Background:Sexually transmitted infections (STIs) remain a major public health concern among people with HIV (PWH) in the Western Pacific region, where systematic long-term surveillance is limited. As the region's largest epidemic country, China has yet to generate longitudinal evidence on STI burden, recurrence, and risk determinants, emphasizing the urgency of integrated monitoring within HIV care systems. Methods:We established a multicenter dynamic cohort including 32,961 PWH who initiated ART between 2010 and 2024 at two major HIV treatment centers in southern China. Five major STIs-syphilis, human papillomavirus (HPV), herpes simplex virus type 2 (HSV-2), gonorrhea, and chlamydia-were identified through linked clinical and laboratory records. Annual incidence rates were calculated, cumulative incidence was estimated using the Aalen-Johansen method, and demographic and clinical determinants were assessed using Fine-Gray models. Recurrence of viral infections and reinfection of bacterial STIs were identified by repeated laboratory-confirmed diagnoses during follow-up. Findings:From 2010 to 2024, 14.1% of participants experienced at least one STI after ART initiation, with the overall incidence of any STI increasing from 7.7 (95% CI 3.3-15.2) to 28.3 (95% CI 26.1-30.6) per 1000 person-years. Syphilis remained the leading infection, showing two distinct peaks in 2018 and 2024. HPV ranked second, with incidence rising steadily until 2021 before a modest decline. Gonorrhea and chlamydia resurged around 2022, while HSV-2 remained at a low but stable level. Younger age, male sex, and men who have sex with men were independent predictors of any STI. Higher baseline CD4+ T cell counts were associated with increased risks of syphilis and HPV, whereas HSV-2 incidence was more common in older or immunocompromised individuals. Among participants with at least one STI during the study period, 28.7% (95% CI 27.7-29.7%) experienced recurrence or reinfection, with the highest recurrence observed for HPV (33.5%, 95% CI 31.7-35.3%) and HSV-2 (29.5%, 95% CI 22.6-37.5%), while syphilis accounted for the largest number of reinfection cases (n = 1334). Interpretation:This long-term multicenter cohort provides the most comprehensive evidence to date on STI epidemiology among people with HIV in China. It reveals a persistently high burden of syphilis and HPV, a sharp resurgence of bacterial STIs, and notable recurrence of viral infections. These findings underscore the importance of strengthening comprehensive STI prevention and monitoring within HIV care settings, particularly through systematic screening and sustained surveillance efforts. By offering regionally relevant data, this study informs integrated HIV-STI control strategies and advances health equity across the Western Pacific. Funding:National Natural Science Foundation of China; the Guangxi Key Research and Development Program; the Guangdong Basic and Applied Basic Research Foundation; and the Guangdong Provincial Medical Science and Technology Research Fund Project.

Background:As survival among people with HIV (PWH) improves in the antiretroviral therapy (ART) era, metabolic comorbidities have become important determinants of long-term outcomes. However, longitudinal evidence quantifying the mortality impact of time-varying metabolic multimorbidity (MM) remains limited. This study aimed to characterise temporal trends in major metabolic conditions and MM patterns after ART initiation, and to quantify their associations with all-cause and non-AIDS-related mortality. Methods:We conducted a prospective two-centre cohort study of PWH who initiated ART in southern China between 2010 and 2024. Dyslipidaemia, diabetes, hypertension, metabolic dysfunction-associated steatotic liver disease, and osteoporosis were ascertained from clinical records and laboratory measurements, and MM was defined as the presence of at least two of these conditions. All-cause and non-AIDS-related deaths were identified through linkage with HIV surveillance, hospital records, and death registries. Associations between MM and mortality were evaluated using Cox regression models with MM treated as a time-varying exposure, and were reported as adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs). Findings:Among 31,630 PWH who initiated ART between 2010 and 2024 (median age 35 years; 83·2% men), 3143 (9·9%) had MM at baseline, defined as present before or within 90 days after ART initiation. The incidence of all five metabolic conditions increased over time, with particularly marked rises after 2020. During follow-up, 8495 MM events occurred, most commonly as two-condition combinations of dyslipidaemia with diabetes or hypertension. All-cause mortality rates were 7·2 (95% CI 6·2-8·3), 10·3 (95% CI 9·7-10·8), and 15·9 (95% CI 14·5-17·4) per 1000 person-years among individuals with 0, 1, and ≥2 conditions, respectively. Compared with those with no metabolic condition, the aHRs for all-cause mortality were 1·7 (95% CI 1·5-2·0) for one condition and 2·1 (1·8-2·5) for ≥2 conditions; a similar dose-response relationship was observed for non-AIDS-related mortality. PWH with hypertension-diabetes-dyslipidaemia doublet or triad had substantially higher risks of all-cause mortality (aHR 2·1 and 4·1, respectively) and non-AIDS-related mortality (aHR 2·3 and 4·2, respectively) than those without metabolic comorbidity. Interpretation:As metabolic comorbidities accumulated over time, the burden of MM increased among PWH. Both overall metabolic burden and specific high-risk combinations were strongly associated with increased mortality. These findings underscore the need to move beyond virological control alone and to integrate structured metabolic comorbidity assessment and long-term metabolic risk management into routine HIV care in the ART era. Funding:National Natural Science Foundation of China, the Guangxi Key Research and Development Program, the project of the Guangdong Basic and Applied Basic Research Foundation, and the Guangdong Provincial Medical Science and Technology Research Fund Project.

