Research Progress on Pathogenesis and Management of HIV-associated Met

Introduction

Human Immunodeficiency Virus (HIV) infection is a global public health issue. According to the latest data, 40.8 million people were living with HIV (PLWH) globally and 31.6 million people were accessing antiretroviral therapy (ART) in 2024.¹ With the widespread application of highly active antiretroviral therapy (HAART), the survival rate of PLWH has significantly improved,² and the causes of death threatening elderly PLWH have gradually shifted from AIDS-related mortality to metabolic diseases, such as cardiovascular diseases.³ Consequently, HIV-associated metabolic syndrome (HIV-MetS) has emerged as a major focus in current research and clinical practice.² The development of metabolic syndrome (MetS) in PLWH leads to diminished quality of life, increased financial burden, and heightened psychological distress. It also significantly elevates the incidence of diabetes and cardiovascular diseases, as well as non-HIV-related mortality, substantially compromising their life expectancy.^4–6

Figure 1 Potential mechanisms of HIV-MetS, and the increased likelihood of metabolic diseases such as T2DM, NAFLD, cardiovascular and cerebrovascular diseases following HIV infection.

Metabolic syndrome (MetS) is a cluster of interrelated metabolic abnormalities, including abdominal obesity, insulin resistance, hyperglycemia, hypertension, and dyslipidemia. This condition is significantly associated with an elevated risk of developing cardiovascular diseases (CVD), type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD), and other related disorders.^7–11 There are multiple diagnostic criteria for MetS internationally¹² (Table 1).^12–15 But they generally rely on five key components: increased waist circumference, elevated blood pressure, elevated fasting or postprandial glucose, elevated serum triglycerides (TG), and reduced high-density lipoprotein (HDL) cholesterol levels.

Table 1 Diagnostic Criteria for Metabolic Syndrome

Studies have found that PLWH have a higher risk of developing MetS compared to the general population, with an average prevalence of approximately 30%.^16–20 Prevalence varies significantly across regions; for example, in the Americas, it ranges from about 15% to 30%,^5,21,22 in Asia from approximately 10% to 33%,^23–28 and in Africa, it is the highest and most variable, ranging from 5.5% to 58%.^29–31 In sub-Saharan countries with lower economic levels, prevalence is markedly higher than in other African regions .^21,32 With increasing age, the prevalence of HIV-associated MetS gradually rises, and female PLWH are generally considered to have a higher prevalence than males.^33–36 These findings indicate that the prevalence of HIV-MetS is influenced by factors such as age, gender, geographical location, ethnicity, economic status, and medical resources. Therefore, in general, elderly and female HIV patients, those living in areas with underdeveloped medical resources, and those of African descent require more attention.

The pathogenesis of HIV-MetS primarily involves inflammation and immune activation induced by HIV infection and ART drugs, dyslipidemia, insulin resistance, mitochondrial dysfunction, gut microbiota dysbiosis, epigenetic alterations, and so on.^37,38 Among these, gut microbiota dysbiosis is a relatively new research topic; it causes sustained inflammation and immune activation through mechanisms such as microbial translocation, endotoxemia, and reduction in anti-inflammatory microbiota, thereby affecting metabolism. The mechanisms of epigenetic alterations may be related to dysregulation of histone modifications, immune function, and cellular senescence. Specific antiretroviral drugs are independent risk factors for HIV-MetS;²⁹ among them, protease inhibitors (PIs) directly affect lipid metabolism and insulin resistance, significantly increasing triglycerides and LDL levels, while nucleoside reverse transcriptase inhibitors (NRTIs) can cause hyperlactatemia, abnormal fat distribution, and hypophosphatemia. The underlying mechanisms require further investigation.

Understanding the specific underlying mechanisms of HIV-MetS is particularly crucial for future treatment, management, and prevention of this condition. However, current research on the mechanisms of HIV-MetS remains limited, and there is a deficiency of effective therapeutic management strategies and optimal lifestyle interventions. Concurrently, the clinical management of metabolic syndrome in this special population also faces significant challenges.

This article focuses on reviewing recent advances in the potential mechanisms underlying HIV-MetS and exploring possible relationships between HIV infection and MetS. We summarize diagnostic criteria for MetS and briefly discuss clinical management and therapeutic recommendations for PLWH with comorbid MetS. This aims to provide insights for improved prevention and treatment of HIV-MetS. Notably, these studies predominantly focus on adult populations, lacking valid data on children living with HIV; therefore, the scope of this review is confined to adults living with HIV.

The Impact of HIV Infection on Multiple Metabolic Diseases

HIV infection and HAART can elevate the risk of developing MetS, thereby increasing the likelihood of progression to neurological disorders (dementia, stroke, etc)., CVD (hypertension, coronary artery disease, etc)., T2DM, and NAFLD. These comorbidities profoundly compromise the quality of life and survival rates among PLWH.

