Lu F M, Wang J, Chen X M, Jiang J N, Zhang W H, Zhao J M, Ren H, Hou J L, Xia N S
Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
The Fist Affiliated Hospital of Guangxi Medical University, Nanning 530021, China.
Zhonghua Gan Zang Bing Za Zhi. 2017 Feb 20;25(2):105-110. doi: 10.3760/cma.j.issn.1007-3418.2017.02.005.
Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) in infected hepatocytes is the main cause of off-therapy viral rebound. The half-life of cccDNA is only 33-50 days, so the conversion of newly synthesized rcDNA to cccDNA in the nucleus is essential for the maintenance of cccDNA pool in infected hepatocytes. Though not directly targeting the existing cccDNA, current nucleos(t)ide analogues (NAs) may exhaust the cccDNA reservoir by blocking the rcDNA formation. Indeed, a prolonged consolidation therapy post loss of serum HBV DNA can achieve sustained remission and thus safe drug discontinuation in a small proportion of chronic hepatitis B (CHB) patients. In recent studies, we and others have demonstrated that it is the serum HBV RNA that reflects the cccDNA activity in infected hepatocytes, particularly among the patients on NAs. Here we suggest that instead of measuring serum HBV DNA only, simultaneous measurement of both viral DNA and RNA would improve the accuracy to reflect the cccDNA activity; therefore, the virological response should be redefined as consistent loss (less than the lower limit of detection) of both serum HBV DNA and RNA, which indicates the safety of drug discontinuation. Accumulating evidence has suggested that for the CHB patients with lower serum HBsAg, switch-to or add-on pegylated interferon (Peg-IFN) treatment would result in loss of serum HBsAg in a relatively large proportion of CHB patients. Since serum HBV RNA is an ideal biomarker to reflect the intrahepatic cccDNA activity, for the patients with a serum HBsAg level lower than 1 500 IU/ml after long-term NAs treatment, the serum HBV RNA should be measured. If serum HBV RNA is detected, peg-IFN should be added on; if serum HBV RNA is not detected, NAs treatment should be switched to peg-IFN treatment. We believe the therapy based on serum HBV RNA would make the functional cure of CHB (serum HBsAg loss or even conversion to anti-HBs) more efficient.
感染的肝细胞中的乙肝病毒（HBV）共价闭合环状DNA（cccDNA）是治疗后病毒反弹的主要原因。cccDNA的半衰期仅为33 - 50天，因此新合成的rcDNA在细胞核中转化为cccDNA对于维持感染肝细胞中cccDNA库至关重要。尽管目前的核苷（酸）类似物（NAs）并非直接靶向现有的cccDNA，但它们可能通过阻断rcDNA的形成来耗尽cccDNA储备。事实上，在血清HBV DNA消失后进行延长的巩固治疗可以在一小部分慢性乙型肝炎（CHB）患者中实现持续缓解，从而安全停药。在最近的研究中，我们和其他人已经证明，血清HBV RNA反映了感染肝细胞中的cccDNA活性，特别是在接受NAs治疗的患者中。在此我们建议，除了仅检测血清HBV DNA外，同时检测病毒DNA和RNA将提高反映cccDNA活性的准确性；因此，病毒学应答应重新定义为血清HBV DNA和RNA均持续消失（低于检测下限），这表明停药的安全性。越来越多的证据表明，对于血清HBsAg水平较低的CHB患者，改用或加用聚乙二醇干扰素（Peg-IFN）治疗将使相当一部分CHB患者的血清HBsAg消失。由于血清HBV RNA是反映肝内cccDNA活性的理想生物标志物，对于长期接受NAs治疗后血清HBsAg水平低于1500 IU/ml的患者，应检测血清HBV RNA。如果检测到血清HBV RNA，应加用Peg-IFN；如果未检测到血清HBV RNA，应将NAs治疗改为Peg-IFN治疗。我们相信基于血清HBV RNA的治疗将使CHB的功能性治愈（血清HBsAg消失甚至转化为抗-HBs）更有效。
