Metabolic Dysfunction-Associated Steatotic Liver Disease in People Living with HIV: A Scoping Review

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously called non-alcoholic fatty liver disease (NAFLD), has become a leading cause of chronic liver disease in people living with HIV (PLWH), especially in the era of effective antiretroviral therapy (ART). As the life expectancy of PLWH continues to increase, non-AIDS-related comorbidities such as metabolic syndrome, insulin resistance, and cardiovascular disease have become more prevalent, contributing to a rising incidence of MASLD and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH). Studies have shown that the prevalence of MASLD in PLWH ranges from 30% to 50%, with biopsy-based estimates of non-alcoholic steatohepatitis (NASH) approaching 49% and advanced fibrosis up to 23%. This burden is influenced not only by traditional metabolic risk factors but also by HIV-specific mechanisms, including chronic immune activation, lipodystrophy, microbial translocation, and mitochondrial dysfunction associated with ART exposure. Despite its high prevalence and clinical significance, MASLD remains underdiagnosed in PLWH. This scoping review aimed to systematically map the existing literature on MASLD in people living with HIV, including epidemiology, risk factors, diagnostic approaches, fibrosis assessment, and management strategies. Understanding the unique interplay between HIV infection and metabolic liver disease is essential for the early diagnosis and prevention of progression to cirrhosis and hepatocellular carcinoma in this growing patient population.

1. Introduction

Metabolic dysfunction-associated steatotic liver disease (MASLD) is defined as the presence of hepatic steatosis (fat accumulation in the liver) in conjunction with one or more cardiometabolic risk factors (CMRFs) and the absence of other discernible causes of liver steatosis [1]. CMRFs include conditions such as obesity, type 2 diabetes mellitus (T2DM), dyslipidemia, hypertension, and metabolic syndrome (MetS). The disease spectrum of steatotic liver disease (SLD) ranges from simple steatosis to more severe forms like metabolic dysfunction-associated steatohepatitis (MASH), formerly non-alcoholic steatohepatitis (NASH), which can progress to fibrosis, cirrhosis, and hepatocellular carcinoma [2]. MASLD is important from a public health standpoint due to its high prevalence, association with severe comorbidities, and substantial economic burden [3].

The shift from non-alcoholic fatty liver disease (NAFLD) to MASLD reflects both scientific and social considerations. The term non-alcoholic was seen as stigmatizing and failed to capture the central role of metabolic dysfunction. The new nomenclature better reflects etiology and removes negative terminology, while ensuring near-complete overlap with previously defined NAFLD populations [4]. The transition represents an important conceptual shift that emphasizes the underlying metabolic drivers of hepatic steatosis while reducing the stigma associated with prior terminology. This change is particularly relevant for people living with HIV, in whom metabolic dysfunction frequently coexists with chronic inflammation, immune dysregulation, and antiretroviral therapy-related effects, contributing to steatosis even in the absence of traditional risk factors. Given the recent name change to MASLD, the data discussed in this review includes prior literature on NAFLD.

People living with HIV (PLWH) constitute a growing demographic of aging individuals, with an estimated 1.2 million persons in the United States living with HIV infection according to latest data from the Centers for Disease Control and Prevention [5,6,7]. Owing to longer survival rates with antiretroviral therapy (ART), PLWH are increasingly affected by non-AIDS-related comorbidities, including cardiovascular diseases, metabolic disorders, liver diseases, renal diseases, and neurocognitive disorders [8,9]. Among these, MASLD has emerged as a significant and underrecognized cause of chronic liver disease [10]. Recognizing MASLD in PLWH is crucial, given its association with increased risk of fibrosis progression, cardiovascular disease, and mortality. Importantly, HIV-related factors, such as systemic inflammation, ART exposure, and lipodystrophy, may alter disease presentation compared to the general population.

The existing evidence on MASLD in people living with HIV is broad but highly heterogeneous, spanning cross-sectional and cohort designs across North America, Europe, Asia, and Latin America and reflecting distinct ART eras and population risk profiles. Reported prevalence and disease severity vary substantially because studies rely on different case definitions (NAFLD, MAFLD, MASLD) and non-uniform diagnostic strategies, ranging from ultrasound, computed tomography (CT), vibration-controlled transient elastography (VCTE)/controlled attenuation parameter (CAP), and magnetic resonance imaging (MRI)-based techniques to liver biopsy in selected cohorts. This variability in methodology and ascertainment limits direct comparability and supports a scoping review approach to map the evidence landscape and identify gaps suitable for future focused systematic reviews.

2. Methods

This review was conducted as a scoping review to map the breadth and characteristics of the existing literature on MASLD in PLWH. Consistent with methodological guidance for scoping reviews, the review was framed using the Population Concept Context (PCC) framework, as the objective was to characterize the scope, heterogeneity, and key concepts of the available evidence, rather than to evaluate the effect of a specific intervention [11].

The population of interest was PLWH; the concept encompassed metabolic syndrome and steatotic liver disease, including hepatic steatosis, NAFLD/MASLD, and non-alcoholic steatohepatitis (NASH/MASH); and the context included observational and interventional studies across clinical and geographic settings.

A literature search of PubMed and Google Scholar was performed to identify relevant studies. Medical Subject Headings (MeSH) and keyword combinations included MASLD or NAFLD; NAFLD and HIV; NAFLD etiology; liver cirrhosis/pathology; and liver cirrhosis/physiopathology. Studies were eligible if they evaluated MASLD/NAFLD in PLWH using non-invasive diagnostic approaches such as VCTE, CAP, MRI-based techniques (including MR elastography and MRI-PDFF), computed tomography, ultrasound, or validated indices of hepatic steatosis, or if they reported histologic prevalence of NASH using established scoring systems. Studies examining prevalence, associated metabolic and HIV-specific risk factors, and the relationship between steatosis, NASH, and fibrosis in PLWH were included. Studies primarily focused on alcohol-associated liver disease were excluded. A prior protocol was not registered.

