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HBV infection in indigenous children, 20 years after immunization in Taiwan: A community-based study
Preventive Medicine 48 (2009) 397–400
Contents lists available at ScienceDirect
Preventive Medicine j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y p m e d
HBV infection in indigenous children, 20 years after immunization in Taiwan: A community-based study Chung-Feng Huang a,b,c, Chia-Yen Dai a,c,d,⁎,1, Wan-Long Chuang c,d, Chi-Kung Ho a, Ta-Chung Wu b, Nai-Jen Hou c,e, Chao-Ling Wang a, Ming-Yen Hsieh c, Jee-Fu Huang c,e, Zu-Yau Lin c,d, Shinn-Cherng Chen c,d, Ming-Yuh Hsieh c,d, Liang-Yen Wang c,d, Jun-Fa Tsai c,d, Wen-Yu Chang c,d, Ming-Lung Yu c,d,⁎,1 a
Department of Occupational and Environmental Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan c Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan d Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan e Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan b
a r t i c l e
i n f o
Available online 12 February 2009 Keywords: Indigenous population HBV Taiwan
a b s t r a c t Objectives. Hepatitis B virus infection is hyperendemic in Taiwan. In the past, the infection rate has been higher in indigenous villages. The prevalence of chronic HBV infection among indigenous children after immunization remains unknown. Methods. A total of 843 indigenous children were checked for the hepatitis B seromarker. Another 606 metropolitan children were enrolled for comparison in 2005. Results. The seroprevalences (%) of HBsAg, (hepatitis B surface antigen) anti-HBs, (antibody to hepatitis B surface antigen) and anti-HBc (antibody to hepatitis B core antigen) among indigenous and metropolitan children were 3.2 vs. 0.17 (p b 0.001), 47.4 vs. 51.2 (p = 0.164), and 10.7 vs. 1.7 (p b 0.001), respectively. Among the indigenous children, who were divided into three age groups, the prevalences of HBsAg and anti-HBc increased with age, while anti-HBs decreased significantly (p = 0.025, 0.002, and b 0.001, respectively). Children with positive HBsAg had a significantly higher mean (SD) age (10.2 (2.2) vs. 9.2 (2.1) years, p = 0.024) and a higher ALT value (16.4 (8.0) vs. 10.6 (8.3) IU/L, p = 0.001). In a multivariable analysis, indigenous residency, older age group and abnormal ALT value were independent factors associated with positive HBsAg. Conclusions. The seroprevalence of hepatitis B infection has obviously declined among indigenous children 20 years after mass immunization programs launched in Taiwan. However, it is still higher than that of metropolitan children. Higher rates of chronic HBV infection in the mothers might be one important explanation for this finding. © 2009 Elsevier Inc. All rights reserved.
Introduction Chronic hepatitis B virus (HBV) infection is a serious clinical problem because of its worldwide distribution and potential adverse sequelae, including liver cirrhosis and hepatic carcinoma (Chen, 1993). Although substantial progress has been made in preventing HBV infection through the use of vaccines, there are still 400 to 500 million persons with chronic hepatitis B worldwide (Lee, 1997).
⁎ Corresponding authors. Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, No. 100, Tz-You 1st Rd, Kaohsiung 807, Taiwan. Fax: +886 7 3234553. E-mail addresses: [email protected] (C.-Y. Dai), [email protected] (M.-L. Yu). 1 These authors contributed equally to this work. 0091-7435/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.ypmed.2009.02.002
HBV infection was hyperendemic in Taiwan until the mid-1980s; approximately 13% to 20% of the general population was chronically infected (Sung et al., 1984; Chen and Sung, 1997; Dai et al., 2008). The infection is often acquired perinatally (Chang, 2000; Lok and Lai, 1988). Over the past 20 years, however, the frequency of hepatitis B infection has declined significantly as a result of social and behavioral changes and the general introduction of public health measures, including refinements in blood virus marker screening. Most importantly, a nationwide vaccination policy was launched in 1984 (Chen et al., 1987) and resulted in a significant decrease in the prevalence of chronic HBV infection in children in urban areas. Over the past two decades, HBsAg seroprevalence declined from about 10% to b1% in children younger than 15 years in Taipei City, the largest city in Taiwan (Ni et al., 2007). In contrast, viral hepatitis infection was reported to be more prevalent among inhabitants of the indigenous areas in Taiwan as a result of isolation of their villages due to high
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C.-F. Huang et al. / Preventive Medicine 48 (2009) 397–400
Table 1 Difference of study population demographics, liver function, and seroprevalence of HBsAg, anti-HBs and anti-HBc (Taiwan, 2005)
Male gender Age (yrs) ALT (IU/L) HBsAg Anti-HBs Anti-HBc
Indigenous children n (%) or mean (SD) (N = 843)
Metropolitan children n (%) or mean (SD) (N = 606)
P value
425 (50.4) 9.3 (2.1) 10.8 (8.3) 27 (3.2) 400 (47.4) 90 (10.7)
308 (50.8) 9.4 (2.2) 10.7 (7.9) 1 (0.17) 310 (51.2) 10 (1.7)
0.46 0.32 0.77 b 0.001 0.16 b 0.001
ALT: alanine aminotransferase.
