after ATI. HIV transcription initiation did not significantly increase after ATI in PTCs or in NCs, whereas completed HIV transcripts increased at early ATI in both groups and multiply-spliced HIV transcripts increased only in NCs. Compared to NCs, PTCs showed lower levels of HIV DNA, more cell-associated HIV transcripts per total RNA at all times, no increase in multiply-spliced HIV RNA at early or late ATI, and a reduction in the ratio of completed/elongated HIV RNA after early ATI. NCs expressed higher levels of the IL-7 pathway before ATI and expressed higher levels of multiple cytokine, inflammation, HIV transcription, and cell death pathways after ATI. Compared to the baseline, the NCs upregulated interferon and cytokine (especially TNF) pathways during early and late ATI, whereas PTCs upregulated interferon and p53 pathways only at early ATI and downregulated gene translation during early and late ATI. In NCs, viral rebound after ATI is associated with increases in HIV transcriptional completion and splicing, rather than initiation. Differences in HIV and cellular transcription may contribute to posttreatment control, including an early limitation of spliced HIV RNA, a delayed reduction in completed HIV transcripts, and the differential expression of the IL-7, p53, and TNF pathways. IMPORTANCE The findings presented here provide new insights into how HIV and cellular gene expression change after stopping ART in both noncontrollers and posttreatment controllers. Posttreatment control is associated with an early ability to limit increases in multiply-spliced HIV RNA, a delayed (and presumably immune-mediated) ability to reverse an initial rise in processive/completed HIV transcripts, and multiple differences in cellular gene expression pathways. These differences may represent correlates or mechanisms of posttreatment control and may provide insight into the development and/or monitoring of therapeutic strategies that are aimed at a functional HIV cure.

HIV-1 establishes a life-long reservoir of virally infected cells which cannot be eliminated by antiretroviral therapy (ART). Here, we demonstrate a markedly altered viral reservoir profile of long-term ART-treated individuals, characterized by large clones of intact proviruses preferentially integrated in heterochromatin locations, most prominently in centromeric satellite/micro-satellite DNA. Longitudinal evaluations suggested that this specific reservoir configuration results from selection processes that promote the persistence of intact proviruses in repressive chromatin positions, while proviruses in permissive chromosomal locations are more likely to be eliminated. A bias toward chromosomal integration sites in heterochromatin locations was also observed for intact proviruses in study participants who maintained viral control after discontinuation of antiretroviral therapy. Together, these results raise the possibility that antiviral selection mechanisms during long-term ART may induce an HIV-1 reservoir structure with features of deep latency and, possibly, more limited abilities to drive rebound viremia upon treatment interruptions., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Direct-acting antivirals (DAA) are highly effective against hepatitis C virus (HCV) infection among persons with human immunodeficiency virus (PWH). However, alcohol use post-DAA treatment poses a continued threat to the liver. Whether the focus on liver health alone during HCV treatment can impact alcohol consumption is unclear. Therefore, we examined the change in alcohol use among HCV-coinfected PWH who received DAA therapy by non-addiction medical providers., Methods: In our longitudinal clinical cohort study, we identified HCV-coinfected PWH who received interferon-free DAA therapy between January 2014 and June 2019 in the Centers for AIDS Research Network of Integrated Clinical Systems. The Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) was the alcohol screening instrument. We used mixed-effects logistic regression models to estimate the longitudinal change in alcohol use upon DAA therapy., Results: Among 738 HCV-coinfected PWH, 339 (46 %) reported any alcohol use at the end of HCV treatment, including 113 (15 %) with high-risk use (i.e., AUDIT-C ≥3 for women, ≥4 for men). Concurrently, 280 (38 %) PWH noted active drug use, and 357 (48 %) were currently smoking. We observed no changes in the odds of any alcohol or high-risk alcohol use over time with DAA therapy. Findings were similar in the