Inflammatory and Immune Mechanisms for Atherosclerotic Cardiovascular Disease in HIV.

Atherosclerotic vascular disease disproportionately affects persons living with HIV (PLWH) compared to those without. The reasons for the excess risk include dysregulated immune response and inflammation related to HIV infection itself, comorbid conditions, and co-infections. Here, we review an updated understanding of immune and inflammatory pathways underlying atherosclerosis in PLWH, including effects of viral products, soluble mediators and chemokines, innate and adaptive immune cells, and important co-infections. We also present potential therapeutic targets which may reduce cardiovascular risk in PLWH.

Heroin Use Is Associated With Vascular Inflammation in Human Immunodeficiency Virus.

BACKGROUND: Heroin use may work synergistically with human immunodeficiency virus (HIV) infection to cause greater immune dysregulation than either factor alone. Unraveling how this affects end-organ disease is key as it may play a role in the excess mortality seen in people with HIV (PWH) who use heroin despite access to care and antiretroviral therapy. METHODS: This is a prospectively enrolled, cross-sectional study of adults with and without HIV who use and do not use heroin using (18)F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) to compare tissue-specific inflammation including aortic (target-to-background ratio [TBR]), splenic, and bone marrow (standardized uptake value [SUV]). RESULTS: A total of 120 participants were enrolled. The unadjusted mean difference in aortic TBR was 0.43 between HIV-positive [HIV+] heroin+ and HIV+ heroin-negative [heroin-] (P = .02); however, among HIV-, aortic TBR was similar regardless of heroin-use status. Further, HIV-by-heroin-use status interaction was significant (P = .02), indicating that the relationship between heroin use and higher aortic TBR depended on HIV status. On the other hand, both HIV (1.54 vs 1.68; P = .04, unadjusted estimated means for HIV+ vs HIV-) and heroin use were associated with lower bone marrow SUV, although the effect of heroin depended on sex (heroin-use-by-sex interaction, P = .03). HIV-by-heroin-use interaction was not significant for splenic or bone marrow SUV. CONCLUSIONS: Aortic inflammation was greatest in PWH who use heroin, but paradoxically, bone marrow activity was the least in this group, suggesting complex and possibly divergent pathophysiology within these different end organs.

The impact of COVID-19 on cardiovascular health behaviors in people living with HIV.

The COVID-19 pandemic's impact on cardiovascular health behaviors including diet, physical activity, medication adherence, and self-care among people living with HIV (PLWH) remains unknown. Using qualitative analyses, we examined the impact of the COVID-19 pandemic on cardiovascular health behaviors among PLWH. Twenty-four PLWH were enrolled in this multisite study from September to October 2020. Individuals participated in semi-structured telephone interviews that were recorded, transcribed, and coded by 4 independent coders. Codes were adjudicated and analyzed for common themes. Participants were, on average, 59.2 years old (+/-9.4), 75% African American (n = 18) and 71% male (n = 17). The pandemic altered cardiovascular disease health behaviors. PLWH changed diet based on stay-at-home orders and food access. Alterations in physical activity included transitioning from gym and group class exercise to home-based exercise. Antiretroviral adherence was maintained, even when other health behaviors wavered, suggesting resilience in PLWH that may be harnessed to maintain other health behaviors.

Plasma Citrate and Succinate Are Associated With Neurocognitive Impairment in Older People With HIV.