Study selection was conducted through title and abstract screening, followed by full-text review for eligibility. The selection process is reported narratively and summarized using a PRISMA-ScR flow diagram, in accordance with recommended reporting standards for scoping reviews (Supplementary Figure S1).

Data extraction (charting) was performed using a standardized approach. Extracted fields included study design, geographic setting, sample size, population characteristics, ART era and regimen (when available), diagnostic modality and disease definition used, prevalence estimates, associated risk factors, and fibrosis or histologic outcomes where reported. The results were synthesized using descriptive mapping to summarize patterns across studies; no quantitative pooling or meta-analysis was performed.

Consistent with scoping review methodology, formal risk-of-bias or quality appraisal was not undertaken, as the primary aim was to map the extent and nature of the evidence base rather than to generate a clinically definitive estimate or recommendation.

3. Results

Sixty-six articles were reviewed, including those from across the United States, France, Canada, Japan, Taiwan, Spain, Italy, Australia, Brazil, and Greece (Supplementary Table S1). NAFLD was diagnosed with MR spectroscopy in 3 studies, CT in 4 studies, ultrasound in 4 studies, and VCTE/CAP in 5 studies, hepatic steatosis index in 1 study, various imaging modalities in 1 study, and biopsy in 1 study. NASH was diagnosed via liver biopsy in 19 studies, and various histological scoring systems were utilized, including Brunt, Ishak, NASH-CRN, Scheuer, Batts-Ludwig, and METAVIR scores [12].

3.1. Metabolic Syndrome in HIV

Metabolic syndrome (MetS) is a cluster of interrelated risk factors that significantly increase the risk of cardiovascular disease (CVD), T2DM, and other health complications. The most widely accepted definition, as proposed by an international consortium of cardiovascular and diabetes organizations, includes the presence of any three of the following five criteria: 1. Elevated waist circumference (indicative of abdominal obesity); 2. Elevated serum triglycerides (≥150 mg/dL); 3. Reduced HDL cholesterol (<40 mg/dL for men and <50 mg/dL for women); 4. Elevated blood pressure (≥130/≥85 mm Hg); 5. Elevated fasting glucose (≥100 mg/dL) [13,14,15].

The prevalence of MetS in patients with HIV is approximately 25.3% globally, as reported in a recent systematic review and meta-analysis [16]. This prevalence is notably higher in individuals on ART, with a pooled prevalence of 25.6% compared to 18.5% in those not receiving treatment.

The findings of Bonfanti et al. indicated that MetS is significantly higher in PLWH compared to the general population [17]. Specifically, the study found that 20.8% of HIV-infected patients had MetS, compared to 15.8% in the control group. The study also highlighted that the age- and gender-adjusted risk of having MetS in HIV-infected patients was twice as high as in the general population. HIV-infected patients exhibited a greater prevalence of impaired fasting glucose, increased plasma triglycerides, and reduced high-density lipoprotein cholesterol components. Interestingly, the prevalence of MetS and its components was similar in both treated and untreated HIV-positive patients, suggesting that the risk of MetS in this population is not solely attributable to antiretroviral therapy but may be related to the HIV infection itself.

Table 1. Prevalence of metabolic syndrome in people living with HIV.

Study (Year)	Sample Size	Country	MS Criteria	Prevalence
Gazzaruso et al. (2002) [18]	533 PLWH	Italy	NCEP-ATPIII	45.4%
Bruno et al. (2002) [19]	201 PLWH	Italy	EGIR	39.8%
Jericó et al. (2005) [20]	710 PLWH	Spain	NCEP-ATPIII	17%
Bonfanti et al. (2007) [17]	12463 PLWH	Italy	NCEP-ATPIII	21%
Samaras et al. (2007) [21]	788 PLWH	USA	IDF	14%
Crum-Cianflone et al. (2009) [22]	216 PLWH	USA	NCEP-ATPIII	75%
Worm et al. (2010) [23]	23 853 PLWH	Europe Australia/USA D.A.D	NCEP	41.6%
Alencastro et al. (2012) [24]	1240 PLWH	Brazil	AHA/NHLBI (higher than NCEP-ATPIII and IDF)	24.7%
Wu et al. (2012) [25]	877 PLWH	Taiwan	NCEP-ATPIII	26.2%

Abbreviations: Metabolic syndrome (MS), National Cholesterol Education Program Third Adult Treatment Panel (NCEP-ATPIII), European Group for the Study of Insulin Resistance (EGIR), International Diabetes Federation (IDF), National Heart, Lung, and Blood Institute (NHLBI), American Heart Association (AHA), persons living with HIV (PLWH), Data Collection on Adverse events of Anti-HIV Drugs (D.A.D), percent (%).

lists the prevalence of MetS from studies across the globe [17,18,19,20,21,22,23,24,25].

PLWH are at increased risk for metabolic syndrome due to the complex interplay of traditional and HIV-specific factors. ART, especially older-generation protease inhibitors like didanosine and stavudine and certain nucleoside reverse transcriptase inhibitors, are associated with lipodystrophy and central adiposity [26,27]. Mitochondrial toxicity induced by some ART drugs can lead to insulin resistance and dyslipidemia [27]. These include older nucleoside reverse transcriptase inhibitors (NRTIs) such as stavudine, didanosine, and zidovudine [28].

