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

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.