AIDS

BackgroundPre-exposure prophylaxis (PrEP) with tenofovir/emtricitabine (TDF/FTC) is highly effective for HIV prevention. While antiretroviral therapy (ART) is linked to chronic inflammation in people living with HIV, its direct effects on immune phenotype, function, and metabolism in HIV-negative individuals remain unclear. MethodsGay, bisexual, and other men who have sex with men (gbMSM) on daily TDF/FTC PrEP underwent immunophenotyping and single-cell metabolic profiling using SCENITH. Cytokine and chemokine responses were measured ex vivo and after lipopolysaccharide or Mycobacterium tuberculosis stimulation. These were compared with a demographically similar PrEP-naive cohort, with five individuals followed 6-9 months after PrEP initiation. FindingsMonocytes from people taking PrEP (n=15; median 533 days) exhibited higher activation marker expression (HLA-DR, CD14) ex vivo and enhanced IL-1{beta} and TNF after bacterial challenge compared with PrEP-naive individuals (n=11). Longitudinal follow-up indicated that PrEP initiation increased monocyte activation markers (HLA-DR, CD14, CD40, TNFRI/II) and cytokine production (IL-1{beta}, TNF, GM-CSF, IFN-{gamma}, Granzyme B, MIP-1). Reduced glucose dependency was observed in monocytes, CD56dim NK cells and CD4+ T cells 6-9 months after PrEP initiation. InterpretationDaily TDF/FTC promotes monocyte activation, enhances pro-inflammatory responses, and reprogrammes immune cell metabolism, highlighting ARTs potential to modulate immune-mediated inflammatory pathways in HIV-negative individuals. FundingTrinity Translational Medicine Institute, Trinity College Dublin, Dublin, The Association of Physicians of Great Britain and Ireland, Health Research Board Ireland. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=85 SRC="FIGDIR/small/698427v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@d48088org.highwire.dtl.DTLVardef@1428926org.highwire.dtl.DTLVardef@13a4facorg.highwire.dtl.DTLVardef@144d1f1_HPS_FORMAT_FIGEXP M_FIG C_FIG Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSDespite effective viral suppression with antiretroviral therapy (ART), people living with HIV (PLWHIV) experience persistent immune activation and chronic inflammation that increase their risk of age-associated comorbidities. The extent to which ART itself contributes to this dysregulated immune state remains unclear, as HIV infection confounds most studies. Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) offers a unique opportunity to examine the direct immunological effects of ART in HIV-negative individuals. However, few studies have explored how PrEP influences immune cell activation, effector function, or cellular metabolism in the absence of viral infection. Added value of this studyThis study is the first to characterise how daily PrEP with TDF/FTC modulates innate immune activation and cellular metabolism independently of HIV infection. We show that PrEP enhances monocyte activation and effector cytokine production while reprogramming metabolic pathways to reduce glucose dependency in monocytes, NK cells, and CD4 T cells. These findings reveal previously unrecognised immunometabolic effects of ART in HIV-negative individuals, providing mechanistic insight into how ART exposure can shape immune homeostasis in the absence of infection. Implications of all the available evidenceOur findings, together with existing data from PLWHIV, suggest that ART itself can remodel immune and metabolic pathways, potentially contributing to both beneficial and detrimental outcomes. ART-induced immunometabolic reprogramming may underlie persistent inflammation and the early onset of comorbidities observed in treated HIV infection, while also enhancing innate responsiveness to bacterial pathogens such as Mycobacterium tuberculosis. Understanding these mechanisms may inform future strategies to optimise ART regimens and mitigate inflammation-associated complications.