Chronic immune activation and inflammation are the hallmarks of HIV infection. They contribute to endothelial dysfunction and metabolic disturbances [29]. Traditional risk factors such as advancing age, sedentary lifestyle, unhealthy diet, and smoking further compound the risk. Hepatitis C virus (HCV) coinfection, low CD4 counts, and longer duration of HIV infection are additional contributors [30,31,32]. Socioeconomic disparities, mental health conditions, and substance use may also influence the development of MetS in this population. Figure 1 shows that the prevalence of MetS in patients with HIV increased significantly, from approximately 20% in 2000/2001 to over 40% in 2006/2007 [23]. During the same period, patients with higher BMI, hypertension, and elevated triglycerides also increased. More recent data suggests that the prevalence of MetS in PLWH ranges from approximately 17% to 30% depending on the diagnostic criteria used, with an overall pooled prevalence of 25.3% globally [16].

3.2. Hepatic Steatosis in PLWH

Hepatic steatosis is characterized by the accumulation of fat in liver cells. PLWH are at increased risk for hepatic steatosis due to a combination of metabolic, viral, and treatment-related factors. According to a diverse cross-sectional US multicenter study, the prevalence of hepatic steatosis in PLWH is approximately 49% by ultrasound and 51% by controlled attenuation parameter [33]. Another systematic review and meta-analysis reported a pooled prevalence of NAFLD in PWH of 34% based on imaging studies [34]. The prevalence of MAFLD was reported to be 27% in a cohort study of PLWH on ART [10].

Table 2. Prevalence of non-alcoholic fatty liver disease in PLWH.

Study (Year)	Country	Sample Size	Modality of Steatosis Assessment	Prevalence of NAFLD (Threshold)	Risk Factors
Hadigan et al. (2007) [35]	USA	33	MR spectroscopy	42%	ALT, triglyceride, BMI, visceral adiposity (p < 0.001)
Moreno-Torres et al. (2007) [36]	Spain	29	MR spectroscopy	58%
Guaraldi et al. (2008) [37]	Italy	225	CT	37%
Crum-Cianflone et al. (2009) [22]	USA	216	Ultrasound	31%
Ryan et al. (2009) [38]	Spain	830	Ultrasound	13% (severe)
Li Vecchi et al. (2013) [39]	Italy	68 (HIV-HCV)	Ultrasound	51% (US)
Borghi et al. (2013) [40]	Italy	205 (HIV-HCV)	Biopsy, Ishak criteria	47.8%
Sterling et al. (2013) [56]	USA	14 HIV mono-infection)	Biopsy	65%
Nishijima et al. (2014) [42]	Japan	435	Ultrasound	31%	Higher BMI, hyperlipidemia, and higher ALT/AST ratio
Price et al. (2014) [43]	USA	465 HIV, HIV/HCV	CT	13%
Macías et al. (2014) [44]	Spain	326 HIV, HCV, HBV	VCTE/CAPTM, CAP threshold of 238 dB/m	40%	BMI highest predictor
Sulyok et al. (2015) [45]	Hungary	136	VCTE/CAPTM (CAP threshold of 238 dB/m)	49% (238 dB/m) 30% 9260 db/m)
Sebastiani et al. (2015) [46]	Canada	796	Hepatic Steatosis Index	24%
Shur et al. (2016) [47]	UK	44	Biopsy	5%
Lui et al. (2016) [48]	Japan	80	MR spectroscopy	28%
Lombardi et al. (2016) [49]	Greece	125	VCTE/CAPTM (threshold not stated)	55%
Vuille-Lessard et al. (2016) [50]	Canada	300	VCTE/CAPTM (CAP threshold of at least 238 dB)	48% (238 dB/m) 33.7% (260 dB/m)
Maurice et al.(2017) [51]	Meta-analysis	1256	Imaging (various)	35%
Perazzo et al. (2018) [52]	Brazil	395	VCTE/CAPTM (CAP threshold ≥ 248 dB/m)	35% (248 dB/M)
Torgersen et al. (2019) [53]	USA (VA study)	171	CT	7.6% (moderate-severe)
Kirkegaard-Klitbo et al. (2020) [54]	Denmark	453	CT	8.6% (moderate-severe)
Gawrieh et al. (2023) [33]	USA	200	VCTE	35–39%	BMI, White, waist circumference, higher AST, T2DM.

Abbreviations: Magnetic resonance (MR), computerized tomography (CT), controlled attenuation parameter (CAP), vibration-controlled transient elastography (VCTE), percent (%), hepatitis C virus (HCV), hepatitis B virus (HBV), human immunodeficiency virus (HIV), decibels per meter (dB/m).

shows the prevalence of NAFLD in various studies, along with the method of detection and risk factors [22,33,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55].

The causes of hepatic steatosis in PLWH are multifactorial. NAFLD accounts for the majority of fatty liver disease in this population, with metabolic syndrome components such as higher BMI, diabetes, and elevated alanine aminotransferase (ALT) levels being significant risk factors [34]. Insulin resistance, dyslipidemia, and central obesity are common in PLWH and strongly associated with MASLD [55]. HIV-specific factors, such as exposure to certain antiretroviral therapies, particularly integrase inhibitors, have also been implicated in the development of hepatic steatosis [54]. ART contributes to hepatic steatosis through both direct metabolic effects and indirect alterations in adipose tissue and insulin signaling. Older nucleoside reverse transcriptase inhibitors induce mitochondrial DNA depletion, impairing hepatic β-oxidation and promoting lipid accumulation [57]. Contemporary ART regimens, particularly integrase strand transfer inhibitor-based therapies, are associated with weight gain and worsening insulin resistance, increasing free fatty acid flux to the liver. ART-related adipose tissue dysfunction, characterized by impaired adipogenesis and reduced adiponectin, further exacerbates hepatic lipid deposition and metabolic stress [58]. The association between hepatic steatosis and HIV treatment is multifactorial and can be influenced by co-infections, such as HCV genotype 3, which is independently associated with hepatic steatosis [59].