mountains and relatively undeveloped public health and education programs. In southern Taiwan, the seroprevalence of HBV infection has been reported to have an infection rate (positive HBsAg and/or anti-HBc) of 95% and a chronic HBV infection rate (positive HBsAg) of 25% in indigenous areas (Chung et al., 1988; Lin et al., 2000). The prevalence of chronic HBV infection was also higher among indigenous children before immunization. The proportions of indigenous children in eastern Taiwan in 1989 who were positive for HBsAg and positive for HBsAg and/or anti-HBc were reported to be 32% and as high as 81%, respectively (Lin et al., 1992). However, there are no data that demonstrate the seroprevalence of HBV infection among indigenous children in Taiwan after the mass immunization program was launched. This community-based study aims to elucidate the present prevalence of HBV infection among indigenous children after the nationwide vaccination program in Taiwan.
1, 1984. From July 1984 to June 1986, all newborns in Taiwan received four doses of plasma-derived hepatitis B vaccine at 0,1, 2, and 12 months of age. All elementary school children have received hepatitis B vaccination since 1988. Since July 1991, all vaccine records for all elementary school students have been checked, and those children who were unvaccinated or incompletely vaccinated were given a catch-up vaccination. After November 1, 1992, the vaccine was changed to a recombinant yeast vaccine. The children in the present study were born after 1992 and received a recombinant yeast vaccine (5 μg of Recombivax or 20 μg of Engerix) within 3 to 5 days of birth, and again at 1 and 6 months. In addition, 0.5 mL (100 IU) of HBV immunoglobulin was given within 24 h of birth to infants whose mothers had positive hepatitis B e antigen (HBeAg) or reciprocal serum HBsAg titer ≥2560 by reverse-passive hemagglutinin assay. The vaccination coverage rates obtained from the database of Taiwan's CDC were N90% in the birth cohort and were similar for the two groups. All vaccines were preserved in refrigerators at 4 °C and monitored under a secure system. Serologic test
Materials and methods
All serum specimens were tested for HBsAg, anti-HBs and anti-HBc by enzyme-linked immunosorbent assay kits (Abbott, North Chicago, IL, USA). The antibody to hepatitis C virus (anti-HCV) was detected using a third-generation commercially available enzyme-linked immunosorbent assay kit (AxSYM 3.0, Abbott Laboratories). Alanine aminotransferase (ALT) was measured on a multichannel autoanalyzer (normal upper limit of serum ALT = 25 IU/L). Anti-HBs results were reported in milliinternational units per milliliter (mIU/mL) according to a World Health Organization reference standard; individuals with anti-HBs concentrations of 10 mIU/mL or more were regarded as protected.
Background
Statistical analysis
There are three indigenous townships located in the eastern part of Kaohsiung County, a distance of 70 to 100 km from Kaohsiung City, the largest city in southern Taiwan. Apart from the Han Chinese, who are descendants of people from the Chinese mainland, Taiwan's indigenous people descended from Malay-Polynesian people. Because the three townships are separated from metropolitan areas by mountains, their socioeconomic status and health-care facilities are poor. Until 2004, there were only 2 doctors, 40 medical staff and 3 health stations in this area. The average disposable income per household was much lower than that of metropolitan areas.
Values were expressed as mean (standard deviation (SD)), and group means were compared using the Student's t-test. Frequency was compared between groups using the x2 test with Yate's correction or the Fisher's exact test. Multivariable logistic regression analyses were used to establish the factors associated with HBV infection. A risk ratio with a 95% confidence interval was denoted for each analysis. The statistical tests were 2-tailed, and a p value b 0.05 was considered statistically significant. All procedures were performed with SPSS for Windows version 12 (SPSS Inc., Chicago, IL, USA). Results
Study subjects The present study was conducted in these three indigenous townships in November 2005. All 1044 indigenous children (aged 4 to 13 years) studying in the elementary schools in these townships were invited to participate in the screening project. With the consent of their parents or guardians, 843 (80.7%) children responded and were enrolled in the present study. Serologic markers for HBV infection, including hepatitis B surface antibody (HBsAg), antibodies to hepatitis-B surface antibody (anti-HBs) and antibodies to hepatitis B core antigen (antiHBc), were checked. We randomly selected 606 Han Chinese metropolitan children studying in one elementary school in Kaohsiung City for comparison. All 606 (100%) children agreed and participated with their guardians' consent. Data on maternal status of HBV infection were obtained from the database of Taiwan's Center of Disease Control (CDC).
The indigenous children enrolled in the study included 425 boys and 417 girls. A comparison of basic characteristics of indigenous and metropolitan children is shown in Table 1. The mean (SD) age of the
Primary vaccination schedules All vaccination programs launched in Taiwan are guided by the National Hepatitis Control Steering Committee and the Hepatitis Control Committee of the Department of Health, which were organized in 1980. The HBV universal vaccination program was launched in Taiwan on July
Fig. 1. Seroprevalence (%) of HBs Ag (grey bars), anti-HBs (black bars) and anti-HBc (white bars) in different age groups among indigenous children in Taiwan, 2005. Among the indigenous children, who were divided into 3 age groups, the seroprevalence of HBsAg and anti-HBc increased whereas anti-HBs decreased significantly with age (p = 0.025, 0.002 and b 0.001, respectively).