BACKGROUND: Neurocognitive impairment (NCI) is associated with monocyte activation in people with HIV (PWH). Activated monocytes increase glycolysis, reduce oxidative phosphorylation, and accumulate citrate and succinate, tricarboxylic acid (TCA) cycle metabolites that promote inflammation-this metabolic shift may contribute to NCI and slowed gait speed in PWH. METHODS: Plasma citrate and succinate were assayed by liquid chromatography-mass spectrometry from 957 participants upon entry to a multicenter, prospective cohort of older PWH. Logistic, linear, and mixed-effects linear regression models were used to examine associations between entry/baseline TCA cycle metabolites and cross-sectional and longitudinal NCI, neuropsychological test scores (NPZ-4), and gait speed. RESULTS: Median age was 51 (range 40-78) years. Each 1 standard deviation (SD) citrate increment was associated with 1.18 higher odds of prevalent NCI at baseline (P = .03), 0.07 SD lower time-updated NPZ-4 score (P = .01), and 0.02 m/s slower time-updated gait speed (P < .0001). Age accentuated these effects. In the oldest age-quartile, higher citrate was associated with 1.64 higher odds of prevalent NCI, 0.17 SD lower NPZ-4, and 0.04 m/s slower gait speed (P ≤ .01 for each). Similar associations were apparent with succinate in the oldest age-quintile, but not with gait speed. In participants without NCI at entry, higher citrate predicted a faster rate of neurocognitive decline. CONCLUSIONS: Higher plasma citrate and succinate are associated with worse cross-sectional and longitudinal measures of neurocognitive function and gait speed that are age-dependent, supporting the importance of altered bioenergetic metabolism in the pathogenesis of NCI in older PWH.

The influence of healthcare financing on cardiovascular disease prevention in people living with HIV.

BACKGROUND: People living with HIV are diagnosed with age-related chronic health conditions, including cardiovascular disease, at higher than expected rates. Medical management of these chronic health conditions frequently occur in HIV specialty clinics by providers trained in general internal medicine, family medicine, or infectious disease. In recent years, changes in the healthcare financing for people living with HIV in the U.S. has been dynamic due to changes in the Affordable Care Act. There is little evidence examining how healthcare financing characteristics shape primary and secondary cardiovascular disease prevention among people living with HIV. Our objective was to examine the perspectives of people living with HIV and their healthcare providers on how healthcare financing influences cardiovascular disease prevention. METHODS: As part of the EXTRA-CVD study, we conducted in-depth, semi-structured interviews with 51 people living with HIV and 34 multidisciplinary healthcare providers and at three U.S. HIV clinics in Ohio and North Carolina from October 2018 to March 2019. Thematic analysis using Template Analysis techniques was used to examine healthcare financing barriers and enablers of cardiovascular disease prevention in people living with HIV. RESULTS: Three themes emerged across sites and disciplines (1): healthcare payers substantially shape preventative cardiovascular care in HIV clinics (2); physician compensation tied to relative value units disincentivizes cardiovascular disease prevention efforts by HIV providers; and (3) grant-based services enable tailored cardiovascular disease prevention, but sustainability is limited by sponsor priorities. CONCLUSIONS: With HIV now a chronic disease, there is a growing need for HIV-specific cardiovascular disease prevention; however, healthcare financing complicates effective delivery of this preventative care. It is important to understand the effects of evolving payer models on patient and healthcare provider behavior. Additional systematic investigation of these models will help HIV specialty clinics implement cardiovascular disease prevention within a dynamic reimbursement landscape. TRIAL REGISTRATION: Clinical Trial Registration Number: NCT03643705 .

Lower Pretreatment Gut Integrity Is Independently Associated With Fat Gain on Antiretroviral Therapy.

BACKGROUND: Fat accumulation and insulin resistance remain a threat to the success of antiretroviral therapy (ART). The role of gut dysfunction in metabolic complications associated with ART initiation is unclear. METHODS: Human immunodeficiency virus (HIV)-infected ART-naive participants were randomized to tenofovir disoproxil fumarate/emtricitabine plus atazanavir/ritonavir, darunavir/ritonavir, or raltegravir (RAL). Changes in the gut integrity markers zonulin, lipopolysaccharide-binding protein (LBP), and intestinal fatty acid and ileal bile acid binding proteins (I-FABP and I-BABP) were assessed over 96 weeks. Wilcoxon rank-sum tests were used to compare changes between groups and linear regression models to quantify associations between gut markers, insulin resistance, body mass index (BMI), and visceral, subcutaneous, and total adipose tissue (VAT, SAT, and TAT). RESULTS: : 90% were male and 48% were White non-Hispanic. The median age was 36 years, HIV-1 ribonucleic acid was 4.56 log10 copies/mL, and CD4 count was 338 cells/µL. An overall 1.7-fold increase in I-FABP was observed throughout 96 weeks, with no difference between arms. Zonulin levels increased with RAL compared to protease inhibitor-based regimens (week 96, P = .02); minimal changes in I-BABP or LBP levels were observed. Higher baseline I-FABP levels were associated with increases in VAT, TAT, and BMI (16%, 9%, and 2.5%, respectively; P < .04) over 96 weeks. CONCLUSIONS: While ART induces changes in the markers of gut barrier dysfunction, the extent to which they improve or worsen the gut barrier function remains unclear. Nevertheless, markers of gut barrier dysfunction in ART-naive individuals predict increases in total and visceral abdominal fat with treatment initiation.

