Transcriptionally Active Defective HIV-1 Proviruses and Their Association With Immunological Nonresponse to Antiretroviral Therapy.

A subset of antiretroviral therapy-treated persons with human immunodeficiency virus (HIV), referred to as immunological nonresponders (INRs), fails to normalize CD4+ T-cell numbers. In a case-control study involving 26 INRs (CD4 < 250 cells/µL) and 25 immunological responders (IRs; CD4 ≥ 250 cells/µL), we evaluated the potential contribution of transcriptionally competent defective HIV-1 proviruses to poor CD4+ T-cell recovery. Compared to the responders, the INRs had higher levels of cell-associated HIV RNA (P = .034) and higher percentages of HLA-DR+ CD4+ T cells (P < .001). While not encoding replication-competent viruses, the RNA transcripts frequently encoded HIV-1 Gag-p17 and Nef proteins. These transcripts and/or resulting proteins may activate pathway(s) leading to the immunological nonresponse phenotype.

Infectious Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Virus in Symptomatic Coronavirus Disease 2019 (COVID-19) Outpatients: Host, Disease, and Viral Correlates.

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.

Increased Body Mass Index and Type 2 Diabetes Are the Main Predictors of Nonalcoholic Fatty Liver Disease and Advanced Fibrosis in Liver Biopsies of Patients With Human Immunodeficiency Virus Monoinfection.

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.

New Drugs for NASH and HIV Infection: Great Expectations for a Great Need.

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.

A Qualitative Systematic Review of Cigarette Smoking Cessation Interventions for Persons Living with HIV.

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.

Rheological determinants for simultaneous staging of hepatic fibrosis and inflammation in patients with chronic liver disease.

The purpose of this study is to investigate the use of fundamental rheological parameters as quantified by MR elastography (MRE) to measure liver fibrosis and inflammation simultaneously in humans. MRE was performed on 45 patients at 3 T using a vibration frequency of 56 Hz. Fibrosis and inflammation scores were obtained from liver biopsies. Biomechanical properties were quantified in terms of complex shear modulus G* as well as shear wave phase velocity c and shear wave attenuation α. A rheological fractional derivative order model was used to investigate the linear dependence of the free model parameters (dispersion slope y, intrinsic speed c0 , and intrinsic relaxation time τ) on histopathology. Leave-one-out cross-validation was then utilized to demonstrate the effectiveness of the model. The intrinsic speed c0 increases with hepatic fibrosis, while an increased relaxation time τ is reflective of more inflammation of the liver parenchyma. The dispersion slope y does not depend either on fibrosis or on inflammation. The proposed rheological model, given this specific parameterization, establishes the functional dependences of biomechanical parameters on histological fibrosis and inflammation. The leave-one-out cross-validation demonstrates that the model allows identification, from the MRE measurements, of the histology scores when grouped into low-/high-grade fibrosis and low-/high-grade inflammation with significance levels of P = 0.0004 (fibrosis) and P = 0.035 (inflammation). The functional dependences of intrinsic speed and relaxation time on fibrosis and inflammation, respectively, shed new light onto the impact hepatic pathological changes on liver tissue biomechanics in humans. The dispersion slope y appears to represent a structural parameter of liver parenchyma not impacted by the severity of fibrosis/inflammation present in this patient cohort. This specific parametrization of the well-established rheological fractional order model is valuable for the clinical assessment of both fibrosis and inflammation scores, going beyond the capability of the plain shear modulus measurement commonly used for MRE.

Unanticipated increases in hepatic steatosis among human immunodeficiency virus patients receiving mineralocorticoid receptor antagonist eplerenone for non-alcoholic fatty liver disease.

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.

Adverse effects of antiretroviral therapy on liver hepatocytes and endothelium in HIV patients: An ultrastructural perspective.

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.

Simtuzumab treatment of advanced liver fibrosis in HIV and HCV-infected adults: results of a 6-month open-label safety trial.

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-ß3 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-ß3 and IL-10 pathways during simtuzumab treatment merits investigation in future trials.

The Association Between Post-traumatic Stress Disorder and Markers of Inflammation and Immune Activation in HIV-Infected Individuals With Controlled Viremia.

BACKGROUND: Post-traumatic stress disorder (PTSD) may be associated with chronic immune dysregulation and a proinflammatory state. Among HIV-infected individuals, PTSD is associated with greater morbidity and mortality, but the association with immune dysfunction has not been evaluated. This study explores the association between PTSD and selected markers of inflammation and immune activation in a cohort of HIV-infected, virally-suppressed individuals. METHODS: HIV-infected adults who were virologically controlled on antiretroviral medications were recruited through a screening protocol for studies of HIV-related neurocognitive disorders. Each participant underwent blood draws, urine toxicology screen, and completed the Client Diagnostic Questionnaire, a semistructured psychiatric interview. RESULTS: Of 114 eligible volunteers, 72 (63%) were male, 77 (68%) African American, and 34 (30%) participants met criteria for PTSD. Participants with PTSD were more likely to be current smokers (79%) than those without (60%) (p = 0.05). The PTSD cohort had significantly higher total white blood cell counts (5318 and 6404 cells/uL, p = 0.03), absolute neutrophil count (2767 and 3577 cells/uL, p = 0.02), CD8% (43 and 48, p = 0.05), and memory CD8% (70 and 78%, p = 0.04); lower naïve CD8% (30 and 22%, p = 0.04) and higher rate of high-sensitivity C-reactive protein >3mg/L (29 and 20, p = 0.03). DISCUSSION: A high prevalence of PTSD was identified in this cohort of HIV-infected adults who were virally suppressed. These results suggest that PTSD may be associated with immune dysregulation even among antiretroviral therapy-adherent HIV-infected individuals.

