Steatotic liver disease in people with human immunodeficiency virus: A narrative review of metabolic steatotic liver disorders

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are increasingly recognized as relevant comorbidities among people living with human immunodeficiency virus (PLWH), even in the absence of viral hepatitis coinfection or significant alcohol consumption. As life expectancy in PLWH improves, the burden of metabolic complications has become a major clinical concern. This narrative review explores the key risk factors implicated in the development of MASLD and MASH in this population, highlighting the complex interplay between traditional metabolic disturbances, chronic human immunodeficiency virus-related inflammation, long-term antiretroviral therapy, and genetic susceptibility. Obesity, type 2 diabetes, and aging remain central contributors, while exposure to certain antiretroviral therapy agents, particularly older thymidine analogues, is associated with higher hepatic risk. In contrast, newer regimens, including integrase strand transfer inhibitors and combinations such as tenofovir disoproxil fumarate with rilpivirine, may offer metabolic or hepatic benefits. Genetic variants such as PNPLA3 and TM6SF2 further influence disease progression. The use of non-invasive diagnostic tools combining serum biomarkers and imaging techniques has shown promising utility in clinical practice. A comprehensive and individualized approach to risk stratification and management is essential to improve liver-related outcomes in PLWH and to mitigate the growing impact of MASLD and MASH in this vulnerable population.

Key Words: Human immunodeficiency virus; Metabolic dysfunction associated steatotic liver disease; Steatotic liver disease; Metabolic associated steatohepatitis; Screening; People living with human immunodeficiency virus; Antiretroviral therapy; Risk factors

Core Tip: Metabolic dysfunction-associated steatotic liver disease and steatohepatitis are increasingly prevalent in people living with human immunodeficiency virus, even in the absence of viral hepatitis or significant alcohol intake. This article summarizes current evidence on epidemiology, pathophysiology, and key risk factors, highlighting the interplay between chronic human immunodeficiency virus-related inflammation, antiretroviral therapy-induced metabolic changes, genetic susceptibility, and traditional cardiometabolic risk factors. We also discuss the clinical utility of non-invasive diagnostic tools and propose a practical, risk-adapted approach to screening and management aimed at improving liver-related outcomes in this growing and vulnerable population.

INTRODUCTION

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly referred to as non-alcoholic fatty liver disease (NAFLD), has recently been redefined to incorporate terminology that is more precise and less stigmatizing[1]. It is now recognized as a major public health concern, with an estimated prevalence exceeding 30% in adults[2], and is associated with severe hepatic complications (including steatohepatitis, cirrhosis, and hepatocellular carcinoma) as well as an increased risk of atherosclerotic cardiovascular disease[3].

People living with human immunodeficiency virus (PLWH) exhibit a heightened risk of developing MASLD and liver fibrosis[4], driven by metabolic alterations, antiretroviral therapy (ART)-related toxicity, and chronic inflammation associated with the viral infection. Reported prevalence ranges from 9% to 23% for MASLD and from 20% to 70% for hepatic steatosis of alternative etiologies without cardiometabolic risk factors[5].

Both MASLD and liver fibrosis are frequently asymptomatic, making early detection essential. Although liver biopsy remains the diagnostic gold standard[6], non-invasive methods (including ultrasonography, elastography, and serum biomarkers) have emerged as effective alternatives[7]. Given the substantial burden of MASLD in PLWH, further research is needed to clarify its true prevalence, underlying pathogenic mechanisms, and clinical implications.

The increasing prevalence of PLWH and MASLD has motivated the development of this narrative review. The aim is to provide recent and updated evidence to improve both diagnosis and management by the different specialists involved in the care of these patients. Electronic databases Embase, Ovid Medicine, and PubMed were searched from inception to October 2025 using multiple search queries. Combinations of the terms “steatotic liver disease”, “metabolic dysfunction-associated steatotic liver disease”, “metabolic dysfunction-associated steatohepatitis”, “MASLD and HIV”, “MASH and HIV” were used. We subsequently narrowed the results to clinical trials in human published within the last 10 years.

IMPORTANCE OF STEATOTIC LIVER DISEASE IN PEOPLE LIVING WITH HUMAN IMMUNODEFICIENCY VIRUS

A recent international consensus redefined the condition previously known as NAFLD, adopting the term MASLD to promote terminology that is more inclusive and less stigmatizing[1]. The updated nomenclature for fatty liver disease replaces NAFLD with MASLD and introduces the overarching term steatotic liver disease (SLD) to encompass all etiologies of hepatic steatosis[1]. This conceptual revision aims to more accurately reflect the underlying pathophysiology while eliminating the pejorative implications associated with the former designation.

