台灣慢性B 型肝炎病毒感染臨床表現及B型肝炎疫苗實施後血清學狀態

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Title:	台灣慢性B 型肝炎病毒感染臨床表現及B型肝炎疫苗實施後血清學狀態 Serostatus after implementation of HBV vaccination and clinical manifestations of chronic HBV infection in Taiwan
Authors:	蘇富雄 Su, Fu-Hsiung
Contributors:	公共衛生學系暨研究所葉志清
Keywords:	台灣,大學學生,慢性腎臟病,自體風濕免疫疾病,癌症,B 型肝炎病毒,C 型肝炎病毒,B 型肝炎病毒表面抗原,B 型肝炎病毒核心抗體,B 型肝炎病毒表面抗體 Taiwan,university students,chronic kidney disease,autoimmune rheumatic diseases,cancer,hepatitis B virus,hepatitis C virus,HBsAg;anti-HBc,anti-HBs
Date:	2013-06-01
Issue Date:	2018-09-27 14:15:23 (UTC+8)
Abstract:	前言慢性B 型肝炎病毒感染在1984 年全國B 型肝炎疫苗施打計畫實施後，仍是台灣地區非常重要的公共衛生議題。慢性B 型肝炎病毒感染除已證實會影響肝臟的臨床表現外，在肝臟以外的部份也有重要的臨床意義。台灣地區現行的B 型肝炎疫苗施打策略實施已逾二十年且建立於高盛行率時代。台灣的疾病管制局與國外其他同性質機構雖然建議對於出生時已施打B型肝炎疫苗之族群毋須追加施苗，但在台灣臨床上，現行仍有三種B 型肝炎追加疫苗的施打策略。新生兒B 型肝炎疫苗施打計畫的實行使台灣從B 型肝炎高盛行率轉變為低盛行率的地區，應有必要重新檢視B 型肝炎病毒血清學指標在臨床上的運用與血清學指標趨勢的改變。因此，本篇研究目的在於:(1)估計B 型肝炎病毒與可能相關臨床疾病(包含癌症、慢性腎臟病、自體風濕免疫疾病)的關聯性;(2)評估調整後的三劑疫苗施打方針之效果;(3)評估三種臨床診斷B 型肝炎病毒的血清學指標(B 型肝炎病毒表面抗原、B 型肝炎病毒表面抗體、B 型肝炎病毒核心抗體)對於新生兒疫苗施打計畫實行26 年後的臨床診斷效果。方法學慢性B 型肝炎病毒感染的臨床表現觀察慢性B 型肝炎病毒感染與癌症、慢性腎臟疾病與自體風濕免疫疾病等臨床表現的相關性，利用全國性族群為基礎的世代研究進行分析。使用2000~2005 年台灣地區全國性健康保險系統隨機抽樣一百萬人檔加以辨別慢性B型肝炎病毒和C 型肝炎病毒感染者並進行年齡、性別配對非B 型肝炎病毒或C型肝炎病毒感染者作為對照組，並追蹤相關的癌症、慢性腎臟病與自體風濕免疫疾病的發生率與風險到2008 年為止。 B 型肝炎疫苗實施後血清學狀態為了探討疫苗全國施打計畫實施後B 型肝炎病毒血清學指標意義，本篇研究觀察出生時已接受完整疫苗施打計劃於2006 年至2008 年入學大學的新生進行B 型肝炎病毒表面抗原、核心抗體、表面抗體等三種B 型肝炎病毒血清學指標檢測，並判斷學生是否為急性或慢性感染、因為疫苗或過去暴露病毒而具有免疫力或不具保護力的易感宿主。當表面抗原結果呈現陽性將進行表面抗原確認試驗並同時進行e 抗原與e 抗體及病毒核酸序列的定性試驗。我們的學生世代中發現核心抗體單獨表現陽性的樣本，須於六個月後重新採檢並使用同樣商用試劑進行確認，如兩次檢驗結果皆為陽性則追加施打一劑遺傳工程疫苗以評估抗體再生反應。2006 年所收案的大學新生，如三種B 型肝炎病毒血清學指標皆呈現陰性則追加施打一劑遺傳工程疫苗再評估表面抗體狀態，如仍維持陰性則繼續追加二劑遺傳工程疫苗並於三年後徵詢自願者評估抗體維持效果。所有自願者三年後再次進行三種B 型肝炎病毒血清學指標濃度檢測。學生分為三組:A 組為易感宿主未曾追加施打疫苗、B 組為易感宿主追加1 劑或3 劑疫苗、C 組為保護宿主未曾追加施打疫苗。結果慢性B 型肝炎病毒感染的臨床表現本篇研究病例組共收集12,369 名單獨B 型肝炎病毒帶原者、5,311 名單獨C型肝炎病毒帶原者與3,519 名B 型合併C 型肝炎病毒帶原者，對照組則選取84,796 名非病毒性肝炎感染個案。比起非病毒性肝炎對照組，新發癌症的校正後危險比在單獨B 型肝炎病毒帶原者為2.72 (95%信賴區間為2.49~2.97)，C 型肝炎病毒帶原者為2.69 (95%信賴區間為2.45~2.95)，B 型合併C 型肝炎病毒帶原者為3.66 (95%信賴區間為3.28~4.08)。在B 型肝炎病毒帶原者與非病毒性肝炎感染個案相比，罹患各種癌症的危險比在肝癌為27.6 倍、膽囊癌為2.41 倍、肝外膽管癌為2.35 倍、胰臟癌為2.06 倍、腎臟癌為1.39 倍。C 型肝炎病毒亦為肝癌(危險比為30.1，95%信賴區間為24.5~36.9)、膽囊癌與肝外膽管癌(危險比為3.49，95%信賴區間為1.65~7.36)的危險因子。而罹患非何杰金氏淋巴瘤的危險比分析中B 型與C 型肝炎病毒處於模糊狀態，B 型肝炎病毒帶原者危險比為1.89，95%信賴區間為0.95~3.74，C 型肝炎病毒帶原者危險比為2.09，95%信賴區間為0.99~4.45。病例對照研究設計顯示乳癌與慢性病毒性肝炎並無相關性。不過在多變項邏輯斯迴歸中觀察到C 型肝炎病毒帶原者與正常族群相比在50 歲以下早發性乳癌有兩倍的風險(勝算比:2.03，95%信賴區間為1.23~3.34)。而在世代研究中顯示B 型肝炎病毒與口腔癌之間亦無相關性存在，但在校正社經地位等共變項後，C型肝炎病毒感染與正常族群相比發生口腔癌的風險也顯著增加(風險比:1.90，95%信賴區間為1.20~3.02)。在校正人口學共變項後，單獨B 型肝炎病毒感染並未增加自體風濕免疫疾病與慢性腎臟病的發生風險。然而單獨C 型肝炎病毒感染會增加罹患自體風濕免疫疾病的風險，包含類風濕性關節炎(風險比:2.87，95%信賴區間為1.81~4.57)、修格蘭氏乾燥症候群(風險比:5.06，95%信賴區間為2.97~8.61)，但並非紅斑性狼瘡的危險因子(風險比:1.70，95%信賴區間為0.65~4.42)。而單獨C 型肝炎病毒感染更是發生慢性腎臟病的危險因子( 風險比:2.14 ， 95% 信賴區間為1.82~2.51)，尤其單獨C 型肝炎病毒發生末期腎衰竭是非肝炎病毒帶原者的2.58倍(95%信賴區間為2.01~3.30)。 250 名出生時曾接受B 型肝炎病毒疫苗施打的大學生，在2006 大一入學時檢查其血清中表面抗原、核心抗體與表面抗體並追蹤三年後觀察表面抗體效價的改變。A 組共收案39 人在大一入學時缺乏表面抗體保護力並未接受一劑B 型肝炎病毒疫苗施打，B 組共收案128 人同樣在大一入學時缺乏表面抗體保護力但接受三劑B 型肝炎病毒疫苗施打，C 組共收案83 人在大一入學時呈現有效表面抗體效價並未接受疫苗施打。經過三年後，A 組具有保護力的比例增加12.8%、C 組增加14.5%具有保護力，B 組仍有53.9%具有保護力，然而三年追蹤期間並未有人新感染到B 型肝炎病毒。推測所有學生在自然暴露到B 型肝炎病毒的狀況下而具有補助效果。 1734 名出生時曾接受B 型肝炎病毒疫苗施打的大學生在2006~2008 年間收案進行核心抗體檢查。