HIV Infection and Cardiovascular Diseases

Studies over recent decades have confirmed that PLWH face a 1.5- to 2-fold increased risk of CVD compared to the general population.^3,39–41 CVD in PLWH encompasses hypertension, cardiomyopathy, heart failure, and coronary artery disease (CAD). A large-scale cohort study has revealed that PLWH exhibit a high prevalence of CAD and a significantly increased burden of coronary plaque.⁴² PLWH are 4.5 times as likely to die of sudden cardiac death as the control group.⁴³ Research on HIV-associated cardiomyopathy has also indicated that PLWH are at a higher risk of developing coronary artery disease and post-myocardial infarction heart failure.⁴⁴ Hypertension is prevalent among PLWH. An Italian multicenter study reported that approximately 30% of adult HIV outpatients had hypertension, while the prevalence surged to as high as 96% in PLWH comorbid with MetS.⁴⁵ A global meta-analysis revealed that the prevalence of hypertension in PLWH ranges from 16.5% to 28.1%.⁴⁶ Mechanisms such as activation of the renin-angiotensin-aldosterone system (RAAS), monocyte/macrophage activation, and endothelial dysfunction may contribute to the development and progression of cardiovascular diseases in PLWH.^19,47

HIV Infection and Nervous System Diseases

The impact of HIV infection on the central nervous system is multifaceted, encompassing direct viral invasion, indirect immune system dysfunction, and cerebrovascular accidents induced by concurrent metabolic syndrome .^48–53 Common neurological disorders include cognitive impairment, psychological issues, dementia, and cerebrovascular disease.⁵⁴ Studies have demonstrated that HIV infection allows the virus to cross the blood-brain barrier and invade the central nervous system, leading to a range of neurological complications such as behavioral abnormalities, motor dysfunction, and HIV-associated dementia (HAD) .⁴⁸ A meta-analysis indicates a heightened prevalence of stroke among people living with HIV (PLWH), particularly in older age groups.⁵⁵ Furthermore, HIV infection may independently increase the risk of stroke,⁵² with pathogenesis closely linked to HIV-induced vasculitis, immune dysregulation, ART side effects, and metabolic disorders.

HIV Infection and NAFLD

Among PLWH, chronic liver disease is the second leading cause of non-HIV-related death.⁵⁶ HIV accelerates the progression of PLWH to MetS by impairing adipokine synthesis and further promotes the development of HIV-associated fatty liver disease (HIV-ALD) through liver-specific mediators.^57–59 A 2018 cross-sectional study in Brazil showed that the prevalence of hepatic steatosis among PLWH was 35%;⁶⁰ A 2023 meta-analysis reported even higher rates of HIV-ALD, with prevalence rates of non-alcoholic steatohepatitis (NASH) and hepatic fibrosis at 48.77% and 23.34%.⁹ The prevalence of HIV-ALD varies across regions, but overall, PLWH is more susceptible to developing hepatic steatosis compared to the general population.⁶¹ Once hepatic steatosis occurs, PLWH faces a heightened risk of progression to fibrosis.^56,62,63

HIV Infection and T2DM

Although T2DM has been extensively documented among PLWH ,⁶⁴ research on the relationship and underlying mechanisms between HIV and diabetes remains limited, with ongoing debates regarding their epidemiological association. Studies have demonstrated that PLWH and those receiving ART exhibit a significantly elevated risk of developing prediabetes and diabetes mellitus compared to the general population.^65–68 However, other research suggests that HIV-specific factors may not independently contribute to increased diabetes prevalence, with conventional risk factors such as aging, obesity, and metabolic abnormalities playing a more dominant role.^69,70 In summary, the majority of research still leans toward the conclusion that HIV and ART play a modest role in predisposing affected populations to diabetes,^71,72 particularly among elderly patients and those with hyperlipidemia.^73,74 The mechanisms likely involve chronic inflammation,⁷⁵ insulin resistance, and impaired glucose metabolism.^76,77 The latest HIV clinical guidelines issued by the National Institutes of Health (NIH) recommend routine blood glucose testing before ART, which indirectly highlights the potential role of HIV in the development and progression of diabetes mellitus.⁶⁴

HIV Infection and Other Non-HIV Comorbidities

PLWH also develop comorbidities such as osteoporosis,⁷⁸ fractures,⁷⁹ and non-AIDS-defining cancers (NADCs).^80–82 These may all be related to aging.The phenomenon of aging in PLWH was observed decades ago.⁸³ PLWH exhibit significant biological age acceleration. Epigenetic studies indicate that their biological age is, on average, 4.9–14.7 years older than their chronological age.⁸⁴ Moreover, PLWH develop age-related comorbidities—such as coronary artery disease (CAD), cancer, osteoporosis, and frailty syndrome—approximately 10–15 years earlier than HIV-uninfected individuals.⁸⁵ Even early initiation of antiretroviral therapy (ART) fails to prevent these complications⁷⁹ fully. Literature has described the aging phenomena in HIV disease (including cellular senescence and immunosenescence), which may be associated with declining immune system functions (such as reduced innate immune cell functionality, decreased CD4+/CD8+ T-cell ratio), chronic inflammation, epigenetic alterations, and metabolic dysregulation.^85–89

All these confirm that PLWH are at greater risk of developing various metabolic diseases (Figure 1), and there is an urgent need to clarify the pathogenesis and develop effective management strategies.

Pathogenic Mechanisms of HIV-Associated Metabolic Syndrome

The pathogenesis of HIV-MetS is complex and remains incompletely elucidated. Currently, several hypotheses exist regarding the pathogenesis of HIV-MetS (Table 2), but these are relatively fragmented. Our analysis of existing data indicates that the development of HIV-MetS involves synergistic interactions of multiple factors, including chronic inflammation and immune activation, mitochondrial dysfunction, abnormalities in glucose and lipid metabolism, mitochondrial and vascular endothelial abnormalities, intestinal dysbiosis, epigenetic modifications, and the use of antiretroviral drugs (Figure 1).