Table 3. Associations of HAART with NAFLD or NASH.

Study	Exposure	Risk Factor/Prevalence of NAFLD	Risk Factor/Prevalence of NASH
Wu et al. (2012) [25]	NRTIs and protease inhibitors	T2DM
Capeau et al. (2012) [60]	NRTIs and protease inhibitors	T2DM
Lemoine et al. (2006) [61]	HAART, with or without T2DM)		HAART-related lipodystrophy with insulin resistance
Jericó et al. (2005) [20]	Protease inhibitors (stavudine and lopinavir/ritonavir only after adjusting for age and BMI)	Stavudine (OR 1.74 (1.01–2.98)), lopinavir/ritonavir (OR 2.46 (1.28–4.71))
Samaras et al. (2007) [21]	Protease inhibitors	MS (p = 0.04)
Nishijima et al. (2014) [42]	Dideoxynucleoside analogues or duration of HAART	No association
Guaraldi et al. (2008) [37]	Each year of nucleoside reverse-transcriptase inhibitor use	11% increase in the odds ratio

Abbreviations: Highly active antiretroviral therapy (HAART), non-alcoholic fatty liver disease (NAFLD), nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), type 2 diabetes mellitus (T2DM), metabolic syndrome (MS), odds ratio (OR).

lists the studies evaluating the effect of ART on NAFLD [20,21,25,37,42,60,61].

HIV infection is associated with chronic immune activation and persistent low-grade inflammation, even in virologically suppressed individuals on ART, which promotes hepatic fat accumulation. Unhealthy dietary habits, including high intake of refined carbohydrates, saturated fats, and fructose, and physical inactivity are common in PLWH and can exacerbate the risk of developing NAFLD [62]. HIV directly disrupts lipid homeostasis through multiple viral proteins. The Nef protein impairs high-density lipoprotein functionality and reduces cholesterol efflux capacity [28]. The vpR protein inhibits peroxisome proliferator-activated receptor-γ (PPARγ) expression, interfering with normal adipocyte cell cycle and function, which increases free fatty acid delivery to the liver and contributes to hepatic steatosis [28]. CD4⁺ T cell depletion triggers systemic metabolic dysfunction. Gut mucosal T cell depletion impairs epithelial barrier integrity, facilitating microbial translocation and lipopolysaccharide entry into circulation [63]. This translocation, combined with viral replication in hepatocytes, Kupffer cells, and hepatic stellate cells, creates a persistent inflammatory environment characterized by elevated tumor necrosis factor-α, C-C chemokine ligands 2, and 3, and integrin-αM levels increased more than 2-fold in those with dyslipidemia.

While hepatitis B virus (HBV) and HCV coinfections do influence liver disease in PLWH, their roles in the development and progression of NAFLD are nuanced. HBV may have a dual role, potentially protective against steatosis but contributing to fibrosis, whereas HCV appears to slow the progression of hepatic steatosis in PLWH [64,65]. HBV has been associated with a decreased level of triglycerides and a potentially protective role against the development of steatosis and metabolic syndrome [66]. However, HBV also has high fibrogenic and oncogenic potential, which can complicate the liver disease landscape in PLWH. Hepatic steatosis progresses faster in HIV mono-infected patients compared to those coinfected with HCV. HCV coinfection was found to be an independent negative predictor of hepatic steatosis progression, suggesting that HCV may have a protective effect against the progression of NAFLD in PLWH [65].

Figure 2 shows the interplay between HIV and steatotic liver disease.

3.3. NASH in PLWH

NASH, in the context of PLWH, is a significant liver disease characterized by hepatic inflammation and damage due to fat accumulation in the liver, not caused by alcohol consumption. The prevalence of NASH in PLWH varies widely, with estimates ranging from 11.4% to 48.77% [34,67]. This variation is due to differences in diagnostic methods and study populations. For instance, a systematic review and meta-analysis reported a prevalence of 48.77% based on biopsy studies, while non-invasive diagnostic tools indicated a prevalence of 11.4%.

The clinical manifestations of NASH in PLWH include nonspecific symptoms like fatigue and abdominal pain, elevated liver enzymes, and imaging or histological evidence of hepatic steatosis and inflammation. These manifestations are often compounded by metabolic risk factors and the effects of chronic HIV infection and ART. Obesity and T2DM are significant predictors of NASH in PLWH [68,69].

3.4. Diagnosis of Steatosis and NASH in PLWH

3.4.1. Non-Invasive Diagnosis

Non-invasive diagnostic tools for identifying NASH in PLWH have become essential for accurate assessment without the need for liver biopsy. TE with CAP is commonly employed to evaluate both liver stiffness and steatosis. CAP had an area under the receiver operating characteristic curve (AUROC) of 0.82, and the ≥248 dB/m cutoff yielded a sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 83%, 72%, 61% and 88%, in a study by Duarte et al., who investigated the use of TE in PLWH, comparing it with non-invasive gold standard magnetic resonance spectroscopy (MRS) [70]. Lemoine et al. found that TE had good performance in diagnosing steatosis and fibrosis in PLWH, with an AUROC of 0.88 for steatosis [71].