MASLD is considered the hepatic manifestation of systemic metabolic dysfunction. It is characterized by the excessive accumulation of triglycerides within hepatocytes (steatosis) and, in a subset of patients, progression to inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma[8-10], as illustrated in Figure 1. Its pathogenesis is best described by a “multiple parallel hits” model, in which metabolic, genetic, environmental, and gut-liver axis alterations act concurrently, with oxidative stress playing a central role as both a trigger and an amplifier of hepatic and extrahepatic injury[11-13].

Figure 1 Progression of metabolic dysfunction-associated steatotic liver disease. Steatosis may progress nonalcoholic steatohepatitis with inflammation, subsequently to fibrosis through hepatic stellate cell activation, and ultimately promote the development of hepatocellular carcinoma, even in the absence of advanced fibrosis. NASH: Nonalcoholic steatohepatitis.

Alterations in hepatic lipid metabolism

The initial step involves an imbalance between lipid influx and efflux in the liver. Fatty acids reach the hepatocyte through adipose tissue lipolysis, dietary intake, and de novo lipogenesis from carbohydrates. Insulin resistance (IR) promotes increased peripheral lipolysis, while hyperinsulinemia stimulates de novo lipogenesis via sterol regulatory element-binding protein 1c and carbohydrate-responsive element-binding protein, whereas mitochondrial β-oxidation and the export of triglycerides in very low-density lipoprotein are insufficient[9,10]. The result is the accumulation of intrahepatic triglycerides (steatosis).

From steatosis to lipotoxicity and oxidative stress

Triglyceride deposition per se appears relatively innocuous; however, the accumulation of toxic lipid species (saturated fatty acids, diacylglycerols, ceramides) induces lipotoxicity, disrupts insulin signaling, and triggers endoplasmic reticulum stress and mitochondrial dysfunction[14,15].

In this article, the liver becomes a major source of reactive oxygen species (ROS). Masarone et al[16] highlight that the principal sources of ROS in NAFLD are: (1) The mitochondrial respiratory chain (overloaded by excess lipid substrates); (2) Peroxisomal β-oxidation; (3) Cytochrome P450 enzymes (particularly CYP2E1); and (4) NADPH oxidases located in hepatocytes and inflammatory cells.

When ROS production exceeds the capacity of antioxidant systems (superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione, vitamin E, etc.), a state of chronic oxidative stress is established. This results in lipid peroxidation, protein oxidation, and DNA damage (including mitochondrial lesions), thereby worsening hepatocellular energetic dysfunction and promoting cell death via apoptosis or necroptosis[16,17]. Lipid peroxidation products (such as malondialdehyde and 4-hydroxynonenal) additionally act as pro-inflammatory and pro-fibrotic signals.

Hepatic inflammation and innate immunity

Hepatocyte injury and death release damage-associated molecular patterns that activate Kupffer cells and other resident macrophages. Added to these are pathogen-associated molecular patterns, such as gut-derived lipopolysaccharide which reach the liver through the portal vein in the context of dysbiosis and increased intestinal permeability[11].

The combination of damage-associated molecular patterns, pathogen-associated molecular patterns, and ROS activates toll-like receptors and signaling pathways such as nuclear factor kappa B and c-Jun N-terminal kinase, inducing the production of pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-1β, interleukin-6) and chemokines, thereby recruiting neutrophils and monocytes. Masarone et al[16] emphasize that oxidative stress not only initiates inflammation but perpetuates it by sustaining these signaling pathways and by modifying lipids and proteins that become neoantigens, enhancing the immune response.

Gut-liver axis, microbiota, and ROS

Intestinal dysbiosis contributes to the development of NAFLD through altered production of metabolites (short-chain fatty acids, endogenous ethanol, etc.) and increased portal endotoxemia. These factors activate TLRs on hepatocytes and Kupffer cells, further increasing ROS production and inflammatory mediator release, thus closing a vicious cycle among microbiota, inflammation, and oxidative stress[17,18].

Genetics, epigenetics, and susceptibility to oxidative injury

Genetic variants such as PNPLA3, TM6SF2, MBOAT7, and HSD17B13 modulate hepatic fat accumulation and the susceptibility to inflammation and fibrosis[1,2,9]. Some of these variants directly alter lipid dynamics and mitochondrial function, influencing ROS production and the effectiveness of antioxidant defenses. Epigenetic mechanisms (DNA methylation, microRNAs), influenced by diet and environmental factors, further regulate key genes involved in lipid metabolism and oxidative stress[19,20].

Hepatic stellate ell activation and fibrosis

Oxidative injury and chronic inflammation lead to the activation of hepatic stellate cells, which transform into myofibroblasts that produce extracellular matrix components. Both pro-fibrotic cytokines (particularly transforming growth factor-β) and lipid peroxidation products derived from oxidative stress facilitate this activation[21]. The consequence is the progressive deposition of collagen and other matrix components, culminating in fibrosis, cirrhosis, and an increased risk of hepatocellular carcinoma[22].

