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Clinical Significance of Hepatitis B Virus Pre-S Deletion Mutants in Patients with Chronic Hepatitis B Virus Infection: A Case Control Study

B型肝炎病毒pre-S基因缺失突變之臨床意義:病例對照研究

摘要


背景:B型肝炎病毒慢性感染的病程會累積pre-S基因自然演化所出現的缺失突變。Pre-S基因的缺失突變減少S基因的轉錄,卻增加pre-S基因的轉錄,導致大蛋白大量堆積於肝細胞之細胞質中。然而此種細胞毒性反應對B型肝炎病毒慢性感染病程的影響,尚待進一步的研究。藉由病例對照研究,我們分析pre-S基因缺失突變之臨床意義。 方法:收集市立聯合醫院仁愛院區及台大醫院B型肝炎病毒慢性感染患者60例,含持續肝功能正常帶原者(對照組)及慢性肝炎病患(實驗組)各80例。對照組及實驗組在男女比例、年齡均互相配對,並且介於20至60歲之間。將病患血清萃取之HBVDNA,分析其pre-S基因缺失突變與臨床表現之相關性。 結果:60例病患pre-S基因缺失突變的盛行率爲20.6%。分析對照組和實驗組發現,實驗組e抗原陽性的比例(57.5% vs. 40%, P=0.04)、及pre-S基因缺失突變的比例明顯高於對照組(3.2% vs. 10%, P=0.002)。e抗原陽性病患pre-S基因缺失突變的比例亦明顯高於e抗原陰性病患(27.8% vs. 3.6%, P=0.032)。進一步以pre-S基因缺失突變存在與否分層分析,pre-S基因缺失突變者其e抗原陽性率(66.7% vs 44.9%, P=0.032)、慢性肝炎的比例(75.8% vs. 43.3%, P=0.002)和基因型C的比例(66.7% vs. 33.9%, P=0.001)均明顯高於無pre-S基因缺失突變的病患。而且基因型C病患pre-S基因缺失突變的比例明顯高於基因型B(33.8% vs. 11.6%, P=0.01)。以multiple logistic regression分析肝炎活性(hepatitis activity)的危險因子,發現只有pre-S基因缺失突變是造成肝炎活性的危險因子(odds ratio, 3.9; 95% CI, 1.57-9.76, P=0.003)。 結論:台灣e抗原陽性B肝帶原者pre-S基因缺失突變的盛行率較e抗原陰性B肝帶原者高。病毒基因型C病患pre-S基因缺失突變的比例亦明顯高於基因型B病患。不論病患HBeAg陽性或陰性,pre-S基因缺失突變均可能增加肝炎活性的危險。

並列摘要


Background and Aim: The cytopathic effects of pre-S deletion mutant on natural course of chronic hepatitis B remain largely unclear. In the case-control study, we therefore investigated the clinical significance of pre-S deletion mutant in Taiwanese hepatitis B virus (HBV) carriers. Methods: By using molecular assays, pre-S deletion mutant of HBV were determined in 160 patients with chronic HBV infection, including 80 carriers with persistently normal serum alanine aminotransferase levels (PNALT) and 80 chronic hepatitis B patients. They were matched for gender and each 10-year categories of age. Results: The overall prevalence of pre-S deletion mutant was 20.6%. Compared to HBV carriers with PNALT, chronic hepatitis B patients had a significantly higher frequency of pre-S deletion mutant (31.2% vs. 10%, P=0.002). The prevalence of pre-S deletion mutant in HBeAg-positive patients was significantly higher than HBeAg-negative patients (27.8% vs. 13.6%; P=0.032). In addition, the frequency of pre-S deletion mutant was significantly higher in genotype C patients than genotype B patients (33.8% vs. 11.6%, P=0.01). By multiple logistic regression analysis, presence of pre-S deletion mutant was the only independently risk factor associated with hepatitis activity (odds ratio, 3.91; 95% CI, 1.57-9.76, P=0.003). Conclusion: Pre-S deletion mutant is more frequent in HBeAg-positive HBV carriers, particular in those with genotype C infection. Taiwanese HBV carriers with pre-S deletion mutants might have an increased risk for hepatitis activity, irrespective of HBeAg status.

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