B型肝炎病毒e抗原血清廓清之決定因子

Abstract

背景 B型肝炎病毒e抗原（HBeAg）的血清廓清通常代表著B型肝炎病毒複製降低以及較緩慢的病程進展，因此，HBeAg的血清廓清對於慢性B型肝炎病患是一個好的指標。然而目前對於HBeAg血清廓清反應的發生機轉仍沒有完整的解答，因此本研究的目的是探討與HBeAg血清廓清反應相關的因子，以期了解有什麼樣的因子可以預測血清廓清反應的發生，並對HBV感染的自然史有更完整的了解。 材料方法 研究個案來自1991-1992年於台灣七個鄉鎮市區開始收案的長期追蹤研究世代中，B型肝炎病毒表面抗原（HBsAg）陽性並且沒有C型肝炎病毒共同感染的1526名男性與女性。針對這些研究對象在納入研究時的血液檢體進行HBeAg、血清ALT濃度、血清HBV DNA濃度及B型肝炎病毒基因型的測量，另外也對其最後一次追蹤的血清進行HBeAg帶原狀態的檢測。以logistic regression分析與HBeAg血清廓清相關因子的多因子校正危險勝算比（odds ratio, OR）及95%信賴區間；並使用分層分析進行不同分層間HBeAg血清廓清可能性的比較。 結果 追蹤的時間、B型肝炎病毒基因型及HBV DNA清濃度都與HBeAg血清廓清有統計顯著相關。經多因子校正後，相對於追蹤時間<5年者，OR（95%信賴區間）分別為5~9年6.30 (2.82-14.05)、≥10年11.68 (5.52-24.71)；B型肝炎病毒基因型C比基因型B其OR為0.23 (0.13-0.41)；HBV DNA血清濃度≥107 相對於 <105 copies/mL其OR為0.24 (0.07-0.77)。性別、ALT、precore (G1896A) 及basal core promoter (A1762T/G1764A)的突變與HBeAg血清廓清則沒有統計顯著相關。基因型C相對於基因型B在男性中有顯著較低的HBeAg血清廓清可能性（OR=0.14, 0.07-0.28），但在女性中則否 (OR=1.71, 0.51-5.72)；男性相對於女性在基因型C的分層中有顯著較低的HBeAg血清廓清可能性（OR=0.38, 0.20-0.74），但在基因型B分層中則否（OR=2.09, 0.67-6.47）。precore及basal core promoter的突變情形與HBeAg血清廓清之間的相關性受到HBV DNA血清濃度的修飾。基因型C相對於基因型B在年齡≥35的分層中有較顯著的相關性 (OR=0.35, 0.20-0.61)。 結論 較長的追蹤時間、B肝病毒基因型B及在納入研究時較低的HBV DNA血清濃度會增加其HBeAg的血清廓清率。然而，性別、ALT血清濃度、precore (G1896A) 及basal core promoter (A1762T/G1764A)的突變與HBeAg血清廓清則沒有發現統計顯著相關。在分層分析中發現，性別、B型肝炎病毒基因型及basal core promoter對於HBeAg血清廓清的效應會分別受到病毒基因型、年齡及HBV DNA血清濃度的修飾。

Background The seroclearance of hepatitis B e antigen (HBeAg) is usually associated with low HBV replication and slow disease progression. It is a favorable sign for patients with chronic hepatitis B. However, the mechanism of HBeAg seroclearance remains incompletely clear. The aim of this study was to examine factors associated with HBeAg seroclearance. Methods There were 1526 HBsAg-seropositive and anti-HCV-seronegative men and women enrolled from seven townships in Taiwan between 1991 and 1992 in this analysis. Their serum samples at cohort entry were tested for HBeAg, ALT, HBV DNA level and genotype. The HBeAg status in last follow-up samples was also tested. Logistic regression analysis was used to derive multivariate-adjusted odds ratio (OR) and 95% confidence interval (CI) for factors associated with HBeAg seroclearance. Stratification analysis was used to evaluate the association of HBeAg seroclearance probability between different strata. Result Follow-up period, HBV genotype and HBV DNA levels at study entry were significantly associated with HBeAg seroclearance. The multivariate-adjusted OR (95% CI) of HBeAg seroclearance was 6.30 (2.82-14.05) and 11.68 (5.52-24.71), respectively, for follow-up periods of 5-9 years and ≧10 years versus <5 years; 0.23 (0.13-0.41) for HBV genotype C versus genotype B; and 0.24 (0.07-0.77) for serum HBV DNA level at study entry ≧107 versus <105 copies/mL. The HBeAg seroclearance was not statistically significantly associated with gender, ALT level, HBV precore (G1896A) and basal core promoter (A1762T/G1764A) mutants. Genotype C showed a significantly lower HBeAg seroclearance probability than genotype B in male subjects （OR=0.14, 0.07-0.28）but not in female(OR=1.71, 0.51-5.72). Male gender showed a significantly lower HBeAg seroclearance probability than female in genotype C strata（OR=0.38, 0.20-0.74）, but not in genotype B strata（OR=2.09, 0.67-6.47）. The association between basal core promoter mutation and HBeAg seroclearance was modified by HBV DNA level. Genotype C had significantly lower HBeAg seroclearance probability than genotype B in age ≧35 participants(OR=0.35, 0.20-0.61). Conclusion Longer follow-up period, HBV genotype B, and HBV DNA levels at study entry were associated with a significantly increased HBeAg seroclearance rate. However, no significant association with HBeAg seroclearance was observed for gender, ALT level, HBV precore (G1896A) and basal core promoter (A1762T/G1764A) mutants. In the subgroup analysis, we found the gender, genotype and basal core promoter effect of HBeAg seroclearance modified by genotype, age and HBV DNA level respectively.