PWH subgroup with a history of alcohol use before DAA treatment., Conclusions: For PWH with HCV, alcohol use did not change following interferon-free DAA treatment by non-addiction medical providers. Thus, clinicians should consider integrating targeted alcohol use interventions into HCV care to motivate reduced alcohol consumption and safeguard future liver health., Competing Interests: Conflict of interest disclosures Po-Hung Chen reports serving as a Medical Safety Officer for the Non-Alcoholic Steatohepatitis Clinical Research Network, a Steering Committee member for the Alcohol-associated Liver Disease Special Interest Group of the American Association for the Study of Liver Diseases (AASLD), and a Practice Guidelines Committee member of AASLD. Edward R. Cachay reports receiving Gilead Sciences Unrestricted Research Grant, Merck Sharp & Dohme Unrestricted Research Grant, and consulting for Thera Technologies. H. Nina Kim reports receiving a grant from Gilead Sciences., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Women represent a meaningful proportion of new HIV diagnoses, with Black women comprising 58% of new diagnoses among women. As HIV infection also increases risk of chronic kidney disease (CKD), understanding CKD risk among women with HIV (WWH), particularly Black women, is critical., Methods: In this longitudinal cohort study of people with HIV (PWH) enrolled in CFAR Network of Integrated Clinical Systems (CNICS), a multicentre study comprised of eight academic medical centres across the United States from Jan 01, 1996 and Nov 01, 2019, adult PWH were excluded if they had ≤2 serum creatinine measurements, developed CKD prior to enrollment, or identified as intersex or transgendered, leaving a final cohort of 33,998 PWH. The outcome was CKD development, defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1·73 m 2 calculated using the CKD-EPI equation, for ≥90 days with no intervening higher values., Findings: Adjusting for demographic and clinical characteristics, WWH were 61% more likely to develop CKD than men (adjusted hazard ratio [aHR]: 1·61, 95% CI: 1·46-1·78, p<0·001). This difference persisted after further adjustment for APOL1 risk variants (aHR female sex: 1·92, 95% CI: 1·63-2·26, p<0·001) and substance abuse (aHR female sex: 1·70, 95% CI: 1·54-1·87, p<0·001)., Interpretation: WWH experienced increased risk of CKD. Given disparities in care among patients with end-stage kidney disease, efforts to engage WWH in nephrology care to improve chronic disease management are critical., Funding: US National Institutes of Health., Competing Interests: JEL reports grands and funding from Hansa, United Therapeutics, honoraria from Sanofi, and non-monetary support from the FDA and Davita, and reports support from the NIH for the present study. KC reports an investigator-initiated grant from Gilead Sciences and serves as a medical advisory board member for Gilead Sciences. GN reports R01-DK127139, R01-HL155915, R56-DK126930, and funding from Renalytix. GN also receives consulting fees from Renalytx (as well as royalties), Variant Bio, Qiming Capital, Cambridge Healthcare, Daiichi Sankyo (as well as honoraria). GN also has patent with Renalytx and participates in advisory boards for Renalytix and Pensieve Health. Finally, GN has stock/stock options in Renaltyx, Pensieve Health, Vierici Dx, Nexus I Connect, and Data2Wisdom LLC. SM reports honoraria from CareDx and serves on their advisory board, and reports NIH grants/contracts for use of CCR5 in HIV-positive transplant recipients and the prospective HOPE In-Action trial. DS has entered into a consulting agreement with IMS Consulting and Expert Services, has been elected as Councilor at Large to the American Society of Transplantation Board of Directors, and reports funding from the NIH for the present study. HC reports funding from the NIH (for the present study), AHRQ, Viiv, and serves on the Office of AIDS Advisory Council for the NIH. MS serves on the advisory or DSMB board for I-SPY, an NIH-funded study, and in a leadership role for IAS-USA. JJE reports financial support for the present study from the NIH; grants (outside the present study) from ViiV Healthcare, Gilead Science and Janssen; and consulting fees (outside the present study) from Merck, ViiV Healthcare, Gilead Sciences, and Jansssen. BJ and BAS report funding from the NIH. RM and IP report financial support from the NIH for the present study. All other authors declare no competing interests., (© 2022 The Author(s).)

