Case Report Open Access
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Cases. Mar 16, 2016; 4(3): 71-75
Published online Mar 16, 2016. doi: 10.12998/wjcc.v4.i3.71
Hepatitis B surface antigen escape mutations: Indications for initiation of antiviral therapy revisited
Jennifer Leong, Derek Lin, Mindie H Nguyen
Jennifer Leong, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Derek Lin, Department of Medicine, Stanford University Medical Center, Palo Alto, CA 94304, United States
Mindie H Nguyen, Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA 94304, United States
Author contributions: Leong J and Lin D contributed to data acquisition and writing the manuscript; Leong J and Nguyen MH provided the study concept and critical revision of the manuscript.
Institutional review board statement: This chart review was approved by the Institutional Review Board at Stanford University, Stanford, CA and at Icahn School of Medicine at Mount Sinai, New York, NY.
Informed consent statement: Informed consent was waived by approval of the Instituional Review Board from both institutions due to the retrospective nature of the study.
Conflict-of-interest statement: Jennifer Leong has received honoraria for serving as an advisory board member for Gilead Sciences. Derek Lin has no conflicts of interest to declare. Mindie H Nguyen has received honoraria and research support from Roche Pharmaceuticals, Bristol-Myers Squibb and Gilead Sciences.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Jennifer Leong, MD, Assistant Professor, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1104, New York, NY 10029, United States.
Telephone: +1-212-2418035 Fax: +1-212-7317340
Received: August 26, 2015
Peer-review started: August 27, 2015
First decision: October 14, 2015
Revised: November 16, 2015
Accepted: December 13, 2015
Article in press: December 14, 2015
Published online: March 16, 2016


Approximately 240 million people are chronically infected with hepatitis B. The implementation of rigorous vaccination programs has led to an overall decrease in the prevalence of this disease worldwide but this may also have led to emergence of viral mutations that can escape the protection of hepatitis B surface antibody. As this phenomenon is increasingly recognized, concern for transmission to vaccinated individuals has also been raised. Herein, we describe two cases where the suspected presence of a hepatitis B surface antigen escape mutation impacted the decision to initiate early antiviral therapy, as well as provide a brief review of these mutations. Our findings described here suggest that a lower threshold for initiating therapy in these individuals should be considered in order to reduce the risk of transmission, as vaccination does not provide protection.

Key Words: Hepatitis B virus, Hepatitis B surface antigen, Escape mutant, Hepatitis B immunoglobulin, Vaccination

Core tip: Hepatitis B surface antigen escape mutations are being increasingly recognized, along with concern for the risk of transmission to vaccinated individuals. The management of these patients and the natural history of the disease remain controversial due to insufficient data. However, transmission of this mutated virus to vaccinated individuals has been reported in the literature. Herein, we discuss two different clinical scenarios that led to the initiation of early antiviral therapy in order to decrease the risk of transmission to others due to the suspected presence of this mutation.


The World Health Organization estimates that over 2 billion people worldwide have been infected with hepatitis B virus (HBV). Approximately 240 million are chronically infected and therefore are at risk for life-threatening complications as a consequence of this disease[1]. The introduction of universal vaccination at birth, as well as other HBV immunization campaigns, has led to a significant reduction in the transmission of HBV in endemic countries[2,3]. However, with the success of these immunization strategies, there have been increasing reports of mutant viruses that develop despite vaccination, leading to concern about the threat they may pose to the public. These mutant viruses have been found to occur as a result of selection pressure from vaccination, hepatitis B immunoglobulin (HBIG) and have even been reported to occur spontaneously[4-6]. Despite increasing awareness of the emergence of hepatitis B surface antigen (HBsAg) escape mutant virus, there is no consensus on the treatment and management of individuals infected with these mutants. At present, there is also no easily available assay to diagnose these individuals when they are suspected of harboring HBsAg escape mutants. Here we highlight two clinical cases in which recognition of the presence of HBsAg escape mutations influenced the decision to initiate early antiviral therapy, as well as provide a brief review of HBsAg escape mutants.

