Zoulim Fabien
INSERM U271, Lyon, France.
Antivir Chem Chemother. 2004 Nov;15(6):299-305. doi: 10.1177/095632020401500602.
Antiviral therapy of chronic HBV infection remains a clinical challenge. Once this infection has been-established, the viral genome persists for life, either as an integrated genome or as episomal covalently closed circular DNA (cccDNA). The latter is the source of renewed viral replication in case of immune depression or after antiviral drug withdrawal. The mechanisms of clearance of infected cells involve CD8+ cell-mediated cytolytic and non-cytolytic pathways. Antiviral therapy, using nucleoside analogues that inhibit the viral polymerase, induces a slow depletion of intrahepatic cccDNA. The persistence of low-grade viral replication under antiviral therapy may then lead to the selection of drug-resistant mutants. New assays have been developed to study the functional consequences of these polymerase mutations in terms of replication capacity and drug susceptibility. Together with the development of new HBV polymerase inhibitors and novel immunostimulatory approaches, this should lead to the design and evaluation of rational treatment combinations for a better control of viral replication and prevention of drug resistance.
慢性乙型肝炎病毒感染的抗病毒治疗仍然是一项临床挑战。一旦这种感染确立，病毒基因组将终身存在，要么以整合基因组的形式，要么以游离的共价闭合环状DNA（cccDNA）的形式。后者是免疫抑制或停用抗病毒药物后病毒重新复制的来源。清除受感染细胞的机制涉及CD8 +细胞介导的细胞溶解和非细胞溶解途径。使用抑制病毒聚合酶的核苷类似物进行抗病毒治疗，可诱导肝内cccDNA缓慢耗竭。抗病毒治疗期间低度病毒复制的持续存在可能会导致耐药突变体的产生。已经开发出新的检测方法来研究这些聚合酶突变在复制能力和药物敏感性方面的功能后果。随着新型乙肝病毒聚合酶抑制剂和新型免疫刺激方法的开发，这应该会促成合理治疗组合的设计和评估，以更好地控制病毒复制并预防耐药性。
