C型肝炎與登革熱病毒間可能的交互作用

The potential viral interference between hepatitis C virus and dengue virus

梁博程(Po-Cheng Liang)

指導教授 ： 余明隆

高雄醫學大學/醫學院/臨床醫學研究所博士班/碩士(2018年)

摘要

背景:
登革熱病毒與C型肝炎病毒之感染皆是全球公衛之重要健康議題。兩者同屬黃熱病毒科，都會引起肝臟發炎，且目前都沒有疫苗可供預防。位處南臺灣之高雄，是C型肝炎較盛行之區域，同時也是近年來登革熱疫情爆發之所在地。關於登革熱與C型肝炎共同感染的研究仍屬稀缺。故此，吾等於南台灣之一家醫學中心，針對被共同感染之族群中，此二者病毒間的病毒學交互作用進行研究。
假設:
吾等假設C型肝炎病毒和登革熱病毒之間可能存在有交互作用或干擾現象。
方法:
本研究檢閱了自2014年7月至2015年12月之間，於高雄醫學大學附設醫院收案之共1192位確診為登革熱之患者，確診之方式多為登革熱NS1(nonstructural protein 1)快速篩檢。其中，有515位接受完整B型肝炎表面抗原與C型肝炎抗體之篩檢。C型肝炎抗體呈陽性者，則是運用登革熱發病當時所收集儲存的檢體，進一步檢驗其C肝病毒基因定量。病毒基因檢測為陽性者，於登革熱痊癒後，安排門診追蹤其血清病毒量之變化。另尋找一群年齡、性別、C肝基因型皆配對且無登革熱之C肝患者，觀察在自然病程中之病毒學變化。
結果:
綜觀這515位登革熱病患中，C型肝炎抗體陽性之盛行率為6.21% (32/515)；而B型肝炎表面抗原之盛行率為18.4% (95/515)。在32位C肝抗體陽性的患者中，有7位 (21.9%)是屬於B型與C型肝炎合併感染，另C肝病毒基因呈陽性者佔14位 (43.8%)。是否有C型肝炎病毒血症與登革熱之預後，如: 登革出血熱 (Dengue hemorrhagic fever) 或嚴重登革熱(Severe dengue)，並無統計學上之關聯。14位陽性C肝病毒量之患者中，有11位於登革熱發病後接受了至少一次的病毒定量追蹤，追蹤間距之中位數為23個月(範圍: 12-35)。登革熱感染後所追蹤之C肝平均病毒量為5.43 (±0.77) log IU/ml，而登革熱感染當下之平均病毒量為3.09 (±1.24) log IU/ml，病毒量在統計上有顯著差異(p= 0.003)，且所有個體的病毒量皆上升大於0.5 log。另一組33人的單純C肝對照組中，在追蹤之中位數為26.5個月(範圍: 14-75)之間距下，C肝病毒量之變化 (△HCV RNA，後測與前測之濃度相減)為 -0.27 (±0.76) log；而11位之登革熱合併C肝的疾病組中，△HCV RNA的值為2.34 (±1.15) log。兩組之△HCV RNA平均值有顯著差異 (p< 0.001)。最終，細胞學實驗證明登革熱病毒不僅可成功感染Con1細胞，且伴隨者登革熱NS1蛋白表現量的上升，C肝之NS5A蛋白則呈現下降趨勢。
結論:
與登革熱感染當下的C肝病毒量比較，大多數個案經歷了超過100倍之C型肝炎病毒量的增加。這也許意味著可能登革熱病毒可能直接或間接地抑制C肝病毒。因此需要更進一步的研究去釐清此議題。臨床醫師需留意C肝患者感染登革熱後，C肝病毒量反彈性上升的情形。

關鍵字

登革熱 ； 登革出血熱 ； C型肝炎 ； 病毒干擾現象 ； NS1蛋白 ； NS5A蛋白

並列摘要

Introduction:
Dengue virus (DENV) and hepatitis C virus (HCV) infections lead to international public health issues. Both are members of Flaviviridae and can cause hepatitis. Kaohsiung, a city in southern Taiwan, is an HCV hyperendemic area and had dengue fever (DF) outbreaks recently. However, DENV/HCV coinfection has rarely been studied. We aimed to investigate the virological interference between the two viruses in coinfected patients in a medical centre in Kaohsiung.
Hypothesis:
The two viruses belong to the same family and replicate in cellular cytoplasm. Thus, we hypothesized there existed viral interference between DENV and HCV.
Method:
We reviewed a total of 1192 dengue-confirmed patients during 2014-15 [mostly diagnosed by positive nonstructural protein 1 (NS1) tests], of whom, 515 cases received the screening with Hepatitis B virus (HBV) surface antigen and antibody to HCV (anti-HCV). Patients with positive anti-HCV were further checked for HCV RNA using the preserved blood samples collected during DF. Those with positive HCV RNA would be arranged at least one subsequent follow-up of HCV viral loads after DF episode.
Results:
HCV prevalence was 6.21% (32/515) in these DF patients. HBV coinfection rate was 21.9% (7/32) in HCV patients. Positive HCV RNA was noted in 14 cases (43.8%). HCV with viremia or not during DF did not determine dengue-related complications (dengue hemorrhagic fever or severe dengue). Of 14 HCV RNA-positive cases, 11 were rechecked for HCV viral loads after DF with a median interval of 23 months (range 12-35). Analysis showed the average post-DF HCV RNA level was significantly higher than that during DF [5.43 (±0.77) vs 3.09 (±1.24) log IU/ml, p= 0.003]. All had an elevation of viral loads by 0.5 logs. Compared with 11 HCV/DENV cases, 33 HCV controls demonstrated a mild decrease in HCV RNA level after a median follow-up period of 26.5 months (range 14-75). The △HCV RNA (later level - previous level) was -0.27 (±0.76) logs in controls, versus 2.34 (±1.15) logs in cases (p< 0.001). Finally, our Con1 cell line experiment supported that DENV could infect the cells and HCV NS5A expression reduced while DENV NS1 protein increased.
Conclusion:
Lower HCV viral loads during DF implied that DENV might have interference with HCV directly or indirectly. Clinicians should be aware of HCV viral rebounding change after DF. Further studies are needed to clarify the mechanism.

並列關鍵字

dengue virus ； DENV ； dengue fever ； hepatitis C virus ； HCV RNA ； viral interference ； NS1 ； NS5A

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