Among 14 049 people with human immunodeficiency virus in care in 2019-2020, 96% were treated with antiretroviral therapy (ART). Current antiretroviral treatment patterns highlight high uptake of guideline-recommended ART regimens including second-generation integrase strand transfer inhibitors (dolutegravir and bictegravir) and tenofovir alafenamide, especially in antiretroviral-naive individuals initiating ART., Competing Interests: Potential conflicts of interest. K. C. is a member of the medical advisory board for Gilead Sciences and reports grants or contracts from Gilead Sciences to their institution, outside the submitted work. G. A. B. has received research grant support from Merck Foundation and Eli Lilly, consulting fees from Med IQ, and payment or honoraria from StateServ and the University of Kentucky. J. K. reports a past relationship with the American Board of Internal Medicine, as an infectious disease specialty board member. J. J. E. reports contracts to their institution from ViiV Healthcare, Gilead Sciences, and Janssen; is an ad hoc consultant to Merck, Gilead Sciences, ViiV, and Janssen; and is an investigator for clinical trials at the University of North Carolina, which receives funding from Gilead, ViiV, and Janssen. E. R. C. has received unrestricted research grants paid to UC Reagents from Gilead Sciences for an unrelated hepatitis C virus project and from Merck Sharp & Dohme for an unrelated project and has received payment or honoraria from Gilead Science. M. S. S. reports money paid to their institution from ViiV and Gilead for clinical trials that are now closed, outside the submitted work; reports participation on the data science monitoring board for the I-SPY COVID trial; and reports serving on the board of directors for International Antiviral Society-USA. H. M. C. has received research grant support from ViiV and the Agency for Healthcare Research and Quality paid to their institution, outside the submitted work, and reports participation on the National Institutes of Health Office of AIDS Research Advisory Council. 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 for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The molecular basis of heterotaxy and congenital heart malformations associated with disruption of left-right asymmetry is broad and heterogenous, with over 25 genes implicated in its pathogenesis thus far., Objective: We sought to elucidate the molecular basis of laterality disorders and associated congenital heart defects in a cohort of 30 unrelated probands of Arab-Muslim descent, using next-generation sequencing techniques., Methods: Detailed clinical phenotyping followed by whole-exome sequencing (WES) was pursued for each of the probands and their parents (when available). Sanger sequencing was used for segregation analysis of disease-causing mutations in the families., Results: Using WES, we reached a molecular diagnosis for 17 of the 30 probands (56.7%). Genes known to be associated with heterotaxy and/or primary ciliary dyskinesia, in which homozygous pathogenic or likely pathogenic variants were detected, included CFAP53 (CCDC11) , CFAP298 ( C21orf59 ), CFAP300 , LRRC6 , GDF1 , DNAAF1 , DNAH5 , CCDC39 , CCDC40 , PKD1L1 and TTC25 . Additionally, we detected a homozygous disease causing mutation in DAND5 , as a novel recessive monogenic cause for heterotaxy in humans. Three additional probands were found to harbour variants of uncertain significance. These included variants in DNAH6 , HYDIN , CELSR1 and CFAP46 ., Conclusions: Our findings contribute to the current knowledge regarding monogenic causes of heterotaxy and its associated congenital heart defects and underscore the role of next-generation sequencing techniques in the diagnostic workup of such patients, and especially among consanguineous families., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To describe retention in HIV care based on various definitions of retention in the modern treatment era., Design: A cohort study of people enrolled in care at seven mostly urban HIV clinics across the United States, 2010-2018., Methods: We estimated retention based on missed visits, kept visits, kept encounters (clinical visits, CD4 counts, and viral loads), and HIV labs. We contrasted risk factors for retention by different definitions and estimated odds ratios for of viral suppression and hazard ratios for mortality in 2 years immediately following the year in which retention was defined (the study year)., Results: Across 108 171 person-years (N = 21 481 