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Over the past 10 years, in conjunction with the broad availability of potent antiretroviral regimens, the care of human immunodeficiency virus (HIV)-infected patients has shifted from prevention and treatment of opportunistic infections and malignancies to management of the metabolic and related complications associated with HIV infection and its treatment. Metabolic disorders, including lipodystrophy, dyslipidemia, and insulin resistance, occur at a high rate in HIV-infected individuals receiving highly active antiretroviral therapy (HAART). These disorders are associated with increased risk of cardiovascular disease and have become an important cause of morbidity and mortality in HIV-infected patients. Herein, we present the case of a patient with HIV infection who responded well to HAART but developed multiple complications potentially related to this therapy. This article reviews the clinical characteristics of the metabolic and skeletal disturbances observed in HIV infection and discusses strategies for their management. [ABSTRACT FROM AUTHOR]

Background: People with HIV (PWH) are at elevated risk for atherosclerotic cardiovascular disease (ASCVD). Underrepresented racial and ethnic groups (UREGs) with HIV in the southern U.S. are disproportionately affected, yet whether cardiology specialist care for this at-risk group improves blood pressure and lipid control or prevents cardiovascular events is unknown., Methods: We evaluated a cohort of PWH from UREGs at elevated ASCVD risk without known cardiovascular disease who received HIV-related care from 2015-2018 at four academic medical centers in the Southern United States with follow up through 2020. Primary outcomes were blood pressure control (<140/90 mmHg) and lipid control (LDL-C ≤ 100 mg/dl) over 2 years and time to first major adverse cardiovascular (MACE) event. Statistical analyses were adjusted for cohort/site and patient factors including HIV measures and comorbidities., Results: Among 3972 included PWH (median age 47 years old, 32.6% female) without diagnosed cardiovascular disease, 276 (6.9%) had a cardiology clinic visit. Cardiology clinic visits were not significantly associated with subsequent blood pressure control (adjusted OR 0.78, 95% CI 0.49-1.24, p=0.29) or lipid control (adjusted OR 2.25, 95% CI 0.72-7.01, p=0.16). Over a median follow up of 5 years, patients who had a cardiology clinic visit had higher risk of MACE, overall mortality, and falsification endpoints (hospitalization or death from accident/trauma and pneumonia/sepsis) indicating a higher risk group overall, even after adjusting for measured risk factors., Conclusions: Among UREG PWH at elevated cardiovascular risk, a cardiology clinic visit was not associated with improved cardiovascular risk factors or reduced risk of cardiovascular events. Our study suggests that seeing a cardiologist is not alone sufficient to promote cardiovascular health or prevent cardiovascular events among PWH, but with low confidence given the higher risk among those who had a cardiology visit., Competing Interests: Disclosures: CTL is on the advisory board for Theratechnologies outside the scope of this work. None of the other authors have pertinent disclosures or relevant conflicts of interest.

Background: Underrepresented racial and ethnic groups (UREGs) with HIV have a higher risk of cardiovascular disease (CVD) compared with the general population. Referral to a cardiovascular specialist improves CVD risk factor management in high-risk individuals. However, patient and provider factors impacting the likelihood of UREGs with HIV to have an encounter with a cardiologist are unknown., Methods: We evaluated a cohort of UREGs with HIV and borderline CVD risk (10-year risk ≥ 5% by the pooled cohort equations or ≥ 7.5% by Framingham risk score). Participants received HIV-related care from 2014-2020 at four academic medical centers in the United States (U.S.). Adjusted Cox proportional hazards regression was used to estimate the association of patient and provider characteristics with time to first ambulatory cardiology encounter., Results: A total of 2,039 people with HIV (PWH) and borderline CVD risk were identified. The median age was 45 years (IQR: 36-50); 52% were female; and 94% were Black. Of these participants, 283 (14%) had an ambulatory visit with a cardiologist (17% of women vs. 11% of men, p < .001). In fully adjusted models, older age, higher body mass index (BMI), atrial fibrillation, multimorbidity, urban residence, and no recent insurance were associated with a greater likelihood of an encounter with a cardiologist., Conclusion: In UREGs with HIV and borderline CVD risk, the strongest determinants of a cardiology encounter were diagnosed CVD, insurance type, and urban residence. Future research is needed to determine the extent to which these encounters impact CVD care practices and outcomes in this population., Trial Registration: ClinicalTrials.gov Identifier: NCT04025125., (© 2023. The Author(s).)

Background: Food insecurity, or the lack of consistent access to nutritionally adequate and safe foods, effects up to 50% of people living with HIV (PWH) in the United States (US). PWH who are food insecure have lower antiretroviral adherence, are less likely to achieve viral suppression, and are at increased risk developing of serious illnesses, including cardiometabolic comorbidities. The objectives of this study are to better understand how food insecurity contributes to the development of cardiometabolic comorbidities among PWH and to test a novel bilingual peer navigation-mHealth intervention (weCare/Secure) designed to reduce these comorbidities in food-insecure PWH with prediabetes or Type 2 diabetes (T2DM)., Methods: In Aim 1, we will recruit a longitudinal cohort of 1800 adult (≥18 years) PWH from our clinic-based population to determine the difference in the prevalence and incidence of cardiometabolic comorbidities between food-secure and food-insecure PWH. Food insecurity screening, indicators of cardiometabolic comorbidities, and other characteristics documented in the electronic health record (EHR) will be collected annually for up to 3 years from this cohort. In Aim 2, we will conduct a randomized controlled trial among a sample of food-insecure PWH who have prediabetes or T2DM to compare changes in insulin sensitivity over 6 months between participants in weCare/Secure and participants receiving usual care. In Aim 3, we will conduct semi-structured individual in-depth interviews to explore the effect of the intervention among intervention participants with varying insulin sensitivity outcomes., Trial Status: Aim 1 (longitudinal cohort) recruitment began in May 2022 and is ongoing. Aim 2 (intervention) recruitment is planned for spring 2023 and is expected to be completed in spring 2024. Aim 3 (process evaluation) data collection will occur after sufficient completion of the 6-month assessment in Aim 2. Final results are anticipated in fall 2025., Conclusions: This research seeks to advance our understanding of how food insecurity impacts the development of cardiometabolic comorbidities among PWH and how food insecurity interventions may alleviate relevant comorbidities. Given the growing interest among health systems in addressing food insecurity, if the intervention is found to be efficacious, it could be broadly disseminated across HIV clinical care settings., Trial Registration: ClinicalTrials.gov NCT04943861 . Registered on June 29, 2021., (© 2022. The Author(s).)