Nonalcoholic Steatohepatitis and Hepatic Fibrosis in HIV-1-Monoinfected Adults With Elevated Aminotransferase Levels on Antiretroviral Therapy.

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.

Assessment of liver fibrosis using fast strain-encoded MRI driven by inherent cardiac motion.

PURPOSE: An external driver-free MRI method for assessment of liver fibrosis offers a promising noninvasive tool for diagnosis and monitoring of liver disease. Lately, the heart's intrinsic motion and MR tagging have been utilized for the quantification of liver strain. However, MR tagging requires multiple breath-hold acquisitions and substantial postprocessing. In this study, we propose the use of a fast strain-encoded (FSENC) MRI method to measure the peak strain (Sp ) in the liver's left lobe, which is in close proximity and caudal to the heart. Additionally, we introduce a new method of measuring heart-induced shear wave velocity (SWV) inside the liver. METHODS: Phantom and in vivo experiments (11 healthy subjects and 11 patients with liver fibrosis) were conducted. Reproducibility experiments were performed in seven healthy subjects. RESULTS: Peak liver strain, Sp , decreased significantly in fibrotic liver compared with healthy liver (6.46% ± 2.27% vs 12.49% ± 1.76%; P < 0.05). Heart-induced SWV increased significantly in patients compared with healthy subjects (0.15 ± 0.04 m/s vs 0.63 ± 0.32 m/s; P < 0.05). Reproducibility analysis yielded no significant difference in Sp (P = 0.47) or SWV (P = 0.56). CONCLUSION: Accelerated external driver-free noninvasive assessment of left liver lobe strain and SWV is feasible using strain-encoded MRI. The two measures significantly separate healthy subjects from patients with fibrotic liver. Magn Reson Med 74:106-114, 2015. © 2014 Wiley Periodicals, Inc.

HIV infection and antiretroviral therapy have divergent effects on mitochondria in adipose tissue.

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.

Cardiology Encounters for Underrepresented Racial and Ethnic Groups with Human Immunodeficiency Virus and Borderline Cardiovascular Disease Risk.

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.

Hydrogen-1 MR spectroscopy for measurement and diagnosis of hepatic steatosis.

OBJECTIVE: Hydrogen-1 MR spectroscopy ((1)H-MRS) is gaining acceptance as a noninvasive technique for assessment of hepatic steatosis, and the findings have been found to correlate closely with histopathologic grade. The aims of this study were to validate (1)H-MRS performed with a 3-T MRI system for quantifying hepatic steatosis and to determine threshold values of (1)H-MRS proton density fat fraction corresponding to standard histopathologic grade in patients undergoing diagnostic liver biopsy. SUBJECTS AND METHODS: We conducted a prospective cross-sectional liver MRS study with 52 subjects undergoing diagnostic liver biopsy. The diagnostic accuracy of (1)H-MRS was evaluated with receiver operating characteristic curves. RESULTS: The diagnostic accuracy of (1)H-MRS for hepatic steatosis was high with an area under the receiver operating characteristic curve of 0.94 (95% CI, 0.88-1.0). Results were similar for three (1)H-MRS measurements obtained at different locations in the liver, for two independent pathologists, and whether fibrosis was present or absent. One third of participants had elevated transaminase concentrations of unknown cause, and (1)H-MRS estimates of steatosis had perfect agreement with histopathologic grade in this group. Calculated (1)H-MRS proton density fat fraction thresholds for histologic grades were less than 17% for grade 0 or trace steatosis, 17-38.6% for grade 1, and greater than 38.6% for grade 2 or higher. CONCLUSION: Hydrogen-1 MR spectroscopy is an effective, noninvasive technique that can be used to diagnose and quantify hepatic steatosis. Hydrogen-1 MR spectroscopy thresholds corresponded with histopathologic grades and may be useful in the workup of patients with elevated transaminase concentrations.

Efficacy of Inhaled Ciclesonide for Outpatient Treatment of Adolescents and Adults With Symptomatic COVID-19: A Randomized Clinical Trial.

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.

Exploring the consequences of food insecurity and harnessing the power of peer navigation and mHealth to reduce food insecurity and cardiometabolic comorbidities among persons with HIV: protocol for development and implementation trial of weCare/Secure.

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.

Short Communication: A Pilot Study of the Effects of Losartan Versus Placebo on Pneumoproteins in HIV: A Secondary Analysis of a Randomized Double Blind Study.

HIV is an independent risk factor for lung disease, including chronic obstructive pulmonary disease (COPD) and emphysema. Angiotensin receptor blockers may be beneficial in COPD and emphysema through pathways that have been implicated in HIV-related lung disease. We performed a randomized comparison of the effects of losartan versus placebo on the plasma concentrations of the pneumoproteins, surfactant protein D (SPD) and club cell secretory protein (CCSP), in people living with HIV (PLWH). A total of 108 PLWH were included (52 assigned to losartan and 56 assigned to placebo). We found no difference in the change from baseline in log2 concentrations of CCSP or SPD over 1 year of follow-up. For SPD, we found a strong interaction by CD4+ counts, where those with CD4+ counts >350 cells/mm3 treated with losartan had more reduction (improvement) in SPD concentration than those treated with placebo (p value for interaction <.001). In conclusion, we did not find a beneficial effect of losartan on pneumoprotein concentrations in PLWH, but PLWH with higher CD4+ counts may have improvement in SPD when treated with losartan.

Prevalence and Correlates of Electrocardiographic Abnormalities in Adults With HIV: Insights From the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE).

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.