people), in 71% of years people kept ≥75% of scheduled visits; in 78%, people kept ≥2 visits >90 days apart; in 74%, people had ≥2 HIV labs >90 days apart; and in 47%, people had no gaps >6 months in clinic visits. Missing >25% of scheduled visits despite attending ≥2 visits >90 days apart was associated with nonwhite non-Hispanic race/ethnicity, history of injection drug use, and prior AIDS diagnosis. In contrast, attending ≥75% of scheduled visits while not attending ≥2 visits >90 days apart was associated with male sex, white race, no injection drug use history, and no prior AIDS diagnosis. Subsequent viral nonsuppression was more strongly associated with missed- than kept-visit measures of retention; 2-year mortality was only associated with failure to be retained by missed-visit measures., Discussion: Missed and kept-visit definitions of retention capture different constructs. Missed-visit measures are more strongly associated with poor HIV outcomes., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Noncommunicable diseases (NCDs) are a growing public health concern in low- and middle-income countries and disproportionately affect people living with HIV (PWH). Hepatitis B virus (HBV) and tuberculosis (TB) coinfection are presumed risk factors in endemic settings; however, supporting evidence is conflicting. We analyzed baseline data of newly diagnosed PWH prospectively enrolled in the Sierra Leone HIV Cohort Study in Freetown, Sierra Leone, from March to September 2021. Logistic regression was used to identify associations between NCDs, HBV and TB. A total of 275 PWH aged ≥18 years were studied (55% female, median age 33 years, median CD4 307 cells/mm3, 15.3% HIV/HBV, 8.7% HIV/TB). NCDs were bimodally distributed, with 1 in 4 PWH clustered around liver disease (fibrosis/cirrhosis), diabetes/prediabetes and obesity/preobesity, while 1 in 8 had renal impairment or hypertension (HTN). Overall, 41.5% had ≥1 NCD, while 17.5% were multimorbid (≥2 NCDs). After adjusting for age, sex, sociodemographic factors and CD4 count, liver fibrosis/cirrhosis was strongly associated with HBV (aOR 8.80, 95% CI [2.46−31.45]; p < 0.001) and diabetes/prediabetes (aOR 9.89, 95% CI [1.14−85.67]; p < 0.037). TB independently predicted diabetes/prediabetes (aOR 7.34, 95% CI [1.87−28.74]; p < 0.004), while renal impairment was associated with proteinuria (aOR 9.34, 95% CI [2.01−43.78]; p < 0.004) and HTN (aOR 6.00, 95% CI [1.10−35.39]; p < 0.049). Our findings warrant the implementation of NCD-aware HIV programs for the prevention, early detection and management of comorbidities.

Osteosclerotic metaphyseal dysplasia is a rare disorder which features osteosclerosis involving long bones, vertebrae, ribs, clavicles and the iliac crests. Additional features which have variably been reported include developmental delay, short stature, hypotonia and seizures. The disease is caused by pathogenic variants in the LRRK1 gene, and inherited in an autosomal recessive manner. We report three siblings (ages 14 years, 11.5 years and 0.9 years), born to consanguineous parents of Arab-Muslim descent, harboring a homozygous pathogenic variant in the LRRK1 gene (Chr15:101068759 AGGGGCT>A, c.5965&#95;5970del TGGGGC, p.Trp1989Gly1990del). The patients displayed variable degrees of skeletal dysplasia, with the oldest sibling most severely affected, and the youngest infant with minor skeletal involvement. Two of the siblings exhibited normal neurological development, while the youngest sibling exhibited global developmental delay. None of the siblings had seizures; however, two of them exhibited nystagmus. Optic nerve involvement has not previously been reported to be part of the clinical spectrum of this disease. The degree of optic nerve involvement did not correlate with the degree of skeletal involvement. This indicates both intra-familial variable expressivity along with a broadening of the spectrum of LRRK1-associated disease. These findings warrant reconsideration of therapeutic strategies, including the possibility of hematopoietic stem cell transplantation (HSCT) as is performed in cases of malignant and intermediate forms of osteopetrosis., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Background: People with HIV (PWH) have a higher hospitalization rate than the general population. The Veterans Aging Cohort Study (VACS) Index at study entry well predicts hospitalization in PWH, but it is unknown if the time-updated parameter improves hospitalization prediction. We assessed the association of parameterizations