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Discussion
Entecavir is effective in the suppression of HBV replication, inducing HBeAg seroclearance, and reduces cirrhosis and hepatocellular carcinoma development. HBeAg clearance induced by entecavir is durable; however, clinical relapse after cessation of therapy is observed and is probably due to residual intrahepatic cccDNA.
In this study, we explored the effect of 48-week entecavir therapy on serum and intrahepatic total HBV DNA and cccDNA levels in patients with HBeAg-positive hepatitis B. Our results showed that, over a treatment period of 48 weeks, the serum total HBV DNA and cccDNA levels decreased by approximately four and three logs, respectively. The reduction in serum cccDNA levels roughly reflected a similar trend in intrahepatic cccDNA content.
In the present study, we also observed that patients showing HBeAg seroconversion had significantly greater reductions in median logarithmic total HBV and cccDNA levels than those who did not undergo HBeAg seroconversion. Although the magnitudes of cccDNA and ALT reductions were not significantly correlated, serum cccDNA reduction in ALT-normalized patients was significantly greater than that in ALT-abnormal patients. Serum HBV cccDNA may come from the destruction or lysis of hepatocytes, and implies the existence of replicative forms of HBV in hepatocytes. Currently, serum HBV DNA measurement is the only way to monitor the virologic response of the therapy in clinical practice. This method, however, cannot distinguish the cccDNA and rcDNA forms of HBV. If detectable, quantitative measurement of serum cccDNA together with HBV DNA may give insight into the decline profile of both the replicative and non-replicative forms of the virus without the necessity for a repeated liver biopsy. Our results, however, also indicated that even when serum HBV DNA and cccDNA were undetectable, HBV cccDNA remained in hepatic cells. Treatment with entecavir for 48 weeks, therefore, cannot eradicate HBV in patients with chronic HBV infection. Serial serum cccDNA measurement only provides information of the reduction magnitudes of HBV cccDNA, which may prove helpful for understanding the efficacy of antiviral therapy, but cannot be used to predict the eradication of HBV in the liver.
HBV cccDNA is detected in patient serum, HBV-infected hepatocytes, and extrahepatic infected cells such as peripheral blood lymphocytes [13–15]. It is likely that the cccDNA in serum originates from HBV-infected hepatocytes and extrahepatic cells owing to the lysis of infected cells, because the release of naked HBV nucleic acid into the circulation has been reported previously [16–18]. Reduction in serum and intrahepatic cccDNA was observed in antiviral therapy with lamivudine, adefovir, entecavir, and peg-interferon plus adefovir [9, 19, 20]. Studies on animal models and clinical trials indicate that the rates of total intracellular HBV DNA and cccDNA loss differ significantly under antiviral therapy [6]. Our results showed that the magnitude of reduction in serum cccDNA was lower than that of total HBV DNA, but did not reach statistical significance. This was probably the result of immune-mediated mechanisms that contribute to the clearance or destruction of infected cells [21, 22].
The HBeAg seroconversion rate was much higher than those reported previously. The exact reason for this discrepancy needs further study. However, many factors contribute to HBeAg seroconverion. HBV genotype, pre-C mutation, and base core promoter mutations are among these factors, which may in turn influence the observed rate of seroconversion.
Although several antiviral agents are available for treatment of chronic hepatitis B, entecavir is one of the most effective drugs recommended by the American Association for the Study of Liver Diseases and is widely used for the treatment of patients with chronic hepatitis B [23]. All patients experiencing viral relapse after the cessation of treatment exhibit significantly higher levels of cccDNA than subjects who do not relapse [24]. A 1-year course of treatment with entecavir cannot eradicate intrahepatic HBV cccDNA and the effect of long-term treatment on intrahepatic HBV cccDNA needs to be further investigated.
In conclusion, the present study demonstrated that entecavir therapy could decrease serum cccDNA levels by a magnitude of three logs in patients with HBeAg-positive chronic hepatitis B. Furthermore, a reduction in serum cccDNA levels was related to HBeAg seroconversion.