Magnetic resonance imaging proton–density fat fraction (MRI-PDFF) offers high accuracy for detecting hepatic steatosis, with an AUROC of 0.98 in this population [72]. Lemoine et al. confirmed the excellent performance of MRI-PDFF with an AUROC of 0.98 for steatosis compared to liver biopsy in PLWH [71]. This study also highlighted that MRI-PDFF outperformed other non-invasive methods such as TE.

Serum biomarkers such as cytokeratin-18 (CK-18) and elevated alanine aminotransferase (ALT) are also associated with NASH. Elevated CK-18 levels (>246 U/L) have been shown to be a reliable marker for diagnosing NASH in PLWH. In a study by Benmassaoud et al., CK-18 combined with TE and CAP demonstrated good diagnostic performance, with histological confirmation of NASH in all cases diagnosed non-invasively [67]. Elevated ALT levels (≥36 IU/L) have also been shown to have good diagnostic performance for NASH in PLWH. Lemoine et al. reported an AUROC of 0.83 for ALT in diagnosing NASH [71]. MicroRNAs, particularly miR-122 and miR-192, show high accuracy and correlate with fibrosis severity, while composite panels such as NIS4 integrate inflammatory and metabolic signals to identify at-risk MASH. Lipidomic and metabolomic approaches, including desmosterol- and phosphatidylcholine-based signatures and multi-metabolite panels, further refine disease discrimination, and emerging machine-learning derived composite scores integrating clinical and molecular features highlight the potential for precision and non-invasive risk stratification in MASLD and MASH. These are yet to be explored in PLWH.

The Fibrosis-4 (FIB-4) index is a non-invasive scoring system used to estimate liver fibrosis in patients with chronic liver disease, by combining age, platelet count, ALT, and AST values [41]. A study by the National Institute of Health-sponsored HIV-NAFLD network reported that the FIB-4 index has an AUROC of 0.70 for identifying advanced fibrosis in PLWH with steatotic liver disease, indicating moderate diagnostic accuracy [73]. The study also reported that the FIB-4 index has a high NPV of 97–98% at a low threshold (<1.3), making it effective for ruling out advanced fibrosis. However, its sensitivity at low thresholds was 64%, and its specificity at high thresholds (>2.67) was 97%. Figure 3 shows the utility of FIB-4 in predicting significant fibrosis.

The FAST score, which integrates liver stiffness, CAP, and AST, helps identify patients with “at-risk” NASH. In a study by Sebastiani et al., a FAST score > 0.35 was used to diagnose NASH with significant fibrosis in PLWH, and it was found to be an independent predictor of liver-related outcomes, with a high specificity for identifying patients at risk [74]. Michel et al. utilized the FAST score and identified that 12% of their cohort of PLWH had at-risk NASH [68]. Newer models for assessing MASLD have not yet been assessed in PLWH [75].

In line with these tools, the American Gastroenterological Association and American Association for the Study of Liver disease recommend using a combination of two or more non-invasive tests for staging and risk stratification in patients with NAFLD, including in PLWH, to enhance diagnostic accuracy and reduce the need for liver biopsy [76,77,78].

Table 4. Diagnostic accuracy of non-invasive markers for advanced fibrosis.

Modality	AUROC, Sensitivity/Specificity	PPV, NPV
VCTE optimal cut off ≥7.8 kPa [79]	AUROC: 0.778, sensitivity: 61.5%, specificity: 94%	PPV 72.7%, NPV 90.5%
FIB-4, optimal cut off ≥1.76 [79]	Sensitivity: 50%, specificity: 76.8
FIB-4 score < 1.45 [79]	Sensitivity: 70%	NPV of 90%
FIB-score > 3.25 [79]	Specificity: 97%	PPV of 65%
APRI [80]	AUROC: 0.69, sensitivity: 62.5%, specificity: 73.2% Optimal cut-off ≥0.42
VCTE [81]	AUROC: 0.70 to 0.87 in identifying steatosis with CAP
VCTE [82]	AUROC: 93% to detect moderate fibrosis (highest sensitivity/specificity over APRI, FIB-4 and NFS)
LSM by VCTE [81]	AUROC: 0.77–0.89
Liver fat Score [80]	AUROC: 0.97, sensitivity: 100%, specificity: 84% Cut-off score −0.234.
LAP score [80]	AUROC of 0.91 with 89% sensitivity, 83% specificity at a cut-off ≥42

Abbreviations: Fibrosis-4 (FIB-4), aspartate aminotransferase-to-platelet ratio index (APRI), controlled attenuation parameter (CAP), vibration-controlled transient elastography (VCTE), percent (%), lipid accumulation product (LAP), area under the receiver operating characteristic (AUROC), positive predictive value (PPV), negative predictive value (NPV).

shows the accuracy of non-invasive tests for advanced fibrosis (F3–4) in PLWH [79,80,81,82].

3.4.2. Histological Diagnosis

A histological diagnosis of NAFLD in PLWH is warranted when non-invasive tests yield inconclusive results or when there is a high clinical suspicion of advanced fibrosis or NASH that necessitates confirmation. This approach is particularly important in patients whose TE, MRI-PDFF, or serum biomarkers suggest significant liver disease, but lack definitive diagnostic clarity or are non-congruent. Liver biopsy remains the gold standard for diagnosing NAFLD and NASH, offering a direct evaluation of hepatic steatosis, inflammation, hepatocyte ballooning, and fibrosis. An adequate specimen, ideally 2–2.5 cm in length, obtained with a 16-G needle, is essential for accurate interpretation [78]. Histological assessment commonly employs scoring systems such as the NAFLD Activity Score (NAS), which quantifies steatosis, lobular inflammation, and ballooning, and the Steatosis, Activity, Fibrosis (SAF) score, which provides a structured evaluation of disease severity [83,84]. Liver biopsy is the most accurate modality for assessing the complex architectural changes associated with liver injury, inflammation, and fibrosis and is critical for grading inflammatory activity and staging fibrosis.

