Role of viral and host factors in determining the outcome of HBV-associated acute liver failure

BACKGROUND: Acute hepatitis B virus (HBV) infection encompasses a broad clinical spectrum, from self-limited hepatitis to acute liver injury (ALI), acute liver failure (ALF), subacute liver failure, and ALF on chronic HBV reactivation. This study investigates how host and viral factors interact to shape the clinical spectrum of HBV-associated ALF. METHODS: We analyzed 231 serial serum samples from 49 well-characterized patients including 36 with HBV-associated ALF and 13 with acute hepatitis B. Among ALF patients, 7 had ALI, 7 acute and 11 subacute liver failure, and 11 ALF on chronic HBV. Viral factors, including HBV replication, genotype, sequence diversity and viral evolution by next-generation sequencing (NGS) were assessed alongside host immune responses and cytokine profiles by proteomics. RESULTS: Demographics were similar across groups. Mortality was highest in subacute liver failure and ALF on chronic HBV (82%) and intermediate in acute liver failure (43%). The three forms of ALF differed by clinical, virologic, and immunologic features. Acute liver failure was characterized by markedly elevated alanine aminotransferase and high IgM anti-HBc titers, whereas ALF on CHB showed higher serum HBV DNA, HBV RNA and HBcrAg levels. HBV genotype A predominated (63%), followed by D (15%), C (9%), and others (2-6%). NGS of the basal core promoter and precore/core regions revealed highly homogeneous viral populations in acute and subacute liver failure throughout follow-up, while ALF on CHB showed marked viral heterogeneity. Genetic diversity was genotype-dependent, unrelated to disease severity, and significantly lower in genotype A than D. Acute liver failure was associated with broad type 1 cytokine response (i.e. IP-10, MIP-1α, MIP-1β, TNF-α, and IFN-γ), restricted type 2 cytokine response (i.e. IL-4 and sCD137), along with proinflammatory (i.e. MCP-1, Il-6, and IL-8) and homeostatic (i.e. IL-7) cytokines, whereas subacute liver failure and ALF on chronic HBV exhibited low and restricted, but distinct cytokine profiles. Elevated GM-CSF and PDGF-BB at admission predicted transplant-free survival. CONCLUSIONS: Distinct clinical, serologic, virologic, and cytokine profiles correlate with disease severity, highlighting differing pathogenic mechanisms across HBV-associated ALF forms. Early biomarkers, including GM-CSF and PDGF-BB, may help predict recovery and guide individualized management to improve survival.