non-AIDS Comorbidities Research Articles

Disproportionate vulnerability to and unique aggregation pattern of non-AIDS comorbidities among women with HIV in China

Abstract Background Whether and how sex plays differential roles in aging-related multimorbidity among people with HIV (PWH) is poorly characterized. Methods We included 2479 PWH and 5376 people without HIV (PWoH) from the baseline assessment of the Comparative HIV and Aging Research in Taizhou (CHART) cohort. Ten non-AIDS comorbidities (NACM) were investigated. Multiple logistic regression was used to assess the correlates of multimorbidity (defined as the coexistence of ≥2 NACM). Multimorbidity patterns were identified through hierarchical cluster analysis. Results The prevalence of multimorbidity was higher in PWH than in PWoH (74.6% vs. 66.9%, p < 0.001). This difference was particularly pronounced in women in each of the age groups from 18 through 59 years and among men in each of the age groups from 18 through 49 years. A significant interaction between sex and HIV on multimorbidity was identified (p < 0.001), with the strength of the association between HIV infection and multimorbidity being stronger in women than in men. Women with HIV presented a unique aggregation pattern of multimorbidity, where neuropsychiatric disorders (depression, neurocognitive impairment) clustered with cardiometabolic diseases. In contrast, all men and women without HIV manifested a similar multimorbidity pattern, where depression and neurocognitive impairment were clustered with hematologic abnormalities but not with cardiometabolic diseases. Conclusions Earlier onset and higher burden of multimorbidity in PWH, as well as disproportionate vulnerability to and unique multimorbidity pattern among women with HIV, underscore the urgent need for early and sexually-oriented integrative interventions and health services targeting multimorbidity in PWH.

Emerging role of natural killer cells in non-AIDS comorbidities during suppressive antiretroviral therapy.

Despite decades of insights about the role of natural killer (NK) cells in HIV infection, their persistent dysregulation despite antiretroviral therapy (ART) and its pathological consequences have been incompletely delineated. In this review, we highlight recent findings on the immunophenotypic and functional alterations of NK cells during virally suppressed HIV infection and explore their potential impact on promoting non-AIDS related comorbidities among people living with HIV (PLWH). Of note are the apparent persistent activated profiles of NK cells and pathophysiological events such as endoplasmic reticulum (ER) stress in potentially driving NK cell derived inflammation and tissue destruction. Additionally, recent interest in trained immunity is discussed as a potential mediator of ongoing NK cell dysregulation, contributing to comorbidities such as cardiovascular disease and neurocognitive disorders, both with an inflammatory etiology. Clinical and mechanistic evidence suggests persistent activation and dysregulation of the innate immune system are major drivers of non-AIDS comorbidities during virally suppressed HIV infection. Delineating the mechanistic role of specific components of innate immunity such as NK cells in inducing these pathologies will lead to the identification of novel therapeutic/prophylactic strategies to improve the overall health of PLWH.

Impaired Bone Tissue Quality Associated with Inflammation in HIV-Immunological Non-Responders: A Cross-Sectional Analysis.

People with HIV (PWH) with poor immune response despite adequate antiretroviral treatment (ART) are susceptible to non-AIDS-related health issues. This study seeks to evaluate bone quality in Immunological Non-Responders (INRs) in comparison to those with proper immune response (IRs) using in vivo microindentation to quantify bone quality, in addition to conventional bone mineral density (BMD) evaluations. A cross-sectional study was conducted at Hospital del Mar in Barcelona from January 2019 to June 2023. Participants were matched in a 1:2-ratio (INRs:IR) based on age, sex, body mass index (BMI), and ART. Participants underwent bone quality assessment using in vivo microindentation, BMD and analysis of bone turnover and inflammation markers. Statistical analyses involved multivariable regression to adjust for potential confounding variables. A total of 159 PWH were included, 53 INRs and 106 IRs. INRs had worse bone quality, with lower median Bone Material Strength index (BMSi) compared to IRs (79 (76-87) vs. 86 (82-89); p<0.001), and similar BMD. INRs shown increased high-sensitive C-Reactive Protein levels with lower 25-(OH)-Vitamin D3. A significant negative correlation between inflammation and bone quality was found, especially noticeable in INRs. Multivariable linear regression shown that INR status is a major predictor of decreased bone quality, regardless of conventional risk factors. INRs condition is significantly associated with higher inflammatory levels, which may contribute to a deleterious effect on bone quality as measured by in vivo microindentation. Further studies are needed to confirm these results and to focus on non-AIDS comorbidities in this subgroup of PWH.