of the VACS Index 2.0 with the 5-year risk of hospitalization., Setting: PWH ≥30 years old with at least 12 months of antiretroviral therapy (ART) use and contributing hospitalization data from 2000 to 2016 in North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) were included. Three parameterizations of the VACS Index 2.0 were assessed and categorized by quartile: (1) "baseline" measurement at study entry; (2) time-updated measurements; and (3) cumulative scores calculated using the trapezoidal rule., Methods: Discrete-time proportional hazard models estimated the crude and adjusted associations (and 95% confidence intervals [CIs]) of the VACS Index parameterizations and all-cause hospitalizations. The Akaike information criterion (AIC) assessed the model fit with each of the VACS Index parameters., Results: Among 7289 patients, 1537 were hospitalized. Time-updated VACS Index fitted hospitalization best with a more distinct dose-response relationship [score <43: reference; score 43-55: aHR = 1.93 (95% CI: 1.66 to 2.23); score 55-68: aHR = 3.63 (95% CI: 3.12 to 4.23); score ≥68: aHR = 9.98 (95% CI: 8.52 to 11.69)] than study entry and cumulative VACS Index after adjusting for known risk factors., Conclusions: Time-updated VACS Index 2.0 had the strongest association with hospitalization and best fit to the data. Health care providers should consider using it when assessing hospitalization risk among PWH., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: A5350, a phase II, randomized, double-blind study, evaluated the safety and tolerability of the probiotic Visbiome Extra Strength (ES) over 24 weeks and measured effects on inflammation and intestinal barrier function., Methods: The primary outcome was change in soluble CD14 (sCD14) levels; secondary outcomes included safety and tolerability, markers of inflammation and cellular activation, and microbiome. In a substudy, gut permeability was assessed by paired colonic biopsies measuring the area of lamina propria occupied by CD4+ cells, interleukin (IL)-17+ cells, and myeloperoxidase (MPO). Changes between arms were compared with the 2-sample t test with equal variance or the Wilcoxon rank-sum test. For safety, the highest graded adverse events (AEs) were compared between arms using the Fisher exact test., Results: Overall, 93 participants enrolled: 86% male, median age 51 years, median CD4 count 712 cells/mm3. Visbiome ES was safe and well tolerated. There was no difference in mean change in sCD14 from baseline to week 25/26 between placebo (mean change, 92.3 µg/L; 95% CI, -48.5 to 233 µg/L) and Visbiome ES (mean change, 41.0 µg/L; 95% CI, -94.1 to 176.2 µg/L; P =.60). Similarly, no statistically significant differences between arms in inflammatory marker changes were identified. In substudy participants, no statistical differences between arms for change in cellular marker expression or gut permeability were observed ( P >.05 for all). The microbiome demonstrated increased probiotic species and a significant decrease in Gammaproteobacteria ( P =.044) in the Visbiome ES arm., Conclusions: Visbiome ES was safe and altered the microbiome but demonstrated no effect on systemic inflammatory markers, pathology, or gut permeability in antiretroviral therapy-treated people with HIV., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Non-invasive biomarkers that predict HIV remission after antiretroviral therapy (ART) interruption are urgently needed. Such biomarkers can improve the safety of analytic treatment interruption (ATI) and provide mechanistic insights into the host pathways involved in post-ART HIV control. Here we report plasma glycomic and metabolic signatures of time-to-viral-rebound and probability-of-viral-remission using samples from two independent cohorts. These samples include a large number of post-treatment controllers, a rare population demonstrating sustained virologic suppression after ART-cessation. These signatures remain significant after adjusting for key demographic and clinical confounders. We also report mechanistic links between some of these biomarkers and HIV latency reactivation and/or myeloid inflammation in vitro. Finally, machine learning algorithms, based on selected sets of these biomarkers, predict time-to-viral-rebound with 74% capacity and probability-of-viral-remission with 97.5% capacity. In summary, we report non-invasive plasma biomarkers, with potential functional significance, that predict both the duration and probability of HIV remission after treatment interruption.

