LAUSR

To the editor, In their recent paper, Erken et al. used AluPCR to quantify integrated HBV DNA in liver tissue and report that the amount of integrations correlated with HBeAg status.[1] Their findings are important and inspire further discussion. Erken et al. reported that the core region was rarely integrated and argued that this finding agrees with a previous observation that core RNA was rare in HBVinfected liver.[2] The absence of integrated core DNA in their study may, however, have a technical explanation. In the final quantitative PCR readout the authors used a primer (HBVCR) that targets nucleotide 1812– 1825 (forward direction) in the HBV genome. Integrations are believed to have doublestranded linear HBV DNA as substrate and thus likely start at nucleotide 1820 or further downstream if a truncation occurs during the integration event. Hence, the HBVCR primer presumably cannot amplify integrated HBV DNA, which may explain the purported lack of integrated HBVcore DNA. Thus, the undetected core RNA expression is not necessarily explained by an absence of integrated core region DNA but more likely by the lack of an upstream promoter after linearization of the genome. We argue that further study is required to determine to what extent the HBVinfected liver contains integration of the core region. The finding by Erken et al. that integrations were more abundant in HBeAgpositive patients agrees well with a previous observation.[3] That study also found that integrated HBV DNA constituted a larger fraction of the total intrahepatic HBV DNA in HBeAgnegative compared with HBeAgpositive patients. These seemingly contradictory findings might be explained if hepatocytes carrying only integrated HBV DNA were eliminated more slowly than those with both covalently closed circular DNA and integrated HBV DNA, an explanation that fits with the finding by Erken et al. that patients with fewer integrations at baseline were more likely to become seronegative for HBsAg at followup 5 years later. Thus, to understand loss of HBsAg (functional cure), studies on the elimination of hepatocytes that express HBsAg from integrations seem essential. CO N FLI CT O F I NT E R EST Nothing to report