Background: Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectious virus isolation in outpatients with coronavirus disease 2019 (COVID-19) has been associated with viral RNA levels and symptom duration, little is known about the host, disease, and viral determinants of infectious virus detection., Methods: COVID-19 adult outpatients were enrolled within 7 days of symptom onset. Clinical symptoms were recorded via patient diary. Nasopharyngeal swabs were collected to quantitate SARS-CoV-2 RNA by reverse transcriptase polymerase chain reaction and for infectious virus isolation in Vero E6-cells. SARS-CoV-2 antibodies were measured in serum using a validated ELISA assay., Results: Among 204 participants with mild-to-moderate symptomatic COVID-19, the median nasopharyngeal viral RNA was 6.5 (interquartile range [IQR] 4.7-7.6 log10 copies/mL), and 26% had detectable SARS-CoV-2 antibodies (immunoglobulin (Ig)A, IgM, IgG, and/or total Ig) at baseline. Infectious virus was recovered in 7% of participants with SARS-CoV-2 antibodies compared to 58% of participants without antibodies (prevalence ratio [PR] = 0.12, 95% confidence interval [CI]: .04, .36; P = .00016). Infectious virus isolation was also associated with higher levels of viral RNA (mean RNA difference +2.6 log10, 95% CI: 2.2, 3.0; P < .0001) and fewer days since symptom onset (PR = 0.79, 95% CI: .71, .88 per day; P < .0001)., Conclusions: The presence of SARS-CoV-2 antibodies is strongly associated with clearance of infectious virus. Seropositivity and viral RNA levels are likely more reliable markers of infectious virus clearance than subjective measure of COVID-19 symptom duration. Virus-targeted treatment and prevention strategies should be administered as early as possible and ideally before seroconversion., Clinical Trials Registration: NCT04405570., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: People with HIV (PWH) are at increased risk of cardiovasvular disease (CVD) and sudden cardiac death. Previous work has suggested an association between HIV infection and electrocardiographic (ECG) abnormalities. There are limited data on the burden of ECG abnormalities among PWH in a multiracial, multiethnic globally representative population., Setting: One hundred twenty sites in the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE)., Methods: ECG findings were grouped into clinically relevant categories using sex-specific thresholds when indicated. We used the Fisher exact tests to assess associations of demographic characteristics and ECG abnormalities. We used logistic regression model to assess associations between demographic and HIV management measures, with adjustment., Results: We analyzed data for 7720 PWH (99% of participants) (median age 50 years, 69% male participants). There were 3346 (43%) Black or African American, 2680 (35%) White, and 1139 (15%) Asian participants. Most of the participants (97%) had viral load that was <400 copies/mL or 400 copies/mL had approximately twice the odds of prolonged QTc compared with those that were undetectable (adjusted OR: 2.05, 95% CI: 1.22 to 3.45)., Conclusions: Prolonged QTc is common among male, Asian, and REPRIEVE participants with higher viral loads. These relationships warrant future investigation of linkages to ensuing CVD events among PWH., Competing Interests: G.S.B. has received a grant from NIH/NIMHD R01MD013493 outside the submitted work. HR has received grants from NIH/NHLBI HL123339 and KOWA Pharmaceuticals during the conduct of the study and grants from NIH/NIAID AI068634, NIH/NIAID AI123001, NIH/NHLBI HL137562, and NIH/NHLBI HL146199 outside the submitted work. K.V.F. has received nonfinancial support from American College of Cardiology and International AIDS Society and personal fees from Gilead Sciences, Inc, outside the submitted work. C.J.F. has received grants from Gilead Sciences during the conduct of the study and grants from ViiV healthcare, Janssen, Merck, Cytodyn, Amgen, and Abbvie outside the submitted work. J.P. has received grants for clinical research from Abbott, American Heart Association, Association for the Advancement of Medical Instrumentation, Bayer, Boston Scientific, and Philips and serves as a consultant to Abbott, Abbvie, Ablacon, Altathera, ARCA Biopharma, Biotronik, Boston Scientific, Bristol Myers Squibb, LivaNova, Medtronic, Milestone, ElectroPhysiology Frontiers, Pfizer, Sanofi, Philips, and Up-to-Date. M.V.Z. has received a research grant from Gilead Sciences during the conduct of the study. M.T.L. has received research grants from NHLBI U01 HL123339 and Kowa during the conduct of the study; and from AstraZeneca CT core laboratory for clinical trials outside the submitted work. U.H. has received research grants from KOWA on behalf of the institution during the conduct of the study, personal fees from Duke University, consulting fees from Recor Medical, and grants from KOWA, AstraZeneca, Medimmune, HeartFlow on behalf of MGH outside the submitted work. S.K.G. has received grants from NIH, KOWA, Gilead Sciences, and Viiv during the conduct of the study, personal fees from Theratechnologies Inc, consulting and personal fees from Viiv outside the submitted work. P.S.D. has received grants from KOWA, Gilead Sciences, and Viiv during the conduct of the study. The remaining authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: Based on contemporary estimates in the US, evidence-based therapies for cardiovascular risk reduction are generally underused among patients with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD)., Objective: To determine the use of evidence-based cardiovascular preventive therapies in a broad US population with diabetes and ASCVD., Design, Setting, and Participants: This multicenter cohort study used health system-level aggregated data within the National Patient-Centered Clinical Research Network, including 12 health systems. Participants included patients with diabetes and established ASCVD (ie, coronary artery disease, cerebrovascular disease, and peripheral artery disease) between January 1 and December 31, 2018. Data were analyzed from September 2020 until January 2021., Exposures: One or more health care encounters in 2018., Main Outcomes and Measures: Patient characteristics by prescription of any of the following key evidence-based therapies: high-intensity statin, angiotensin-converting enzyme inhibitor (ACEI) or angiotensin-receptor blocker (ARB) and sodium glucose cotransporter-2 inhibitors (SGLT2I) or glucagon-like peptide-1 receptor agonist (GLP-1RA)., Results: The overall cohort included 324 706 patients, with a mean (SD) age of 68.1 (12.2) years and 144 169 (44.4%) women and 180 537 (55.6%) men. A total of 59 124 patients (18.2% ) were Black, and 41 470 patients (12.8%) were Latinx. Among 205 885 patients with specialized visit data from the prior year, 17 971 patients (8.7%) visited an endocrinologist, 54 330 patients (26.4%) visited a cardiologist, and 154 078 patients (74.8%) visited a primary care physician. Overall, 190 277 patients (58.6%) were prescribed a statin, but only 88 426 patients (26.8%) were prescribed a high-intensity statin; 147 762 patients (45.5%) were prescribed an ACEI or ARB, 12 724 patients (3.9%) were prescribed a GLP-1RA, and 8989 patients (2.8%) were prescribed an SGLT2I. Overall, 14 918 patients (4.6%) were prescribed all 3 classes of therapies, and 138 173 patients (42.6%) were prescribed none. Patients who were prescribed a high-intensity statin were more likely to be men (59.9% [95% CI, 59.6%-60.3%] of patients vs 55.6% [95% CI, 55.4%-55.8%] of patients), have coronary atherosclerotic disease (79.9% [95% CI, 79.7%-80.2%] of patients vs 73.0% [95% CI, 72.8%-73.3%] of patients) and more likely to have seen a cardiologist (40.0% [95% CI, 39.6%-40.4%] of patients vs 26.4% [95% CI, 26.2%-26.6%] of patients)., Conclusions and Relevance: In this large cohort of US patients with diabetes and ASCVD, fewer than 1 in 20 patients were prescribed all 3 evidence-based therapies, defined as a high-intensity statin, either an ACEI or ARB, and either an SGLT2I and/or a GLP-1RA. These findings suggest that multifaceted interventions are needed to overcome barriers to the implementation of evidence-based therapies and facilitate their optimal use.