Background: Direct-acting antivirals can cure hepatitis C virus (HCV). Persons with HCV/HIV and living with substance use are disadvantaged in benefiting from advances in HCV treatment., Methods: In this randomized controlled trial, participants with HCV/HIV were randomized between February 2016 and January 2017 to either care facilitation or control. Twelve-month follow-up assessments were completed in January 2018.Care facilitation group participants received motivation and strengths-based case management addressing retrieval of HCV viral load results, engagement in HCV/HIV care, and medication adherence. Control group participants received referral to HCV evaluation and an offer of assistance in making care appointments. Primary outcome was number of steps achieved along a series of 8 clinical steps (eg, receiving HCV results, initiating treatment, sustained virologic response [SVR]) of the HCV/HIV care continuum over 12 months postrandomization., Results: Three hundred eighty-one individuals were screened and 113 randomized. Median age was 51 years; 58.4% of participants were male and 72.6% were Black/African American. Median HIV-1 viral load was 27 209 copies/mL, with 69% having a detectable viral load. Mean number of steps completed was statistically significantly higher in the intervention group vs controls (2.44 vs 1.68 steps; χ  2 [1] = 7.36, P  = .0067). Men in the intervention group completed a statistically significantly higher number of steps than controls. Eleven participants achieved SVR with no difference by treatment group., Conclusions: The care facilitation intervention increased progress along the HCV/HIV care continuum, as observed for men and not women. Study findings also highlight continued challenges to achieve individual-patient SVR and population-level HCV elimination., Clinical Trials Registration: NCT02641158., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Antiretroviral therapy (ART) has significantly reduced the rate of mortality in HIV infected population, but people living with HIV (PLWH) show higher rates of cardiovascular disease (CVD). However, the effect of antiretroviral (ARV) drug treatment on cardiac cells is not clear. In this study, we explored the effect of ARV drugs in cardiomyocyte epigenetic remodeling. Primary cardiomyocytes were treated with a combination of four ARV drugs (ritonavir, abacavir, atazanavir, and lamivudine), and epigenetic changes were examined. Our data suggest that ARV drugs treatment significantly reduces acetylation at H3K9 and H3K27 and promotes methylation at H3K9 and H3K27, which are histone marks for gene expression activation and gene repression, respectively. Besides, ARV drugs treatment causes pathological changes in the cell through increased production of reactive oxygen species (ROS) and cellular hypertrophy. Further, the expression of chromatin remodeling enzymes was monitored in cardiomyocytes treated with ARV drugs using PCR array. The PCR array data indicated that the expression of epigenetic enzymes was differentially regulated in the ARV drugs treated cardiomyocytes. Consistent with the PCR array result, SIRT1, SUV39H1, and EZH2 protein expression was significantly upregulated in ARV drugs treated cardiomyocytes. Furthermore, gene expression analysis of the heart tissue from HIV+ patients showed that the expression of SIRT1, SUV39H1, and EZH2 was up-regulated in patients with a history of ART. Additionally, we found that expression of SIRT1 can protect cardiomyocytes in presence of ARV drugs through reduction of cellular ROS and cellular hypertrophy. Our results reveal that ARV drugs modulate the epigenetic histone markers involved in gene expression, and play a critical role in histone deacetylation at H3K9 and H3K27 during cellular stress. This study may lead to development of novel therapeutic strategies for the treatment of CVD in PLWH., Competing Interests: The 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 © 2021 Kashyap, Mukker, Gupta, Datta, Rappaport, Jacobson, Ebert and Gupta.)

MazF is an Escherichia coli-derived endoribonuclease that selectively cleaves ACA sequences of mRNA prevalent in HIV. We administered a single infusion of autologous CD4 T lymphocytes modified to express a Tat-dependent MazF transgene to 10 HIV-infected individuals (six remaining on antiretroviral therapy [ART]; four undergoing treatment interruption post-infusion) in order to provide a population of HIV-resistant immune cells. In participants who remained on ART, increases in CD4 and CD8 T cell counts of ~200 cells/mm 3 each occurred within 2 weeks of infusion and persisted for at least 6 months. Modified cells were detectable for several months in the blood and trafficked to gastrointestinal lymph tissue. HIV-1 Tat introduced ex vivo to the modified CD4 + T cells induced MazF expression in both pre- and post-infusion samples, and MazF expression was detected in vivo post-viral-rebound during ATI. One participant experienced mild cytokine release syndrome. In sum, this study of a single infusion of MazF-modified CD4 T lymphocytes demonstrated safety of these cells, distribution to lymph tissue and maintenance of Tat-inducible MazF endoribonuclease activity, as well as sustained elevation of blood CD4 and CD8 T cell counts. Future studies to assess effects on viremia and latent proviral reservoir are warranted., Competing Interests: Declaration of Interests S.F.L. is a consultant for Gilead/Kite. J.A.F. is a scientific founder of DeCart Therapeutics and is also a consultant for Guidepoint and L.E.K. Consulting. B.L.L. is an inventor of intellectual property licensed by the University of Pennsylvania to Novartis and Tmunity