Mortality after Chronic Hepatitis B Virus Infection: A Linkage Study Involving 2 Million Parous Women from Taiwan

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1 MAJOR ARTICLE Mortality after Chronic Hepatitis B Virus Infection: A Linkage Study Involving 2 Million Parous Women from Taiwan Chyng-Wen Fwu, 1 Yin-Chu Chien, 2,3 Kenrad E. Nelson, 1 Gregory D. Kirk, 1 San-Lin You, 2,3 Hsu-Sung Kuo, 4 Manning Feinleib, 1 and Chien-Jen Chen 2,3 1 Johns Hopkins University, Baltimore, Maryland; 2 National Taiwan University, 3 Genomics Research Center, Academia Sinica, and 4 Center for Disease Control, Taipei, Taiwan Background. Few studies have evaluated survival rates among women who have chronic hepatitis B virus infection. We investigated the overall and disease-specific mortality rates in a nationwide cohort of women after they were screened for hepatitis B surface antigen (HBsAg) during pregnancy. Methods. HBsAg prenatal screening data were available for 2,087,994 women in Taiwan between 1 January 1986 and 31 March 2000 in the National Hepatitis B Vaccination Registry. Their vital status and cause of death were ascertained by computerized linkage with the National Death Certification Registry. Cox proportional hazards models were used to estimate the association between HBsAg status and specific causes of death. Results. Overall, 14,524 deaths were identified after a mean of years of follow-up. The age-adjusted hazard ratio for mortality among HBsAg carriers compared with noncarriers was 1.24 (95% confidence interval [CI], ), 6.59 (95% CI, ), and 1.09 (95% CI, ) for all-cause, liver-specific, and non liver-related deaths, respectively. In addition to liver-specific causes, a significantly increased risk of mortality from non-hodgkin lymphoma ( P!.001) and gallbladder and extrahepatic bile duct cancer ( P p.01) was observed. Conclusions. Our study found an excess risk of death due to both liver-specific and non liver-related causes for HBsAg-positive women in Taiwan. Effective prevention and treatment of hepatitis B virus infection is an important public health priority. The association between chronic hepatitis B virus (HBV) infection and excess mortality due to cirrhosis and hepatocellular carcinoma (HCC) has been well documented [1]. However, few studies have examined prospectively the overall and disease-specific mortality associated with chronic HBV infection among women. Received 11 May 2009; accepted 6 November 2009; electronically published 26 February Potential conflicts of interest: none reported. Presented in part: 13th International Symposium on Viral Hepatitis and Liver Disease, Washington DC, March 20 24, 2009 (oral presentation 97). Financial support: Department of Health, Executive Yuan, Taiwan. The funding source had no role in study design, data analysis, data interpretation, or writing of the report. Taiwan Centers for Disease Control staff was involved in data collection. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Taiwan Centers for Disease Control. Reprints or correspondence: Dr Chien-Jen Chen, Genomics Research Center, Academia Sinica, 128 Academia Rd, Section 2, Nankang, Taipei 11529, Taiwan (cjchen@ntu.edu.tw). The Journal of Infectious Diseases 2010; 201: by the Infectious Diseases Society of America. All rights reserved /2010/ $15.00 DOI: / Several extrahepatic manifestations of HBV infection have been reported [2 14]. Immune-complex deposition resulting in polyarteritis nodosa among persons with HBV infection has been reported primarily from Western countries [3, 4]. Several investigators have examined the possible role of chronic HBV infection in the pathogenesis of carotid atherosclerosis, perhaps due to HBV activation of inflammatory pathways [5 7]. Findings in other studies have suggested that HBV may play a role in the etiology of non-hodgkin lymphoma (NHL) [8 13]. In addition to these clinical observations, virological studies have detected HBV DNA in tissues other than the liver, such as the kidney, pancreas, and peripheral mononuclear cells [14, 15]. Chronic active HBV infection could promote the pathogenesis of some non liver-related diseases because of chronic inflammation or persistent antigenemia. In order to examine the association of chronic HBV infection with all-cause and disease-specific mortality, we evaluated mortality rates in a cohort of women in Taiwan who were screened for hepatitis B surface an JID 2010:201 (1 April) Fwu et al