Case 1

A 35-year-old G1P0 Korean woman presented at 13 wk gestation for evaluation of HBV discovered on routine prenatal screening. She was HBV treatment naïve and had never received a liver biopsy. She otherwise had no significant past medical or surgical history. She moved to the United States from South Korea at the age of 17. Her family history is significant for chronic HBV in both her mother and sister but no history of hepatocellular carcinoma (HCC). She reported a history of vaccination for HBV as a child.

Screening for virologic markers was positive for HBsAg, hepatitis B surface antibody (anti-HBs), hepatitis B core IgG antibody (anti-HBc IgG) and hepatitis B e antigen (HBeAg). She had negative markers to hepatitis B core IgM antibody (anti-HBc IgM) and hepatitis B e antibody (anti-HBe). Serum HBV DNA was detected with a viral level of 1707 copies/mL, mildly elevated alanine aminotransferase (ALT) level of 31 U/L (normal < 19 U/mL) for women)[7] and aspartate aminotransferase (AST) level of 31 U/L. Her alpha-fetoprotein (AFP) level was mildly elevated at 29.7 ng/mL, but this was felt to be consistent with her pregnancy, as AFP is known to be produced by human fetus and an abdominal ultrasound was negative for any suspicious liver lesion.

Her HBV DNA and ALT levels were monitored closely during her pregnancy without any evidence of hepatitis flare. She was sexually active with her husband who had previously been vaccinated for HBV but had not developed anti-HBs.

The patient was counseled on standard prevention of perinatal transmission with active and passive immunization of the infant. However, due to the concerns of transmission with HBV escape mutant, despite maintaining a low viral load throughout her pregnancy, she was started on treatment with tenofovir 300 mg orally once a day at 32 wk gestation, as HBV vaccination and administration of HBIG would be ineffective against HBsAg escape mutant HBV. The infant received hepatitis B vaccination as well as HBIG at birth and follow-up so far has shown the child to free of HBV infection.

Case 2

A 49-year-old Laotian man with chronic hepatitis B was referred for evaluation of a liver lesion discovered on screening ultrasound. He had previously been diagnosed with HBV in 2008, had no prior anti-HBV therapy, no prior liver biopsy, nor jaundice or other signs of hepatic decompensation. His past medical history was significant for latent tuberculosis, not treated given concern for isoniazid hepatotoxicity, and chronic sinusitis. He was born in Laos to Chinese immigrant parents and moved to the United States at the age of 16. He is married to a registered nurse, and they have a 17-year-old son. His family history is significant for a sister with chronic HBV, his father with HCC, and his mother with gastric cancer.

Screening for virologic markers was positive for HBsAg, anti-HBs, anti-HBc IgG, and anti-HBe. He had negative markers to anti-HBc IgM and HBeAg. Serum HBV DNA was detected with a viral level of 6100 copies/mL and mildly elevated ALT of 52 U/L (normal < 30 U/L for men)[7] and normal AST of 25 U/L. His AFP was normal at 2 ng/mL. Liver ultrasound showed a stable 9 mm × 10 mm × 8 mm lesion consistent with a hemangioma and a new 3 mm × 3 mm × 3 mm lesion in the right lobe of the liver. Follow-up magnetic resonance imaging did not demonstrate any evidence of HCC or cirrhosis. FIBROspect II analysis was consistent with F0-F1 (no fibrosis-portal tract fibrosis).

His wife was previously vaccinated against HBV and had protective anti-HBs as part of her employment screening as a nurse but reported that three years ago she was prevented from donating blood due to positive HBsAg. Previously, she was a regular blood donor. Although the patient was asymptomatic with a low HBV DNA level, normal ALT, and a reassuring FIBROspect, given the possibility that he likely infected his previously vaccinated wife with HBV escape mutant, the decision was made to start him on antiviral therapy to prevent further transmission among household contacts such as his son.


