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Combined viral quasispecies diversity and hepatitis B core-related antigen predict off-nucleos(t)ide analog durability in HBeAg-negative patients

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A Correction to this article was published on 25 September 2021

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Abstract

Background

Viral quasispecies dynamics between pre- and post-nucleos(t)ide analog (NA) therapy remains unclear.

Aim

This study aimed to investigate the HBV quasispecies evolution and its relationship with durability of off-therapy responses in HBeAg-negative chronic hepatitis B (CHB) patients who stopped NA therapy.

Methods

Fifty-four HBeAg-negative CHB patients who stopped NAs, including 19 virological controllers (VC) who maintained serum HBV DNA < 2000 IU/mL beyond 1-year off-therapy, and 35 virological relapsers (VR) experiencing virological relapse within 1-year off-therapy were recruited. Viral quasispecies was analyzed by deep sequencing. Hepatitis B core-related antigen (HBcrAg) and HBsAg were also measured.

Results

VC had significantly higher baseline viral quasispecies diversity of the precore/core gene, measured by nucleotide diversity, than VR. Low baseline viral nucleotide diversity (< 0.01) and high HBcrAg (≧ 2.0 KU/mL), but not HBsAg, at end of treatment (EOT) were significantly associated with higher risk of 1-year virological relapse (hazard ratio [HR] 6.09 and 3.31, respectively). Combination of low baseline viral nucleotide diversity and high HBcrAg at EOT could identify patients at high risk (HR 15.82). Further analysis of the evolution of HBV whole genome showed that HBV nucleotide diversity negatively correlated with serum HBV DNA levels. Notably, the viral quasispecies diversity between pre- and post-NA treatment remained relatively unchanged.

Conclusion

Higher baseline HBV quasispecies diversity associates with more durable off-therapy viral suppression in HBeAg-negative CHB patients. Combination of baseline viral nucleotide diversity and HBcrAg at EOT can identify patients at high risk for virological relapse after stop** NAs.

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Data availability

Yes.

Change history

Abbreviations

NAs:

Nucleos(t)ide analog

CHB:

Chronic hepatitis B

VC:

Virological controllers

VR:

Virological relapsers

HBV:

Hepatitis B virus

HCC:

Hepatocellular carcinoma

AASLD:

American Association for the Study of the Liver Disease

EOT:

End-of-treatment

HBsAg:

Hepatitis B surface antigen

HBcrAg:

Hepatitis B core-related antigen

NGS:

Next-generation sequencing

ETV:

Entecavir

TDF:

Tenofovir disoproxil fumarate

ORFs:

Open reading frames

P:

Polymerase

S:

PreS1/S2/S

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Acknowledgements

We thank Dr. Chi-Ling Chen and Dr. Hurng-Yi Wang for their helpful discussion and suggestions on preparation of this manuscript. We also acknowledge the MiSeq and sequencing service provided by the Medical Microbiota Center of the First Core Laboratory, National Taiwan University College of Medicine and the Department of Medical Research, National Taiwan University Hospital.

Funding

The work was supported by grants from the Ministry of Science Technology (MOST-106-2314-B-002-075-MY3), the Ministry of Science Technology, Taiwan (MOST-106–2314-B-002-075, HCY), and National Taiwan University Hospital (NTUH-105-S3046, HCY).

Author information

Author notes

  1. Huei-Ru Cheng, Hung-Chih Yang contributed equally.

Authors and Affiliations

  1. Department of Internal Medicine, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 1 Chang-Te St., Taipei, 10002, Taiwan

    Huei-Ru Cheng, Hung-Chih Yang, Su-Ru Lin, You-Yu Lin & Jia-Horng Kao

  2. Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan

    Hung-Chih Yang & Ta-Yu Yang

  3. Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

    Hung-Chih Yang, Tung-Hung Su, Tai-Chung Tseng, Chun-Jen Liu & Jia-Horng Kao

  4. Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan

    Tung-Hung Su, Tai-Chung Tseng, Chun-Jen Liu & Jia-Horng Kao

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Contributions

Concept and design: H-RC, H-CY, S-RL, T-YY, Y-YL, T-HS, T-CT, C-JL, J-HK. Writing of article: H-RC, H-CY, J-HK. Statistical analysis: H-RC, S--RL, T-YY, Y-YL. Critical revision of the manuscript: H-CY, J-HK.

Corresponding author

Correspondence to Jia-Horng Kao.

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Conflict of interest

HRC, H-CY, SRL, T-YY, Y-YL, T-HS, T-CT, C-JL, J-HK declare no competing interests related to this manuscript.

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The study conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected by a priori approval by the Institutional Review Board of the National Taiwan University Hospital. All patients gave their written informed consents at enrollment.

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Cheng, HR., Yang, HC., Lin, SR. et al. Combined viral quasispecies diversity and hepatitis B core-related antigen predict off-nucleos(t)ide analog durability in HBeAg-negative patients. Hepatol Int 15, 582–592 (2021). https://doi.org/10.1007/s12072-021-10186-7

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