Therapeutics. C.H.J. is a scientific founder of Tmunity Therapeutics, for which he has founder’s stock but no income. C.H.J. and J.A.F. also work under a research collaboration involving the University of Pennsylvania and the Novartis Institutes of Biomedical Research, Inc. and are inventors of intellectual property licensed by the University of Pennsylvania to Novartis. C.H.J. is also a scientific founder of DeCart Therapeutics., (Copyright © 2020 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the prevalence of serological markers of HBV and endemic acute and chronic infections (HAV, HCV, CMV, HTLV-1/2 and syphilis) in HIV-infected children, adolescents and pregnant women in Sierra Leone., Method: We conducted a cross-sectional study at the national children's and women's hospitals in Freetown. Logistic regression was used to assess predictors of HBsAg positivity., Results: 183 HIV-infected participants were enrolled, comprising children (n = 88), adolescents (n = 47) and pregnant women (n = 48). All participants (100%) were CMV IgG-positive, while 56.8%, 93.6% and 100% of children, adolescents and pregnant women, respectively, were HAV IgG-positive. The prevalence of HCV, HTLV-1/2 and syphilis were <4%. HBV markers were distributed as follows-children: HBsAg (2.3%), HBeAg (0%), anti-HBc (5.7%); adolescents: HBsAg (17.0%), HBeAg (6.4%), anti-HBc (27.7%); and pregnant women: HBsAg (18.8%), HBeAg (4.2%), anti-HBc (77.1%). Age >10 years, i.e., being born pre-2009 before implementation of routine hepatitis B immunization (aOR 5.05 [1.18-21.28]; p = 0.029) and CD4 count <350 cells/mm 3 (aOR 3.97 [1.07-14.71]; p = 0.039) predicted HBsAg positivity., Conclusion: A high burden of chronic HBV and other endemic infections was observed among HIV-infected patients born pre-2009 before implementation of routine HBV immunization in Sierra Leone, warranting targeted screening and immunization of this high-risk population., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: There are limited data to help guide implementation of differentiated HIV service delivery (DSD) in resource-limited settings in sub-Saharan Africa., Objectives: This pre-implementation study sought to assess the proportion of patients eligible for DSD and HIV services utilization, as well as risk factor analysis of virologic failure in Sierra Leone., Methods: We conducted a retrospective study of adult HIV-infected patients aged 18 years and older receiving care at the largest HIV treatment center in Sierra Leone 2019-2020. Multiple logistic regression was used to identify predictors of virologic failure., Results: Of 586 unique patients reviewed, 210 (35.8%) qualified as 'stable' for antiretroviral therapy (ART) delivery. There was high utilization of certain HIV service programs (e.g. HIV status disclosure to partners (83%) and treatment 'buddy' program participation (62.8%)), while other service programs (e.g. partner testing and community HIV support group participation) had low utilization (<50%). Of 429 patients with available viral load, 277 (64.6%) were virologically suppressed. In the multivariate logistic regression analysis of risk factors of virologic failure, CD4 < 350 cells/mm 3 (p = 0.009), atazanavir-based ART (p = 0.032), once monthly versus once two- or three-monthly ART dispensing (p = 0.028), history of ART switching (p = 0.02), poor adherence (p = 0.001) and not having received adherence support (p < 0.001) were independent predictors of virologic failure., Conclusion: Approximately one in three HIV-infected patients on ART were eligible for DSD. We identified gaps in HIV care (i.e. low partner testing, treatment 'buddy', program participation and a substantially high rate of virologic failure) that need to be addressed in preparation for full implementation of DSD in Sierra Leone.

Objective: Glycosylation plays a critical role in mediating several antibody (mainly immunoglobulin G; IgG) immunological functions, including antibody-dependent cell-mediated cytotoxicity (ADCC), and anti-inflammatory activities. We investigated whether IgG glycosylation and immune profile patterns are differentially modulated in mono and dual infection using samples from untreated hepatitis C virus (HCV)-infected individuals with and without co-infection with antiretroviral therapy (ART)-suppressed HIV., Design: IgG glycosylation, immune subsets, natural killer cell function, and liver enzymes were assessed in 14 HCV mono-infected and 27 ART-suppressed HIV/HCV co-infected participants naïve to HCV treatment. Historic IgG glycosylation data from 23 ART-suppressed chronically HIV-infected individuals were also used for comparisons., Methods: Plasma IgG glycosylation was assessed using capillary electrophoresis. Whole blood was used for immune subset characterization by flow cytometry. Peripheral blood mononuclear cells were used to measure constitutive and interferon-α-induced K562 target cell lysis. Statistical analysis was performed using R (3.5.0)., Results: HIV/HCV had lower levels of pro-ADCC-associated nonfucosylated glycans when compared with HIV [e.g. di-sialylated A2 percentage (%): P = 0.04], and higher levels of T and myeloid cell activation/exhaustion when compared with HCV (e.g. CD3CD8CD38 %: P < 0.001). Finally, in HCV high levels of the anti-inflammatory galactosylated and sialylated glycans were associated with low plasma levels of aspartate aminotransferase (AST), low CD8 T-cell activation, and high CD8 T-cell exhaustion., Conclusion: HCV modulates IgG glycosylation profile in HIV co-infected individuals on suppressive ART. These results could inform on the modulation of IgG glycans in other mono and dual infections.