單獨只有核心抗體陽性盛行率為1.2%(21/1734)。並未觀察到B 型肝炎病毒潛溶性感染的證據。21 名單獨只有核心抗體陽性個案在接受一劑B 型肝炎病毒疫苗追加施打後，95%(共20 名個案)的表面抗體效價呈陽性(表面抗體效價≧10mIU/mL)。這21 名個案接受疫苗追加施打六個月後，其中13 名 (62%)核心抗體仍維持陽性者，將其重新分組為過去曾遭受病毒暴露但表面抗體效價消失，其餘8 名(38%)在追加施打後核心抗體轉為陰性(偽陽性)並重分組為因抗體自然降解與生成效應(waning-off)的HBV 易感宿主(HBV naive)。追加一劑疫苗後，核心抗體性與陰性兩組在產生抗體效價上並未有統計學上顯著差異(幾何平均數效價為50.6 vs 47.7 mIU/mL，P 值為0.90)。在2008年針對1745名大學生(平均年齡為18.6歲± 1.0歲)與403名大學研究所學生(平均年齡為22.8歲± 0.7歲)和367名成人自願參加者(平均年齡為41.1歲± 15.8歲)進行血清表面抗原檢查，並針對陽性個案進一步利用表面抗原確認試驗進行分析，用以評估B型肝炎病毒疫苗計畫之影響。表面抗原陽性率從成人自願參加者的16.3%下降至研究所學生的5.2%到大學生的2.8%(P值為0.0007)。表面抗原的陽性預測值從成人自願參加者的0.97下降至已大學畢業學生的0.81到大學生的0.56(P值小於0.0001)。結論在台灣健保資料庫分析發現慢性B型肝炎病毒帶原者發生膽囊癌、肝外膽管癌、胰臟癌、腎臟癌與肝癌有較高的風險。單獨B型肝炎病毒感染亦對於發生非何杰金氏淋巴瘤有偏高的機率。不同於C型肝炎病毒感染，B型肝炎病毒感染與乳癌、口腔癌、慢性腎臟病與自體風濕免疫疾病無相關性存在。本篇研究顯示調整後的三劑疫苗追加施打策略對於出生時曾接受疫苗施打但抗體效價低於有效保護力之族群可增加超過50%的保護力。然而部分抗體效價低於有效保護力之族群在未接受疫苗施打的狀況下仍會自然提高抗體效價，這可能意味嬰兒時期曾接受過疫苗施打雖然抗體效價較低但仍可抵抗B型肝炎病毒。此外，出生時接受B型肝炎病毒疫苗施打族群在大學入學時呈現單獨只有核心抗體呈現陽性個案可能是暴露過B型肝炎病毒或接受疫苗施打後表面抗體效價降解所致。由此，針對該族群建議給予一劑疫苗施打。而出生時曾接受B 型肝炎病毒疫苗施打的族群與出生時非計畫施打之族群相比，B 型肝炎病毒表面抗原真陽性明顯降低(44%)。因此，台灣地區接受B 型肝炎病毒疫苗全國性新生兒施打計畫之族群運用額外的B 型肝炎病毒表面抗原中和試驗可能有其必要。 Introduction Chronic hepatitis B virus (HBV) infection still remains an extremely important health issue in Taiwan after the introduction of HBV vaccination program in 1984. Besides its well-reported intra-hepatic manifestations, chronic HBV infection is thought to have many important extra-hepatic manifestations. In addition, the current HBV vaccination protocol has been administrated for over twenty years, and was developed during a time of high endemicity for HBV in Taiwan. International consensus as well as the Taiwan Centers of Disease Control currently does not recommend HBV vaccine boosters for immunocompetent individuals who received neonatal vaccines. However, in Taiwan there are currently three HBV vaccine booster protocols in standard practice. The significance and application of the three HBV serological markers used in the clinical diagnosis of HBV is perhaps worthy to be reexamined as the country is currently in a transitional stage to a low HBV endemic country, and the screening pattern may have changed since the time prior to the implementation of the national HBV vaccination program. Hence, the purposes of this research proposal are to estimate the associations between chronic HBV infection and its three possible clinical manifestations (cancers, chronic kidney disease (CKD) and autoimmune rheumatic diseases (ARDs)), to evaulate the efficacy of the modified-3-dose HBV booster protocol, and to assess the clinical application and significance of the three HBV seromarkers (HBsAg, anti-HBc and anti-HBs) in the clinical diagnosis of HBV in an environment 26 years after the implementation of the national HBV vaccination program in Taiwan. Methods Clinical manifestations of chronic HBV infection The purpose of this investigation was to assess the three possible clinical manifestations (cancers, CKD and ARDs) associated with chronic HBV infection by conducting a nationwide population-based cohort analysis. Our data were retrieved from the insurance claims data of 1,000,000 randomly sampled individuals covered under the Taiwan National Health