Extrahepatic Malignancies Are the Leading Cause of Death in Patients with Chronic Hepatitis B without Cirrhosis: A Large Population-Based Cohort Study

Simple Summary This study investigated the mortality rates and causes of death in patients with chronic hepatitis B (CHB) according to cirrhosis. Over a 10-year follow-up period of 223,424 patients (cohort 1) with CHB, the overall mortality was 1.54 per 100 person-years. The mortality associated with HCC was the highest (0.65 per 100 person-years), followed by mortality related to extrahepatic malignancies (0.26 per 100 person-years), and cardio/cerebrovascular diseases (0.18 per 100 person-years). In the non-cirrhotic CHB (87.4%), 70% (11,198/15,996) of patients died due to non-liver related causes, and mortality due to extrahepatic malignancies had the highest rate (0.23 per 100 person-years). Considering that mortality related to HCC decreased and mortality related to extrahepatic malignancies increased in the antiviral era of CHB, it will be important to develop customized strategies for aging CHB cohort to reduce mortality. Abstract (1) Background: Accurate statistics on the causes of death in patients with chronic hepatitis B (CHB) are lacking. We investigated mortality rates and causes of death over time. (2) Methods: Data on patients newly diagnosed with CHB from 2007 to 2010 (cohort 1, n = 223,424) and 2012 to 2015 (cohort 2, n = 177,966) were retrieved from the Korean National Health Insurance Service. Mortality data were obtained from Statistics Korea. The causes of death were classified as liver-related (hepatic decompensation or hepatocellular carcinoma [HCC]) or extrahepatic (cardiovascular-related, cerebrovascular-related, or extrahepatic malignancy-related). (3) Results: Over a 10-year follow-up period of 223,424 patients (cohort 1) with CHB, the overall mortality was 1.54 per 100 person-years. The mortality associated with HCC was the highest (0.65 per 100 person-years), followed by mortality related to extrahepatic malignancies (0.26 per 100 person-years), and cardio/cerebrovascular diseases (0.18 per 100 person-years). In the non-cirrhotic CHB (87.4%), 70% (11,198/15,996) of patients died due to non-liver-related causes over ten years. The 10-year overall mortality was 0.86 per 100 person-years. Among these, mortality due to extrahepatic malignancies had the highest rate (0.23 per 100 person-years), followed by mortality related to HCC (0.20 per 100 person-years), and cardio/cerebrovascular diseases (0.16 per 100 person-years). The 5-year mortality associated with extrahepatic malignancies increased from 0.36 per 100 person-years (cohort 1) to 0.40 per 100 person-years (cohort 2). (4) Conclusions: Mortality related to HCC decreased, whereas mortality related to extrahepatic malignancies increased in the antiviral era. Extrahepatic malignancies were the leading cause of death among patients with CHB without cirrhosis.


Introduction
Chronic hepatitis B (CHB) infection is a major cause of chronic liver disease and hepatocellular carcinoma (HCC) [1,2].Over the past several decades, remarkable progress has been made in terms of CHB prevention and treatment given the introduction of hepatitis B virus (HBV) vaccination programs and extensive use of highly efficient antiviral therapy (AVT) with nucleos(t)ide analogs (NUCs) [3,4].The National Progress Report of the World Health Organization (WHO) found that the age-adjusted HBV-related death rate in the United States gradually fell from 0.53/100,000 persons in 2013 to 0.45/100,000 persons in 2020 [5].However, in another study that used data from the U.S. National Vital Statistics System, the number of deaths from extrahepatic disease increased despite the decrease in liver-related mortality [6].The age-standardized liver-related mortality rate in patients with CHB declined steadily from 0.392/100,000 persons in 2007 to 0.303/100,000 persons in 2017, whereas the age-standardized extrahepatic mortality rate in patients with CHB increased by an average of 2% annually.Moreover, when liver-related mortality was modeled in the Asian Pacific region, HBV-related mortality gradually increased from 2015 to 2020 [7].Therefore, accurate statistics on overall and specific mortalities, causes of death, and changes over time in a CHB cohort of Asia where HBV is endemic, are essential.
As CHB management seeks to reduce mortality, it is of paramount importance to investigate changes in mortality rates and the causes of death in patients with CHB and manage individual patients in a holistic manner.Here, we investigated the mortality rates and causes of death in patients with CHB according to cirrhosis, antiviral treatment status, and time period.

Data Collection and Study Design
This large, population-based retrospective study used data from the Korean National Health Insurance Service (KNHIS).Mortality rates and causes of death were obtained from Statistics Korea.We derived causes of death in all CHB patients from KNHIS database by linking the data to Statistics Korea.This study was approved by the institutional review board of CHA University, Seoul, Republic of Korea (approval no.2020-06-035).