C.-F. Huang et al. / Preventive Medicine 48 (2009) 397–400 Table 2 Multivariable logistic regression analysis of the factors associated with positive-HBsAg (Taiwan, 2005) Variable Residency Metropolitan Indigenous ALT level Normal Abnormal Age group (yrs) 4–8 8–10 10–13
n
Odds ratio
(95% CI)
606 843
1 21.9
(2.9, 163.7)
1390 59
1 6.2
(1.9, 19.6)
523 405 521
1 1.2 3.02
(0.4, 4.1) (1.1, 8. 3)
ALT: alanine aminotransferase.
indigenous children and the metropolitan children was 9.3 (2.1) years and 9.4 (2.2) years, respectively (p = 0.46). The seroprevalences (%) of HBsAg and anti-HBc were significantly higher among indigenous children than metropolitan children [3.2 (27/843) vs. 0.17 (1/606) and 10.7 (90/843) vs. 1.7 (10/606), respectively, all p b 0.001]. The seroprevalences of anti-HBs were similar between the two groups of children [47.4 (400/843) vs. 51.2 (310/606), p = 0.164]. Mean ALT values were similar between the two study groups (p = 0.77). Among the indigenous children, who were divided into three age groups, the seroprevalence of HBsAg and anti-HBc increased, whereas anti-HBs decreased with age significantly (p = 0.025, 0.002 and b0.001, respectively) (Fig. 1). In univariate analysis, indigenous children with positive HBsAg were significantly older (10.2 (2.2) vs. 9.2 (2.1) years, p = 0.024) and had higher ALT values (16.4 (8.0) vs. 10.6 (8.3 IU/mL, p = 0.001). In multivariable analysis, indigenous residency, belonging to an older age group, and a higher ALT value were independent factors associated with positive HBsAg; their odds ratios with 95% confidence intervals are shown in Table 2. Maternal status of positive-HBsAg in the indigenous area is shown in Fig. 2. Discussion The prevalence of hepatitis B infection was previously reported to be much higher in indigenous children in Taiwan (Lin et al., 1992). The present study showed a marked reduction in the rate of chronic HBV infection (3.2%) and in the overall infection rate (10.7%) of indigenous children 20 years after the hepatitis B vaccination program was launched in Taiwan. A 0.6% rate of chronic HBV infection among children younger than 15 was reported by Ni et al. (2007) in Taipei City, the largest city in Taiwan, 20 years after the immunization program. We observed a similar result in the urban area of Kaohsiung in southern Taiwan, finding a very low rate of chronic HBV infection (0.17%) among metropolitan children in Kaohsiung City. These findings indicate that the nationwide vaccination program launched since 1984 in Taiwan resulted in a significant reduction in the chronic infection rate not only of metropolitan children, but also of the indigenous children who live in HBV hyperendemic areas. Even with the marked reduction in the rate of chronic HBV infection, a significantly higher seroprevalence of positive-HBsAg among indigenous children was observed in the present study. The significantly higher prevalence of positive-anti-HBc among indigenous children, which indicates a higher exposure rate, might provide one explanation. Host factors such as ethnic differences (Chung et al., 1988; Lin et al., 2000) and horizontally transmitted environmental factors have been reported to contribute to high HBV infection rates in indigenous areas, and person-to-person infectious transmission might be facilitated in indigenous areas because of overcrowding (Lin et al., 2004). In light of the similar vaccination coverage rate in the indigenous and metropolitan areas in our study, a higher maternal infection rate in indigenous areas might be one of the most important causes of the higher seroprevalence of positive-HBsAg in indigenous
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children. The rate of maternal chronic HBV infection was found to be as high as 15% in Taiwan. In contrast, data from the CDC showed that a higher rate of positive-HBsAg, more than 20%, was observed among indigenous mothers. The same concept was observed by Lu et al. (2006), who showed that higher baseline infection rates caused a greater increase in prevalence of HBV infection in rural areas than in urban areas. Several factors are known to be associated with a low hepatitis B vaccine response; these include site of injection, increased age (Fang et al., 1994), being male (Pasko and Beam, 1990; Shaw et al., 1989), smoking (Shaw et al., 1989) and genetic diversity may also play a role(Hsu et al., 1993a; Huang et al., 2001). Indigenous ethnicities were reported to be more hyporesponsive to hepatitis B vaccine than were Han Chinese populations (Hsu et al., 1996), which might lead to vaccine failure; a genetic basis for immune hyporesponsiveness to hepatitis B vaccine in the Bunun ethnicity, one of the largest tribes in Taiwan, has also been mentioned (Huang et al., 2001). However, the difference in efficacy of hepatitis B vaccination among indigenous ethnicities is a controversial issue (Wang et al., 2006). The seroprevalence of positive-anti-HBs in indigenous children did not differ from that of metropolitan Han Chinese children in the current study. Further studies are needed to clarify these issues. The prevalence of anti-HBs decreased as age increased. The present study showed waning of protective anti-HBs in older indigenous children; this result is similar to the observations of Lin et al. in Taipei City (Lin et al., 2003). Further investigation seems necessary to determine whether a booster vaccination is needed for those individuals with negative-anti-HBs after vaccination in infancy, especially in this endemic area. The HBV infection rate among indigenous children increased with age; possible explanations include the presence of intrauterine HBV infection (Tang et al., 1998), inadequate vaccine response or vaccine escape variants (Carman et al., 1990; Hsu et al., 1999). The seroprevalence of positive-HBsAg in the indigenous mothers did not reveal an increasing trend in the older cohorts in this study. Long-term prospective follow-up is required to determine whether there was an actual increase in horizontal transmission. Nevertheless, the significantly lower seroprevalence of HBsAg in younger children in the present study indicates an expectation of further reduction in the prevalence of chronic HBV infection in the future. Although they are somewhat less necessary after the vaccination era, methods for prevention of horizontal transmission, such as blood bank screening, avoidance of skin tattooing, and use of disposable needles, require continuous implementation (Hsu et al., 1993b). Most importantly, catch-up vaccination of unvaccinated subjects, as well as efforts to improve the vaccination coverage rate, is necessary to prevent HBV infection in this endemic area.
