Metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated alcohol-related liver disease in human immunodeficiency virus

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated alcohol-related liver disease (MetALD) have emerged as increasingly important sources of morbidity among people living with human immunodeficiency virus (HIV). Advances in antiretroviral therapy have substantially improved life expectancy in people living with HIV (PLWH), but have also unmasked a growing burden of metabolic comorbidities which contribute to steatotic liver disease. Recent shifts in nomenclature and the introduction of MetALD emphasize metabolic dysfunction and graded alcohol exposure as central drivers of disease and are particularly relevant to PLWH, a population in whom overlapping metabolic and behavioral risk factors are common. Epidemiologic studies demonstrate that MASLD affects approximately one-third to one-half of PLWH worldwide, often occurring at younger ages and lower body mass index thresholds than in HIV-negative individuals. Emerging data further highlight the synergistic contribution of metabolic dysfunction and alcohol use to accelerated fibrosis progression in PLWH. Pathophysiologic mechanisms linking HIV infection to MASLD and MetALD include chronic immune activation and systemic inflammation, antiretroviral therapy-associated metabolic effects, altered adipose tissue distribution, gut-liver axis dysregulation, and alcohol-metabolic synergy. This review synthesizes contemporary evidence on the definitions, epidemiology, pathogenesis, clinical assessment, and management of MASLD and MetALD in PLWH.

Key Words: Metabolic dysfunction-associated steatotic liver disease; Metabolic dysfunction-associated alcohol-related liver disease; Steatotic liver disease; People living with human immunodeficiency virus; Antiretroviral therapy; Metabolic syndrome; Gut-liver axis; Chronic inflammation

Core Tip: This review synthesizes emerging evidence on metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated alcohol-related liver disease in people living with human immunodeficiency virus. The authors highlight the implications of recent nomenclature changes and critically evaluate non-invasive fibrosis tools. The review advances a multi-hit conceptual model integrating antiretroviral therapy effects, immune activation, metabolic dysfunction, and alcohol effects to guide future research and clinical care.

INTRODUCTION

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic condition characterized by hepatic fat accumulation in the presence of metabolic dysfunction and absence of other dominant causes of liver disease. Formerly known as non-alcoholic fatty liver disease (NAFLD), MASLD was adopted to reflect a more inclusive and mechanistic understanding of disease pathogenesis, moving away from a diagnosis of exclusion and toward a diagnosis based on metabolic risk[1]. While obesity remains a central driver for disease contribution, several other factors (genetics, diet, medications, etc.) also play a significant role in the pathogenesis of MASLD[2]. MASLD is now the most common cause of chronic liver disease in the world and is the leading cause of liver-related morbidity and mortality. Furthermore, MASLD has shown a sharp rise in prevalence over the past decade. Recent data from the United Network of Organ Sharing indicated that MASLD is now the second leading indication of all liver transplants in the United States[3].

In parallel to this, another recent shift in terminology involves metabolic dysfunction-associated alcohol-related liver disease (MetALD). This term describes steatotic liver disease (SLD) in individuals with metabolic dysfunction who consume moderate amounts of alcohol, representing an overlap between MASLD and alcohol-related liver injury[4]. The introduction of MetALD recognizes the synergistic effect of metabolic risk factors and alcohol on liver injury, reflecting real-world patient populations with overlapping risk factors[4]. Patients with MetALD have higher rates of advanced liver fibrosis compared with MASLD alone, and disease progression itself may occur at lower alcohol thresholds in the presence of metabolic dysfunction[5,6]. However, alcohol intake assessment is frequently subject to misclassification and underreporting, particularly in vulnerable populations, which may influence epidemiologic estimates of MetALD prevalence.

Human immunodeficiency virus (HIV) is a retrovirus that infects CD4+ T-cells in the body, causing progressive immunodeficiency which can be fatal if left untreated[7]. Globally, HIV infects more than 37 million people. By the end of 2019, there were 1189700 people living with HIV (PLWH) in the United States alone, and around 30635 people received a new diagnosis of HIV in 2020[8]. Continued advancements in antiretroviral therapy (ART) coupled with improved accessibility to treatments have made HIV a more manageable chronic condition for the long term[9,10]. With increasing life expectancy, other chronic comorbidities are becoming more prevalent in PLWH, including cardiovascular diseases, dyslipidemias, and renal diseases[11]. In addition, liver diseases are also becoming more common in PLWH and contributing towards 13%-18% of all-cause mortality in this population[11].

Emerging data suggests that PLWH may develop more advanced liver fibrosis at lower body mass index (BMI) thresholds and younger ages compared with HIV-negative individuals, underscoring the unique pathophysiology of SLD in this population[12]. Rather than HIV infection acting as an isolated driver of accelerated fibrosis, it is increasingly recognized that HIV-related immune activation interacts with traditional metabolic risk factors and treatment-related exposures to create a multifactorial risk environment. Despite the growing clinical burden, MASLD and MetALD remain underdiagnosed in routine HIV care and evidence-based screening and management strategies tailored specifically to PLWH are lacking. This review aims to synthesize contemporary data on the epidemiology, pathophysiology, clinical assessment, and management of MASLD and MetALD in PLWH while highlighting key knowledge gaps and future research priorities.

DEFINITIONS AND NOMENCLATURE

The nomenclature surrounding fatty liver disease has undergone a major paradigm shift in recent years to more precisely reflect underlying pathophysiology and improve clinical recognition across different patient populations. The key incentive for change has been the recognition that traditional labels such as NAFLD and non-alcoholic steatohepatitis (NASH), which required exclusion of significant alcohol use, did not adequately capture the metabolic drivers of disease and often defined the condition in reference to what it was not[1]. In response, international hepatology societies have established a new, inclusion-focused nomenclature under the umbrella term SLD which encompasses steatosis from metabolic dysfunction, alcohol use, and other etiologies[13]. Within this framework, MASLD and MetALD have been defined to better reflect disease biology and risk factors, with metabolic dysfunction-associated steatohepatitis (MASH) replacing NASH to denote histologic injury characterized by inflammation and hepatocellular ballooning in the context of metabolic dysfunction[14].