Statin Therapy Does Not Reduce Liver Fat Scores in Patients Receiving Antiretroviral Therapy for HIV Infection.

BACKGROUND & AIMS: Therapies are needed to limit progression of fatty liver diseases in patients with human immunodeficiency virus (HIV) infection. We analyzed data from a prospective study of the effects of rosuvastatin (a statin) on hepatic steatosis in HIV-positive adults. METHODS: We performed a secondary analysis of data from a double-blind trial of adult patients with HIV infection (78% male; 68% African American; mean age, 46 y; body mass index, 29 kg/m2; HIV1 RNA < 1000 copies/mL; low-density lipoprotein cholesterol, <130 mg/dL) receiving antiretroviral therapy. The patients were randomly assigned to groups given 10 mg daily rosuvastatin (n = 72) or placebo (n = 75). Demographic and clinical data were collected, and blood samples were analyzed. Changes in liver fat score (LFS, a composite score calculated from metabolic and liver function parameters) and markers of systemic inflammation and immune activation were assessed through 96 weeks of drug or placebo administration. We performed multivariable linear and logistic regressions to study relationships among variables. RESULTS: The placebo and rosuvastatin groups each had significant increases in LFS, compared with baseline, at 96 weeks (P = .01 and P < .01; P = .49 for difference increase between groups). Baseline LFS was independently associated with blood level of C-X-C motif chemokine ligand 10 (P = .04) and the soluble CD163 molecule (P = .01). After we adjusted for baseline characteristics, an increase in LFS over time was significantly associated with the blood level of C-X-C motif chemokine ligand 10 (P = .04), insulin resistance (P < .01), and viral load (P = .02), but not rosuvastatin use (P = .06). CONCLUSIONS: In a secondary analysis of data from a trial of patients receiving treatment for HIV infection, hepatic steatosis increased over time, regardless of statin treatment, and was independently associated with markers of immune activation. Patients who received rosuvastatin appeared to have a nonsignificant increase in hepatic steatosis over 96 weeks. Despite their ability to reduce the risk of cardiovascular disease, statins do not appear to reduce hepatic steatosis. Clinicaltrials.gov no: NCT01218802.

Rationale and design of a nurse-led intervention to extend the HIV treatment cascade for cardiovascular disease prevention trial (EXTRA-CVD).

Persons living with human immunodeficiency virus (PLHIV) are at increased risk of atherosclerotic cardiovascular disease (ASCVD). In spite of this, uptake of evidence-based clinical interventions for ASCVD risk reduction in the HIV clinic setting is sub-optimal. METHODS: EXTRA-CVD is a 12-month randomized clinical effectiveness trial that will assess the efficacy of a multi-component nurse-led intervention in reducing ASCVD risk among PLHIV. Three hundred high ASCVD risk PLHIV across three sites will be randomized 1:1 to usual care with generic prevention education or the study intervention. The study intervention will consist of four evidence-based components: (1) nurse-led care coordination, (2) nurse-managed medication protocols and adherence support (3) home BP monitoring, and (4) electronic health records support tools. The primary outcome will be change in systolic blood pressure and secondary outcome will be change in non-HDL cholesterol over the course of the intervention. Tertiary outcomes will include change in the proportion of participants in the following extended cascade categories: (1) appropriately diagnosed with hypertension and hyperlipidemia (2) appropriately managed; (3) at treatment goal (systolic blood pressure <130 mm Hg and non-HDL cholesterol < National Lipid Association targets). CONCLUSIONS: The EXTRA-CVD trial will provide evidence appraising the potential impact of nurse-led interventions in reducing ASCVD risk among PLHIV, an essential extension of the HIV care continuum beyond HIV viral suppression.

