Katherine Tassiopoulos

Background: Potential harms of preventable/modifiable use of substances, such as cannabis, among aging people with HIV (PWH) are unclear. We characterized longitudinal associations between current cannabis use and subsequent fall risk among aging PWH. Method: Participants in the Advancing Clinical Therapeutics Globally (ACTG) A5322 study self-reported current cannabis use and any fall(s) annually and semiannually, respectively. Generalized linear models and inverse probability weighting were used to assess associations between cannabis use and subsequent fall risk, adjusting for baseline covariates (age, sex assigned at birth, and race/ethnicity), time-varying confounders, and study attrition. Results: Among 957 participants (median age, 51 years), 18.2% reported current cannabis use at baseline; 18.6% reported falling in the first year of the longitudinal study. Current cannabis use was associated with moderate risk of any falls in the following year in baseline covariate-adjusted analysis (risk ratio [RR], 1.27 95% CI, 1.02, 1.57; P = .029), but not in analyses additionally adjusted for fall history, nonprescribed psychoactive substance use, psychotropic and analgesic medication use, heavy alcohol use, peripheral neuropathy, and cigarette smoking status (adjusted RR, 1.11 [95% CI, .83, 1.49]; P = .49). Cigarette smoking status was the main variable that attenuated the association between falls and cannabis use. Conclusions: Among aging PWH, the association between current cannabis use and fall risk was primarily confounded by cigarette smoking status. Future studies should incorporate more granular cannabis use data on falls risk, including cannabis composition or strain and dose.

Background: People with HIV (PWH) are living longer due to effective antiretroviral therapy (ART) but face accelerated aging, accumulating comorbidities, and high rates of polypharmacy. Whether neuroinflammatory biomarkers are associated with polypharmacy and adverse clinical outcomes such as falls in this population is unknown. Methods: We performed a cross-sectional analysis of baseline data from 600 virally suppressed PWH ≥40 years enrolled in the ACTG A5322 HAILO cohort. Plasma neurofilament light chain (NfL), neopterin, and soluble CD14 (sCD14) were measured. Multivariable logistic regression examined associations between each biomarker and polypharmacy (five or more non-ART medications), recurrent falls (two or more falls/6 months), and slow gait speed less than one m/s), adjusting for age, sex, and comorbidity burden. Results: The median age was 54 years, 78% of participants were male, and 232 participants (39%) had polypharmacy. Elevated NfL was independently associated with polypharmacy in multivariable analysis (aOR 1.16 [95% CI 1.07–1.26]). In the total population, elevated NfL (OR 1.24 [1.05–1.46]) and sCD14 (OR 1.12 [1.01–1.23]) were each associated with recurrent falls. Among participants with polypharmacy, only elevated sCD14 remained associated with recurrent falls on stratified multivariable analysis (OR 1.15 [1.02–1.30]). No biomarker was significantly associated with slow gait speed. Conclusions: In older virally suppressed PWH, plasma NfL and sCD14 are associated with distinct adverse clinical phenotypes—medication burden and fall risk, respectively, and may serve as complementary biomarkers of distinct biological pathways relevant to aging in HIV.

Introduction: Literature on hospitalization incidence and risks among people with HIV (PWH) in the current antiretroviral therapy era is limited. Methods: Using data (2017 to 2021) on PWH ≥40 years of age from the Advancing Clinical Therapeutics Globally (ACTG) HAILO Study, cumulative probabilities of first hospitalization were estimated using Kaplan-Meier plots. Cox proportional hazards regression was used to identify factors associated with first hospitalization. Results: Among 891 participants (median age 50 years; 80% male), 38 with prevalent hospitalization at baseline were excluded. The remaining 853 participants had a follow-up of 2721 person-years, during which 170 (20%) had at least 1 hospitalization event (incidence rate, 6.2 per 100 person-years [95% CI=5.4-7.3]). The leading causes of hospitalization included infections (14%), elective surgery (13%), cardiovascular conditions (12%), and lung problems (12%). Former and current smokers had higher hospitalization risk (adjusted hazard ratio [aHR] 1.51 [95% CI=1.03-2.20], aHR 1.85 [95% CI=1.24-2.76], respectively) than never smokers. Hospitalization risk was higher for participants who were frail (aHR 2.31 [95% CI=1.38-3.86]) compared to those that were robust (not frail), and lower in the Western region compared with the Northeast region (HR= 0.55, 95% CI: 0.32–0.93). Hospitalization risk was also higher for participants with diabetes (aHR 1.69 [95% CI=1.13-2.52]. Conclusion: We observed a lower hospitalization risk than in previous studies among PWH. Interventions to reduce smoking, prevent frailty, and improve diabetes management may further lower hospitalization risk.