BackgroundDespite effective antiretroviral therapy, HIV-1 remains a global health challenge. Most people living with HIV (PWH) are diagnosed in the chronic stage and around half globally are diagnosed late. Within the group with a chronic diagnosis, insight into the effect of time of therapy initiation on reservoir dynamics and immune reconstitution from diagnosis onwards is limited. MethodsIn this prospective cohort study of PWH diagnosed during the chronic stage (from Fiebig VI) were stratified into late (<350 CD4+ T cells/mm3 or an AIDS-defining illness) or non-late diagnosis groups. We analyzed the viral reservoir by IPDA, SQuHIVLa and FISH-Flow, and the immune compartment with the AIM assay and a 45-color spectral flow cytometry panel in the first year after ART initiation. FindingsAlthough proviral DNA decreased in the first year of ART, the inducible reservoir remained stable. PWH with a late diagnosis had a significantly higher inducible reservoir and lower CD4+ T-cell counts than the non-late HIV diagnosis group. A year after ART initiation, the group with a late diagnosis showed a higher abundance of exhausted CD8+ T cells, higher expression of activation/exhaustion markers, and a lower naive CD4+ T-cell abundance than the non-late diagnosis group. Moreover, activation and exhaustion marker expression on T cells correlated significantly with CD4+ T cell count pre-ART. InterpretationOur results show that late diagnosis is associated with a persistently higher inducible viral reservoir and impaired immune recovery. These findings underline the importance of early diagnosis and treatment, and rationalize the use of late diagnosis as a covariate in future studies. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSPrior research has demonstrated that initiation of antiretroviral therapy (ART) during the acute stage of HIV-1 infection limits reservoir seeding, reduces immune activation and preserves immune function. Therefore, studies have focused on reservoir and immune dynamics in this acutely diagnosed group. However, only 8,4% of diagnoses in Europe are made at an acute stage. Despite the fact that the far majority of diagnoses are made at chronic infection, heterogeneity within this group has been overlooked. In clinical settings, late HIV-1 diagnosis, defined as CD4+ T cell count <350 or AIDS-defining illness, has been shown to lead to more opportunistic infections, slower time to viral suppression and increased mortality when compared to a non-late (but still chronic) diagnosis. Yet, the reservoir and immune dynamics in these groups remains poorly characterized. Added value of this studyIn this study, PBMCs from a prospective cohort of people with a chronic HIV diagnosis in the first year after ART initiation were analyzed using integrated approaches - reservoir quantification and in depth immunophenotyping to simultaneously characterize reservoir dynamics and the immune compartment. We show a significant decrease in the intact viral reservoir for all participants within the first year of ART, whereas the inducible reservoir remained stable. A comparison was performed between the group with late and non-late (but still chronic) diagnosis, shedding light on the heterogeneity within the chronic diagnosis group. The late diagnosis group had a significantly higher inducible reservoir and immune exhaustion, both in marker expression as well as exhausted T cell abundance. All but four of these activation and exhaustion markers differentially expressed between the two groups correlate with CD4+ T cell count pre-ART, highlighting the large heterogeneity in this group. Implications of all the available evidenceTogether, these findings provide insight into the reservoir and immune dynamics within the first year after ART initiation. The data can especially inform both reservoir-targeting strategies that intervene at or shortly after ART initiation, as well as strategies that aim to harness the immune system. Moreover, these results reinforce the importance of early diagnosis, even after the acute stage. The differences in the reservoir and immune compartments between the late and non-late diagnosis groups underscore the need for the use of late diagnosis or time to diagnosis as a covariate in future cure studies.

BackgroundPlasma C-X-C-motif chemokine ligand-13 (CXCL13) has been linked to disease progression and mortality in people living with HIV (PLWH) and is a candidate target for immune-based strategies for HIV cure. Its role in central nervous system (CNS) of PLWH has not been detailed. We described CSF CXCL13 levels and its potential associations with neurological outcomes. MethodsCross-sectional study enrolling PLWH without confounding for CXCL13 production. Subjects were divided according to CSF HIV-RNA in controllers (<20 cp/mL) and viremics. CSF CXCL13, and biomarkers of blood-brain barrier (BBB) impairment, intrathecal synthesis, and immune activation were measured by commercial immunoturbidimetric and ELISA assays. All subjects underwent neurocognitive assessment. Sensitivity analyses were conducted in subjects with intact BBB only. Results175 subjects were included. Prevalence of detectable CSF CXCL13 was higher in viremics (31.4%) compared to controllers (13.5%; OR 2.9 [1.4-6.3], p=0.006), but median CSF levels did not change (15.8 [8.2-91.0] vs 10.0 [8.1-14.2] pg/mL). In viremics (n=86), CXCL13 associated with higher CSF HIV-RNA, proteins, neopterin, Tourtelotte index, and CSF-to-serum albumin ratio. In controllers (n=89), CXCL13 associated with higher CD4+T-cells count, CD4/CD8 ratio, CSF proteins, neopterin, and several intrathecal synthesis markers. Detection of CSF CXCL13 in controllers increased the likelihood of HIV-associated neurocognitive disorders (58.3% vs 28.6%, p=0.041) and HIV-related CNS disorders (8.3% vs 0%, p=0.011). Sensitivity analyses confirmed all these findings. ConclusionsCSF CXCL13 identified a subgroup of PLWH presenting increased CNS IgG synthesis, and immune activation. In controllers, CSF CXCL13 associated with increased likelihood of neurocognitive impairment and HIV-related CNS disorders. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=161 SRC="FIGDIR/small/22283427v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@bfe68aorg.highwire.dtl.DTLVardef@b87cc4org.highwire.dtl.DTLVardef@766cdorg.highwire.dtl.DTLVardef@1ee510f_HPS_FORMAT_FIGEXP M_FIG C_FIG

AimsHIV infection is associated with dyslipidemia and an increased risk for cardiovascular diseases. HIV Nef protein downregulates the generation of nascent HDL. The interplay between HIV-RNA, HDL-c level and CD4/CD8 ratio in naive HIV patients remains to be elucidated. MethodsWe included untreated persons living with HIV (PLWH) of the ICONA Foundation Study cohort if they also had [&ge;]2 viral load (VL) measurements prior to ART initiation. We performed unadjusted correlation and linear regression analyses evaluating the effect of VLset on HDL-C. Vlset and CD4/CD8 ratio were fit in the log10 scale, while HDL-c, was fitted in the untransformed raw scale. ResultsWe included 3,980 untreated PLWH. Fifty-eighty (1.5%) were aviremic. We observed a negative correlation between HDL-c and VLset (Pearson R2=0.03), from fitting an unadjusted linear regression model -8.5 mg/dl (95% CI: -15,9 --0,84 p<0.03). There was a dose-response relationship between HDL-c levels and VLset, however, this association was somewhat attenuated after further controlling for gender. Despite a positive correlation between HDL-c and CD4/CD8 ratio, the HDL-c plasma concentration does not satisfy the criteria for a strong surrogate marker. ConclusionsOur data show that HDL-c plasma concentration is significantly lower per higher level of VLSet although this was in part explained by gender. Further analyses should be promoted to better understand the molecular mechanisms that underline the relationship between HIV replication, HDL-c formation, and diseases progression.