The Opioid Epidemic: Impact on Inflammation and Cardiovascular Disease Risk in HIV.

PURPOSE OF REVIEW: People infected with HIV through injection drug use are more likely to experience progression to AIDS, death due to AIDS, and all-cause mortality even when controlling for access to care and antiretroviral therapy. While high-risk behavior and concurrent infections most certainly are contributors, chronic immune activation, downstream metabolic comorbidities may play an important role. RECENT FINDINGS: Altered intestinal integrity plays a major role in HIV-related immune activation and microbial translocation markers are heightened in active heroin users. Additionally, greater injection frequency drives systemic inflammation and is associated with HIV viral rebound. Finally, important systemic inflammation markers have been linked with frailty and mortality in people who inject drugs with and without concurrent HIV infection. Heroin use may work synergistically with HIV infection to cause greater immune activation than either factor alone. Further research is needed to understand the impact on downstream metabolic comorbidities including cardiovascular disease. Medication-assisted treatment for opioid use disorder with methadone or buprenorphine may ameliorate some of this risk; however, there is presently limited research in humans, including in non-HIV populations, describing changes in immune activation on these treatments which is of paramount importance for those with HIV infection.

Inflammation, Immune Activation, and Antiretroviral Therapy in HIV.

PURPOSE OF REVIEW: This review focuses on the differential effects of contemporary antiretrovirals on systemic inflammation as heightened immune activation is linked to important co-morbidities and mortality with HIV infection. RECENT FINDINGS: Antiretroviral therapy (ART) reduces dramatically systemic inflammation and immune activation, but not to levels synchronous with HIV-uninfected populations. In one ART initiation trial, integrase inhibitors appear to reduce inflammation to a greater degree than non-nucleoside reverse transcriptase inhibitors (NNRTIs); however, it is not clear that there are beneficial effects on inflammation resulting from treatment with integrase inhibitors compared to PIs, between PIs and NNRTIs, between specific nucleoside reverse transcriptase inhibitors, or with maraviroc in ART-naïve patients. In ART switch studies, changing to an integrase inhibitor from a PI-, NNRTI-, or enfuvirtide-containing regimen has resulted in improvement in several markers of inflammation. Additional research is needed to conclusively state whether there are clear differences in effects of specific antiretrovirals on inflammation and immune activation in HIV.

Differential Reduction in Monocyte Activation and Vascular Inflammation With Integrase Inhibitor-Based Initial Antiretroviral Therapy Among HIV-Infected Individuals.

BACKGROUND: Little is known about how different antiretrovirals effect inflammation and monocyte activation in human immunodeficiency virus (HIV) infection. METHODS: We examined plasma specimens obtained during a randomized, double-blinded trial in antiretroviral therapy (ART)-naive HIV-infected adults which compared the efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/c/FTC/TDF) with that of efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF). From a random sample achieving an HIV type 1 RNA load of <50 copies/mL by week 48, changes over 24 and 48 weeks in levels of biomarkers of monocyte activation (soluble CD14 [sCD14] and soluble CD163 [sCD163]), systemic inflammation (soluble tumor necrosis factor α receptor I [sTNF-RI], interleukin 6 [IL-6], and high-sensitivity C-reactive protein [hsCRP]), and vascular inflammation (lipoprotein-associated phospholipase A2 [Lp-PLA2]) were compared. Multivariable linear regression was used. RESULTS: A total of 200 participants were included. Significant differences favoring EVG/c/FTC/TDF were noted for changes in sCD14, hsCRP, and Lp-PLA2 levels. Factors independently associated with a larger decrease in the sCD14 level included random assignment to receive EVG/c/FTC/TDF, higher baseline sCD14 level, and larger decreases in hsCRP and sCD163 levels; factors associated with a larger Lp-PLA2 decrease included higher baseline Lp-PLA2 and IL-6 levels, smaller increases in total cholesterol and triglycerides levels, a larger decrease in the sCD14 level, and a smaller decrease in the sCD163 level. CONCLUSIONS: EVG/c/FTC/TDF led to greater decreases in sCD14, hsCRP, and Lp-PLA2 levels, compared with EFV/FTC/TDF. Randomization group independently predicted the change in sCD14 level, and changes in monocyte activation independently predicted the change in Lp-PLA2 level. There appears to be a more favorable effect of the integrase inhibitor EVG over efavirenz on immune activation, which may affect vascular inflammation.