Background and objectivesPeople living with HIV (PLWH) are increasingly at risk for cardiovascular disease (CVD) due to chronic inflammation, metabolic dysregulation, and long-term antiretroviral therapy (ART). However, limited data exist regarding coronary anatomy and long-term outcomes in PLWH with acute coronary syndrome (ACS), particularly in Chinese populations. This study aimed to compare coronary angiographic characteristics, metabolic-inflammatory profiles, and 2-year prognosis between PLWH and HIV-uninfected patients with ACS.MethodsWe conducted a single-center observational cohort study including 129 patients with a first episode of ACS between 2019 and 2023. 43 PLWH were analyzed with 86 HIV-uninfected controls. Coronary artery lesions were assessed by angiography and SYNTAX score. Laboratory parameters including CRP and lipid levels, among others, were collected. The primary outcome was the incidence of major adverse cardiovascular and cerebrovascular events during the 2-year follow-up period.ResultsPLWH had significantly higher SYNTAX scores compared to HIV-free patients (21.56 vs. 16.77, P = 0.001). They also showed elevated levels of LDL-C (3.18 vs. 2.66 mmol/L, P = 0.009) and CRP (median 9.10 vs. 5.10 mg/L, P < 0.001). At 2 years, PLWH had a higher rate of ACS recurrence (18.6% vs. 7.0%, P = 0.089), but mortality and other adverse events were similar. In multivariate analyses, HIV status was not an independent predictor of relapse, while calcified lesions were significantly associated with relapse.ConclusionPLWH with ACS have more complex coronary heart disease and a higher risk of recurrence, partly due to vascular calcific changes. These findings suggest the need for enhanced metabolic monitoring and individualized secondary prevention strategies in this high-risk population.

Background:Although widespread antiretroviral therapy has extended the life expectancy of people living with HIV, cardiovascular disease (CVD) has emerged as a primary comorbidity. Persistent cross-specialty knowledge gaps in routine clinical practice lead to suboptimal adherence to guidelines. Integrated, evidence-based tools are urgently needed to overcome these interdisciplinary barriers. While large language models (LLMs) have demonstrated significant capabilities in medicine, no systematic evaluation has assessed their ability to facilitate multidisciplinary CVD management for people living with HIV. Objective:This study compared the performance of 4 mainstream AI models (DeepSeek-V3, DeepSeek-R1, ChatGPT-4o, and ChatGPT-o4-mini) against 12 human clinicians (8 infectious disease specialists and 4 cardiologists) in addressing guideline-based CVD management tasks for people living with HIV. Methods:Based on 4 authoritative domestic and international HIV/CVD guidelines, a structured 25-question assessment was developed via 2 rounds of Delphi consultation. Standard reference answers and an evaluation framework were finalized through expert consensus. LLM responses were generated using standardized prompts. Clinicians answered identical questions via one-on-one structured interviews, transcribed verbatim. Six multidisciplinary experts independently rated all responses across 4 dimensions-accuracy, completeness, readability, and reliability-using a 4-point ordinal scale (1=poor to 4=excellent). Cumulative link mixed models analyzed intergroup differences. Results:All AI models achieved significantly higher scores than clinicians across all dimensions (P<.001). The AI group's mean scores ranged from 3.44 to 3.68 (median 4, IQR 3.0-4.0; coefficient of variation=0.145-0.178). Conversely, clinicians' scores were lower (mean 1.78-2.05; median 2, IQR 1.0-3.0; coefficient of variation=0.428-0.473) with marked dispersion. DeepSeek-R1 delivered the optimal performance, significantly outperforming the other 3 models (all P<.001). Specialty-stratified analysis revealed no significant overall score difference between cardiologists and infectious disease specialists (odds ratio 0.92, 95% CI 0.84-1.01; P=.09). However, dimension-specific analysis indicated that cardiologists scored higher in accuracy (odds ratio 0.81, 95% CI 0.67-0.97; P=.03). Domain-specific divergence was evident: cardiologists outperformed infectious disease specialists in CVD risk assessment (2.26 vs 1.83), whereas infectious disease specialists led in drug adverse effect evaluation (2.23 vs 1.65). Conclusions:In this structured question-and-answer study, LLMs outperformed human clinicians across all metrics for HIV-associated CVD management, with DeepSeek-R1 achieving superior composite scores. These findings validate DeepSeek-R1's potential as a cross-disciplinary decision-support tool capable of integrating complex clinical knowledge, mitigating specialty gaps, and enhancing information precision. Integrating AI systems into multidisciplinary workflows, complemented by targeted clinical training, may optimize the management of complex comorbidities in people living with HIV.

OBJECTIVE:Dolutegravir plus lamivudine (DTG + 3TC) and bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) are guideline-recommended first-line regimens for people with HIV (PWH), but their comparative renal safety remains unclear. We aimed to compare kidney outcomes between these regimens in antiretroviral therapy (ART)-naive PWH, stratified by baseline renal function. METHODS:We conducted a multicenter, prospective cohort study in China (2018-2025) enrolling 2655 ART-naive PWH initiating DTG + 3TC ( n = 788) or BIC/FTC/TAF ( n = 1867). Participants were stratified by baseline estimated glomerular filtration rate (eGFR; <90 versus ≥90 ml/min/1.73 m 2 ). Stabilized inverse probability of treatment weighting was applied to evaluate incident chronic kidney disease (CKD) and longitudinal eGFR changes over 24 months. RESULTS:Among participants with baseline creatinine-based eGFR (eGFRcreat) <90 ml/min/1.73 m 2 , DTG + 3TC was associated with greater declines in eGFRcreat compared with BIC/FTC/TAF at 12 and 24 months. In contrast, no significant differences were observed when kidney function was assessed using the cystatin C-based or creatinine-cystatin C-based equation. In the eGFRcreat ≥90 ml/min/1.73 m 2 stratum, trajectories were comparable. CKD incidence was comparable between regimens in both strata (eGFRcreat <90 ml/min/1.73 m 2 : 29.9% versus 16.8%; ≥90 ml/min/1.73 m 2 : 5.1% versus 4.7%; both P > 0.05), and adjusted Cox models showed no significant difference in CKD risk. CONCLUSION:DTG + 3TC and BIC/FTC/TAF showed comparable renal safety over 24 months among ART-naive PWH. However, when a decline in eGFRcreat is observed during DTG treatment, cystatin C-based assessment may help clarify true kidney function.

