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The enigma of concurrent hepatitis B surface antigen (HBsAg) and antibodies to HBsAg.

Received 22 January 2007; accepted 29 January 2007; electronically published 19 March 2007. Reprints or correspondence: Dr. Wolfram H. Gerlich, Institute of Medical Virology, Justus Liebig University of Giessen, Frankfurter Strasse 107, D 35392 Giessen, Germany (wolfram.h.gerlich@viro.med.uni-giessen.de). Clinical Infectious Diseases 2007; 44:1170–2 2007 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2007/4409-0006$15.00 DOI: 10.1086/513296 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 (i.e., 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 antiHBs 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 HBsAg escape mutants in 1990, another explanation became likely and could be tested experimentally. Several studies employing PCR amplification and sequencing of the gene for HBsAg (S gene) suggested that there were indeed escape mutations in the HBsAg if anti-HBs were concomitantly present. These studies, however, suffered from low numbers of patients and lack of adequate control subjects. This criticism is not applicable to the recent study from Lada et al. [7] that compared the rate of amino acid exchanges in the S genes from chronic HBsAg carriers with and without concomitant anti-HBs. These authors indeed found an enhanced number of mutations (9.5% in anti-HBs carriers vs. 2.4% in those without antiHBs) in the HBsAg a-determinant in antiHBs–positive carriers and concluded that anti-HBs would significantly favor selection of escape mutants. The previous conclusion that concomitant anti-HBs were not protective seemed to be disproved, but in this issue of Clinical Infectious Diseases, Zhang et al. [8] quite convincingly demonstrate that chronic HBsAg carriers with anti-HBs did not have significantly more mutations than well-matched carriers without anti-HBs. In fact, the proportion of mutations in the a-determinant was very low (0.7%) and restricted mostly (in 0.5%) to position 126, which seems to be polymorphic even without immune selection. Furthermore, the authors confirmed