Chronic neuroinflammation is associated with comorbidities in people with HIV (PWH) on antiretroviral therapy (ART). While cannabis use is associated with reduced neuroinflammation and neurocognitive impairment (NCI) in PWH, the underlying mechanisms are unknown. To address this gap in knowledge, we analyzed monocyte-derived macrophages (MDMs) from a cohort of 50 PWH and 33 people without HIV (mean age: 61.9 years), categorized by frequency of cannabis use (naive/low, moderate, daily). We performed immunocytochemistry, RNA sequencing, and qPCR on MDMs and quantified related biomarkers in donor plasma. In this cohort study, daily cannabis use in PWH was associated with less global neurocognitive deficits, and with an anti-inflammatory immunometabolic-phenotype in MDMs characterized by (1) a metabolic shift from glycolysis to oxidative phosphorylation, (2) higher mitochondrial numbers, (3) altered cytokine profiles (pro-inflammatory downregulation, anti-inflammatory upregulation), and (4) higher brain-derived neurotrophic factor (BDNF) expression. These cellular changes were corroborated by a plasma biomarker profile in PWH including (1) lower levels of growth differentiation factor 15 and soluble triggering receptor expressed on myeloid cells 2, and (2) higher mature BDNF/precursor BDNF ratios that correlated with better cognition. Thus, cannabis use may mitigate NCI in PWH by immunometabolically reprogramming MDM function towards an anti-inflammatory and neuroprotective state. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/709579v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@15fb1adorg.highwire.dtl.DTLVardef@189d79corg.highwire.dtl.DTLVardef@aa6a89org.highwire.dtl.DTLVardef@3852f8_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundFor optimal functionality, immune cells require a robust and adaptable metabolic program that is fueled by dynamic mitochondrial activity. In this study, we investigate the metabolic alterations occurring in immune cells during HIV infection and antiretroviral therapy by analyzing the uptake of metabolic substrates and mitochondrial homeostasis. By delineating changes in immune cell metabolic programming during HIV, we may identify novel potential therapeutic targets to improve antiviral immune responses. MethodsWhole blood was drawn from HIV uninfected female volunteers and women with chronic HIV infection on combination antiretroviral therapy. Peripheral blood mononuclear cells-derived immune cells were directly incubated with different fluorescent markers: FITC-2-NBDG (2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose), FITC-BODIPY (4,4-Difluoro-5,7-Dimethyl-4-Bora-3a,4a-Diaza-s-Indacene-3-Hexadecanoic Acid), FITC-MitoTracker Green and APC-MitoTracker Deep Red. The uptake of glucose and fats and the mitochondrial mass and potential were measured using flow cytometry. All values are reported quantitatively as geometric means of fluorescence intensity. ResultsDuring chronic HIV infection, cellular uptake of glucose increases in HIV+ dendritic cells (DCs) in particular. CD4+ T cells had the lowest uptake of glucose and fats compared to all other cells regardless of HIV status, while CD8+ T cells took up more fatty acids. Interestingly, despite the lower utilization of glucose and fats in CD4+ T cells, mitochondrial mass increased in HIV+ CD4+ T cells compared to HIV negative CD4+ T-cells. HIV+ CD4+ T cells also had the highest mitochondrial potential. ConclusionsSignificant disparities in the utilization of substrates by leukocytes during chronic HIV/cART exist. Innate immune cells increased utilization of sugars and fats while adaptive immune cells displayed lower glucose and fat utilization despite having a higher mitochondrial activity. Our findings suggest that cART treated HIV-infected CD4+ T cells may prefer alternative fuel sources not included in these studies. This underscores the importance of understanding the metabolic effects of HIV treatment on immune function.

BackgroundPeople with HIV (PWH), even with sustained viral suppression on antiretroviral therapy (ART), remain at increased risk for cardiovascular disease. Coronary endothelial dysfunction, a sensitive marker of early vascular injury and a potential target for intervention is common in this population, but its biological basis remains unknown. MethodsWe performed a cross-sectional study combining in vivo coronary MRI and high-throughput serum proteomics to investigate mechanisms of coronary endothelial dysfunction in treated HIV. Forty-five virally suppressed PWH and twenty-nine age- and sex-matched healthy controls underwent coronary MRI during isometric handgrip exercise to quantify coronary endothelial function, defined as the percentage change in coronary cross-sectional area (%CSA) from rest to stress. An increase in coronary CSA <2% indicated endothelial dysfunction. Parallel serum proteomic profiling was performed using the SomaScan 7K platform, and differential protein expression between groups was analyzed using linear modeling (LIMMA). ResultsCoronary endothelial dysfunction was more prevalent in PWH with suppressed viral load compared to controls (67% vs 10%, p<0.001). Pathway analysis of differentially expressed proteins between participants with and without endothelial dysfunction highlighted significant dysregulation of glutathione dependent detoxification, oxidative metabolism and fatty acid {beta}-oxidation pathways in individuals with endothelial dysfunction (adjusted p value <0.05). ConclusionsEndothelial dysfunction in PWH on ART is associated with metabolic and redox imbalance. These findings highlight glutathione and fatty acid oxidation related pathways as potential therapeutic targets for reducing cardiovascular risk in this patient population.