Zinc and selenium supplementation on treated HIV-infected individuals induces changes in body composition and on the expression of genes responsible of naïve CD8+ T cells function.

Deficiency of zinc and selenium is common in persons living with human immunodeficiency virus (PLWHIV) and has been associated with the development of non-AIDS related comorbidities, impaired immune system function and mortality. Micronutrient supplementation on long-term-treated PLWHIV could bring potential clinical and immunological benefits improving their health status and quality of life. The aim of the present study is to analyze the effect of zinc and selenium supplementation on body composition, bone mineral density, CD4+ T-cell counts, metabolic profile and immune system status on clinical stable PLWHIV on long-term antiretroviral therapy (ART). This is a randomized pilot clinical trial in which we recruited 60 PLWHIV on ART who were assigned to the intervention groups: zinc (30 mg of zinc gluconate), selenium (200 μg of selenium yeast), zinc + selenium (same doses and presentations) or to a control group (without nutritional supplementation) who received supplementation during 6 months. Primary outcome was defined as changes in body composition (weight, muscle and fat mass and bone mineral density) and secondary outcomes as changes in biochemical and immunological parameters (CD4+ T-cell count, cholesterol, glucose, triglycerides and seric zinc and selenium seric concentrations) before and after supplementation. Peripheral blood mononuclear cells (PBMCs) of one individual of each intervention group were analyzed for single cell transcriptomics before and after supplementation. BMI (p = 0.03), fat mass (p = 0.03), and trunk fat (p = 0.01) decreased after 6 months of selenium supplementation. No changes were observed for cholesterol, glucose or triglycerides after supplementation (p > 0.05 in all cases). CD4+ T cells percentage increased after 6 months of selenium supplementation (p = 0.03). On the transcriptome analysis, zinc and selenium supplementation induced changes on de expression of genes associated with the function of naive and memory CD8+ T-cells (p < 0.05 in all cases). Zinc and selenium supplementation could represent a complementary intervention that may improve the health status and immune response of treated PLWHIV.

Consequences of low-level viremia among women with HIV in the United States.

Investigate the outcomes of women with HIV (WWH) with low-level viremia (LLV). The prevalence of LLV and potential clinical sequelae, such as virologic failure and non-AIDS comorbidity (NACM) development, are poorly characterized among WWH. We analyzed data from the Women's Interagency HIV Study among WWH enrolled from 2003 to 2020 who reported antiretroviral therapy use at least 1 year followed by an HIV-1 viral load less than 200 copies/ml. Consecutive viral load measurements from four semi-annual visits were used to categorize women at baseline as having: virologic suppression (all viral load undetectable), intermittent LLV (iLLV; nonconsecutive detectable viral load up to 199 copies/ml), persistent LLV (pLLV; at least two consecutive detectable viral load up to 199 copies/ml), or virologic failure (any viral load ≥200 copies/ml). Adjusted hazard ratios quantified the association of virologic category with time to incident virologic failure and multimorbidity (≥2 of 5 NACM) over 5-year follow-up. Of 1598 WWH, baseline median age was 47 years, 64% were Black, 21% Hispanic, and median CD4 + cell count was 621 cells/μl. After excluding 275 women (17%) who had virologic failure at baseline, 58, 19, and 6% were categorized as having virologic suppression, iLLV, and pLLV, respectively. Compared with WWH with virologic suppression, the adjusted hazard ratio [aHR; 95% confidence interval (CI)] for incident virologic failure was 1.88 (1.44-2.46) and 2.51 (1.66-3.79) for iLLV and pLLV, respectively; and the aHR for incident multimorbidity was 0.81 (0.54-1.21) and 1.54 (0.88-2.71) for iLLV and pLLV, respectively. Women with iLLV and pLLV had an increased risk of virologic failure. Women with pLLV had a trend towards increased multimorbidity risk.

