Department of Medicine, The University of Hong Kong, Hong Kong; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong.
Department of Pathology, The University of Hong Kong, Hong Kong.
J Hepatol. 2017 Feb;66(2):275-281. doi: 10.1016/j.jhep.2016.08.022. Epub 2016 Sep 14.
Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA), a mini-chromosome essential for HBV replication, is supposed to be resistant to nucleos(t)ide analogue treatment. We investigated the effect of long-term nucleos(t)ide analogue treatment on cccDNA.
Among 129 patients who had been enrolled in previous international nucleos(t)ide analogue clinical trials and had liver biopsies at baseline and one year after treatment, we recruited 43 patients on long-term continuous treatment for 72 to 145months for a third liver biopsy. Serum HBV DNA, hepatitis B surface antigen (HBsAg) levels, total intrahepatic HBV DNA (ihHBV DNA), cccDNA, HBV pregenomic RNA (pgRNA) as well as histologic changes were examined.
At the time of the third biopsy, serum HBV DNA levels were undetectable in all but one patient. The median levels of HBsAg, ihHBV DNA, and cccDNA were 2.88logIU/ml, 0.03copies/cell, and 0.01copies/cell, respectively. Compared to baseline levels, there was reduction of HBsAg levels by 0.54log (71.46%), ihHBV DNA levels by 2.81log (99.84%), and cccDNA levels by 2.94log (99.89%), with 49% having cccDNA levels below the detection limit. One patient had undetectable HBsAg. The median pgRNA level, measured only in the third biopsy, was 0.021copies/cell, with 40% of patients having undetectable pgRNA.
Long-term nucleos(t)ide analogue treatment induced marked depletion of cccDNA in the majority of patients while serum HBsAg levels, though reduced, were detectable in all but one patient. Whether cccDNA depletion is sustained and associated with better patient outcome requires further study.
It is generally presumed that a form of hepatitis B virus DNA, called covalently closed circular DNA (cccDNA), which hides inside the nuclei of liver cells of patients with chronic hepatitis B, cannot be reduced by antiviral treatment. The present study showed that with prolonged treatment (median period 126months), cccDNA can be markedly reduced, with 49% of liver biopsies having undetectable cccDNA. This suggests that viral replication capacity would be very low after prolonged antiviral treatment.
乙型肝炎病毒（HBV）共价闭合环状 DNA（cccDNA）是 HBV 复制所必需的微型染色体，被认为对核苷（酸）类似物治疗具有抗性。我们研究了长期核苷（酸）类似物治疗对 cccDNA 的影响。
在之前参与国际核苷（酸）类似物临床试验并在基线和治疗 1 年后进行肝脏活检的 129 名患者中，我们招募了 43 名长期连续治疗 72 至 145 个月的患者进行第三次肝活检。检测血清 HBV DNA、乙型肝炎表面抗原（HBsAg）水平、肝内总 HBV DNA（ihHBV DNA）、cccDNA、HBV 前基因组 RNA（pgRNA）以及组织学变化。
在第三次肝活检时，除 1 例患者外，所有患者的血清 HBV DNA 水平均无法检测到。HBsAg、ihHBV DNA 和 cccDNA 的中位数水平分别为 2.88logIU/ml、0.03 拷贝/细胞和 0.01 拷贝/细胞。与基线水平相比，HBsAg 水平降低了 0.54log（71.46%），ihHBV DNA 水平降低了 2.81log（99.84%），cccDNA 水平降低了 2.94log（99.89%），49%的患者 cccDNA 水平低于检测下限。1 例患者的 HBsAg 无法检测到。pgRNA 水平仅在第三次肝活检中进行测量，中位水平为 0.021 拷贝/细胞，40%的患者 pgRNA 无法检测到。
长期核苷（酸）类似物治疗诱导大多数患者的 cccDNA 明显耗竭，尽管 HBsAg 水平降低，但除 1 例患者外，所有患者均能检测到 HBsAg。cccDNA 耗竭是否持续存在以及是否与患者更好的预后相关，需要进一步研究。
乙型肝炎病毒（HBV）感染是一个严重的健康问题，会导致慢性乙型肝炎、肝硬化和肝癌。目前有一些有效的治疗方法可以控制 HBV 的复制和减少病毒载量。核苷（酸）类似物是一种常用的抗病毒药物，可以抑制 HBV 的复制。本研究表明，长期核苷（酸）类似物治疗（中位治疗时间 126 个月）可以显著降低 cccDNA，49%的肝活检标本中无法检测到 cccDNA。这表明经过长期抗病毒治疗后，病毒复制能力会非常低。因此，长期核苷（酸）类似物治疗可能是一种有效的治疗慢性乙型肝炎的方法，可以减少病毒载量并降低肝硬化和肝癌的风险。但是，这种治疗需要长期进行，并且可能会有一些不良反应，如药物耐药性和肝功能异常等。因此，患者需要在医生的指导下进行治疗，并定期进行检查和监测。
