治疗儿童乙肝免疫耐受

StephenW

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Journal of Viral Hepatitis

Cure for Immune-Tolerant Hepatitis B in Children
Is It an Achievable Target With Sequential Combo Therapy With Lamivudine
and Interferon?

U. Poddar, S. K. Yachha, J. Agarwal, N. Krishnani
Disclosures
J Viral Hepat. 2013;20(5):311-316.

Abstract
We prospectively studied the HBsAg seroconversion with sequential
combination therapy of lamivudine (LAM) and interferon (IFN) in hitherto
untreatable 'immune-tolerant' chronic hepatitis B in children. In this
case–control study, 28 children with immune-tolerant hepatitis B [HBsAg
positive for>6 months with near normal aminotransferase level, minimal/no
inflammation in liver histology and high viral load (HBV DNA>107
copies/mL)] were treated with LAM alone at 3 mg/kg/day for 8 weeks followed
by LAM plus IFN alpha (5 MU/m2 three times a week) for another 44 weeks.
They were compared with 34 untreated children. HBV markers (HBsAg, HBeAg,
anti-HBe, quantitative HBV DNA) were carried out at baseline, at the end of
therapy and 6 monthly thereafter. The mean age was 5.9 ± 3.2 years and 24
were boys. End therapy response: HBe seroconversion was achieved in 11,
and of these, five had complete response (HBsAg clearance), 11 did not
respond and six had virologic response (DNA undetectable but no HBe
seroconversion). Six months after therapy, 10 of the 11 (91%) originally
seroconverted children remained seroconverted while one seroreverted. Six
of the 28 (21.4%) children lost HBsAg and they remained HBsAg negative and
anti-HBs positive on follow-up. After a mean follow-up of 21.1 ± 11.9
months, the status remained same in the responders but one of the
nonresponders HBe seroconverted (39.3%). There were no serious side effects
of therapy. It is possible to achieve a cure in more than one-fifth of
immune-tolerant children with hepatitis B with the sequential combination
of LAM and IFN. Introduction Hepatitis B is a major health problem in
developing countries despite the availability of an effective vaccine. In
fact, one of the common causes of chronic liver disease in children in this
part of the world is chronic hepatitis B.[1,2] Three-fourth of the world's
hepatitis B infected population is in Asia, and the majority of children
with CHB in Asia are due to perinatally acquired infection.[3,4] The
characteristic feature of perinatally acquired hepatitis B is a long
immune-tolerant phase lasting for decades with risk of developing
hepatocellular carcinoma (HCC) and cirrhosis in adulthood.[5,6] In fact, it
has been shown that the risk of HCC is higher in Asian population with
perinatally acquired hepatitis B as compared with horizontally acquired
hepatitis B.[7]

Ideally, a child with perinatally acquired hepatitis B should be treated
early to prevent the development of HCC and cirrhosis. Nevertheless, till
date, barring a pilot study of combination therapy of lamivudine (LAM)
followed by LAM and interferon,[8] no therapy has been shown to be
effective in immune-tolerant phase of CHB as the body's immune system is
unresponsive to HBV infection.[9–11] It has been shown that the
hyporesponsiveness of peripheral blood HBV-specific cytotoxic T lymphocytes
(CTL) is mainly due to high viral load,[12–14] and viral load reduction
with LAM therapy successfully reconstitutes CTL responses.[12,15] The
authors have suggested that combined sequential LAM and interferon therapy
might favourably influence the HBV-specific T-cell response. In a pilot
study, D'Antiga et al.[8] used LAM for 8 weeks followed by combination of
LAM and interferon for 44 weeks in 23 children with perinatally acquired
hepatitis B and documented cure (HBsAg seroconversion) in 17% of cases. We
used the same protocol in this case–control study in an effort to reduce
the viral load with LAM first and then added interferon to eliminate the
virus with the help of the body's immune system. The aim of our study was
to prospectively assess HBsAg seroconversion or 'cure' with sequential
combination therapy of LAM and interferon in children with immune-tolerant
phase of hepatitis B.

