Hepatitis B e Antigen Seroconversion

StephenW

Extract
From Journal of Viral HepatitisEndpoints of Hepatitis B Treatment

W. Chotiyaputta; A. S. F. Lok

http://www.medscape.com/viewarticle/739466

Posted: 03/24/2011; J Viral Hepat. 2010;17(10):675-684. © 2010 Blackwell Publishing

Serological Endpoints
Hepatitis B e Antigen SeroconversionHepatitis B e antigen seroconversion is an important endpoint in clinical trials of antiviral therapy in HBeAg-positive patients. Phase III clinical trials showed that a 1-year course of peg-IFN resulted in HBeAg seroconversion in 24–30% of patients at the end of treatment, and addition of lamivudine did not increase the rate of HBeAg seroconversion (Table 2). HBeAg seroconversion was durable in most (81%) patients after peg-IFN was stopped, and incremental HBeAg seroconversion was observed during post-treatment follow-up.[34]                       
Phase III clinical trials showed that a 1-year course of NUC resulted in HBeAg seroconversion rates of 16–22% (Table 2a). The durability of NUC-induced HBeAg seroconversion has been reported to vary from 62 to 77% when treatment was stopped after 1 year.[45,46] Factors associated with durability of HBeAg seroconversion include a longer duration of consolidation therapy (12 months), younger age of the patient (<40 years), HBV genotype B (vs C), and lower HBV DNA level at the time treatment was stopped.[47–50] Continued treatment with NUC resulted in increasing rates of HBeAg seroconversion to 26–31% after 2 years and to 40–50% after 5 years of treatment.[20,35,51]                        
Studies of patients not receiving antiviral therapy showed that presence of HBeAg was associated with a higher risk of development of cirrhosis and HCC. In a prospective study of 2361 HBsAg-positive men followed for 92 359 person-years, those who were HBeAg positive at enrolment had a relative risk of HCC sixfold higher than those who were HBeAg negative.[52] Cohort follow-up studies showed that patients who underwent spontaneous HBeAg seroconversion had favourable outcome particularly if the HBeAg seroconversion occurred early in the course of chronic HBV infection and was durable, and the outcome was improved compared to patients who remained HBeAg positive. In one study, 88% of 223 patients who underwent HBeAg seroconversion had sustained normalization of ALT and 79% had histologic improvement.[53] In a follow-up report of the same cohort, 66% remained as inactive carriers after a median follow-up of 25 years.[54] The 25-year probability of survival was 40% for those who remained HBeAg positive, 50% for those progressing to HBeAg-negative chronic hepatitis or reverting to HBeAg positive, and 95% for those whose HBeAg seroconversion was maintained. In another study, 283 patients underwent spontaneous HBeAg seroconversion. Of the 269 patients who had no evidence of cirrhosis at the time of HBeAg seroconversion, 21 developed cirrhosis during a mean follow-up of 9 years, 14 of 62 patients who progressed to HBeAg-negative hepatitis, five of nine who had HBeAg reversion, one of 14 patients who had active hepatitis of undetermined causes, and one of 184 who had sustained HBeAg seroconversion.[55] A third study of 483 patients followed for a mean of 11.7 years found that patients who underwent HBeAg seroconversion before age 30 had excellent prognosis when compared to those who did so at an older age. The cumulative incidence of cirrhosis was 3.7%, 12.9%, and 42.9% and for HCC 2.1%, 3.2%, and 7.7% in patients who underwent HBeAg seroconversion before age 30 years, at age 31–40 years and after age 40 years, respectively.[56]                  
Follow-up studies of patients who received HBV treatment also support the use of HBeAg seroconversion as a surrogate marker for clinical outcome. In a study by Niederau et al., 103 patients who were treated with IFN alfa and 53 untreated controls were followed for a mean of 50.0 ± 19.8 months. Fifty (49%) of the IFN-treated patients lost HBeAg compared to 7 (13%) of the untreated controls. Liver-related complications occurred in 16 (16%) treated patients all but one of whom failed to lose HBeAg and in 13 (25%) controls. Survival until liver transplantation or death and lack of clinical complications was significantly better in treated patients who cleared HBeAg than in patients who did not (P = 0.004 for survival and P = 0.018 for absence of clinical complications). In another study, Lau et al. [57] followed 103 patients who received IFN treatment for a mean of 6.2 years. Patients who did not clear HBeAg had higher rates of liver-related complications and mortality (HR = 13.7, 95% CI 3.0–63.5) compared to those who lost HBeAg within 1 year of treatment.
These studies demonstrate that HBeAg seroconversion, spontaneous or treatment related, is associated with improvement in liver histology and clinical outcomes including survival. Therefore, HBeAg seroconversion is a valid surrogate endpoint for clinical outcome, and treatment guidelines have recommended that NUC treatment can be stopped in patients who completed at least 6- month consolidation therapy after confirmed HBeAg seroconversion. Many experts have questioned the validity of HBeAg seroconversion as an endpoint of HBV treatment citing that HBV DNA remains detectable in most patients albeit at lower levels and reactivation of HBV replication with recrudescence of hepatitis leading to progressive liver disease will ultimately occur in most patients. However, one study involving 283 patients followed for a median of 8.6 years (range, 1–18.4 years) after HBeAg seroconversion found that only 4.2% had HBeAg reversion and 24% developed HBeAg-negative hepatitis with detectable HBV DNA, while the other 71.8% remained in remission.[55] Given the high costs of NUCs and the risks of adverse events and antiviral resistance during long-term therapy, withdrawal of treatment in patients who have completed 12 months of consolidation therapy after confirmed HBeAg seroconversion and who have undetectable serum HBV DNA is a reasonable approach as long as the patients continue to be monitored. A recent study of patients who achieved HBeAg seroconversion during lamivudine treatment showed that durability of HBeAg seroconversion was 92% after 5 years of post-treatment follow-up among the patients who completed at least 12 months of consolidation therapy.[48] These data indicate that durable HBeAg seroconversion can be accomplished with NUC treatment.