BackgroundWhile the role of CD4+ T-cells in HIV-1 reservoir persistence during antiretroviral therapy (ART) is well-established, studies on tissue-resident macrophages (M{Phi}) in people with HIV-1 (PWH) are restricted by difficulties in accessing deep tissue samples. Investigations in myeloid-only humanized mouse models demonstrated the contribution of M{Phi} to viral rebound upon ART interruption. Two distinct M{Phi} subsets exist in mice and humans: one of embryonic origin and self-renewal capacity generating long-lived tissue-resident M{Phi} (LL-TRM), and another one of short-lived M{Phi} (SL-M{Phi}), constantly replenished by bone marrow monocytes. The relative contribution of LL-TRM versus SL-M{Phi} to tissue HIV-1 reservoir persistence during ART remains understudied. Here, we used a humanized BM-liver-thymus (hu-BLT) mouse model to quantify integrative HIV-1 infection in liver/lung M{Phi} versus CD4+ T-cells before/after ART and document their expression of LL-TRM/SL-M{Phi} markers. ResultsLung/liver immune cells were extracted from ART-naive (ART-) and ART-treated (ART+) HIV-infected (HIV+) hu-BLT mice, as well as HIV-uninfected mice (HIV-). M{Phi} were identified as cells expressing the myeloid markers CD33/HLA-DR and/or CD68 and flow-cytometry sorted based on their differential expression of CD14 and/or CCR2. Matched CD3+CD4+ T-cells were sorted in parallel and used as controls. HIV-DNA integration was measured by nested real-time PCR. In contrast to CD4+ T-cells that carried the highest levels of proviral HIV-DNA before and after ART, integrative infection in liver/lung M{Phi} was detected before ART, but was drastically reduced in HIV+ART+ hu-BLT mice, regardless of CD14 or CCR2 expression on M{Phi}. Markers of LL-TRM (CD163/CX3CR1/Ki67/c-Kit) were expressed on a small fraction of liver but not lung M{Phi}, indicative of a deficient LL-TRM development in this hu-BLT model. ConclusionsTogether our results demonstrate that lung/liver M{Phi} in hu-BLT mice support integrative HIV-1 infection in vivo, but their contribution to viral reservoir persistence during ART is minor when compared to CD4+ T-cells. This is consistent with the deficient development of LL-TRM we observed in hu-BLT mice. However, HIV-1 permissive M{Phi} present in this model likely contribute to viral rebound upon ART interruption. Therefore, HIV-1 cure interventions that are tested in such preclinical models should consider targeting HIV-1 replication in both M{Phi} and CD4+ T-cells.

BackgroundTenofovir disoproxil fumarate (TDF) is the antiretroviral drug most commonly associated with renal dysfunction. However, few studies have examined this association in sub-Saharan Africa despite recent scale-up of antiretroviral therapy (ART) to all people living with HIV (Treat All) in this region. We assessed estimated glomerular filtration rate (eGFR) change among HIV infected Rwandan adults following first line TDF-based therapy initiation. MethodsThis prospective, observational study was conducted in 10 Rwandan health centers. Participants were ART-naive adults ([&ge;]18 years) living with HIV who initiated TDF-based ART from 1st July 2016 through 30th July 2018. The primary outcome was eGFR change from pre-(within 12 months) to post-TDF initiation (within 6 months). ResultsOf 476 patients with pre- and post-TDF eGFR measurements, 264 (55.5%) were women and mean age was 35.9 years (SD 9.6). Mean pre-TDF eGFR was 92.4 (SD 24.0) and mean post-TDF was 96.0 (SD 21.0) mL/min/1.73m2. Mean pre-to post-TDF change thus increased 3.60 (SD, 26.6) mL/min/1.73m2 (p=0.001). ConclusionWe detected a statistically significant clinically small renal function improvement within 6 months following TDF initiation among 476 ART-naive patients. This supports continued TDF use for first-line treatment.