MASLD DIAGNOSTIC CRITERIA

MASLD is defined by the presence of hepatic steatosis - documented through imaging (e.g., ultrasound, computed tomography, or magnetic resonance imaging), histology, or validated non-invasive biomarkers such as transient elastography with controlled attenuation parameter (CAP) - in conjunction with at least one cardiometabolic risk factor[1]. Cardiometabolic risk factors typically include overweight/obesity (e.g., BMI ≥ 25 kg/m² or elevated waist circumference), prediabetes or type 2 diabetes mellitus (T2DM), dyslipidemia (elevated triglycerides or low high-density lipoprotein), or hypertension[15].

This new definition marks a departure from earlier exclusion-based definitions by emphasizing positive inclusion criteria anchored in metabolic dysfunction which is the primary driver of disease progression in MASLD[16]. By replacing NAFLD, MASLD recognizes that metabolic risk factors are central to the development and natural history of SLD. Evidence shows a near-complete overlap between NAFLD and MASLD cohorts when reclassified under these new criteria, with minimal reclassification of individuals who met older NAFLD definitions[16].

However, the implications of reclassification in PLWH have not been fully characterized. In HIV populations, lower BMI thresholds, lipodystrophy phenotypes, and ART-associated metabolic changes may result in individuals meeting MASLD criteria despite atypical body composition[16].

METALD DIAGNOSTIC CRITERIA AND ALCOHOL THRESHOLDS

Within the SLD framework, MetALD denotes a spectrum of disease in which metabolic dysfunction and alcohol consumption both contribute to hepatic steatosis. MetALD is distinguished from pure MASLD by higher levels of alcohol consumption in the context of coexisting cardiometabolic risk factors[17]. The alcohol intake thresholds for MetALD are approximately 140-350 g per week for females and 210-420 g per week for males, which roughly translates to daily averages of 20-50 g per day for females and 30-60 g per day for males[18]. Individuals who consume alcohol above these thresholds and have underlying metabolic dysfunction are categorized as having MetALD, while those exceeding higher alcohol intake (e.g., > 50 g per day in females or > 60 g per day in males) without having substantial metabolic risk factors are classified as having alcohol-associated liver disease (ALD)[17,18]. This nuanced classification scheme acknowledges the synergistic effect of alcohol and metabolic risk on liver injury and clinical outcomes[18]. However, in practice, there is slight overlap between MASLD and ALD such that individuals with lower levels of alcohol consumption but significant metabolic dysfunction may fall closer to the MASLD end of the spectrum, whereas those with heavier alcohol use and mild metabolic risk may align more closely with ALD-predominant disease.

Several challenges also arise when these definitions are placed in the context of a population such as PLWH. Alcohol use patterns in PLWH may be episodic or hazardous rather than consistently moderate, complicating application of weekly gram-based thresholds. Furthermore, ART-related transaminase elevations and immune activation may obscure attribution of liver injury to alcohol vs metabolic drivers. These factors suggest that MetALD prevalence estimates in PLWH may be sensitive to how alcohol exposure is assessed and categorized.

COMPARISON TO NAFLD/NASH TERMINOLOGY

Under the pre-existing NAFLD framework, diagnosis required the exclusion of significant alcohol consumption (defined as less than 10-20 g/day for females and less than 20-30 g/day for males) alongside exclusion of other causes of steatosis and chronic liver disease[19]. NASH denoted a subset of NAFLD that showed histologic evidence of inflammation, hepatocellular injury, and varying degrees of fibrosis[20]. These exclusionary definitions limited applicability in populations with overlapping etiologies, such as those with moderate alcohol use, metabolic syndrome, HIV infection, etc., and often underemphasized the role of metabolic dysfunction itself as a primary driver of liver injury[20].

The new MASLD and MetALD nomenclature reconfigures this schema by centering metabolic dysfunction and recognizing the role of alcohol without strict exclusion. MASH replaces NASH in order to denote steatohepatitis in the setting of metabolic dysfunction[19,20]. SLD is applied to individuals with steatosis lacking clearly defined metabolic or alcohol-related drivers, emphasizing the need for ongoing evaluation for less common etiologies.

RELEVANCE TO PLWH

These new terminologies of MASLD and MetALD hold particular relevance for PLWH in whom overlapping metabolic and lifestyle risk factors are common and traditional exclusion criteria may obscure accurate disease characterization. PLWH frequently exhibit weight changes, central adiposity, insulin resistance, and dyslipidemia due to chronic inflammation, ART, and immune dysregulation - all of which contribute to metabolic dysfunction and steatosis[21]. It is also important to address the varying pattern of alcohol use in this population, with a substantial proportion reporting moderate to heavy alcohol consumption which may exacerbate liver injury especially in the presence of metabolic disease[22]. By emphasizing positive criteria for metabolic dysfunction and graded alcohol exposure, the MASLD/MetALD designations enable more inclusive identification of SLD in PLWH, facilitate more precise risk stratification, and align diagnostic criteria with pathophysiological drivers that are highly prevalent in this group[22].

Application of the MASLD/MetALD framework in PLWH must also be contextualized within HIV-related confounders. Hepatitis B and hepatitis C co-infection, which remain disproportionately prevalent in certain HIV subpopulations, may accelerate fibrosis progression. Furthermore, socioeconomic determinants, healthcare access disparities, substance use beyond alcohol, and racial disparities in metabolic risk all influence disease expression and outcomes[22]. Table 1 below summarizes and compares the diagnostic criteria between the aforementioned terms.

Table 1 Comparison of diagnostic criteria for nonalcoholic fatty liver disease, metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated alcoholic liver disease, and alcohol-associated liver disease.