Maurice et al. conducted a study that included 116 HIV-monoinfected patients who underwent liver biopsy due to abnormal liver biochemistry or clinical suspicion of liver fibrosis [69]. They found that 54% had NAFLD and 92% of those had NASH. Advanced fibrosis (≥F3) was present in 31% of the patients, highlighting the importance of liver biopsy in identifying the extent of liver disease in this population. Morse et al. also emphasized the necessity of liver biopsy in HIV-infected adults with persistent aminotransferase elevations on antiretroviral therapy [82]. Their study showed that 65% of the subjects had clinically significant liver pathology, including 55% with NASH and 18% with bridging fibrosis.

Table 5. Histologic prevalence of NASH in PLWH.

Study (Year)	Country	Sample Size	Prevalence of NASH	Significant Fibrosis	Histologic Scoring System
Monto et al. (2005) [97]	USA	92 (HIV-HCV)	50% Stage 0–1 Fibrosis		Batts–Ludwig
Lemoine et al. (2006) [61]	France	14 (on HAART, with or without T2DM)	56%	29%	Brunt
Gaslightwala et al. (2006) [85]	USA	154 (HIV-HCV)	Stage 3/4 fibrosis (43.5%)		Brunt/Ishak/Scheuer
Sterling et al. (2006) [41]	USA	222 (HIV-HCV)			Brunt/Ishak
Castéra et al. (2007) [86]	France	137 (HIV-HCV)	Severe fibrosis F3–F4: 33.1%		METAVIR
Mohammed et al. (2007) [87]	Canada	26	55%	-	Brunt
Crum-Cianflone et al. (2009) [22]	USA	55	20%	-	Ishak
Ingiliz et al. (2009) [88]	France	30	53%	30%	NASH-CRN
Halfon et al. (2009) [89]	France	170 (HIV-HCV)	OR = 5.56 (1.64–20)	≥F2	METAVIR
Sterling et al. (2013) [56]	USA	14	26%	14%	Ishak, NASH-CRN, Brunt
Rivero-Juarez et al. (2013) [90]	Spain	10	20%	30%	Scheuer, Brunt
Morse et al. (2015) [82]	USA	62	55%	18%	Ishak, NASH-CRN
Vodkin et al. (2015) [91]	USA	33	63%	18.2%	NASH-CRN
Hoffmann et al. (2015) [98]	South Africa	108	14%		Not stated
Lombardi et al. (2016) [49]	Greece	125	17.6% (>7.4 kPa) by VCTE
Shur et al. (2016) [47]	UK	44	66% ≥ Grade F1 fibrosis, 21% Grade F3–4 fibrosis by biopsy		METAVIR
Maurice (2017) [51]	Meta-analysis	208	35%		Not stated
Sterling et al. (2020) [79]	NA	112	10%	-	Ishak, NASH-CRN
Maurice et al. (2021) [69]	USA	116	49%	31%	NASH-CRN
Fourman et al. (2021) [99]	USA	58	43%		NASH CRN
Gawrieh (2023) [33]			7–20% by VCTE

Abbreviations: Persons living with HIV (PLWH), non-alcoholic steatohepatitis (NASH), hepatitis C virus (HCV), odds ratio (OR).

lists various studies with histological prevalence of NASH in PLWH [22,33,41,47,49,51,56,69,72,79,82,85,86,87,88,89,90,91,92]. Histological scoring systems employed in these studies have been included [84,93,94,95,96].

3.5. Management of NAFLD/MASLD in PLWH

Management of NAFLD/MASLD in PLWH centers on lifestyle interventions, with pharmacologic therapy and antiretroviral regimen adjustments considered in selected cases.

3.5.1. Lifestyle Modifications

Lifestyle modification remains the cornerstone of MASLD treatment. This includes adopting a Mediterranean diet, which is rich in fruits, vegetables, whole grains, lean proteins, and healthy fats. Engaging in regular physical activity is encouraged, with current guidelines recommending 150–300 min of moderate-intensity exercise per week [100]. These strategies are supported by the American Association for the Study of Liver Diseases (AASLD) and have shown benefits in reducing hepatic fat and improving metabolic health [78]. In a recently published trial, a structured, dietitian-led lifestyle intervention in people with HIV and MASLD resulted in a significantly higher rate of MASLD resolution compared to standard care (28% vs. 10% at 12 months, p = 0.040) [101].

3.5.2. Pharmacotherapy

Although there are no FDA-approved pharmacotherapies specifically for NAFLD/MASLD in PLWH, certain medications used to treat comorbid conditions have demonstrated efficacy. Vitamin E may be beneficial in non-diabetic patients with biopsy-proven NASH in PLWH [102]. Pioglitazone and GLP-1 receptor agonists such as liraglutide and semaglutide have been shown to improve liver histology in patients with type 2 diabetes and NASH [103]. In the open-label single-arm SLIM LIVER study, PLWH who received semaglutide 1 mg weekly had clinically significant improvements in liver fat and cardiovascular disease risk factors [104].