Taken together, MASLD results from the interaction among systemic metabolic dysfunction, excessive and dysregulated hepatic lipid handling, lipotoxicity, inflammation, alterations in the gut-liver axis, and genetic-epigenetic susceptibility. The specific contribution of the article by Masarone et al[16] is to emphasize that, within this “multiple parallel hits” model, oxidative stress constitutes a central axis linking steatosis to inflammation, fibrosis, and extrahepatic complications, and therefore represents a key therapeutic target[23]. In people with human immunodeficiency virus (HIV), SLD results from the combined effects of HIV-related factors, ART, and classical metabolic risk determinants[24,25].

Chronic inflammation and immune activation in HIV

Even with suppressed viral load, many individuals with HIV maintain a state of low-grade chronic inflammation and persistent immune activation, which is associated with an increased risk of metabolic syndrome, IR, and alterations in glucose and lipid metabolism[25,26]. This enhances adipose tissue lipolysis, increases the flux of free fatty acids to the liver, and promotes the development of hepatic steatosis[25,27].

Direct effects of HIV on adipose tissue and hepatocytes

HIV can impair adipogenesis and the secretion of adipokines (such as leptin and adiponectin), altering communication between adipose tissue and the liver and promoting a pro-steatogenic and pro-inflammatory environment[24]. These abnormalities facilitate redistribution of body fat (with increased visceral and ectopic fat) and the deposition of triglycerides within the liver[28].

Mitochondrial and metabolic toxicity of certain antiretrovirals

Several antiretrovirals, particularly first-generation nucleoside reverse transcriptase inhibitors (NRTIs) (stavudine, didanosine, zidovudine), are associated with mitochondrial toxicity, inhibiting polymerase-γ and reducing the oxidative capacity of hepatocytes[29]. This decreases fatty acid β-oxidation, increases the production of ROS, and promotes intrahepatic fat accumulation[30].

Among currently used ART regimens, switching from tenofovir disoproxil fumarate to tenofovir alafenamide fumarate and, in particular, its combination with integrase strand transfer inhibitors appears to have the most significant impact on metabolic alterations by increasing IR, thereby accelerating the progression of the cascade that leads to metabolic syndrome, MASLD, and ultimately MASH over time[31].

HIV/ART-associated lipodystrophy

HIV/ART-associated lipodystrophy, characterized by peripheral lipoatrophy and central or visceral fat accumulation, has been described with several classical treatment regimens[32].

The ART drugs most clearly associated with classical lipodystrophy (particularly lipoatrophy) are: (1) Stavudine (d4T); (2) Didanosine (ddI); and (3) Zidovudine (AZT).

In the setting of mixed lipodystrophy syndrome (lipoatrophy + lipohypertrophy and metabolic disturbances), combination with older protease inhibitors (indinavir, nelfinavir, lopinavir/r) was particularly problematic.

This pattern is associated with a high-risk metabolic phenotype (IR, atherogenic lipid profile) and greater ectopic fat deposition, including hepatic fat, thereby increasing the likelihood of MASLD[32].

Gut-liver axis alterations and microbiota

HIV causes early injury to the intestinal mucosa and CD4+ T cells of the lamina propria, facilitating bacterial translocation and portal endotoxemia[27]. Together with dysbiosis, this enhances toll-like receptor activation in Kupffer cells and hepatocytes, stimulates the production of pro-inflammatory cytokines and ROS, and favors progression from simple steatosis to nonalcoholic steatohepatitis (NASH) and fibrosis[33].

Convergence with classical metabolic risk factors

To all these HIV- and ART-specific mechanisms, one must add classical metabolic factors (obesity, type 2 diabetes, hypertension, dyslipidemia), which are highly prevalent in this aging population[24]. The convergence of metabolic dysfunction, chronic inflammation, mitochondrial toxicity, lipodystrophy, and gut-liver axis disturbances explain the high burden of SLD, MASLD, and significant fibrosis among people with HIV[25,34].

For all these reasons, MASLD has become one of the leading causes of chronic liver disease in the general population. According to Younossi et al[35], approximately 38% of adults and 7%-14% of children/adolescents have MASLD in contemporary population-based studies; moreover, MASLD prevalence in adults is projected to exceed 55% by 2040, driven by the rising prevalence of obesity, type 2 diabetes, and metabolic syndrome.

Although not all patients with MASLD progress to advanced stages, the clinical burden is substantial. Among individuals with MASLD, a fraction (e.g., 3%-5% according to some models) may advance to cirrhosis over decades[36]. Concurrently, overall mortality in MASLD is more frequently associated with cardiovascular disease than with liver-related causes[37,38].