Table 2 Mechanistic Hypotheses of HIV-Associated Metabolic Syndrome

Chronic Inflammation and Immune Dysregulation

HIV infection is a complex systemic disease characterized by chronic inflammation and persistent immune activation. Its key features include elevated levels of multiple pro-inflammatory cytokines (such as tumor necrosis factor-α (TNF-α), integrin-αM, interferon-α (IFN-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β)), activation of immune cells, alterations in other immunologically active substances, and increased coagulation biomarkers.^90,91 It is well known that adipose tissue serves as a reservoir for HIV and is abundant in immune cells, such as CD4+ T cells and macrophages.⁹² Following HIV infection, the virus triggers the release of substantial cytokines that induce oxidative stress responses, mitochondrial dysfunction, inflammatory alterations, and apoptosis in adipocytes. On the one hand, these alterations lead to adipose tissue dysfunction, exacerbating the release of inflammatory cytokines, impairing adiponectin function, and compromising insulin signaling in skeletal muscles, thereby inducing a cascade of metabolic disorders such as hypertriglyceridemia and systemic insulin resistance. On the other hand, they provoke vascular endothelial damage and dysfunction, contributing to the development of hypertension, coronary heart disease, and other cardiometabolic pathologies.⁹³ Certainly, persistent systemic inflammation also exacerbates immunosenescence (eg, telomere shortening in T cells and expansion of senescent phenotypes), accelerating biological aging processes.^94,95 This significantly increases the risk of MetS and advances its onset.⁹⁶

Mitochondrial Dysfunction

Mitochondria play a pivotal role in energy metabolism and oxidative stress while also being a critical link in HIV-induced inflammatory states and cellular immune dysregulation. A report reveals that specific mitochondrial haplogroups exhibit significant associations with the development of MetS in PLWH, suggesting that mitochondrial genetic backgrounds may play a critical role in this population.⁹⁷ Mitochondrial dysfunction can lead to disruptions in energy metabolism, subsequently triggering characteristic manifestations of MetS, such as insulin resistance, obesity, and hypertension. Specifically, HIV infection induces mitochondrial dysfunction—including mitochondria-mediated apoptosis, mitochondrial DNA (mtDNA) depletion, impaired calcium signaling, and mitochondrial membrane dysfunction. These alterations impair fatty acid oxidation and energy production, thereby driving metabolic abnormalities.³⁸ The mechanisms involve HIV-related activation of inflammatory pathways, oxidative stress from excessive reactive oxygen species (ROS), and direct mitochondrial toxicity from antiretroviral drugs (eg, nucleoside reverse transcriptase inhibitors like zidovudine), which inhibit mitochondrial DNA polymerase γ and reduce mtDNA synthesis.^98–100 This cascade of mitochondrial damage amplifies systemic inflammation and perpetuates metabolic dysregulation through lipid accumulation, insulin signaling defects, and impaired cellular homeostasis.¹⁰¹

Vascular Endothelial Dysfunction

The activation, injury, and dysfunction of vascular endothelium have been extensively documented in HIV-MetS, representing a pivotal mechanism through which chronic inflammation contributes to the development of MetS.¹⁰² PLWH exhibits elevated levels of endothelial activation markers such as von Willebrand factor (vWF), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1).^103–106 Although ART can reduce these marker levels, they remain significantly higher than those observed in the general population.¹⁰⁷ A study of untreated PLWH reported that HIV infection is associated with impaired arterial elasticity in both large and small vascular systems.¹⁰⁸ Evidence indicates that PLWH exhibits significantly increased arterial stiffness, which is associated with impaired cerebrovascular reactivity, heightened immune activation, elevated inflammatory markers, and accelerated cellular senescence. Severe endothelial dysfunction may further correlate with increased microvascular oxidative stress and reduced levels of nitric oxide (NO) and arginine. These alterations collectively destabilize circulatory homeostasis and elevate the risk of MetS.^{102,109–111}

Abnormalities of Glucose and Lipid Metabolism

The lipid metabolism abnormalities caused by HIV have been extensively studied. Most PLWH develop lipodystrophy, primarily characterized by central lipohypertrophy with increased visceral fat deposition and peripheral lipoatrophy (limb fat reduction).¹¹² Lipidomic studies have revealed that the most common lipid abnormalities in PLWH include hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C) levels, and elevated low-density lipoprotein cholesterol (LDL-C) and total cholesterol levels.¹¹³

HIV infection can also lead to glucose metabolism disorders,¹¹⁴ although the specific mechanisms remain unclear. Current research suggests that most PLWH exhibit insulin resistance(IR). Compared to uninfected individuals, PLWH demonstrate elevated glucose uptake rates and increased levels of glycolytic intermediates.¹¹⁵