StephenW

提取物
从病毒性肝炎杂志
乙型肝炎治疗的端点

W · Chotiyaputta; A. S. F.乐

http://www.medscape.com/viewarticle/739466

发表于：2011年3月24日，J病毒Hepat。 2010，17（10）:675 - 684。 © 2010布莱克韦尔出版
血清端点
B型肝炎e抗原血清转换

乙型肝炎e抗原血清学转换是在HBeAg阳性患者的抗病毒治疗临床试验的重要端点。三期临床试验表明，一个1年的课程，PEG - IFN在24-30％的患者在治疗结束后在HBeAg血清转换，此外拉米夫定没有增加HBeAg血清转换率（见表2）。 [34]在大多数（81％）患者HBeAg血清转换持久PEG - IFN停止后，增量HBeAg血清学转换是在治疗后观察的跟进。

三期临床试验表明，在HBeAg血清转换率16-22％（表2A），1年期的国统会的当然结果。有报道国统会诱导HBeAg血清转换的持久性变化从62％至77％时停止治疗后1年。[45,46]与HBeAg血清学转换的耐久性相关的因素包括持续时间较长（12个月）的巩固治疗，低龄（<40岁）的患者，HBV B基因型（VS三），并降低乙肝病毒DNA水平的治疗时间停止 - [47-50]与国统会继续治疗增加HBeAg血清转换至26率。 31％，2年后，到40-50％，经过5年的治疗[20,35,51]。

