High‐Throughput Viral Integration Detection Reveals Baseline Breakpoints Burden Associated With HBsAg Seroclearance

ABSTRACT Background The profiles of hepatitis B virus (HBV) integration related to hepatitis B surface antigen (HBsAg) loss remain largely unknown. Aims We aimed to delineate the patterns of HBV integration in virally suppressed chronic hepatitis B (CHB) patients and their association with HBsAg loss following antiviral therapy. Methods Forty‐five patients with paired liver biopsies were randomly selected from the Anchor study for high‐throughput viral integration detection. The primary endpoint was HBsAg loss at Week 96. In Group II (pegylated interferon alpha‐2b & entecavir), 13 patients achieved HBsAg loss, whereas all patients in Group I (entecavir monotherapy) and 17 in Group II failed to achieve HBsAg loss. Results At baseline, the level of clonal expansion was positively correlated with the duration of nucleos(t)ide analogue (NUC) treatment, the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, whereas no association was observed with the HBsAg, hepatitis B core‐related antigen (HBcrAg), HBV RNA or covalently closed circular DNA (cccDNA) levels. Patients with less than 28 breakpoint types achieved a significantly higher rate of HBsAg loss following Peg‐IFN‐based therapy at Week 48 and 96, compared to those with more than 28. Conclusions The duration of NUC treatment, as well as ALT and AST levels, were associated with the level of clonal expansion in virally‐suppressed patients. A lower number of breakpoint types at baseline may be related to a higher HBsAg loss rate following Peg‐IFN‐based treatment and serve as a useful marker in guiding treatment decision‐making (NCT02327416). Trial Registration The Anchor study is registered at ClinicalTrials.gov , NCT02327416