People with human immunodeficiency virus (HIV) have an earlier occurrence of aging complications, including cognitive impairment (CI). Chronic immune activation from cytomegalovirus (CMV) may contribute to increased inflammation and CI. We explored this association using several measures of CMV immune response among people with HIV (PWH). In a case-control design, we compared CMV immunoglobulin G (IgG), enzyme-linked immunospot (ELISpot), and flow cytometry between cases (subsequent CI) and controls (no CI). Baseline CMV IgG, CMV ELISpot, or flow measures were not associated with subsequent CI. This exploratory analysis supports larger studies using more nuanced immunophenotyping to clarify relationship between CMV and development of CI in PWH.

Background: Despite effective antiretroviral therapy (ART), serious non-AIDS events (SNAEs), including cardiovascular disease and death, remain prevalent among people with HIV (PWH). Imperfect ART adherence despite viral suppression may contribute to this risk, underscoring the need to clarify the relationship between adherence, viral load dynamics, and SNAE development. Methods: We performed an analysis of deidentified data of participants in the prospective observational Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACTG) A5001 and A5322 studies. The baseline was defined as the time at the first viral suppression to 90% versus ≤90% adherence. Data were primarily analyzed using inverse probability of censoring weights modeling. Results: Among 2940 participants followed for a median of 6.2 years, 237 SNAEs occurred, comprising 103 deaths and 134 cardiovascular events. Nearly all participants (95.9%) remained virally suppressed to 90% showed a protective effect on the development of all SNAEs: adjusted hazard ratio (aHR) 0.612 (95% confidence interval .390–.961). When only the development of the first SNAE was considered, the association remained substantially similar: aHR 0.641 (95% confidence interval .400–1.027). Conclusions: Adherence to ART >90% compared to ≤90% reduces SNAE risk even in virally suppressed PWH, underscoring the need for continued adherence support to improve long-term health outcomes for PWH.

Background: Little is known about the specific inflammatory networks and immune parameters that drive frailty outcomes in people with HIV (PWH). Methods: Plasma analytes and T-cell phenotypes from PWH without frailty (0 Fried score, n = 60) and with frailty (≥3 Fried score, n = 60) were measured by Luminex assay or flow cytometry. Multiple least-squares linear regression analysis was used to determine the association of each marker with frailty in unadjusted and adjusted models. Spearman correlations were used to determine the association of plasma analytes with T-cell phenotypes. Results: We found that 19 of 75 markers measured in plasma were significantly associated with frailty, most of which are downstream of NF-κB signaling and are senescence-associated secretory phenotype (SASP) components. In frail individuals, the proportions of CD4 and CD8 T cells with a naïve phenotype were significantly reduced, and the proportions of CD4 T cells expressing TIGIT and PD-1 were significantly elevated. Of the frailty-associated analytes, we found that only osteoprotegerin and TNF levels were significantly correlated with percent naïve, TIGIT+, and PD-1+ CD4 T cells among PWH with frailty. Osteoprotegerin levels were negatively correlated with CD4/CD8 T-cell ratio. Conclusions: We found a strong association of the SASP and NF-κB-related inflammation with frailty in PWH. Osteoprotegerin can inhibit osteoclast formation and prevent bone resorption. Low proportion of naïve CD4 T cells and increased TIGIT and PD-1 expression were associated with both osteoprotegerin levels and frailty, suggesting a link between inflammation, T-cell activation, bone health, and frailty in PWH.

Glycation is a class of modifications arising from non-enzymatic reactions of reducing sugars with proteins, lipids, and/or DNA, generating advanced glycation end-products (AGEs). AGEs are linked to many age-related comorbidities. In response to HIV-1 infection, activated T-cells and macrophages shift their predominate metabolism from oxidative phosphorylation to glycolysis. Increased glycolytic flux enhances AGE formation, which may increase age-related comorbidities. In this prospective, multicenter cohort study of antiretroviral therapy treated people with HIV, we explored predictive associations by baseline plasma AGE concentrations and their corresponding detoxification metabolites, with incident comorbidities and mortality. AGEs included dicarbonyl sugars: 3-deoxyglucosone, glyoxal, and methylglyoxal. Methylglyoxal-derived metabolites included carboxyethyl-arginine, carboxyethyl-lysine, and methylglyoxal hydroimidazolone-1. Detoxification metabolites included reduced and oxidized glutathione, and the glyoxalase cycle products lactoyl-glutathione and lactoyl-Lysine modified proteins. Plasma was collected at study entry, in the fasting state, and assayed by liquid chromatography-mass spectroscopy. Incident clinical outcomes included diabetes, chronic kidney disease, hypertension, neurocognitive impairment, peripheral neuropathy, frailty, fractures, recurrent falls, and all-cause mortality. Among 376 participants, higher baseline plasma concentrations of methylglyoxal derived AGEs predicted increased risks of diabetes, chronic kidney disease, and recurrent falls, while higher 3-deoxyglucosone predicted an increased risk of peripheral neuropathy. By contrast, higher baseline concentrations of reduced or oxidized glutathione, lactoyl-glutathione, and/or lactoyl-Lysine modified proteins predicted lower risks of diabetes, neurocognitive impairment, frailty, fractures, recurrent falls, and all-cause mortality. These findings support growing experimental evidence of the potential to mitigate age-related declines by interventions that reduce glycation or increase glutathione.