Did you mean: Discussion Entecavir is effective in the suppression of HBV replication, inducing HBsAg seroclearance, and reduces cirrhosis and hepatocellular carcinoma development. HBeAg clearance induced by entecavir is durable; however, clinical relapse after cessation of therapy is observed and is probably due to residual intrahepatic cccDNA. In this study, we explored the effect of 48-week entecavir therapy on serum and intrahepatic total HBV DNA and cccDNA levels in patients with HBeAg-positive hepatitis B. Our results showed that, over a treatment period of 48 weeks, the serum total HBV DNA and cccDNA levels decreased by approximately four and three logs, respectively. The reduction in serum cccDNA levels roughly reflected a similar trend in intrahepatic cccDNA content. In the present study, we also observed that patients showing HBeAg seroconversion had significantly greater reductions in median logarithmic total HBV and cccDNA levels than those who did not undergo HBeAg seroconversion. Although the magnitudes of cccDNA and ALT reductions were not significantly correlated, serum cccDNA reduction in ALT-normalized patients was significantly greater than that in ALT-abnormal patients. Serum HBV cccDNA may come from the destruction or lysis of hepatocytes, and implies the existence of replicative forms of HBV in hepatocytes. Currently, serum HBV DNA measurement is the only way to monitor the virologic response of the therapy in clinical practice. This method, however, cannot distinguish the cccDNA and rcDNA forms of HBV. If detectable, quantitative measurement of serum cccDNA together with HBV DNA may give insight into the decline profile of both the replicative and non-replicative forms of the virus without the necessity for a repeated liver biopsy. Our results, however, also indicated that even when serum HBV DNA and cccDNA were undetectable, HBV cccDNA remained in hepatic cells. Treatment with entecavir for 48 weeks, therefore, cannot eradicate HBV in patients with chronic HBV infection. Serial serum cccDNA measurement only provides information of the reduction magnitudes of HBV cccDNA, which may prove helpful for understanding the efficacy of antiviral therapy, but cannot be used to predict the eradication of HBV in the liver. HBV cccDNA is detected in patient serum, HBV-infected hepatocytes, and extrahepatic infected cells such as peripheral blood lymphocytes [13–15]. It is likely that the cccDNA in serum originates from HBV-infected hepatocytes and extrahepatic cells owing to the lysis of infected cells, because the release of naked HBV nucleic acid into the circulation has been reported previously [16–18]. Reduction in serum and intrahepatic cccDNA was observed in antiviral therapy with lamivudine, adefovir, entecavir, and peg-interferon plus adefovir [9, 19, 20]. Studies on animal models and clinical trials indicate that the rates of total intracellular HBV DNA and cccDNA loss differ significantly under antiviral therapy [6]. Our results showed that the magnitude of reduction in serum cccDNA was lower than that of total HBV DNA, but did not reach statistical significance. This was probably the result of immune-mediated mechanisms that contribute to the clearance or destruction of infected cells [21, 22]. The HBeAg seroconversion rate was much higher than those reported previously. The exact reason for this discrepancy needs further study. However, many factors contribute to HBeAg seroconverion. HBV genotype, pre-C mutation, and base core promoter mutations are among these factors, which may in turn influence the observed rate of seroconversion. Although several antiviral agents are available for treatment of chronic hepatitis B, entecavir is one of the most effective drugs recommended by the American Association for the Study of Liver Diseases and is widely used for the treatment of patients with chronic hepatitis B [23]. All patients experiencing viral relapse after the cessation of treatment exhibit significantly higher levels of cccDNA than subjects who do not relapse [24]. A 1-year course of treatment with entecavir cannot eradicate intrahepatic HBV cccDNA and the effect of long-term treatment on intrahepatic HBV cccDNA needs to be further investigated. In conclusion, the present study demonstrated that entecavir therapy could decrease serum cccDNA levels by a magnitude of three logs in patients with HBeAg-positive chronic hepatitis B. Furthermore, a reduction in serum cccDNA levels was related to HBeAg seroconversion.