Plasma Selenium Concentrations Are Sufficient and Associated with Protease Inhibitor Use in Treated HIV-Infected Adults.

BACKGROUND: Selenium is an essential constituent of selenoproteins, which play a substantial role in antioxidant defense and inflammatory cascades. Selenium deficiency is associated with disease states characterized by inflammation, including cardiovascular disease (CVD). Although HIV infection has been associated with low selenium, the role of selenium status in HIV-related CVD is unclear. OBJECTIVES: We sought to assess associations between plasma selenium and markers of inflammation, immune activation, and subclinical vascular disease in HIV-infected adults on contemporary antiretroviral therapy (ART) and to determine if statin therapy modifies selenium status. METHODS: In the Stopping Atherosclerosis and Treating Unhealthy bone with RosuvastatiN trial, HIV-infected adults on stable ART were randomly assigned 1:1 to rosuvastatin or placebo. Plasma selenium concentrations were determined at entry, week 24, and week 48. Spearman correlation and linear regression analyses were used to assess relations between baseline selenium, HIV-related factors and markers of inflammation, immune activation, and subclinical vascular disease. Changes in selenium over 24 and 48 wk were compared between groups. RESULTS: One hundred forty-seven HIV-infected adults were included. All participants were on ART. Median current CD4+ count was 613, and 76% had HIV-1 RNA ≤48 copies/mL (range: <20-600). Median plasma selenium concentration was 122 µg/L (range: 62-200). At baseline, higher selenium was associated with protease inhibitor (PI) use, lower body mass index, and a higher proportion of activated CD8+ T cells (CD8+CD38+human leukocyte antigen-DR+), but not markers of inflammation or subclinical vascular disease. Over 48 wk, selenium concentrations increased in the statin group (P < 0.01 within group), but the change did not differ between groups (+13.1 vs. +5.3 µg/L; P = 0.14 between groups). CONCLUSIONS: Plasma selenium concentrations were within the normal range for the background population and were not associated with subclinical vascular disease in HIV-infected adults on contemporary ART. The association between current PI use and higher selenium may have implications for ART allocation, especially in resource-limited countries. Also, it appears that statin therapy may increase selenium concentrations; however, larger studies are necessary to confirm this finding. This trial was registered at clinicaltrials.gov as NCT01218802.

Rosuvastatin preserves renal function and lowers cystatin C in HIV-infected subjects on antiretroviral therapy: the SATURN-HIV trial.

BACKGROUND: In chronic human immunodeficiency virus (HIV) infection, plasma cystatin C may be influenced by factors other than glomerular filtration rate such as inflammation. Statins may improve cystatin C by improving glomerular function or by decreasing inflammation. METHODS: The Stopping Atherosclerosis and Treating Unhealthy Bone With Rosuvastatin in HIV (SATURN-HIV) trial randomized 147 patients on stable antiretroviral therapy (ART) with low-density lipoprotein cholesterol ≤130 mg/dL to blinded 10 mg daily rosuvastatin or placebo. We analyzed relationships of baseline and 0- to 24-week changes in plasma cystatin C concentration with measures of vascular disease, inflammation, and immune activation. RESULTS: Median age was 46 (interquartile range, 40-53) years; 78% were male, 68% African American. Tenofovir and protease inhibitors were used in 88% and 49% of subjects, respectively. Baseline cystatin C was associated with higher carotid intima-media thickness and epicardial adipose tissue independent of age, sex, and race. Biomarkers of endothelial activation and inflammation were associated with cystatin C in a multivariable model independent of creatinine-based estimated glomerular filtration rate (eGFRcr). After 24 weeks, statin use slowed mean eGFRcr decline (1.61 vs -3.08 mL/minute/1.73 m(2) for statin vs placebo; P = .033) and decreased mean cystatin C (-0.034 mg/L vs 0.010 mg/L; P = .008). Within the statin group, changes in cystatin C correlated with changes in endothelial activation, inflammation, and T-cell activation. CONCLUSIONS: Rosuvastatin 10 mg daily reduces plasma cystatin C and slows kidney function decline in HIV-infected patients on ART. Reductions in cystatin C with statin therapy correlate with reductions in inflammatory biomarkers. Relationships between cystatin C, kidney function, and cardiovascular risk in HIV may be mediated in part by inflammation. Clinical Trials Registration. NCT01218802.

