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

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.

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.

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.