Importance: Systemic corticosteroids are commonly used in treating severe COVID-19. However, the role of inhaled corticosteroids in the treatment of patients with mild to moderate disease is less clear., Objective: To determine the efficacy of the inhaled steroid ciclesonide in reducing the time to alleviation of all COVID-19-related symptoms among nonhospitalized participants with symptomatic COVID-19 infection., Design, Setting, and Participants: This phase 3, multicenter, double-blind, randomized clinical trial was conducted at 10 centers throughout the US and assessed the safety and efficacy of a ciclesonide metered-dose inhaler (MDI) for treating nonhospitalized participants with symptomatic COVID-19 infection who were screened from June 11, 2020, to November 3, 2020., Interventions: Participants were randomly assigned to receive ciclesonide MDI, 160 μg per actuation, for a total of 2 actuations twice a day (total daily dose, 640 μg) or placebo for 30 days., Main Outcomes and Measures: The primary end point was time to alleviation of all COVID-19-related symptoms (cough, dyspnea, chills, feeling feverish, repeated shaking with chills, muscle pain, headache, sore throat, and new loss of taste or smell) by day 30. Secondary end points included subsequent emergency department visits or hospital admissions for reasons attributable to COVID-19., Results: A total of 413 participants were screened and 400 (96.9%) were enrolled and randomized (197 [49.3%] in the ciclesonide arm and 203 [50.7%] in the placebo arm; mean [SD] age, 43.3 [16.9] years; 221 [55.3%] female; 2 [0.5%] Asian, 47 [11.8%] Black or African American, 3 [0.8%] Native Hawaiian or other Pacific Islander, 345 [86.3%] White, and 1 multiracial individuals [0.3%]; 172 Hispanic or Latino individuals [43.0%]). The median time to alleviation of all COVID-19-related symptoms was 19.0 days (95% CI, 14.0-21.0) in the ciclesonide arm and 19.0 days (95% CI, 16.0-23.0) in the placebo arm. There was no difference in resolution of all symptoms by day 30 (odds ratio, 1.28; 95% CI, 0.84-1.97). Participants who were treated with ciclesonide had fewer subsequent emergency department visits or hospital admissions for reasons related to COVID-19 (odds ratio, 0.18; 95% CI, 0.04-0.85). No participants died during the study., Conclusions and Relevance: The results of this randomized clinical trial demonstrated that ciclesonide did not achieve the primary efficacy end point of reduced time to alleviation of all COVID-19-related symptoms., Trial Registration: ClinicalTrials.gov Identifier: NCT04377711.