	NAFLD	MASLD	MetALD	ALD
Criteria	Hepatic steatosis ± metabolic dysfunction (not required)	Hepatic steatosis + metabolic dysfunction with ≥ 1 of following criteria: (1) BMI ≥ 25 kg/m2 or increased waist circumference (> 94 cm in men, > 80 cm in women); (2) HbA1c ≥ 5.7% or on diabetes medication(s); (3) Plasma triglycerides ≥ 150 mg/dL; (4) Low plasma HDL (< 40 mg/dL in men, < 50 mg/dL in women); and (5) Blood pressure ≥ 130/85 mmHg	Hepatic steatosis + alcohol consumption (above MASLD thresholds but below ALD thresholds) + metabolic dysfunction with ≥ 1 of following criteria: (1) BMI ≥ 25 kg/m2 or increased waist circumference (> 94 cm in men, > 80 cm in women); (2) HbA1c ≥ 5.7% or on diabetes medication(s); (3) Plasma triglycerides ≥ 150 mg/dL; (4) Low plasma HDL (< 40 mg/dL in men, < 50 mg/dL in women); and (5) Blood pressure ≥ 130/85 mmHg	Hepatic steatosis + alcohol consumption above MetALD thresholds ± metabolic dysfunction
Alcohol thresholds	Men: < 30 g/day; women: < 20 g/day	Men: < 30 g/day; women: < 20 g/day	Men: 30-60 g/day; women: 20-50 g/day	Men: > 60 g/day; women: > 50 g/day
Diagnostic approach	Exclusion-based	Inclusion-based	Inclusion-based	Alcohol-dominant

NAFLD: Non-alcoholic fatty liver disease; MASLD: Metabolic dysfunction-associated steatotic liver disease; BMI: Body mass index; HbA1c: Glycated hemoglobin; HDL: High-density lipoprotein; MetALD: Metabolic dysfunction-associated alcohol-related liver disease; ALD: Alcohol-associated liver disease.

EPIDEMIOLOGY OF MASLD AND METALD IN PLWH

Global prevalence

MASLD has emerged as one of the most prevalent non-infectious comorbidities among PLWH, reflecting the intersection of cardiometabolic risk factors, chronic immune activation, aging, and long-term exposure to ART. Across diverse cohorts, the prevalence of hepatic steatosis in PLWH consistently exceeds that observed in HIV-negative populations, even after adjustment for traditional metabolic risk factors[23-25]. Recent estimates suggest that approximately one-third to one-half of PLWH worldwide meet MASLD criteria, positioning it as the dominant cause of chronic liver disease in this population[21,26,27].

In a large, contemporary United States multicenter cohort of 1065 PLWH undergoing systematic liver phenotyping, Gawrieh et al[21] reported a prevalence of SLD of 52%, with MASLD accounting for 38% of cases and MetALD accounting for approximately 10%. Of note, 15% of this cohort demonstrated clinically significant liver fibrosis, underscoring that MASLD in PLWH is not merely a benign steatotic disease process but can often be associated with advanced liver injury[21]. Obesity and elevated aminotransferases (alanine aminotransferase, aspartate aminotransferase) were identified as the strongest metabolic predictors of MASLD, consistent with established mechanisms of hepatic lipotoxicity that are increasingly recognized in aging PLWH[21].

Earlier observational studies anticipated these findings. Guaraldi et al[26] reported a prevalence of hepatic steatosis approaching 37% among HIV-infected individuals without viral hepatitis co-infection or significant alcohol use, emphasizing the fundamental role of metabolic dysfunction (including central adiposity, insulin resistance, and dyslipidemia) in MASLD pathogenesis. In addition, this study also demonstrated a cumulative ART effect with an 11% increase in MASLD odds per additional year of nucleoside reverse-transcriptase inhibitor (NRTI) exposure, suggesting that long-term ART may amplify metabolic processes and promote steatosis/fibrogenesis[26].

Regional and population-specific data

Other international studies corroborate the high prevalence of MASLD among PLWH across geographic regions despite heterogenous metabolic risk profiles, ART regimens, and background prevalence of obesity. In a pilot study from a tertiary care center in North India, Ram et al[23] reported a MASLD prevalence of 41% among PLWH receiving routine HIV care. And even after excluding individuals with T2DM, obesity, and viral hepatitis co-infection, MASLD prevalence remained substantial at 16.6% of the above cohort with more than 28% of affected individuals exhibiting advanced hepatic fibrosis[23]. These findings suggest that HIV infection, independent of metabolic risk factors, may contribute to SLD pathogenesis and even fibrosis. However, the absence of longitudinal follow-up limits conclusions regarding causality or accelerated progression attributable to HIV alone.

European cohorts have similarly demonstrated a high prevalence of MASLD in PLWH. Studies from Italy and Spain have reported MASLD prevalence ranging from 30%-45%, with lean or non-obese phenotypes representing a clinically significant subset[24,28]. And in sub-Saharan Africa and other parts of Southeast Asia, where obesity prevalence is lower but HIV burden remains high, emerging data suggest that MASLD remains common though often underdiagnosed due to the limited access of disease assessment resources[29]. Healthcare infrastructure constraints and competing infectious disease burdens may further influence detection rates and reported prevalence, further complicating global comparisons[29].

These observations raise important concerns regarding under-recognition of MASLD in PLWH who do not meet conventional BMI-based screening thresholds. Furthermore, differences in ART exposure, genetic susceptibility, and nutrition may further influence regional disease patterns, thus highlighting a growing need for additional population-specific epidemiologic studies.

Alcohol use and MetALD in PLWH

Alcohol consumption remains highly prevalent among PLWH and frequently coexists with metabolic dysfunction, creating a clinical circumstance in which MetALD is increasingly recognized. As discussed earlier, the introduction of the MetALD category acknowledges the synergistic contribution of metabolic risk factors and moderate alcohol intake to liver injury which is particularly relevant in HIV populations[30]. In the United States. multicenter cohort study described by Gawrieh et al[21], approximately 10% of PLWH met criterial for MetALD, highlighting that a substantial subset of HIV patients falls between MASLD and ALD designations.

Alcohol use in PLWH has been independently associated with increased hepatic steatosis, accelerated fibrosis progression, and higher rates of liver-related morbidity/mortality, particularly when combined with insulin resistance and obesity[31,32]. Specifically, Lyu et al[31] demonstrated that daily intake > 50 g alcohol in PLWH was linked to significantly higher odds of fibrosis compared with lower consumption levels. Furthermore, analyses from other cohort studies such as the NOAH study demonstrated that current hazardous drinking habits are strongly associated with non-invasive markers of advanced liver disease in PLWH, with particular prominence among individuals co-infected with hepatitis C[32]. In this manner, alcohol may exacerbate HIV-related immune activation and gut barrier dysfunction, further amplifying hepatic inflammation and fibrogenesis[30]. These interactions are clinically significant as individuals with MetALD may be at higher risk for progression to fibrosis than those with MASLD alone, despite alcohol consumption levels that would previously have been considered “moderate”[30].