Gut Mucosal Immunity in HIV-Exposed Infants: A Review

Gut mucosal immunity in infants exposed to Human Immunodeficiency Virus (HIV) presents a complex interplay of developmental processes, viral dynamics, and therapeutic interventions that significantly impact clinical outcomes. This review synthesizes current knowledge on the mechanisms, clinical implications, and therapeutic strategies concerning gut mucosal immunity in HIV-exposed infants. The gut mucosa serves as a critical site for immune maturation and defense against pathogens, but HIV infection disrupts this delicate balance, leading to compromised immune function and increased susceptibility to infections. Infants born to HIV-positive mothers experience unique challenges in gut mucosal immunity due to vertical transmission of the virus and exposure to antiretroviral therapy (ART). HIV infection disrupts gut-associated lymphoid tissue (GALT), resulting in early depletion of CD4+ T cells and compromised mucosal barrier function. These alterations contribute to microbial translocation, chronic inflammation, and immune dysregulation, impacting overall immune competence and increasing susceptibility to opportunistic infections. Despite advances in ART, persistent immune activation and residual gut mucosal damage pose ongoing challenges in achieving optimal immune reconstitution and preventing long-term complications in HIV-exposed infants. Clinical implications of compromised gut mucosal immunity in HIV-exposed infants extend beyond gastrointestinal health to encompass systemic immune dysfunction and increased risks of non-AIDS comorbidities. Impaired gut barrier function exacerbates microbial translocation, leading to systemic inflammation that may contribute to neurodevelopmental abnormalities and metabolic disorders. Keywords: Gut, Immunity, HIV, Infants

Cardiometabolic Differences in People Living with HIV Receiving Integrase Strand Transfer Inhibitors Compared to Non-nucleoside Reverse Transcriptase Inhibitors: Implications for Current ART Strategies.

In people living with HIV (PLHIV), integrase strand transfer inhibitors (INSTIs) are part of the first-line combination antiretroviral therapy (cART), while non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens are alternatives. Distinct cART regimens may variably influence the risk for non-AIDS comorbidities. We aimed to compare the metabolome and lipidome of INSTI and NNRTI-based regimens. The 2000HIV study includes asymptomatic PLHIV (n = 1646) on long-term cART, separated into a discovery cohort with 730 INSTI and 617 NNRTI users, and a validation cohort encompassing 209 INSTI and 90 NNRTI users. Baseline plasma samples from INSTI and NNRTI users were compared using mass spectrometry-based untargeted metabolomic (n = 500) analysis. Perturbed metabolic pathways were identified using MetaboAnalyst software. Subsequently, nuclear magnetic resonance spectroscopy was used for targeted lipoprotein and lipid (n = 141) analysis. Metabolome homogeneity was observed between the different types of INSTI and NNRTI. In contrast, higher and lower levels of 59 and 45 metabolites, respectively, were found in the INSTI group compared to NNRTI users, of which 77.9% (81/104) had consistent directionality in the validation cohort. Annotated metabolites belonged mainly to 'lipid and lipid-like molecules', 'organic acids and derivatives' and 'organoheterocyclic compounds'. In pathway analysis, perturbed 'vitamin B1 (thiamin) metabolism', 'de novo fatty acid biosynthesis', 'bile acid biosynthesis' and 'pentose phosphate pathway' were detected, among others. Lipoprotein and lipid levels in NNRTIs were heterogeneous and could not be compared as a group. INSTIs compared to individual NNRTI types showed that HDL cholesterol was lower in INSTIs compared to nevirapine but higher in INSTIs compared to doravirine. In addition, LDL size was lower in INSTIs and nevirapine compared to doravirine. NNRTIs show more heterogeneous cardiometabolic effects than INSTIs, which hampers the comparison between these two classes of drugs. Targeted lipoproteomic and lipid NMR spectroscopy showed that INSTI use was associated with a more unfavorable lipid profile compared to nevirapine, which was shifted to a more favorable profile for INSTI when substituting nevirapine for doravirine, with evidently higher fold changes. The cardiovascular disease risk profile seems more favorable in INSTIs compared to NNRTIs in untargeted metabolomic analysis using mass-spectrometry.

The Potential of Clostridium butyricum to Preserve Gut Health, and to Mitigate Non-AIDS Comorbidities in People Living with HIV.

