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研究生:文萬欣
研究生(外文):Wan-Hsin Wen
論文名稱:接種B型肝炎疫苗兒童發生B型肝炎病毒感染之研究
論文名稱(外文):Hepatitis B Virus Infection in Vaccinated Children
指導教授:張美惠張美惠引用關係陳慧玲陳慧玲引用關係
口試委員:簡榮南吳子聰高嘉宏倪衍玄許宏遠
口試日期:2013-06-20
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:中文
論文頁數:118
中文關鍵詞:周產期傳染防疫失敗母子傳染B型肝炎病毒基因型B型肝炎病毒濃度
外文關鍵詞:perinatal transmissionimmunoprophylactic failuremother-to-infant transmissionhepatitis B virus genotypehepatitis B viral load
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B型肝炎病毒感染所造成的疾病是全球性的重要問題。在全民預防接種計畫實施後,台灣民眾的B型肝炎表面抗原陽性率及相關疾病發生率已明顯下降。預防注射可減少,但無法完全根除B型肝炎病毒的傳染。曾接受預防注射卻仍感染到B型肝炎病毒者,最主要的感染源是母子傳染。台灣地區的B型肝炎病毒以基因型B和C為主,兩者相比,基因型C的感染者的臨床病程較嚴重。本研究的第一部分是:比較調查在預防接種實施前後,台灣B型肝炎帶原兒童的病毒基因型分布是否改變。本研究的第二部分則是一項前瞻性的B型肝炎帶原母親及其子女的追蹤研究,希望了解在現行預防措施下,B型肝炎病毒母子傳染的發生率及危險因子。
在研究的第一部分,我們收集了107位曾接受過完整B型肝炎預防注射,卻仍得到慢性B型肝炎病毒感染的兒童,稱之為「接受過預防注射的B型肝炎病毒感染者」。每一位「接受過預防注射的B型肝炎病毒感染者」會配上兩位在收案時年齡相仿的「未接種過預防注射的對照者」(214位對照者)。B型肝炎病毒基因型由分子學方法測定。和「未接種過預防注射的對照者」相比,「接受過預防注射的B肝病毒感染者」的母親B肝表面抗原陽性率明顯較高 (65.9% 比 100%, P值 < 0.001),且感染基因型C的人也較多 (16.4% 比 42.1%, P值 < 0.001)。若這些兒童的母親也是B肝帶原者的話,母親和小孩的B肝病毒基因型非常一致,無論是「未接種過預防注射的對照者」(kappa值= 0.97, 95%信賴區間=0.90-1.00),或「接受過預防注射的B型肝炎病毒感染者」(kappa值= 0.97, 95%信賴區間=0.92-1.00) 都是如此。在控制了小孩性別、母親生產時年齡、生產方式是否為剖腹等因素後,母親為B肝帶原者的「接受過預防注射的B型肝炎病毒感染者」比「未接種過預防注射的對照者」感染基因型C的可能性更高 (勝算比 = 3.03, 95%信賴區間:1.62-5.65, P = 0.001)。
在研究的第二部分,我們收集了303位B型肝炎帶原母親的孩子。小孩按現行預防接種規定接受疫苗(及免疫球蛋白)注射。母親的B型肝炎病毒濃度以即時聚合酶鏈鎖反應的方法測定。小孩在4-8個月大及/或1-3歲時接受B型肝炎表面抗原檢驗。我們用一多變項迴歸模式來預測小孩感染B型肝炎病毒的機率。和e抗原陰性的母親相比,e抗原陽性母親 (81/303, 26.7%) 的B型肝炎病毒濃度較高 (2.7 ± 1.4 versus 7.4 ± 1.9 log10 copies/ml, P < 0.0001)。有10個孩子成為慢性B型肝炎帶原,這10個孩子的母親均為e抗原陽性,且母親有高濃度的B型肝炎病毒量 (中位數:8.4;範圍:6.5-9.5 log10 copies/ml)。在控制母親生產時年齡、是否為剖腹產、是否有增加母子間出血的危險因子、懷孕週數、小孩性別、小孩出生體重、B型肝炎疫苗注射時間、是否餵食母奶等項目後,母親的病毒濃度量是小孩得到B型肝炎病毒感染的顯著危險因子(每升高一個log10 copies/ml,勝算比:3.49,95%信賴區間:1.63-7.48;P = 0.001)。當母親的病毒濃度在7、8、9 log10 copies/ml時,她的小孩得到B肝病毒感染的預測機率分別為:6.6% (95%信賴區間:0.5-12.6%;P = 0.033)、14.6% (95%信賴區間:5.6-23.6%;P = 0.001)、27.7% (95%信賴區間:13.1-42.4%;P < 0.001)。
總結來說,基因型B及基因型C的B型肝炎病毒兩者均可以經由母子傳染及水平傳染的方式傳播。母子傳染是接種疫苗兒童感染B型肝炎病毒的最主要感染途徑。和「未接種過預防注射的對照者」相比,在「接受過預防注射的B型肝炎病毒感染兒童」中,感染基因型C的比例變高了。這些兒童需要更謹慎的追蹤和醫療照護。其次,母親的病毒濃度量是導致B型肝炎病毒母子傳染的最重要因素。在現行的預防接種措施外,應考慮給予病毒濃度大於10^7-10^8 copies/ml的母親治療,以進一步減少B型肝炎病毒之母子傳染。

