We read with great interest the recent study by Lau et al, who reported distinct intrahepatic hepatitis B virus (HBV) integration patterns according to HBeAg status and observed marked enrichment of viral breakpoints within the DR2-DR1 region in HBeAg-negative chronic hepatitis B (CHB).1 The authors proposed that this enrichment reflects preservation of HBV regulatory elements, including Enhancer II and the core promoter (CP).

While this interpretation is plausible, we suggest that the observed pattern may be better explained by a combination of structural constraints, DNA repair-mediated remodelling and biological selection.

The predominant substrate for HBV integration is double-stranded linear DNA (dslDNA), which is generated following failed template switching during reverse transcription. As integration substrates, dslDNA differs fundamentally from circular HBV genomes because the termini of dslDNA map to regions surrounding DR1 or DR2, respectively. Importantly, initiation of plus-strand DNA synthesis occurs three to four nucleotides upstream of DR1.2…