B型肝炎病毒量的長期變化趨勢和肝細胞癌的危險性:病例世代研究

Long-Term Patterns of Hepatitis B Viral Load and Risk of Hepatocellular Carcinoma: A Case-Cohort Study

吳志峰(Chih-Feng Wu)

指導教授 ： 于明暉

國立臺灣大學/公共衛生學院/流行病學研究所/碩士(2006年)

https://doi.org/10.6342/NTU.2006.00656

摘要

背景: B型肝炎病毒量已被報告和肝細胞癌的危險性有關。本研究主要有三個目的: 1) 探討B型肝炎病毒量的長期變化趨勢; 2) 評估B型肝炎基因型和其它因子對於病毒量循跡現象的影響; 以及3)研究B型肝炎病毒量的長期變化趨勢與肝細胞癌危險性的關係。方法: 以1989-1992年收案的男性B型肝炎帶原者世代為基礎進行病例-世代研究。經過16年的追蹤，共有112位肝細胞癌患者發生，連同1031位健康帶原者，一共納入7706個時點的血液檢體。B型肝炎病毒量和基因型是利用以聚合酵素鏈鎖反應為原理的方法測量。我們使用weighted Cox’s proportional hazards model和廣義線性混合模型分別探討病毒因子和肝細胞癌的關係，以及B型肝炎病毒量的循跡現象。結果: 帶有基因型C者比帶有基因型B者具有較高的病毒量 (P值<0.001)，而且B型肝炎病毒的基因型會影響病毒量隨年齡的變化趨勢 (年齡與基因型之交乘項的P值<0.001)。在16年的追蹤期間，B型肝炎病毒量呈現相當良好的循跡現象，在基線時所測得的病毒量對於16年以內的病毒量測量值有很高的預測力。肝細胞癌的危險性會隨著病毒量持續處於危險值 (>4.386 log10 copies/mL)的時間越長而越高。持續3、6和9年的多變項調整之危險比分別為：5.00 (95%信賴區間：2.73-9.16)，6.71 (95%信賴區間：3.07-14.67)，和9.17 (95%信賴區間：2.59 -32.48)。結論: 經過長期的追蹤評估，B型肝炎病毒量具有良好的循跡現象。病毒量持續處於危險值以上的時間長短和肝細胞癌的危險性呈現正相關。我們建議30歲以上、病毒量處於活躍複製時期的B型肝炎帶原者，應及早接受介入治療。

關鍵字

B型肝炎病毒 ； B型肝炎病毒量 ； 病例世代研究 ； 重覆性測量 ； 循跡分析 ； B型肝炎病毒之基因型

並列摘要

Background: Hepatitis B viral load measured in terms of circulating hepatitis B virus (HBV) DNA levels has been associated with hepatocellular carcinoma (HCC) risk. The specific aims of this study were threefold: 1) to explore the long-term patterns of HBV viral load; 2) to assess the influence of HBV genotype and other factors on the tracking of HBV viral load over time; and 3) to examine the long-term patterns of HBV viral load and subsequent risk of developing HCC after adjusting for viral genotype. Methods: A case-cohort study was conducted within a cohort of male HBV carriers whose initial blood samples were taken in 1989-1992. We used PCR-based assays to determine HBV viral load and genotype on 7706 plasma samples, collected during a period of up to 16 years of follow-up, from a total of 112 individuals who subsequently developed HCC and 1031 unaffected individuals. A weighted Cox’s proportional hazards model was used to assess the association between viral factors and HCC. We evaluated tracking of HBV viral load using the generalized linear mixed model. Results: Carriers of genotype C HBV had a significantly higher HBV viral load than carriers of genotype B HBV (P < 0.001). HBV genotype influenced the decreasing trend of viral load with age (P for age×genotype interaction < 0.001). Over a period of 16 years, both stability coefficients and tracking for subjects at risk for HBV viral load were high, indicating high predictability of initial measurements for values within 16 years. The HCC risk increased with increasing duration of having at-risk viral load, defined as ≥ 4.386 log10 copies/mL, showing adjusted hazard ratios were 5.00 (95% confidence interval [CI] = 2.73 to 9.16), 6.71 (95% CI = 3.07 to 14.67), 9.17 (95% CI = 2.59 to 32.48), respectively, for duration of persistence within 3, 6, 9 years of the initial measurement. Conclusions: Tracking of HBV viral load after long-term follow-up was high. Duration of persistence for having at-risk viral load was positively associated risk of HCC. Our data recommend that the prophylactic intervention for active viral infection should be at earlier ages among HBV carriers aged 30 years or older.

並列關鍵字

HBV ； HBV viral load ； case-cohort study ； repeated measurements ； tracking analysis ； HBV genotype

參考文獻

1. Globocan 2002, IARC. Available from URL: http://www-dep.iarc.fr/.

2. Robinson WS. Hepatitis D virus. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Disease. 4th ed. New York: Churchill Livingstone; 1995:1406-1439.

4. Chen CJ, Wang LY, Yu MW. Epidemiology of hepatitis B virus infection in the Asia-Pacific region. J Gastroenterol Hepatol 2000;15 Suppl:E3-6.

5. Chen DS. From hepatitis to hepatoma: lessons from type B viral hepatitis. Science 1993;262:369-370.

6. Lee WM. Hepatitis B virus infection. N Engl J Med 1997;337:1733-1745.