Recent studies indicate that the burden of SLD in people living with HIV remains very high even in the era of effective ART, with a substantial proportion of patients maintaining virologic suppression. In a large multicenter cohort of 1065 PLWH in the United States, in which 74% had undetectable HIV RNA, the prevalence of SLD reached 52%, meaning approximately half of all participants. Within this group, the predominant category was MASLD (39%), followed by metabolic dysfunction-associated alcohol-related liver disease (10%) and alcohol-associated liver disease (3%), indicating that most cases of SLD in PLWH are related to metabolic dysfunction, whereas only a minority are attributable primarily to alcohol use[4].

At the same time, advances in ART have transformed HIV into a chronic condition with increasing life expectancy and, consequently, a growing global prevalence. This therapeutic success has shifted the clinical profile of HIV from infectious complications toward chronic non-communicable comorbidities, particularly metabolic, cardiovascular, and hepatic disorders. Thus, the sustained increase in the number of people living with HIV poses new public health challenges focused on the comprehensive management of an aging population with a heightened risk of metabolic diseases such as MASLD, requiring a multidisciplinary and preventive approach[39].

Additionally, HIV infection (even when viral load is suppressed) entails persistent immune activation, oxidative stress, mitochondrial dysfunction, and chronic inflammation, mechanisms that may predispose the liver to a more aggressive response to metabolic insults[40].

Multiple studies and meta-analyses have estimated that the prevalence of MASLD in people with HIV is high, with variations according to geographic region, diagnostic criteria, and cohort characteristics. For example, a recent meta-analysis found MASLD prevalences of 33%-43% among PLWH, while the prevalence of significant fibrosis in these patients was approximately 24.6%[41]. This figure is particularly concerning, as it indicates that nearly one in four patients with this diagnosis already exhibit relevant structural liver damage. By comparison, some estimates in the general population suggest a lower prevalence of significant fibrosis (around 7%), although these comparisons vary depending on risk profile and methodology[2,35].

Recent research also shows that metabolic dysfunction and weight gain have become key determinants of fibrosis progression in PLWH, independent of hepatotropic viral coinfection or the specific antiretroviral regimen used[42].

In a multicenter cohort study involving 1183 individuals with HIV, the baseline prevalence of significant fibrosis was 14.4%, and MASLD was present in 46.8%. During a median follow-up of 2.5 years, rates of fibrosis progression and regression were 2.8 and 2.2 per 100 person-years, respectively. Major factors associated with fibrosis progression included weight gain and the presence of MASLD, whereas regression was less likely in men and in those who experienced weight gain. These findings indicate that transitions across fibrosis stages are strongly influenced by metabolic variables rather than virologic or pharmacologic factors[40].

Similar findings are reported in a cross-sectional study of 361 people with HIV, where 39.1% had MASLD. Notably, nearly 70% of participants had a body mass index (BMI) below 24 kg/m², highlighting the relevance of the so-called lean MASLD phenotype[38]. In this group, the prevalence of significant fibrosis was high, reaching 48.3% among individuals with normal weight and MASLD, and 56.6% among those who were overweight. Independent risk factors for significant fibrosis included elevated aminotransferases and type 2 diabetes; furthermore, in the lean MASLD subgroup, a possible association with non-NRTI (NNRTI) use was identified[43]. These findings underscore that metabolic liver disease in HIV is not limited to individuals with obesity, and that clinically relevant liver injury may occur even in those with normal weight.

Finally, a recent systematic review protocol and meta-analysis highlights the need to synthesize global evidence on the prevalence of MASLD in individuals with HIV receiving ART. This work is grounded in the recognition that metabolic-associated liver disease is currently the most frequent cause of liver pathology worldwide and, in the context of HIV, represents a growing challenge linked to an aging population, treatment-induced metabolic alterations, and lifestyle factors[44].

Taken together, these studies reinforce the importance of incorporating routine liver screening into the care of people living with HIV, even in the absence of overweight or obesity. Liver elastography, along with the evaluation of metabolic parameters, should form part of clinical practice to enable early detection of fibrosis and guide interventions aimed at weight reduction, glycemic control, and optimization of ART. In the era of effective ART, liver disease (particularly associated with metabolic dysfunction) has emerged as a key component of long-term risk in people with HIV, requiring an integrated approach that combines hepatologic and metabolic care with HIV management.

RISK FACTORS INVOLVED IN THE DEVELOPMENT OF MASLD AND MASH IN PLWH

Another important finding is that, in people with HIV, hepatic steatosis may manifest even at relatively low BMI (“lean MASLD”), suggesting that classical metabolic factors are not the only contributors. In the cited meta-analysis, several studies documented that individuals with HIV and NAFLD had a lower BMI than HIV-negative patients, and that central obesity or elevated triglycerides were more consistent predictors[45]. HIV- and ART-specific factors also emerge as modulators of risk: Prolonged exposure to certain antiretrovirals (with mitochondrial toxicity or effects on lipid metabolism), fat redistribution (lipodystrophy), ART-induced dyslipidemia, and IR constitute plausible contributors to the etiology of MASLD in this context[46].