不接受抗病毒药物治疗的患者的研究表明，HBeAg的存在与肝硬化和肝癌的发展的风险较高有关。有意在2361乙肝表面抗原阳性的男性为92 359人，年的研究，为HBeAg在入学的积极六倍了肝癌的相对危险性高于那些为HBeAg阴性。[52]队列随访研究表明，自发性HBeAg血清转换的患者谁接受了有利的结果，特别是如果发生HBeAg血清转换的慢性乙肝病毒感染的过程中，是持久的，其结果仍然HBeAg阳性的患者相比，改善。在一项研究中，88％的223例患者接受HBeAg血清转换的持续ALT正常化和79％组织学改善。[53]在同一队列的报告的后续行动，66％为非活动携带者后保持中位随访25年。[54] 25年的生存概率是那些仍然进展HBeAg阴性的慢性肝炎或恢复到HBeAg阳性者e抗原为阳性，50％，40％和95％的HBeAg血清转换维持。在另一项研究中，283例患者进行自发的HBeAg血清转换。曾在HBeAg血清转换，21个开发性肝硬化的时候没有证据显示肝硬化，在9年的随访，62例HBeAg阴性肝炎，发展到14 269例中有9家，曾HBeAg的回归，其中14例患者有活动性肝炎不明的原因，和184曾持续HBeAg血清转换。[55] 483例患者的第三份研究报告随后发现，30岁，术前HBeAg血清转换的患者具有良好的平均为11.7岁相比，那些年龄较大的预后。肝硬化的累积发生率为3.7％，12.9％，42.9％和2.1％，3.2％和7.7％的病人岁前接受HBeAg的血清转换30岁，年龄31-40岁和40岁后，肝癌， [56]

谁收到的患者，乙肝病毒治疗也支持作为临床结果的替代标记的HBeAg血清转换的使用的后续研究。 Niederau等人的研究，103谁是与干扰素α和53个未经处理的对照治疗的患者随访平均为50.0 ± 19.8个月。五十（49％）的干扰素治疗的患者失去了HBeAg的比较7（13％）的未经处理的对照。 16（16％）治疗的患者的肝脏相关并发症发生的所有，但其中一人没有失去HBeAg和控制在13（25％）。直到肝移植或死亡和缺乏临床并发症的生存率显着好转，在治疗的患者谁的患者HBeAg的清除比，谁没有生存和临床并发症的情况下，P = 0.018（P = 0.004）。在另一项研究中，刘等人。 [57]其次，谁获得了平均6.2年干扰素治疗的103例。患者谁没有明确大三阳率较高的肝脏相关的并发症和死亡率（HR = 13.7，95％CI为3.0-63.5）相比，那些失去了在治疗1年的HBeAg的。

这些研究表明，HBeAg血清学转换，自发或治疗相关的，是与改善肝脏组织学和临床结果，包括生存的相关。因此，HBeAg血清学转换是一个有效的替代终点的临床结果和治疗指南建议可以停止国统会处理在患者完成至少6 - 确认HBeAg血清转换后的巩固治疗一个月。许多专家都质疑为由，乙肝病毒DNA仍然检测到，尽管在较低的水平，并导致渐进性肝病，乙肝病毒复制的激活与肝炎复发，大多数患者最终会发生，大多数患者的乙肝治疗的终点为HBeAg的血清转换的有效性。然而，一项研究涉及283例患者中位数为8.6年（范围为1-18.4年）发现，只有4.2％，HBeAg的回归和24％HBeAg阴性肝炎检测到HBV DNA的的HBeAg血清转换后，而其他71.8 ％的缓解。[55]鉴于NUCs的成本高和不良事件和病毒抗药性，长期治疗期间，撤回已完成12个月的巩固治疗后证实HBeAg血清转换的患者治疗的风险，并有检测不到血清HBV DNA是一种合理的方法，只要病人继续进行监测。期间取得拉米夫定治疗HBeAg血清转换的患者最近的一项研究表明，HBeAg血清转换的持久性是92％，治疗后5年后的后续完成至少12个月的巩固治疗的患者中。[48]这些数据表明能够做到的，持久的HBeAg血清转换与国统会处理。