Coexistence of hepatitis B surface antigen and antibody to hepatitis B surface may increase the risk of hepatocellular carcinoma in chronic hepatitis B virus infection: A retrospective cohort study

Seo, Seung In; Choi, Hyeok Soo; Choi, Bo Youn; Kim, Hyoung Su; Kim, Hak Yang; Jang, Myoung Kuk

doi:10.1002/jmv.23779

Cited by 37 publications

(56 citation statements)

References 30 publications

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“…A retrospective cohort study has shown that HBeAg and HBV DNA persist for several decades in most carriers, and their risk of hepatocellular carcinoma (HCC) is increased. 20 Fortunately, the HBsAg disappeared and HBeAg seroconversion was achieved in this patient, who eventually cleared the HBV and recovered.…”

Section: Discussionmentioning

confidence: 67%

Clinical features and viral quasispecies characteristics associated with infection by the hepatitis B virus G145R immune escape mutant

Xue

Wang

Yang

et al. 2017

Emerging Microbes & Infections

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Coexistence of the hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (anti-HBs) is an uncommon phenomenon, and the underlying mechanisms remain largely unknown. Amino-acid (aa) substitution from glycine to arginine at aa 145 (G145R), in the major hydrophilic region, has been reported in patients with HBsAg and anti-HBs coexistence. However, there is limited knowledge about the clinical features and viral quasispecies characteristics associated with G145R mutant hepatitis B virus (HBV) infection. We herein describe the dynamic changes in the serological and virological markers in a case of hepatitis B with coexisting HBsAg and anti-HBs, caused by a G145R immune escape mutant (genotype C). Entecavir was administered during the 4th week after admission. Alanine aminotransferase peaked in the 16th week, while both the HBsAg and HBeAg declined rapidly. HBsAg clearance and hepatitis B e antigen (HBeAg)/hepatitis B e antibody (anti-HBe) seroconversion were achieved in the 36th week, and then entecavir was withdrawn. A follow-up of 96 weeks showed that HBV DNA remained undetectable and that anti-HBs was maintained above 100 mIU/mL. The quasispecies characteristics of the G145R mutant HBV were investigated via ultra-deep sequencing. The complexity and genetic distance of the S and RT regions were much higher in the 8th week than at baseline or in the 4th week. Moreover, the frequencies of mutations (L173P, Q181R and A184V) in cytotoxic T lymphocyte epitopes increased before entecavir treatment. These findings extend understanding of the evolution of HBV under host immune pressure and of the clinical outcomes of affected patients.

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Section: Discussionmentioning

confidence: 67%

Clinical features and viral quasispecies characteristics associated with infection by the hepatitis B virus G145R immune escape mutant

Xue

Wang

Yang

et al. 2017

Emerging Microbes & Infections

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“…No NA resistance-related primary mutations were found, which is in accordance with the treatment-naive HBV-infected samples. The pathogenesis of coexisting HBsAg and anti-HBs antibodies remains unclear; however increasing evidence suggests that the coexistence of HBsAg and anti-HBs antibodies is associated with the severity of liver disease and the active replication/reactivation of virus 6, 8, 39 . Mutations of the core promoter (CP) and precore are prevalent in HBV chronic infection 40 and the severity of liver disease associated with core promoter (T1753C, A1762T, G1764A, T1768A and A1846T/C) and precore (G1896A and G1899A) mutations has been widely discussed 41–44 .…”

Section: Discussionmentioning

confidence: 99%

“…Hence it is a conundrum when both HBsAg and anti-HBs are present in same serological profile 5 . However, incidences of coexisting of HBsAg and anti-HBs among HBsAg positive patients has been increasingly reported, which is nearly 5% in China 5 , 21% in Japan 6 , 36% in Netherlands 7 , 2.8% in France 8 , 2.9% in South Korea 9 , varies from 2.8% to 36% 5–10 and progressively increases with patient age from 40 to 70 years old 11 .…”

Section: Introductionmentioning

confidence: 99%

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Evolution of full-length genomes of HBV quasispecies in sera of patients with a coexistence of HBsAg and anti-HBs antibodies