Fig. 2. Maternal status of positive-HBsAg in the indigenous area, Taiwan, 2005.
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Mother-to-child transmission is an important reason for vaccine failure, especially if the mothers are highly viremic or HBe antigen– seropositive (Wang et al., 2003). HBeAg can cross the placental barrier and be transmitted to the infant. Transplacental HBeAg from seropositive mothers induced a specific unresponsiveness of helper T cell to HBeAg and HBcAg (Hsu et al., 1992). More than 90% of the infants of HBeAg-positive mothers and approximately b5% of infants of HBeAg-negative mothers become chronically infected without vaccination. With the help of immunoprophylaxis, less than 1% of the infants of HBeAg-negative mothers but still 10% to 15% of the infants of HBeAg-positive mothers become chronically infected (Chang, 2007). Active immunization with hepatitis B vaccines plus passive immunoglobulin administration could effectively block the route of perinatal transmission, especially in high-risk infants. Three main methods of universal immunoprophylaxis are currently used worldwide, depending on the resources of the countries and the prevalence of HBV infection. In low prevalence areas such as the United States, HBsAg, but not HBeAg, is checked during pregnancy. It is recommended that every infant of an HBsAg-positive mother receive hepatitis B vaccines plus immunoglobulin. This measure saves the cost of maternal HBeAg screening but increases the cost of the expensive immunoglobulin. In countries with intermediate/low prevalence of chronic HBV infection or poor resources, all infants receive only hepatitis B vaccines, without any screening of maternal status or post-delivery immunoglobulin. Although this approach reduces cost, its efficacy is modest. The world's first universal hepatitis B vaccination program was launched in 1984. All mothers are checked for both HBsAg and HBeAg. All infants receive the hepatitis B vaccine, and infants of HBeAg-positive mothers receive additional immunoglobulin in consideration of cost-effectiveness (Chang, 2007). Although the cost, which is paid by the government, is higher, the prevalence of hepatitis B infection has dramatically decreased in the post-vaccination era, as seen in Taiwan. Isolated reactivity to anti-HBc (isolated positive anti-HBc), defined as positive for anti-HBc but negative for both HBsAg and anti-HBs, is observed relatively frequently in immunocompromised individuals and illicit intravenous drug users, as well as in the presence of HCV infection and with the failure of commercial HBsAg screening assays to detect HBsAg (genetic variability of S gene, low-level HBsAg and immune complexes) (Weber et al., 2001; Alhababi et al., 2003). It might also occur as a result of false-positivity or undetectable anti-HBs after vaccination; either false-positive results (primary response) or prior infection by HBV (anamnestic response) can be detected by antiHBs response after hepatitis B vaccination (Ural and Findik, 2001). In the present study, 15 (16.7%) of the 90 positive anti-HBc indigenous children had isolated positive anti-HBc; none of these children had positive anti-HCV or abnormal liver function. Further long-term monitoring of the hepatitis markers or future prospective studies is warranted to elucidate the natural course of individuals with isolated anti-HBc. In conclusion, the seroprevalence of hepatitis B infection 20 years after mass immunization programs in Taiwan has obviously declined among indigenous populations living in rural areas. This result illuminates the notable accomplishment of HBV infection control in not only urban areas, but also in the indigenous areas of Taiwan. However, the rate of chronic HBV infection among indigenous children remains higher than that of children living in urban areas. Conflict of interest statement The authors have no financial and personal relationships with other organizations.
