Matthew S. Durstenfeld

Persistence of SARS-CoV-2 has been proposed as a biological driver of Long COVID, a disabling chronic illness with no proven treatments. We conducted an exploratory, placebo-controlled, double-blind, 2:1 randomized mechanistic trial (NCT05877508) of the SARS-CoV-2-specific monoclonal antibody AER002 in 36 participants who met the World Health Organization case definition of Long COVID. After baseline characterization, participants received a single infusion and were followed for 360 days. The primary endpoint was the PROMIS-29 Physical Health Summary Score (PHSS) at 90 days; secondary and exploratory endpoints included patient-reported and objective measures of physical and neurocognitive function as well as blood-, imaging-, and tissue-based biomarkers. While AER002 was safe and well tolerated, no significant differences in physical health, quality of life, objective measures of physical function or cognition, or blood-based biomarkers were demonstrated between the treatment and control arms. In a post-hoc analysis, participants with a lower baseline SARS-CoV-2 antibody level and higher drug exposure were more likely to perceive treatment benefit based on the Patient Global Impression of Change scale ( p < 0.05 for anti-S, S1, and RBD). Although AER002 was not efficacious in this proof-of-concept study, our findings could inform future trials using monoclonal antibodies to target viral persistence in Long COVID.

Obesity is a major risk factor for CKD, which contributes to a complex interplay of metabolic, inflammatory, and hemodynamic disturbances that accelerate kidney function decline and heighten cardiovascular risk. Obesity contributes to kidney injury through direct mechanisms, including glomerular hyperfiltration and increased intraglomerular pressure, and indirect pathways mediated by diabetes, hypertension, and cardiovascular–metabolic disease, while also promoting tubular injury. Emerging evidence also suggests that adipose tissue distribution influences end-organ damage, with visceral and ectopic perirenal fat depots linked to CKD. These inter-relationships are corroborated by population-based studies showing that markers of adiposity are associated with higher risk of incident CKD, CKD progression, and ESKD. With the advent of newer therapeutics, the management of obesity in CKD has shifted from a predominantly lifestyle-focused approach to a more comprehensive, multimodal strategy that integrates pharmacologic therapies with established cardiovascular–kidney–metabolic benefits, alongside structured nutritional guidance, individualized physical activity, and sustained behavioral support. Incretin-based therapies, particularly glucagon-like peptide-1 receptor agonists (GLP1ra) and dual incretin agonists, have redefined treatment paradigms by addressing metabolic dysfunction, CKD progression, and cardiovascular risk. Emerging agents, including triple incretin agonists, promise even greater efficacy in weight reduction and metabolic control, although data on efficacy and safety in kidney disease remain limited. Sodium–glucose cotransporter 2 inhibitors also promote modest weight loss, largely through urinary glucose-mediated caloric loss, while providing cardio-kidney protection. With respect to nonpharmacological interventions, clinical studies show bariatric surgery achieves substantial weight loss and is associated with improved cardio-kidney outcomes in CKD. In this review, we examine ( 1 ) the pathophysiology of obesity-induced kidney disease and its cardiometabolic complications, ( 2 ) risk stratification of obesity and CKD, ( 3 ) current and emerging evidence on pharmacotherapies for obesity, including practical considerations in CKD, and ( 4 ) an integrated stepwise antiobesity management approach aligned with the cardiovascular–kidney–metabolic framework.