Zhou¹,

Li²,

Li³

et al. 2017

Sci Rep

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Although the evolutionary changes of viral quasispecies are correlated to the pathological status of a disease, little is known in the coexistence of hepatitis B surface antigen (HBsAg) and antibodies to these antigens (anti-HBs). To examine evolutionary changes in hepatitis B virus (HBV) and their relationship to the coexistence of HBsAg and anti-HBs antibodies, HBV genomes in patients with a coexistence of HBsAg and anti-HBs antibodies (experimental group) and HBsAg positive without anti-HBs (control group) were assessed. Our results showed that quasispecies diversity was significantly higher in the experimental group for large HBsAg (LHBsAg), middle HBsAg (MHBsAg), and HBsAg genes. LHBsAg harbored dN/dS values eight times higher in the experimental group; however, the mean dN/dS ratios in genes HbxAg, Pol and PreC/C of the experimental patients had an opposite trend. Phylogenetic trees in the experimental group were more complex than the control group. More positive selection sites, mutations and deletions were observed in the experimental group in specific regions. Furthermore, several amino acid variants in epitopes were potentially associated with the immune evasion. In conclusion, cumulative evolutionary changes in HBV genome that facilitate immune evasion provide insights into the genetic mechanism of a coexistence of HBsAg and anti-HBs antibodies.

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“…Coexistence of HBsAg and anti‐HBs is uncommon, but has been described during resolution of acute HBV infection, in HBV carriers exposed to heterologous subtypes of HBsAg, and in patients with chronic HBV infection and serious liver disease . Its prevalence ranges in different populations from 2% to 7% of HBsAg positive (HBsAg[+]) patients . The variability of HBV strains in cases of HBsAg and anti‐HBs coexistence has been linked to higher variability of the N‐terminal region, the major hydrophilic region (MHR) of the small hepatitis B surface antigen (SHB), the preS region, and the reverse transcriptase region (RT) .…”

Section: Introductionmentioning

confidence: 99%

Clinical patterns associated with the concurrent detection of anti‐HBs and HBV DNA

Anastasiou

Widera

Korth

et al. 2017

Journal of Medical Virology

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Simultaneous detection of anti-HBs and HBV DNA is a rare serological combination and has been described in acute and chronic HBV infection. To scrutinize viral and clinical patterns associated with concurrent detection of anti-HBs and HBV DNA. Simultaneous detection of anti-HBs and HBV DNA was observed in 64/1444 (4.4%) patients treated for HBV infection at the University Hospital of Essen from 2006 to 2016 (8 with acute, 20 with reactivated, and 36 chronic HBV infection). Clinical data and laboratory parameters were analyzed. Regions of the small hepatitis B surface antigen (SHB) and the reverse transcriptase (RT) were sequenced using next generation sequencing (NGS). Among the 64 patients with detectable HBV DNA and anti-HBs, 17 were HBsAg negative (HBsAg[-]), and two had acute liver failure. Patients with acute HBV infection had fewer genotype specific amino acid substitutions in the SHB region than patients with reactivated HBV infection (4 [4.5] vs 9 [16.25], P = 0.043). However, we could observe a significantly higher number of mutations in the a-determinant region when comparing chronically infected patients to patients with acute infection (0 [1] vs 1 [1], P = 0.044). The ratio of nonsynonymous to synonymous mutations (Ka/Ks) was on average >1 for the SHB region and <1 for the RT region. The Ka/Ks ratio (>1) in the SHB region indicates that anti-HBs might have exerted selection pressure on the HBsAg. In three cases the diagnosis of acute HBV infection would have been at least delayed by only focusing on HBsAg testing.

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Coexistence of hepatitis B surface antigen and antibody to hepatitis B surface may increase the risk of hepatocellular carcinoma in chronic hepatitis B virus infection: A retrospective cohort study

Cited by 37 publications

References 30 publications

Clinical features and viral quasispecies characteristics associated with infection by the hepatitis B virus G145R immune escape mutant

Clinical features and viral quasispecies characteristics associated with infection by the hepatitis B virus G145R immune escape mutant

Evolution of full-length genomes of HBV quasispecies in sera of patients with a coexistence of HBsAg and anti-HBs antibodies

Clinical patterns associated with the concurrent detection of anti‐HBs and HBV DNA

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