Resmetirom, a liver-directed thyroid hormone receptor beta-selective agonist, received conditional FDA approval in March 2024 for adults with non-cirrhotic MASH and F2–F3 fibrosis. In the phase 3 MAESTRO-NASH trial involving 966 patients, resmetirom at 80–100 mg daily for 52 weeks achieved MASH resolution without worsening fibrosis in 26–30% of patients (vs. 10% with placebo, p < 0.001) and fibrosis reduction by at least one stage in 24–26% (vs. 14% with placebo, p < 0.001) [105]. Lanafibrinor, a pan-PPAR agonist, remains investigational following positive phase 2b results. achieved 49% MASH resolution (vs. 22% with placebo, p < 0.01) and 48% fibrosis improvement (vs. 29% with placebo, p < 0.01) in 247 patients with biopsy confirmed MASH and F1–F3 fibrosis [106].

Despite promising pharmacologic options in MASH, clinical trials in PLWH remain limited. The MAVMET trial, which evaluated maraviroc and metformin, did not demonstrate significant reductions in liver fat, underscoring the need for further targeted research [107].

Tesamorelin, a growth hormone-releasing hormone analog, has been studied for its effects on NAFLD in HIV-infected patients. The findings from multiple studies indicate that tesamorelin significantly reduces liver fat and may prevent fibrosis progression in this population. Evidence from a randomized control trial (RCT) suggests that tesamorelin significantly reduced liver fat over 6 months [108]. Another study showed that tesamorelin led to a greater reduction in hepatic fat fraction (HFF) compared to placebo, with an absolute effect size of −4.1% (p = 0.018) over 12 months [109]. Additionally, it has been shown to downregulate hepatic gene sets involved in inflammation, tissue repair, and cell division, which are pathways relevant to NAFLD progression. This suggests a potential mechanism by which tesamorelin exerts its beneficial effects on liver health [99].

3.5.3. HIV Management

In addition to lifestyle and pharmacologic approaches, modifications in ART may help mitigate liver-related complications in this population. Switching from efavirenz (EFV) or ritonavir-boosted protease inhibitors (PI/r) to raltegravir (RAL) has been associated with significant reductions in hepatic steatosis, as evidenced by improved CAP scores [110,111]. Integrase strand transfer inhibitors (INSTIs), especially when used with tenofovir alafenamide (TAF), have been linked to metabolic disturbances such as insulin resistance, and their impact on hepatic outcomes is still being elucidated [112]. Therefore, the selection of ART should be individualized, balancing virologic control with the potential impact on metabolic and hepatic health.

Suppressing HIV viral load is a critical component in the management of NAFLD in PLWH. Chronic HIV infection is associated with persistent systemic inflammation, which can exacerbate hepatic injury and accelerate the progression from simple steatosis to NASH and fibrosis [113]. Effective ART and viral suppression mitigate this inflammatory milieu, thereby reducing liver disease progression. Moreover, HIV infection and certain ART regimens contribute to the development of metabolic syndrome, insulin resistance and dyslipidemia, all key drivers of NAFLD. By achieving viral suppression, clinicians can stabilize these metabolic abnormalities, which is essential for halting or reversing fatty liver disease. In addition, maintaining undetectable viral loads allows for greater flexibility in selecting ART regimens with lower hepatotoxic potential, which is particularly important for patients with coexisting liver disease. Hence, viral suppression not only controls HIV but also plays a central role in reducing hepatic inflammation, improving metabolic outcomes, minimizing drug-induced liver injury, and preserving long-term liver health in PLWH with NAFLD.

In summary, the management of NAFLD/MASLD in PLWH should be multifaceted, emphasizing lifestyle change as first-line therapy, with pharmacologic interventions and ART regimen adjustments considered for patients with advanced disease or metabolic comorbidities. Ongoing monitoring of liver function and metabolic parameters is essential to guide individualized treatment strategies.

3.5.4. Role of Genetics and Epigenetics

Genetic factors account for approximately 50% of MASLD variability, with the most common genetic determinants involving interference with lipid and lipid-droplet remodeling [114]. Genetic variations in PNPLA3 (patatin-like phospholipase domain containing 3 gene) and other main genetic determinants increase the risk of hepatic fat accumulation in patients with MASH and liver fibrosis, cirrhosis, or hepatocellular carcinoma [115]. Epigenetic biomarkers, particularly DNA methylation patterns of lipid metabolism genes, show promise, but remain investigational. Changes in methylation levels of genes regulating hepatic lipid handling contribute to disease heterogeneity and progression from steatosis to MASH, though standardized clinical assays are not yet available [116]. The same genetic variants (PNPLA3, TM6SF2) that drive MASLD progression in the general population are relevant in PLWH, though specific validation studies of Polygenic Risk Scores (PRS) in HIV-positive cohorts are limited. The black race was protective against MASLD in PLWH, while obesity and elevated transaminases increased risk similar to patterns in HIV-negative populations [117].

4. Discussion

This scoping review highlights the substantial and multifactorial burden of MASLD in PLWH, with the convergence of traditional metabolic risk factors and HIV-specific contributors. Across diverse geographic settings and ART eras, MASLD and its progressive form, MASH, are highly prevalent yet remain underrecognized in routine HIV care. The heterogeneity in study design, diagnostic definitions, and assessment tools further complicates the interpretation of disease burden and reinforces the need for an evidence-mapping approach.