2 tigen (HBsAg) during their pregnancy as part of a national program to prevent HBV transmission to newborn infants. METHODS Data sources and study population. A retrospective population-based cohort study was conducted by linking individual records from 2 nationwide databases, the National Hepatitis B Vaccination Registry and the National Death Certification Registry, by use of the resident-registry number, which is a unique identifier that is assigned to each resident of Taiwan. The National Hepatitis B Vaccination Registry has been described elsewhere [16]. Briefly, it was established in 1983 and records information on pregnant women s HBV status. Enzyme immunoassay (EIA), radioimmunoassay (RIA), and reversed passive hemagglutination assay (RPHA) were used to test for HBV antigens. For the first several years after the initiation of the national vaccination program, RPHA was used as an alternate testing method if the standard EIA or RIA was unavailable at some laboratories. Prior experience with the use of RPHA as a substitute for EIA or RIA was satisfactory [17]. The National Death Certification Registry contains information about the date and causes of death of all Taiwan residents. The cause of death was coded according to the International Classification of Diseases, Ninth Revision (ICD-9). Because the National Death Certification Registry was available from the year 1985, we included in our analysis all women in the National Hepatitis B Vaccination Registry whose HBsAg status was determined between 1 January 1986 and 31 March The sample for analysis in this study consisted of 2,087,994 women, after excluding those women whose age was not recorded at the time of their test ( n p 1075). In total, 1,529,191 (73%) of the test results were from either EIA or RIA. No statistically significant differences in geographic distributions were observed between testing methods using EIA/ RIA or RPHA. Ascertainment of HBV carrier and vital status. We determined the HBsAg status of each woman in this study from her first serological test result that was reported by prenatal care providers to the National Hepatitis B Vaccination Registry. Vital status was ascertained by computerized linkage of the National Hepatitis B Vaccination Registry data with the National Death Certification Registry. Persons not linked to a death record were considered to be alive through the end of follow-up and were censored on 31 December Statistical analyses. Entry into the cohort was defined as the date of first prenatal testing for HBV. The duration of follow-up for each subject was calculated from enrollment to the date of death, or the date of last available information from the National Death Certification Registry on 31 December Censored individuals were those still living at the end of followup. For analyses of cause-specific mortality, persons who died of other causes were also censored at the date of death. The number of events and the mortality rate by specific cause of death (ie, event number divided by person-years of follow-up) were calculated. Associations between HBsAg status at enrollment and all-cause or disease-specific mortality, adjusted for age at enrollment, were estimated using the Cox proportional hazards model to calculate hazard ratios (HRs) and their corresponding 95% confidence interval (CI). Follow-up duration was used as the time metric in the analysis. The assumption of proportionality for the Cox analysis was tested by examining the interaction between HBsAg status and follow-up time, and no violation of this assumption was observed. The mortality curves by follow-up years were derived with the Kaplan-Meier method. The log-rank test was used to compare curves. Statistical significance level was defined as a P-value of!.05 by 2- tailed tests. We also calculated the population-attributable risk, which was expressed as the percentage change of mortality rate from the rate among the overall HBsAg-positive and HBsAgnegative population to that among the HBsAg-negative population for all-cause and liver-specific mortality. The causes of death of greatest interest were liver-specific causes: malignant neoplasm of the liver and intrahepatic bile ducts (ICD-9 code 155), viral hepatitis (ICD-9 code 070), acute and subacute necrosis of the liver (ICD-9 code 570), chronic liver disease and cirrhosis (ICD-9 code 571), liver abscess and sequelae of chronic liver disease (ICD-9 code 572), and other disorders of the liver (ICD-9 code 573). The other non liverrelated causes of death were divided into 2 groups: cancer deaths and noncancer deaths. In addition, the leading causes of death from cancer among women in Taiwan during the period from 1991 to 2004 [18] were evaluated as well, comparing the mortality rate among HBsAg-positive women