A dramatic reduction in mortality among people living with HIV (PLWH) has been achieved during the modern antiretroviral therapy (ART) era. However, ART does not restore gut barrier function even after long-term viral suppression, allowing microbial products to enter the systemic blood circulation and induce chronic immune activation. In PLWH, a chronic state of systemic inflammation exists and persists, which increases the risk of development of inflammation-associated non-AIDS comorbidities such as metabolic disorders, cardiovascular diseases, and cancer. Clostridium butyricum is a human butyrate-producing symbiont present in the gut microbiome. Convergent evidence has demonstrated favorable effects of C. butyricum for gastrointestinal health, including maintenance of the structural and functional integrity of the gut barrier, inhibition of pathogenic bacteria within the intestine, and reduction of microbial translocation. Moreover, C. butyricum supplementation has been observed to have a positive effect on various inflammation-related diseases such as diabetes, ulcerative colitis, and cancer, which are also recognized as non-AIDS comorbidities associated with epithelial gut damage. There is currently scant published research in the literature, focusing on the influence of C. butyricum in the gut of PLWH. In this hypothesis review, we speculate the use of C. butyricum as a probiotic oral supplementation may well emerge as a potential future synergistic adjunctive strategy in PLWH, in tandem with ART, to restore and consolidate intestinal barrier integrity, repair the leaky gut, prevent microbial translocation from the gut, and reduce both gut and systemic inflammation, with the ultimate objective of decreasing the risk for development of non-AIDS comorbidities in PLWH.

1486. The Association of Aging-related Comorbidity Burden and Quality of Life Among Women with and without HIV in the U.S.

Abstract Background Women with HIV (WWH) are at higher and earlier risk of developing aging-related non-AIDS comorbidities (NACM) compared to those without HIV; however, the impact on health-related quality of life (QoL) is largely unknown. Methods We analyzed data from the Women’s Interagency HIV Study to evaluate the effect of comorbidity burden (total NACM of 10 assessed) on nine QoL domains and a summary QoL index (QoLI; measured by the MOS-HIV instrument). We included women followed on/after 2009 (when &amp;gt;80% of WWH reported antiretroviral therapy use) and ascertained covariates, NACM, and QoL through the last study visit by 03/2018. Unadjusted (HIV, age, NACM burden or prevalence separately), partially adjusted (unadjusted + all possible interaction terms) and adjusted (partially adjusted + covariates) linear regression assessed impact on QoL. Results Among 3036 women (2173 HIV+, 863 HIV-), median age was 50 (Q1-Q3 43-56) yrs, 66% were Black, 51% had annual income &amp;lt; $12K, and mean (sd) NACM burden was 3.4 (2.2). In unadjusted models, each additional NACM decreased the mean QoLI by -4.4 (95%CI -4.7,-4.1; p&amp;lt; 0.0001). Mean QoLI did not differ in WWH vs without HIV (68 vs 69, p=0.40) but decreased with older age (&amp;lt; 40, 40-49, 50-59, 60-69 yrs): 75 (95%CI 73,77), 71 (70,73), 65 (63,66), 63 (61,65), respectively (p&amp;lt; 0.0001). Unadjusted QoLI was negatively associated with each prevalent NACM (Table). NACM burden was associated with all nine QoL domains in unadjusted models: physical function, role function, energy/fatigue, social function, cognitive function, emotional well-being, health perception, pain, and perceived health index. In the partially adjusted model, the impact of NACM burden on QoLI was modified by age (p=0.02) but not HIV serostatus (p=0.40) (Figure). In covariate-adjusted models (race, BMI, cigarette, alcohol or crack use, menopausal status, socioeconomic status), NACM burden was associated with QoLI (p&amp;lt; 0.0001) but age and HIV did not modify this effect (age*HIV*NACM burden, p=0.83). Summary quality of life index and aging-related comorbidity burden by HIV serostatus and age Conclusion Among women with a high prevalence of multimorbidity, HIV, and health disparities, total comorbidity burden was associated with QoL, independent of age or HIV serostatus. Research is needed to optimize multimorbidity screening and prevention strategies in this population. Disclosures Lauren F. Collins, MD, MSc, Curio Science: Honoraria Igho Ofotokun, MD, MSc, FIDSA, Merck: Grant/Research Support Phyllis C. Tien, MD, MSc, Merck: Grant/Research Support Cyra Christina Mehta, PhD, MSPH, Merck: Grant/Research Support

Platelet and HIV Interactions and Their Contribution to Non-AIDS Comorbidities.

Platelets are anucleate cytoplasmic cell fragments that circulate in the blood, where they are involved in regulating hemostasis. Beyond their normal physiologic role, platelets have emerged as versatile effectors of immune response. During an infection, cell surface receptors enable platelets to recognize viruses, resulting in their activation. Activated platelets release biologically active molecules that further trigger host immune responses to protect the body against infection. Their impact on the immune response is also associated with the recruitment of circulating leukocytes to the site of infection. They can also aggregate with leukocytes, including lymphocytes, monocytes, and neutrophils, to immobilize pathogens and prevent viral dissemination. Despite their host protective role, platelets have also been shown to be associated with various pathophysiological processes. In this review, we will summarize platelet and HIV interactions during infection. We will also highlight and discuss platelet and platelet-derived mediators, how they interact with immune cells, and the multifaceted responsibilities of platelets in HIV infection. Furthermore, we will give an overview of non-AIDS comorbidities linked to platelet dysfunction and the impact of antiretroviral therapy on platelet function.