It is important to address that alcohol use patterns may vary substantially by region, socioeconomic status, and sex, complicating epidemiologic assessments[31]. Self-reported alcohol intake also often underestimates true consumption, raising concern than MetALD prevalence in PLWH may actually be underdiagnosed in both clinical and research settings[31]. Therefore, recognition of MetALD has important implications for patient education and risk stratification, particularly given the existing evidence that metabolic-induced liver injury and alcohol-related liver injury confers elevated risks of fibrosis.

Extrahepatic outcomes and cardiometabolic risk

Beyond liver-specific outcomes, MASLD in PLWH is increasingly recognized as a marker of systemic cardiometabolic risk. In a large United States veteran cohort, Wong et al[27] demonstrated that PLWH with MASLD experienced a higher incidence of major adverse cardiovascular events compared with HIV-negative individuals with MASLD (5.18 per 100 person-years vs 4.48 per 100 person-years) despite similar rates of cirrhosis and hepatocellular carcinoma between the two groups. These findings may reflect persistent immune activation, endothelial dysfunction, and metabolic comorbidities in PLWH rather than direct hepatic effects alone. MASLD in PLWH may therefore function as both a hepatic disease entity and an indicator of broader cardiometabolic vulnerability.

Metabolic comorbidities appear to synergize with HIV infection in driving MASLD risk. In a retrospective multicenter analysis, Abosheaishaa et al[33] demonstrated that individuals with both HIV and T2DM developed MASLD at significantly higher rates than those with T2DM alone, reinforcing the concept of additive metabolic injury in PLWH.

However, failure to account for prevalent confounders in the HIV population, including hepatitis, ART exposure, and healthcare access, risks oversimplifying the relationship between HIV infection and SLD[22]. Future longitudinal studies with careful adjustment for confounders are needed to clarify whether HIV independently accelerates fibrosis progression or primarily modifies risk through interaction with metabolic and behavioral factors. Table 2 summarizes the global epidemiology of MASLD and MetALD in PLWH across these major studies.

Table 2 Epidemiology of metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated alcohol-related liver disease in people living with human immunodeficiency virus.

Study	Study design	Steatosis/MASLD prevalence	MetALD prevalence	Fibrosis/key outcomes	Key epidemiologic insights
Gawrieh et al[21]	Cross-sectional; n = 1065 PLWH	SLD 52%; MASLD 38%	Approximately 10%	15% with clinically significant fibrosis	MASLD is dominant liver disease; obesity and ALT/AST are strongest predictors
Guaraldi et al[26]	Observational cohort; HIV mono-infected	Approximately 37% hepatic steatosis	Not assessed	Fibrosis risk increased with ART duration	11% increased odds of MASLD per year of NRTI exposure
Ram et al[23]	Single-center pilot study	MASLD 41%; 16.6% after excluding obesity/T2DM	Not assessed	> 28% with advanced fibrosis	HIV may contribute independently to MASLD and fibrosis
Lyu et al[31]	Observational cohort	Not primary outcome	Not assessed	Higher odds of fibrosis with alcohol consumption > 50 g/day	Alcohol synergizes with metabolic dysfunction in PLWH
Wong et al[27]	Retrospective cohort	MASLD prevalent in all subjects	Not assessed	Higher MACE rates in PLWH with MASLD	MASLD in PLWH confers excess cardiovascular risk

PLHW: People living with human immunodeficiency virus; HIV: Human immunodeficiency virus; MASLD: Metabolic dysfunction-associated steatotic liver disease; SLD: Steatotic liver disease; T2DM: Type 2 diabetes mellitus; MetALD: Metabolic dysfunction-associated alcohol-related liver disease; ART: Antiretroviral therapy; MACE: Major adverse cardiovascular events; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; NRTI: Nucleoside reverse transcriptase inhibitor.

PATHOPHYSIOLOGICAL MECHANISMS LINKING HIV TO MASLD/METALD

Rather than representing a single linear pathway, MASLD and MetALD in PLWH likely arise from a multi-hit, interacting model in which traditional metabolic risk factors, ART-related metabolic effects, chronic immune activation, adipose tissue redistribution, and alcohol exposure converge to promote hepatic steatosis and fibrogenesis. Importantly, the relative contribution of each pathway varies across individuals and clinical contexts.

Chronic inflammation and immune activation

Major risk factors driving MASLD in PLWH overlap substantially with those underlying metabolic syndrome, including central adiposity, hypertension, insulin resistance, and dyslipidemia. A systematic review and meta-analysis by Todowede et al[34] demonstrated that PLWH have an approximately two-fold increased risk of metabolic syndrome compared with HIV-negative individuals, underscoring the heightened susceptibility of this population to downstream metabolic complications such as MASLD and MetALD. While traditional metabolic risk factors clearly contribute, HIV-specific mechanisms (particularly chronic immune activation and systemic inflammation) play a central role in shaping the metabolic milieu that promotes hepatic steatosis and fibrogenesis[34]. Persistent immune activation remains a biologically plausible contributor to MASLD in PLWH; however, much of the evidence is associative rather than directly causal[34].

Despite durable viral suppression with ART, PLWH exhibit persistent immune activation characterized by elevated circulating inflammatory markers, activated monocytes and T cells, and viral replication within tissue reservoirs[35,36]. This chronic inflammatory state is driven by multiple mechanisms, including microbial translocation from a compromised gut barrier, immune dysregulation induced by HIV itself, and co-infections[37]. Elevated levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor (TNF)-α are consistently observed in treated PLWH and have been independently associated with cardiometabolic disease, insulin resistance, and mortality[37]. As it is highlighted in Figure 1 below, these cytokines exert direct effects on hepatic and peripheral insulin signaling pathways, promoting adipose tissue lipolysis, increased delivery of free fatty acids to the liver, and subsequent intrahepatic triglyceride accumulation[37].