BACKGROUND:Integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) might be associated with weight gain. The impact of different INSTIs has not been determined, particularly in combination with tenofovir disproxil fumarate (TDF) or tenofovir alafenamide fumarate (TAF). METHODS:We conducted a retrospective cohort study using real-world data from people with HIV (PWH) aged ≥18 years who newly started ART between 2019 and May 2023 in Shenzhen, China. We performed linear mixed models to assess whether body mass index (BMI) changes of PWH differed significantly over time across ART classes, among INSTIs, and between TAF- and TDF-containing regimens. RESULTS:A total of 5102 PWH (4771 [93.5%] men; median age 31 [IQR 26-40]) were included in the study. Significant differences in BMI changes were observed among regimens. Compared to PWH who contemporaneously used non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens, people who used INSTI-based regimens 0-0.5 years after ART initiation experienced 1.27 greater BMI gain (95% CI 1.14 to 1.50), 0.5-1.5 years after ART initiation 0.18 greater BMI gain (95% CI 0.03 to 0.33). Compared to PWH who newly started TDF + lamivudine [3TC] + DTG, TAF/emtricitabine [FTC]/EVG/c, and TAF/FTC/BIC, those who used 3TC/DTG experienced greater BMI increases after ART initiation. Compared to people who contemporaneously used TAF-containing regimens, people who used TDF-containing regiments 0.5-1.5 years after ART initiation experienced 1.07 less BMI gain (-1.34 to -0.79). CONCLUSIONS:The increase in BMI associated with 3TC/DTG is particularly prominent. Additionally, TDF showed potential weight-neutral or weight-suppressive effects.

While bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) and dolutegravir plus lamivudine (DTG+3TC) are first-line regimens for treatment-naive people with HIV (PWH), long-term real-world head-to-head comparisons of their metabolic and renal outcomes remain limited. We conducted a retrospective cohort study of ART-naive PWH initiating these regimens in China, utilizing 1:2 propensity score matching (PSM) to balance baseline covariates for 1,445 participants (901 BIC/FTC/TAF; 544 DTG+3TC). Over a 24-month follow-up, the study demonstrated comparable virologic suppression (99.7% vs. 100.0%; p = 0.623), weight changes, and cumulative incidence of metabolic abnormalities between the two groups. Conversely, although the crude 24-month incidence of eGFR decline was higher with DTG+3TC (54.8% vs. 40.7%; p = 0.039), adjusted Cox models revealed that the regimen was not independently associated with this decline (HR 1.20; 95% CI 0.97-1.48; p = 0.18).These findings indicate that both regimens offer comparable long-term virologic efficacy and metabolic safety profiles, supporting their routine clinical utility while highlighting the need for cautious interpretation of renal markers during integrase inhibitor-based therapy.

Objective:With increased longevity among people with HIV (PWH), multimorbidity has become a major challenge, but its long-term evolution remains poorly described. We aimed to characterize the longitudinal evolution of comorbidity and identify risk profiles for metabolic and mixed infectious-non-infectious multimorbidity among PWH initiating antiretroviral therapy in China. Methods:We conducted a retrospective cohort study of 5,950 PWH initiating antiretroviral therapy (ART) in Shenzhen, China (2009-2016), with follow-up through 2024. Twenty-six predefined comorbid conditions were classified as curable or incurable. Multimorbidity was defined as ≥2 conditions and grouped into six mutually exclusive comorbidity states. Evolution over 8 years was described using Sankey diagrams and stratified analyses. Multivariable Cox and logistic regression models were used to identify risk factors for incident metabolic multimorbidity and mixed infectious-non-infectious multimorbidity. Results:At ART initiation, 25.9% of participants had multimorbidity; by year 8 this had increased to 42.5%, mainly due to incurable multimorbidity (7.7 to 25.5%). Among 1,464 participants free of all 26 conditions at baseline, 36.1% developed multimorbidity. Younger PWH (≤ 32 years) experienced a steeper decline in comorbidity-free status, whereas older participants (≥46 years) were more likely to accumulate incurable multimorbidity. Dyslipidemia was the earliest and most persistent comorbidity and formed the core of the most frequent multimorbidity clusters. In the metabolic model, older age (≥46 vs. ≤ 25 years; hazard ratio [HR] 3.42, 95% confidence interval [CI] 2.60-4.49), higher body mass index (BMI), male sex, elevated fasting glucose, non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen and reduced estimated glomerular filtration rate (eGFR) were associated with increased risk. For mixed infectious-non-infectious multimorbidity, male sex, injection drug use (IDU), low CD4 count, thrombocytopenia and opportunistic infections were risk factors, whereas higher BMI and being married were protective. Conclusion:Among relatively young Chinese PWH, multimorbidity increases rapidly after ART initiation, driven by metabolic and other incurable conditions centered on dyslipidemia. Distinct risk profiles for metabolic and mixed infectious-non-infectious patterns support integrating early cardiometabolic screening, intensifying infection control and proactive management of dyslipidemia into routine HIV care.