Patients
Patients with CHB were defined as those who were assigned with the International Classification of Diseases (ICD) codes for CHB infection (B18.0,B18.1, Z22.51, and K74.69H) twice during the study period or who were receiving AVT for CHB (having drug codes for lamivudine, adefovir, entecavir, tenofovir alafenamide, tenofovir fumarate, telbivudine, clevudine, or besifovir).Patients diagnosed with CHB from the KNHIS database between January 2002 and December 2020 were screened.To filter out newly diagnosed CHB cases, those with CHB diagnostic codes assigned before the index date (the date of first diagnosis of CHB within the study period) were excluded.Finally, we included patients newly diagnosed with CHB between January 2007 and December 2010 (cohort 1) and January 2012 and December 2015 (cohort 2).We excluded patients infected with acute hepatitis B virus, hepatitis C virus, or human immunodeficiency virus.

Statistical Analyses
Data are presented as numbers (percentages), means ± standard deviations, numbers, or rates per 100,000 person-years as appropriate.The Student's t test or the Mann-Whitney U-test was used to compare continuous variables and the chi-square or Fisher's exact test was employed to compare categorical variables.Cox's regression analysis was performed to assess the associations between mortality and all variables, and to calculate hazard ratios (HRs) with 95% confidence intervals (CIs).All analyses were conducted using SAS software (version 9.4; SAS Institute, Cary, NC, USA) and R version 3.6.0(http://cran.r-project.org/(accessed on 1 May 2022)).Two-sided p-values < 0.05 were considered statistically significant.

Ten-Year Mortality of Patients with CHB
During the 10-year follow-up of cohort 1, which included 223,424 patients with CHB, the overall mortality was 1.54 deaths per 100 person-years (Table 2).Among the various mortalities, HCC was responsible for 0.65 deaths per 100 person-years.Mortality related to extrahepatic malignancies accounted for 0.26 deaths per 100 person-years, while cardiovascular/cerebrovascular diseases contributed to 0.17 deaths per 100 person-years.Additionally, decompensation accounted for 0.16 deaths per 100 person-years.When examining the specific causes of death among patients with CHB, HCC emerged as the most common cause, responsible for 42.0% of all mortality cases.Extrahepatic malignancies followed closely, accounting for 17.2% of deaths.Cardio/cerebrovascular diseases constituted the cause of 11.6% of deaths.Among the extrahepatic malignancies classified under the category of "other", lung cancer held the highest prevalence, followed by stomach, pancreatic, colon, and biliary cancers.

Ten-Year Mortality among Cirrhotic and Non-Cirrhotic CHB Patients
When comparing the 10-year mortality rates based on the presence or absence of liver cirrhosis, distinct patterns emerged.Among patients with cirrhosis, the overall mortality rate was higher at 53.7% (equivalent to 9.23 deaths per 100 person-years), whereas those without cirrhosis exhibited a substantially lower overall mortality rate of 8.2% (equivalent to 0.86 deaths per 100 person-years) (Table 3).In the cirrhotic CHB subgroup, mortality primarily attributed to liver-related causes, such as hepatic decompensation or HCC, accounting for 75.4%.The mortality rate due to HCC was the highest within this subgroup, reaching 5.76 per 100 person-years.This was followed by mortality related to extrahepatic malignancies (0.61 per 100 person-years), and cardio/cerebrovascular diseases (0.40 per 100 person-years).Interestingly, among non-cirrhotic CHB patients, approximately 70% (11,198 out of 15,996) of deaths occurred due to non-liver-related causes over the course of ten years.The 10-year overall mortality rate for this subgroup was notably lower at 0.86 deaths per 100 person-years.Among these cases, mortality stemming from extrahepatic malignancies had the highest rate at 0.23 deaths per 100 person-years, followed by mortality associated with HCC (0.20 deaths per 100 person-years) and cardio/cerebrovascular diseases (0.16 deaths per 100 person-years).