HBV with coexisting HBsAg and anti-HBs have long been reported in up to 10%-25% of patients with chronic hepatitis B, but were initially felt to be variants of no clinical importance[8]. However, several studies have since shown that the coexistence of HBsAg and anti-HBs is associated with mutations in the a determinant region of the HBsAg[9-12]. The significance and impact of these mutations was first recognized in 1988 when Zanetti et al[13] reported infants born to HBsAg carrier mothers who developed breakthrough infections despite receiving HBIG and HBV vaccine at birth. A single point mutation was identified in the surface antigen region from guanosine to adenosine at nucleotide position 587, resulting in amino acid (aa) substitution from glycine to arginine at position 145 in the a determinant of the HBsAg. This G145R mutation alters the conformation of the a determinant so that the neutralizing antibodies induced by vaccination are no longer able to recognize the virus, thereby resulting in breakthrough infection[13]. Since this discovery, other surface gene (S-gene) mutations with the same ability to evade immunization and infect vaccinated individuals have been reported, leading to increasing concern that these mutations may overcome the wild type and infect those who have been vaccinated. These mutations were also later recognized to occur after administration of HBIG in liver transplant recipients[14]. In addition, S-gene mutations have also been found to occur spontaneously, hypothesized to be due to the pressure of the host immune system, although the mechanism by which this occurs remains unclear[10,15].

At present, the clinical significance of HBsAg escape mutations remains controversial. A mathematical model proposed in 1998 by Wilson et al[16] predicted the disappearance of wild-type HBV in 200 years and the emergence of the G125R mutant as the common HBV in 60-100 years, based on the assumption that the current vaccination does not protect against this mutation. Several surveys in Taiwan have shown that the proportion of mutant viruses in HBV-infected children had increased significantly since the implementation of the universal vaccination program: 7.8% in 1984 just before the program implementation to 28.1% in 1994 and 23.1% in 1999[3,17]. A more recent epidemiologic survey published by Hsu et al[18] on the other hand, showed that with the reduction in the total number of children infected with HBV as a result of universal vaccination program, the prevalence of HBV mutants has actually decreased over time. This was also followed by a study published by Lai et al[19] which confirmed the decreased prevalence of HBV mutants in Taiwan. By measuring HBsAg, anti-HBs and anti-HBc from various age groups in 2007, the authors found that the HBsAg carrier rate, anti-HBc seropositive rate and infection rate was significantly lower in those who were born after the initiation of the vaccination program in Taiwan as compared to those who were born before the program. However, when compared across age groups, there was a significant increase in the HBV DNA positive rate for those who were 18-21 years of up to 3% as compared to those of younger age. In addition, the prevalence of HBsAg mutants was 2.63% in those > 18 years of age, but only 0.10% in those younger than 18. Thus, the authors concluded that although the prevalence of HBV infection has decreased with universal vaccination, continued monitoring for the presence of HBV infection is important due to the risk of mutant strains developing, particularly as this population continues to age[19].

As discussed above, the long-term impact that these HBsAg escape mutations may have on the natural history of chronic HBV remains unknown. On a public health level, some studies have suggested that these viruses lack stability and tend to result in lower levels of viremia, thus perhaps explaining why the viruses have not become as large of a threat to immunization programs as originally predicted[20]. On an individual level, however, there has been data to suggest that these patients may be at increased risk for active chronic hepatitis with higher HBV DNA levels and more advanced fibrosis[9]. There is also concern that the accumulation of mutations may lead to failure of recognition of HBsAg by currently available diagnostic assays, thereby leading to a missed diagnosis of chronic HBV infection[21,22]. In addition, there is a real concern regarding the risk of transmission to others, as vaccination does not provide protection from these mutated viruses. The risk of horizontal transmission is not currently well defined, but there are prior case reports in the literature[23,24]. One Taiwanese study identified that at least 26% of the HBV mutant-infected children who experienced immunization failure were born to non-carrier mothers, implying the possibility of horizontal infection or a spontaneous emergence of the mutant during the course of chronic infection[18].