New-onset autoimmune disease after COVID-19.

Introduction: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may trigger autoimmune disease (AD) through initial innate immune activation with subsequent aberrations in adaptive immune cells leading to AD. While there are multiple reports of incident AD diagnosed after COVID-19, the risk in the context of key circulating strains is unknown. Methods: TriNetX, a global, federated, health research network providing access to electronic medical records across 74 healthcare organizations, was utilized to define an adult cohort between January 1, 2020, and March 3, 2023. Exposure was defined as COVID-19 diagnosis (ICD-10 code or positive laboratory test). Age- and sex-propensity score-matched controls never had COVID-19 diagnosed. Outcomes were assessed 1 month to 1 year after the index date. Patients with AD prior to or within 1 month after the index date were excluded from the primary analysis. Incidence and risk ratios of each AD were assessed. Results: A total of 3,908,592 patients were included. Of 24 AD patients assessed, adjusted risk ratios for eight AD patients who had COVID-19 were higher compared to those who had no COVID-19. Cutaneous vasculitis (adjusted hazard ratio (aHR): 1.82; 95% CI 1.55-2.13), polyarteritis nodosa (aHR: 1.76; 95% CI 1.15-2.70), and hypersensitivity angiitis (aHR: 1.64; 95% CI 1.12-2.38) had the highest risk ratios. Overall, psoriasis (0.15%), rheumatoid arthritis (0.14%), and type 1 diabetes (0.13%) had the highest incidence during the study period, and of these, psoriasis and diabetes were more likely after COVID-19. The risk of any AD was lower if COVID-19 was diagnosed when Omicron variants were the predominant circulating strains. A positive antinuclear antibody was more likely and predictive of AD after COVID-19. Discussion: SARS-CoV-2 may be a potential trigger for some AD, but the risk for AD may decrease with time given the apparent lower risk after infection with Omicron variants.

Nurse-Led Strategy to Improve Blood Pressure and Cholesterol Level Among People With HIV: A Randomized Clinical Trial.

Importance: Despite higher atherosclerotic cardiovascular disease (ASCVD) risk, people with HIV (PWH) experience unique barriers to ASCVD prevention, such as changing models of HIV primary care. Objective: To test whether a multicomponent nurse-led strategy would improve systolic blood pressure (SBP) and non-high-density lipoprotein (HDL) cholesterol level in a diverse population of PWH receiving antiretroviral therapy (ART). Design, Setting, and Participants: This randomized clinical trial enrolled PWH at 3 academic HIV clinics in the US from September 2019 to January 2022 and conducted follow-up for 12 months until January 2023. Included patients were 18 years or older and had a confirmed HIV diagnosis, an HIV-1 viral load less than 200 copies/mL, and both hypertension and hypercholesterolemia. Participants were stratified by trial site and randomized 1:1 to either the multicomponent EXTRA-CVD (A Nurse-Led Intervention to Extend the HIV Treatment Cascade for Cardiovascular Disease Prevention) intervention group or the control group. Primary analyses were conducted according to the intention-to-treat principle. Intervention: The EXTRA-CVD group received home BP monitoring guidance and BP and cholesterol management from a dedicated prevention nurse at 4 in-person visits (baseline and 4, 8, and 12 months) and frequent telephone check-ins up to every 2 weeks as needed. The control group received general prevention education sessions from the prevention nurse at each of the 4 in-person visits. Main Outcomes and Measures: Study-measured SBP was the primary outcome, and non-HDL cholesterol level was the secondary outcome. Measurements were taken over 12 months and assessed by linear mixed models. Prespecified moderators tested were sex at birth, baseline ASCVD risk, and trial site. Results: A total of 297 PWH were randomized to the EXTRA-CVD arm (n = 149) or control arm (n = 148). Participants had a median (IQR) age of 59.0 (53.0-65.0) years and included 234 males (78.8%). Baseline mean (SD) SBP was 135.0 (18.8) mm Hg and non-HDL cholesterol level was 139.9 (44.6) mg/dL. At 12 months, participants in the EXTRA-CVD arm had a clinically significant 4.2-mm Hg (95% CI, 0.3-8.2 mm Hg; P = .04) lower SBP and 16.9-mg/dL (95% CI, 8.6-25.2 mg/dL; P < .001) lower non-HDL cholesterol level compared with participants in the control arm. There was a clinically meaningful but not statistically significant difference in SBP effect in females compared with males (11.8-mm Hg greater difference at 4 months, 9.6 mm Hg at 8 months, and 5.9 mm Hg at 12 months; overall joint test P = .06). Conclusions and Relevance: Results of this trial indicate that the EXTRA-CVD strategy effectively reduced BP and cholesterol level over 12 months and should inform future implementation of multifaceted ASCVD prevention programs for PWH. Trial Registration: ClinicalTrials.gov Identifier: NCT03643705.

