Hepatitis B surface antigen (HBsAg) is the serologic hallmark of acute Hepatitis B virus (HBV) infection. It can be detected in serum using immunoassays a few weeks after HBV infection, and normally disappears after 4-6 months in recovered patients (1). Antibodies against HBsAg (anti-HBs) appears as a response from the host immune system, and these antibodies neutralize HBV infectivity and clear circulating HBsAg (2). Anti-HBs generally persist in life, indicating recovery and immunity from HBV infection.
Some of us may simply assume that the presence of anti-HBs should always associated with the loss of HBsAg. However, it is possible to see concurrent anti-HBs and HBsAg in patients. In fact, coexistence of HBsAg and anti-HBs is not rare, and has been reported in 10 to 25 percent of HBV chronic carriers in previous studies (3-4). The underlying mechanism is not fully understood but several reports explained it as HBsAg mutants escaping the immune system (2-4). HBsAg mutants are believed to arise under the selective pressure from the host immune system, or from vaccinations (4-6).
“a” determinant in HBsAg is one of the main target of anti-HBs. It has been reported that mutations in the “a” determinant of the surface gene (S-gene) result in amino acid substitutions in HBsAg, and reduce the binding of anti-HBs to HBsAg, leading to immune escape (4). The first HBV mutant was reported by Zanetti et al in 1988 as G145R mutation. In their report, infants born to HBsAg carrier mothers developed breakthrough infections despite receiving HBIG and HBV vaccine at birth (5). Since this report, several other HBsAg mutations have been reported (4, 6).
Currently, there is no easily available assay to diagnose individuals who are suspected of harboring HBsAg escape mutants. Moreover, mutated HBsAg may leads to false negativity in some serologic assays, leading to a missed diagnosis of chronic HBV infection (6). Another concern is the potential risk of transmission to others, as vaccination does not provide protection from these mutated viruses (8); this is especially important in liver transplant recipient and newborns from HBsAg positive mothers.
- Lok A, Esteban R, Mitty J. Hepatitis B virus: Screening and diagnosis. UpToDate. Retrieved Feb 2018 from https://www.uptodate.com/contents/hepatitis-b-virus-screening-and-diagnosis#H3
- Liu W, Hu T, Wang X, Chen Y, Huang M, Yuan C, Guan M. Coexistence of hepatitis B surface antigen and anti-HBs in Chinese chronic hepatitis B virus patients relating to genotype C and mutations in the S and P gene reverse transcriptase region. Arch Virol 2012;157:627–34.
- Colson P, Borentain P, Motte A, Henry M, Moal V, Botta-Fridlund D, Tamalet C, Gérolami R. Clinical and virological significance of the co-existence of HBsAg and anti-HBs antibodies in hepatitis B chronic carriers. Virology 2007;367:30–40.
- Lada O, Benhamou Y, Poynard T, Thibault V. Coexistence of hepatitis B surface antigen (HBs Ag) and anti-HBs antibodies in chronic hepatitis B virus carriers: influence of “a” determinant variants. J Virol. 2006 Mar;80(6):2968-75.
- Zanetti AR, Tanzi E, Manzillo G, Maio G, Sbreglia C, Caporaso N, Thomas H, Zuckerman AJ. Hepatitis B variant in Europe. 1988 Nov 12; 2(8620):1132-3.
- Leong J, Lin D, Nguyen M. Hepatitis B surface antigen escape mutations: Indications for initiation of antiviral therapy revisited. World J Clin Cases 2016;4:71.
- Colson P, Borentain P, Motte A, Henry M, Moal V, Botta-Fridlund D, Tamalet C, Gérolami R. Clinical and virological significance of the co-existence of HBsAg and anti-HBs antibodies in hepatitis B chronic carriers. 2007;367:30–40.
- Thakur V, Kazim S, Guptan R, Hasnain S, Bartholomeusz A, Malhotra V, Sarin S. Transmission of G145R mutant of HBV to an unrelated contact. J Med Virol 2005;76:40–6.
-Xin Yi, PhD, DABCC, FACB, is a board-certified clinical chemist, currently serving as the Co-director of Clinical Chemistry at Houston Methodist Hospital in Houston, TX and an Assistant Professor of Clinical Pathology and Laboratory Medicine at Weill Cornell Medical College.