The incidence of human immunodeficiency virus (HIV)-infected individuals is greater, and outcomes are worse following cerebral stroke, despite widespread access to antiretroviral therapy. As the major reservoir of HIV, resident microglia and infiltrative macrophages in the brain can be aberrantly activated by HIV after stroke. However, the underlying reason driving these pathological processes in poststroke brain injury remains unclear. Herein, with the use of ischemia mice and oxygen-glucose deprivation models, we revealed that HIV infection induced a proinflammatory phenotype and impaired the phagocytic clearance of dead/dying neurons by macrophages/microglia, which was accompanied by a marked reduction in complement C1q-like protein (C1ql) 2 in both peri-infarct macrophages/microglia and cerebrospinal fluid. Importantly, these pathological changes, with ischemia-induced neural demyelination, were strongly mitigated by the intracerebral delivery of recombinant C1ql2, which culminated in a reduced infarct volume and neurological deficits poststroke. Notably, delivering recombinant C1ql2 in the presence of gavage antiretroviral drug Biktarvy further promoted functional recovery and rescued tissue loss following chronic ischemia in HIV-bearing mice, underscoring its potential therapeutic relevance. Collectively, these findings reveal a previously unrecognized C1ql2-dependent mechanism through which HIV infection impairs poststroke repair, which highlights C1ql2 restoration as a promising neuroprotective strategy for HIV-infected stroke patients.

Antiretroviral therapy (ART) has transformed HIV infection into a manageable chronic condition, but pathological weight gain, adipose dysfunction, and persistent inflammation are increasingly prevalent among aging people with HIV (PWH). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual GIP/GLP-1 RAs have emerged as transformative therapies, although PWH were underrepresented in pivotal trials. This review integrates randomized trials, observational cohorts, pharmacogenomic studies, and emerging mechanistic evidence within a framework of GLP-1-mediated immunometabolic reprogramming. HIV-specific trials demonstrate reductions in visceral adiposity, body weight, inflammatory biomarkers, and liver fat. Exploratory or preliminary studies suggest possible effects on gut epithelial integrity, immune-cell trafficking, lymphoid pyroptosis, and DNA-methylation aging measures; however, several of these findings remain conference-level, preprint, or post hoc evidence and require prospective validation. We also examine lean-mass loss, weight regain after discontinuation, pharmacogenomic variation, drug access, and research priorities. Overall, GLP-1 RAs are promising components of cardiometabolic care for PWH, but immunologic, gerotherapeutic, and HIV-reservoir applications should currently be considered hypothesis-generating.

ABSTRACT The persistence of latent HIV-1 reservoirs remains a critical barrier to cure. Current “shock and kill” strategies are limited by ineffective latency-reversing agents (LRAs) and poor understanding of epigenetic regulation. Here, we identify chromatin assembly factor 1 subunit A (CHAF1A), a histone chaperone enforcing HIV-1 latency, as a therapeutic target regulated by antagonistic post-translational modifications: ubiquitination promotes its degradation, while O-GlcNAcylation stabilizes it. We demonstrate that trifluridine, a Food and Drug Administration-approved antiviral drug, reactivates latent HIV-1 by disrupting O-GlcNAcylation, triggering CHAF1A ubiquitination and proteasomal degradation. Notably, CHAF1A expression increases with age in CD4+ T cells (>60 years), correlating with deeper proviral reservoirs. This age-dependent accumulation inversely associates with reduced O-GlcNAcase levels, suggesting O-GlcNAcylation-mediated stabilization in aging. Our findings establish CHAF1A as both a therapeutic target and an age-stratifying biomarker, advancing trifluridine as a translatable LRA to enhance reservoir clearance in aging populations—a demographic increasingly impacted by HIV-1 persistence.IMPORTANCEHIV-1 latency continues to represent a significant barrier to achieving a cure, particularly in aging populations characterized by expanded viral reservoirs and compromised immune recovery—a challenge further intensified by the absence of therapies specifically designed to target age-related mechanisms. Current latency-reversing agents (LRAs) are insufficient in addressing the metabolic and epigenetic dysregulation that sustains viral persistence in older individuals. In this study, we reveal a dynamic interplay between ubiquitination and O-GlcNAcylation that regulates the stability of CHAF1A, a histone chaperone essential for maintaining HIV-1 latency. We identify trifluridine as a novel LRA capable of disrupting O-GlcNAcylation to degrade CHAF1A, thereby effectively reversing latency in primary cells. This research bridges a critical gap between fundamental virology and clinical gerontology. These findings establish a robust foundation for refining strategies aimed at HIV-1 eradication, with a focus on targeting host metabolic-epigenetic networks to address latency in underserved aging populations.