Background: Tocilizumab, an interleukin 6 receptor (IL-6R) antagonist monoclonal antibody, has shown efficacy in patients with coronavirus disease 2019 (COVID-19) pneumonia, but the optimal dose is unknown., Methods: Patients hospitalized for moderate to severe COVID-19 pneumonia were randomized 1:1 to receive standard of care treatment and 1-2 doses of intravenous tocilizumab 4 mg/kg or 8 mg/kg (open-label). Primary pharmacokinetic and pharmacodynamic end points were serum concentrations of tocilizumab and soluble interleukin 6 receptor (sIL-6R), IL-6, ferritin, and C-reactive protein (CRP), from baseline to day 60. The secondary end point was safety. Key exploratory efficacy end points included clinical status, time to discharge, mortality rate, and incidence of mechanical ventilation., Results: Of 100 patients randomized, 49 received tocilizumab 4 mg/kg and 48 received 8 mg/kg. In pharmacokinetic and sIL-6R assessments, dose-dependent differences were seen in patients who received 1 or 2 doses of 4 or 8 mg/kg. Serum concentrations of IL-6, ferritin, and CRP and safety outcomes were comparable between groups. Through day 60, serious adverse events were reported in 30.6% and 25.0% of patients in the 4- and 8-mg/kg groups, respectively. Eight patients (16.3%) in the 4-mg/kg group and 6 (12.5%) in the 8-mg/kg group died. Exploratory time-to-event outcomes favored 8 mg/kg within the first 2 weeks., Conclusions: In patients with moderate to severe COVID-19 pneumonia who received tocilizumab 4 or 8 mg/kg, pharmacokinetic and sIL-6R assessments showed expected dose-dependent effects; pharmacodynamic assessments and safety were comparable, with no new safety signals. Further study is required before a lower dose of tocilizumab can be recommended in patients with COVID-19 pneumonia., Clinical Trials Registration: NCT04363736., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Liver disease is an important cause of morbidity and mortality in people living with human immunodeficiency virus (PLWH), of which nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized cause. There are limited data investigating NAFLD in HIV monoinfection and histologically defined disease. We aimed to identify who is at risk of fibrosis, NAFLD, and nonalcoholic steatohepatitis (NASH) among PLWH and explore the diagnostic accuracy of noninvasive markers of fibrosis., Methods: This was a retrospective, cross-sectional, international, multicenter study including patients with HIV monoinfection, without chronic viral hepatitis or other known causes of chronic liver disease, who underwent liver biopsy for abnormal liver biochemistry and/or clinical suspicion of liver fibrosis., Results: A total of 116 patients from 5 centers were included. Sixty-three (54%) had NAFLD, of whom 57 (92%) had NASH. Overall, 36 (31%) had advanced fibrosis (≥F3) and 3 (3%) had cirrhosis. Of the 53 cases without NAFLD, 15 (28%) had advanced fibrosis. Collagen proportionate area was similar between cases with and without NAFLD (3% vs 2%). Body mass index was independently associated with NAFLD (aOR, 1.2; 95% CI, 1.08-1.34), and type 2 diabetes was independently associated with advanced fibrosis (aOR, 3.42; 95% CI, 1.00-11.71). The area under the curve for advanced fibrosis was 0.65 and 0.66 for both NAFLD Fibrosis Score (NFS) and FIB-4. Cutoff values of -1.455 (NFS) and 1.3 (FIB-4) have negative-predictive values of 0.80 and 0.82, respectively., Conclusions: Advanced fibrosis is strongly associated with type 2 diabetes in PLWH. Serological markers require further optimization., (© Crown copyright 2020.)

In recent years, there has been an increasing number of clinical trials for the treatment of nonalcoholic steatohepatitis (NASH). People living with human immunodeficiency virus (PLWH) are commonly excluded from these studies, usually due to concerns over drug-drug interactions associated with antiretroviral therapy. The Steatohepatitis in HIV Emerging Research Network, a group of international experts in hepatology and infectious diseases, discusses our current understanding on the interaction between human immunodeficiency virus and NASH, and the issues related to the inclusion of PLWH in NASH clinical trials. Recent trials addressing NASH treatment in PLWH are discussed. The risk of drug-drug interactions between antiretroviral therapy and aramchol, cenicriviroc, elafibranor, obeticholic acid and resmetirom (MGL-3196), which are currently in phase 3 trials for the treatment of NASH, are reviewed. A model for trial design to include PLWH is proposed, strongly advocating for the scientific community to include this group as a subpopulation within studies., (© 2020 The Authors. Hepatology published by Wiley Periodicals, Inc. on behalf of American Association for the Study of Liver Diseases. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.)

Persons living with HIV (PLWH) have disproportionately high rates of both cigarette smoking and tobacco-induced negative health outcomes. The goal of this qualitative systematic review was to identify gaps in the existing literature and future directions for smoking cessation support for PLWH. Three online databases were searched from their inception through December 31, 2017, using designated search terms. Peer-reviewed English-language articles that documented an intervention designed to increase smoking cessation among PLWH were reviewed. Data were abstracted using a standardized form to document study and intervention characteristics and results. Thirty-two articles, describing 28 unique intervention studies, met inclusion criteria. Interventions consisted primarily of combinations of counseling, pharmacotherapy, and the use of information and communications technology; few interventions were implemented at the clinic level. Thirteen interventions resulted in significant improvements in cessation-related outcomes. Information and communications technology and clinic-level interventions had the greatest potential for increasing smoking cessation among PLWH. Efficacious interventions designed for PLWH in the US South, and for groups of PLWH facing additional health disparities (e.g., communities of color and sexual and gender minorities), are needed. There is also a need for more rigorous research designs to test the efficacy of interventions designed to increase cessation-related outcomes among PLWH.

BACKGROUNDHIV-infected patients with poor virologic control and multidrug-resistant virus have limited therapeutic options. The current study was undertaken to evaluate the safety, immunologic effects, and antiviral activity of peripheral lymphocytes transferred from an elite controller, whose immune system is able to control viral replication without antiretroviral medications, to an HLA-B*2705-matched progressor.METHODSApproximately 22 billion cells were collected from an elite controller by lymphapheresis and infused within 6 hours into a recipient with a preinfusion CD4+ T cell count of 10 cells/μL (1%) and HIV plasma viral load of 114,993 copies/mL.RESULTSDonor cells were cleared from the recipient's peripheral blood by day 8. A transient decrease in viral load to 58,421 (day 3) was followed by a rebound to 702,972 (day 6) before returning to baseline values by day 8. The decreased viral load was temporally associated with peak levels of donor T cells, including CD8+ T cells that had high levels of expression of Ki67, perforin, and granzyme B. Notably, recipient CD8+ T cells also showed increased expression of these markers, especially in HIV-specific tetramer-positive cells.CONCLUSIONThese results suggest that the adoptive transfer of lymphocytes from an HIV-infected elite controller to an HIV-infected patient with progressive disease may be able to perturb the immune system of the recipient in both positive and negative ways.TRIAL REGISTRATIONClinicalTrials.gov NCT00559416.FUNDINGIntramural Research Programs of the US NIH Clinical Center and the National Institute of Allergy and Infectious Diseases (NIAID); the National Cancer Institute.