with that among HBsAg-negative women in this cohort. SAS statistical software (version 9.2; SAS Institute) was used for all analyses. The graphs of Kaplan-Meier estimates were plotted using STATA statistical software (version 8.2; STATA Corp). All personal identifiers were removed before the linked data were transferred for data analysis. Because there were no identifiers or links to identifiers in this data set, the study was exempt from human subject review by the Committee on Human Research at the Johns Hopkins Bloomberg School of Public Health, which included a waiver of the requirement for informed consent of participating women. RESULTS A total of 2,087,994 women were included in this analysis. Among them, 313,749 (15.03%) women were HBsAg positive at enrollment. The prevalence of HBsAg was consistent with prior estimates in Taiwan [19, 20]. The mean age at enrollment was years ( standard deviation [SD]; median, Mortality of Hepatitis B Virus Infection JID 2010:201 (1 April) 1017

3 Table 1. Distribution of Age at Enrollment and Prevalence of Hepatitis B Surface Antigen (HBsAg) among Women Enrolled in the Study ( n p 2,087,994) Age at enrollment, years Total Number of women HBsAgnegative HBsAgpositive HBsAg prevalence , ,559 30, , , , , , , , ,017 38, ,901 61, Total 2,087,994 1,774, , NOTE. HBsAg status was determined between 1 January 1986 and 31 March 2000 in Taiwan. 26 years). The detailed age distribution and the prevalence of HBsAg for each age group are shown in Table 1. All-cause mortality. After a mean of years ( SD; median, years) of follow-up, there were 14,524 deaths during 23,858,711 person-years. The number of deaths, mortality rate, age-adjusted HR, and population-attributable risk are shown in Table 2. The all-cause mortality rate was per 100,000 person-years; it was and per 100,000 person-years in HBsAg-positive and HBsAg-negative women, respectively. HBsAg-positive women had a 24% increase in all-cause mortality, compared with HBsAg-negative women (age-adjusted HR, 1.24; 95% CI, ). Figure 1 shows the cumulative mortality rate of all-cause mortality by HBsAg status at enrollment. After 4 5 years of follow-up, women who were HBsAg positive had persistently higher allcause cumulative mortality. The overall mortality for HBsAgpositive women was statistically significantly higher than that of HBsAg-negative women ( P!.001). Liver-specific mortality. There were 740 liver-specific deaths overall, 356 in the cancer group and 384 in the noncancer group (Table 2). Compared with HBsAg-negative group, the age-adjusted HR (95% CI) for the HBsAg-positive group was 6.59 ( ) for all liver-specific causes of death, ( ) for liver cancer deaths, and 3.13 ( ) for non cancer-related, liver-specific causes of death. The population-attributable risks were 44.96%, 67.60%, and 23.98% for all liver-specific causes of death, liver cancer deaths, and non cancer-related, liver-specific causes of death, respectively. Excluding other disorders of liver, all liver-specific causes of death were significantly associated with HBsAg-positive status. The age-adjusted HR for liver cancer was (95% CI, ; P!.001), viral hepatitis 6.77 (95% CI, ; P!.001), acute and subacute necrosis of liver 6.03 (95% CI, ; P!.001), chronic liver disease and cirrhosis 2.56 (95% CI, ; P!.001), and liver abscess and sequelae of chronic liver disease 4.43 (95% CI, ; P!.001). Table 2. Hazard Ratios (HRs) of Total and Liver-Specific Mortality and Hepatitis B Surface Antigen (HBsAg) Status Causes of death (ICD-9 code) All (n p 2,087,994; PY, 23,858,711) HBsAg-negative (n p 1,774,245; PY, 20,268,283) HBsAg-positive (n p 313,749; PY, 3,590,428) No. Mortality No. Mortality No. Mortality Adjusted HR a for HBsAg-positivity vs HBsAg-negativity (95% CI) Populationattributable risk, % All causes 14, , , ( ) b 3.24 Liver-specific causes ( ) b Liver cancer (155) ( ) b Liver-specific noncancer ( ) b Viral hepatitis (070) ( ) b Acute and subacute necrosis of liver (570) ( ) b Chronic liver disease and cirrhosis (571) ( ) b Liver abscess and sequelae of chronic liver disease (572) ( ) b Other disorders of liver (573) ( ) 3.69 NOTE. Hazard ratios of total and liver-specific mortality comparing HBsAg-positive to HBsAg-negative women in Taiwan whose HBsAg status was determined between 1 January 1986 and 31 March 2000; also shown are estimates of population-attributable risks due to HBsAg seropositivity. No. and mortality indicate the number of deaths per 100,000 person-years. CI, confidence interval; PY, person-years. a Age at enrollment (as a continuous variable) was included in Cox proportional hazards regression model. b P! JID 2010:201 (1 April) Fwu et al