Background: Most young adults with perinatal HIV (PHIV) transition from pediatric or adolescent to adult clinical care. Although guidelines to increase transition success have been recommended, we know little about uptake of these guidelines, particularly by adult care clinics. Methods: We administered web-based surveys to adult care providers of young adults with PHIV in Massachusetts to evaluate transition preparation and post-transition evaluation practices. We compared transition practices and HIV care continuum outcomes by clinic setting. Results: Twenty-four providers submitted information on 23 adult care clinics. Ten were hospital-based and 13 were community-based clinics. Community-based clinics were more likely than hospital-based clinics to conduct pre-transition (33% vs. 10%) and post-transition (67% vs. 30%) evaluation of patients' readiness to self-manage health care, and to share health outcome information with the pediatric/adolescent care team (50% vs. 20%). Community-based clinics were also more likely to have personnel dedicated to the transition process and to facilitate communication between the patient and pediatric/adolescent care team. Engagement in care was similar for young adults with PHIV seen at community-based and hospital-based clinics (88.2% vs. 85.5%; P = 1.00), but retention in care (76.5% vs. 50.5%; P = 0.05) and viral suppression (88.2% vs. 65.1%; P = 0.08) were higher in community-based than in hospital-based clinics. Conclusions: In Massachusetts, transition practices vary across adult clinics that care for young adults with PHIV. Recommended practices, and HIV care continuum outcomes, were more likely to be met at community-based clinics than hospital-based clinics. Community-based adult care may provide more comprehensive transition practices and serve as a model for hospital-based clinics.

Ferroptosis is implicated in viral neuropathogenesis and may underlie HIV-associated neurocognitive impairment (NCI). Emerging data also suggest differences in brain iron transport by sex. We hypothesized that circulating ferritins that inhibit ferroptosis associate with neurocognitive function and NCI in people with HIV (PWH) in a sex-biased manner. Serum ferritin heavy-chain-1 (FTH1), ferritin light-chain (FTL), and urinary F₂-isoprostanes (uF₂-isoPs, specific lipid peroxidation marker) were quantified in 324 PWH (including 61 women) with serial global (NPZ-4) and domain-specific neurocognitive testing. Biomarker associations with neurocognitive test scores and NCIs were evaluated by multivariable regression; correlations with uF₂-isoPs were also assessed. Higher FTL and FTH1 levels were associated with less NCI in all PWH (adjusted odds ratios 0.53, 95% confidence interval (95% CI) 0.36–0.79 and 0.66, 95% CI 0.45–0.97, respectively). In women, higher FTL and FTH1 were also associated with better NPZ-4 (FTL adjusted beta (β) = 0.15, 95% CI 0.02–0.29; FTL-by-sex β_interaction = 0.32, p = 0.047) and domain-specific neurocognitive test scores. Effects on neurocognitive performance persisted for up to 5 years. Levels of both ferritins correlated inversely with uF₂-isoPs in women (FTL: rho = −0.47, p < 0.001). Circulating FTL and FTH1 exert sustained, sex-biased neuroprotective effects in PWH, possibly by protecting against iron-mediated lipid peroxidation (ferroptosis). Larger studies are needed to confirm the observed sex differences and further delineate the underlying mechanisms.

Ferroptosis is implicated in viral neuropathogenesis and may underlie HIV-associated neurocognitive impairment (NCI). Emerging data also suggest differences in brain iron transport by sex. We hypothesized that circulating ferritins that inhibit ferroptosis associate with neurocognitive function and NCI in people with HIV (PWH) in a sex-biased manner. Serum ferritin heavy-chain-1 (Fth-1), ferritin light-chain (Ftl), and urinary F2-isoprostanes (uF2-isoPs, specific lipid peroxidation marker) were quantified in 324 PWH (including 61 women) with serial global (NPZ4) and domain-specific neurocognitive testing. Biomarker associations with neurocognitive test scores and NCI were evaluated by multivariable regression; correlations with uF2-isoPs were also assessed. Higher Ftl and Fth-1 associated with less NCI in all PWH (adjusted odds ratios 0.53, 95% Confidence Interval (95% CI) 0.36-0.79 and 0.66, 95% CI 0.45-0.97, respectively). In women, higher Ftl and Fth-1 associated with better NPZ-4 (Ftl: adjusted beta (β)=0.15, 95% CI 0.02-0.29; Ftl-by-sex βinteraction=0.32, p=0.047) and domain-specific neurocognitive test scores. Effects on neurocognitive performance persisted for up to 5 years. Levels of both ferritins correlated inversely with uF2-isoPs in women (Ftl: rho=-0.47, p<0.001). Circulating Ftl and Fth-1 exert sustained, sex-biased neuroprotective effects in PWH, possibly by protecting against iron-mediated lipid peroxidation (ferroptosis). Larger studies are needed to confirm the observed sex differences and further delineate underlying mechanisms.