于明暉臺灣大學：流行病學研究所康珮瑱Kang, Pei-JenPei-JenKang2007-11-272018-06-292007-11-272018-06-292007http://ntur.lib.ntu.edu.tw//handle/246246/56199研究背景/目的：臺灣是B型肝炎病毒慢性感染盛行地區，B和C型肝炎病毒雙重感染並不少見。目前對於雙重感染者自然史的研究，尚有所不足。本研究目的在利用縱斷研究分析雙重感染者，其B型肝炎病毒量的長期狀態及影響因子；以及雙重感染和慢性肝病之關係。 材料和方法：1989-1992年收集5,189接受健檢的公務人員資料及血液檢體，其中單獨HBsAg陽性、單獨anti-HCV陽性、HBsAg和anti-HCV均陽性、以及兩者均陰性的人數各為2,643、176、161和2,209。利用每年健檢、檢索全國癌症和死亡登記檔進行追蹤至2005年底。以PCR為基礎的方法分析雙重感染者之B型肝炎病毒基因型及基線和追蹤期間所有血液檢體的病毒量。所有統計檢定均為雙尾檢定。 結果：肝細胞癌發生率及肝病死亡率（每10萬人年）在單獨HBsAg陽性、單獨anti-HCV陽性、HBsAg和anti-HCV均陽性、以及兩者均陰性者中依序為296.8和202.9，202.0和39.9，221.9和176.4，以及12.6和9.5。B和C型肝炎病毒雙重感染者在追蹤期間有35名發生慢性肝病（包括肝細胞癌、肝硬化、和ALT持續異常−定義是>=50%的檢體異常）及6名發生肝炎急性發作（ALT>5倍正常值）。B型肝炎病毒量長期維持相當穩定的狀態，基線高病毒量（>=10^4.45 copies/mL）和追蹤期間的慢性肝病為持續高病毒量的預測因子。研究個案具有>=50%的檢體為高病毒量（相對危險性：2.71；95%信賴區間：1.15~6.36）及anti-HCV optical density（相對危險性：1.25；95%信賴區間：1.01~1.55）和慢性肝病顯著相關，而高於10^5.81 copies/mL以上的病毒量和發生肝炎急性發作有強相關（相對危險性：13.36；95%信賴區間：1.49~120.0）。 結論：B和C型雙重感染者罹患肝細胞癌及肝病死亡的危險性接近B型肝炎病毒單一慢性感染者。B型肝炎病毒量呈現長期相當穩定的狀態，持續高病毒量及anti-HCV optical density和慢性肝病發展的危險性有關。Background and Aims: Taiwan is an endemic area of hepatitis B. Dual infection of hepatitis B virus (HBV) and hepatitis C virus (HCV) is not unusual. However, the natural history of dual infection in the population remained unknown. We sought to determine the liver-related morbidity and mortality and the long-term viremia profiles of HBV for dual infection in a population-based longitudinal cohort study. Materials and Methods: The cohort consisted of 5189 men (2643 HBsAg (+) alone, 176 anti-HCV (+) alone, 161 HBsAg (+) and anti-HCV (+), and 2209 HBsAg (−) and anti-HCV (−)) aged 30 years or older who were enrolled between 1989 and 1992, and followed through December 31, 2005. HBV genotype and DNA levels were measured using polymerase chain reaction-based assays. Plasma HBV DNA levels were assessed for multiple samples consecutively collected from each man with dual infection of HBV and HCV. All statistical tests were two-sided. Results: The incidence of hepatocellular carcinoma and liver-related mortality (per 100000 persons) were 296.8 and 202.9, 202.0 and 39.9, 221.9 and 176.4, and 12.6 and 9.5, respectively, in those who were positive for HBsAg alone, those who were positive for anti-HCV alone, those who were positive for HBsAg and anti-HCV, and those who were negative for both markers. During follow-up, 35 men with dual infection developed chronic liver disease (i.e., hepatocellular carcinoma, liver cirrhosis, or longitudinal alanine aminotransferase [ALT] elevation defined as abnormality detected in >=50% of the visits), and 6 had hepatic flare (ALT>5×upper limit of the normal levels). Initial viral load was positively associated with the persistence of high viral load (>=10^4.45 copies/mL). High tracking for viral load, as evidenced by the high predictability of initial viral load, was observed within 6 years. Longitudinal high HBV viral load detected in >=50% of the visits (adjusted odds ratio [OR]=2.71, 95% confidence interval [CI]=1.15~6.36) and anti-HCV optical density (adjusted OR=1.25, 95% CI=1.01~1.55) were significantly associated with the development of chronic liver disease. An extremely high viral load (defined as >=10^5.81 copies/mL) (OR=13.36, 95% CI=1.49~120.0) was the only predictor for hepatic flare. Conclusions: The incidence of HCC and liver-related mortality among men with dual infection were similar to those among men with HBV monoinfection. HBV viral load was fairly stable, as evidenced by long-term persistence of high viral load. Persistently high viral load and anti-HCV optical density were associated with the development of chronic liver disease.口試委員會審定書i 讀謝ii 中文摘要 iii 英文摘要 iv 壹、研究背景 1 貳、研究材料及方法 4 一、研究世代 二、基線資料收集 三、追蹤資料收集 四、實驗分析 五、品質管制 六、統計分析 參、研究結果 7 一、肝細胞癌發生率及肝病死亡率 二、研究族群基線特性 三、長期HBV病毒量之影響因子及穩定度 四、HBV 病毒量長期狀態、anti-HCV optical density和慢性肝病的關係 肆、討論 9 伍、參考文獻 13 表一 HBV基因型的PCR Primers序列表 19 表二 B及C型肝炎病毒感染和肝細胞癌發生率及肝病死亡率 20 表三 B及C型肝炎病毒雙重感染之研究對像的基線特性 21 表四 HBV基因型及基線病毒量分佈特性 22 表五 血漿HBV DNA濃度隨時間變化狀態 23 表六 HBV病毒量在追蹤期間的穩定度 24 表七 影響長期追蹤期間HBV病毒量的因子：縱斷分析 25 表八 HBV DNA、anti-HCV和慢性肝病的關係 26 表九 追蹤期間HBV DNA濃度與肝炎急性發作之關係 27 圖一 研究族群選取流程 28 圖二 HBV病毒量長期趨勢 29 圖三 HBV DNA病毒量下降至< 104.45 copies/mL之年數 30 圖四 HBV DNA病毒量下降至偵測極限102.34 copies/mL以下之年數31379493 bytesapplication/pdfen-USB型肝炎C型肝炎DNA雙重感染基因型長期追蹤研究Hepatitis BHepatitis CDual infectionGenotypeLongitudinal study[SDGs]SDG3thesishttp://ntur.lib.ntu.edu.tw/bitstream/246246/56199/1/ntu-96-R91842006-1.pdf