Hepatitis B virus (HBV) infection is a serious health problem worldwide. Since the launch of the universal immunization program, the seropositive rate of hepatitis B surface antigen (HBsAg) and the incidence rates of related complications in Taiwanese people have declined substantially. Immunoprophylaxis reduces but does not completely eradicate HBV transmission. Mother-to-infant transmission causes the majority of cases with immunoprophylactic failure. Genotypes B and C are the major HBV genotypes in Taiwan, and genotype C is associated with more severe liver disease than genotype B. The first part of the study aimed at investigating the HBV genotypes in HBsAg carrier children born before and after the implementation of the universal immunization program. The second part of the study was a prospective study to assess the rate and risk factors of maternally transmitted HBV infection in a cohort of HBV-infected women and their children.
In the first part of the study, 107 HBV-infected children despite appropriate immunization were enrolled as the immunized cases with HBV infection. Each case was matched with two un-immunized HBsAg carriers based on the age at enrollment. HBV genotypes were determined using molecular methods. Compared with un-immunized HBsAg carriers, more immunized children had HBsAg-positive mothers (65.9% versus 100%; P < 0.001), and were infected with genotype C (16.4% versus 42.1%; P < 0.001). Among the children born to HBsAg-positive mothers, maternal and children’s HBV genotypes were highly concordant in both un-immunized (kappa, 0.97; 95% confidence interval [CI], 0.90-1.00) and immunized children (kappa, 0.97; 95% CI, 0.92-1.00). After adjustment for gender, maternal age, and delivery mode, immunized HBsAg carrier children born to HBsAg-positive mothers had a higher likelihood of genotype C infection than un-immunized children (odds ratio, 3.03; 95% CI, 1.62-5.65; P = 0.001).
In the second part of the study, we enrolled 303 mother-infant pairs with positive maternal HBsAg under current immunization program. Maternal viral load was determined by a real-time PCR-based assay. The children were tested for HBsAg at 4-8 months and/or 1-3 years of age. Rates of HBV infection were estimated using a multivariate logistic regression model. Hepatitis B e antigen (HBeAg)-positive mothers (81/303, 26.7%) had higher viral loads than HBeAg-negative mothers (7.4 ± 1.9 versus 2.7 ± 1.4 log10 copies/ml, P < 0.0001). Ten children, born to HBeAg-positive mothers with high viral load (median, 8.4; range, 6.5-9.5 log10 copies/ml), were chronically infected. After adjustment for maternal age, birth type, factors related to maternal-fetal hemorrhage, gestational age, infant gender, birth weight, timeliness of vaccination, and feeding practice, maternal viral load was significantly associated with the risk of infection (adjusted odds ratio for each log10 copy/ml increase, 3.49; 95% CI, 1.63-7.48; P = 0.001). The predictive rates of infection at maternal viral load levels of 7, 8, and 9 log10 copies/ml were 6.6% (95% CI, 0.5-12.6%; P = 0.033), 14.6% (95% CI, 5.6- 23.6%; P = 0.001), and 27.7% (95% CI, 13.1-42.4%; P < 0.001), respectively.
In summary, both HBV genotypes B and C can be transmitted from maternal and horizontal origins and maternal transmission is responsible for most HBV infections in children with immunoprophylactic failure. Compared with un-immunized HBsAg carriers, more immunized children had genotype C infection. These children need more careful long-term follow-up. Second, maternal HBV DNA level is the most important risk factor causing maternally transmitted HBV infection. Additional strategies to further reduce transmission should be considered in mothers with a viral load above 10^7-10^8 copies/ml.

一、緒論
1.1 B型肝炎病毒感染 …………………………………………………………… 1
1.2 B型肝炎疫苗接種計畫 ……………………………………………………… 3
1.3 接種B型肝炎疫苗兒童發生B型肝炎病毒感染 …………………………… 7
1.4 接種疫苗兒童發生B型肝炎病毒感染之原因 ……………………………… 9
1.4.1 子宮內感染 ………………………………………………………………… 9
1.4.2 高濃度的母親B型肝炎病毒量 …………………………………………… 11
1.4.3 表面基因突變的B型肝炎病毒感染 ……………………………………… 16
1.4.4 人體因素無法對B型肝炎疫苗產生抗體 ………………………………… 20
1.5 B型肝炎病毒基因型 ………………………………………………………… 21
1.6 研究目的及假說 …………………………………………………………… 23
1.6.1 預防注射後B型肝炎帶原兒童病毒基因型分布之變化 ………………… 23
1.6.2 B型肝炎病毒母子傳染的前瞻性研究 …………………………………… 24