Objective: "Bovine aortic arch" is the second most common variant of aortic arch branching, in which only two branches originate directly from the aorta. The prevalence of this condition has been reported in different studies to be around 6% in human fetuses and 11-27% in the adult population. In this study, we describe the prevalence of bovine aortic arch in fetuses, and assess the prevalence of concomitant fetal anomalies., Methods: A retrospective analysis of 417 fetuses between 15-40 weeks of gestation. Data regarding branching of the fetal aortic arch and other fetal anomalies were collected by fetal echocardiography and/or fetal ultrasonography., Results: A bovine arch was found in 20/413 fetuses (4.8%, 95CI 3.1-7.3%), of whom 14/310 (4.5%) had no fetal anomalies, and 6/77 (7.8%) exhibited minor changes (P = .241). None of the 26 fetuses with major anomalies had a bovine arch., Conclusion: Fetuses in this study had a lower prevalence of bovine aortic arch than that previously reported in adults, most probably due to differences in the population examined. This study was underpowered to determine that bovine arch is a common anatomic variant, and is not associated with fetal anomalies., (© 2019 Wiley Periodicals, Inc.)

The CRISPR/Cas9 system has been proposed as a cure strategy for HIV. However, few published guide RNAs (gRNAs) are predicted to cleave the majority of HIV-1 viral quasispecies (vQS) observed within and among patients. We report the design of a novel pipeline to identify gRNAs that target HIV across a large number of infected individuals. Next generation sequencing (NGS) of LTRs from 269 HIV-1-infected samples in the Drexel CARES Cohort was used to select gRNAs with predicted broad-spectrum activity. In silico, D-LTR-P4-227913 (package of the top 4 gRNAs) accounted for all detectable genetic variation within the vQS of the 269 samples and the Los Alamos National Laboratory HIV database. In silico secondary structure analyses from NGS indicated extensive TAR stem-loop malformations predicted to inactivate proviral transcription, which was confirmed by reduced viral gene expression in TZM-bl or P4R5 cells. Similarly, a high sensitivity in vitro CRISPR/Cas9 cleavage assay showed that the top-ranked gRNA was the most effective at cleaving patient-derived HIV-1 LTRs from five patients. Furthermore, the D-LTR-P4-227913 was predicted to cleave a median of 96.1% of patient-derived sequences from other HIV subtypes. These results demonstrate that the gRNAs possess broad-spectrum cutting activity and could contribute to an HIV cure.

Background: Infantile cortical hyperostosis (ICH)/Caffey disease is an inflammatory collagenopathy of infancy, manifested by subperiosteal bone hyperplasia. Genetically, ICH was linked with heterozygosity for an R836C mutation in the COL1A1 gene. Although an autosomal-recessive trait is also suspected, it has not been proven thus far., Methods: A case of an infant male born to consanguineous parents is reported, presenting with classical findings, course, and clinical outcome of ICH. Whole-exome sequencing (WES) was performed in order to identify a possible underlying genetic defect., Results: WES analysis revealed a novel homozygous nonsense mutation in lysine 2 of fetuin-A, encoded by the ALPHA-2-HS-GLYCOPROTEIN (AHSG) gene (c.A4T; p.K2X). Fetuin-A is an important regulator of bone remodeling and an inhibitor of ectopic mineralization. By enzyme-linked immunosorbent assay (ELISA), we show a complete deficiency of this protein in the patient's serum, compared to controls., Conclusion: A novel homozygous nonsense mutation in AHSG gene has been found in ICH patient with a typical phenotype, resulting in fetuin-A deficiency. This finding postulates an autosomal-recessive mode of inheritance in ICH, which, unlike the autosomal-dominant inheritance associated with COL1A1, is associated with AHSG and fetuin-A deficiency.