Acknowledgments The authors thank Taiwan's Center of Disease Control, which provided the data on maternal carrier rates and vaccination coverage
rates for the study populations. The authors also thank the secretary of the Taiwan Liver Research Foundation (TLRF) for assistance in processing serum samples and the help of Tsu-Nai Wang from the Statistical Analysis Laboratory, Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University. References Alhababi, F., Sallam, T.A., Tong, C.Y., 2003. The significance of ‘anti-HBc only’ in the clinical virology laboratory. J. Clin. Virol. 27, 162–169. Carman, W.F., Zanetti, A.R., Karayiannis, P., et al., 1990. Vaccine-induced escape mutant of hepatitis B virus. Lancet 336, 325–329. Chang, M.H., 2000. Natural history of hepatitis B virus infection in children. J. Gastroenterol. Hepatol. 15 Suppl, E16–E19. Chang, M.H., 2007. Hepatitis B virus infection. Semin Fetal Neonatal Med. 12, 160–167. Chen, D.S., 1993. From hepatitis to hepatoma: lessons from type B viral hepatitis. Science 262, 369–370. Chen, D.S., Sung, J.L., 1997. 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Contents lists available at ScienceDirect
Preventive Medicine j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y p m e d
HBV infection in indigenous children, 20 years after immunization in Taiwan: A community-based study Chung-Feng Huang a,b,c, Chia-Yen Dai a,c,d,⁎,1, Wan-Long Chuang c,d, Chi-Kung Ho a, Ta-Chung Wu b, Nai-Jen Hou c,e, Chao-Ling Wang a, Ming-Yen Hsieh c, Jee-Fu Huang c,e, Zu-Yau Lin c,d, Shinn-Cherng Chen c,d, Ming-Yuh Hsieh c,d, Liang-Yen Wang c,d, Jun-Fa Tsai c,d, Wen-Yu Chang c,d, Ming-Lung Yu c,d,⁎,1 a
Department of Occupational and Environmental Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan c Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan d Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan e Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan b
a r t i c l e
i n f o
Available online 12 February 2009 Keywords: Indigenous population HBV Taiwan
a b s t r a c t Objectives. Hepatitis B virus infection is hyperendemic in Taiwan. In the past, the infection rate has been higher in indigenous villages. The prevalence of chronic HBV infection among indigenous children after immunization remains unknown. Methods. A total of 843 indigenous children were checked for the hepatitis B seromarker. Another 606 metropolitan children were enrolled for comparison in 2005. Results. The seroprevalences (%) of HBsAg, (hepatitis B surface antigen) anti-HBs, (antibody to hepatitis B surface antigen) and anti-HBc (antibody to hepatitis B core antigen) among indigenous and metropolitan children were 3.2 vs. 0.17 (p b 0.001), 47.4 vs. 51.2 (p = 0.164), and 10.7 vs. 1.7 (p b 0.001), respectively. Among the indigenous children, who were divided into three age groups, the prevalences of HBsAg and anti-HBc increased with age, while anti-HBs decreased significantly (p = 0.025, 0.002, and b 0.001, respectively). Children with positive HBsAg had a significantly higher mean (SD) age (10.2 (2.2) vs. 9.2 (2.1) years, p = 0.024) and a higher ALT value (16.4 (8.0) vs. 10.6 (8.3) IU/L, p = 0.001). In a multivariable analysis, indigenous residency, older age group and abnormal ALT value were independent factors associated with positive HBsAg. Conclusions. The seroprevalence of hepatitis B infection has obviously declined among indigenous children 20 years after mass immunization programs launched in Taiwan. However, it is still higher than that of metropolitan children. Higher rates of chronic HBV infection in the mothers might be one important explanation for this finding. © 2009 Elsevier Inc. All rights reserved.
Introduction Chronic hepatitis B virus (HBV) infection is a serious clinical problem because of its worldwide distribution and potential adverse sequelae, including liver cirrhosis and hepatic carcinoma (Chen, 1993). Although substantial progress has been made in preventing HBV infection through the use of vaccines, there are still 400 to 500 million persons with chronic hepatitis B worldwide (Lee, 1997).
⁎ Corresponding authors. Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, No. 100, Tz-You 1st Rd, Kaohsiung 807, Taiwan. Fax: +886 7 3234553. E-mail addresses: [email protected] (C.-Y. Dai), [email protected] (M.-L. Yu). 1 These authors contributed equally to this work. 0091-7435/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.ypmed.2009.02.002
HBV infection was hyperendemic in Taiwan until the mid-1980s; approximately 13% to 20% of the general population was chronically infected (Sung et al., 1984; Chen and Sung, 1997; Dai et al., 2008). The infection is often acquired perinatally (Chang, 2000; Lok and Lai, 1988). Over the past 20 years, however, the frequency of hepatitis B infection has declined significantly as a result of social and behavioral changes and the general introduction of public health measures, including refinements in blood virus marker screening. Most importantly, a nationwide vaccination policy was launched in 1984 (Chen et al., 1987) and resulted in a significant decrease in the prevalence of chronic HBV infection in children in urban areas. Over the past two decades, HBsAg seroprevalence declined from about 10% to b1% in children younger than 15 years in Taipei City, the largest city in Taiwan (Ni et al., 2007). In contrast, viral hepatitis infection was reported to be more prevalent among inhabitants of the indigenous areas in Taiwan as a result of isolation of their villages due to high
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Table 1 Difference of study population demographics, liver function, and seroprevalence of HBsAg, anti-HBs and anti-HBc (Taiwan, 2005)
Male gender Age (yrs) ALT (IU/L) HBsAg Anti-HBs Anti-HBc
Indigenous children n (%) or mean (SD) (N = 843)
Metropolitan children n (%) or mean (SD) (N = 606)
P value
425 (50.4) 9.3 (2.1) 10.8 (8.3) 27 (3.2) 400 (47.4) 90 (10.7)
308 (50.8) 9.4 (2.2) 10.7 (7.9) 1 (0.17) 310 (51.2) 10 (1.7)
0.46 0.32 0.77 b 0.001 0.16 b 0.001
ALT: alanine aminotransferase.