The mechanism may involve dysregulated expression of adipocyte regulatory genes, aberrant secretion of various cytokines, and subsequent disruptions in adipocyte maturation, lipid distribution, and glucose metabolism pathways.^19,112 Specifically, after infecting the human body, HIV can persist long-term in adipose tissue reservoirs, continuously releasing viral proteins such as Nef protein, glycoprotein 120 (gp120), and the HIV accessory protein Vpr.⁹² These transcriptional disturbances cause abnormal adipocyte differentiation and dysfunction, simultaneously increasing free fatty acids’ transport to skeletal muscle and liver.^116,117 Concurrently, HIV infection triggers the production of antiviral-related cytokines like IFN-α and IL-6. These cytokines may contribute to elevated serum triglycerides by interfering with lipid clearance processes.¹¹⁸ For instance, Nef protein and gp120 can upregulate cytokine levels, including IL-6, IL-1βand TNF-α.¹¹⁹ These changes disrupt insulin signaling by affecting the insulin receptor substrate 1 (IRS-1) and phosphoinositide 3-kinase (PI3K) pathway, thereby inducing IR. These alterations further promote hepatic gluconeogenesis and stimulate triglyceride secretion from the liver. Meanwhile, elevated TNF-α exacerbates insulin resistance through dual mechanisms: by reducing insulin receptor kinase activity and downregulating IRS-1 and glucose transporter 4 (GLUT4), which subsequently induces adipocyte apoptosis and lipolysis.¹²⁰ IR impairs the inhibitory effect of insulin on lipolysis, leading to increased release of FFA. Elevated FFA are taken up by peripheral tissues, interfering with insulin signaling and exacerbating IR; simultaneously, they promote hepatic gluconeogenesis and triglyceride synthesis, resulting in hyperglycemia and dyslipidemia.^121,122 They also promote vascular endothelial dysfunction and increased renal sodium reabsorption, contributing to the development of hypertension and coronary heart disease.¹²³

Gut Microbiota

The microbiota has been recognized as a pivotal player capable of tipping the balance between health and disease. The human gut constitutes a nutrient-rich environment colonized by a vast array of microbial species, collectively referred to as the “gut microbiota” (GM). The gut microbiota is closely associated with numerous diseases, including metabolic syndrome, AIDS, and obesity.^124,125

An increasing number of scholars believe that the occurrence of HIV-MetS is closely linked to abnormalities in gut microbiota. Specific mechanisms may involve the following aspects:

Impairment of the Intestinal Barrier and Microbial Translocation

HIV (particularly its gp120 envelope glycoprotein) downregulates tight junction proteins (such as claudin, occludin, and ZO-1), and increases intestinal permeability. This leads to the translocation of microbes and their products into the systemic circulation,^126,127 resulting in metabolic endotoxemia. For instance, lipopolysaccharide (LPS) from Gram-negative bacteria enters the bloodstream and triggers systemic inflammation via activation of the TLR/CD14 pathway, promoting IR and dyslipidemia.^128–130 Furthermore, LPS activates the coagulation cascade and increases the production of procoagulant tissue factors, thereby impacting metabolism.⁹⁵ Moreover, during the early stages of infection, HIV preferentially destroys CCR5+ CD4+ T cells in the gut-associated lymphoid tissue (GALT), exacerbating CD4+ T cell depletion, weakening mucosal immune defenses, and further promoting the loss of barrier function.¹³¹ Even early initiation of antiretroviral therapy may not fully prevent gut microbiota dysbiosis or bacterial translocation.¹²⁷

Dysbiosis and Immune Activation

Studies have found that in HIV-infected individuals, there is an enrichment of pathogenic bacteria such as Proteobacteria in the gut, while commensal bacteria such as Bacteroidetes are reduced.^126,127,132 The dysbiotic microbiota directly activates gut immune cells, leading to T-cell activation and the release of pro-inflammatory cytokines (such as IL-6 and TNF-α), triggering chronic inflammation. Moreover, dysbiotic microbiota can lead to a deficiency in short-chain fatty acids (SCFAs), affecting metabolic homeostasis.¹³³ SCFAs deficiency is associated with chronic inflammation and increased morbidity/mortality.¹³³

Abnormal Tryptophan Metabolism

Dysbiotic microbiota enhances tryptophan catabolism, activating the kynurenine pathway. This process depletes tryptophan and generates neurotoxic metabolites, further exacerbating inflammatory responses and T-cell dysfunction, and is positively correlated with disease progression markers such as elevated IL-6.¹³²

Impaired AhR Signaling Pathway

Reduced production of aryl hydrocarbon receptor (AhR) ligands by a dysbiotic microbiota impairs gut barrier repair, attenuates IL-22 signaling (affecting mucosal immunity), and decreases GLP-1 secretion (affecting glycemia regulation), collectively exacerbating metabolic disorders.^95,130

Reduction in Anti-Inflammatory Microbiota

In HIV-MetS patients, anti-inflammatory gut bacteria such as Alistipes are significantly reduced, impairing the microbiota’s negative regulatory role in inflammation and further amplifying inflammation associated with metabolic abnormalities. The depletion of Alistipes can be considered a core feature of gut dysbiosis in HIV-MetS patients, leading to elevated inflammatory markers of metabolic syndrome and increased cardiovascular risk.^134,135

Epigenetic Alterations

In addition to the aforementioned mechanisms, epigenetic alterations have also been implicated in recent research. Specifically, HIV infection can induce aberrant global DNA methylation levels in host cells, characterized by downregulation of DNA methyltransferase (DNMT) and upregulation of methyl-CpG-binding proteins (such as MBD2).¹³⁶ This increases monocyte activation status and the production of pro-inflammatory cytokines (eg, TNF-α, IL-6),⁹¹ thereby exacerbating insulin resistance and lipid metabolism disorders. For instance, HIV infection induces DNA methylation changes in essential genes (eg, IL-2, PD-1, and FOXP3) within T cells, triggering monocyte dysfunction and enhanced pro-inflammatory cytokine production.^38,137 During HIV latent infection, histone modifications in the viral promoter region (such as increased H3K9me3 methylation and reduced H3 acetylation) suppress viral gene transcription, establishing the latent reservoir.¹³⁸ Concurrently, aberrant histone modifications (eg, acetylation imbalance) in host inflammation-related genes further sustain chronic inflammation and promote metabolic complications.