Examining the Association Between a Modified Quan-Charlson Comorbidity Index and HIV Viral Suppression: A Cross-Sectional Analysis of DC Cohort Participants.

With the advancement of effective antiretroviral therapy, people with HIV live longer, and many are developing non-AIDS comorbidities. It is important to assess how comorbidities are associated with HIV-related health outcomes, such as viral suppression (VS). The aim of this study was to analyze the association between comorbidity burden, measured using a modified Quan-Charlson Comorbidity Index (QCCI), and VS (viral load result of <200 copies/mL). We hypothesized that an increase in QCCI score, indicating a higher risk for mortality, would correlate with lower likelihood of VS because of the burden of comorbidity treatment, possibly leading to worse antiretroviral adherence. Our analysis included participants from the DC Cohort Longitudinal HIV Study in Washington, DC. Eligible participants were aged ≥18 years and enrolled in the cohort as of January 1, 2018 (n = 2,471). A modified QCCI score, which weighs selected comorbidities (not including HIV/AIDS) and predicts mortality, was calculated using International Classification of Disease-9/10 codes from electronic health records. Multivariable logistic regressions were used to characterize the association between QCCI composite scores and VS. Participants were predominantly virally suppressed (89.6%), male (73.9%), non-Hispanic Black (74.7%), and between 18 and 55 years (59.3%). The median QCCI score was 1 (range = 1-12, interquartile range = 0-2), demonstrating predominately low mortality risk. We did not establish a statistically significant association between QCCI score and VS (adjusted odds ratio = 1.06, 95% confidence interval 0.96-1.17). Our findings suggest that a higher QCCI score was not associated with lower VS in this population, which may be partly due to the high retention in care among cohort participants.

Translocation of bacterial LPS is associated with self-reported cognitive abilities in men living with HIV receiving antiretroviral therapy

BackgroundGut damage allows translocation of bacterial lipopolysaccharide (LPS) and fungal β-D-glucan (BDG) into the blood. This microbial translocation contributes to systemic inflammation and risk of non-AIDS comorbidities in people living with HIV, including those receiving antiretroviral therapy (ART). We assessed whether markers of gut damage and microbial translocation were associated with cognition in ART-treated PLWH.MethodsEighty ART-treated men living with HIV from the Positive Brain Health Now Canadian cohort were included. Brief cognitive ability measure (B-CAM) and 20-item patient deficit questionnaire (PDQ) were administered to all participants. Three groups were selected based on their B-CAM levels. We excluded participants who received proton pump inhibitors or antiacids in the past 3 months. Cannabis users were also excluded. Plasma levels of intestinal fatty acid binding protein (I-FABP), regenerating islet-derived protein 3 α (REG3α), and lipopolysaccharides (LPS = were quantified by ELISA, while 1–3-β-D-glucan BDG) levels were assessed using the Fungitell assay. Univariable, multivariable, and splines analyses were performed.ResultsPlasma levels of I-FABP, REG3α, LPS and BDG were not different between groups of low, intermediate and high B-CAM levels. However, LPS and REG3α levels were higher in participants with PDQ higher than the median.Multivariable analyses showed that LPS association with PDQ, but not B-CAM, was independent of age and level of education. I-FABP, REG3α, and BDG levels were not associated with B-CAM nor PDQ levels in multivariable analyses.ConclusionIn this well characterized cohort of ART-treated men living with HIV, bacterial but not fungal translocation was associated with presence of cognitive difficulties. These results need replication in larger samples.

Relevance of biomarkers indicating gut damage and microbial translocation in people living with HIV.

