慢性乙型肝炎临床治愈新策略——病毒抑制联合免疫调节及其路线图

摘要

HBV感染仍是目前影响全球的重大公共卫生问题.现有的抗病毒治疗药物包括核苷和核苷酸类药物(NAs)以及干扰素(IFN)或聚乙二醇干扰素(PEG-IFN).NAs治疗安全且耐受良好,但停药后病毒学复发率高,疗程长甚至可能需要终身服药.PEG-IFN治疗的优势包括疗程有限、应答更持久以及不产生耐药,然而,仅部分患者对IFN可获得持续应答,且副作用普遍存在,因而限制了其临床广泛应用.由于HBV cccDNA和整合的HBV基因组在感染的肝细胞核中稳定存在,HBV的彻底清除(完全治愈)很难实现,目前多数指南推荐慢性乙型肝炎抗病毒治疗的理想终点为:治疗结束后持久的HBsAg消失,伴或不伴抗-HBs血清学转换(即功能性治愈).理论上,联用不同抗HBV作用机制的抗病毒药物——病毒抑制联合免疫调节(如NAs和PEG-IFN联合治疗),是具有前景的慢性乙型肝炎抗病毒治疗新策略.最新研究表明,与NAs单药治疗相比,NAs和PEG-IFN初始联合或序贯联合治疗在病毒学和血清学应答方面具有一定的优势.笔者应邀于2015年在《Journal of Hepatology》、2017年12月在《Journal ofInfectious Disease》阐述了目前慢性乙型肝炎联合治疗策略的研究进展,并根据国内外研究结果初步提出慢性乙型肝炎临床治愈思考和线路图,现将概况进行更新.%Chronic hepatitis B virus (HBV) infection remains a major global health issue.At present,nucleos(t) ide analogues (NAs) and interferon (IFN) or pegylated interferon (PEG-IFN) are used as the antiviral therapy.NA therapy is generally safe and well tolerated,but it has a high virological recurrence rate after drug withdrawal and a long course of treatment which may require lifelong medication.PEG-IFN therapy has the advantages of relatively shorter course of treatment,longer response,and lower rate of resistance;however,only some patients can achieve sustained response to IFN,and IFN has a high rate of adverse events,which limits the wide application of IFN in clinical practice.Since HBV covalently closed circular DNA and the integrated HBV genome stably exist in the nuclei of infected hepatocytes,it is difficult to achieve the elimination (complete cure) of HBV.The ideal endpoint of antiviral therapy for chronic hepatitis B recommended by most guidelines is the sustained disappearance of HBsAg,with or without HBsAb seroconversion (functional cure).Theoretically,a combination of antiviral agents with different anti-HBV mechanisms,including the drugs for viral suppression and immune modulation,is a promising strategy for the treatment of chronic hepatitis B.Latest studies have demonstrated that compared with NA alone,NA given concurrently or sequentially with PEG-IFN has certain advantages in virologic and serological response.Our articles published in Journal of Hepatology in 2015 and Journal of Infectious Diseases in December 2017 introduce the research advances in treatment strategies for chronic hepatitis B and put forward our thoughts on clinical cure of chronic hepatitis B and related clinical routes,with reference to research findings in China and foreign countries.This article provides some updated information.