In the ART population, alterations in epigenetic modifications are associated with changes in micro-RNA expression. Studies have shown that ART drugs can reduce the expression of miR-140 and miR-106a and increase the levels of miR-192. This, in synergy with HIV, exacerbates abnormalities in epigenetic modifications, amplifies inflammatory responses and mitochondrial dysfunction, promotes immune activation,³⁴ immune senescence,¹³⁶ and drives the development of MetS.

Therefore, the epigenetic alterations induced by HIV or ART ultimately require synergy with inflammation, immune dysregulation, metabolic disturbances, and mitochondrial dysfunction to collectively promote the development of HIV-associated metabolic syndrome (HIV-MetS). The precise mechanisms underlying this process require further investigation.

Antiretroviral Therapy

Numerous studies have demonstrated that PLWH receiving ART exhibits a higher incidence of MetS compared to untreated PLWH. A prospective analysis revealed that the prevalence of MetS among PLWH increased by 8.4% after 48 weeks of ART.¹³⁹ Current perspectives suggest that both HIV infection and long-term ART collectively elevate the risk of MetS,¹⁴⁰ with the role of ART medications receiving increasing attention. Antiretroviral drugs for HIV/AIDS are diverse, including protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), integrase strand transfer inhibitors (INSTIs), HIV entry inhibitors, and fusion Inhibitors (FIs).

The differential effects of various antiretroviral drugs on the metabolic profile of PLWH have been controversial, while research on lipid metabolism is relatively well-established (Table 3). HIV entry inhibitors exert minimal impact on lipid profiles, while other antiretroviral drugs may potentially induce dyslipidemia. PIs and NRTIs demonstrate the most pronounced metabolic toxicities,^141,142 primarily involving mitochondrial dysfunction, suppression of lipid synthesis pathways, and interference with insulin signaling. INSTIs are associated with weight gain and hypertriglyceridemia. NNRTIs typically induce milder dyslipidemia.

Table 3 The Impact of Different ART Drugs on Blood Lipids

The specific mechanisms are detailed below:

PIs

Almost all protease inhibitors (PIs) can cause metabolic abnormalities, while atazanavir is among the PIs with relatively minor effects on lipids. The specific mechanism is as follows:^143–150

① Inhibition of mitochondrial DNA polymerase, causing oxidative stress and mitochondrial dysfunction and leading to respiratory chain dysfunction, insulin resistance, and lipodystrophy.

② Suppression of the degradation of sterol regulatory element-binding protein-1 (SREBP-1) in adipose tissue and the liver, resulting in dyslipidemia and hepatic steatosis.

③ ER stress induced by PIs activates the unfolded protein response (UPR), which enhances hepatic lipid synthesis and inflammatory cytokine release, aggravating metabolic disorders.

④ Inhibition of cellular retinoic acid-binding protein-1 (CRABP-1), which reduces peroxisome proliferator-activated receptor gamma (PPAR-γ) activity. This leads to increased adipocyte apoptosis, impaired adipocyte maturation, and lipodystrophy.

⑤ Impairment of glucose transporter GLUT4 induces IR.

⑥ Reduction in adiponectin levels suppresses lipoprotein lipase on capillary endothelium, elevating triglyceride and insulin concentrations, thereby promoting adipose tissue dysfunction.

NRTIs

NRTIs can cause hyperlactatemia, abnormal fat distribution, and hypophosphatemia. The proposed mechanisms are:^38,150 ① Inhibition of mitochondrial DNA polymerase gamma, leading to mitochondrial dysfunction and subsequent lactic acidosis, hepatic steatosis, and insulin resistance; ② Direct interference with adipocyte differentiation by certain drugs (such as stavudine (d4T) and zidovudine (ZDV)), resulting in lipoatrophy.

INSTIs

Some INSTIs (eg, Elvitegravir) may cause weight gain and hypertriglyceridemia. The mechanism is likely associated with epigenetic modifications (such as DNA methylation) affecting metabolic gene expression and disrupting energy balance regulation,³⁸ though further investigation is needed.

NNRTIs

The impact of NNRTIs on blood lipids is relatively mild. For instance, efavirenz (EFV) can mildly induce CYP450 enzymes, indirectly affecting lipid metabolism, whereas nevirapine (NVP) can cause abnormalities in HDL and LDL,¹⁴⁸ and its mechanism requires further investigation.

The exact mechanisms by which ART induces MetS have not yet been fully elucidated. Current evidence suggests potential associations with post-ART alterations in hepatic synthetic function, inflammatory responses, oxidative stress, and genetic factors.¹¹³ Additionally, the pathogenesis involves multiple interrelated mechanisms, including abnormal secretion of adipokines, lipodystrophy, insulin resistance, impaired glucose metabolism, and endothelial dysfunction.

