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Residual HBV DNA and pgRNA viraemia is associated with hepatocellular carcinoma in chronic hepatitis B patients on antiviral therapy

  • Original Article―Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

We aimed to assess whether residual hepatitis B virus (HBV) viraemia is associated with HCC development.

Methods

This is a case–control study of 104 patients [52 HCC and 52 non-HCC (matched with age, gender, cirrhosis and treatment duration)] on ≥ 3 years entecavir (ETV) with unquantifiable HBV DNA by Cobas Taqman assay v2.0 (Roche Diagnostics; lower limit of quantification [LLOQ] 20 IU/mL). Serial sera within 1, 1–2, and > 2 years prior to HCC diagnosis or last follow-up (LFU) were measured for HBV DNA and pre-genomic (pg) RNA using a highly sensitive semi-quantitative PCR assay with lower limit of detection of 10 IU/mL and LLOQ of 51.5 IU/mL, respectively.

Results

Among the 104 patients (80.8% male, median age 61.2 years old, 38.5% cirrhosis, median duration of ETV 45.5 months), 38.5% and 9.6% HCC patients had undetectable serum DNA and pgRNA, respectively, compared to 65.4% and 36.5% in non-HCC patients; P = 0.005 & 0.001, respectively, at the time of HCC diagnosis/LFU. Detectable HBV DNA and pgRNA were associated with a higher 2-year risk of HCC development (HR 2.79, 95% CI 1.424–5.468 & HR 4.544, 95% CI 1.07–19.289, respectively). No significant differences were observed for qHBsAg levels between HCC and non-HCC patients.

Conclusions

More than 50% CHB patients on ETV with HBV DNA < LLOQ by standard assay had persistent viraemia as determined by a more sensitive assay. Detectable HBV DNA or pgRNA by more sensitive assays was associated with HCC development. More potent viral suppression is required to further reduce the risk of HCC.

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Abbreviations

HBV:

Hepatitis B virus

HCC:

Hepatocellular carcinoma

CHB:

Chronic hepatitis B infection

NRTI:

Reverse transcriptase inhibitors

ALT:

Alanine aminotransferase

HBcrAg:

Hepatitis B core-related antigen

qHBsAg:

Quantitative hepatitis B surface antigen

pgRNA:

Pre-genomic RNA

cccDNA:

Covalently closed circular DNA

ETV:

Entecavir

AFP:

Alpha fetoprotein

LFU:

Last follow-up

PCR:

Polymerase chain reaction

LLOD:

Lower limit of detection

LLOQ:

Lower limit of quantification

DNQ:

Detectable but not quantifiable

IQR:

Interquartile range

HR:

Hazard ratio

BCLC:

Barcelona Clinic Liver Cancer staging system

RFA:

Radiofrequency ablation

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Funding

HBV RNA and DNA measurements are provided by Assembly Biosciences.

Author information

Authors and Affiliations

  1. Department of Medicine, Queen Mary Hospital, The University of Hong Kong, 4/F, Professorial Block, Pokfulam Road 102, Pok Fu Lam, Hong Kong

    Lung-Yi Mak, Danny Ka-Ho Wong, Ka-Shing Cheung, Kwan-Lung Ko, James Fung, Wai-Kay Seto & Man-Fung Yuen

  2. State Key Laboratory of Liver Research, The University of Hong Kong, Pok Fu Lam, Hong Kong

    Lung-Yi Mak, Danny Ka-Ho Wong, James Fung, Wai-Kay Seto & Man-Fung Yuen

  3. Assembly Biosciences, Inc., South San Francisco, USA

    Qi Huang, Luisa Stamm, Ran Yan & Lea Ouyang

  4. Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China

    Ka-Shing Cheung & Wai-Kay Seto

Authors
  1. Lung-Yi Mak
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  2. Qi Huang
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  6. Kwan-Lung Ko
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  7. Ran Yan
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Contributions

LYM was responsible for data interpretation, statistical analysis and drafting of the manuscript. DKHW, KSC and KLK were responsible for data acquisition and study design. QH, RY and LO were responsible for data acquisition and data analysis. LMS, WKS and JF were responsible for critical revision of the manuscript. MFY was responsible for study concept, study design, overall supervision of study and critical revision of the manuscript.

Corresponding author

Correspondence to Man-Fung Yuen.

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Conflict of interests

QH, LMS, RY and LO are employees of Assembly Biosciences. WKS received speaker’s fee from AstraZeneca and Mylan, is an advisory board member and received speaker’s fees from AbbVie, and is an advisory board member, received speaker’s fees and researching funding from Gilead Sciences. J Fung is an advisory board member of Gilead Sciences. MFY received research funding from Assembly Biosciences, Arrowhead Pharmaceuticals, Bristol Myer Squibb, Fujirebio Incorporation, Gilead Sciences, Merck Sharp and Dohme, Springbank Pharmaceuticals, Sysmex Corporation, and is an advisory board member and/or received research funding from Abbvie, Arbutus Biopharma, Assembly Biosciences, Bristol Myer Squibb, Dicerna Pharmaceuticals, GlaxoSmithKline, Gilead Sciences, Janssen, Merck Sharp and Dohme, Clear B Therapeutics, Springbank Pharmaceuticals. LYM, DKHW, KSC and KLK declared no conflict of interest.

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Mak, LY., Huang, Q., Wong, D.KH. et al. Residual HBV DNA and pgRNA viraemia is associated with hepatocellular carcinoma in chronic hepatitis B patients on antiviral therapy. J Gastroenterol 56, 479–488 (2021). https://doi.org/10.1007/s00535-021-01780-5

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  • DOI: https://doi.org/10.1007/s00535-021-01780-5

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