Case Series of People With HIV on the Long-Acting Combination of Lenacapavir and Cabotegravir: Call for a Trial.

Background: Injectable cabotegravir (CAB)/rilpivirine (RPV) is the only combination long-acting (LA) antiretroviral regimen approved for HIV. RPV may not be effective among individuals with non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance, which has >10% prevalence in many countries. Lenacapavir (LEN) is an LA capsid inhibitor given every 6 months, but has not been studied in combination with other LA agents. Methods: We assembled a case series from 4 US academic medical centers where patients with adherence challenges were prescribed LEN subcutaneously every 26 weeks/CAB (+/- RPV) intramuscularly every 4 or 8 weeks. Descriptive statistics, including viral load (VL) outcomes, were summarized. Results: All patients (n = 34: 76% male; 24% cis/trans female; 41% Black; 38% Latino/a; median age [range], 47 [28-75] years; 29% and 71% on CAB every 4 or 8 weeks) reported challenges adhering to oral ART. The reasons for using LEN/CAB with or without RPV were documented or suspected NNRTI mutations (n = 21, 59%), integrase mutations (n = 5, 15%), high VL (n = 6, 18%), or continued viremia on CAB/RPV alone (n = 4, 12%). Injection site reactions on LA LEN were reported in 44% (32% grade I, 12% grade 2). All patients but 2 (32/34; 94%) were suppressed (VL <75 copies/mL) after starting LEN at a median (range) of 8 (4-16) weeks, with 16/34 (47%) suppressed at baseline. Conclusions: In this case series of 34 patients on LEN/CAB, high rates of virologic suppression (94%) were observed. Reasons for using LEN/CAB included adherence challenges and underlying resistance, mostly to NNRTIs. These data support a clinical trial of LEN/CAB among persons with NNRTI resistance.

Sex-Biased Associations of Circulating Ferroptosis Inhibitors with Reduced Lipid Peroxidation and Better Neurocognitive Performance in People with HIV.

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 (ß) = 0.15, 95% CI 0.02-0.29; FTL-by-sex ßinteraction = 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.

Perceived Risks and Benefits and Frequency of Cannabis Use Among People with HIV in Different Legal Environments.

