Hepatitis B virus (HBV) infection continues to be a major health problem worldwide. The large-scale immunization programs for persons in high-risk groups, newborns, and adolescents have greatly reduced the incidence of new infection, but the∼ 400 million HBV carriers with HBV surface antigen (HBsAg) in the blood remain a burden that will dwindle only within decades. Furthermore, an unknown disease potential is hidden in the carriers of “occult” HBV infection. In fact, the majority of people with “resolved” HBV infection (ie, 40% of the world population) harbor the virus intrahepatically, but its replication is controlled by cytotoxic T lymphocytes, and its spread is blocked by the host’s neutralizing antibodies to HBsAg (anti-HBs). Anti-HBs are also the major protective component of vaccine-induced immunity. In view of their important protective role, occurrence of anti-HBs in HBsAg-positive patients with active chronic HBV infection is extremely puzzling. This phenomenon has been known since at least 1976 [1, 2].

Patients with chronic HBV infection may test persistently positive for HBsAg and anti-HBs without significant change in the infection status. This paradoxical pattern led to a seemingly obvious explanation: the subtype of the HBsAg and anti-HBs were heterologous. HBsAg subtype determinants were first described as allelic exclusive determinants d or y, in addition to the common HBsAg determinant a. Thus, HBsAg/ad was accompanied by anti-HBs/y and vice versa [1–4]. These findings were later confirmed for the second pair of subtype determinants, w and r, in patients in East Asia [5]. These studies from the 1970s and 1980s suggested that anti-HBs in HBV carriers had no significant protective or pathogenic effect and were usually associated with high replicative activity. It was speculated that the production of anti-HBs was not completely blocked in chronic HBV carriers, but B cells encoding high-affinity antibodies to the carrier’s own HBsAg would be somehow ineffective, whereas B cell clones encoding antibodies with low affinity to the homologous HBsAg could expand and express their antibody [6]. These anti-HBs would not be bound to the carrier’s own HBsAg but to HBsAg with slightly different antigenicity. The possibility that the heterotypic anti-HBs were induced by superinfection with a second HBV strain was dismissed by most studies. After the discovery of vaccine-induced