Aging in HIV: A Review of Common Comorbidities in People Living With HIV

With the advent and ongoing development of novel antiretroviral agents, people living with HIV (PLWHIV) are living longer and experiencing the effects of HIV infection on aging. The success of antiretroviral therapy (ART) has transformed HIV from a fatal disease into a manageable chronic condition, with PLWHIV on effective ART having life expectancies approaching those of the general population.¹ As a result, a growing proportion of PLWHIV are 50 and older.² The interplay between chronic HIV infection, the adverse effects of ART, and the natural aging process gives rise to unique challenges. These include an increased risk for conditions such as cardiovascular disease, metabolic syndrome, renal dysfunction, neurocognitive disorders, immunosenescence, and more.² This review explores the impact of HIV and aging on these key comorbidities.

Cardiovascular Disease

PLWHIV have a heightened risk of atherosclerotic cardiovascular disease (ASCVD) compared with age-matched peers without HIV.³ This increased risk is believed to stem in part from ongoing immune system activation and inflammation, which persist even in those with well-controlled viral loads.³ Studies have shown that PLWHIV exhibit significantly higher levels of proinflammatory cytokines, including interleukin-6 and tumor necrosis factor-α, even in the context of viral suppression.^3,4 Rates of traditional risk factors, including hypertension and tobacco use, are also higher in PLWHIV, contributing to the additive risk in this population. Moreover, some older protease inhibitors and ritonavir- boosted darunavir increase ASCVD risk likely through metabolic disturbances and dyslipidemia.

Abacavir is also associated with heightened ASCVD risk by way of mechanisms involving endothelial dysfunction, vascular inflammation, and platelet hyperreactivity.³ Centers for Disease Control and Prevention guidelines recommend lipid screening at ART initiation, 4 to 8 weeks after ART modification, and annually if ASCVD risk factors are present or every 5 years if no risk factors are present.⁵ The REPRIEVE trial notably demonstrated that pitavastatin reduced major cardiovascular events in PLWHIV at low to moderate ASCVD risk, even when low-density lipoprotein cholesterol levels were normal.6 Many ASCVD risk prediction tools used for the general population, not including risk enhancers, can underestimate ASCVD risk in PLWHIV.⁷ The 2024 Infectious Diseases Society of America (IDSA) Primary Care Guidance for Persons With HIV document recommends the initiation of statin therapy for the primary prevention of cardiovascular disease in PLWHIV aged 40 to 75 years, regardless of lipid levels and ASCVD risk. However, the choice of statin and the dose should be carefully selected considering drug-drug interactions, renal function, hepatic function, and patient age. Highintensity statins are recommended for those with a 10-year ASCVD risk above 20%, and moderate-intensity statins for those at lower risks.⁸ Prioritizing the management of traditional risk factors such as hypertension, diabetes, and tobacco use is essential for ASCVD risk reduction, in addition to minimizing inflammation by ensuring viral suppression is maintained and coinfections are appropriately treated.^3,7

Metabolic Syndrome

Metabolic syndrome—a collection of conditions including central obesity, high blood pressure, insulin resistance, and lipid abnormalities—is increasingly observed among older PLWHIV. Chronic inflammation from HIV can disrupt metabolic processes, and certain antiretrovirals, namely protease inhibitors such as lopinavir and ritonavir, may directly induce insulin resistance or dyslipidemia.⁹ Research indicates that PLWHIV are approximately 1.6 times more likely to develop metabolic syndrome compared with the general population, with an elevated risk among women and those on long-term ART.^9,10 Changes in fat distribution, such as increased visceral fat and ectopic fat deposits, contribute to this metabolic imbalance, raising the likelihood of developing type 2 diabetes and cardiovascular complications.¹¹ When evaluating for insulin resistance or diabetes in PLWHIV, clinicians should be aware that hemoglobin A1c levels can underestimate glycemic status in patients on ART. While an HbA1c level greater than or equal to 6.5% remains diagnostic for diabetes, IDSA guidelines recommend using fasting plasma glucose as a more reliable screening tool in PLWHIV.⁸

Glucagon-like peptide-1 (GLP-1) agonists are increasingly used to manage diabetes mellitus and obesity, but data on their use in PLWHIV remains limited. Although no major safety concerns have been identified, one review article highlights that GLP-1 agonists may reduce gastric acidity, potentially impairing the absorption of the antiretrovirals atazanavir and rilpivirine, which depend on an acidic environment.¹² Until more data are available, lifestyle interventions remain the cornerstone of management of metabolic syndrome in PLWHIV.⁸

Renal Dysfunction

Chronic kidney disease (CKD) is another significant concern in the aging PLWHIV population. HIV-associated nephropathy, once a major cause of CKD, is rare in our current ART era. However, other forms of kidney disease, including hypertensive nephrosclerosis and diabetic nephropathy, are increasingly seen as PLWHIV age.^13,14 There are several risk factors associated with a higher risk of kidney disease progression, including Black race, higher HIV viral loads, lower CD4 count, hepatitis C virus coinfection, and treatment with certain ARTs, including tenofovir disoproxil fumarate and the ritonavir-boosted protease inhibitors lopinavir and atazanavir.¹³