Management Recommendations

Diagnostic Criteria

Current diagnostic criteria for HIV-MetS primarily reference internationally recognized definitions, varying across countries and ethnicities.¹² Commonly used standards include:

NCEP/ATP III criteria (National Cholesterol Education Program Adult Treatment Panel III, 2001),¹³ IDF criteria (International Diabetes Federation, 2005),¹⁵ Harmonized criteria (IDF/AHA/NHLBI consensus,2009),¹² DS criteria (Chinese Diabetes Society, 2004/2013)¹⁵¹ and so on. Detailed components of these criteria are summarized in Table 1.

In clinical practice, it is recommended to integrate HIV-specific factors (eg, ART types) with general criteria and adjust waist circumference cutoff points based on population characteristics (eg, ethnicity, age, gender). Future efforts should focus on standardizing HIV-MetS diagnostic criteria to enhance comparability across studies.

Risk Factors and Risk Assessment

The risk factors for HIV-MetS encompass HIV-related factors (eg, HIV infection, CD4 T-cell count, ART) and traditional factors (eg, genetic predisposition, gender, age, high-fat/high-sugar diets, smoking, alcohol consumption, insulin resistance, obesity, physical inactivity).¹⁵²

Due to the heightened MetS among PLWH, CVD risk assessment is imperative for this population. However, there is currently no specific risk assessment model tailored for MetS in PLWH. In 2020, the Infectious Diseases Society of America (IDSA) emphasized for the first time that cardiovascular risk assessment should be universally conducted for elderly PLWH. Their guidelines recommend the use of the 2013 American College of Cardiology/American Heart Association (ACC/AHA) Pooled Cohort Equations. Studies have also proposed alternative scoring systems, such as the D:A:D model and VACS score. However, these existing systems may underestimate the cardiovascular risk in PLWH,¹⁵³ underscoring the urgent need to develop updated and more comprehensive risk assessment frameworks.¹⁵⁴

Health Education and Lifestyle Intervention

Health education serves as a crucial foundation for the prevention and treatment of HIV-MetS, with lifestyle interventions forming the cornerstone of management. Diversified and accessible educational approaches—utilizing manuals, instructional videos, and digital media platforms—can effectively raise awareness about metabolic syndrome and encourage early adoption of healthy lifestyle modifications.¹⁵⁵ Lifestyle intervention refers to the management of modifiable risk factors, as detailed below:

1. Smoking Cessation: Research indicates that PLWH exhibit a significantly higher prevalence of smoking compared to the general population^156–159 Smoking cessation has been shown to improve life expectancy among middle-aged and elderly PLWH¹⁶⁰ Therefore, it is strongly recommended that HIV-MetS abstain from smoking to mitigate health risks.
2. Limiting alcohol intake: Excessive alcohol consumption is commonly associated with HIV transmission and disease progression.¹⁶¹ Alcohol abuse has clear detrimental effects on PLWH, potentially increasing the risk of metabolic disorders, and it is strongly recommended that PLWH restrict alcohol consumption.^162–164 However, the specific safe threshold for alcohol intake among HIV-MetS remains to be further investigated.
3. Dietary: Dietary intervention serves as an early and effective strategy against MetS ¹²⁵ and can precede pharmacological treatment.¹⁶⁵ Multiple studies on nutritional counseling and management in PLWH have demonstrated that dietary modifications significantly improve body mass index (BMI), lipid profiles,^166–169 and reduce cardiovascular disease risk.¹⁷⁰ Various dietary patterns are recommended for MetS management, including the Mediterranean diet, New Nordic diet, DASH (Dietary Approaches to Stop Hypertension) diet, and the Chinese Balanced Dietary Pattern for Residents.^7,171,172 For PLWH with MetS, adherence to these patterns is advised, emphasizing adequate energy intake, sufficient protein, vitamins, and minerals, while prioritizing low refined sugars, low-carbohydrate, low-cholesterol, and low-sodium diets .¹⁶⁸ However, due to variations in metabolic demands and nutritional status among PLWH, individualized dietary planning remains crucial.
4. Physical exercise and weight management: Considering individual factors such as age and cardiopulmonary capacity, select appropriate exercise types and adjust intensity. Moderate-intensity physical activity is generally recommended, with a focus on aerobic exercises, work-related activities, and muscle-strengthening training, while regularly monitoring BMI.¹⁷³ Overweight individuals are advised to regularly (every 3–6 months) assess organ function, endocrine status, and mental health during exercise to effectively manage weight-related complications.¹⁷⁴

Lipid Management

Lipid management is crucial in the management of both general MetS patients and PLWH. The American College of Cardiology/American Heart Association/Multi-Society (ACC/AHA/MS) guidelines identify HIV as a potential risk-enhancing factor for cardiovascular events.¹⁷⁵ Recent studies on HIV-associated cardiovascular events have shown that daily administration of 4 mg pitavastatin reduced cardiovascular events by 35% in PLWH compared to the control.¹⁷⁶ However, statins may also increase the incidence of diabetes and muscular adverse events.^177–179 The current mainstream consensus holds that statins are the foundation for lipid-lowering and cardiovascular risk reduction in PLWH with dyslipidemia.¹⁸⁰ It is recommended that all PLWH at high 10-year ASCVD risk (assessed using the 2013 ACC/AHA Pooled Cohort Equations) receive statin therapy, while treatment decisions for intermediate- to low-risk individuals should be made on a case-by-case basis, considering clinical contexts.