The intestinal barrier has the daunting task of allowing nutrient absorption while limiting the entry of microbial products into the systemic circulation. HIV infection disrupts the intestinal barrier and increases intestinal permeability, leading to microbial product translocation. Convergent evidence has shown that gut damage and an enhanced level of microbial translocation contribute to the enhanced immune activation, the risk of non-AIDS comorbidity, and mortality in people living with HIV (PLWH). Gut biopsy procedures are invasive, and are not appropriate or feasible in large populations, even though they are the gold standard for intestinal barrier investigation. Thus, validated biomarkers that measure the degree of intestinal barrier damage and microbial translocation are needed in PLWH. Hematological biomarkers represent an objective indication of specific medical conditions and/or their severity, and should be able to be measured accurately and reproducibly via easily available and standardized blood tests. Several plasma biomarkers of intestinal damage, i.e., intestinal fatty acid-binding protein (I-FABP), zonulin, and regenerating islet-derived protein-3α (REG3α), and biomarkers of microbial translocation, such as lipopolysaccharide (LPS) and (1,3)-β-D-Glucan (BDG) have been used as markers of risk for developing non-AIDS comorbidities in cross sectional analyses and clinical trials, including those aiming at repair of gut damage. In this review, we critically discuss the value of different biomarkers for the estimation of gut permeability levels, paving the way towards developing validated diagnostic and therapeutic strategies to repair gut epithelial damage and to improve overall disease outcomes in PLWH.

478 Incidence and Risk Factors for Comorbidities Following COVID-19 Disease in People Living with HIV

OBJECTIVES/GOALS: COVID-19 disproportionately affects patients with prior health conditions and those living at a lower socioeconomic status. Persons living with HIV (PLWH) are infected with SARS-CoV-2 at a higher rate than seronegative patients. Risk factors and incidence of post-COVID-19 comorbidities in PLWH, specifically, are still unknown METHODS/STUDY POPULATION: We will study PLWH enrolled in the Emory Centers for AIDS Research (CFAR) Registry who receive care at the Grady Ponce de Leon Center in Atlanta, Georgia to 1) investigate the incidence of, and 2) identify risk factors that predispose PLWH to post-COVID-19 comorbidities. All PLWH with documented COVID-19 (by positive SARS-CoV-2 PCR or antigen test) between March 1, 2020, and September 30, 2021, with a clinic visit within 12 months will be included. We will identify comorbidities using problem list diagnoses and ICD9/10 codes. With a predicted sample size of 395, we will use a Cox proportional hazards model for time-to-detection of comorbidity, and bivariate and multivariate logistic regression models to identify predictors of incident comorbidity within 12 months of COVID-19. RESULTS/ANTICIPATED RESULTS: o Previous work demonstrated that in PLWH, age and non-AIDS comorbidities, but not HIV-related factors, were associated with hospitalization for COVID-19 in a dose dependent fashion.18 We anticipate that rate of incident comorbidities will be significantly higher in PLWH after COVID-19 compared to PLWH without a history of COVID-19. We also expect that pre-existing comorbidities including obesity and cardiovascular disease, male sex, Black race, and older age are associated with higher incidence of post-COVID-19 comorbidities in PLWH. When stratifying by organ system, we also anticipate that prior comorbidities of an organ system will predispose patients to later complications of that same system. DISCUSSION/SIGNIFICANCE: By understanding the incidence and risk factors associated with developing post-COVID-19 comorbidities we can improve guidelines for treatment of groups experiencing the disproportionate impact of co-infection with HIV and SARS-CoV-2.

The challenge of dealing with non-AIDS comorbidities for people living with HIV: Perspectives and experiences of patients and healthcare providers

ABSTRACT As the cohort of People Living with HIV (PLHIV) ages, so does the spectrum and burden of non-AIDS define HIV-associated conditions (NARC). PLHIV are likely to need different and increased healthcare services. It requires health systems to adapt to this disease trend and conform to a chronic care model, which respects the distinct needs of the ageing population. In this article, we explore the lived experiences of PLHIV and their healthcare providers in managing the challenges of dealing with NARC in Arba Minch, Southern Ethiopia. This study utilises interpretative substantive methods, encompassing qualitative interviews and Focus Group Discussions. The Normalisation Practice Theory (NPT) guided the semi-structured questions concerning routine screenings and current models of HIV care for ageing individuals. The main structural challenges in providing adequate geriatric care included: (i) the lack of awareness of the risk of NARCs; (ii) the absence of blended care; (iii) an HIV-centred approach exclusive of multidisciplinary care; and (iv) financial constraints. In an era with increasing NARCs, traditional HIV care models must adapt to the emerging challenges of a ‘greying’ and growing population.

The 2000HIV study: Design, multi-omics methods and participant characteristics.