Changes in Mortality Trends in Patients with CHB by Period
The patient population with CHB was stratified into two cohorts, early (cohort 1) and late (cohort 2) (Table 4).Over a 5-year observation period, cohort 1 exhibited an overall mortality risk of 2.16 deaths per 100 person-years, while cohort 2 demonstrated a slightly lower overall mortality risk of 1.77 deaths per 100 person-years.In relation to cohort 1, patients in cohort 2 displayed a notably reduced overall mortality risk, with an adjusted hazard ratio (aHR) of 0.83 (95% CI: 0.81-0.85),adjusting for age, sex, and AVT status.The 5-year mortality rate attributed to HCC decreased from 1.03 deaths per 100 person-years in cohort 1 to 0.76 deaths per 100 person-years in cohort 2 (aHR, 0.63; 95% CI, 0.62-0.65;adjusted by age, sex, and AVT status).In contrast, the mortality rate linked to extrahepatic malignancies increased from 0.36 deaths per 100 person-years in cohort 1 to 0.40 deaths per 100 person-years in cohort 2 (aHR, 1.21; 95% CI, 1.18-1.23;adjusted by age, sex, and AVT status).HCC-hepatocellular carcinoma.A-all; M-male; F-female, Pt-patient.

Discussion
This study demonstrated the first large-scale investigation in the Asian population that delves into the evolving causes of mortality over the time in a HBV cohort with substantial number of patients.The analysis involved a comparison between two distinct cohorts spanning different timeframes.This research encompassed assessments of overall mortality rates and the underlying causes of death.Over the years, there has been a discernible shift in the predominant cause of death among CHB patients.Overall, 10-year mortality was 1.54 per 100 person-years in total CHB cohort.The mortality associated with HCC was the highest at 0.65 per 100 person-years, followed by mortality related to extrahepatic malignancies (0.26 per 100 person-years).Meanwhile, 70% non-cirrhotic CHB patients died due to non-liver related cause.Among these, mortality due to extrahepatic malignancies was the highest, followed by mortality related to HCC.Over the years, mortality related to HCC decreased, and the mortality associated with extrahepatic malignancies increased.
This study has several important implications.First, special attention should be paid to extrahepatic malignancies as a cause of death in HBV cohorts.As CHB patient cohorts age and life expectancy is extended, the numbers of patients with extrahepatic malignancies who die of such conditions will increase.Several studies have shown that the incidence of extrahepatic malignancies is higher in patients with CHB than in general populations.Allaire et al. investigated the incidences of primary liver and extrahepatic malignancies in 1671 cirrhotic patients with CHB or chronic hepatitis C infections and found that the rates were higher than in a healthy normal population (primary liver cancer, 2910.7 vs. 28.3/100,000person-years, p < 0.001; malignancies, 1181.2 vs. 985.8/100,000person-years, p = 0.003) [8].In the present study, extrahepatic malignancy was the leading cause of death in non-cirrhotic CHB patients.Another Korean study reported that patients with CHB were at increased risk not only for liver cancer but also for multiple extrahepatic malignancies [9].HBV is known to trigger hematological malignancies such as non-Hodgkin's lymphoma, and the incidence of solid tumors such as nasopharyngeal cancer is higher among HBV patients than general populations [10][11][12].One plausible explanation for higher cancer prevalence in CHB patients than in general population may be the modified immune system in patients with chronic viral infection.CD4+CD25+ regulatory T-cells are thought to contribute to the impaired immune response in CHB and chronic hepatitis C patients [13,14].In patients with HCC, tumor microenvironments with dominant regulatory T-cells which prohibit CD8+ cytotoxic T-cells can indirectly support tumor growth and progression [15,16].Plasma-soluble human leukocyte antigen-G (HLA-G) levels are elevated in CHB and chronic hepatitis C patients compared to healthy controls [17,18].Upregulated expression of HLA-G by virus-infected cell is proposed to inhibit cytolytic action of natural killer cells and T-cells, and this is also associated to tumor growth and disease progression in various types of cancers [19][20][21][22][23].In the present study, the most frequent deaths from extrahepatic malignancies were from lung, stomach, pancreas, colon, and biliary cancers.This ranking is similar to the '2019 cancer death rankings of the general population in Korea' (lung, liver [HCC and other liver cancers], colon, stomach, and pancreatic cancers), which is annually provided by Statistics Korea [24].More research is needed to determine which extrahepatic malignancy is most common and causes most deaths in patients with CHB.Extrahepatic malignancy surveillance may be strongly recommended in HBV cohorts, and whether surveillance of HBV patients should differ from that of the general population should be determined in the future study.
Second, we found that cardiovascular/cerebrovascular conditions were major causes of death in HBV patients.In both our total CHB and non-cirrhotic HBV cohorts, mortality related to cardiovascular/cerebrovascular disease was higher than that related to decompensation (11.6% vs. 10.1% in the total CHB cohort; 18.5% vs. 7.3% in the non-cirrhotic HBV cohort).Lee et al. found that the risks for HCC and non-HCC cancers, and the all-cause mortality rate, increased as the number of metabolic syndrome components increased in patients with CHB [25].Thus, risk assessment and management of metabolic diseases is important in an era when liver-related mortality is decreasing because of complete virological suppression of HBV and the metabolic risk posed by obesity is increasing.
Third, to reduce mortality, different strategies are required for CHB patients with cirrhosis and those without.In the former patients, deaths related to liver disease made up 75% of all deaths; thus, HCC surveillance and management of cirrhotic complications are very important.The Korean HCC surveillance program measures serum levels of alpha-fetoprotein and performs ultrasound evaluation of patients at high risk for HCC [26].The surveillance rate was 68.4% in 2020, and must be improved [27].It is also important to increase the linkage-to-care rate of patients who undergo HCC surveillance.Compared to patients without cirrhosis, patients with cirrhosis exhibit higher rates of mortality related to other cancer types and cardiovascular/cerebrovascular disease, which require more attention.In particular, these risks for death remained even after adjusting for age, sex, and the use of antiviral drugs.In patients without cirrhosis, liver-related mortality accounts about 30% of the total, other cancer-related mortality is about 27%, and cardiovascular/cerebrovascular-related mortality is about 20%.The causes of death remain at a similar rate in patients who are not receiving AVT during 10 year of follow-up.Therefore, both HCC surveillance and holistic management of extrahepatic morality (extrahepatic cancer-and cardiovascular/cerebrovascular disease-related) are required.Considering that alcohol intake was a predictor of death in subjects with chronic HBV infection in a community-based study, education to avoid alcohol drinking will be an important strategy to reduce mortality [28].
Finally, the patient characteristics and the causes of death differed by the time period.Patients in the late cohort (cohort 2) tended to be older.Given their (probable) older age at diagnosis, patients in cohort 2 may exhibit higher rates of comorbidities such as HCC, hypertension, type 2 diabetes mellitus, chronic renal failure, cardiovascular/cerebrovascular disease, and cancers other than HCC.Another previous Korean study found that CHB patients in a later cohort were of older age at diagnosis and had more comorbidities [29].Compared to patients of cohort 1, those of cohort 2 exhibited reduced mortality (relative risk, 80%).HCC-and decompensation-related mortality also decreased in cohort 2 compared to cohort 1, which is in line with a US study that reported that all-cause and liver disease-related mortality of CHB patients declined significantly from 2007 to 2017 [6].However, mortality related to extrahepatic malignancies and the proportion of extrahepatic malignancies as causes of death in cohort 2 increased compared to cohort 1.Therefore, in the long-term, the absolute and relative proportions of mortalities related to extrahepatic malignancies in CHB patients will increase.
Our work had several limitations.First, we did not derive sex-or age-adjusted mortality rates.Second, there were no details regarding the viral burden or control status of HBV.Thirdly, there is no information about the period of AVT or information on which NUCs were used.Lastly, data on lifestyles such as alcohol consumption or tobacco use have not been investigated.Studies incorporating all the above information should be conducted in the future.