Metabolic syndrome emerges as a central driver of MASLD in PLWH, with prevalence estimates consistently exceeding those of the general population. While traditional cardiometabolic risk factors such as age, obesity, dyslipidemia, and insulin resistance are highly prevalent, HIV-related mechanisms add an additional layer of complexity. Chronic immune activation, persistent inflammation despite virologic suppression, and ART-associated metabolic effects contribute to a phenotype that may differ from primary MASLD. Importantly, earlier ART regimens were strongly associated with lipodystrophy and insulin resistance, whereas contemporary regimens, particularly integrase strand transfer inhibitors combined with tenofovir alafenamide, are increasingly linked to weight gain and metabolic derangements. These evolving ART-related effects likely influence MASLD risk trajectories over time and complicate comparisons across studies conducted in different treatment eras.

Hepatic steatosis is highly prevalent among PLWH, with imaging-based estimates ranging from approximately one-third to one-half of the studied cohorts. Variability in reported prevalence is driven largely by differences in diagnostic modality, thresholds, and population characteristics. Ultrasound and controlled attenuation parameters are widely used due to accessibility, whereas MRI-based techniques provide greater sensitivity but are less available. Traditional metabolic factors remain the dominant predictors of steatosis; however, HIV-specific factors, including ART exposure and chronic inflammation, appear to modulate risk and progression. The interplay between viral suppression, immune activation, and metabolic health likely explains why steatosis can occur even in PLWH with a lower body mass index or fewer conventional risk factors compared with HIV-negative populations.

Progression from steatosis to steatohepatitis represents a critical inflection point in disease course. Biopsy-based studies demonstrate a strikingly high prevalence of NASH among selected PLWH, often exceeding that reported in general MASLD populations. In contrast, non-invasive estimates yield substantially lower prevalence, reflecting the limitations of current tools in distinguishing simple steatosis from steatohepatitis. Obesity and type 2 diabetes are consistent predictors of NASH in PLWH, but HIV-related factors such as lipodystrophy and long-standing ART exposure also appear contributory. These findings reinforce that liver biopsy remains the reference standard for diagnosing NASH, particularly in PLWH with discordant non-invasive test results or unexplained aminotransferase elevations.

Non-invasive assessment has become central to MASLD evaluation in PLWH, yet important gaps remain. Serum biomarkers and composite scores offer incremental value, but have not been fully validated in HIV-specific populations. Fibrosis assessment represents a particular challenge; commonly used thresholds for APRI and transient elastography were derived largely from non-HIV cohorts and may misclassify disease severity in PLWH. Emerging tools such as the FAST score show promise for identifying at-risk NASH, but broader validation is required. Imaging modalities such as CAP and MRI-PDFF reliably detect steatosis but do not diagnose NASH. A stepwise approach using multiple non-invasive tests, with selective biopsy, remains the most pragmatic strategy.

Management of MASLD in PLWH requires a multidisciplinary approach. Lifestyle modification remains first-line therapy and has demonstrated efficacy even in HIV-specific cohorts. Pharmacologic options, including vitamin E, pioglitazone, GLP-1 receptor agonists, and tesamorelin, show promise but remain understudied in PLWH. ART optimization is an important but nuanced component of care. While switching from older protease inhibitor-based regimens may improve steatosis, the metabolic effects of newer regimens must be carefully balanced against virologic efficacy. Ongoing viral suppression remains fundamental, as uncontrolled HIV-related inflammation likely accelerates hepatic injury.

This review has limitations inherent in its scoping design. We did not perform a formal risk-of-bias assessment or quantitative synthesis, as the primary objective was to map the breadth and heterogeneity of existing evidence. The included studies varied widely in design, diagnostic definitions, and populations, limiting direct comparability. Additionally, most data are derived from high-income settings, potentially underrepresenting regions with a growing HIV burden. Despite these limitations, this scoping review provides a comprehensive framework to inform future targeted systematic reviews and prospective studies.

5. Conclusions

MASLD represents an increasingly important cause of chronic liver disease in people living with HIV, driven by the intersection of traditional cardiometabolic risk factors and HIV-specific mechanisms such as chronic inflammation, immune dysregulation, and antiretroviral therapy-related metabolic effects. MASLD and its progressive form, MASH, are highly prevalent in this population and frequently underdiagnosed, in part due to heterogeneity in disease definitions, overlapping liver disease etiologies, and the limitations of currently available non-invasive diagnostic tools.

With sustained virologic suppression and marked improvements in life expectancy and quality of life, people living with HIV increasingly face age-related and metabolic comorbidities, making systematic evaluation for MASLD clinically imperative. Early identification of steatotic liver disease enables timely risk stratification, facilitates detection of coexisting liver pathologies such as advanced fibrosis or hepatocellular carcinoma, and provides an opportunity for targeted metabolic and lifestyle interventions before irreversible liver injury occurs.

Future research should prioritize the development and validation of HIV-specific diagnostic algorithms that integrate imaging, serum biomarkers, and clinical risk factors to accurately identify steatosis, steatohepatitis, and fibrosis. In particular, biomarker panels capable of distinguishing MASH from simple steatosis and differentiating MASLD from alcohol-associated liver disease, viral hepatitis, and drug-induced liver injury are critically needed in PLWH, where mixed etiologies are common. Prospective, longitudinal studies incorporating standardized definitions and contemporary ART regimens will be essential for clarifying disease trajectories and causal pathways.

In parallel, well-designed interventional trials evaluating lifestyle strategies, metabolic therapies, and emerging antifibrotic agents in PLWH are required to establish evidence-based, population-specific management approaches. As the HIV population continues to age, a multidisciplinary framework that integrates hepatology, infectious diseases, and metabolic care, supported by improved diagnostic precision, will be central to mitigating liver-related morbidity and mortality in this growing patient population.