Even during long-term combination antiretroviral therapy (cART), people living with HIV (PLHIV) have a dysregulated immune system, characterized by persistent immune activation, accelerated immune ageing and increased risk of non-AIDS comorbidities. A multi-omics approach is applied to a large cohort of PLHIV to understand pathways underlying these dysregulations in order to identify new biomarkers and novel genetically validated therapeutic drugs targets. The 2000HIV study is a prospective longitudinal cohort study of PLHIV on cART. In addition, untreated HIV spontaneous controllers were recruited. In-depth multi-omics characterization will be performed, including genomics, epigenomics, transcriptomics, proteomics, metabolomics and metagenomics, functional immunological assays and extensive immunophenotyping. Furthermore, the latent viral reservoir will be assessed through cell associated HIV-1 RNA and DNA, and full-length individual proviral sequencing on a subset. Clinical measurements include an ECG, carotid intima-media thickness and plaque measurement, hepatic steatosis and fibrosis measurement as well as psychological symptoms and recreational drug questionnaires. Additionally, considering the developing pandemic, COVID-19 history and vaccination was recorded. Participants return for a two-year follow-up visit. The 2000HIV study consists of a discovery and validation cohort collected at separate sites to immediately validate any finding in an independent cohort. Overall, 1895 PLHIV from four sites were included for analysis, 1559 in the discovery and 336 in the validation cohort. The study population was representative of a Western European HIV population, including 288 (15.2%) cis-women, 463 (24.4%) non-whites, and 1360 (71.8%) MSM (Men who have Sex with Men). Extreme phenotypes included 114 spontaneous controllers, 81 rapid progressors and 162 immunological non-responders. According to the Framingham score 321 (16.9%) had a cardiovascular risk of >20% in the next 10 years. COVID-19 infection was documented in 234 (12.3%) participants and 474 (25.0%) individuals had received a COVID-19 vaccine. The 2000HIV study established a cohort of 1895 PLHIV that employs multi-omics to discover new biological pathways and biomarkers to unravel non-AIDS comorbidities, extreme phenotypes and the latent viral reservoir that impact the health of PLHIV. The ultimate goal is to contribute to a more personalized approach to the best standard of care and a potential cure for PLHIV.

1274. Implementation of Pharmacist-led Medication Reconciliation in Older PLHIV

Abstract Background Older (age ≥ 50) people living with HIV (PLHIV) have a higher prevalence of non-AIDS associated comorbidities and polypharmacy. Optimal care requires accurate knowledge of the number and types of medications older PLHIV take. Most providers use the electronic health record (EHR) to obtain this information, despite reported inaccuracy in other cohorts. Recent efforts have focused on engaging pharmacists to assist with EHR medication reconciliation. This abstract describes the results of a pilot study of phone-based, pharmacist-driven EHR medication reconciliation. Methods Older PLHIV reported via an online questionnaire the number of prescription medications they took, with response options ranging from “0” to “11 or more.” Then, a clinic-based pharmacist called each participant to review the daily and prn prescription medications they were taking. Finally, a physician reviewed EHR pharmacy data to count the number of daily and prn prescription medications listed. Wilcoxon rank sum tests compared the medians between the phone review, the self-reported questionnaire, and the EHR review. Results Forty participants were offered the intervention, and 26 (65%) were reachable by phone and agreed. Of those, the mean age was 61 years (range 51-73), 89% were male, 67% were White, and the mean number of self-reported comorbid conditions was 11.7 (SD=7.7). In 25/26 (96%) cases, both the number and type of HIV medications in the EHR matched what the pharmacist verified on the phone call. Median number of non-HIV medications are reported in Table 1. Assuming that pharmacist phone calls provided the most accurate data, the EHR overestimated the number of non-HIV medications by 5 medications (P = 0.01), whereas patients’ self-report underestimated by 1.5 medications (P &amp;lt; 0.01). Conclusion Among older PLHIV, EHR pharmacy data significantly overestimated, and patient self-report significantly underestimated, the number of non-HIV prescription medications. Phone-based, pharmacy-driven medication reconciliation improved upon both EHR-based and self-reported medication accuracy. Based on these findings, future interventions designed to decrease polypharmacy in older PLWHIV can rely upon pharmacist-led, phone-based outreach to ensure that baseline medication information is accurate. Disclosures Maile Y. Karris, MD, Gilead Sciences: Grant/Research Support|Gilead Sciences: I have received honorarium to speak at conferences|ViiV Healthcare: Grant/Research Support Peter J. Mazonson, MD, MBA, ViiV Healthcare: Grant/Research Support Lucas Hill, PharmD, AAHIVP, Gilead Sciences: Speakers Bureau Emily Huang, MPH, ViiV Healthcare: Grant/Research Support Jeff Berko, MPH, ViiV Healthcare: Grant/Research Support.