4 Figure 1. Cumulative all-cause mortality by hepatitis B surface antigen (HBsAg) status. Non liver-related mortality. The mortality rates were per 100,000 person-years for all non liver-related causes, for cancers, and for noncancer diseases. The HBsAg-positive group had significantly higher mortality rate for all non liver-related causes (age-adjusted HR, 1.09; 95% CI, ) and cancers (HR, 1.20; 95% CI, ), compared with that in the HBsAg-negative group. The noncancer group had a slight but insignificant increased mortality risk of 1.03 (95% CI, ). In contrast, mortality related to diseases of the skin and subcutaneous tissue and of the musculoskeletal system and connective tissue occurred less frequently among HBsAg-positive women (Table 3). Table 4 lists the HRs for the leading causes of death from cancer among HBsAg-positive women compared with those among HBsAg-negative women. In addition to liver cancer, women with HBV infection experienced a significantly increased risk of malignant neoplasm of the cervix uteri (ICD-9 code 180; age-adjusted HR, 1.35; 95% CI, ), malignant neoplasm of gallbladder and extrahepatic bile ducts (ICD-9 code 156; HR, 2.02; 95% CI, ), and non-hodgkin lymphoma (ICD-9 code 200, 202; HR, 2.43; 95% CI, ). DISCUSSION We found an increased all-cause mortality associated with HBsAg seropositivity among a nationwide, population-based cohort study involving more than 2 million parous women in Taiwan, with a mean follow-up period of more than 11 years. As expected, the risk of mortality from liver cancer and other liver-specific causes was markedly increased among HBsAg carriers. However, we also found significantly increased mortality among HBsAg-infected women due to several non liver-related causes, raising questions concerning whether HBV infection could play a role in their etiology or whether confounding exists between HBV infection and other etiologic factors. Several other studies from various populations have revealed elevated mortality associated with chronic HBV infection, as measured by HBsAg seropositivity [21 25]. The design of this study more closely resembled a study reported from China, in which a community cohort was screened for HBsAg, and the population was followed up prospectively for overall and causespecific mortality [21, 22]. Both this study and the study in China had similar length of follow-up (ie, 10 years) and found an increase in all-cause mortality associated with baseline HBsAg seropositivity among women. However, the adjusted risk estimate in the Chinese study was more than double (ageadjusted HR, 3.0) [21] that in our population (age-adjusted HR, 1.2). This difference might be due to the fact that our population was significantly younger than subjects in the Chinese study (ie, only 26 years of median age at enrollment, whereas 75% of the women in the Chinese study were years old). Our population had an age-adjusted HR of 6.6 for liver-specific death compared with an age-adjusted HR of 20.9 in the study from China, which suggests that much of the overall mortality difference in these 2 studies was related to the risk for liver disease. This study involving a cohort of young women found an important impact of chronic HBV carriage on subsequent mortality, which was similar to women observed in other older populations. Another cohort study in Taiwan with 12 years of follow-up also found a significantly higher allcause mortality (adjusted HR, 1.7) in HBsAg-positive women compared with that in HBsAg-negative women at recruitment [26]. In the study of a middle-aged population, liver-specific causes accounted for 179 (42%) of 425 deaths among HBsAgpositive participants and only 71 (5%) of 1389 deaths among participants without evidence of chronic HBV infection. The proportion of liver-specific deaths in this study was smaller (15% for HBsAg-positive women and 3% for HBsAg-negative women). Because the mean age of diagnosis of HCC among women in Taiwan is 55 years [27], our study population was still younger than the age associated with the highest risk of HCC. Because HCC has been documented to be the second leading cause of death from cancer among women in Taiwan since the early 1980s [28, 29], we anticipate that the age-adjusted HR for HCC among HBV-infected women in this study will increase with additional follow-up. Compared with the risk estimates for liver-specific causes of death, our age-adjusted HRs for non liver-related causes of death were much closer to those of an older Chinese cohort that was recruited by means of community screening in Haimen City, China [21] (HR, 1.1 vs 1.4). The risk for non liver-related mortality in women was elevated in our cohort and the cohort from China but not in studies reported from other countries where the HBsAg prevalence was lower [23, 30]. The reason for this difference is unclear. However, the increased risk of deaths from non liver-related causes in this study may be bi- Mortality of Hepatitis B Virus Infection JID 2010:201 (1 April) 1019

