Impact of age and gender on risk of hepatocellular carcinoma after hepatitis B surface antigen seroclearance

doi:10.1016/j.jhep.2017.06.019

Journal of Hepatology

Volume 67, Issue 5, November 2017, Pages 902-908

https://doi.org/10.1016/j.jhep.2017.06.019 Get rights and content

Highlights

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Age >50 years and male gender were two risk factors of HCC after HBsAg loss.
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Female patients aged 50 years or below had zero risk of HCC in 5 years.
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Female patients aged above 50 years and all male patients are still at risk of HCC.

Background and Aims

Previous studies suggested spontaneous seroclearance of hepatitis B surface antigen (HBsAg) was still associated with an increased risk of hepatocellular carcinoma (HCC), in patients ⩾50 years of age. This study aimed to evaluate the risk of HCC after HBsAg seroclearance and the impact of gender on HCC.

Methods

All chronic hepatitis B patients under medical care in Hospital Authority, Hong Kong who had cleared HBsAg between January 2000 and August 2016 were identified. The age of the patient at HBsAg seroclearance, gender, and subsequent development of HCC were analyzed.

Results

A total of 4,568 patients with HBsAg seroclearance were identified; 793 (17.4%) were treated by nucleos(t)ide analogues and 60 (1.3%) had received interferon treatment. At a median (interquartile range) follow-up of 3.4 (1.5–5.0) years, 54 patients developed HCC; cumulative incidences of HCC at 1, 3 and 5 years were 0.9%, 1.3% and 1.5%, respectively. Age above 50 years (adjusted hazard ratio 4.31, 95% confidence interval 1.72–10.84; p = 0.002) and male gender (2.47, 1.24–4.91; p = 0.01) were two independent risk factors of HCC. Female patients aged ⩽50 years (n = 545) had zero risk of HCC within 5 years of follow-up. Male patients aged ⩽50 years (n = 769), female patients aged >50 years (n = 1,149) and male patients aged >50 years (n = 2,105) had a 5-year cumulative incidence of HCC 0.7%, 1.0% and 2.5%, respectively. Similar findings were observed in patients with spontaneous and antiviral treatment-induced HBsAg seroclearance.

Conclusions

Female patients aged 50 years or below have zero risk of HCC after HBsAg seroclearance, whereas female patients aged above 50 years and all male patients are still at risk of HCC.

Lay summary: We investigated 4,568 patients with hepatitis B surface antigen (HBsAg) seroclearance. Female patients aged 50 years or below have zero risk of hepatocellular carcinoma (HCC) after HBsAg seroclearance, whereas female patients aged above 50 years and all male patients are still at risk of HCC.

Graphical abstract

Introduction

Chronic hepatitis B (CHB) is the leading cause of hepatocellular carcinoma (HCC) worldwide.¹ Hepatitis B surface antigen (HBsAg) seroclearance is a surrogate of ultimate immune control of hepatitis B virus (HBV). The annual incidence of spontaneous HBsAg seroclearance varies from 0.12% to 2.38% in Asian cohorts and from 0.54% to 1.98% in Western cohorts.² The rate and durability of HBsAg seroclearance induced by nucleos(t)ide analogues (NA) were recently found to be similar to those developed spontaneously.³ Patients who achieve this endpoint often have a much more favorable clinical course and very low risk of HCC.[4], [5], [6]

Despite a favorable clinical course, the risk of HCC still exists in patients achieving HBsAg seroclearance. Among all the well-established risk factors, age of HBsAg seroclearance, co-infection with hepatitis C and/or D virus, and presence of cirrhosis are the most important.[5], [7], [8] In particular, age above 50 years at the time of HBsAg seroclearance has been considered as a clinically important cut-off in previous studies, and shown to be independently associated with the development of HCC after HBsAg seroclearance.[9], [10] However, because of the limited sample size of female patients, there has been little data concerning the impact of gender, a well-defined risk factor for HCC development in CHB patients,[1], [11] as well as age on the risk of HCC after HBsAg seroclearance. In this large cohort study, we aimed to determine the impact of age and gender on the HCC risk in CHB patients who achieved HBsAg seroclearance and the potential interaction between these two factors.

Section snippets

Study design and data source

We performed a retrospective cohort study using data from the Clinical Data Analysis and Reporting System (CDARS) of the Hospital Authority (HA), Hong Kong. CDARS facilitates the retrieval of clinical data captured from different operational systems for analysis and reporting, and provides good quality information to support retrospective clinical and management decisions by integrating the clinical data stored in Data Warehouse.¹² All individuals who tested positive for HBsAg between January

Results

We identified 73,493 subjects who had a positive HBsAg result at least once; 68,925 were excluded according to the inclusion and exclusion criteria (Fig. 1). Finally, 4,568 CHB patients with HBsAg seroclearance were included for analysis (Table 1). Their mean age was 56.7 ± 13.8 years, and 2,874 (62.9%) patients were male. Most patients had compensated liver function and normal alanine aminotransferase (ALT) level at the time of HBsAg seroclearance. Their mean serum albumin was 41.4 ± 5.9 g/L, total

Discussion

This is one of the largest cohorts of CHB patients with HBsAg seroclearance studied with the aim of examining the effects of gender, as well as age and their interaction on the risk of HCC after HBsAg seroclearance. Our findings showed that CHB patients who achieve HBsAg seroclearance were associated with low yet definite risk of HCC, with a 5-year incidence of 1.5%. We further established that male gender is an independent risk factor of HCC in patients with HBsAg seroclearance, on top of the

Financial support

This work was supported by the Research Fund for the Control of Infectious Diseases from the Food and Health Bureau of the Hong Kong Government (Reference no: CU-16-01-A10).

