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.
在感染肝细胞中的乙型肝炎病毒（HBV）共价闭合环状DNA（cccDNA）是引起停药后病毒学反弹的主要因素。cccDNA的半衰期仅为33～50 d，故新合成的部分双链、松弛环状DNA（rcDNA）进入细胞核转换为cccDNA是维持cccDNA池的关键。虽然不直接靶向cccDNA，但通过阻断rcDNA的合成，现有的核苷（酸）类似物（NAs）存在使cccDNA池耗竭的可能性。确实，慢性乙型肝炎（慢乙肝）患者在抗病毒治疗达到HBeAg血清转换，HBV DNA消失后，再巩固治疗半年以上，20%～30%的患者可以安全停药。我国一些课题组最近已经证实血清中的HBV RNA来自感染肝细胞内cccDNA的活性转录，特别是在接受NAs治疗的慢乙肝患者，DNA合成被阻断后，其血清中的HBV RNA能反映肝细胞内cccDNA的状态。故此建议应将传统的基于病毒DNA检测的病毒学应答重新定义为血清HBV DNA和RNA的共同持续消失（低于检测下限），并以此作为安全停药的病毒学指标。血清HBV RNA是反映肝细胞内cccDNA活性的理想指标，因而，对接受长期NAs治疗后HBsAg水平< 1 500 IU/ml的慢乙肝患者，应依据血清HBV RNA的检测结果，换用或加用聚乙二醇干扰素（peg-IFN）治疗。如果血清HBV RNA阳性，则加用peg-IFN治疗；如果血清HBV RNA消失，应停止NAs治疗，并转为peg-IFN治疗。有理由相信，以血清HBV RNA指导的治疗策略，会进一步优化慢乙肝的功能性治愈（血清HBsAg消失甚至出现抗-HBs转换）路线图。.
Keywords: Antiviral therapy; Functional cure; Hepatitis B, chronic; Safe discontinuation; Serum HBV RNA; cccDNA.