5 Table 3. Hazard Ratios of Nonliver Mortality and Hepatitis B Surface Antigen (HBsAg) Status Causes of death (ICD-9 code) All (n p 2,087,994; PY, 23,858,711) HBsAg-negative (n p 1,774,245; PY, 20,268,283) HBsAg-positive (n p 313,749; PY, 3,590,428) No. Mortality No. Mortality No. Mortality Adjusted HR a for HBsAg positivity vs HBsAg negativity (95% CI) Non liver-related causes 13, , ( ) b Non liver-specific cancer ( ) b Malignant neoplasm of digestive organs and peritoneum ( ) c ( ) d Other malignant neoplasm ( ) e ( ) b Non-liver noncancer ( ) Infectious and parasitic diseases ( ) f ( ) Endocrine/nutritional/metabolic/immunity disorders ( ) ( ) Disease of blood and bloodforming organs ( ) ( ) Mental disorders ( ) ( ) Diseases of the nervous system and sense organs ( ) ( ) Disease of the circulatory system ( ) ( ) Diseases of the respiratory system ( ) ( ) Diseases of the digestive system ( ) g ( ) Diseases of the genitourinary system ( ) ( ) Complications of pregnancy/ childbirth/puerperium ( ) ( ) Disease of the skin and subcutaneous tissue ( ) ( ) h Diseases of the musculoskeletal system/connective tissue ( ) ( ) i Congenital anomalies ( ) ( ) Symptoms, signs, and ill-defined conditions ( ) ( ) Injury and poisoning ( ) , ( ) NOTE. Hazard ratios of non liver-related mortality comparing HBsAg-positive to HBsAg-negative women in Taiwan whose HBsAg status was determined between 1 January 1986 and 31 March No. and mortality indicate the number of deaths per 100,000 person-years. CI, confidence interval; PY, person-years. a Age at enrollment (as a continuous variable) was included in Cox proportional hazards regression model. b P!.001 c Excludes liver cancer (155). d P p.07 e Excludes malignant neoplasm of digestive organs and peritoneum ( ) f Excludes viral hepatitis (070). g Excludes acute and subacute necrosis of liver, chronic liver disease and cirrhosis, liver abscess and sequelae of chronic liver disease, and others disorder of liver ( ) h P p.01 i P p.002

6 Table 4. Hazard Ratios of the Leading Causes of Death due to Cancer among Women Rank a Causes of death (ICD-9 code) HBsAg-negative HBsAg-positive No. Mortality No. Mortality Adjusted HR b (95% CI) 1 Trachea, bronchus, and lung (162) ( ) 2 Liver (155) ( ) c 3 Colon, rectum, rectosigmoid junction, and anus (153, 154) ( ) 4 Female breast (174) 1, ( ) 5 Cervix uteri (180) ( ) d 6 Stomach (151) ( ) 7 Gallbladder and extrahepatic bile ducts (156) ( ) e 8 Pancreas (157) ( ) 9 Non-Hodgkin lymphoma (200, 202) ( ) c 10 Leukemia ( ) ( ) NOTE. Hazard ratios of the leading causes of death from cancer, comparing HBsAg-positive women to HBsAg-negative women in Taiwan, whose HBsAg status was determined between 1 January 1986 and 31 March No. and mortality indicate the number of deaths per 100,000 person-years. CI, confidence interval; HBsAg, hepatitis B surface antigen. a The rank of the leading causes of death was based on the crude cancer death rates among women in Taiwan. b Age at enrollment (as a continuous variable) was included in Cox proportional hazards regression model. c P!.001 d P p.03 e P p.01 ased to some extent because the death certificates recorded only the primary cause of death. Other secondary causes of death were not available in our database. We could not exclude the possibility that the increased risk of death from non liver-related causes was confounded by analyzing only the primary cause of death in persons who had multiple causes of death. However, there is no reason to believe that the primary cause of death among HBsAg-positive individuals would frequently be recorded as non liver-related diseases. Therefore, although there might be the potential for nondifferential misclassification of the cause of death in this study, it may result in only an underestimate of the true association. The association between HBV infection and NHL has been examined in several case-control studies. Most of these studies have found a higher prevalence of HBV infection among NHL patients than among patients with other non liver-related cancers [8 12]. Two prospective studies have found chronic HBV infection to be significantly associated with NHL [13, 30]. Because NHL affects males