To the Editor: As antiretroviral therapy (ART) transforms HIV into a chronic condition, metabolic abnormalities, particularly hyperglycemia, have become a significant concern for people living with HIV (PLWH). Although PLWH are at higher risk for hyperglycemia due to both ART and HIV-related factors, the prevalence and associated factors of hyperglycemia and diabetes in treatment-naive PLWH in China remain underexplored. This study aims to investigate the trend of hyperglycemia and diabetes prevalence in newly diagnosed PLWH in Shenzhen, China, from 2013 to 2019. We conducted a surveillance study including newly diagnosed PLWH who sought HIV care at the Third People's Hospital of Shenzhen from January 2013 to December 2019. This study was approved by the Research Ethics Committee of the Third People's Hospital of Shenzhen (No. 2022-143), and all enrolled PLWH signed an informed consent form. We obtained data from the hospital's routine diagnosis and treatment information systems. Blood and urine samples were collected after 8–10 hours of overnight fasting for routine clinical testing, which included fasting blood glucose, hepatitis B virus surface antigen (HBsAg), hepatitis C virus antibody (anti-HCV), total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), T lymphocyte subsets, and plasma HIV RNA. All assays were conducted using certified standard diagnostic equipment and techniques appropriate for each marker. We defined hyperglycemia as fasting blood glucose (FBG) ≥6.0 mmol/L, with impaired fasting glucose (IFG) being FBG ≥6.1 to <7.0 mmol/L, and diabetes defined as FBG ≥7.0 mmol/L or ongoing treatment with insulin or oral hypoglycemic agents.[1] It is important to note that hyperglycemia is a general term that includes both impaired fasting glucose and diabetes. In this study, we chose to analyze hyperglycemia as a single group to focus on the overall trends and determinants of elevated blood glucose levels. Although the 2020 Chinese Guidelines for the Prevention and Treatment of Diabetes recommend screening individuals aged 40 years and above for diabetes, we selected 35 years as a stratification point to better capture early metabolic changes and associated risks in PLWH, given their higher cardiovascular disease risk and more complex metabolic abnormalities compared to the general population.[1] All statistical analyses were conducted using R, version 3.6.1 (R Foundation, Vienna, Austria). P <0.05 indicated that the difference was statistically significant. Detailed methods are described in the Supplementary Material, https://links.lww.com/CM9/C385. Among the 11,287 newly diagnosed PLWH, 10,275 (91.03%) were male; the median age was 31 years (interquartile range 26–39); 3989 (35.34%) of PLWH were classified as World Health Organization (WHO) clinical stages III and IV, and 9280 (82.22%) had a normal body mass index (BMI). At HIV diagnosis, 3637 (32.22%) had a CD4+ T cell count <200 cells/μL, and 5729 (50.76%) had plasma HIV RNA >105 copies/mL. The overall prevalence of hyperglycemia, impaired fasting glucose, and diabetes was 5.39% (n = 608), 3.33% (n = 376), and 2.06% (n = 232), respectively. The prevalence of hyperglycemia and diabetes exhibited a consistent upward trend from 2013 to 2019. Specifically, the prevalence of hyperglycemia increased from 3.0% in 2013 to 7.0% in 2019 (χ2 = 25.032, P <0.001), while the prevalence of diabetes increased from 0.5% in 2013 to 2.6% in 2019 (χ2 = 10.097, P = 0.001) [Figure 1A].Figure 1: (A) The blue curvere presents the prevalence of hyperglycemia (%) in individuals, while the red curve represents the prevalence of DM, from 2013 to 2019. (B) The blue bars represents the prevalence of hyperglycemia (%) in individuals under 35 years, while the red bars represents the prevalence of hyperglycemia in individuals 35 years and older, from 2013 to 2019. DM: Diabetes mellitus; PLWH: People living with HIV.The prevalence of dyslipidemia among treatment-naive PLWH varied across different age groups from 2013 to 2019. In participants aged <35 years, the highest prevalence was observed in 2017, followed by 2016, with the lowest prevalence recorded in 2013. There was no significant year-to-year difference in this age group. In contrast, the prevalence of hyperglycemia in participants aged ≥35 years exhibited a continuous upward trend, increasing from 7.6% in 2013 to 14.2% in 2019 (χ2 = 190.023, P <0.001) [Figure 1B]. Due to the limited number of participants with diabetes, we did not conduct an age-stratified analysis. The prevalence of hyperglycemia increased gradually with the increase in BMI (χ2 = 161.243, P <0.001). In addition, the prevalence of hyperglycemia was also higher in participants aged ≥35 years, CD4+ T cell count <200 cells/μL, CD8+ T cell count <500 cells/μL, WHO stage III–IV, high TC, high TG, high LDL-C, and low HDL-C than their respective comparator group (all P values <0.05). However, there was no significant difference in the prevalence of hyperglycemia between the male and female participants (χ2 = 0.579, P >0.05). The prevalences of diabetes in different subgroups were generally consistent with those of hyperglycemia [Supplementary Tables 1 and 2, https://links.lww.com/CM9/C385]. Multivariable logistic regression analysis showed that age ≥35 years (odds ratio [OR] = 4.73, 95% confidence interval [CI]: 3.91–5.75), overweight (OR = 1.87, 95% CI: 1.53–2.29), obesity (OR = 3.77, 95% CI: 2.68–5.22), CD8+ T cell count <500 cells/μL (OR = 1.43, 95% CI: 1.11–1.83), and high TG (OR = 1.82, 95% CI: 1.47–2.24) were the independent factors associated with hyperglycemia. There was no significant correlation between hyperglycemia and HIV infection route, CD4+ T cell count, WHO stage, high TC, high LDL-C, or low HDL-C [Supplementary Figure 1, https://links.lww.com/CM9/C385]. Independent factors associated with diabetes were identified through multiple logistic regression analysis. The following factors were found to be significant: male gender (OR = 2.27, 95% CI: 1.30–4.35), age ≥35 years (OR = 6.15, 95% CI: 4.42–8.74), overweight (OR = 1.95, 95% CI: 1.42–2.65], obesity (OR = 3.58, 95% CI: 2.13–5.75), CD8+ T cell count <500 cells/μL (OR = 1.52, 95% CI: 1.02–2.24), and high TG (OR = 2.60, 95% CI: 1.92–3.50). There was no significant correlation between diabetes and CD4+ T cell count, WHO stage, high TC, high LDL-C, and low HDL-C [Supplementary Figure 2, https://links.lww.com/CM9/C385]. This study explored the long-term trends and associated factors of hyperglycemia and diabetes in treatment-naive PLWH in China. Between 2013 and 2019, the prevalence of hyperglycemia increased from 3.0% to 7.0%, while the prevalence of diabetes increased from 0.5% to 2.6% in Shenzhen. Independent factors associated with hyperglycemia or diabetes included male gender, age ≥35 years, overweight, obesity, high TG, and CD8+ T cell count <500 cells/μL. Continuous monitoring of this cohort has revealed a similar upward trend in hyperglycemia and diabetes, indicating a growing risk of metabolic diseases among PLWH. These findings underscore the urgent need for blood glucose management before the initiation of ART in newly diagnosed PLWH, especially given their elevated cardiovascular disease risks compared to the general population. Traditional ART drugs, such as non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs), are closely linked to an increased risk of dyslipidemia and other metabolic disturbances. In addition, newer integrase strand transfer inhibitors (INSTIs), like dolutegravir and bictegravir, have been associated with weight gain, which may further increase the risk of diabetes.[2,3] Clinicians should closely monitor weight and glucose levels in PLWH who are starting or switching to these medications. This study showed that while hyperglycemia and diabetes prevalence has increased in older PLWH (≥35 years), there was no significant change in younger individuals (<35 years). This lack of change may be attributed to factors such as better insulin sensitivity, a delayed onset of metabolic dysfunction, and influences related to pancreatic function and lifestyle, as well as the limited number of diabetes cases in this cohort.[4,5] In the 2022 edition of the Expert Consensus on Screening and Intervention for High-risk Population with Diabetes, individuals aged ≥40 years are identified as being at risk for diabetes in the general population. However, based on our findings, we propose that PLWH aged ≥35 years should also be considered a high-risk group for hyperglycemia screening and management. We acknowledge that age 35 is not a definitive risk threshold, but rather an initial marker based on observed trends. Further research is essential to determine the most appropriate age for initiating screening in this population. This study revealed that men living with HIV are more likely to experience abnormal blood glucose levels, which aligns with the findings from a previous study.[6] One possible mechanism for this increased vulnerability is the role of male sex hormones in their binding to sex hormone-binding globulin, which may contribute to alterations in glucose metabolism among men living with HIV. Consequently, in regions where the HIV epidemic predominantly affects men, it is imperative to enhance the screening and management of abnormal blood glucose levels. In addition, our findings indicate that overweight and obesity are associated with hyperglycemia and diabetes, suggesting that PLWH who are overweight should be prioritized for management interventions. Furthermore, we found that hypertriglyceridemia was associated with abnormal blood glucose levels, illustrating the interconnectedness of lipid and glucose metabolism. Persistent high inflammation, premature aging, and the effects of the HIV contribute to metabolic abnormalities in PLWH even before ART initiation. The study also highlighted the association between CD8+ T cell count <500 cells/μL and abnormal blood glucose. There are several limitations in this study. First, we only included treatment-naive PLWH who were ready to initiate ART, excluding PLWH who were not yet eligible or ready to start ART. This may have led to an underestimation of the prevalence of hyperglycemia or diabetes. Second, some of the information such as smoking, drinking, lifestyle, and family history was incomplete; therefore, we were unable to examine the impact of these factors on the trends of hyperglycemia and diabetes observed in this study. Third, the surveillance study design precluded us from demonstrating the causal relationship between hyperglycemia and diabetes and the associated factors identified. Finally, because this study did not include a concurrent control group, we are unable to confirm whether the increase in hyperglycemia and diabetes prevalence in the PLWH cohort is more pronounced than in the general population. In conclusion, the prevalence of hyperglycemia and diabetes continues to rise among newly diagnosed PLWH in China, presenting an emerging metabolic challenge for treatment-naive individuals. Traditional metabolic abnormalities, such as overweight, obesity, and dyslipidemia, are significantly associated with abnormal blood glucose, highlighting the urgent need for early screening and management of metabolic conditions at the initiation of ART. Specifically, for overweight, obese, or dyslipidemic PLWH, regular blood glucose monitoring, weight management, and lipid control are crucial to prevent hyperglycemia and diabetes. Weight management strategies should include dietary counseling, physical activity promotion, and, if necessary, pharmacological treatments. In addition, for those with dyslipidemia, lipid-lowering therapies, such as statins, should be considered to enhance metabolic health and reduce long-term cardiovascular disease risks. Conflicts of interest None. Funding This work was supported by grants from Science and Technology Innovation Committee of Shenzhen Municipality (No. JCYJ20220531102202005), the Natural Science Foundation of Guangdong Province (No. 2024A1515012118), the Shenzhen High-level Hospital Construction Fund (No. G2022153), and the high-level medical specialist team introduction training project of Dongguan.