Insurance (NHI) system. We identified participants with chronic HBV and HCV infections from 2000-2005. The comparison group comprised sex- and age-matched subjects without HBV and/or HCV infections during the same study period. The incidence and risk of subsequent cancers, CKD, and ARDs were measured separately until 2008. Significance of HBV seromarkers in post-HBV vaccination era To explore the clinical significance and application of the HBV serological markers post-HBV vaccination era, three HBV seromarkers (HBsAg, anti-HBc, and anti-HBs) were tested among new university entrants recruited between 2006 and 2008, who had completed a full neonatal HBV vaccination course. We determined whether they had acute or chronic HBV infection, were immune to HBV as a result of prior infection or vaccination, or were susceptible to infection. The reactive HBsAg result was confirmed by an HBsAg neutralization test. Qualitative assays for anti-HBe and HBeAg, and HBV DNA for those subjects with HBsAg positive status were also checked. Isolated anti-HBc subjects were identified among our student cohort and were retested 6 months later for the true isolated anti-HBc using the same enzyme immunoassay kit. Subjects with the true isolated anti-HBc were offered one dose of recombinant HBV DNA vaccine to measure their anamnestic response to the HBV vaccine booster. The university freshmen recruited in 2006 that were seronegative for all three markers were offered one booster dose of a recombinant DNA HBV vaccine upon admission to the university. All the students who remained negative for all three HBV markers after receiving one dose of HBV vaccine completed two subsequent doses of HBV vaccine and were asked to voluntarily return to participate in this project three years later. The students were then stratified into 3 groups: Group A (non-protective titers of anti-HBs upon university entry and received no HBV vaccine booster); Group B (non-protective titers of anti-HBs upon admission and received a modified three-booster-dose protocol); and Group C (protective anti-HBs titers upon admission and received no revaccination). The levels of the three HBV serologic tests were rechecked three years following their initial antibody titer test during university matriculation. Results Clinical manifestations of chronic HBV infection In our study, 12,369 sole HBV carriers, 5,311 sole HCV carriers, and 3,519 dual HBV/HCV carriers were selected and compared with 84,796 non-viral hepatitis counterparts. The adjusted hazard ratios (HRs) of developing cancer among subjects infected with HBV alone, HCV alone, and dual HBV/HCV were 2.72 (95% confidence interval (CI): 2.49-2.97), 2.69 (CI: 2.45-2.95), and 3.66 (CI: 3.28-4.08) respectively compared with participants without chronic viral hepatitis. Participants with chronic HBV infection had 27.6, 2.41, 2.35, 2.06, and 1.39-fold higher risks of developing liver, gallbladder and extra-hepatic bile duct, pancreas, and kidney cancers than subjects without chronic viral hepatitis. HCV was also a significant risk factor for liver cancer (HR: 30.1, CI: 24.5-36.9) and gallbladder and extra-hepatic bile cancer (HR: 