Figure 1 Chronic inflammation and immune activation in people living with human immunodeficiency virus increase risk of metabolic syndrome. The images were created using BioRender (Supplementary material). PLWH: People living with human immunodeficiency virus; IL: Interleukin; TNF: Tumor necrosis factor.

TNF-α plays a particularly important role in MASLD pathogenesis by impairing insulin receptor signaling through serine phosphorylation of insulin receptor substrate-1, thereby exacerbating hepatic insulin resistance and promoting de novo lipogenesis (Figure 2)[38]. Similarly, IL-6 has been implicated in hepatic lipid accumulation through its effects on adipocyte dysfunction, mitochondrial metabolism, and inflammatory signaling cascades within hepatocytes[39]. In PLWH, sustained elevations of these cytokines amplify metabolic stress on the liver, even in the absence of overt obesity or diabetes, potentially explaining observations of steatosis and fibrosis at lower BMI thresholds compared with HIV-negative populations[37].

Figure 2 Elevated tumor necrosis factor-α levels in people living with human immunodeficiency virus promotes phosphorylation of insulin receptor substrate-1 and decreases translocation of glucose transporter type 4, thereby worsening insulin resistance and promoting metabolic syndrome. The images were created using BioRender (Supplementary material). TNF: Tumor necrosis factor; IRS-1: Insulin receptor substrate-1; GLUT4: Glucose transporter type 4; P: Phosphorylation.

Chronic immune activation in HIV is also closely linked to alterations in adipose tissue distribution, including preferential visceral fat accumulation and lipodystrophy, which further contribute to metabolic dysfunction[40]. Visceral adipose tissue is metabolically active and serves as a source of inflammatory cytokines and adipokines, reinforcing a vicious cycle of inflammation and insulin resistance[40].

Chronic inflammation may also potentiate the hepatotoxic effects of alcohol, providing a mechanistic link between immune activation and the development of MetALD. Alcohol consumption itself induces gut permeability and endotoxemia, further amplifying hepatic inflammation through toll-like receptor signaling and cytokine release[41]. In PLWH, where baseline immune activation is already heightened, even moderate alcohol intake may exert disproportionate effects on hepatic inflammation and fibrogenesis, contributing to the observed overlap between MASLD and MetALD phenotypes in this specific population[30].

However, direct longitudinal evidence linking specific inflammatory biomarkers to steatosis severity or fibrosis progression in PLWH remains limited. While cross-sectional associations are consistent, causative analyses are sparse, and inflammatory markers may reflect broader metabolic dysregulation rather than independently driving hepatic injury.

Traditional and age-related risk factors, including advancing age, physical inactivity, and suboptimal dietary patterns, further compound immune-mediated metabolic disturbances in PLWH[35]. Genetic predisposition and host factors may also modulate individual susceptibility to inflammation-driven MASLD, although data in HIV-specific populations remain limited. Notably, studies have yielded inconsistent findings regarding whether HIV infection independently increases the prevalence of metabolic syndrome compared with uninfected controls, reflecting heterogeneity in study design and population characteristics[34]. Nevertheless, converging mechanistic evidence supports a central role for chronic inflammation and immune activation in linking HIV infection to metabolic dysfunction and SLD.

ART

The widespread implementation of ART has transformed HIV into a chronic, manageable condition, markedly reducing AIDS-related morbidity and mortality. However, despite early concerns that effective viral suppression might mitigate liver disease risk in PLWH, the incidence of hepatic steatosis has not declined[35]. While ART is indispensable for HIV control, specific drug classes and agents exert off-target metabolic effects that promote insulin resistance, abnormal fat distribution, hepatic lipid accumulation, and dyslipidemia.

Nucleoside reverse transcriptase inhibitors (NRTIs) form the foundation of most ART regimens and are typically administered as dual therapy alongside a third agent. First-generation NRTIs, including didanosine, stavudine, and zalcitabine, have been strongly associated with mitochondrial toxicity through inhibition of mitochondrial DNA polymerase-γ[42]. This disruption impairs oxidative phosphorylation, increases reactive oxygen species production, and leads to defective fatty acid oxidation, thereby promoting hepatic steatosis and steatohepatitis in a manner that closely parallels MASLD pathogenesis[42].

Beyond mitochondrial toxicity, NRTIs have been implicated in the development of insulin resistance, dyslipidemia, and lipodystrophy, all of which contribute to hepatic lipid accumulation and fibrogenesis[43]. Modern NRTIs, including emtricitabine, lamivudine, tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF), exhibit substantially improved safety profiles; however, clinically relevant metabolic differences persist. TAF has been consistently associated with weight gain, increases in lipid levels, and a higher prevalence of metabolic syndrome compared with TDF, whereas switching from TAF back to TDF has been shown to reverse lipid elevations[43]. These observed associations seem to have less to do with direct hepatotoxicity, however, and the prospective data remain limited. Nevertheless, these metabolic effects are particularly relevant in PLWH with pre-existing cardiometabolic risk factors in whom ART-related weight gain may accelerate MASLD[34].

Protease inhibitors and non-NRTIs have also been linked to adverse metabolic effects, although their use has declined in favor of newer medications[44]. Protease inhibitors are associated with dyslipidemia and lipodystrophy, likely mediated by interference with adipocyte differentiation and lipid regulatory pathways[44]. These effects contribute to increased free fatty acid flux in the liver and central adiposity, intensifying the drivers of hepatic steatosis and insulin resistance.

Integrase strand transfer inhibitors (INSTIs) are now the cornerstone of first-line ART due to their potent antiviral activity and favorable tolerability. Nevertheless, accumulating evidence implicates INSTI-based regimens in excess weight gain, particularly with dolutegravir and raltegravir[45]. In a large North American cohort of approximately 20000 treatment-naïve PLWH, INSTI-based regimens were associated with significantly greater weight gain over five years compared with non-NRTIs-based regimens, with the greatest increases observed among individuals receiving dolutegravir or raltegravir[45]. However, direct evidence linking INSTIs to steatohepatitis or fibrosis independent of weight gain is still limited with current data supporting an indirect metabolic pathway rather than intrinsic hepatotoxicity[45].