In the selection of lipid-lowering medications, decisions should be based on varying cardiovascular risks and the concurrent use of different antiviral drugs.¹⁸¹

The American College of Cardiology and the HIV Medicine Association recommend the following¹⁸²(specific drug options in Table 4):

Table 4 Classification of Statin Therapy Intensity

• For HIV-infected individuals aged <40 years with low-to-moderate 10-year ASCVD risk (<20%), lifestyle modifications are prioritized for lipid control.

• For PLWH (People Living with HIV) aged 40–75 years with an estimated 10-year ASCVD risk of 5%–20% or diabetes alone, moderate-intensity statins are recommended.

• For high-risk groups (≥20% 10-year ASCVD risk for those aged 40–75, or LDL-C ≥190 mg/dL for individuals aged 20–75), high-intensity statins should be initiated.

• Other cases should be determined based on specific clinical circumstances.

Regarding the combined use with ART medications, generally, pitavastatin, low-dose atorvastatin, and rosuvastatin have a lower likelihood of interacting with ART and can be safely used. In contrast, ezetimibe, PCSK9 inhibitors, fibrates, and some newer drugs may pose certain risks and require cautious selection.¹¹³

Other lipid-lowering agents, such as ezetimibe, PCSK9 inhibitors, high-purity fish oil (eg, icosapent ethyl), bempedoic acid, and small interfering RNA (siRNA) had been reported in hyperlipidemic patients.^179,183 However, their specific usage data and indications still require further validation.

Blood Glucose Management

There is currently no unified guideline for blood glucose management in patients with HIV-associated metabolic syndrome. Most studies recommend that persons living with HIV (PLWH) undergo annual diabetes screening, with regular monitoring of blood glucose and glycemic markers (eg, HbA1c) based on specific national guidelines.⁶⁴ For PLWH who do not meet the diagnostic criteria for diabetes, blood glucose management can be achieved through lifestyle interventions alone.¹⁸⁴ For those who meet the diagnostic criteria, a metformin-based pharmacotherapy regimen is required, with insulin therapy introduced as needed to achieve glycemic control.^185,186

Blood Pressure Management

National Institutes of Health (NIH) recommends continuous blood pressure monitoring for PLWH, including those with MetS. Similar to blood glucose management, there are currently no established mandatory standards for blood pressure management in HIV- MetS patients. However, the blood pressure targets for HIV-only patients (<140/90 mmHg or <130/80 mmHg) remain consistent with those for non-HIV individuals¹⁸⁷ and should be tailored based on individual risk profiles.

Antiretroviral Drug

The selection of antiretroviral drug regimens requires careful consideration, as different classes of drugs exert distinct metabolic effects (Table 3). Current international guidelines primarily recommend first-line ART regimens based on INSTI-based triple therapy.¹⁸⁸ Commonly used INSTIs, such as dolutegravir, raltegravir, and elvitegravir, effectively suppress viral load. However, they may significantly affect lipid metabolism, leading to notable weight gain and increasing the risk of metabolic syndrome in PLWH. Therefore, when selecting an ART regimen, it is essential to balance efficacy, adverse effects, patient adherence, and potential metabolic comorbidities. Newer agents, such as long-acting intramuscular INSTIs (eg, cabotegravir) and HIV entry inhibitors (including CCR5 antagonists, attachment inhibitors, and fusion inhibitors), offer promising alternatives due to their minimal adverse effects on metabolic parameters .¹¹³

Inequality of Medical Resources

The development of HIV-MetS is linked to multiple factors, including income disparities and inequitable distribution of healthcare resources. In underrepresented regions (such as many low- and middle-income countries), the scarcity of medical resources significantly constrains the diagnosis and management of HIV-MetS. This not only exacerbates the disease burden for affected individuals but also impedes the achievement of public health objectives.

Sub-Saharan African countries (eg, Ghana, Nigeria, Cameroon) bear nearly two-thirds of the global burden of HIV infection. However, due to weak healthcare infrastructure, limited laboratory resources, and shortages of specialized medical personnel, metabolic abnormalities among PLWH are often unrecognized. This leads to missed opportunities for early intervention, increases comorbidity management challenges, and ultimately results in significantly higher non-HIV-related mortality rates in this region compared to developed countries or regions.^2,189,190 In Latin America (eg, Brazil, Peru) and parts of South America (eg, Colombia, Argentina), the prevalence of HIV-MetS varies substantially, ranging from 8% to 52%.^191,192 Similarly, in resource-limited Asian regions (eg, Cambodia, Laos, Vietnam, India), the prevalence is approximately 10% to 42%.^21,193 This reflects regional disparities in healthcare resource allocation, particularly in remote areas, where limited access to antiviral drugs, insufficient specialist coverage, and inadequate primary care resources increase the difficulty of identifying and managing HIV-MetS, thereby compromising CVD risk control in patients.¹⁹⁴ Additionally, inequalities faced by transgender populations are highlighted. A US study indicates that transgender women living with HIV encounter greater barriers to viral suppression and health management compared to cisgender individuals with HIV, underscoring the compounded disadvantages in resource access among marginalized groups.¹⁹⁵

Scholars have advocated for international collaboration, technological innovation, and policy support to optimize resource allocation regionally, promote equitable treatment access, and enhance the overall quality of life and health outcomes for HIV-MetS patients. Specific measures include introducing low-cost screening tools, strengthening training for primary healthcare workers, optimizing medication supply and utilization, promoting health education, and establishing sustainable monitoring systems in resource-limited settings.