Background & Aims: Non-alcoholic fatty liver disease is common in human immunodeficiency virus, but there are no approved therapies. The aim of this open-label proof-of-concept study was to determine the effect of the mineralocorticoid receptor antagonist eplerenone on hepatic fat in human immunodeficiency virus-infected patients with hepatic fat ≥5% by magnetic resonance spectroscopy., Methods: Five subjects received eplerenone (25 mg daily × 1 week followed by 50 mg daily × 23 weeks). Laboratory tests were done at each visit, and the primary endpoint, change in hepatic fat content, was determined by MRI spectroscopy at baseline and week 24., Results: The study was stopped early after observing unexpected significant increases in hepatic fat at week 24 (mean increase 13.0 ± 7.3%, P = .02). The increases in steatosis were accompanied by a tendency for transaminase values to decrease (alanine aminotransferase mean change -14 ± 16 IU/L, P = .14). There were no consistent changes in other metabolic parameters or blood pressure. Repeat assessment of hepatic steatosis 1-2 months after stopping study medication revealed improvements in steatosis towards baseline values., Conclusions: The unexpected observation of increased hepatic steatosis with the administration of eplerenone led to early termination of the investigation. While limited because of the small number of participants and the open-label design, this study provides data to suggest that mineralocorticoid receptor antagonism with eplerenone may not be an effective approach to treat hepatic steatosis in human immunodeficiency virus or the general population. Additional research is needed to determine the pathophysiological mechanism behind these unanticipated observations., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Rapid point-of-care, antibody-based testing is not currently available for the diagnosis of most autoimmune and infectious diseases. Here we report a simple, robust and ultrafast fluid-phase immunocapture method for clinical measurements of antibody levels. This method employs neodymium magnetic sticks that capture protein A/G-coated paramagnetic beads bound to antibody-luciferase-labeled antigen complexes. We demonstrate the ability to effectively measure specific antibody levels in serum samples from patients with varied infectious or autoimmune disorders, and in the case of Sjögren's syndrome directly in saliva, requiring about a minute per assay. We also show the feasibility of coupling this method with a hand-held luminometer for portable testing. Our method offers the potential to quickly diagnose a multitude of autoimmune and infectious diseases in point-of-care settings.

Human immunodeficiency virus and antiretroviral therapy (ART) together can be far more detrimental to liver cells than either of the two unaided. However, ultrastructural aspects of the synergistic effects of HIV and ART have been understudied. In a patient cohort receiving ART, this study characterizes ultrastructurally sinusoidal degeneration, hepatocytic aberrations, mitochondrial dysfunction, accumulation of bulky lipid droplets (steatosis), and occlusion of sinusoidal lumina. Mitochondrial dysfunction causes the accumulation of acetyl-CoA which leads to insulin upregulation and resistance, lipid synthesis, and steatosis. Lipid droplets deposited in the sinusoids could be the source of the blood's lipid profile alterations in HIV patients on ART.

Background. Portal hypertension, an elevation in the hepatic venous pressure gradient (HVPG), can be used to monitor disease progression and response to therapy in cirrhosis. Since obtaining HVPG measurements is invasive, reliable noninvasive methods of assessing portal hypertension are needed. Methods. Noninvasive markers of fibrosis, including magnetic resonance elastography (MRE) shear wave velocity, were correlated with histologic fibrosis and HVPG measurements in hepatitis C (HCV) and/or HIV-infected patients with advanced liver disease enrolled in a clinical trial of treatment with simtuzumab, an anti-LOXL2 antibody. Results. This exploratory analysis includes 23 subjects: 9 with HCV monoinfection, 9 with HIV and HCV, and 5 with HIV and nonalcoholic steatohepatitis. Median Ishak fibrosis score was 4 (range 1-6); 11 subjects (48%) had cirrhosis. Median HVPG was 6 mmHg (range 3-16). Liver stiffness measured by MRE correlated with HVPG ( r = 0.64, p = 0.01), histologic fibrosis score ( r = 0.71, p = 0.004), noninvasive fibrosis indices, including APRI ( r = 0.81, p < 0.001), and soluble LOXL2 ( r = 0.82, p = 0.001). On stepwise multivariate regression analysis, MRE was the only variable independently associated with HVPG ( R 2 = 0.377, p = 0.02). Conclusions. MRE of the liver correlated independently with HVPG. MRE is a valid noninvasive measure of liver disease severity and may prove to be a useful tool for noninvasive portal hypertension assessment. Trial Registration Number . This trial is registered with NCT01707472.

Background: Chronic liver injury can result in fibrosis that may progress over years to end-stage liver disease. The most effective anti-fibrotic therapy is treatment of the underlying disease, however when not possible, interventions to reverse or slow fibrosis progression are needed., Aim: The aim of this study was to study the safety and tolerability of simtuzumab, a monoclonal antibody directed against lysyl oxidase-like 2 (LOXL2) enzyme, in subjects with hepatitis C virus (HCV), human immunodeficiency virus (HIV), or HCV-HIV co-infection and advanced liver disease., Methods: Eighteen subjects with advanced liver fibrosis received simtuzumab 700 mg intravenously every 2 weeks for 22 weeks. Transjugular liver biopsies were performed during screening and at the end of treatment to measure hepatic venous pressure gradient (HVPG) and to stage fibrosis., Results: Treatment was well-tolerated with no discontinuations due to adverse events. No significant changes were seen in HVPG or liver biopsy fibrosis score after treatment. Exploratory transcriptional and protein profiling using paired pre- and post-treatment liver biopsy and serum samples suggested up-regulation of TGF-β3 and IL-10 pathways with treatment., Conclusion: In this open-label, pilot clinical trial, simtuzumab treatment was well-tolerated in HCV- and HIV-infected subjects with advanced liver disease. Putative modulation of TGF-β3 and IL-10 pathways during simtuzumab treatment merits investigation in future trials., Competing Interests: Dr. Meissner receives grant support from Gilead Sciences, Inc. Drs. Kanwar, Myers and Subramanian are employed by and own stock in Gilead Sciences Inc. Dr. Goodman reports grant support from Gilead Sciences, Inc., Tobira, Intercept, Galectin, Conatus, and Alexion. All other co-authors report no conflicts of interest., (© 2016 This article is a U.S. Government work and is in the public domain in the USA.)