ART exposure has been shown to induce insulin resistance through activation of inflammatory pathways and disruption of insulin signaling cascades[46]. Experimental and clinical studies demonstrate that ART can promote inflammasome activation and dysregulation of the insulin receptor substrate-1/phosphatidylinositol 3-kinase/protein kinase B pathway. Evidenced by increased expression of nod-like receptor protein 3, IL-1β, and Jun N-terminal kinase, alongside reduced protein kinase B and phosphatidylinositol 3-kinase signaling[46]. These alterations impair glucose uptake and lipid metabolism, fostering hepatic triglyceride accumulation and enhancing susceptibility to MASLD and MetALD[46]. While mechanistically compelling, large-scale longitudinal human data confirming these pathways as dominant drivers of MASLD and MetALD in PLWH are lacking. Table 3 summarizes the metabolic and hepatic effects of major ART classes in PLWH, highlighting ART-associated mechanisms that may contribute to weight gain, insulin resistance, and increased risk of MASLD and MetALD.

Table 3 Effects of antiretroviral therapy on metabolic dysfunction and hepatic steatosis in people living with human immunodeficiency virus.

ART class/agent	Metabolic effects	Hepatic implications
ART (overall exposure)	Persistent insulin resistance; inflammatory pathway activation; disrupted insulin signaling	Ongoing risk of hepatic steatosis and progression to MASLD/MetALD
First-generation NRTIs (didanosine, stavudine, zalcitabine)	Mitochondrial toxicity; increased ROS; impaired fatty acid oxidation	Hepatic steatosis and steatohepatitis resembling MASLD
NRTIs	Insulin resistance, dyslipidemia, lipodystrophy	Hepatic lipid accumulation and fibrogenesis
TAF and TDF	TAF associated with weight gain and dyslipidemia; effects reversible with TDF	Accelerated MASLD risk, especially with baseline cardiometabolic risk
PIs	Dyslipidemia and lipodystrophy via impaired adipocyte differentiation	Increased free fatty acid flux; central adiposity; worsened steatosis
NNRTIs	Adverse metabolic effects; declining use	Contribution to metabolic dysfunction and steatosis
INSTIs	Excess weight gain compared with NNRTI-based regimens	Indirect promotion of hepatic steatosis
INSTIs: Dolutegravir, raltegravir	Greatest long-term weight gain	Increased MASLD risk mediated by adiposity
ART-induced inflammatory signaling	NLRP3 inflammasome activation; ↑IL-1β, JNK; ↓PI3K/AKT	Hepatic triglyceride accumulation; MASLD/MetALD susceptibility

ART: Antiretroviral therapy; NRTI: Nucleoside reverse transcriptase inhibitor; TAF: Tenofovir alafenamide; TDF: Tenofovir disoproxil fumarate; PI: Protease inhibitor; NNRTI: Non-nucleoside reverse-transcriptase inhibitor; INSTI: Integrase strand transfer inhibitor; ROS: Reactive oxygen species; NLRP3: Nod-like receptor protein 3; IL: Interleukin; JNK: Jun N-terminal kinase; P13K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; MetALD: Metabolic dysfunction-associated alcohol-related liver disease.

Lipodystrophy

Lipodystrophy further amplifies metabolic risk and remains a clinically relevant complication in aging PLWH despite declining incidence with modern ART. Characterized by peripheral lipoatrophy, central fat accumulation, or mixed phenotypes, HIV-associated lipodystrophy promotes insulin resistance and dysregulated lipid flux through increased visceral adiposity and adipose tissue inflammation[47]. Visceral fat expansion is particularly pathogenic, serving as a source of pro-inflammatory cytokines and free fatty acids that are delivered directly to the liver via the portal circulation, exacerbating hepatic lipid accumulation and oxidative stress[48]. Even in the absence of overt obesity, PLWH with lipodystrophy exhibit adverse adipokine profiles, including reduced adiponectin and elevated leptin levels, which further impair insulin sensitivity and promote steatogenesis[49].

Gut-liver axis

The gut-liver axis has also emerged as a central mechanistic link between HIV infection and metabolic liver disease, with HIV-associated intestinal dysbiosis and microbial translocation contributing to chronic hepatic inflammation and steatogenesis[50]. Even in the setting of sustained viral suppression with ART, PLWH exhibit persistent alterations in gut microbiota composition, characterized by reduced microbial diversity and depletion of beneficial commensals (e.g., Bacteroides and Faecalibacterium)[50,51]. These microbial shifts are accompanied by structural and functional impairment of the intestinal epithelial barrier, resulting in increased intestinal permeability and translocation of microbial products such as lipopolysaccharide (LPS) into the portal circulation[37]. Elevated circulating levels of LPS and other pathogen-associated molecular patterns (PAMPs) have been consistently observed in PLWH and are strongly associated with systemic immune activation, metabolic syndrome, and insulin resistance which are all key drivers of MASLD development[52].

Upon reaching the liver, translocated microbial products activate resident macrophages called Kupffer cells via pattern recognition receptors including toll-like receptor 4, triggering downstream inflammatory signaling cascades[53]. Kupffer cell activation promotes the release of pro-inflammatory cytokines such as TNF-α and IL-6 which exacerbate hepatic insulin resistance, stimulate de novo lipogenesis, and impair fatty acid oxidation within hepatocytes[54]. In PLWH, this inflammatory signaling is further amplified by baseline immune activation and ART-related metabolic effects, creating a permissive environment for hepatic lipid accumulation and progression from simple steatosis to steatohepatitis/fibrosis[55].

But while gut dysbiosis and microbial translocation are well documented in HIV infection, direct longitudinal evidence demonstrating that microbiome alterations independently drive MASLD progression in virologically suppressed PLWH is limited. Most of the above data remain purely associative and therefore future intervention studies targeting the microbiome in HIV-related MASLD and MetALD are needed.