二、研究方法與材料
2.1 研究對象 …………………………………………………………………… 25
2.1.1 預防注射後B型肝炎帶原兒童病毒基因型分布之變化 ………………… 25
2.1.2 B型肝炎病毒母子傳染的前瞻性研究 …………………………………… 26
2.2 研究方法 …………………………………………………………………… 27
2.2.1 B型肝炎病毒血清學標記 ………………………………………………… 27
2.2.2 B型肝炎病毒基因型鑑定 ………………………………………………… 27
2.2.3 B型肝炎病毒量測定 ……………………………………………………… 30
2.3 統計方法 …………………………………………………………………… 30

三、結果
3.1 預防注射後B型肝炎帶原兒童病毒基因型分布之變化 …………………… 33
3.1.1 B型肝炎帶原兒童之臨床資料 …………………………………………… 33
3.1.2 B肝帶原兒童病毒基因型分布和預防注射及母親B肝帶原的關係 …… 33
3.1.3 B型肝炎帶原兒童和其母親的B型肝炎病毒基因型比較 ……………… 34
3.1.4 B型肝炎病毒基因型分布的長期趨勢 …………………………………… 35
3.1.5 預防接種對B型肝炎病毒基因型分布的影響 …………………………… 36
3.2 B型肝炎病毒母子傳染的前瞻性研究 ……………………………………… 36
3.2.1 B型肝炎帶原母親的臨床資料 …………………………………………… 37
3.2.2 小孩的預防注射及追蹤 …………………………………………………… 38
3.2.3 B型肝炎病毒母子傳染的個案 …………………………………………… 39
3.2.4 B型肝炎病毒母子傳染的危險因子 ……………………………………… 39
3.2.5 B型肝炎病毒母子傳染的預測發生率 …………………………………… 40

四、討論
4.1 預防注射實施前後B型肝炎帶原兒童的感染途徑 ………………………… 41
4.2 B型肝炎病毒基因型分布的長期趨勢及和預防接種的關係 ……………… 45
4.3 B型肝炎病毒基因型和e抗原及病毒濃度的關係 ………………………… 48
4.4 B型肝炎病毒母子傳染的危險因子 ………………………………………… 53
4.5 進一步防止B型肝炎病毒母子傳染的策略 ………………………………… 56

五、展望 ………………………………………………………………………… 60

六、論文英文簡述
Introduction …………………………………………………………………… 66
Subjects………………………………………………………………………… 68
I. HBV genotype distribution after universal infant immunization ………… 68
II. Prospective study of mother-to-infant transmission of HBV infection … 69
Methods ………………………………………………………………………… 70
HBV serology …………………………………………………………………… 70
HBV genotyping ………………………………………………………………… 71
HBV DNA quantification ……………………………………………………… 71
Statistical analyses …………………………………………………………… 72
Results ………………………………………………………………………… 73
I. HBV genotype distribution after universal infant immunization ………… 73
II. Prospective study of mother-to-infant transmission of HBV infection … 75
Discussion ……………………………………………………………………… 78

七、參考文獻 …………………………………………………………………… 83

八、圖示
圖1. 預防注射後B型肝炎帶原兒童病毒基因型分布變化之分組流程圖 …… 104
圖2. B型肝炎帶原母親及其子女收案追蹤流程圖 …………………………… 105
圖3. B肝帶原兒童病毒基因型分布和預防注射及母親B肝帶原的關係 …… 106
圖4. B肝帶原兒童病毒基因型分布和預防注射及出生年分的關係 ………… 107
圖5. 母親的B型肝炎病毒濃度分布和e抗原的關係 ………………………… 108
圖6. B型肝炎病毒母子傳染的預測發生率 …………………………………… 109

九、表格
表1. B型肝炎帶原兒童之臨床資料 …………………………………………… 110
表2. B型肝炎帶原兒童和其母親的B型肝炎病毒基因型比較 ……………… 111
表3. 母親為B肝帶原者的不同基因型B肝病毒感染兒童之比較 …………… 112
表4. 母親為B肝帶原的兒童感染B肝病毒基因型C之多變項迴歸分析 …… 113
表5. B肝帶原母親的小孩,接受和未接受B肝表面抗原檢驗者之比較 …… 114
表6. B型肝炎帶原母親的臨床資料 …………………………………………… 115
表7. B型肝炎病毒母子傳染的個案及其母親的資料 ………………………… 116
表8. B型肝炎病毒母子傳染相關因素之單變項及多變項迴歸分析 ………… 117

十、附錄 ………………………………………………………………………… 118

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