Objective: Vibration-controlled transient elastography (VCTE) is increasingly used to assess liver fibrosis in viral hepatitis and fatty liver disease populations. Because the accuracy of VCTE in HIV-monoinfected populations has not been established, we evaluated its performance in assessing liver fibrosis in a cohort of HIV-monoinfected adults undergoing liver biopsy as part of a recently published clinical trial., Methods: HIV-infected adults with elevated aminotransferase levels for at least 6 months while receiving antiretroviral therapy, and without chronic viral hepatitis or other known causes of liver disease, were prospectively evaluated by VCTE, other noninvasive markers of fibrosis, and percutaneous liver biopsy as part of a cross-sectional study examining liver pathology., Results: Sixty-six patients were evaluated by VCTE and liver biopsy. The cohort was in the majority male (92%), with a median age of 50 years (range 17-68). Biopsy identified bridging fibrosis in 14 (21%) and nonalcoholic steatohepatitis in 38 (58%) participants. VCTE was unsuccessful or unreliable in seven participants (11%). In the 59 participants with reliable results, median liver stiffness measurement (LSM) was 5.9 kPa (range 3.3-29.2 kPa); 25 participants (42%) had a LSM above 7.1 kPa, a value consistent with increased liver stiffness in other populations. VCTE had good sensitivity and specificity with an area under the receiver-operating characteristic curve (AUROC) of 93% for detection of moderate fibrosis (Ishak F ≥ 2; 95% confidence interval 86-99%)., Conclusions: In HIV-monoinfected adults with biopsy-proven liver disease, LSM by VCTE was the best noninvasive predictor of fibrosis. Our findings support the continued use of VCTE for fibrosis screening in HIV-monoinfected patients with elevated aminotransferases.

Chronic hepatitis C infection frequently coexists with human immunodeficiency virus (HIV) and together are associated with increased hepatic steatosis. Steatosis is a risk factor for progression of liver disease and may persist despite a sustained virologic response to hepatitis C treatment. Therefore, therapies to target hepatic steatosis are important for individuals with HIV and hepatitis C virus (HCV) coinfection. We completed a 48-week, randomized, double-blind, placebo-controlled trial of pioglitazone (45 mg/day) in 13 subjects with HIV/HCV coinfection. The primary outcome variable was hepatic fat content, measured by magnetic resonance spectroscopy (MRS) imaging. Individuals randomized to pioglitazone had a significant decrease in hepatic fat content measured by MRS from baseline (15.1 ± 7.0%) to week 48 (7.6 ± 3.9%), with a mean difference of -7.4% (p = 0.02, n = 5). There was no significant change in hepatic fat content with placebo. Glycemic control as measured by oral glucose challenge improved significantly with pioglitazone (p = 0.047). Though not statistically significant, there were trends toward improved alanine aminotransferase (ALT) and histopathologic grade of steatosis in subjects who received pioglitazone. Pioglitazone was well tolerated and no one discontinued due to side effects. This study demonstrates that 48 weeks of pioglitazone therapy, and not placebo, results in significant reductions in hepatic fat content as measured by MRS in subjects with HIV and HCV coinfection and hepatic steatosis. This small study shows that pioglitazone helps ameliorate steatosis in the context of HIV/HCV coinfection.

Background: Persistent aminotransferase elevations are common in human immunodeficiency virus (HIV)-infected patients on antiretroviral therapy (ART), including those without hepatitis B or C coinfection, but their clinical significance is unknown., Methods: HIV-infected adults with aminotransferase levels elevated above the upper limit of normal for ≥6 months while receiving ART, and without chronic viral hepatitis or other known causes of chronic liver disease, underwent a detailed metabolic assessment and liver biopsy., Results: Sixty-two HIV-infected subjects completed the study. Forty (65%) had clinically significant liver pathology, including 34 (55%) with nonalcoholic steatohepatitis (NASH) and 11 (18%) with bridging fibrosis, 10 of whom also had NASH. Nonspecific abnormalities alone were seen in 22 (35%) subjects, including mild steatosis, mild to moderate inflammation, and evidence of drug adaptation. Insulin resistance, obesity, and the presence of either of 2 minor alleles in the PNPLA3 gene were significantly associated with increased risk of NASH and fibrosis. NASH and/or fibrosis were not associated with duration of HIV infection or ART, specific antiretroviral drugs, history of opportunistic infection, immune status, or duration of aminotransferase elevation., Conclusions: HIV-infected adults with chronic aminotransferase elevations while receiving ART have a high rate of liver disease. Noninvasive testing can help identify liver disease in such patients, but liver biopsy is necessary to definitively identify those at risk for liver disease progression and complications. Longitudinal follow-up of this cohort will better characterize the natural history of aminotransferase elevations in this population and identify noninvasive biomarkers of liver disease progression., (Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Despite the important diagnostic value of evaluating antibody responses to individual human pathogens, antibody profiles against multiple infectious agents have not been used to explore health and disease mainly for technical reasons.  We hypothesized that the interplay between infection and chronic disease might be revealed by profiling antibodies against multiple agents. Here, the levels of antibodies against a panel of 13 common infectious agents were evaluated with the quantitative Luciferase Immunoprecipitation Systems (LIPS) in patients from three disease cohorts including those with pathogenic anti-interferon-γ autoantibodies (IFN-γ AAB), HIV and Sjögren's syndrome (SjS) to determine if their antibody profiles differed from control subjects.  The IFN-γ AAB patients compared to controls demonstrated statistically higher levels of antibodies against VZV (p=0.0003), EBV (p=0.002), CMV (p=0.003), and C. albicans (p=0.03), but lower antibody levels against poliovirus (p=0.04). Comparison of HIV patients with blood donor controls revealed that the patients had higher levels of antibodies against CMV (p=0.0008), HSV-2 (p=0.0008), EBV (p=0.001), and C. albicans (p=0.01), but showed decreased levels of antibodies against coxsackievirus B4 (p=0.0008), poliovirus (p=0.0005),   and HHV-6B (p=0.002). Lastly, SjS patients had higher levels of anti-EBV antibodies (p=0.03), but lower antibody levels against several enteroviruses including a newly identified picornavirus, HCoSV-A (p=0.004), coxsackievirus B4 (p=0.04), and poliovirus (p=0.02). For the IFN-γ AAB and HIV cohorts, principal component analysis revealed unique antibody clusters that showed the potential to discriminate patients from controls.  The results suggest that antibody profiles against these and likely other common infectious agents may yield insight into the interplay between exposure to infectious agents, dysbiosis, adaptive immunity and disease activity.