Conflict of interest

Henry Chan is a consultant for Abbvie, Bristol-Myers Squibb, Gilead, Janssen and Roche, has received honorarium for lecture for Abbvie, Bristol-Myers Squibb, Echosens, Gilead, Glaxo-Smith-Kline, Merck, Novartis and Roche, and has received an unrestricted grant from Roche for hepatitis B research.

Vincent Wong has served as an advisory committee member for Abbvie, Roche, Novartis, Gilead and Otsuka. He has also served as a speaker for Abbvie, Bristol-Myers Squibb, Roche, Novartis, Abbott

Authors’ contributions

Terry Yip, Yee-Kit Tse, Kelvin Lam and Grace Wong had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors were responsible for the study concept and design. Terry Yip, Yee-Kit Tse, Kelvin Lam and Grace Wong were responsible for the acquisition and analysis of data. All authors were responsible for the interpretation of data, the drafting, and critical revision of the manuscript for important

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Reply to: “For long-term outcomes, is the impact of cirrhosis more important than HBsAg seroclearance?”
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Risk of hepatic decompensation but not hepatocellular carcinoma decreases over time in patients with hepatitis B surface antigen loss
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Citation Excerpt :
Previous studies reported a small yet non-negligible risk of HCC persists in CHB patients after HBsAg seroclearance.9-11 Older age, male gender, presence of cirrhosis and diabetes mellitus (DM), and family history of HCC are associated with the development of HCC after HBsAg loss.9,12,13 While it is generally believed that the progression of liver disease to cirrhosis and hepatic decompensation will stop after HBsAg seroclearance if there are no other causes of liver injury,14-16 whether the risk of developing hepatic decompensation after HBsAg loss continues to decline over time and finally become negligible remains poorly understood.
We examined the long-term incidence of hepatocellular carcinoma (HCC) and hepatic decompensation among chronic hepatitis B (CHB) patients who have achieved hepatitis B surface antigen (HBsAg) seroclearance.
All adult CHB-monoinfected patients who cleared HBsAg between January 2000 and December 2020 were identified using a territory-wide database in Hong Kong. Patients who underwent liver transplantation and/or developed HCC before HBsAg seroclearance or less than 6 months follow-up were excluded. The primary and secondary endpoints were HCC and hepatic decompensation respectively.
We identified 9,769 patients with CHB who achieved HBsAg seroclearance (mean age 57 years, 60.0% male, 13.2% cirrhosis); most had compensated liver function at HBsAg loss. At a median (25^th–75^th percentile) follow-up of 4.6 (2.2–8.4) years, 106 (1.1%) patients developed HCC. Patients who developed HCC were older, more likely to be male and have cirrhosis, and had higher alanine aminotransferase and lower platelets at the time of HBsAg loss than patients without HCC. The cumulative incidence of HCC remained steady 0–7 and 8–12 years after HBsAg loss (p = 0.898) (crude annual incidence drop: −0.04%, 95% CI −0.13% to 0.04%, p = 0.265). Moreover, 124/9,640 (1.3%) patients developed hepatic decompensation. The growth in cumulative incidence of hepatic decompensation decelerated 8–12 years after HBsAg loss (p = 0.009) (crude annual incidence drop: −0.23%, 95% CI −0.40% to −0.06%, p = 0.012). In multivariable analysis, HBsAg loss for over 7 years was associated with a reduced risk of hepatic decompensation (adjusted subdistribution hazard ratio [aSHR] 0.55, 95% CI 0.31–0.97, p = 0.039) but not HCC (aSHR 1.35, 95% CI 0.83–2.19, p = 0.230).
HCC risk persists in patients after HBsAg loss, whereas the risk of hepatic decompensation decreases over time.
Patients with chronic hepatitis B (CHB) still have a non-negligible risk of hepatocellular carcinoma (HCC) after 12 years of HBsAg seroclearance, especially among those with cirrhosis. The risk of developing hepatic decompensation decreases over time after HBsAg seroclearance. In clinical practice, although patients with CHB who cleared HBsAg have a more favourable clinical outcome than those who remain chronically infected, long-term HCC surveillance would still be necessary for patients with cirrhosis and other high-risk subgroups after HBsAg seroclearance.
Clinical Consequences of Hepatitis B Surface Antigen Loss in Chronic Hepatitis B Infection: A Systematic Literature Review and Meta-Analysis
2023, Gastro Hep Advances
Functional cure, which requires sustained hepatitis B surface antigen (HBsAg) loss after treatment cessation, is currently the optimal treatment endpoint for chronic hepatitis B virus infection. We performed a systematic literature review (SLR) and meta-analyses to assess the association between HBsAg loss and long-term clinical outcomes.