We sought to describe the prevalence of and motivation for cannabis use and whether legalization of cannabis impacts the frequency and perceived risks and benefits of use in people living with HIV (PWH). The study was based on two HIV clinics located in Cleveland, Ohio, and Aurora, Colorado. Participants responded to a 45-question survey, and responses were summarized in aggregate and stratified by the frequency of cannabis use and site. Three hundred ninety-seven participants completed the survey. The frequency of use was not different between the sites. Daily cannabis users compared with yearly or never users identified the benefits of cannabis as relief from stress, anxiety, or depression, improved sleep, improved creativity, improved focus or concentration, and increased energy. The benefits of pain management, improved appetite, and helping to decrease or stop other medications were selected at similar rates, regardless of the frequency of use. Daily users were less likely to identify treatment of disease as a benefit and legal problems, addiction to cannabis, impaired memory, increased use of other drugs, personal or relationship problems, decrease in intelligence, new or worsening health problems, and getting high as risks of use compared with yearly or never users. Compared with participants in Ohio, Coloradoans were more likely to identify cannabis benefits as decreasing/stopping other medications and getting high, and less likely to identify legal problems and addiction as risks. Legalization of cannabis did not affect the frequency of cannabis use in PWH. Daily cannabis users are more likely to identify benefits and less likely to identify risks of use compared with yearly or never users. A better understanding of the potential benefits and risks of cannabis use can help guide safer use of cannabis in PWH and allow physicians to provide better counseling on risk reduction.

Bone effects of rosiglitazone in HIV-infected patients with lipoatrophy.

OBJECTIVES: Thiazoledinediones increase limb fat in HIV+ patients with lipoatrophy. However, their use in the general population has been associated with bone loss and fracture. We sought to determine the effects of rosiglitazone on bone metabolism in HIV-infected patients. METHODS: HIV+ patients with lipoatrophy were randomized to rosiglitazone versus placebo for 48 weeks in a double-blind, placebo-controlled trial. Limb fat, bone mineral density (BMD), bone formation markers (procollagen type 1 amino-terminal propeptide [P1NP], osteocalcin [OC]) and bone resorption markers (C-terminal telopeptide of type I collagen [CTX]) were measured, along with receptor activator for nuclear factor kappa ß ligand (RANKL), osteoprotegerin (OPG), and inflammatory cytokines. RESULTS: Seventy-one subjects were randomized to rosiglitazone or placebo: 17% female and 51% white. Total BMD did not change significantly in either group. In the rosiglitazone group, P1NP showed statistically significant decreases at 24 and 48 weeks; however, changes compared to placebo were only significant at 24 weeks. OC decreased significantly in the rosiglitazone group at 24 weeks, but there were no between-group differences. CTX, RANKL, or OPG did not change for either group. Multivariable regression within the rosiglitazone arm showed P1NP changes were inversely associated with limb fat changes, protease inhibitors, and tenofovir use. CONCLUSION: Rosiglitazone use was associated with decreased bone formation, but it did not alter bone resorption or total BMD. The increase in limb fat that accompanies rosiglitazone use appears to be associated with decreased osteoblast activity. Further studies are needed to determine the effect of thiazoledinediones on bone health in HIV-infected persons.

Impact of Heroin and HIV on Gut Integrity and Immune Activation.

BACKGROUND: Altered gut integrity is central to HIV-related immune activation. Opioids may promote similar changes in gut permeability and/or increase systemic inflammation, potentially augmenting processes already occurring in people with HIV (PWH). SETTING: Urban hospital systems in Cleveland, Ohio, and surrounding communities. METHODS: This is a prospectively enrolled, cross-sectional study including people with and without HIV using heroin and people with and without HIV who have never used heroin, matched by age, sex, and CD4+ T-cell count (PWH only) to compare markers of gut integrity, microbial translocation, systemic inflammation, and immune activation. RESULTS: A total of 100 participants were enrolled. Active heroin use was associated with higher concentrations of lipopolysaccharide-binding protein (LBP), beta-D-glucan (BDG), high-sensitivity C-reactive protein (hsCRP), soluble tumor necrosis factor-α-receptors I and II, soluble CD163, inflammatory monocytes, and activated CD4+ lymphocytes in adjusted models. HIV status tended to modify the effect between heroin use and LBP, BDG, hsCRP, patrolling monocytes, and activated CD4+ lymphocytes (P < 0.15 for interactions); however, it was not as expected. The effect of heroin on these markers (except patrolling monocytes) was greatest among those without HIV rather than among those with HIV. CONCLUSIONS: Heroin use is associated with heightened microbial translocation, systemic inflammation, and immune activation. Concurrent HIV infection in virologically suppressed individuals does not seem to substantially worsen the effects heroin has on these markers.