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is associated with cardiovascular disease (CVD) in the general population and is more common among people with HIV (PWH). The mechanisms by which CHIP contributes to atherosclerosis in PWH are unknown. We hypothesized that CHIP is associated with carotid atherosclerosis and arterial inflammation among PWH. Methods: In a cohort study, we studied PWH ages 31-74 years with treated, suppressed HIV. CHIP mutations were detected with a validated targeted sequencing assay. Carotid intima-media thickness (IMT) was measured longitudinally with ultrasound. Aortic inflammation and lymph node activity were assessed cross-sectionally using ¹⁸ F-FDG-PET. Inflammatory biomarkers were measured using multiplex electrochemiluminescence assay. Linear regression was employed, with adjustments for traditional and HIV-related factors. Results: We included 230 PWH (52±9 years, 7% female); 32 (14%) had CHIP with median variant allele fraction of 2.8%. Common mutations were in DNM3TA (n=21) and TET2 (n=6). Age was associated with CHIP (OR 2.0 per decade older, 95% CI 1.3-3.01; p=0.002). Among 166 participants with IMT measurements (CHIP=23), CHIP was not associated with IMT (p=0.21; unchanged after adjustment). Among 80 with FDG-PET, CHIP (n=12) was not associated with arterial inflammation (p=0.89), but was associated with higher lymph node metabolic activity (p=0.017) that was attenuated in reference to background activity and adjusted for risk factors. CHIP was not associated with soluble inflammatory markers or viral persistence markers. Conclusions: Among PWH, CHIP mutations were not associated with subclinical atherosclerosis, arterial inflammation, or soluble inflammatory markers but may be related to lymph node metabolic activity. The mechanism by which CHIP increases HIV-associated atherosclerosis may preferentially involve lymph nodes and merits additional evaluation. Visual Visual Abstract Legend: We hypothesized that clonal hematopoeiesis of indeterminate potential (CHIP) may be a mediator of the association between HIV and atherosclerosis; we investigated this hypothesis by measuring CHIP mutations in human blood samples from people with HIV (PWH) and determining whether CHIP mutations were associated with carotid intima media thickness assessed using ultrasound (longitudinal, n=166) and aortic inflammation using ¹⁸ F-FDG-PET-CT (cross-sectional, n=80). In our study of 230 PWH (32 with CHIP), we did not find evidence for an association between the presence of any CHIP mutation and either carotid atherosclerosis or arterial inflammation. Condensed People with HIV (PWH) ave increased risk of clonal hematopoiesis of indeterminate potential (CHIP) and atherosclerosis, but whether clonal hematopoiesis accelerates atherosclerosis among PWH is unknown. We hypothesized that CHIP is associated with carotid atherosclerosis and arterial inflammation among PWH. In a cohort study that conducted longitudinal carotid ultrasound and 18F-FDG-PET, we studied PWH ages 31-74 years with treated, suppressed HIV. We measured CHIP mutations with a validated targeted sequencing assay. We included 230 PWH (52+9 years, 7% female); 32 (14%) had CHIP (66% DNMT3A) with median variant allele fraction of 2.8%. Overall, CHIP was not associated with carotid intima media thickness or arterial inflammation assessed with FDG PET. CHIP was associated with increased lymph node metabolic activity, a hypothesis-generating finding. Among PWH, CHIP was not associated with markers of subclinical atherosclerosis.

Background: Autonomic symptoms and orthostatic syndromes have been reported in Long COVID, but few studies have characterized findings using head up tilt table testing. Objective: To characterize autonomic responses to positional changes among individuals with Long COVID. Methods: We assessed autonomic symptoms using the Composite Autonomic Symptom Scale 31 (COMPASS 31) instrument and performed head up tilt table testing for 30 minutes at 70 degrees among individuals with Long COVID and recovered comparators. Results: We included 26 participants (median age 56 years, 50% female median 25 months after first COVID): 16 with Long COVID and 10 recovered comparators. COMPASS 31 scores (0–100, higher is worse) were higher among those with Long COVID (median 30.5 vs 8, p = 0.003). Heart rate was 8 beats per minutes higher throughout tilt among those with Long COVID (95% CI 1.1 to 14.4; p = 0.02); there were no differences in blood pressure. Ten (63%) with Long COVID had symptoms during tilt compared to none among recovered participants (p = 0.003). Three (19%) with Long COVID had clinically abnormal findings: one each with orthostatic hypotension, and delayed orthostatic hypotension, and cardioinhibitory/vasovagal presyncope. Conclusions: Among those with chronic autonomic symptoms in the setting of Long COVID, symptoms were common during tilt testing, and heart rate was increased, but most did not meet diagnostic criteria for a clinically abnormal hemodynamic response. Further research into mechanisms of autonomic symptoms in Long COVID is urgently needed.