Background: Human immunodeficiency virus (HIV) infection is associated with significant metabolic disruptions, and understanding how these disruptions contribute to cardiovascular disease (CVD) is essential for improving patient management and therapeutic strategies. By integrating metabolomics and transcriptomics, we aimed to elucidate the cardiometabolic disease spectrum of people living with HIV (PLWH) and to identify biomarkers and pathways associated with disease progression in this population. Methods: We conducted a cross-sectional observational study between October 2022 and June 2023 at the Third People’s Hospital of Shenzhen, China. Participants were categorized into one of four groups: HIV+ without metabolic abnormalities (healthy control [HC]), HIV + with untreated metabolic (UM) abnormalities (HIV + UM), HIV + with treated metabolic (TM) abnormalities (HIV + TM), and HIV + with CVD (HIV + CVD). Key metabolic and transcriptomic features were identified through a comparative analysis using untargeted metabolomics and RNA sequencing, followed by statistical and pathway enrichment analyses. Results: This study included 114 PLWH: HC group ( n = 30), HIV + UM group ( n = 19), HIV + TM group ( n = 46), and HIV + CVD group ( n = 19). Through comparative analyses of untargeted metabolomic and transcriptomic data across these four groups, we identified 580 dysmetabolic features (DMFs) based on significant changes between the HC group and the HIV + UM/TM groups, with no statistically significant differences in the HIV + UM/TM vs. HIV + CVD comparisons. Notably, 90.52% of these DMFs (525/580) exhibited reduced abundance in the HIV + CVD group. In contrast, 241 CVD-specific features were identified based on significant differences between the HIV + CVD group and the HIV + UM/TM groups. These features, primarily found in the HIV + CVD group, included metabolites and genes strongly associated with chronic inflammation and endothelial dysfunction—key processes in the pathogenesis of CVD among PLWH. Features that indicated a transition from metabolic abnormalities to CVD were termed escalation features (ESCFs). ESCFs included early biomarkers of lipid dysregulation, such as phosphatidylcholine (O-22:1/20:4), and upregulated genes, such as CAMP , both of which showed progressive changes from the HC group through the HIV + UM/TM groups to the HIV + CVD group. Features that indicated a reversal in expression trends—such as those increasing from the HC group to the HIV + UM/TM groups but decreasing in the HIV + CVD group, or vice versa—were termed de-escalation features (DSCFs). DSCFs included lipid species and genes involved in lipid metabolism and mitochondrial function. The integration of metabolomic and transcriptomic data revealed disruptions in pathways, such as glycerophospholipid and arachidonic acid metabolism, with concurrent upregulation of genes involved in cholesterol biosynthesis and the immune response. Receiver operating characteristic curve analysis based on the integration of metabolomic and transcriptomic data markedly improved CVD prediction among PLWH, with an area under the curve of 0.965, sensitivity of 84.2%, and specificity of 96.9%. Conclusions: This study identified key metabolic and transcriptomic alterations associated with CVD among PLWH. These alterations, primarily driven by immune activation, inflammation, and metabolic dysregulation, reflect unique molecular characteristics of CVD in PLWH. Our findings underscore the importance of early detection and tailored interventions to manage CVD risk in this population, providing insights into potential biomarkers for disease progression.