mountains and relatively undeveloped public health and education programs. In southern Taiwan, the seroprevalence of HBV infection has been reported to have an infection rate (positive HBsAg and/or anti-HBc) of 95% and a chronic HBV infection rate (positive HBsAg) of 25% in indigenous areas (Chung et al., 1988; Lin et al., 2000). The prevalence of chronic HBV infection was also higher among indigenous children before immunization. The proportions of indigenous children in eastern Taiwan in 1989 who were positive for HBsAg and positive for HBsAg and/or anti-HBc were reported to be 32% and as high as 81%, respectively (Lin et al., 1992). However, there are no data that demonstrate the seroprevalence of HBV infection among indigenous children in Taiwan after the mass immunization program was launched. This community-based study aims to elucidate the present prevalence of HBV infection among indigenous children after the nationwide vaccination program in Taiwan.
1, 1984. From July 1984 to June 1986, all newborns in Taiwan received four doses of plasma-derived hepatitis B vaccine at 0,1, 2, and 12 months of age. All elementary school children have received hepatitis B vaccination since 1988. Since July 1991, all vaccine records for all elementary school students have been checked, and those children who were unvaccinated or incompletely vaccinated were given a catch-up vaccination. After November 1, 1992, the vaccine was changed to a recombinant yeast vaccine. The children in the present study were born after 1992 and received a recombinant yeast vaccine (5 μg of Recombivax or 20 μg of Engerix) within 3 to 5 days of birth, and again at 1 and 6 months. In addition, 0.5 mL (100 IU) of HBV immunoglobulin was given within 24 h of birth to infants whose mothers had positive hepatitis B e antigen (HBeAg) or reciprocal serum HBsAg titer ≥2560 by reverse-passive hemagglutinin assay. The vaccination coverage rates obtained from the database of Taiwan's CDC were N90% in the birth cohort and were similar for the two groups. All vaccines were preserved in refrigerators at 4 °C and monitored under a secure system. Serologic test
Materials and methods
All serum specimens were tested for HBsAg, anti-HBs and anti-HBc by enzyme-linked immunosorbent assay kits (Abbott, North Chicago, IL, USA). The antibody to hepatitis C virus (anti-HCV) was detected using a third-generation commercially available enzyme-linked immunosorbent assay kit (AxSYM 3.0, Abbott Laboratories). Alanine aminotransferase (ALT) was measured on a multichannel autoanalyzer (normal upper limit of serum ALT = 25 IU/L). Anti-HBs results were reported in milliinternational units per milliliter (mIU/mL) according to a World Health Organization reference standard; individuals with anti-HBs concentrations of 10 mIU/mL or more were regarded as protected.
Background
Statistical analysis
There are three indigenous townships located in the eastern part of Kaohsiung County, a distance of 70 to 100 km from Kaohsiung City, the largest city in southern Taiwan. Apart from the Han Chinese, who are descendants of people from the Chinese mainland, Taiwan's indigenous people descended from Malay-Polynesian people. Because the three townships are separated from metropolitan areas by mountains, their socioeconomic status and health-care facilities are poor. Until 2004, there were only 2 doctors, 40 medical staff and 3 health stations in this area. The average disposable income per household was much lower than that of metropolitan areas.
Values were expressed as mean (standard deviation (SD)), and group means were compared using the Student's t-test. Frequency was compared between groups using the x2 test with Yate's correction or the Fisher's exact test. Multivariable logistic regression analyses were used to establish the factors associated with HBV infection. A risk ratio with a 95% confidence interval was denoted for each analysis. The statistical tests were 2-tailed, and a p value b 0.05 was considered statistically significant. All procedures were performed with SPSS for Windows version 12 (SPSS Inc., Chicago, IL, USA). Results
Study subjects The present study was conducted in these three indigenous townships in November 2005. All 1044 indigenous children (aged 4 to 13 years) studying in the elementary schools in these townships were invited to participate in the screening project. With the consent of their parents or guardians, 843 (80.7%) children responded and were enrolled in the present study. Serologic markers for HBV infection, including hepatitis B surface antibody (HBsAg), antibodies to hepatitis-B surface antibody (anti-HBs) and antibodies to hepatitis B core antigen (antiHBc), were checked. We randomly selected 606 Han Chinese metropolitan children studying in one elementary school in Kaohsiung City for comparison. All 606 (100%) children agreed and participated with their guardians' consent. Data on maternal status of HBV infection were obtained from the database of Taiwan's Center of Disease Control (CDC).
