Focusing on vulnerable populations in HIV

The global human immunodeficiency virus (HIV) epidemic remains a major public health challenge, with an estimated 40.8 million people living with HIV (PLWH) worldwide by the end of 2024. Despite expanding combination antiretroviral therapy (cART) coverage to 31.6 million in 2024, HIV-related illnesses still caused approximately 630,000 global deaths.[1] cART has successfully suppressed HIV replication and transmission, significantly extending the life expectancy of PLWH. However, the mortality burden has shifted toward non-acquired immunodeficiency syndrome (AIDS)-defining diseases (NADs), including metabolic syndrome, cardiovascular and cerebrovascular diseases, non-AIDS-defining cancers (NACs), and organ dysfunctions (liver, renal, and bone).[2] Achieving sustained survival requires a more comprehensive approach to HIV management. Improving the prognosis of PLWH depends on clinicians’ ability to identify those in need of specialized care. To better identify PLWH at elevated risk of poor outcomes and guide targeted interventions, we propose the concept of “vulnerable populations in HIV”, encompassing those who require intensified monitoring and individualized management. Definition The concept of “vulnerable populations in HIV” encompasses PLWH at heightened risk of adverse outcomes despite effective cART. This category includes: (1) Advanced age ( ≥50 years old); (2) Incomplete immune reconstitution despite virologic suppression; (3) Presence of at least one comorbidity (NAD, e.g., metabolic syndrome, cardiovascular or cerebrovascular disease, chronic liver, renal, or bone disorder, or NACs); (4) Coexisting mental disorders (e.g., depression, anxiety, insomnia, and substance abuse); (5) Polypharmacy (≥2 long-term medications in addition to cART); (6) Intravenous drug use; (7) Special populations (e.g., children, pregnant and postpartum women). Reasons for Proposing “Vulnerable Populations in HIV” Advanced age The number of older PLWH, defined as those ≥50 years of age,[3] is growing worldwide.[4] Older PLWH constitute a uniquely vulnerable demographic due to converging biological and psychosocial risks. First, older PLWH experience higher burdens of chronic multimorbidity than the general population, increasing treatment complexity, adverse events, and the likelihood of polypharmacy.[5] They also show evidence of earlier onset of age-related comorbidities; for example, this study reports that more than half of PLWH aged ≥50 years have a heart age at least ten years older than their chronological age.[6] Second, evidence showed that they experience accelerated biological aging and immunosenescence even under effective cART.[7] Third, older PLWH face compounded challenges, including insufficient HIV knowledge and risk awareness, poor health literacy, limited patient–provider communication,[8] and the “double stigma” of HIV and ageism.[9] Incomplete immune reconstitution Although the introduction of cART has reduced AIDS-related mortality among PLWH, a subset of patients fails to achieve adequate CD4+ T-cell recovery despite sustained viral suppression, a condition termed immunological nonresponse (INR). Across studies, INRs have been defined inconsistently, either as failure to reach a specified CD4+ T-cell threshold (e.g., >200, >250, >350, >400, or >500 cells /µL) or as failure to achieve a minimum percentage increase from baseline (e.g., <5%, <20%, or <30%) over varying follow-up periods. The burden of INR remains substantial, with prevalence estimates ranging from 10% to 40% of treated individuals.[10] Given this heterogeneity, we adopt a common threshold CD4+ T-cell ≤500 cells/µL after several years of cART who maintain viral suppression according to the Department of Health and Human Services.[11] This cutoff is well supported by evidence showing that CD4+ T-cell ≥500 cells/µL approximates immunologic normalization according to the World Health Organization,[12] and patients who achieve it have morbidity and mortality comparable to HIV-negative individuals.[13] Large-scale cohort studies indicate that INRs face an increased risk of mortality compared to immune responders.[14] Additionally, this population exhibits heightened vulnerability to NADs, such as cardiovascular disease[15] and NACs.[16] Therefore, INR patients constitute a vulnerable group requiring a comprehensive management strategy that combines extending prophylaxis for opportunistic infections, optimizing vaccinations, and rigorously screening for coinfections. Crucially, clinicians must prioritize preventing NADs through aggressive cardiovascular risk management, routine cancer screening, and lifestyle interventions.