HIV and aging, biological mechanisms, and therapies: What do we know?

Aging, a time-dependent loss of physiological function, and its drivers are turning into a significant topic of researchas the population's mean age increases. Epigenetic alterations, telomere shortening or dysfunction, mitogenic stress,oxidative stress, or accumulation of DNA damage can drive the cell to senescence a permanent cell cycle arrest sometimes associated with a secretory phenotype and inflammatory consequences in the surrounding tissue. The amount of senescent cellsgrows over time in older organisms and may induce tissue inflammation and threaten overall tissue homeostasis, favoring aging. Senolytic and senomorphic therapeuticsare an emerging approach to eliminate senescent cells or to block their secretoryphenotypes respectively. Given that people living with HIV suffer non-AIDS comorbidities in a higher prevalence than the general population, aging is accentuated among them. Inflammation biomarkers may be helpful to assess prognosis or act as surrogate endpoints for studies of strategies focused on reversal of HIV-associated accelerated aging. This review summarizes the latest findings in aging and its major drivers, under the light of HIV infection. Since the number of older PLWH is currently rising, it will be of great importance to address and treat their age-related conditions, as well as to better decipher their biological mechanisms.

Elevated Foxp3+ double-negative T cells are associated with disease progression during HIV infection.

Persistent immune activation, which occurs during the whole course of HIV infection, plays a pivotal role in CD4+ T cells depletion and AIDS progression. Furthermore, immune activation is a key factor that leads to impaired immune reconstitution after long-term effective antiretroviral therapy (ART), and is even responsible for the increased risk of developing non-AIDS co-morbidities. Therefore, it’s imperative to identify an effective intervention targeting HIV-associated immune activation to improve disease management. Double negative T cells (DNT) were reported to provide immunosuppression during HIV infection, but the related mechanisms remained puzzled. Foxp3 endows Tregs with potent suppressive function to maintain immune homeostasis. However, whether DNT cells expressed Foxp3 and the accurate function of these cells urgently needed to be investigated. Here, we found that Foxp3+ DNT cells accumulated in untreated people living with HIV (PLWH) with CD4+ T cell count less than 200 cells/µl. Moreover, the frequency of Foxp3+ DNT cells was negatively correlated with CD4+ T cell count and CD4/CD8 ratio, and positively correlated with immune activation and systemic inflammation in PLWH. Of note, Foxp3+ DNT cells might exert suppressive regulation by increased expression of CD39, CD25, or vigorous proliferation (high levels of GITR and ki67) in ART-naive PLWH. Our study underlined the importance of Foxp3+ DNT cells in the HIV disease progression, and suggest that Foxp3+ DNT may be a potential target for clinical intervention for the control of immune activation during HIV infection.

Comprehensive phenotyping of circulating immune cell subsets in people living with HIV

Systemic chronic inflammation and immune dysfunction are recognized as drivers of the development of non-AIDS related comorbidities (NARCs) in people living with HIV (PLHIV). In order to lower the risk of NARCs, it is critical to elucidate what is the contribution of alterations in the composition and function of circulating immune cells to NARCs-related pathogenesis. Findings from previous immunophenotyping studies in PLHIV are highly heterogeneous and it is not fully understood to what extent phenotypic changes on immune cells play a role in the dysregulated inflammatory response observed.In this study, three flow cytometry panels were designed and standardized to phenotypically and functionally identify the main circulating immune cell subsets in PLHIV. To reduce variability, up to 10 markers out of the approximately 20 markers in each panel were used in a custom dry format DURA Innovations (LUCID product line). Intra-assay precision tests performed for the selected cell subsets showed that the three panels had a %CV below 18% for percent of positive cells and the MFI (mean fluorescent intensity) of lineage markers. Our reported pipeline for immunophenotypic analysis facilitated the discrimination of 1153 cell populations, providing an integrated overview of circulating innate and adaptative immune cells as well as the cells’ functional status in terms of activation, exhaustion, and maturation. When combined with unsupervised computational techniques, this standardized immunophenotyping approach may support the discovery of novel phenotypes with clinical relevance in NARCs and demonstrate future utility in other immune-mediated diseases.