The indigenous children enrolled in the study included 425 boys and 417 girls. A comparison of basic characteristics of indigenous and metropolitan children is shown in Table 1. The mean (SD) age of the
Primary vaccination schedules All vaccination programs launched in Taiwan are guided by the National Hepatitis Control Steering Committee and the Hepatitis Control Committee of the Department of Health, which were organized in 1980. The HBV universal vaccination program was launched in Taiwan on July
Fig. 1. Seroprevalence (%) of HBs Ag (grey bars), anti-HBs (black bars) and anti-HBc (white bars) in different age groups among indigenous children in Taiwan, 2005. Among the indigenous children, who were divided into 3 age groups, the seroprevalence of HBsAg and anti-HBc increased whereas anti-HBs decreased significantly with age (p = 0.025, 0.002 and b 0.001, respectively).
C.-F. Huang et al. / Preventive Medicine 48 (2009) 397–400 Table 2 Multivariable logistic regression analysis of the factors associated with positive-HBsAg (Taiwan, 2005) Variable Residency Metropolitan Indigenous ALT level Normal Abnormal Age group (yrs) 4–8 8–10 10–13
n
Odds ratio
(95% CI)
606 843
1 21.9
(2.9, 163.7)
1390 59
1 6.2
(1.9, 19.6)
523 405 521
1 1.2 3.02
(0.4, 4.1) (1.1, 8. 3)
ALT: alanine aminotransferase.
indigenous children and the metropolitan children was 9.3 (2.1) years and 9.4 (2.2) years, respectively (p = 0.46). The seroprevalences (%) of HBsAg and anti-HBc were significantly higher among indigenous children than metropolitan children [3.2 (27/843) vs. 0.17 (1/606) and 10.7 (90/843) vs. 1.7 (10/606), respectively, all p b 0.001]. The seroprevalences of anti-HBs were similar between the two groups of children [47.4 (400/843) vs. 51.2 (310/606), p = 0.164]. Mean ALT values were similar between the two study groups (p = 0.77). Among the indigenous children, who were divided into three age groups, the seroprevalence of HBsAg and anti-HBc increased, whereas anti-HBs decreased with age significantly (p = 0.025, 0.002 and b0.001, respectively) (Fig. 1). In univariate analysis, indigenous children with positive HBsAg were significantly older (10.2 (2.2) vs. 9.2 (2.1) years, p = 0.024) and had higher ALT values (16.4 (8.0) vs. 10.6 (8.3 IU/mL, p = 0.001). In multivariable analysis, indigenous residency, belonging to an older age group, and a higher ALT value were independent factors associated with positive HBsAg; their odds ratios with 95% confidence intervals are shown in Table 2. Maternal status of positive-HBsAg in the indigenous area is shown in Fig. 2. Discussion The prevalence of hepatitis B infection was previously reported to be much higher in indigenous children in Taiwan (Lin et al., 1992). The present study showed a marked reduction in the rate of chronic HBV infection (3.2%) and in the overall infection rate (10.7%) of indigenous children 20 years after the hepatitis B vaccination program was launched in Taiwan. A 0.6% rate of chronic HBV infection among children younger than 15 was reported by Ni et al. (2007) in Taipei City, the largest city in Taiwan, 20 years after the immunization program. We observed a similar result in the urban area of Kaohsiung in southern Taiwan, finding a very low rate of chronic HBV infection (0.17%) among metropolitan children in Kaohsiung City. These findings indicate that the nationwide vaccination program launched since 1984 in Taiwan resulted in a significant reduction in the chronic infection rate not only of metropolitan children, but also of the indigenous children who live in HBV hyperendemic areas. Even with the marked reduction in the rate of chronic HBV infection, a significantly higher seroprevalence of positive-HBsAg among indigenous children was observed in the present study. The significantly higher prevalence of positive-anti-HBc among indigenous children, which indicates a higher exposure rate, might provide one explanation. Host factors such as ethnic differences (Chung et al., 1988; Lin et al., 2000) and horizontally transmitted environmental factors have been reported to contribute to high HBV infection rates in indigenous areas, and person-to-person infectious transmission might be facilitated in indigenous areas because of overcrowding (Lin et al., 2004). In light of the similar vaccination coverage rate in the indigenous and metropolitan areas in our study, a higher maternal infection rate in indigenous areas might be one of the most important causes of the higher seroprevalence of positive-HBsAg in indigenous
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children. The rate of maternal chronic HBV infection was found to be as high as 15% in Taiwan. In contrast, data from the CDC showed that a higher rate of positive-HBsAg, more than 20%, was observed among indigenous mothers. The same concept was observed by Lu et al. (2006), who showed that higher baseline infection rates caused a greater increase in prevalence of HBV infection in rural areas than in urban areas. Several factors are known to be associated with a low hepatitis B vaccine response; these include site of injection, increased age (Fang et al., 1994), being male (Pasko and Beam, 1990; Shaw et al., 1989), smoking (Shaw et al., 1989) and genetic diversity may also play a role(Hsu et al., 1993a; Huang et al., 2001). Indigenous ethnicities were reported to be more hyporesponsive to hepatitis B vaccine than were Han Chinese populations (Hsu et al., 1996), which might lead to vaccine failure; a genetic basis for immune hyporesponsiveness to hepatitis B vaccine in the Bunun ethnicity, one of the largest tribes in Taiwan, has also been mentioned (Huang et al., 2001). However, the difference in efficacy of hepatitis B vaccination among indigenous ethnicities is a controversial issue (Wang et al., 2006). The seroprevalence of positive-anti-HBs in indigenous children did not differ from