In summary, while the threat that HBsAg escape mutants poses to the world at this time does not seem to be on as large a scale as initially feared, its significance may be considerable on individual patient levels. The possibility of transmitting the virus to other household and sexual contacts is real and needs to be addressed. In situations where the risk of sexual, vertical, or horizontal transmission is present, patients and their family members should be counseled carefully, and consideration should be given towards having a lower threshold to initiating potent antiviral therapy in these individuals to reduce the risk of transmission. Studies have clearly shown that the coexistence of HBsAg and anti-HBs is not as rare as once thought. Therefore, screening tests for HBV should routinely include HBsAg, anti-HBs and anti-HBc, especially in those who have close contact with individuals with chronic HBV infection.

Case characteristics

Herein are two cases of individuals with chronic hepatitis B presenting with coexisting hepatitis B surface antigen (HBsAg) and anti-HBs without symptoms.

Clinical diagnosis

Case 1 is a 35-year-old pregnant, but otherwise asymptomatic woman presenting with newly diagnosed hepatitis B virus (HBV) infection and Case 2 is a 49-year-old man with chronic HBV infection who likely transmitted HBV to his wife despite immunity from prior vaccination.

Differential diagnosis

Due to the history of prior vaccination and the presence of concomitant HBsAg and anti-HBs, it was felt likely that both patients were infected with HBsAg escape mutants.

Laboratory diagnosis

Both patients had serologies positive for HBsAg, anti-HBs, slightly abnormal liver enzymes and quantifiable HBV DNA tests.


Initiation of antiviral therapy with tenofovir in both cases.

Related reports

Reports of HBsAg mutant strains of HBV have been increasingly recognized with the introduction of universal vaccination. There have been published case reports of this mutation transmitted to others despite the presence of protective antibodies from prior HBV vaccination.

Term explanation

HBsAg escape mutants are due to mutations in the a determinant region of the HBsAg. These mutations allow the virus to escape neutralizing antibodies from the administration of hepatitis B immunoglobulin and HBV vaccine.

Experiences and lessons

Physicians should maintain a level of suspicion in patients with coexisting HBsAg and anti-HBs in the appropriate clinical situation, and should counsel their patients on the risks and benefits of early treatment.


A limitation of this paper is the inability to perform molecular confirmation of HBsAg escape mutations. However, this is not available in real-world clinical practice. This manuscript describes two interesting case studies that generate clinically relevant questions for an infrequent but important issue in the management of patients with HBV infection.


P- Reviewer: Ciftci S, Kanda T, Larrubia JR, Zhang J S- Editor: Qi Y L- Editor: A E- Editor: Wu HL