Introduction: People with long-term virologically suppressed HIV (PWH) experience chronic inflammation. Beneficial effects such as lower levels of inflammation were reported for cannabis-based medicine but data on the safety of standardized low-dose full-spectrum cannabidiol (CBD) are limited. Methods: This double-blind randomized placebo-controlled trial (NCT05306249) included 80 ART-treated PWH with undetectable viremia (median time on efficient ART 14 years, median age 54 years), encompassing 30% women. Participants received 1 mg/kg CBD oil twice daily (full-spectrum, THC <0.3%) or placebo for 12 weeks plus a 4 week follow-up. Primary trial endpoint (autophagy gene expression) will be described elsewhere; here we evaluate the treatment impact on prespecified safety outcomes such as hemodynamic with electrocardiograms, HIV immunovirological parameters and comprehensive assessments of liver and kidney functions, performed using standard blood tests. Mixed-effects models adjusted for baseline age, sex, BMI, CD4 count and duration of viral suppression assessed longitudinal changes. Results: Of 80 randomized participants, 35 PWH in CBD and 37 in placebo groups completed week 12. No clinically meaningful differences emerged in creatinine, aminotransferases (ALT, AST), or conjugated bilirubin. Total bilirubin decreased in the CBD arm vs placebo (mixed effect model considering time, group and time*group, adjusted for covariates p=0.046). In exploratory sex-stratified analysis, a significant difference starting at week 12 (-8.0 bpm [95% CI -15.6; -0.4], p=0.0425) and persisting at week 16 (-7.9 bpm [95% CI -14.6; -1.3], p=0.0191) evidences a lower heart rate in men belonging to the CBD group compared to the placebo group; no change in females. There was no change in plasma viral load, cell-associated HIV-DNA levels and CD4/CD8 ratio. Discussion: Low-dose full-spectrum GMP-certified CBD was well tolerated over 12 weeks in virally suppressed people with HIV. Observed reductions in total bilirubin and male heart rate are exploratory and warrant confirmation in adequately powered trials incorporating inflammatory biomarkers and pharmacokinetics.

BackgroundAngiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are established antihypertensive treatments that reduce cardiovascular disease (CVD) risk. However, their comparative effectiveness in people with HIV (PWH) is not well examined. This study evaluated the comparative effectiveness of ACEIs and ARBs head-to-head and versus no antihypertensive treatment in preventing primary CVD. MethodsUsing a target trial emulation framework and data from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD), we estimated observational analogs of intention-to-treat (ITT) and per-protocol (PP) effects of antihypertensive treatments in preventing primary CVD (myocardial infarction, non-MI coronary artery disease, stroke, transient ischemic attack, peripheral vascular disease, cardiovascular death) among hypertensive PWH, with subgroup analyses for Black and White PWH. ResultsCompared with no antihypertensive treatment, ACEIs and ARBs were both associated with lower CVD risk in PWH, with similar effect sizes in ITT and PP analyses (ACEI ITT adjusted hazard ratio (HR): 0.79, 95% CI [0.70-0.89]; ACEI PP: 0.71 [0.55-0.90]; ARB ITT: 0.87 [0.65-1.16]; ARB PP: 0.37 [0.18-0.76]). Race-stratified ITT and PP analyses suggested somewhat greater risk reductions in White than Black PWH, although differences were not statistically significant. In head-to-head comparisons, ACEIs and ARBs showed comparable effectiveness overall (ITT: 1.14 [0.84-1.55]; PP: 0.54 [0.25-1.18]), and within race strata. ConclusionsOur study found that both ACEIs and ARBs were effective in reducing CVD risk among PWH, with similar effectiveness observed for both medications. The analysis did not reveal statistically significant differences in effectiveness between Black and White PWH for either drug.

ImportanceEstimating the medical complexity of people aging with HIV can inform clinical programs and policy to meet future healthcare needs. ObjectiveTo project the prevalence of comorbidities and multimorbidity among people with HIV (PWH) using antiretroviral therapy (ART) in the US through 2030. DesignAgent-based simulation model SettingHIV clinics in the United States in the recent past (2020) and near future (2030) ParticipantsIn 2020, 674,531 PWH were using ART; 9% were men and 4% women with history of injection drug use; 60% were men who have sex with men (MSM); 8% were heterosexual men and 19% heterosexual women; 44% were non-Hispanic Black/African American (Black); 32% were non-Hispanic White (White); and 23% were Hispanic. Exposure(s)Demographic and HIV acquisition risk subgroups Main Outcomes and MeasuresProjected prevalence of anxiety, depression, stage [&ge;]3 chronic kidney disease (CKD), dyslipidemia, diabetes, hypertension, cancer, end-stage liver disease (ESLD), myocardial infarction (MI), and multimorbidity ([&ge;]2 mental or physical comorbidities, other than HIV). ResultsWe projected 914,738 PWH using ART in the US in 2030. Multimorbidity increased from 58% in 2020 to 63% in 2030. The prevalence of depression and/or anxiety was high and increased from 60% in 2020 to 64% in 2030. Hypertension and dyslipidemia decreased, diabetes and CKD increased, MI increased steeply, but there was little change in cancer and ESLD. Among Black women with history of injection drug use (oldest demographic subgroup in 2030), CKD, anxiety, hypertension, and depression were most prevalent and 93% were multimorbid. Among Black MSM (youngest demographic subgroup in 2030), depression was highly prevalent, followed by hypertension and 48% were multimorbid. Comparatively, 67% of White MSM were multimorbid in 2030 (median age in 2030=59 years) and anxiety, depression, dyslipidemia, CKD, and hypertension were highly prevalent. Conclusion and relevanceThe distribution of multimorbidity will continue to differ by race/ethnicity, gender, and HIV acquisition risk subgroups, and be influenced by age and risk factor distributions that reflect the impact of social disparities of the health on women, people of color, and people who use drugs. HIV clinical care models and funding are urgently required to meet the healthcare needs of people with HIV in the next decade. KEY POINTS QuestionHow will the prevalence of multimorbidity change among people with HIV (PWH) using antiretroviral therapy in the US from 2020 to 2030? FindingsIn this agent-based simulation study using data from the NA-ACCORD and the CDC, multimorbidity ([&ge;]2 mental/physical comorbidities other than HIV) will increase from 58% in 2020 to 63% in 2030. The composition of comorbidities among multimorbid PWH vary by race/ethnicity, gender, and HIV acquisition risk group. MeaningHIV clinical programs and policy makers must act now to identify resources and care models to meet the increasingly complex medical needs of PWH over time, particularly mental healthcare needs.

