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APASL2019熱點丨丙型肝炎直介面服抗病毒藥物治療時代的B肝再激活

編者按

抗HCV直接抗病毒藥物(DAA)的出現,解決了干擾素時代的大問題——療效不足和安全性差,但同時也出現了一些新的問題。這些新的問題從整體層面上看,是「小」問題,但對於個別患者而言,就可能成為影響預後的「大」問題,不可忽視。例如HCV/HBV共感染人群使用DAA治療期間的HBV再激活問題。在第28屆亞太肝病學會年會(APASL2019)上,中國香港天下仁心醫療集團主席廖家傑教授就此話題發表了專題演講。演講的主要內容如下。

廖家傑教授

近年,全口服直接抗病毒藥物(DAA)為丙型肝炎的治療提供了短期、低副作用的治癒可能。由於傳播途徑相似,HBV和HCV的共感染並不少見。尤其在高危人群中,包括靜脈葯癮、血液透析、器官移植、HIV陽性以及β地中海貧血患者。

和干擾素時代一樣,HBsAg陽性的慢性丙型肝炎患者接受全口服DAAs治療後出現B肝再激活的案例也有報導。因為早期DAA的臨床試驗都排除了HBsAg陽性的慢性丙型肝炎患者,所以直至DAA藥物進入臨床使用後,應用DAA清除HCV後B肝再激活的現象才浮出水面,嚴重程度從不伴肝炎的HBV再激活到需要肝移植的暴發性肝衰竭不等。另一方面,B肝再激活在HBsAg陰性、抗-HBc陽性的人群中罕見。

慢性丙型肝炎治療過程中出現B肝再激活的機理並不完全明晰,可能與HCV誘導的I型和II型干擾素相關。I型和II型干擾素均有抗HBV作用。當給予DAA治療時,HCV被迅速抑製,導致與HCV相關的干擾素級聯反應的活化也迅速下降,引起HBV複製增強,最早可以出現在DAA治療的第4周。

HBV複製增強後的臨床結局與DAA治療前的免疫控制有關,這也許可以解釋為什麼隱匿性HBV感染的慢性丙型肝炎患者接受DAA治療後出現B肝再激活的風險明顯低於HBsAg陽性的患者。更好地理解其中的機制,能夠幫助我們更好地在DAA治療前進行風險分層。

DAA上市後陸續報導的B肝再激活事件,促使美國FDA和歐洲醫藥機構藥物警戒風險評估委員會確認,HBsAg陽性的慢性丙型肝炎患者接受全口服DAA治療後存在B肝再激活的風險。因此,所有準備接受全口服DAA治療的慢性丙型肝炎患者均應接受HBsAg篩查,並在必要時在啟動DAA治療前開始預防性核苷(酸)類似物抗B肝治療。

專家簡介

廖家傑(George Lau)

中國香港內科醫學院院士,中國香港大學內科醫學博士,英國皇家內科醫學院院士,中國香港大學內外全科醫醫學士,中國香港醫學專科醫學院院士(腸胃及肝臟科),愛丁堡皇家內科醫學院榮授院士,倫敦大學皇家內科醫學院榮授院士

中國香港天下仁心醫療集團主席,中國香港天下仁心胃腸及肝臟中心主任,中國人民解放軍總醫院第五醫療中心聯合中國香港天下仁心醫療集團C肝診斷治療中心共同主任,中國人民解放軍總醫院第五醫療中心聯合肝病轉化醫學研究所共同所長

HBV reactivation in CHC patients treated with DAAs

Recently, pan-oral direct-acting antiviral (DAAs) therapy has allowed a cure of chronic hepatitis C infection with a finite duration of therapy, with little side effects. Due to the shared modes of transmission, coinfection with both hepatitis B virus (HBV) and hepatitis C virus (HCV) is not uncommon. This is especially so in high‐risk populations such as intravenous drug abusers, patients on hemodialysis, patients who have received an organ transplant, human immunodeficiency virus–positive patients, and β‐thalassemia patients.

Similar to patients coinfected with HBV and HCV treated with interferon (IFN)‐based therapy, hepatitis due to HBV reactivation in chronic hepatitis C (CHC) patients who are also hepatitis B surface antigen (HBsAg) positive has been reported after treatment with pan‐oral direct‐acting antiviral agents (DAAs).

As HBsAg-positive individuals were excluded from clinical trials of DAAs, HBV reactivation after HCV clearance was only reported after DAAs entered clinical use. The severity of hepatitis ranged from HBV reactivation without hepatitis to fulminant hepatic failure, requiring liver transplantation.

On the other hand, it is very rare among patients with resolved HBV infection. The underlying mechanism of HBV reactivation owing to HCV treatment is not entirely clear. This might be related to the induction of types I and III interferons by HCV, both of which are active against HBV. With DAAs, rapid HCV suppression leads to reduced activation of the interferon cascade, allowing for enhanced HBV replication as early as 4 weeks into therapy.

The clinical outcome of increased HBV replication likely relates to the degree of immune control that predated therapy, which may explain why those with occult HBV had a much lower or negligible risk than HBsAg positive CHC patients treated with pan-oral DAAs. A better understanding of the mechanisms involved may aid in pretreatment risk stratification.

Nonetheless, the occurrence of these events had prompted both the US Food and Drug Administration and the European Medicine Agency"s Pharmacoviglance Risk Assessment Committee to confirm the risk of HBV reactivation in HBsAg positive CHC patients treated with pan-oral DAAs. Hence, all CHC planned for pan-oral DAAs therapy should be screened for HBsAg and pre-emptive anti-HBV nucleos(t)ide therapy should be considered before initiation of DAAs therapy.


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