Alcohol-metabolic synergy

Alcohol consumption and metabolic dysfunction act synergistically to accelerate liver injury in PLWH, even at alcohol intake levels previously considered low risk. There is strong biological plausibility regarding this association, supported by multiple experimental models in general liver disease populations. Alcohol metabolism generates reactive oxygen species through alcohol dehydrogenase, cytochrome P450 2E1, and mitochondrial pathways, resulting in oxidative stress, lipid peroxidation, and hepatocellular injury[30]. In parallel, metabolic dysfunction associated with visceral adiposity and insulin resistance promotes excess delivery of free fatty acids to the liver, further exacerbating mitochondrial overload and oxidative stress[56].

Beyond oxidative stress, alcohol-metabolic synergy also impairs hepatic regeneration and repair mechanisms, accelerating fibrosis progress in PLWH[57]. Chronic alcohol exposure disrupts hepatocyte proliferation by inhibiting growth factor signaling pathways, including hepatocyte growth factor and Wnt/β-catenin signaling, while promoting cellular senescence and apoptosis[57]. Metabolic dysfunction further impairs regenerative capacity through insulin resistance, lipotoxicity, and altered adipokine signaling, particularly reduced adiponectin and increased leptin levels which favor fibrogenesis over tissue repair[58]. In the context of HIV, Kupffer cell activation and microbial translocation-derived inflammation further suppress regenerative signaling and promote activation of hepatic stellate cells, leading to extracellular matrix deposition and fibrosis[53]. Clinical studies increasingly demonstrate that PLWH with both metabolic syndrome and hazardous alcohol use exhibit disproportionately higher rates of steatohepatitis and advanced fibrosis compared with those with either risk factor alone[59]. However, the precise quantification of incremental fibrosis risk attributable to alcohol intake in PLWH remains incompletely defined and warrants longitudinal studies. Figure 3 shows a mechanistic framework involving HIV-related mechanisms and their roles in driving MASLD/MetALD.

Figure 3 Human immunodeficiency virus-related mechanisms and their roles in metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated alcohol-related liver disease. The images were created using BioRender (Supplementary material). HIV: Human immunodeficiency virus; NRTI: Nucleoside reverse-transcriptase inhibitor; INSTI: Integrase strand transfer inhibitor; LPS: Lipopolysaccharide; PAMP: Pathogen-associated molecular pattern; MASLD: Metabolic dysfunction-associated steatotic liver disease; MetALD: Metabolic dysfunction-associated alcohol-related liver disease; TLR4: Toll-like receptor 4; IL: Interleukin; PLHW: People living with human immunodeficiency virus; ROS: Reactive oxygen species; CYP2E1: Cytochrome P450 2E1.

CLINICAL PRESENTATION AND DIAGNOSIS: NON-INVASIVE ASSESSMENT

Given the high and growing burden of MASLD and MetALD among PLWH, non-invasive tools for the detection of hepatic steatosis and fibrosis are essential for risk stratification and clinical decision-making. Liver biopsy, while considered the historical gold standard, is invasive, costly, and impractical for routine screening, particularly in PLWH who often have multiple comorbidities and require repeated assessments over time[2]. Therefore, contemporary clinical practice has increasingly relied on a combination of serum-based biomarkers and imaging-based studies to assess disease severity and progression in this population[2]. Importantly, interpretation of liver enzyme abnormalities in PLWH requires careful contextualization. Liver function tests elevations, for example, may reflect ART-related hepatotoxicity, viral hepatitis co-infection, opportunistic infections, or drug-induced liver injury[2]. Conversely, normal aminotransferase levels do not exclude advanced fibrosis. Therefore, reliance on liver enzymes to trigger evaluation may underestimate disease burden in PLWH.

Serum-based fibrosis scores such as the fibrosis-4 (FIB-4) index and the NAFLD fibrosis score are widely used first-line tools due to their accessibility and low cost. Several studies have demonstrated that FIB-4 retains reasonable accuracy in PLWH for identifying advanced fibrosis, though this precision may be influenced by HIV-related factors such as chronic inflammation, thrombocytopenia, and ART-associated transaminase elevations[60]. Importantly, recent guidelines emphasize the utility of FIB-4 scoring as an initial screening tool to rule out advanced fibrosis, followed by subsequently testing individuals with indeterminate or high scores[61]. Emerging biomarker panels incorporating markers of extracellular matrix turnover and apoptosis, such as the enhanced liver fibrosis testing, have shown promise in PLWH, although data remain more limited compared with HIV-negative populations[62]. At present, there is insufficient evidence to recommend alternative cutoff thresholds exclusively for PLWH, but clinicians should interpret indeterminate or borderline values within the broader clinical context rather than relying on calculated scores in isolation.

Imaging-based modalities play a central role in the non-invasive assessment of SLD in PLWH. Vibration-controlled transient elastography (VCTE) with CAP enables simultaneous quantification of liver stiffness and steatosis, and has been extensively validated in PLWH across diverse demographics[63]. CAP demonstrates good sensitivity for detecting hepatic steatosis, while liver stiffness measurement correlates with fibrosis stage and outcomes[63]. However, factors related to PLWH such as obesity, hepatic congestion, and inflammation may affect measurement reliability, necessitating careful interpretation[64]. Magnetic resonance-based techniques, including magnetic resonance imaging-proton density fat fraction and magnetic resonance elastography, offer superior accuracy for quantifying steatosis and fibrosis but remain limited by cost and availability[65]. Collectively, a stepwise, non-invasive approach integrating serum markers and elastography is ultimately recommended for PLWH with suspected MASLD or MetALD, allowing for early identification of high-risk individuals while minimizing the need for invasive procedures like liver biopsy[64,65].

Taking the above into consideration, a pragmatic stepwise screening approach would first include identifying at-risk individuals (type 2 diabetes, central adiposity, long-standing ART-associated weight gain, metabolic syndrome) and then calculating the FIB-4 score. If the FIB-4 score is between 1.3-2.67, then the risk would be deemed indeterminate and the patient can proceed to elastography[64,65]. If the FIB-4 score is greater than 2.67, however, a hepatology referral would be strongly warranted[64,65]. A VCTE can be performed if indicated (or if there is an indeterminate risk based on the FIB-4 score)[64,65]. An elevated VCTE stiffness in this scenario would qualify the patient for specialist evaluation[64,65]. This structured approach aligns with AASLD guidance while incorporating HIV-specific considerations.