3.49, CI: 1.65-7.36). Subjects with sole HBV infection and sole HCV infection had borderline higher risks of developing non-Hodgkin lymphoma (HR: 1.89, CI: 0.95-3.74 and HR: 2.09, CI: 0.99-4.45 respectively) than their non-viral hepatitis counterparts. In our case-control analysis of the association of breast cancer with chronic viral hepatitis, there was no significant difference in the prevalence of HBV infection between breast cancer patients and control subjects. Multivariate logistic regression analysis, however, revealed that HCV carriers with age<50 years were associated with a 2-fold greater risk of developing breast cancer (odds ratio: 2.03, CI: 1.23-3.34). In our cohort analysis of the association of oral cavity cancer with chronic viral hepatitis, there was no significant association between sole HBV infection and the risk for oral cavity cancer. However, after adjusting for sociodemographic covariates, HCV alone was significantly associated with an increased risk for oral cavity cancer (HR: 1.90, CI: 1.20-3.02). After adjusting for sociodemographic covariates, there were no significant associations between HBV alone and risks for ARDs and CKD. However, HCV alone was significantly associated with an increased risk for rheumatoid arthritis (HR: 2.87, CI: 1.81-4.57) and for Sjogren syndrome (HR: 5.06, CI: 2.97-8.61) but not for systematic lupus erythmatosus (HR: 1.70, CI: 0.65-4.42). The incidence of CKD was 3.63-fold higher (adjusted HR: 2.14, CI: 1.82-2.51) among patients with sole HCV infection than among patients without evidence of viral hepatitis. In addition, the incidence of end stage renal disease (ESRD) was 4.57-fold higher among patients with HCV alone (HR: 2.58, CI: 2.01-3.30). Significance of HBV seromarkers in post-HBV vaccination era Upon university entry in 2006, HBsAg, anti-HBc, and anti-HBs titers were checked among 250 neonatally HBV vaccinated students. Changes in the levels of antibodies to the anti-HBs were examined over a 3-year period. Group A (n = 39) lacked seroprotective levels of anti-HBs, and declined to receive a booster dose of the HBV vaccine. Group B (n = 128) lacked seroprotective levels of anti-HBs, and received booster doses of the HBV vaccine according to the modified 3-dose booster protocol. Group C (n = 83) had seroprotective levels of anti-HBs, and did not receive a booster dose. The number of students with seroprotective levels of anti-HBs increased by 12.8% in Group A and 14.5% in Group C, suggesting that our entire cohort had experienced booster effects from natural HBV exposure. However, no new HBV infections were observed, and 53.9% of Group B maintained protective levels of anti-HBs during the follow-up period. Anti-HBc titers were assessed among 1,734 neonatally HBV vaccinated university students who matriculated between 2006 and 2008. The overall prevalence of isolated anti-HBc in our student cohort was 1.2% (21 of 1734). No evidence of occult HBV infection was observed. A “booster” anamnestic response (anti-HBs titer ≥10 mIU/mL) was noted in 95% (20 of 21) of the subjects with isolated anti-HBc. When anti-HBc was measured again 6 months later, 13 (62%) of the 21 