Background: A high incidence of nontraumatic osteonecrosis has been reported in HIV-infected patients. We investigated the levels of D-dimer and C-reactive protein (CRP) in a cohort of HIV-infected adults with and without osteonecrosis of the femoral head., Methods: Forty-three HIV-infected patients with osteonecrosis of the femoral head and a comparison group of 50 HIV-infected patients with negative MRI of the hips and for whom serial plasma samples were available were included. D-dimer and CRP levels were measured prior to and at the time of diagnosis for osteonecrosis patients, at the time of negative MRI of the hips for controls, and at least 6 months later for both groups., Results: Biomarker levels were elevated at the time of diagnosis in the osteonecrosis cohort compared with controls. Median D-dimer value was 0.32 μg/ml in the osteonecrosis group compared with less than 0.22 μg/ml in the control group (P = 0.016). For CRP, the corresponding values were 2.52 mg/l and 1.23 mg/l (P = 0.003). Postdiagnosis, D-dimer and CRP levels were also elevated in the osteonecrosis patients compared with controls. Linear regression demonstrated a rise in D-dimer levels from prediagnosis to diagnosis in the osteonecrosis patients whereas CRP levels did not change significantly over time., Conclusion: Compared to controls, patients who developed osteonecrosis had elevated levels of D-dimer and CRP at diagnosis. D-dimer levels increased whereas CRP levels did not change significantly from prediagnosis to diagnosis. These data suggest that patients with higher levels of inflammation are at an increased risk of osteonecrosis.

Vanishing bile duct syndrome (VBDS) is a group of rare disorders characterized by ductopenia, the progressive destruction and disappearance of intrahepatic bile ducts leading to cholestasis. Described in association with medications, autoimmune disorders, cancer, transplantation, and infections, the specific mechanisms of disease are not known. To date, only 4 cases of VBDS have been reported in human immunodeficiency virus (HIV) infected patients. We report 2 additional cases of HIV-associated VBDS and review the features common to the HIV-associated cases. Presentation includes hyperbilirubinemia, normal liver imaging, and negative viral and autoimmune hepatitis studies. In HIV-infected subjects, VBDS occurred at a range of CD4+ T-cell counts, in some cases following initiation or change in antiretroviral therapy. Lymphoma was associated with two cases; nevirapine, antibiotics, and viral co-infection were suggested as etiologies in the other cases. In HIV-positive patients with progressive cholestasis, early identification of VBDS and referral for transplantation may improve outcomes.

Liver disease in HIV-infected patients is complex and multifactorial. Drug toxicity and infections are common causes of elevations in liver-associated enzymes. Immune reconstitution and unmasking of autoimmune disease may also play a role, particularly in the era of effective combination antiretroviral therapy. In this case report, we describe the first reported biopsy-confirmed case of autoimmune hepatitis and primary biliary cirrhosis overlap syndrome presenting in an HIV-infected patient following initiation of antiretroviral therapy.

Background: Although human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) affect mitochondrial DNA (mtDNA) content and function, comprehensive evaluations of their effects on mitochondria in muscle, adipose tissue, and blood cells are limited., Methods: Mitochondrial DNA quantification, mitochondrial genome sequencing, and gene expression analysis were performed on muscle, adipose tissue, and peripheral blood mononuclear cell (PBMC) samples from untreated HIV-positive patients, HIV-positive patients receiving nucleoside reverse transcriptase inhibitor (NRTI)-based ART, and HIV-negative controls., Results: The adipose tissue mtDNA/nuclear DNA (nDNA) ratio was increased in untreated HIV-infected patients (ratio, 353) and decreased in those receiving ART (ratio, 162) compared with controls (ratio, 255; P < .05 for both comparisons); the difference between the 2 HIV-infected groups was also significant (P = .002). In HIV-infected participants, mtDNA/nDNA in adipose tissue correlated with the level of activation (CD38+ /HLA-DR+) for CD4+ and CD8+ lymphocytes. No significant differences in mtDNA content were noted in muscle or PMBCs among groups. Exploratory DNA microarray analysis identified differential gene expression between patient groups, including a subset of adipose tissue genes., Conclusions: HIV infection and ART have opposing effects on mtDNA content in adipose tissue; immune activation may mediate the effects of HIV, whereas NRTIs likely mediate the effects of ART.