Thus, HIV may modify the natural history of fatty liver disease: It has been proposed that fibrosis progression may occur more rapidly or with a lower threshold of risk factors, although prospective data remain limited[47]. Many MASLD studies have systematically excluded individuals with HIV, resulting in underrepresentation of this group in clinical trials of antifibrotic and metabolic therapies and creating significant knowledge gaps regarding disease evolution.

The interaction between HIV infection and MASLD as concomitant syndromes -described as a “syndemic” (constitutes another relevant phenomenon. In this context, social determinants of health including stigma, unequal access to care, and psychosocial comorbidities) may amplify metabolic trajectories and hepatic injury in PLWH[42]. Accordingly, research and public health strategies must consider not only biological mechanisms but also structural factors that influence prevention, diagnosis, and treatment, often in unequal ways.

A range of clinical, metabolic, and ART-related factors significantly contribute to the development and progression of hepatic fibrosis in PLWH, even in the absence of overt obesity. Recent evidence indicates that MASLD has become a central determinant of liver injury in this population, progressively replacing viral coinfections as the primary driver of hepatic morbidity[48,49]. In a cross-sectional study including 361 PLWH without hepatotropic viral coinfection or excessive alcohol intake, 39.1% presented MASLD and, among them, 53.2% showed significant fibrosis (liver stiffness measurement ≥ 7.1 kPa). Notably, clinically relevant liver injury was observed both in overweight individuals (56.6%) and in those with normal weight (the lean MASLD phenotype) where the prevalence of fibrosis reached 48.3%[48].

In that study, type 2 diabetes mellitus [odds ratio (OR) = 5.45; 95% confidence interval (CI): 1.33-22.36] and elevated alanine aminotransferase (ALT) (OR = 1.03; 95%CI: 1.02-1.05) were independently associated with significant fibrosis[48]. Among overweight subjects, these factors retained predictive value, whereas in the lean group, elevated aspartate aminotransferase (OR = 1.22; 95%CI: 1.07-1.38) and the use of NNRTIs (OR = 7.53; 95%CI: 1.49-37.98) were independently associated with advanced fibrosis[48].

These findings support the hypothesis that, in addition to metabolic dysfunction, exposure to certain antiretroviral agents may contribute to liver injury, particularly among individuals with normal weight. Factors associated with the lean MASLD phenotype included prior exposure to zidovudine, the presence of metabolic syndrome components, older age, higher BMI values within the normal range, and elevated ALT[48]. Overall, these data suggest that hepatic susceptibility in the context of HIV does not depend solely on excess body weight but rather on a complex interaction of metabolic dysfunction, ART exposure, and aging.

Complementarily, a larger multicenter longitudinal study confirmed the high frequency of dynamic changes in hepatic fibrosis among PLWH[2]. In this cohort, nearly half of participants (48.5%) presented MASLD, and fibrosis progression occurred at an incidence of 2.8 per 100 person-years, while regression was less frequent (2.2 per 100 person-years), rates lower than those described in HIV-negative populations. The main determinants of progression were overweight, weight gain, and the presence of MASLD, while both weight gain and male sex were associated with a reduced likelihood of fibrosis regression. In contrast, treated viral coinfections and contemporary ART regimens did not show a significant relationship with fibrosis evolution[2].

Within this framework, weight gain in PLWH emerges as a central risk factor with a dual role: It is associated with fibrosis progression and decreases the probability of fibrosis regression. Although this phenomenon may partly reflect a “return-to-health” effect following ART initiation (particularly in individuals with advanced HIV infection) the persistence and magnitude of weight gain suggest deeper metabolic and cellular alterations. It has been proposed that integrase strand transfer inhibitors may promote increased fat mass, lipogenesis, IR, and oxidative stress, although evidence regarding their direct impact on fibrosis progression remains heterogeneous[50]. Additionally, prior exposure to dideoxynucleoside analogues (d-nucleosides) has been linked to lipodystrophy and residual metabolic dysfunction, factors that may sustain an unfavorable metabolic phenotype even after discontinuation of these drugs[51,52].

Added to these therapeutic determinants are host-related factors, such as older age and male sex, both associated with increased risk of progression and lower capacity for fibrosis regression. The latter association may be partially mediated by the hepatoprotective effect of estrogens in women, previously described in the pathophysiology of chronic liver disease[53]. Collectively, findings from both studies indicate that type 2 diabetes mellitus, IR, weight gain, overweight, male sex, older age, and exposure to specific antiretroviral agents represent the main determinants of hepatic fibrosis progression in PLWH. Far from being an isolated phenomenon, hepatic fibrosis in the context of HIV should be understood as a manifestation of metabolic syndrome, whose prevalence increases as survival improves thanks to ART.

