LAUSR

Hepatitis B virus reactivation (HBVr) following cancer chemotherapy or immunosuppressive therapies can occur via both virological and host factors. In the current issue of Hepatology Research, Tsuruya et al. from the TokaiUniversity School of Medicine reported virological factors in an HBVr case following ibrutinib therapy. The patient remained negative for hepatitis B surface antigen (HBsAg) throughout the clinical course because of the presence of the triple HBsAg escape mutants Q101K, M133L and G145A in the envelope protein. Typically,HBsAg becomes positivewhen HBVr occurs in patients with resolvedHBV infection.However, triple HBsAg escape mutants are considered to create an occult HBV infection phenotype, defined as the presence of replication-competent HBV DNA in the liver and/ or HBV DNA in the blood of individuals who test negative for HBsAg using currently available assays. HBV mutations in the envelope region (e.g., immune escapemutants, preS/S promoter mutants, or preS/S splice variants) cause occult HBV infection. Amino acid substitutions at position 145, particularly the G145R mutation, in the α determinant or major hydrophilic loop of the envelope protein are known as immune escape or vaccine escape mutants.Q101KandM133Lmutations have also been reported as escape mutants. Neutralizing antibodies directed against the wild-type virus show poor recognition of these mutations. Additionally, the impaired virion secretion and the diminished stability of immune escape mutants may limit the global spread of the mutant. Why was the HBV DNA level so high in this case even though escape mutants were detected? Our previous study showed that additional N-linked glycosylation sites (e.g., M133T mutation) in the α determinant of the envelope protein rescued the virion secretion impaired by the immune escape mutants. Recently, the clinical importance of additional N-linked glycosylation mutations were reported in patients with HBVr, those who were HBsAg and anti-HBs double-positive, and patients with hepatocellular carcinoma. A previous review article described the importance of N-glycosylation and N-glycan processing in HBV biology and pathogenesis. In the current case, additional N-linked glycosylation mutations were not detected by direct sequencing. Recent studies detected additional glycosylation mutations by using only ultradeep next-generation sequencing. Therefore, ultradeep sequencing may have detected these types of mutations in this case. As the prevalence of escapemutants is increasing because of widespread HBV vaccination worldwide,mutations that create additional glycosylation sites in the major hydrophilic loop of the envelope protein should be considered. As reported by Tsuruya et al., 14 mutations in the envelope protein other than triple escape mutants were detected. Many mutations in the envelope protein may reflect a longer exposure time by the host immune system. We previously compared the virological factors between patients with HBVr and acute hepatitis B (AHB) by next-generation sequencing and found that the frequency of mutation sites in the whole genome of HBV derived from patients with HBVr was significantly higher than that in patients with AHB. This tendency was more apparent in the envelope region compared with the region from the core promoter to the precore. In Japan, although resolved after AHB infection via horizontal transmission during adulthood could cause HBVr, it is assumed that most patients with HBVr are infected via vertical transmission or horizontal infection in childhood. On the other hand, most adult patients with AHB are infected by Financial support: This workwas supported byAMEDunder grant number JP19fk0310118, Grant-in Aid for Scientific Research C (grant number JP19K08479). Disclosure: K.I. received research funding from AbbVie and Gilead Sciences. Received 8 December 2020; revision 31 December 2020; accepted 10 January 2021. See article in Hepatology Research 52: 239-244. Case of hepatitis B virus reactivation after ibrutinib therapy in which the patient remained negative for hepatitis B surface antigens throughout the clinical course Kota Tsuruya, Kazuya Anzai, Shunsuke Shioyama, Ayano Ito, Yoshitaka Arase, Shunji Hirose, Yasuhito Tanaka, Hidekazu Suzuki and Tatehiro Kagawa Hepatology Research 2021; 51: 151–153 doi: 10.1111/hepr.13619