StephenW

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治疗儿童乙肝免疫耐受
它是一个可以实现的目标与顺序组合治疗与拉米夫定
和干扰素？

U.波达，N. Krishnani的，S.，J. K. Yachha阿加瓦尔
披露
Ĵ的病毒Hepat。 2013，20（5）:311-316。

抽象
我们前瞻性研究HBsAg血清学转换顺序
联合治疗拉米夫定（LAM）和干扰素（IFN）迄今
治疗的“免疫耐受”慢性乙型肝炎的儿童。在这种
病例对照研究中，28名儿童与免疫耐受肝炎B [乙肝表面抗原
阳性> 6个月接近正常，转氨酶水平，最小/无
肝脏组织学炎症和高病毒载量（HBV DNA> 107
林拷贝/ ml）]，用8周，随后独自在3毫克/公斤/天
林加干扰素α（5 MU/m2每周三次），另外44周。
他们比较了34例未经治疗的孩子。乙肝病毒标志物（乙肝表面抗原，e抗原，
进行抗-HBe，HBV DNA的定量）在基线时，在结束了
治疗6个月以后。平均年龄为5.9±3.2岁和24
是男孩。结束治疗反应：实现11 HBe的血清转换，
这些，五（HBsAg清除）完全缓解，11没有
响应，并有六个病毒学应答（DNA检测不到，但没有HBE
血清转换）。 6个月后治疗，10 11（91％），最初
儿童血清转换维持血清转换，同时seroreverted。六
的28个（21.4％），孩子们失去他们仍然HBsAg和HBsAg阴性，
抗-HBs阳性的后续。在平均随访21.1±11.9
个月时，状态保持应答相同但其中的
HBe的血清转换无应答者（39.3％）。没有严重的副作用
治疗。这是可能的，以实现在超过五分之一治愈
儿童乙肝免疫耐受的顺序组合
林和IFN。简介乙型肝炎是一个主要的健康问题
发展中国家尽管有有效的疫苗。在
事实上，中的儿童的慢性肝病的常见原因之一
世界的一部分，是慢性B型肝炎[1,2]三十四的世界
B型肝炎感染的人口是在亚洲，大部分孩子
慢性乙型肝炎在亚洲由于围产期获得感染[3,4]
围产期获得乙肝是一个漫长的特征
免疫耐受阶段可能会持续几十年的发展与风险
在成年后的肝细胞癌（HCC）及肝硬化[5,6]事实上，它
已经表明，HCC的风险是在亚洲人群中高
围产期获得水平收购相比，B型肝炎
B型肝炎[7]

理想的情况下，孩子应被视为围产期获得乙肝
早预防肝癌和肝硬化的发展。然而，直到
日期，除非试点研究西医结合治疗拉米夫定（LAM）
其次LAM和干扰素，[8]没有治疗方法已被证明是
在慢性乙肝免疫耐受期，人体的免疫系统是有效
HBV感染的反应迟钝。[9-11]，它已被证明
外周血HBV特异性细胞毒性T淋巴细胞的低反应性的
（CTL），主要是由于病毒载量高，[12-14]和病毒载量下降
，LAM治疗成功重组CTL应答[12,15]。
作者认为合并顺序林和干扰素治疗
可能有利地影响HBV特异性T细胞应答。在试点
研究，D'安蒂加的等人[8]使用8周，随后由组合的林
林和干扰素44个星期的23名儿童围产期获得
乙肝和成文的治愈率在17％的情况下（HBsAg血清学转换）。我们
在这种情况下，对照研究，在努力减少使用相同的协议
林的病毒载量，然后再添加干扰素，以消除
病毒与人体的免疫系统的帮助下。本研究的目的是
前瞻性地评估乙肝表面抗原血清学转换或“治愈”的顺序
林和干扰素联合治疗儿童免疫耐受
相B型肝炎。