In parallel, several studies have described the risk factors implicated in the development of MASLD and its progressive form, MASH, in this population, underscoring the complex interplay between traditional metabolic disturbances, HIV-related chronic inflammation, prolonged ART exposure, and genetic susceptibility[54-57].

DIAGNOSIS AND NON-INVASIVE TESTING

On the one hand, both MASLD and hepatic fibrosis are typically asymptomatic until advanced stages. On the other hand, the prevalence of MASLD in this population is high and may occur even at lower BMI than in the general population, representing the most frequent cause of transaminase elevation in the absence of viral hepatitis or excessive alcohol intake. Therefore, early detection is crucial to prevent irreversible complications and major cardiovascular events. Although liver biopsy remains the reference standard for the diagnosis and staging of liver disease[58], its invasive nature limits its routine use. Consequently, the use of non-invasive methods has increased, including ultrasound, computed tomography, and magnetic resonance imaging, together with serum biomarkers and elastography techniques, all of which have shown adequate diagnostic accuracy even in people with HIV[59].

Abdominal ultrasound is the recommended initial tool for detecting hepatic steatosis due to its wide availability and low cost. However, its sensitivity decreases in cases of mild fat infiltration[60,61]. For more precise quantification of hepatic lipid content -particularly in specialized centers - advanced techniques such as magnetic resonance imaging-proton density fat fraction or magnetic resonance spectroscopy may be employed, although their use is generally restricted to research settings and clinical trials[61].

For fibrosis risk stratification, serological methods remain first-line tools. The fibrosis-4 (FIB-4) and the NAFLD fibrosis score have demonstrated a high negative predictive value and good specificity for ruling out advanced fibrosis, particularly in people with HIV, thereby reducing the need for additional assessments in most cases[62,63]. When the FIB-4 exceeds the threshold of 1.3, complementary evaluation with transient elastography (FibroScan) is recommended, as it allows non-invasive measurement of liver stiffness and estimation of steatosis through the controlled attenuation parameter (CAP)[64,65].

In studies focused on people with HIV, the combination of elevated CAP values (≥ 248 dB/m) and serum markers such as cytokeratin-18 has shown strong correlation with the histological diagnosis of NASH[64]. Additionally, indices such as the liver fat score and the lipid accumulation product have been validated in this population, demonstrating favorable diagnostic performance for detecting steatosis[66,67].

In addition to transient elastography, several other elastography techniques are currently available for the assessment of liver stiffness. Although magnetic resonance elastography is the modality with the highest diagnostic accuracy, its use is limited - due to its scarce availability relative to the number of patients - to clinical trial settings, severe obesity, and cases of elastography technique failure[68]. Shear wave elastography (SWE) is an increasingly widespread technique available on modern ultrasound systems. It is based on the generation of shear waves within the hepatic tissue by means of a focused acoustic pulse. This pulse, produced by the ultrasound transducer, induces a small deformation in the hepatic parenchyma, generating shear waves that propagate laterally through the tissue. The propagation velocity of these shear waves is directly proportional to tissue stiffness; that is, the greater the stiffness, the higher the wave velocity. As with FibroScan, the results are reported in kilopascals (kPa) and may also be expressed in meters per second (m/second)[69,70].

Two types of SWE are available. One is known as point SWE, also referred to as acoustic radiation force impulse. This technique employs acoustic pulses at a specific point within the hepatic parenchyma or operator-selected region of interest (ROI). The other technique is termed two-dimensional SWE. This method also analyzes an operator-selected ROI, but uses a larger, adjustable ROI, allowing assessment of a broader area and providing a more extensive representation of the hepatic parenchyma[71,72]. These techniques are already included in clinical practice guidelines[73] and offer several key advantages, including integration within ultrasound systems, the ability to select the analysis area, and improved utility in patients with obesity and ascites. Nonetheless, it is important to consider the requirement for an ultrasound device equipped with the appropriate software, operator experience and interobserver variability, as well as differences in cutoff values across various models and manufacturers[74,75].

Taken together, the recommended non-invasive approach incorporates ultrasound as the initial test, followed by calculation of the FIB-4 or NAFLD fibrosis score, and performance of elastography with CAP when serological results do not allow advanced fibrosis to be ruled out. This stepwise strategy, endorsed by the Infectious Diseases Society of America[76], reserves liver biopsy for situations in which diagnostic uncertainty persists or advanced NASH is suspected.

Although no universal consensus exists regarding screening in the general population, the European Acquired Immunodeficiency Syndrome Clinical Society recommends systematic assessment of liver disease in PWH with risk factors (including overweight, metabolic syndrome, persistent ALT elevation, or exposure to d-drugs) using ultrasound or serum biomarkers[77].