We performed a SLR of scientific literature published in Medline and Embase reporting the incidence of cirrhosis, hepatic decompensation (HD), hepatocellular carcinoma (HCC), liver-related mortality (LRM), and all-cause mortality (ACM) in relation to HBsAg status. Bayesian hierarchical commensurate prior meta-analyses synthesized evidence on the association between HBsAg loss and each outcome.
Thirty-eight studies, comprising 50,354 patients with 350,734 patient-years of follow-up, were included in the meta-analyses, reporting on cirrhosis (n = 12), HD (n = 12), HCC (n = 36), LRM (n = 12), and ACM (n = 16). Pooled incidence rate ratios (IRRs; vs HBsAg persistence) and respective credible intervals (Crls) were 0.28 (0.060–1.070) for cirrhosis, 0.13 (0.013–0.38) for HD, 0.27 (0.11–0.53) for HCC, 0.17 (0.028–0.61) for LRM, and 0.64 (0.24–1.17) for ACM. Single-predictor-adjusted IRRs remained consistent with those from the primary analyses for all outcomes except cirrhosis and LRM. Outcome incidence rates were modified by selected study, patient and infection characteristics, but trended in the same direction of reduced risk after loss.
Overall, HBsAg loss was associated with a reduced risk of most clinically relevant outcomes. While the magnitude of the effect differed across subgroups, the direction of the association remained similar. Our results validate the need to develop new strategies to achieve HBsAg loss.
A risk prediction model for hepatocellular carcinoma after hepatitis B surface antigen seroclearance
2022, Journal of Hepatology
After hepatitis B surface antigen (HBsAg) seroclearance, the risk of hepatocellular carcinoma (HCC) remains, and the optimal surveillance strategy has yet to be determined. Herein, we aimed to evaluate incidence and risk factors for HCC and establish a novel prediction model for HCC development after HBsAg seroclearance.
A total of 1,443 patients with chronic hepatitis B who achieved HBsAg seroclearance between 1991 and 2020 were retrospectively screened for study eligibility. The data from 831 of these patients were included in the final analysis. A prediction model was developed based on multivariable Cox models. Harrell’s C-index and a time-dependent AUROC were used for discrimination. Bootstrap analysis was performed for internal validation.
Overall, 40 patients (4.8%) developed HCC after HBsAg seroclearance during a follow-up of 4,644 person-years (0.86%/year). Age at HBsAg seroclearance, presence of cirrhosis, family history of HCC, and more-than-moderate alcohol consumption were independently predictive of HCC, and these 4 independent variables were used to develop the prediction model. The C-index of the model was 0.804. The time-dependent AUROCs of the score for HCC prediction at 5, 10, and 15 years were 0.799, 0.835, and 0.817, respectively. The score also showed good discrimination in the internal validation and sensitivity analysis.
The novel prediction model based on age, cirrhosis, family history of HCC, and alcohol consumption enables reliable risk estimation of HCC after HBsAg seroclearance and may serve as a useful reference for decision-making in HCC surveillance for HBsAg-cleared patients.
After spontaneous hepatitis B surface antigen (HBsAg) seroclearance, the risk of hepatocellular carcinoma (HCC) remains. Age at HBsAg seroclearance, presence of cirrhosis, family history of HCC, and more-than-moderate alcohol consumption were independently associated with HCC development after HBsAg seroclearance. The novel prediction model using these 4 variables enables reliable risk estimation of HCC and serves as a useful reference for decision-making in HCC surveillance and management for HBsAg-cleared patients.
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View full text

Research ArticleImpact of age and gender on risk of hepatocellular carcinoma after hepatitis B surface antigen seroclearance

Highlights

Background and Aims

Methods

Results

Conclusions

Graphical abstract

Introduction

Section snippets

Study design and data source

Results

Discussion

Financial support

Conflict of interest

Authors’ contributions

J Hepatol

Gastroenterology

J Hepatol

Lancet Oncol

Gastroenterology

Lancet

J Hepatol

Infection and cancer: the case of hepatitis B

J Clin Oncol

Hepatitis B surface antigen seroclearance during chronic HBV infection

Antivir Ther

Hepatitis B surface antigen seroclearance in a cohort of 154,740 patients with chronic hepatitis B: a 15-year follow-up study

Hepatol Int

Spontaneous seroclearance of hepatitis B seromarkers and subsequent risk of hepatocellular carcinoma

Gut

Clearance of hepatitis B surface antigen and risk of hepatocellular carcinoma in a cohort chronically infected with hepatitis B virus

Hepatology

HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B: clinical outcomes and durability

Gut

Research Article
Impact of age and gender on risk of hepatocellular carcinoma after hepatitis B surface antigen seroclearance