Hepatitis B flare is a common complication of Chronic Hepatitis B (CHB) and is defined as an increase in HBV viral load associated with abnormal alanine aminotransferases (ALT), the consensus being an ALT≥5xupper limit of normal. The immunopathogenesis is related to induction of inflammatory cells and cytokines by the rise in HBV DNA. There are multiple causes of flares, and they carry the risk of progression to hepatic decompensation and acute-on-chronic liver failure (ACLF) with its associated mortality, potentially requiring liver transplantation. Initial assessment should be exclusion of other causes of liver dysfunction, determine severity, and prognosis. General prognostic models of ACLF are useful but the COSSH-ACLF II score is specific for HBV. Initiation of nucleos(t)ide analogues early is crucial and even in severe HBV flares reduces mortality by 73.6%. Once jaundice and coagulopathy occur, salvage by antivirals is challenging, and such patients should be considered for liver transplantation. However, many patients may not be suitable for transplant or may not have available donor livers as is common in Asia. Recently, there has been increasing evidence of benefit with adjunctive therapies such as corticosteroids and plasma exchange, but this needs to be balanced with the risks and should be considered as rescue therapies in severe HBV flares or ACLF. Liver transplant is the ultimate intervention when these other strategies fail to rescue patients. In summary, HBV flares are clinically serious events that can lead to hepatic decompensation and ACLF but strategies for rescue should be considered before liver transplantation.
Background/Aims Four-week treatment of linvencorvir (RO7049389) was generally safe and well tolerated, and showed anti-viral activity in chronic hepatitis B (CHB) patients. This study evaluated the efficacy, safety, and pharmacokinetics of 48-week treatment with linvencorvir plus standard of care (SoC) in CHB patients.
Methods This was a multicentre, non-randomized, non-controlled, open-label phase 2 study enrolling three cohorts: nucleos(t)ide analogue (NUC)-suppressed patients received linvencorvir plus NUC (Cohort A, n=32); treatment-naïve patients received linvencorvir plus NUC without (Cohort B, n=10) or with (Cohort C, n=30) pegylated interferon-α (Peg-IFN-α). Treatment duration was 48 weeks, followed by NUC alone for 24 weeks.
Results 68 patients completed the study. No patient achieved functional cure (sustained HBsAg loss and unquantifiable HBV DNA). By Week 48, 89% of treatment-naïve patients (10/10 Cohort B; 24/28 Cohort C) reached unquantifiable HBV DNA. Unquantifiable HBV RNA was achieved in 92% of patients with quantifiable baseline HBV RNA (14/15 Cohort A, 8/8 Cohort B, 22/25 Cohort C) at Week 48 along with partially sustained HBV RNA responses in treatment-naïve patients during follow-up period. Pronounced reductions in HBeAg and HBcrAg were observed in treatment-naïve patients, while HBsAg decline was only observed in Cohort C. Most adverse events were grade 1–2, and no linvencorvir-related serious adverse events were reported.
Conclusions 48-week linvencorvir plus SoC was generally safe and well tolerated, and resulted in potent HBV DNA and RNA suppression. However, 48-week linvencorvir plus NUC with or without Peg-IFN did not result in the achievement of functional cure in any patient.
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