subjects with isolated anti-HBc were reclassified as having resolved HBV infections and had lost their protective anti-HBs levels. The remaining 8 subjects (38%) with isolated anti-HBc were determined to be false positives. These 8 subjects were classified as being HBV naive due to the waning-off effect of anti-HBs levels gained from neonatal HBV vaccination. There was no significant difference in anamnestic response to a single HBV booster dose of vaccine between students with isolated anti-HBc (n=13) and those with HBV naive (n=323) status (geometric mean titers 50.6 vs 47.7 mIU/mL, P= 0.90). In 2008, 1,745 undergraduate students (18.6 ± 1.0 years), 403 graduate students (mean age 22.8 ± 0.7 years), and 367 adult participants (41.1 ± 15.8 years) were recruited to evaluate the feasibility of the HBsAg confirmatory test among young persons with complete neonatal HBV vaccinations. All HBsAg positive subjects were tested with an HBsAg confirmatory test. The prevalence of HBsAg positivity was 16.3% among adults, 5.2% among graduate students, and 2.8% among the undergraduate students (P=0.0007). The positive predictive value (PPV) of HBsAg testing when determining cases of hepatitis B was 0.97 for adults, 0.81 for graduate students, and 0.56 for undergraduate students (P<0.0001). Conclusion: By analyzing data sourced from the Taiwan NHIRD, we found that chronic HBV carriers had higher risks of developing gallbladder and extra-hepatic bile duct, pancreas, and kidney cancers in addition to liver cancer. Subjects with sole HBV infections also had borderline higher risks of developing non-Hodgkin lymphoma. Unlike chronic HCV infection, chronic HBV infection is not associated with breast cancer, oral cavity cancer, CKD, or ARDs. Our study also showed that the use of the modified 3-dose booster protocol induced significant long-term increases anti-HBs titers among over 50% of the neonatally vaccinated participants with previously non-protective titers. However, in the absence of a vaccine booster, some neonatally vaccinated people with low anti-HBs titers may nonetheless produce anamnestic responses to HBV upon exposure, suggesting that protection from neonatal vaccination may persist, despite low titers of anti-HBs. In addition, the presence of isolated anti-HBc among our neonatally HBV vaccinated university participants can be attributed to post-HBV infection with a loss of anti-HBs titer levels and a decline in anti-HBs elicited by vaccine. A single HBV booster dose of vaccine is recommended for subjects with isolated anti-HBc who were fully vaccinated for HBV as infants. A significant decrease in the true-positive rate of HBsAg (44%) among neonatally HBV vaccinated university participants was observed only when HBsAg testing was applied. Additional neutralization tests may therefore become mandatory for persons with a positive HBsAg test who were born after the initiation of the universal neonatal hepatitis B vaccination program in Taiwan.
Description:	博士論文指導教授-葉志清委員-宋鴻樟委員-謝玲玲委員-張定宗委員-李中一委員-邱弘毅委員-薛玉梅
Data Type:	thesis
Appears in Collections:	[School of Public Health] Thesis

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