Current product labels for maraviroc and raltegravir provide no dosing guidance for patients with end-stage liver disease and worsening renal function. We describe a 41-year-old man with human immunodeficiency virus (HIV) infection and rapidly progressive liver failure and vanishing bile duct syndrome at presentation. Despite discontinuation of all potential offending drugs, the patient's liver function continued to deteriorate. To achieve and maintain HIV suppression while awaiting liver transplantation, a regimen consisting of maraviroc, raltegravir, and enfuvirtide was started. These agents were chosen because the patient was not exposed to them before the onset of liver failure. While receiving product label-recommended twice-daily dosing of these drugs, he achieved and maintained HIV suppression. During a complicated and prolonged hospitalization, the patient also developed renal dysfunction. As hepatic metabolism is the primary route of clearance of maraviroc and raltegravir, we predicted that using approved doses of these drugs could result in significant drug accumulation. Since the safety profiles of supratherapeutic concentrations of these agents are not well defined, we chose to use therapeutic drug monitoring to guide further dosing. The reported concentrations showed severely impaired metabolic clearance of both drugs, with markedly prolonged elimination half-lives of 189 hours for maraviroc and 61 hours for raltegravir. Previously reported half-lives for maraviroc and raltegravir in HIV-infected patients with normal hepatic and renal function are 14-18 hours and 9-12 hours, respectively. Based on these results, the dosing intervals were extended from twice/day to twice/week for maraviroc and every 48 hours for raltegravir. Unfortunately, the patient's clinical condition continued to deteriorate, and he eventually died of complications related to end-stage liver disease. This case illustrates the difficulties in managing antiretroviral therapy in an HIV-infected patient with combined severe liver and renal failure. Prolonged excessively high exposure to maraviroc and raltegravir is likely to result in some level of concentration-dependent toxicity. Until more data are available, therapeutic drug monitoring remains the only evidence-based approach to optimize dosage selection of these drugs in this patient population., (© 2012, Pharmacotherapy Publications, Inc.)

Background: Osteonecrosis is increasingly recognized as a debilitating complication of human immunodeficiency virus (HIV) infection, but the natural history has not been well described. We previously documented a high prevalence (4.4%) of magnetic resonance imaging (MRI)-documented osteonecrosis of the hip in a cohort of 339 asymptomatic HIV-infected patients. The present study was designed to determine the incidence of newly diagnosed osteonecrosis in this cohort and to describe the natural history of osteonecrosis in HIV-infected patients., Methods: Asymptomatic HIV-infected patients with a previous hip MRI negative for osteonecrosis underwent follow-up MRI. Patients with asymptomatic or symptomatic osteonecrosis were enrolled in a natural history study, which included serial MRIs and a physiotherapy follow-up., Results: Two hundred thirty-nine patients underwent a second MRI a median of 23 months after the initial MRI. Osteonecrosis of the femoral head was diagnosed in 3 patients (incidence, 0.65 cases per 100 person-years). During the period of January 1999 through April 2006, symptomatic hip osteonecrosis developed in 13 clinic patients (incidence, 0.26 cases per 100 person-years). Among 22 patients enrolled with symptomatic hip osteonecrosis, 18 had bilateral involvement of the femoral heads, and 7 had osteonecrosis involving other bones. Two (11%) of 18 asymptomatic patients and 13 (59%) of 22 symptomatic patients underwent total hip replacement. The percentage of involvement of the weight-bearing surface of the femoral head and the rate of progression to total hip replacement was significantly greater (P<.001) in symptomatic patients than in asymptomatic patients., Conclusions: HIV-infected patients are at approximately 100-fold greater risk of developing osteonecrosis than the general population. Disease progression is slower in asymptomatic patients than in symptomatic patients. Given the high frequency of total hip replacement in symptomatic patients, studies to assess preventive and treatment strategies are essential.

Objective: The increase in asthma prevalence has been documented worldwide, affecting many races living in many different climates. Multiple studies have demonstrated that the most striking prevalence and morbidity of asthma in the United States has been in black children, but little research has determined the scale of the increase, or specifically when the disease became severe in this group. This study sought to determine exactly when the rise in asthma hospitalizations among black patients began and what the pattern of asthma hospitalizations has been in different races and age groups over a 40-year period in 1 urban area., Methods: A retrospective chart review of discharges from the Medical University of South Carolina was conducted from 1956 to 1997. Charts with the primary discharge diagnosis of asthma were examined for discharge date, race, and age group (0- to 4-year-olds, 5- to 18-year-olds, 19- to 50-year-olds, > or =51-year-olds). The diagnostic codes used were based on the International Classification of Diseases (ICD)-6, 1956-1957; ICD-7, 1958-1967; ICD-8, 1968-1978; and ICD-9, 1979-1997. Over the period studied, this hospital was the primary inpatient provider for children in this area, and the only provider for uninsured children. Between 1960 and 1990, the racial makeup of the area remained stable, as did the percentage of blacks living at the poverty level. The raw number of asthma discharges, rate per 10 000 discharges of the same race, and rate per 100 000 population in Charleston County were tabulated for each age group and racial category., Results: Over the time period examined, there has been a progressive increase in asthma hospitalizations in black individuals of all age groups and in whites under 18 years. The most striking increase has been in black children 0 to 18 years old (figure). The increase either as raw values or as a rate per 100 000 began around 1970, and was linear. This increase in black children discharged with asthma as a rate per 100 000 population was 20-fold: the rate increased from 18 in 1970 to 370 in 1997. Asthma discharges as a rate per 10 000 black children discharged increased by 24-fold from 1960 to 1997. Total discharges from the hospital increased from 49 000 to 128 000 per year over this period. Blacks made up only 28% of discharges in 1957, but that proportion increased to 56% in 1960 and remained relatively stable over the following 35 years. The increase seen in white children 0 to 18 years of age as a rate per 100 000 population was 5-fold and began around 1980. Both increases seem to be consistent over the time period studied, and continued to 1997. [figure: see text]., Conclusions: Among a predominantly poor black population living in a southern US city, there has been a steady increase in childhood asthma hospitalizations over the past 30 years. A significant although less dramatic rise has occurred in white children. Over this time period, although there have been many changes in lifestyle that could have contributed to this rise, there have been no major changes in housing conditions for poor patients. In addition, Medicaid coverage for children in South Carolina did not change significantly until 1999. The time course of these increases parallels increases reported in other Western populations, suggesting that there must be 1 or more common factors contributing to the rise. Many explanations have been offered for the changes in incidence and severity of asthma. The scale of the change, time course, and linearity of the increase in this study represent a challenge to many of the hypotheses proposed to explain this epidemic.