The monitoring of renal function including serum creatinine (every 6 months) and urinalysis (annually) should be considered for early detection of kidney disease.⁸ In addition, the measurement of urine protein and albumin levels should be considered to identify renal disease. If concerns about renal impairment are noted, an assessment of ART may be indicated to mitigate the progression of kidney disease.^8,13 As the number of PLWHIV requiring dialysis continues to grow, the field of transplantation has made important strides.^13,15 The passage of the HIV Organ Policy Equity (HOPE) Act in 2013 marked a major milestone, allowing organ transplants from HIV-positive donors to HIV-positive recipients for research purposes. More recently, an observational study demonstrated that kidney transplant recipients from HIV-positive donors have comparable survival and rejection rates to those receiving organs from HIV-negative donors.¹⁵

Neurocognitive Disorders

In an aging population of PLWHIV, neurocognitive manifestations of HIV are an important concern.¹⁶ PLWHIV face a significantly higher risk of cognitive decline compared with people without HIV, with an odds ratio of approximately 2.44 per the results of one meta-analysis.¹⁷ HIV-associated neurocognitive disorder (HAND) can affect PLWHIV even with effective ART, and those with asymptomatic neurocognitive impairment have a 2- to 6-fold increased risk of symptomatic HAND compared with PLWHIV with no neurocognitive impairment.¹⁸ Other neurocognitive conditions, such as cerebrovascular disease and depression, may exacerbate cognitive impairment further.^16,17 Additionally, HIV has also been associated with lower gray matter volume as well as white matter microstructural abnormalities, even among those whose condition is virally suppressed.¹⁹ Studies suggest that effective ART can help improve cognition.²⁰ Cognitive decline in older PLWHIV significantly affects their quality of life and potentially medication adherence. To address these challenges, clinicians should be able to recognize clues suggestive of dementia and have a proactive approach to formal cognitive screening to enable timely diagnosis and early intervention. This includes managing comorbid conditions and the provision of mental health support—both essential components of comprehensive HIV care.^8,16

Immunosenescence

Immunosenescence—the gradual decline in immune system function with age—is accelerated in PLWHIV. Even with viral suppression, chronic immune activation can lead to premature aging of the immune system. Manifestations may include reduced naive T-cell production, decreased T-cell proliferation, diminished vaccine responses, and increased susceptibility to infections. ^21,22 More research is needed into the pathophysiology and outcomes of immunosenescence.

Bone Health

PLWHIV have higher rates of low bone mineral density (BMD), which raises the risk of fractures in both PLWHIV on ART and those who are treatment-naive.^23,24 The cause of accelerated bone loss is multifactorial in the context of chronic inflammation, as well as potentially alterations in bone metabolism secondary to ART agents, particularly tenofovir disoproxil fumarate.^23,24 Therefore, current guidelines recommend screening for low BMD in postmenopausal women and men 50 years and older.^8,23 Condition management includes a combination of weight-bearing exercise, calcium and vitamin D supplementation, and lifestyle modifications, such as tobacco cessation. Medications such as bisphosphonates are also often used for the treatment of osteoporosis, and ART optimization should be considered to halt further bone loss.⁸

Frailty

Unlike chronological aging, frailty describes a cumulative loss of physiologic reserve and is a predictor of mortality and comorbidity.²⁵ Studies have demonstrated that PLWHIV are more frail than matched cohorts who are living without HIV.²⁶ A multimodal approach to frailty is needed for PLWHIV. Early identification through frailty screening and interventions for comorbid conditions is required. Additional strategies include interventions targeting nutrition as well as promoting physical activity within this population. Other considerations include addressing polypharmacy; concurrent tobacco, alcohol, and/or recreational drug use; and psychosocial/behavioral health interventions.8

Conclusion

As the population of PLWHIV continues to age, clinicians must adapt strategies to address the complex interplay between HIV, ART, and aging. Cardiovascular disease, metabolic syndrome, renal dysfunction, neurocognitive decline, immunosenescence, and bone health represent key areas of concern that warrant proactive screening and management. Understanding the interconnections is essential for optimizing care. Viral suppression is an important goal to minimize comorbid risks further.

Standard management algorithms for the general population without HIV may not always apply, and clinical guidelines are increasingly recognizing the need for HIV-specific considerations in risk assessment and treatment strategies. A multidisciplinary approach that incorporates geriatric principles, such as frailty, into HIV care is needed to ensure good quality of life in the aging PLWHIV population. Moving forward, ongoing research is needed to better understand the long-term effects of chronic HIV infection and ART on aging physiology, as well as to identify biomarkers that can guide the prevention and treatment of age-associated comorbidities in PLWHIV.

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