1.  World Health Organization. Fact Sheet 204 [updated 2015 Mar].  Available from:  [PubMed]  [DOI]
2.  Ni YH, Chang MH, Wu JF, Hsu HY, Chen HL, Chen DS. Minimization of hepatitis B infection by a 25-year universal vaccination program. J Hepatol. 2012;57:730-735.  [PubMed]  [DOI]
3.  Hsu HM, Lu CF, Lee SC, Lin SR, Chen DS. Seroepidemiologic survey for hepatitis B virus infection in Taiwan: the effect of hepatitis B mass immunization. J Infect Dis. 1999;179:367-370.  [PubMed]  [DOI]
4.  Alavian SM, Carman WF, Jazayeri SM. HBsAg variants: diagnostic-escape and diagnostic dilemma. J Clin Virol. 2013;57:201-208.  [PubMed]  [DOI]
5.  Yamamoto K, Horikita M, Tsuda F, Itoh K, Akahane Y, Yotsumoto S, Okamoto H, Miyakawa Y, Mayumi M. Naturally occurring escape mutants of hepatitis B virus with various mutations in the S gene in carriers seropositive for antibody to hepatitis B surface antigen. J Virol. 1994;68:2671-2676.  [PubMed]  [DOI]
6.  Carman WF, Zanetti AR, Karayiannis P, Waters J, Manzillo G, Tanzi E, Zuckerman AJ, Thomas HC. Vaccine-induced escape mutant of hepatitis B virus. Lancet. 1990;336:325-329.  [PubMed]  [DOI]
7.  Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:661-662.  [PubMed]  [DOI]
8.  Mimms LHepatitis B virus escape mutants: “pushing the envelope” of chronic hepatitis B virus infection. Hepatology. 1995;21:884-887.  [PubMed]  [DOI]
9.  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.  [PubMed]  [DOI]
10.  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;80:2968-2975.  [PubMed]  [DOI]
11.  Pondé RAThe underlying mechanisms for the “isolated positivity for the hepatitis B surface antigen (HBsAg)” serological profile. Med Microbiol Immunol. 2011;200:13-22.  [PubMed]  [DOI]
12.  Shiels MT, Taswell HF, Czaja AJ, Nelson C, Swenke P. Frequency and significance of concurrent hepatitis B surface antigen and antibody in acute and chronic hepatitis B. Gastroenterology. 1987;93:675-680.  [PubMed]  [DOI]
13.  Zanetti AR, Tanzi E, Manzillo G, Maio G, Sbreglia C, Caporaso N, Thomas H, Zuckerman AJ. Hepatitis B variant in Europe. Lancet. 1988;2:1132-1133.  [PubMed]  [DOI]
14.  Protzer-Knolle U, Naumann U, Bartenschlager R, Berg T, Hopf U, Meyer zum Büschenfelde KH, Neuhaus P, Gerken G. Hepatitis B virus with antigenically altered hepatitis B surface antigen is selected by high-dose hepatitis B immune globulin after liver transplantation. Hepatology. 1998;27:254-263.  [PubMed]  [DOI]
15.  Mesenas SJ, Chow WC, Zhao Y, Lim GK, Oon CJ, Ng HS. Wild-type and ‘a’ epitope variants in chronic hepatitis B virus carriers positive for hepatitis B surface antigen and antibody. J Gastroenterol Hepatol. 2002;17:148-152.  [PubMed]  [DOI]
16.  Wilson JN, Nokes DJ, Carman WF. Current status of HBV vaccine escape variants--a mathematical model of their epidemiology. J Viral Hepat. 1998;5 Suppl 2:25-30.  [PubMed]  [DOI]
17.  Hsu HY, Chang MH, Ni YH, Chen HL. Survey of hepatitis B surface variant infection in children 15 years after a nationwide vaccination programme in Taiwan. Gut. 2004;53:1499-1503.  [PubMed]  [DOI]
18.  Hsu HY, Chang MH, Ni YH, Chiang CL, Chen HL, Wu JF, Chen PJ. No increase in prevalence of hepatitis B surface antigen mutant in a population of children and adolescents who were fully covered by universal infant immunization. J Infect Dis. 2010;201:1192-1200.  [PubMed]  [DOI]
19.  Lai MW, Lin TY, Tsao KC, Huang CG, Hsiao MJ, Liang KH, Yeh CT. Increased seroprevalence of HBV DNA with mutations in the s gene among individuals greater than 18 years old after complete vaccination. Gastroenterology. 2012;143:400-407.  [PubMed]  [DOI]
20.  Kalinina T, Iwanski A, Will H, Sterneck M. Deficiency in virion secretion and decreased stability of the hepatitis B virus immune escape mutant G145R. Hepatology. 2003;38:1274-1281.  [PubMed]  [DOI]
21.  Coleman PF, Chen YC, Mushahwar IK. Immunoassay detection of hepatitis B surface antigen mutants. J Med Virol. 1999;59:19-24.  [PubMed]  [DOI]
22.  Weber BGenetic variability of the S gene of hepatitis B virus: clinical and diagnostic impact. J Clin Virol. 2005;32:102-112.  [PubMed]  [DOI]
23.  Oon CJ, Lim GK, Ye Z, Goh KT, Tan KL, Yo SL, Hopes E, Harrison TJ, Zuckerman AJ. Molecular epidemiology of hepatitis B virus vaccine variants in Singapore. Vaccine. 1995;13:699-702.  [PubMed]  [DOI]
24.  Thakur V, Kazim SN, Guptan RC, Hasnain SE, Bartholomeusz A, Malhotra V, Sarin SK. Transmission of G145R mutant of HBV to an unrelated contact. J Med Virol. 2005;76:40-46.  [PubMed]  [DOI]