that of metropolitan Han Chinese children in the current study. Further studies are needed to clarify these issues. The prevalence of anti-HBs decreased as age increased. The present study showed waning of protective anti-HBs in older indigenous children; this result is similar to the observations of Lin et al. in Taipei City (Lin et al., 2003). Further investigation seems necessary to determine whether a booster vaccination is needed for those individuals with negative-anti-HBs after vaccination in infancy, especially in this endemic area. The HBV infection rate among indigenous children increased with age; possible explanations include the presence of intrauterine HBV infection (Tang et al., 1998), inadequate vaccine response or vaccine escape variants (Carman et al., 1990; Hsu et al., 1999). The seroprevalence of positive-HBsAg in the indigenous mothers did not reveal an increasing trend in the older cohorts in this study. Long-term prospective follow-up is required to determine whether there was an actual increase in horizontal transmission. Nevertheless, the significantly lower seroprevalence of HBsAg in younger children in the present study indicates an expectation of further reduction in the prevalence of chronic HBV infection in the future. Although they are somewhat less necessary after the vaccination era, methods for prevention of horizontal transmission, such as blood bank screening, avoidance of skin tattooing, and use of disposable needles, require continuous implementation (Hsu et al., 1993b). Most importantly, catch-up vaccination of unvaccinated subjects, as well as efforts to improve the vaccination coverage rate, is necessary to prevent HBV infection in this endemic area.
Fig. 2. Maternal status of positive-HBsAg in the indigenous area, Taiwan, 2005.
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Mother-to-child transmission is an important reason for vaccine failure, especially if the mothers are highly viremic or HBe antigen– seropositive (Wang et al., 2003). HBeAg can cross the placental barrier and be transmitted to the infant. Transplacental HBeAg from seropositive mothers induced a specific unresponsiveness of helper T cell to HBeAg and HBcAg (Hsu et al., 1992). More than 90% of the infants of HBeAg-positive mothers and approximately b5% of infants of HBeAg-negative mothers become chronically infected without vaccination. With the help of immunoprophylaxis, less than 1% of the infants of HBeAg-negative mothers but still 10% to 15% of the infants of HBeAg-positive mothers become chronically infected (Chang, 2007). Active immunization with hepatitis B vaccines plus passive immunoglobulin administration could effectively block the route of perinatal transmission, especially in high-risk infants. Three main methods of universal immunoprophylaxis are currently used worldwide, depending on the resources of the countries and the prevalence of HBV infection. In low prevalence areas such as the United States, HBsAg, but not HBeAg, is checked during pregnancy. It is recommended that every infant of an HBsAg-positive mother receive hepatitis B vaccines plus immunoglobulin. This measure saves the cost of maternal HBeAg screening but increases the cost of the expensive immunoglobulin. In countries with intermediate/low prevalence of chronic HBV infection or poor resources, all infants receive only hepatitis B vaccines, without any screening of maternal status or post-delivery immunoglobulin. Although this approach reduces cost, its efficacy is modest. The world's first universal hepatitis B vaccination program was launched in 1984. All mothers are checked for both HBsAg and HBeAg. All infants receive the hepatitis B vaccine, and infants of HBeAg-positive mothers receive additional immunoglobulin in consideration of cost-effectiveness (Chang, 2007). Although the cost, which is paid by the government, is higher, the prevalence of hepatitis B infection has dramatically decreased in the post-vaccination era, as seen in Taiwan. Isolated reactivity to anti-HBc (isolated positive anti-HBc), defined as positive for anti-HBc but negative for both HBsAg and anti-HBs, is observed relatively frequently in immunocompromised individuals and illicit intravenous drug users, as well as in the presence of HCV infection and with the failure of commercial HBsAg screening assays to detect HBsAg (genetic variability of S gene, low-level HBsAg and immune complexes) (Weber et al., 2001; Alhababi et al., 2003). It might also occur as a result of false-positivity or undetectable anti-HBs after vaccination; either false-positive results (primary response) or prior infection by HBV (anamnestic response) can be detected by antiHBs response after hepatitis B vaccination (Ural and Findik, 2001). In the present study, 15 (16.7%) of the 90 positive anti-HBc indigenous children had isolated positive anti-HBc; none of these children had positive anti-HCV or abnormal liver function. Further long-term monitoring of the hepatitis markers or future prospective studies is warranted to elucidate the natural course of individuals with isolated anti-HBc. In conclusion, the seroprevalence of hepatitis B infection 20 years after mass immunization programs in Taiwan has obviously declined among indigenous populations living in rural areas. This result illuminates the notable accomplishment of HBV infection control in not only urban areas, but also in the indigenous areas of Taiwan. However, the rate of chronic HBV infection among indigenous children remains higher than that of children living in urban areas. Conflict of interest statement The authors have no financial and personal relationships with other organizations.
Acknowledgments The authors thank Taiwan's Center of Disease Control, which provided the data on maternal carrier rates and vaccination coverage
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