Background:High-density lipoprotein cholesterol (HDL-C) is a well-established marker of lipid metabolism and increasingly recognized as an indicator of inflammatory status. This study investigates HDL-C's role as a predictor of immune reconstitution in people living with HIV (PLWH). Methods:We performed a prospective cohort study of 15,434 PLWH initiating antiretroviral therapy at the Third People's Hospital of Shenzhen, China, between 2005 and 2022. Baseline quartile grouping and Group-Based Trajectory Modeling (GBTM) explored the relationship between HDL-C and immune reconstitution. Restricted cubic spline plots identified nonlinear association. Results:Over a median follow-up of 17.9 months, 9,609 PLWH achieved the CD4+ T-cell count of 500 cells/μL or higher. Multivariate-adjusted Cox proportional hazards regression model showed that hazard ratios (HR) [95% confidence intervals (CI)] for CD4+ T-cell recovery in Q2, Q3, and Q4 versus Q1 of the HDL-C were 0.94 (95% CI: 0.88-0.99), 0.92 (95% CI: 0.87-0.98), and 0.85 (95% CI: 0.80-0.91), respectively. GBTM identified two HDL-C trajectories: Low-floating and High-floating. Relative to Low-floating, High-floating demonstrated a reduced likelihood of CD4+ T-cell recovery (HR=0.86, 95% CI: 0.82-0.90, p < 0.001). A nonlinear association was observed between HDL-C and the outcome (p for nonlinear association = 0.037, p for overall < 0.001), with a threshold at 1.13 mmol/L. Negative correlations between HDL-C and CD4+ T-cell recovery were observed both below the threshold (HR=0.72, 95% CI: 0.57-0.92) and above the threshold (HR=0.78, 95% CI: 0.69-0.87) (both p < 0.05). Conclusions:Our study highlights HDL-C's role in immune recovery, suggesting its potential in guiding prevention and treatment strategies for PLWH.

A substantial proportion of people with HIV (PWH) fail to achieve full immune recovery despite long-term antiretroviral therapy (ART), potentially increasing their risk of serious comorbidities. This study investigated the association between immune non-responder (INR) and the incidence of AIDS-defining diseases (ADs) and non-AIDS-defining diseases (NADs) in a prospective cohort at the Third People's Hospital of Shenzhen, China. The low - and high-threshold cohorts included 7,874 and 8,077 individuals with baseline CD4+ T-cell counts < 350 and < 500cells/μL, respectively. INR was defined as failure to reach CD4+ T-cell thresholds (350 or 500 cells/μL) in two consecutive measurements during follow-up. Kaplan-Meier curves and Cox proportional hazards models were used to assess associations. Median follow-up after immune classification was 49.4 and 42.2 months in the low - and high-threshold cohorts, respectively. In the low-threshold cohort, INR was independently associated with significantly increased risks of ADs, including pneumocystis pneumonia (adjusted hazard ratio [aHR], 10.10; 95% confidence interval [CI]: 4.94-20.70), talaromycosis marneffei (aHR, 7.38; 95% CI: 3.51-15.50), and AIDs-defining cancers (aHR, 3.67; 95% CI: 1.20-11.20); and NADs, including end-stage liver disease (aHR, 15.00; 95% CI: 5.59-40.00), cardiovascular disease (aHR, 3.83; 95% CI: 2.14-6.87), chronic kidney disease (aHR, 1.78; 95% CI: 1.23-2.58), and non-AIDS-defining cancers (aHR, 4.75; 95% CI: 2.31-9.74). Similar associations were observed in the high-threshold cohort. INR is strongly associated with long-term morbidity in PWH. These findings highlight the need for improved risk assessment beyond CD4+ T-cell monitoring to reduce disease burden in PWH.

