Highlights
- •Ratios of large (L), medium (M) and small (S) HBsAg varied before and during antiviral treatment in patients achieving or not achieving HBsAg loss.
- •The proportion of MHBs is a suitable marker for early prediction of HBsAg loss.
- •Quantification of HBsAg proteins might be a novel tool to predict HBsAg loss early on treatment.
- •With this tool, treatment approaches may be individualized and HBsAg loss rates increased.
Background & Aims
During treatment of chronic HBV infections, loss or seroconversion of the HBV surface
antigen (HBsAg) is considered a functional cure. HBsAg consists of the large (LHBs),
middle (MHBs), and small surface protein (SHBs) and their relative proportions correlate
strongly with disease stage. Our aim was to assess the association between HBsAg composition
and functional cure during treatment.
Methods
A total of 83 patients were retrospectively analyzed. HBsAg loss was achieved by 17/64
patients during nucleos(t)ide analogue (NA) treatment and 3/19 patients following
treatment with pegylated interferon-alfa2a (PEG-IFN) for 48 weeks. Sixty-three patients
without HBsAg loss were matched as controls. LHBs, MHBs and SHBs were quantified in
sera collected before and during treatment.
Results
Before treatment, median MHBs levels were significantly lower in patients with subsequent
HBsAg loss than in those without (p = 0.005). During treatment, MHBs and LHBs proportions showed a fast decline in patients
with HBsAg loss, but not in patients with HBV e antigen seroconversion only or patients
without serologic response. MHBs became undetectable by month 6 of NA treatment in
all patients with HBsAg loss, which occurred on average 12.8 ± 8.7 (0–52) months before
loss of total HBsAg. Receiver-operating characteristic analyses revealed that the
proportion of MHBs was the best early predictor of HBsAg loss before NA treatment
(AUC = 0.726, p = 0.019). In patients achieving HBsAg loss with PEG-IFN, the proportions of MHBs
and LHBs showed similar kinetics.
Conclusion
Quantification of HBsAg proteins shows promise as a novel tool to predict early treatment
response. These assessments may help optimize individual antiviral treatment, increasing
the rates of functional cure in chronically HBV-infected patients.
Lay summary
The hepatitis B surface antigen (HBsAg) is a key serum marker for viral replication.
Loss of HBsAg is considered stable remission, which can be achieved with antiviral
treatments. We have investigated whether the ratios of the different components of
HBsAg, namely the large (LHBs) and medium (MHBs) HBsAg during different treatments
are associated with the occurrence of HBsAg loss. We found that LHBs and MHBs decrease
earlier than total HBsAg before HBsAg loss and we propose LHBs and MHBs as promising
novel biomarker candidates for predicting cure of HBV infection.
Graphical abstract
Graphical Abstract
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of HepatologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity.Vaccine. 2012; 30: 2212-2219
- Hepatitis B fact sheet, updated April 2017.(Available at:)http://www.who.int/mediacentre/factsheets/fs204/en/Date accessed: December 6, 2018
- Liver Cancer Fact Sheet. IARC; International Agency for Research on Cancer. Globocan, Lyon2012 (Accessed 06 December 2018)
- Global epidemiology of hepatocellular carcinoma (HCC Epidemiology).J Gastrointest Cancer. 2017; 48: 238-240
- AASLD guidelines for treatment of chronic hepatitis B.Hepatology. 2016; 63: 261-283
- EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.J Hepatol. 2017; 67: 370-398
- Ten-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B virus infection.Liver Int. 2019; 39: 1868-1875
- The role of quantitative hepatitis B surface antigen revisited.J Hepatol. 2017; 66: 398-411
- Large surface proteins of hepatitis B virus containing the pre-s sequence.J Virol. 1984; 52: 396-402
- The molecular virology of hepatitis B virus.Semin Liver Dis. 2013; 33: 103-112
- Quantification of large and middle proteins of hepatitis B virus surface antigen (HBsAg) as a novel tool for the identification of inactive HBV carriers.Gut. 2018; 67: 2045-2053
- Divergent preS sequences in virion-associated hepatitis B virus genomes and subviral HBV surface antigen particles from HBV e antigen-negative patients.J Infect Dis. 2018; 218: 114-123
- Performance of hepatitis B surface antigen tests with the first WHO international hepatitis B virus genotype reference panel.J Clin Virol. 2013; 58 (Erratum in: J Clin Virol. 2013 Nov;58(3):598-9): 47-53
- Pre-S encoded surface proteins in relation to the major viral surface antigen in acute hepatitis B virus infection.Gastroenterology. 1987; 92: 1864-1868
- Functions of the internal pre-S domain of the large surface protein in hepatitis B virus particle morphogenesis.J Virol. 1995; 69: 6652-6657
- The pre-s2 domain of the hepatitis B virus is dispensable for infectivity but serves a spacer function for L-protein-connected virus assembly.J Virol. 2010; 84: 3879-3888
- Myristoylated PreS1-domain of the hepatitis B virus L-protein mediates specific binding to differentiated hepatocytes.Hepatology. 2013; 58: 31-42
- Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus.Elife. 2012; 1: e00049
- Infectious hepatitis B virus variant defective in pre-S2 protein expression in a chronic carrier.Virology. 1993; 194: 137-148
- The middle hepatitis B virus envelope protein is not necessary for infectivity of hepatitis delta virus.J Virol. 1994; 68: 4063-4066
- Drastic reduction in the production of subviral particles does not impair hepatitis B virus virion secretion.J Virol. 2009; 83: 11152-11165
- Hepatitis B virus genomes that cannot synthesize pre-S2 proteins occur frequently and as dominant virus populations in chronic carriers in Italy.Virology. 1992; 188: 948-952
- Non-sequencing molecular approaches to identify preS2-defective hepatitis B virus variants proved to be associated with severe liver diseases.J Hepatol. 2004; 40: 515-519
- Genomic DNA double-strand breaks are targets for hepadnaviral DNA integration.Proc Natl Acad Sci U S A. 2004; 101: 11135-11140
- Reductions in cccDNA under NUC and ARC-520 therapy in chimpanzees with chronic hepatitis B virus infection implicate integrated DNA in maintaining circulating HBsAg.in: Diseases AAftSoL The AASLD Liver Meeting. Hepatology, San Francisco2015
- RNAi-based treatment of chronically infected patients and chimpanzees implicates integrated hepatitis B virus DNA as a source of HBsAg.Sci Transl Med. 2017; 9: eaan0241
- HBV DNA integration: molecular mechanisms and clinical implications.Viruses. 2017; 9: 75
- Nucleic acid polymers: broad spectrum antiviral activity, antiviral mechanisms and optimization for the treatment of hepatitis B and hepatitis D infection.Antivir Res. 2016; 133: 32-40
Article info
Publication history
Published online: September 12, 2020
Accepted:
August 27,
2020
Received in revised form:
July 27,
2020
Received:
January 3,
2020
Footnotes
Author names in bold designate shared co-first authorship
Identification
Copyright
© 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