[11] Comorbidities With increasing life expectancy and prolonged cART, PLWH face an elevated burden of NADs compared to uninfected controls, affecting approximately 38% of PLWH.[17] Specifically, meta-analyses indicate a 2.16-fold increased risk of cardiovascular events[18] and a 1.5-fold higher incidence of NACs despite viral suppression.[19] Metabolic syndrome affects approximately 21.5% of PLWH, 2-fold higher than in uninfected populations.[20] PLWH with comorbidities constitute a distinctively vulnerable subgroup because studies confirm that multimorbidity is now the strongest predictor of mortality in virally suppressed PLWH.[2] This burden precipitates adverse outcomes, including frailty, functional decline, and disability, which drive recurrent hospitalizations and reduced quality of life. Furthermore, the complexity of managing these conditions exacerbates the risk of polypharmacy, introducing safety concerns.[21] To mitigate these risks, management must shift toward an integrated, multidisciplinary model. Clinicians should prioritize medication reconciliation to minimize drug–drug interactions (DDIs) and adopt aggressive preventive strategies. Comprehensive care must integrate routine screening for malignancies and lifestyle interventions to preserve long-term quality of life. Mental disorders Mental disorders (e.g., depression, anxiety, insomnia, and substance abuse) affecting 28–62% of the PLWH,[22] substantially higher than in the general population, significantly influence both the life expectancy and quality of life of PLWH. Furthermore, studies indicate that insomnia symptoms affect more than half of PLWH.[23] Mental disorders affect HIV testing uptake, cART initiation and adherence, retention in care, and are associated with increased mortality.[24] Therefore, early identification and management of mental disorders in PLWH constitute a critical component of comprehensive HIV care. Polypharmacy PLWH are at increased risk of polypharmacy and potential DDIs, largely driven by the growing burden of comorbidities.[21] DDIs can compromise treatment by increasing drug toxicity, reducing cART efficacy, and promoting the development of drug resistance. In clinical practice, these risks can be mitigated by selecting regimens with minimal interaction potential and by appropriate dose adjustment and monitoring. Comprehensive management of PLWH should emphasize the prevention, detection, and management of concomitant medication issues to preserve cART effectiveness, minimize adverse drug reactions, prevent DDIs, improve adherence, and reduce healthcare costs. Intravenous drug use Studies indicate that individuals who inject drugs exhibit poorer medication adherence, which increases the risk of viral resistance and limits subsequent treatment options.[25] In managing this population, clinicians should not only optimize antiretroviral regimens but also provide support for substance use cessation, enhance education on drug-related risks, and facilitate access to appropriate social and rehabilitation services. Special physiological populations Children face developmental challenges, dependence on caregivers for seeking care, and lifelong treatment burdens. Pregnant and postpartum women undergo physiological changes that alter pharmacokinetics and carry the critical risk of vertical transmission. Both require specialized medication counseling and monitoring to mitigate vulnerabilities. Conclusion The concept of vulnerable populations in HIV underscores the need to move beyond virologic suppression as the sole marker of treatment success and to address the broader spectrum of health risks faced by PLWH. By systematically identifying and prioritizing high-risk individuals, this framework can inform clinical decision-making, optimize resource allocation, and support more comprehensive, patient-centered care. Ultimately, addressing the needs of these vulnerable groups is integral to improving long-term outcomes and advancing the global HIV response. Funding This study was supported by the Special Research Fund for the Central High-level Hospitals of Peking Union Medical College Hospital (No. 2022-PUMCH-D-008), Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (No. 2021-I2M-1-037) and National Key Technologies R&D Program for the 13th Five-year Plan (No. 2017ZX10202101-001). Conflics of interest None.