Conclusions
The WHO declared viral hepatitis as a global public health problem that should be eliminated by 2030 [30].The target is a 65% mortality reduction compared to 2015, and an annual mortality <4/100,000.Considering that mortality related to HCC decreased and mortality related to extrahepatic malignancies increased in the antiviral era of CHB, it will be important to develop customized strategies for aging CHB cohort to reduce mortality.In particular, meticulous surveillance will be needed in non-cirrhotic CHB patient group where extrahepatic malignancy-related mortality is high.

Supplementary Materials:
The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cancers16040711/s1, Figure S1: Flow chart of patient selection in this study; Table S1: Baseline characteristics of patients comparing cohort 1 vs. cohort 2.

Institutional Review Board Statement:
The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board (or Ethics Committee) of CHA Bundang Medical Center (IRB no.2020-06-035).

Table 1 .
Baseline characteristics of total patients.

Table 2 .
All cause and specific mortality rates during 10 years of follow up in cohort 1.

Table 3 .
All cause and specific mortality rates during 10 years of follow up in cohort 1 according to liver cirrhosis.Pt-patient.* The unadjusted HR is the risk of death in patients with liver cirrhosis compared to those without liver cirrhosis.** Adjusted HR is the risk of death adjusted by age, sex, and antiviral treatment in patients with liver cirrhosis compared to those without liver cirrhosis.

Table 4 .
All cause and specific mortality rates during 5 years of follow up according to periods (cohort 1 vs. cohort 2).

Table 5 .
All cause and specific mortality rates in patients without antiviral treatment for 10 years in cohort 1.