讨论
恩替卡韦是有效的HBV复制的抑制，诱导HBeAg的血清清除，并减少了肝硬化和肝细胞癌的发展。 HBeAg清除诱发替卡韦是持久的;然而，停止治疗，观察和后临床复发可能是由于残余肝内cccDNA的。
在这项研究中，我们探索了48周的恩替卡韦治疗对血清和肝内总HBV DNA和cccDNA的水平的影响患者HBeAg阳性乙型肝炎我们的研究结果表明，在48周时，血清总HBV治疗期间DNA和cccDNA的水平下降了大约四和三个日志，分别。血清中cccDNA的水平减少大约反映肝内cccDNA的内容类似的趋势。
在本研究中，我们还观察到患者显示HBeAg血清转换有中位总对数和HBV cccDNA的水平比那些谁没有接受HBeAg血清转换显著较大幅度的削减。虽然cccDNA的和ALT降低的幅度没有显著相关，在ALT-归患者血清cccDNA的减少是显著大于在ALT-异常的患者。血清HBV cccDNA的可能来自破坏或肝细胞的裂解，并且意味着HBV的肝细胞中复制的形式存在。目前，血清HBV DNA的测量是监测疗法在临床实践中的病毒学反应的唯一途径。这种方法，但是，不能区分的cccDNA和rcDNA形式乙肝。如果检测，血清cccDNA的连同HBV DNA定量测量可以深入了解的病毒都复制和非复制形式的下降曲线而不需要重复肝活检。我们的结果，但是，也指出，即使当血清HBV DNA和cccDNA的检测不到，HBV cccDNA的留在肝细胞中。治疗用恩替卡韦治疗48周，因此，不能消除HBV慢性HBV感染。串行血清cccDNA的测量仅提供HBV的cccDNA的减少幅度，这可能证明对理解抗病毒治疗的疗效有帮助的信息，但不能用来预测在肝脏消除HBV的。
HBV cccDNA的是在病人血清，乙肝病毒感染的肝细胞，和肝外感染的细胞中检测到，如外周血淋巴细胞[13-15]。很可能是在血清中的cccDNA从HBV感染的肝细胞和肝外的细胞由于感染细胞的溶胞来源，因为裸的HBV核酸的释放到循环中先前已被[16-18]的报道。降低血清和肝内cccDNA的观察的抗病毒治疗拉米夫定，阿德福韦，恩替卡韦，和PEG-干扰素加阿德福韦[9，19，20]。研究的动物模型和临床试验表明，总的细胞内HBV DNA和cccDNA的损失率下的抗病毒疗法[6]显著不同。我们的研究结果表明，降低血清cccDNA的幅度比总HBV DNA的低，但没有达到统计学显着性。这可能是对有助于间隙或破坏受感染的细胞[21，22]的免疫介导的机制的结果。
在HBeAg血清转换率比以前报道的要高得多。这种差异的确切原因有待进一步研究。然而，许多因素促成了大三阳seroconverion。 HBV基因型，前C突变和碱核心启动子突变是在这些因素的影响，这可能反过来影响血清转化的观察速率。
虽然有几种抗病毒药物可用于治疗慢性乙型肝炎，恩替卡韦是肝病研究建议的美国协会的最有效的药物之一，被广泛用于治疗慢性乙型肝炎[23]的治疗。所有患者经历病毒复发治疗展品停止后的cccDNA的显著水平高于科目谁不复发[24]。 A 1年的疗程与恩替卡韦不能消除肝内HBV cccDNA的和长期的治疗对肝内HBV cccDNA的效果有待进一步调查。
总之，本研究表明，恩替卡韦疗法可通过三个日志患者HBeAg阳性慢性乙型肝炎此外，在血清中的cccDNA水平的降低是有关HBeAg血清转换的幅度降低血清cccDNA的水平。
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发表于 2015-2-12 02:18