MANAGEMENT STRATEGIES

Lifestyle interventions

Lifestyle modifications remain the cornerstone of management for MASLD and MetALD in PLWH. Weight reduction through calorie restriction and increased physical activity has been consistently associated with improvements in hepatic steatosis, cardiometabolic risk, and insulin sensitivity in both HIV-positive and HIV-negative populations, with evidence suggesting that a sustained weight loss of 7%-10% can lead to histologic and non-invasive improvements in steatosis and fibrosis[66]. Dietary patterns emphasizing reduced intake of saturated fats, refined carbohydrates, and fructose (such as the Mediterranean diet) have demonstrated beneficial effects on liver content and systemic inflammation and may be particularly advantageous in PLWH[67]. Regular exercise independently improves hepatic lipid metabolism and insulin signaling even in the absence of significant weight loss, highlighting its importance for patients who experience ART-related weight gain or lipodystrophy[68]. In the context of MetALD, alcohol reduction or abstinence is a critical therapeutic strategy, as even moderate alcohol intake may synergize with metabolic risk factors to accelerate fibrosis progression in PLWH[69]. However, counseling should recognize that alcohol use in PLWH may be influenced by mental health comorbidities, substance use disorders, and social determinants of health. Integration of addiction medicine, behavioral therapy, and social support services may be necessary for sustained risk reduction.

Pharmacologic therapies

Pharmacologic management of MASLD and MetALD in PLWH primarily targets the underlying metabolic dysfunction driving hepatic steatosis. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as particularly promising agents due to their potent effects on weight loss, insulin sensitivity, and hepatic fat reduction[70]. Randomized controlled trials in the general population have demonstrated that agents such as liraglutide and semaglutide significantly reduce liver fat content[70]. Notably, semaglutide has recently received Food and Drug Administration approval for the treatment of MASH with moderate to advanced fibrosis (F2-F3), representing a major therapeutic milestone for advanced MASLD[71]. Although PLWH have been underrepresented in MASLD-specific trials, observational studies suggest that GLP-1 RAs are effective and well tolerated in PLWH, including those receiving INSTI-based ART regimens associated with weight gain[72]. Given their favorable cardiovascular profile and efficacy in treating obesity and T2DM, GLP-1 RAs are particularly attractive for PLWH with coexisting cardiometabolic disease.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors represent another class of metabolic agents with potential benefit in MASLD and MetALD. In patients with T2DM, SGLT2 inhibitors have been shown to reduce hepatic steatosis, improve aminotransferase levels, and attenuate markers of systemic inflammation[73]. Importantly, these agents also provide cardiovascular and renal protection which is highly relevant for aging PLWH who face disproportionate risks of cardiovascular and kidney disease[73]. Early clinical studies suggest that SGLT2 inhibitors can be safely co-administered with contemporary ART therapies with no major drug-drug interactions[74].

Several emerging agents targeting key pathogenic pathways in MASLD may hold future relevance for PLWH. These include fibroblast growth factor analogs (e.g., pegbelfermin) and peroxisome proliferator-activated receptor agonists[75,76]. Resmetirom, a selective thyroid hormone receptor-β agonist, recently received Food and Drug Administration accelerated approval for the treatment of adults with MASH and moderate to advanced fibrosis (F2-F3)[77]. Although the efficacy of resmetirom in PLWH has not been fully established, a randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety profile of the drug in PLWH with MASLD is underway, underscoring the promising potential of this agent in a population with unique risk factors[78]. Conclusions from this study will be critical to expanding evidence-based therapeutic options for MASLD in this underserved demographic.

ART modification and multidisciplinary care model

In select patients with significant metabolic deterioration temporally associated with ART therapy, multidisciplinary discussion regarding ART regimen modification may be appropriate. However, switching ART solely to mitigate MASLD risk must be balanced against virologic stability and resistance considerations[43]. Therefore, ART modification should be individualized and coordinated with HIV specialists rather than applied broadly. These multifactorial considerations are therefore best approached in a multidisciplinary manner, involving hepatologists, endocrinologists, nutritionists, addiction medicine specialists, and HIV specialists. Such integration is particularly important given the overlapping cardiometabolic, psychosocial, and infectious considerations unique to medication modification in PLWH.

CONCLUSION

MASLD and MetALD have emerged as leading causes of chronic liver disease among PLWH, reflecting the convergence of traditional metabolic risk factors, HIV-related immune dysregulation, long-term ART therapy, and alcohol exposure. As life expectancy in PLWH continues to improve, the burden of noninfectious comorbidities such as SLD is increasing, with important implications for liver-related morbidity, cardiovascular risk, and mortality. Epidemiologic data consistently demonstrate a high global prevalence of MASLD in PLWH, while other studies underscore the roles of chronic inflammation, metabolic syndrome, gut-liver axis disturbances, and ART-associated metabolic effects in disease pathogenesis and progression. However, associations between HIV infection and accelerated fibrosis progression are frequently confounded by viral hepatitis co-infection, metabolic syndrome, ART class exposure, socioeconomic determinants and behavioral factors. Effective management of MASLD and MetALD in PLWH requires an integrated, multidisciplinary approach centered on early identification, non-invasive risk stratification, and individualized treatment of metabolic and behavioral risk factors. Lifestyle interventions remain paramount, while emerging pharmacological therapies targeting metabolic dysfunction offer promise to this population. Advancing this field is essential to mitigating the growing impact of SLD and improving long-term outcomes for PLWH.

Future research priorities should include longitudinal studies clarifying whether HIV independently accelerates fibrosis progression, validation of non-invasive fibrosis thresholds specific to PLWH, and evaluation of the impact of MASLD/MetALD reclassification on epidemiologic trends in PLWH. A nuanced, multidisciplinary, and evidence-based approach grounded in recognition of both metabolic drivers and HIV-specific modifiers will be critical to improving long-term outcomes in this unique population.