Highlights
- •Whether HBsAg seroclearance affects the risk of late (≥2 years) HCC recurrence after liver resection remains unanswered.
- •2,520 consecutive Korean patients who underwent curative-intent liver resection for HBV-related HCC of BCLC 0 or A were analyzed.
- •HBsAg seroclearance after liver resection was independently associated with a reduced risk of late (≥2 years) HCC recurrence.
Background & Aims
It is unknown whether HBsAg seroclearance affects the risk of hepatocellular carcinoma
(HCC) recurrence after liver resection. We aimed to investigate the impact of HBsAg
seroclearance on the recurrence of HCC after curative liver resection, with a focus
on late recurrence.
Methods
This study comprised 2,520 consecutive patients who received curative liver resection
for HBV-related HCC of Barcelona Clinic Liver Cancer stage 0 or A in Korea between
2000 and 2017. To focus on late recurrence, patients with recurrence or a follow-up
duration less than 2 years were excluded. The impact of HBsAg seroclearance on HCC
recurrence was assessed by landmark analysis (2-, 5-and 8-year after liver resection),
time-dependent Cox and multistate modeling.
Results
The mean patient age was 54.4 years and 75.7% were men. A total of 891 (35.4%) patients
developed HCC recurrence at rates of 11.2%, 25.5%, and 46.8% at 3, 5, and 10 years
after resection. HBsAg seroclearance was achieved in 172 (6.8%) patients during a
median follow-up duration of 6.9 years after resection. HBsAg seroclearance, compared
with persistent HBsAg positivity, was associated with a lower risk of late HCC recurrence
in the 2-, 5-, and 8-year landmark analysis (p = 0.04, p = 0.02 and p = 0.03, respectively) and on time-dependent multivariable Cox modeling (adjusted
hazard ratio 0.62; p = 0.005). Based on a 3-state unidirectional illness–death model, patients without
HBsAg seroclearance transitioned to HCC recurrence more rapidly than patients who
experienced HBsAg seroclearance.
Conclusions
HBsAg seroclearance is associated with a lower risk of late recurrence of HBV-related
HCC among Korean patients who undergo curative liver resection.
Lay summary
Hepatitis B virus (HBV) infection is a leading cause of chronic liver disease and
hepatocellular carcinoma (HCC). Suppression of HBV replication is known to lower the
risk of HCC recurrence after liver resection (a procedure used to treat and in some
cases cure HCC). However, whether the loss of a specific HBV protein (hepatitis B
surface antigen or HBsAg) has an impact on recurrence after liver resection remains
unknown. Herein, we show that loss of HBsAg is associated with a reduce risk of late
recurrence of HCC after liver resection in patients with HBV-related HCC.
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 cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2018; 68: 394-424
- EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.J Hepatol. 2017; 67: 370-398
- A global view of hepatocellular carcinoma: trends, risk, prevention and management.Nat Rev Gastroenterol Hepatol. 2019; 16: 589-604
- Recurrence of hepatocellular cancer after resection: patterns, treatments, and prognosis.Ann Surg. 2015; 261: 947-955
- Positive serum hepatitis B e antigen is associated with higher risk of early recurrence and poorer survival in patients after curative resection of hepatitis B-related hepatocellular carcinoma.J Hepatol. 2007; 47: 684-690
- Risk of recurrence in hepatitis B-related hepatocellular carcinoma: impact of viral load in late recurrence.J Hepatol. 2009; 51: 842-844
- Antiviral therapy improves post-operative survival outcomes in patients with HBV-related hepatocellular carcinoma of less than 3 cm - a retrospective cohort study.Am J Surg. 2020; 219: 717-725
- Effects of antiviral therapy on long-term outcome after liver resection for hepatitis B virus-related hepatocellular carcinoma.J Hepatobiliary Pancreat Sci. 2012; 19: 685-696
- Antiviral therapy improves postoperative survival in patients with hepatocellular carcinoma: a randomized controlled trial.Ann Surg. 2015; 261: 56-66
- Risk factors and management for early and late intrahepatic recurrence of solitary hepatocellular carcinoma after curative resection.HPB (Oxford). 2015; 17: 422-427