The triglyceride-glucose (TyG) index has been validated as a novel biomarker for cardiovascular disease (CVD) risk. However, the prospective relationship between baseline and long-term trajectories of the TyG index and CVD risk in people living with HIV (PLWH) remains unexplored. This cohort study included 16,122 treatment-naive PLWH who initiated antiretroviral therapy (ART) at the Third People's Hospital of Shenzhen from 2005 to 2022. The TyG index was calculated as Ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. Group-based trajectory modeling was used to identify distinct TyG index trajectories over the follow-up period. Hazard ratios (HRs) and 95

Background: With increased longevity among people living with HIV (PLWH), multimorbidity has emerged as a critical challenge, occurring at younger ages and involving both non-communicable diseases and persistent infections. Yet its long-term evolution and risk factors remain insufficiently described. Methods: We conducted a retrospective cohort study of 5,950 PLWH initiating antiretroviral therapy (ART) in Shenzhen, China, between 2009 and 2016, with follow-up through 2024. Multimorbidity was defined as ≥2 predefined 26 conditions and categorized into six evolving patterns. Longitudinal changes were assessed using Sankey plots and multivariable regression models. Results: At ART initiation, 25.9% had multimorbidity. Over 8 years, the overall prevalence rose to 42.5%, driven mainly by a threefold increase in incurable multimorbidity (7.7% to 25.5%). Nearly 36% of initially disease-free individuals developed multimorbidity during follow-up. Younger PLWH experienced the faster decline in comorbidity-free status over time, while older individuals more frequently progressed to multimorbidity. Dyslipidemia was the most frequent and persistent condition. Risk factors for metabolic multimorbidity included age at diagnosis ≥ 46 years (HR = 3.44, P < 0.01), body mass index (BMI) ≥ 24 (HR=1.69, P < 0.01), etc. In contrast, higher BMI appeared protective against mixed infectious–non-infectious patterns (HR = 0.72, P < 0.01). Conclusions: Multimorbidity is increasingly prevalent among PLWH in the ART era, with a shift from infectious to metabolic and behavioral comorbidities. Distinct risk profiles highlight the need for early identification and tailored interventions, especially among high-risk subgroups. Early identification and tailored management of key risk factors, particularly dyslipidemia, are essential for integrated HIV care.

The persistence of latent HIV-1 reservoirs remains a critical barrier to functional curing AIDS, as current latency-reversing agents (LRAs) exhibit limited clinical efficacy. While RNA modifications like N⁶-methyladenosine (m⁶A) regulate viral replication, their role in maintaining HIV-1 latency is poorly defined. Here, we identify the RNA-binding protein RBM39 as a scaffold organizing an m⁶A-dependent silencing complex that enforces viral latency. Through proteomic and functional analyses, we demonstrate that RBM39 recruits the m⁶A reader YTHDC1 and the RNA helicase DDX5, forming a tripartite complex that accelerates Tat RNA decay and enforces viral quiescence. Genetic or pharmacological degradation of RBM39 (using the clinically explored molecular glue indisulam) potently reactivates latent HIV-1 in J-Lat cell models, primary CD4⁺ T cells from people living with HIV-1 (PLWH), and synergizes with established LRAs (Bryostatin-1, JQ-1, SAHA) to broadly activate proviral reservoirs. Our work reveals a previously unrecognized host pathway in which RBM39-organized RNA decay complexes silence HIV-1 through epitranscriptomic regulation of Tat. In addition to establishing RBM39 as a promising therapeutic target for addressing the limitations of current "shock and kill" strategies, our findings establish a novel mechanistic framework for m⁶A-dependent regulation of viral gene expression. This framework may serve as a valuable reference for investigating similar regulatory mechanisms in other latent viral infections or oncogenic processes where RNA methylation plays a pivotal role.

Men who have sex with men and people living with HIV are disproportionately affected in the 2022 multi-country monkeypox epidemic. The smallpox vaccine can induce cross-reactive antibodies against the monkeypox virus (MPXV) and reduce the risk of infection. Data on antibodies against MPXV induced by historic smallpox vaccination in people with HIV are scarce. In this observational study, plasma samples were collected from people living with and without HIV in Shenzhen, China. We measured antibodies binding to two representative proteins of vaccinia virus (VACV; A27L and A33R) and homologous proteins of MPXV (A29L and A35R) using an enzyme-linked immunosorbent assay. We compared the levels of these antibodies between people living with and without HIV. Stratified analyses were performed based on the year of birth of 1981 when the smallpox vaccination was stopped in China. Plasma samples from 677 people living with HIV and 746 people without HIV were tested. A consistent pattern was identified among the four antibodies, regardless of HIV status. VACV antigen-reactive and MPXV antigen-reactive antibodies induced by historic smallpox vaccination were detectable in the people born before 1981, and antibody levels reached a nadir during or after 1981. The levels of smallpox vaccine-induced antibodies were comparable between people living with HIV and those without HIV. Our findings suggest that the antibody levels against MPXV decreased in both people living with and without HIV due to the cessation of smallpox vaccination.