Background: People with HIV (PWH) are at elevated cardiovascular risk, but existing calculators have suboptimal calibration for this population. The American Heart Association developed new prediction equations (PREVENT) to replace the pooled cohort equations (PCE). PREVENT has not been validated among PWH. Methods: Within the Center for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort, we included individuals aged 40–75 without myocardial infarction or stroke at baseline from 2001 to 2021. We calculated predicted 10-year atherosclerotic cardiovascular disease (ASCVD) risk at baseline using the PCE and the PREVENT 10-year ASCVD base equation. Myocardial infarction and stroke were systematically adjudicated. To assess discrimination, we calculated Harrell's C-index and to assess calibration we used the Greenwood–Nam–D’Agostino goodness-of-fit tests. Results: We included 13 135 individuals from five sites across the United States. Mean age at enrollment was 44 ± 9 years and 18% were female. Mean predicted 10-year ASCVD risk was 5.8% by PCE and 2.9% by PREVENT. Over 5.7 ± 3.5 years of follow-up, 628 individuals had myocardial infarction or stroke. Discrimination was improved with PREVENT compared to PCE, with Harrell's C-indexes of 0.722 (95% CI 0.701, 0.741) and 0.708 (95% CI 0.687, 0.729), respectively (P = 0.008). Both equations underpredicted risk: the observed-to-expected ratio was 2.69 for PREVENT (P < 0.001) and 1.35 for PCE (P < 0.001). Calibration slopes were 1.998 for PREVENT and 0.932 for PCE, respectively. Conclusions: Among this cohort of PWH, the PREVENT 10-year ASCVD equations were poorly calibrated and underestimated composite risk for myocardial infarction and stroke, with observed risks more than double predicted risks.

Background: People with HIV (PWH) are at elevated risk of atherosclerotic cardiovascular disease (ASCVD), and current risk prediction tools underestimate risk among PWH. The American Heart Association developed new risk prediction equations, Predicting Risk of cardiovascular disease EVENTs (PREVENT), which have not been studied among PWH. Objective: To compare predicted 10-year ASCVD risk using PREVENT with the pooled cohort equations (PCE) and the implications for statin recommendations among PWH. Design: A cross-sectional observational study using real-world, electronic health records Participants: All people with HIV ages 40 to 75 without cardiovascular disease at 23 primary care and HIV clinics affiliated with two health systems in San Francisco, California from 2019 to 2024 Main Measures: We compared predicted 10-year ASCVD using the PREVENT equations and the PCE. Then we considered implications of PREVENT for statin therapy using current guidelines. Key Results: Among 3357 PWH (median 57 years old; 73% male,12% female, 15% transgender/nonbinary/nondisclosed; 20% Black and 25% Latino), 91% were on antiretroviral therapy and 86% had virologic suppression. Among 2853 PWH with complete data for both calculators, the median predicted risk was 7.7% (interquartile range (IQR) 3.7, 14.0) using the PCE and 3.3% (IQR 1.9, 5.4) using PREVENT. Predicted risk was lower for 97% of individuals using PREVENT. Using a 10-year ASCVD risk threshold of 5%, only 28.6% of PWH would be strongly recommended for statins with PREVENT compared to 67.3% with PCE. The difference in predicted risk between the two equations varied across sex and race/ethnicity. Conclusions: The PREVENT equations predict lower 10-year ASVCD risk for PWH compared to the PCE, which underpredicts risk for PWH. Underprediction of ASCVD risk, which —using new guidelines —would translate to 58% fewer PWH strongly recommended for statins using PREVENT compared to PCE, has the potential to increase cardiovascular disease and worsen healthcare disparities among PWH.