GENETIC VARIANTS WITH A KEY ROLE IN THE PROGRESSION OF MASLD IN PLWH

Genetic variants play a key role in the progression of MASLD in people with HIV. Among them, the PNPLA3 G variant (rs738409) stands out as the major risk determinant, consistently associated with a higher likelihood of steatohepatitis and fibrosis[78]. In contrast, TM6SF2 (rs58542926) has not shown a significant association with steatosis or steatohepatitis in HIV populations, despite its well-established relevance in the general population[79,80]. The utility of these variants is oriented more toward prognostic stratification than direct diagnosis.

In addition to PNPLA3 and TM6SF2, other variants contribute to MASLD progression: MBOAT7 (rs641738) and GCKR (rs1260326) have been linked to increased risk of fibrosis and cirrhosis[81], whereas HSD17B13 (rs72613567: TA) and MTARC1 (AA) confer protective effects against disease progression[82,83]. Likewise, genes such as SIRT5 (rs12216101) and others involved in lipid remodeling - including VKORC1, LYPLAL1, and GPAM - have emerged as additional modulators of risk[84,85]. The American Association for the Study of Liver Diseases recognizes MBOAT7, GCKR, and HSD17B13, alongside PNPLA3 and TM6SF2, as the principal genetic determinants of disease progression in MASLD[86].

The incorporation of these variants into polygenic scores has been shown to improve prediction of advanced fibrosis and cirrhosis, surpassing the performance of each individual marker[87]. Although genotyping does not replace recommended non-invasive methods, it may assist in identifying subgroups of people with HIV and MASLD who require more intensive monitoring.

TREATMENT AND CHANGES IN PATIENT MANAGEMENT WITH AND WITHOUT MASLD

The management of ART in people with HIV who present with MASLD requires specific considerations that differ from those applied in individuals without this condition. Regarding the selection of the ART regimen, patients with MASLD benefit from treatments with a more favorable metabolic and hepatotoxicity profile. Older nucleoside analogues (particularly stavudine, didanosine, and zidovudine) should be avoided due to their association with an increased risk of hepatic steatosis and mitochondrial toxicity. Instead, combinations based on tenofovir alafenamide fumarate/emtricitabine, integrase inhibitors, or next-generation NNRTIs are generally preferred, given their more favorable metabolic and hepatic profile[34]. In contrast, individuals without MASLD may receive standard first-line regimens recommended by current guidelines, as the risk of ART-induced steatosis is lower.

Clinical monitoring also differs between these groups. In patients with MASLD, closer surveillance is required, including frequent measurement of liver enzymes, non-invasive fibrosis tests such as FIB-4 and transient elastography, as well as regular monitoring of metabolic parameters such as plasma lipids and glucose, given their higher risk of hepatic progression and associated comorbidities. Conversely, in individuals without MASLD, routine monitoring recommended for standard HIV care (focused on basic liver function, viral load, and CD4 count) may be followed[88,89].

Management of comorbidities is of particular importance in people with MASLD. These individuals require intensive control of metabolic syndrome, actively addressing obesity, diabetes, dyslipidemia, and hypertension. In selected cases, adjunctive therapies targeting MASLD or MASH may be considered, such as glucagon-like peptide-1 (GLP-1) agonists, sodium-glucose cotransporter 2 inhibitors, or resmetirom, recently approved by the Food and Drug Administration for MASH with significant fibrosis, although it has not yet been specifically evaluated in the HIV population. While PLWH without MASLD should receive general recommendations on healthy lifestyle habits[88], those with MASLD should receive more targeted lifestyle guidance[90,91].

The first step in all patients with MASLD involves lifestyle interventions. It is essential to emphasize the need to achieve significant weight reduction, with a therapeutic goal of at least ≥ 5% of body weight to reduce hepatic steatosis. Weight loss of 7%-10% leads to improvement in inflammation, while reductions ≥ 10% can reverse or stabilize hepatic fibrosis. The Mediterranean diet and regular physical exercise are the first-line treatment recommendations for these patients[81,92,93]. Unfortunately, fewer than 10% are able to maintain such weight loss long term. Most patients neither achieve nor maintain these goals after one year of structured intervention, and fewer than half of those who succeed maintain the weight loss at five years[68].

As a result of the limited effectiveness of lifestyle modifications alone, pharmacologic therapy is often necessary. GLP-1 receptor agonists and dual GLP-1/glucose-dependent insulinotropic polypeptide agonists such as tirzepatide provide substantial benefits in MASLD, particularly in patients with lipid dysfunction. Meta-analyses and systematic reviews show that GLP-1 agonists (semaglutide, liraglutide, dulaglutide) significantly reduce hepatic fat content, improve liver histology, and decrease transaminases, in addition to exerting favorable effects on lipid profiles and body weight[94,95]. However, dual agonists such as tirzepatide demonstrate superior efficacy in reducing hepatic fat and resolving MASH, as well as greater weight reduction and improved insulin sensitivity, which may be especially relevant in individuals with dyslipidemia and IR[96,97]. Selection should be based on the degree of obesity, presence of diabetes, lipid profile, and need for weight reduction. Both semaglutide and tirzepatide have demonstrated MASH resolution and reduction of hepatic fibrosis[98]. Semaglutide is preferred in patients at high cardiovascular risk, whereas tirzepatide has shown more pronounced weight reduction[91,99].