BackgroundIn the European Union (EU), HIV disproportionately affects men who have sex with men (MSM), with prevalence rates ranging from 2.4% to 29%. Despite the high efficacy of pre-exposure prophylaxis (PrEP) in preventing HIV, its accessibility and uptake remain uneven across countries. This study examines the effectiveness and cost-effectiveness of different PrEP policies across 20 EU countries. MethodsWe employed a stochastic agent-based model of HIV transmission among MSM. The model incorporated data on sexual behavior, PrEP adherence and healthcare costs to evaluate the impact of five distinct PrEP eligibility policies. Outcomes included HIV infections averted, HIV-related deaths prevented, PrEP coverage, and incremental cost-effectiveness ratio. FindingsPolicies by the US, CDC, and Belgian authorities were the most effective in reducing HIV infections and deaths, driven by higher PrEP coverage. However, the WHO policy emerged as the most cost-effective across the 20 countries, despite its current use being limited to Denmark. The European AIDS Clinical Society guidelines also showed potential, although not currently implemented. In countries without PrEP reimbursement, reducing drug costs would significantly expand the range of cost-effective policy options. InterpretationOptimizing PrEP policies is crucial for reducing HIV incidence among MSM in the EU. Broad eligibility criteria maximize effectiveness, while WHO guidelines offer a cost-effective alternative in constrained economic contexts. Our findings highlight the need for policy adjustments to enhance PrEP accessibility, inform national health strategies, and achieve sustainable HIV prevention across diverse settings. FundingCampus France PHC Pessoa, French Government; Portugal-France Bilateral Co-operation 2022 Programa Pessoa ref. 2022.15068.CBM; FCT -- Fundacao para a Ciencia e Tecnologia -- through the LASIGE Research Unit, ref. UIDB/00408/2020 and ref. UIDP/00408/2020; Horizon Europe grant SIESTA (101131957).

BackgroundThere has been significant progress in combating the HIV/AIDS pandemic in the last 15 years. In order to describe towards epidemic control, UNAIDS convened a Global Task Team to recommend targets for 2030 for key HIV interventions. This paper describes the approach to estimate the impact and cost of achieving those targets. Methods and dataWe used an HIV simulation model, Goals, to simulate key epidemiological indicators through 2030 is targets are reached in 134 countries with the highest HIV burden. To estimate the cost of achieving the targets we compiled a unit cost database and applied it to estimate the cost of each intervention in each country for the years 2025 through 2030. ResultsAchieving the UNAIDS 2030 targets would reduce the annual number of new HIV infections globally by 77% from 2023 to 2030, from 1.3 million to 300,000. The number of AIDS deaths would decline by 50% over the same period. The number of people living with HIV would decline slightly, from 40 million to 39 million, but would continue declining to 35 million by 2040. The number of people receiving ART would increase from about 31 million to almost 36 million by 2030 before declining to 32 million by 2040. If the targets are achieved the number of new infections would drop below the number of deaths to people living with HIV by 2026. By 2030 there would be 330,000 fewer new infections than deaths DiscussionAchieving the UNAIDS targets for 2030 would reduce the annual number of new HIV infections to just 9% of the peak value in 1995 and AIDS deaths to 13% of the peak value in 2004. In 2030 new infections would be 60% less than deaths to PLHIV, setting us on a path to achieve the end of AIDS as a public health threat. The resources required to achieve these targets are substantial but $ 5 billion less than previous estimates of $ 29.3 billion. Several donors have announced reductions to assistance for HIV programs in 2025. Thus, the task of mobilizing these additional resources is challenging, but if it can be done, we can achieve substantial success in combating this epidemic which has affected so many lives since it began 54 years ago.