Others

Measures for the prevention, diagnosis, and treatment of HIV-MetS are under ongoing investigation.

For diagnostic evaluation, studies propose using estimated pulse wave velocity (ePWV) as a novel non-invasive biomarker for MetS in PLWH ,¹⁸⁹ while machine learning-based retinal image analysis has shown a potential to improve the accuracy of CAD risk in this population.^190,191

For prevention and treatment, probiotics have emerged as a potential therapeutic target for non-AIDS comorbidities like metabolic disorders and CAD,¹⁹² though interventions such as probiotic supplementation, prebiotics, and fecal microbiota transplantation require further validation of efficacy.¹⁹³ Traditional Chinese medicine (TCM) may correct “lipid metabolism imbalance” and restore systemic homeostasis, offering a therapeutic approach for HAART-induced hyperlipidemia.^194,195 Other modalities, including plant-based antioxidant therapies, await further development .¹⁷¹

For management, advocate for establishing a patient-centered, stigma-free specialized healthcare environment, creating a research-oriented big data platform, and implementing a “one-stop service” model that integrates real-time follow-up management for HIV/AIDS patients and multidisciplinary team support comprising infectious disease specialists, nutritionists, metabolic disease experts, pharmacists, and social workers to deliver comprehensive, refined, and individualized patient care throughout the entire treatment process¹⁵⁵.

Conclusions and Future Perspectives

Research over recent decades has demonstrated that PLWH exhibit a higher incidence of MetS compared to the general population. HIV-MetS also elevates the risk of complications including cardiovascular disease, diabetes, fatty liver disease, stroke, dementia, and premature aging, significantly compromising patients’ quality of life and survival rates. Consequently, early identification, intervention, and standardized management for this population are critically important.

The pathogenesis of HIV-MetS is complex, primarily centered on the HIV virus itself and ART. It involves chronic inflammation and immune activation, glucose and lipid metabolism abnormalities, mitochondrial dysfunction, vascular endothelial abnormalities, gut microbiota dysbiosis, epigenetic alterations, and the use of specific ART drugs. These mechanistic insights provide potential avenues for developing novel therapeutic drugs for HIV-MetS. Research into these mechanisms, however, should not stop at this point, as significant gaps remain that require in-depth, systematic, and detailed exploration.

HIV-MetS involves numerous contributing factors, making clinical management and treatment notoriously challenging. In recent years, personalized integrated management strategies aimed at improving the long-term prognosis of PLWH have emerged. These include optimizing ART regimens, implementing lifestyle interventions (such as smoking cessation, alcohol restriction, dietary control, exercise, and weight management), and managing glycemia, blood pressure, and dyslipidemia. Among these, lipid management and treatment are of paramount importance. Additionally, risk assessment utilizing inflammatory markers and genetic factors, establishment of a multidisciplinary integrated care model, application of probiotics or gut barrier restoratives, and stratification of patients based on metabolomic/microbiome profiles were also addressed in this article.

Certainly, significant research gaps remain to be addressed. Current limitations include insufficient longitudinal data, ethnic and regional epidemiological variations, regional disparities in healthcare resource allocation, and inadequate research data on HIV-MetS in children. Equally lacking are effective HIV-MetS risk assessment models, large-scale clinical trials for MetS prevention and management in PLWH, and evidence-based MetS guidelines tailored for specific PLWH populations (such as the elderly, children, and women).

Future research directions on HIV-MetS may include developing novel antiretroviral drugs with reduced metabolic impact, exploring antioxidant and anti-inflammatory targeted therapies, investigating gut microbiota modulation approaches, and developing immunomodulatory agents (eg, cytokines and small-molecule drugs) as well as therapeutics targeting metabolic signaling pathways. Additionally, low-cost metabolic screening models should be promoted in aging PLWH. Crucially, future research should not only focus on mechanistic studies, risk model development, and pharmacological interventions but also consider establishing metabolic specialty clinics in resource-limited settings (eg, Africa) to enhance cardiovascular risk assessment; promote gender-, age-, and ethnicity-specific management guidelines; integrate comprehensive care models encompassing assessment, treatment, nursing, follow-up, and psychological support; and strengthen global public health strategies targeting prevention and intervention in low-resource environments.

This comprehensive review synthesizes the pathogenesis, diagnostic criteria, risk factors, and clinical management strategies of HIV-MetS. These findings directly provide a foundation for developing evidence-based risk models for HIV-MetS, and inform WHO guidelines for HIV care and national HIV management protocols, particularly in aging populations with comorbid metabolic disorders. It is hoped that in the near future, individualized management for the HIV-MetS population will reduce global health inequities, alleviate the growing burden of HIV-related diseases and economic costs, and advance comprehensive health equity.

Acknowledgments

We heartily appreciate all those who contributed to this research.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This work was supported by Hangzhou Medical and Health Science and Technology Project (No. B20253650) and Xiaoshan District Scientific and Technological Projects (No.2024341).

Disclosure

The authors report no conflicts of interest in this work.

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