- Differentiating early and late recurrences after resection of HCC in cirrhotic patients: implications on surveillance, prevention, and treatment strategies.Ann Surg Oncol. 2009; 16: 792-794
- Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma.J Hepatol. 2009; 51: 890-897
- Early and late recurrence after liver resection for hepatocellular carcinoma: prognostic and therapeutic implications.Ann Surg. 2006; 243: 229-235
- Prediction of hepatocellular carcinoma recurrence in patients with low hepatitis B virus DNA levels and high preoperative hepatitis B surface antigen levels.JAMA Surg. 2014; 149: 519-527
- 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
- HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B: clinical outcomes and durability.Gut. 2014; 63: 1325-1332
- Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases.Hepatology. 2018; 68: 723-750
- Metformin and the risk of cancer: time-related biases in observational studies.Diabetes Care. 2012; 35: 2665-2673
- Challenges of guarantee-time bias.J Clin Oncol. 2013; 31: 2963-2969
- Tutorial in biostatistics: competing risks and multi-state models.Stat Med. 2007; 26: 2389-2430
- Management of hepatocellular carcinoma.J Hepatol. 2018; 69: 182-236
- Hepatocellular carcinoma: clinical frontiers and perspectives.Gut. 2014; 63: 844-855
- Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy.J Hepatol. 2003; 38: 200-207
- Selection criteria for repeat hepatectomy in patients with recurrent hepatocellular carcinoma.Ann Surg. 2003; 238: 703-710
- Appropriate treatment strategies for intrahepatic recurrence after curative resection of hepatocellular carcinoma initially within the Milan criteria: according to the recurrence pattern.Eur J Gastroenterol Hepatol. 2015; 27: 933-940
- Different risk factors and prognosis for early and late intrahepatic recurrence after resection of hepatocellular carcinoma.Cancer. 2000; 89: 500-507
- Risk factors associated with early and late recurrence after curative resection of hepatocellular carcinoma: a single institution's experience with 398 consecutive patients.Hepatobiliary Pancreat Dis Int. 2014; 13: 153-161
- Early recurrence after curative resection in oligonodular hepatocellular carcinoma.Hepatogastroenterology. 2013; 60: 28-31
- Risk factors for early recurrence of small hepatocellular carcinoma after curative resection.Hepatobiliary Pancreat Dis Int. 2010; 9: 33-37
- Lamivudine for patients with chronic hepatitis B and advanced liver disease.New Engl J Med. 2004; 351: 1521-1531
- Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.Hepatology. 2018; 67: 1560-1599
- KASL clinical practice guidelines: management of chronic hepatitis B.Clin Mol Hepatol. 2016; 22: 18-75
- Systematic review with meta-analysis: development of hepatocellular carcinoma in chronic hepatitis B patients with hepatitis B surface antigen seroclearance.Aliment Pharmacol Ther. 2016; 43: 1253-1261
- Spontaneous seroclearance of hepatitis B seromarkers and subsequent risk of hepatocellular carcinoma.Gut. 2014; 63: 1648-1657
- Incidence of hepatocellular carcinoma after HBsAg seroclearance in chronic hepatitis B patients: a need for surveillance.J Hepatol. 2015; 62: 1092-1099
- Comparison of long-term clinical outcomes between spontaneous and therapy-induced HBsAg seroclearance.Hepatology. 2021; 73: 2155-2166
- Guidance for design and endpoints of clinical trials in chronic hepatitis B - report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference(double dagger).J Hepatol. 2020; 72: 539-557
- Early and late recurrence of hepatitis B virus-associated hepatocellular carcinoma.Oncologist. 2020; 25: e1541-e1551
- Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma: a two-stage longitudinal clinical study.J Clin Oncol. 2013; 31: 3647-3655
Article info
Publication history
Published online: May 25, 2022
Accepted:
May 13,
2022
Received in revised form:
May 4,
2022
Received:
October 2,
2021
Footnotes
Author names in bold designate shared co-first authorship
Identification
Copyright
© 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