Coding and noncoding single-nucleotide variants (SNVs) of EIF2AK3, which encodes an integrated stress response (ISR) kinase, may play a role in neurodegenerative disorders. We used a candidate gene approach to determine the correlation of EIF2AK3 SNVs with neurocognitive (NC) impairment (NCI), which can persist with viral suppression from antiretroviral therapy (ART) in people with HIV (PWH). This retrospective study of prospectively collected data included participants of the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort, after excluding participants with severe neuropsychiatric comorbidities. Genome-wide data previously obtained in the CHARTER cohort participants (n=1,047) were analyzed to interrogate the association of three noncoding EIF2AK3 SNVs with the continuous global deficit score (GDS) and global NCI (GDS[&ge;]0.5). Targeted sequencing (TS) was performed in 992 participants with available genomic DNA to determine the association of three coding EIF2AK3 SNVs with GDS and NCI. Analyses included univariable and multivariable methods such as analysis of variance and regression. Multivariable models covaried demographic, disease-associated, and treatment characteristics. The cohort characteristics were as follows: median age, 43.1 years; females, 22.8%; European ancestry, 41%; median CD4+ T cell counts, 175/{micro}L (nadir) and 428/{micro}L (current). At first assessment, 70.5% used ART and 68.3% of these had plasma HIV RNA [&le;] 200 copies/mL. A minority of participants had at least one risk allele for rs6739095 (T,41.7%), rs1913671 (C,41.4%), and rs11684404 (C,39.4%). All three noncoding EIF2AK3 SNVs were associated with significantly worse GDS and more NCI (all p<0.05). By TS, fewer participants had at least one risk allele for rs1805165 (G,30.9%), rs867529 (G,30.9%), and rs13045 (A,41.2%). Homozygosity for all three coding SNVs was associated with significantly worse GDS and more NCI (all p<0.001). By multivariable analysis, the rs13045 A risk allele, current ART use, and Beck Depression Inventory-II (BDI) > 13 were independently associated with GDS and NCI (p<0.001). The other two coding SNVs did not significantly correlate with GDS or NCI after including rs13045 in the model. The coding EIF2AK3 SNVs were specifically associated with worse performance in executive functioning, motor functioning, learning, and verbal fluency. Coding and non-coding SNVs of EIF2AK3 were associated with global NC and domain-specific performance. The effects were small-to-medium in size but were present in multivariable analyses. Specific SNVs in EIF2AK3 may be an important component of genetic vulnerability to NC complications in PWH. Identification of host factors that predict NCI could allow for earlier interventions, including those directly modulating the ISR, to improve NC outcomes.

BackgroundPeople with HIV (PWH) experience an increased burden of cardiovascular disease (CVD), partly driven by chronic immune activation despite antiretroviral therapy (ART). Tuberculosis (TB), a frequent co-infection, may leave persistent inflammatory sequelae even after cure, potentially accelerating hypertension and cardiovascular risk. Evidence on long-term cardiometabolic consequences of prior TB in virally suppressed PWH, particularly sex-specific effects, remains limited. MethodsIn a pilot cross-sectional study of 318 PWH, we compared demographics, cardiovascular parameters, and a panel of circulating inflammatory biomarkers between those with and without a history of TB. Logistic regression was used to identify factors associated with TB history in the whole cohort and stratified by sex. ResultsIn the 31 participants (9.7%) with prior TB, univariate analysis identified significant associations with older age, hypertension, longer ART duration, and elevated IL-6 and soluble ST2. Hypertension was strongly associated with TB history in females (OR 4.41, 95% CI: 3.41 (1.57, 7.41) p=0.003) but not males. In multivariate models adjusted for clinical variables, longer ART duration remained an independent correlate in the full cohort. Sex-stratified multivariate analysis revealed that lower IFN-{gamma} was associated with TB history in males (AOR 0.99, p=0.048), while lower IL-5 was associated with TB history in females (AOR 0.99, p=0.042). ConclusionA history of TB is associated with hypertension in PWH, particularly among females, and is linked to sex-specific differences in residual inflammatory pathways. These findings suggest that prior TB may contribute to cardiovascular risk in a sex-disparate manner, warranting further investigation.

BackgroundBoth SARS-CoV-2 and HIV infection exhibit alterations in the senescence profile and immune checkpoint (IC) molecules. However, the midterm impact of SARS-CoV-2 on these profiles in people with HIV (PWH) remains unclear. This study aimed to evaluate differences in plasma biomarker levels related to ICs, the senescence-associated secretory phenotype (SASP), and pro- and anti-inflammatory cytokines in PWH following recovery from SARS-CoV-2 infection. MethodsWe conducted a cross-sectional study of 95 PWH receiving antiretroviral therapy, stratified by SARS-CoV-2 infection status: a) 48 previously infected (HIV/SARS) and b) 47 controls without previous infection (HIV). Plasma biomarkers (n=44) were assessed using Procartaplex Multiplex Immunoassays. Differences were analyzed using a generalized linear model adjusted for sex and ethnicity and corrected for the false discovery rate. Significant values were defined as an adjusted arithmetic mean ratio [&ge;]1.2 or [&le;]0.8 and a qvalue<0.1. Spearman correlation evaluated relationships between plasma biomarkers (significant correlations, rho[&ge;]0.3 and q value<0.1). ResultsThe median age of the PWH was 45 years, and 80% were men. All SARS-CoV-2-infected PWH experienced symptomatic infection; 83.3% had mild symptomatic infection, and sample collection occurred at a median of 12 weeks postdiagnosis. The HIV/SARS group showed higher levels of ICs (CD80, PDCD1LG2, CD276, PDCD1, CD47, HAVCR2, TIMD4, TNFRSF9, TNFRSF18, and TNFRSF14), SASP (LTA, CXCL8, and IL13), and inflammatory plasma biomarkers (IL4, IL12B, IL17A, CCL3, CCL4, and INF1A) than did the HIV group. ConclusionsSARS-CoV-2 infection in PWH causes significant midterm disruptions in plasma ICs and inflammatory cytokine levels, highlighting SASP-related factors, which could be risk factors for the emergence of complications in PWH.