Another option for the management of MASLD is bariatric surgery. Current indications recommend bariatric surgery in patients with MASLD and obesity (BMI > 35 kg/m²), particularly when lifestyle interventions or pharmacotherapy fail to achieve sufficient response[100]. The procedures with the best outcomes include Roux-en-Y gastric bypass and sleeve gastrectomy. Randomized clinical trials and prospective studies demonstrate rapid and sustained improvement in steatosis, inflammation, and fibrosis, with significant reductions in major hepatic events (progression to cirrhosis, hepatocellular carcinoma, liver transplantation, hepatic mortality) and long-term cardiovascular events[91,101,102]. Surgery should be avoided in decompensated cirrhosis and performed cautiously in compensated cirrhosis, preferably in specialized centers with multidisciplinary teams. In patients with compensated cirrhosis, the postoperative risk of decompensation is similar to that of patients with less advanced liver disease, provided the procedure is performed by experienced surgeons[99,103]. However, with the emergence of agents such as tirzepatide, current data on bariatric surgery require reassessment in comparison with these therapies.

When surgery is contraindicated, or when considering patient preferences, endoscopic management is an alternative. Techniques such as intragastric balloon placement or endoscopic sleeve gastroplasty offer less invasive alternatives to bariatric surgery and have demonstrated efficacy in weight reduction and improvement of hepatic parameters in the short and intermediate term. Nonetheless, histological improvement of fibrosis remains limited, as sustained weight loss > 10% is required to achieve this goal[68,101].

Finally, given the context of hepatotoxic risk and drug-drug interactions, patients with MASLD require heightened surveillance owing to their increased susceptibility to liver injury. Dose adjustments or ART regimen modifications are frequently necessary when hepatic function deteriorates, and potential pharmacological interactions should be assessed with greater rigor. In individuals without MASLD, these precautions follow standard clinical practice given the lower risk of ART-associated hepatic complications[34].

In summary, the main differences in antiretroviral management between patients with and without MASLD lie in the careful selection of ART regimens to minimize hepatotoxicity and metabolic disturbances, the need for closer monitoring of hepatic and metabolic parameters, and the intensive management of metabolic comorbidities and lifestyle factors. In patients with MASLD, older NRTIs should be avoided and regimens with more favorable metabolic and hepatic profiles prioritized, alongside consideration of Food and Drug Administration-approved adjunctive therapies for MASH in selected cases, although evidence in HIV remains limited. Management should be multidisciplinary and tailored to individual risk, whereas individuals without MASLD may follow the standard recommendations outlined in HIV treatment guidelines. To present this information in a clear and visual manner, Figure 2 illustrates a proposed approach to the management and follow-up of these patients.

Figure 2 Summary of the main differences in antiretroviral therapy selection, monitoring, and treatment modifications in patients with and without metabolic dysfunction-associated steatotic liver disease. TAF: Tenofovir alafenamide fumarate; FTC: Emtricitabine; NNRTIs: Non-nucleoside reverse transcriptase inhibitor; MASLD: Metabolic dysfunction-associated steatotic liver disease; GLP-1RA: Glucagon-like peptide-1 receptor agonists; SGLT2i: Sodium-glucose cotransporter 2 inhibitors; ART: Antiretroviral therapy; HIV: Human immunodeficiency virus.

CONCLUSION

In conclusion, MASLD has become a leading cause of chronic liver disease in people living with HIV, driven primarily by metabolic dysfunction, chronic inflammation, ART-related toxicity, and genetic susceptibility. The high prevalence of MASLD and significant fibrosis, even in phenotypes with normal BMI (lean MASLD) and its strong association with diabetes, weight gain, and metabolic syndrome indicate that metabolic determinants outweigh virologic factors in driving liver injury progression in this population. In this context, systematic screening through stepwise non-invasive strategies (combining ultrasound, serum fibrosis scores, and elastography with CAP (particularly transient elastography and SWE) which together provide accurate, scalable alternatives to biopsy for identifying individuals at risk of advanced liver disease) and intensive management of cardiometabolic risk factors are essential to prevent progression to cirrhosis and hepatocellular carcinoma. Moreover, careful selection of ART (avoiding older NRTIs and prioritizing regimens with more favorable metabolic and hepatic profiles) intensified metabolic and hepatic monitoring, targeted lifestyle measures, and consideration of pharmacologic options such as GLP-1 receptor agonists and dual GLP-1/glucose-dependent insulinotropic polypeptide agonists to mitigate hepatotoxicity and disease progression should be integrated into a multidisciplinary, risk-adapted approach.