more frequently and is more common in non-hispanic whites than in other racial or ethnic groups [31], prospective studies of the disease are more commonly conducted in Western countries. To our knowledge, our study is the first cohort study to document the association between chronic HBV infection and increased NHL mortality in a female Asian population. Recently, the International Agency for Research on Cancer has documented NHL as having a positive association with hepatitis C virus and possibly with HBV [32]. Through chronic immune stimulation, persistent hepatitis C infection is associated with essential mixed cryoglobulinemia, a low-grade lymphoproliferative disorder that can progress to NHL [33]. HBV infections are also lymphotropic, and the virus can be detected in mononuclear cells [34]. The significantly positive association of chronic HBV infection with NHL mortality in this study provides important epidemiological evidence to support an etiological role for HBV infection in NHL. Women who were HBsAg positive in our study also experienced significantly increased rates of mortality from carcinoma of the gallbladder and extrahepatic bile ducts. This increased risk has not been found in most other studies of HBV-infected women. However, our population of HBsAg-positive women is considerably larger than that of previously reported studies. One population-based case-control study conducted in China found a 2.4-fold increased prevalence of HBsAg among patients with extrahepatic bile duct cancer compared with healthy control participants and subjects with biliary tract stones [35]. The mechanism by which HBV infection may lead to the development of extrahepatic bile duct cancer is unknown; however, a clinical investigation has detected HBV DNA in tissue specimens from extrahepatic bile duct cancers [36]. Inconsistent with the findings of other studies [5 7, 37, 38], we found an association of chronic HBV infection with cervical cancer and skin or musculoskeletal diseases, but not with pancreatic cancer and cardiovascular disease. The numbers of deaths from pancreatic cancer and skin or musculoskeletal diseases were relatively small in this study. Data were not available in this study to adjust for the effect of known risk factors for these diseases, such as family history, socioeconomic class, cigarette smoking, dietary intake, and coinfection with other agents. The observed associations may be confounded by some of these unmeasured variables. Additional studies are needed to evaluate these associations and explore underlying mechanisms in other populations with varying risks of chronic HBV Mortality of Hepatitis B Virus Infection JID 2010:201 (1 April) 1021

7 infection. As previously reported [16], other limitations of this administrative data set also included the concern of internal validity and the generalizability of the findings. Despite these limitations, our study involving a large cohort of women with a high prevalence of chronic HBV infection with excellent follow-up and careful documentation of mortality yielded important new information on the effect of HBV on mortality rates among women. Specifically, our study evaluated mortality in the Taiwanese population during a period when treatment of asymptomatic carriers of HBV was extremely uncommon; therefore, HBV therapy is unlikely to have influenced our findings. After an average of more than 11 years follow-up of the cohort, we found significantly increased mortality due to both liver and non liver-related causes. Overall, mortality was increased by 25% among women with chronic HBV infection. In addition to markedly increased risk for hepatocellular carcinoma and chronic liver disease, we also observed substantially increased mortality risk for non liverrelated cancers, namely, NHL and extrahepatic biliary cancers. Our data strongly support the public health importance of programs to vaccinate against and successfully treat chronic HBV infections in women; benefits are likely to be observed not only in prevention of liver disease progression but also in ameliorating morbidity and mortality from other causes. References 1. Beasley RP, Hwang LY, Lin CC, Chien CS. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22,707 men in Taiwan. Lancet 1981; 2: Han SH. Extrahepatic manifestations of chronic hepatitis B. Clin Liver Dis 2004; 8: Trepo C, Guillevin L. Polyarteritis nodosa and extrahepatic manifestations of HBV infection: the case against autoimmune intervention in pathogenesis. J Autoimmun 2001; 16: Guillevin L, Mahr A, Callard P, et al. 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