BackgroundThe universal test-and-treat (T&T) policy has improved HIV outcomes but may influence hypertension (HTN) risk due to prolonged antiretroviral therapy (ART) exposure. We compared HTN prevalence and risk factors among PLHIV before and after T&T implementation in Zambia. MethodsA retrospective cohort study analyzed 6,409 PLHIV (2,920 pre-T&T and 3,489 post-T&T) from 12 Southern Province districts. Data on demographics, ART regimens, blood pressure, and laboratory measures were extracted from electronic (SmartCare) and paper records. Multivariable logistic regression identified HTN-associated factors (p<0.05). ResultsHTN prevalence increased from 8.8% pre-T&T to 10.2% post-T&T. Each year of age increased HTN odds by 5-6% in both cohorts (adjusted odds ratio [AOR]: 1.06 pre-T&T, 1.05 post-T&T p<0.0001). Urban residence was protective (AOR: 0.72 pre-T&T, 0.67 post-T&T p[&le;]0.041), while males had higher HTN risk than females (12.2% vs. 8.8% post-T&T p=0.0015). Post-T&T, higher hemoglobin marginally increased HTN odds (AOR: 1.08; p=0.049). INSTI-based regimens rose from 26.3% to 41.5% post-T&T but showed no significant association with hypertension on multivariate analysis. Rural residents had higher HTN prevalence (11.5% vs. 8.4% urban post-T&T p=0.0027). ConclusionsHTN prevalence increased post-T&T, and was driven by aging and potentially ART-related metabolic effects. Urban residence was unexpectedly protective, possibly due to better healthcare access. The hemoglobin-HTN link post-ART warrants further study. Strengths include a large, representative sample, though unmeasured confounders (e.g., lifestyle factors) and retrospective design limit causal inferences. Integrated HTN screening in HIV programs is critical to address this growing burden.

IntroductionTo enable comparable global assessments of viral load suppression (VLS) among people living with HIV on antiretroviral therapy (ART), UNAIDS applies a model to adjust VLS estimates reported at different thresholds to a common VL [&le;]1000 copies/mL definition. We assessed performance of the current reverse Weibull model and alternatives using survey data from sub-Saharan Africa. MethodsUsing data from 21 Population-based HIV Impact Assessment surveys (PHIAs) in 16 sub-Saharan African countries (2015-2022), we assessed six models (Weibull, reverse Weibull, Pareto, Frechet, gamma, and lognormal) in adjusting VLS reported at VL <50, <200, <400 copies/mL to [&le;]1000. We compared predictions using parameters from Johnson et al. and recalibrated using PHIAs, assessing whether new shape parameters improved adjustments and varied by sex and age. ResultsIn adjustments from all thresholds, the Weibull model had the lowest prediction errors (Root-mean-squared error for <200 to [&le;]1000: Weibull: 1.9%; reverse Weibull: 3.1%; Pareto: 2.5%). Prediction errors for reverse Weibull and Pareto models were higher in subgroups with low VLS, compared to Weibull. Across 21 surveys, in adjustments from <200 to [&le;]1000, reverse Weibull overestimated VLS by 2.3%, compared to 1.5% by Weibull and Pareto. The Frechet, gamma, and lognormal models performed similarly to Weibull. Shape parameter estimates for the Weibull and reverse Weibull were slightly higher after recalibration and varied by sex and age. ConclusionThe Weibull, Frechet, gamma, and lognormal models, provided more reliable VLS adjustments across thresholds than the previously recommended reverse Weibull model, avoiding inflated VLS estimates which could obscure gaps in HIV treatment programmes and underestimate HIV transmission risks.

BackgroundChronic inflammation persists in some people living with HIV (PLWH), even during antiretroviral therapy (ART) and is associated with premature aging. The gp120 subunit of the HIV-1 envelope glycoprotein can shed from viral and cellular membranes and can be detected in plasma and tissues, showing immunomodulatory properties even in the absence of detectable viremia. We evaluated whether plasmatic soluble gp120 (sgp120) and a family of gp120-specific anti-cluster A antibodies, which were previously linked to CD4 depletion in vitro, could contribute to chronic inflammation, immune dysfunction, and sub-clinical cardiovascular disease in participants of the Canadian HIV and Aging cohort (CHACS) with undetectable viremia. MethodsCross-sectional assessment of plasmatic sgp120 and anti-cluster A antibodies was performed in 386 individuals from CHACS. Their association with pro-inflammatory cytokines, as well as subclinical coronary artery disease measured by computed tomography coronary angiography was assessed using linear regression models. ResultsIn individuals with high levels of sgp120, anti-cluster A antibodies inversely correlated with CD4 count (p=0.042) and CD4:CD8 ratio (p=0.004). The presence of sgp120 was associated with increased plasma levels of IL-6. In participants with detectable atherosclerotic plaque and detectable sgp120, sgp120 levels, anti-cluster A antibodies and their combination correlated positively with the total volume of atherosclerotic plaques (p=0.01, 0.018 and 0.006, respectively). ConclusionSoluble gp120 may act as a pan toxin causing immune dysfunction and sustained inflammation in a subset of PLWH, contributing to the development of premature comorbidities. Whether drugs targeting sgp120 could mitigate HIV-associated comorbidities in PLWH with suppressed viremia warrants further studies. Key pointsSoluble gp120 is detected in the plasma of people living with HIV-1 with undetectable viremia. The presence of soluble gp120 and anti-cluster A antibodies is associated with immune dysfunction, chronic inflammation, and sub-clinical cardiovascular disease.