韩国儿童与成人慢性乙型肝炎治疗的主要区别是什么？

StephenW

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J Korean Med Sci. 2018 Feb 19;33(8):e69. English.
Published online Jan 19, 2018.  https://doi.org/10.3346/jkms.2018.33.e69
© 2018 The Korean Academy of Medical Sciences.
   
What Are the Main Differences in the Treatment of Chronic Hepatitis B between Korean Children and Adults?
Byung-Ho Choe
Department of Pediatrics, Kyungpook National University School of Medicine, Daegu, Korea.

Address for Correspondence: Byung-Ho Choe, MD, PhD. Department of Pediatrics, Kyungpook National University School of Medicine, 130 Dongdeok-ro, Jung-gu, Daegu 41944, Republic of Korea. Email: [email protected]
Received January 12, 2018; Accepted January 15, 2018.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

See the article "A Multicenter Study of the Antiviral Efficacy of Entecavir Monotherapy Compared to Lamivudine Monotherapy in Children with Nucleos(t)ide-naïve Chronic Hepatitis B" in volume 33, e63.



The most common misconception among physicians is that chronic hepatitis B (CHB) in children can be monitored without treatment until they become adults. The risk of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) in Asian children is higher than that of western children, which can occur after suffering moderate to severe hepatitis for a prolonged period during active hepatitis (immune-clearance or immune-reactive phase), even in childhood. Therefore, timely treatment in the immune-reactive phase is crucial as delayed or no treatment in this phase results in increased incidences of liver cirrhosis (LC) or HCC.1 However, the duration of the immune-tolerance phase (hepatitis B e antigen [HBeAg] positive chronic HBV infection) is unpredictable. It may exceed three decades in patients vertically infected by HBeAg-positive mothers. Furthermore, almost 90% of children remain HBeAg-positive by the age of 10–15 years. In Korea, where genotype C is predominant, the proportion of CHB patients entering the initial period of immune-reactive phase was 11.7% in younger children < 12 years and 39.7% in children < 18 years, respectively.2 This indicates that every child with HBV will not remain a HBV carrier, and a ‘wait and see’ option could be dangerous in 2/5 of children.

In the current issues of Journal of Korean Medical Science, Choe et al.3 and Lee et al.4 have reported the antiviral efficacy of tenofovir monotherapy and entecavir monotherapy in Korean children. Considering that the prevalence rate of pediatric hepatitis B has decreased from 2%–3% to 0.1%–0.2% during the past 20 years, results from these multi-center studies are noteworthy, despite the small number of enrolled children. Limitations arise from the retrospective design of these studies, which leads to difficulty in accurately comparing the cut-off values of virologic suppression between non-concurrent groups. Meanwhile, a positive aspect is that tenofovir is expected to be covered by national health insurance in the same way as entecavir in children over 2 years of age.

Entecavir was approved by the FDA in 2014 for children with CHB over 2 years of age. Tenofovir was approved for children with CHB aged 12 years or older in 2012. However, it was not until 2015 when both drugs were covered by the national health insurance for Korean children. Tenofovir and tenofovir alafenamide are currently being studied in phase 3 global clinical trials for approval of usage in children over ages of 2 and 12 years, respectively. Currently, lamivudine is no longer the first-line drug as a result of high rates of antiviral drug resistance, though it was estimated to be effective in Korean children aged 6 years or younger before the introduction of entecavir.5 Choe et al.5 reported that 2 years of treatment with lamivudine was significantly effective in achieving HBeAg seroconversion and HBsAg clearance when compared with 6 months of treatment with interferon-α. This superiority in efficacy was observed especially in children under 6 years, despite the fact that they were all infected vertically.
Another misconception among physicians is that patients with high HBV DNA levels and positive HBeAg titers should be treated, despite normal hepatic enzyme levels. Treatment indications should be carefully evaluated in children with CHB. Treatment should not be considered in patients in the immune-tolerance phase. Pretreatment serum alanine aminotransferase (ALT) levels must exceed two times the upper limit of the normal value to achieve a better clinical response. If ALT levels are persistently elevated in an eligible patient, other hepatic related situations that can cause this elevation should be excluded. One example is in cases of reactive hepatitis, which could be associated with pneumonia or urinary tract infection. For obese children with CHB, it would be very difficult to differentiate whether the cause of the elevated liver enzyme is attributable to an HBV-related active hepatitis or a fatty liver disease. Thus, if such patients fail to reduce their body weight, liver biopsies should be conducted in order to determine whether to start an antiviral treatment.

A treatment strategy is also important to prevent treatment failure. Inadequate drug compliance is one of the major causes of treatment failure in children. Physicians should educate the patients and parents that it is important to take medicines every day on all counts. Another crucial point that physicians should remember is to not quit medication several months after achieving clinical response and HBeAg seroconversion. As part of a consolidation therapy, an additional treatment period is required after HBeAg seroconversion to prevent relapse.1 It is desirable to continue the nucleos(t)ide analogues for two additional years after complete remission (HBeAg seroconversion and HBV DNA clearance) is achieved. Furthermore, a longer consolidation period may be required, if HBeAg seroconversion is delayed or HBV DNA is detected again and remains positive by very low levels after complete remission.6

StephenW

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J Korean Med Sci。 2018年2月19日; 33（8）：e69。英语。
在线发布2018年1月19日。https://doi.org/10.3346/jkms.2018.33.e69
韩国医学科学院。

韩国儿童与成人慢性乙型肝炎治疗的主要区别是什么？
Byung-Ho Choe
韩国大邱庆北国立大学医学部小儿科。

通信地址：Byung-Ho Choe博士，博士。大韩民国大邱市中区洞东路130号庆北大学医学部小儿科。电子邮件：[email protected]
2018年1月12日收到; 2018年1月15日接受。

这是根据知识共享署名非商业许可条款（https://creativecommons.org/licenses/by-nc/4.0/）分发的开放获取文章，其允许无限制的非商业使用，分发和复制任何媒体，只要原创作品被正确引用。

参见第33卷第e63期的文章“恩替卡韦单药治疗与拉米夫定单药治疗慢性乙型肝炎核苷酸儿童抗病毒疗效的多中心研究”。



医生们最常见的误解是，儿童慢性乙型肝炎（CHB）可以不经治疗就可以监测，直到他们成为成年人。亚洲儿童乙型肝炎病毒（HBV）相关性肝细胞癌（HCC）的风险高于西方儿童，这可能在活动性肝炎（免疫清除或免疫相关性肝炎）期间长时间患有中重度肝炎后发生。反应阶段），甚至在童年。因此，及时治疗免疫反应阶段是至关重要的，因为在该阶段延迟或不治疗导致肝硬化（LC）或HCC的发病率增加[1]。然而，免疫耐受期（乙肝e抗原[ HBeAg阳性慢性HBV感染）是不可预测的。 HBeAg阳性母亲垂直感染的患者可能超过三十年。此外，几乎90％的儿童在10至15岁时仍保持HBeAg阳性。在以基因型C为主的韩国，进入初始免疫反应阶段的CHB患者比例分别为12岁以下儿童的11.7％和18岁以下儿童的39.7％[2]。这表明每个患有乙肝病毒不会是乙肝病毒携带者，在2/5的孩子中，“等等看”选项可能是危险的。

在当前韩国医学期刊中，Choe等[3]和Lee等[4]报道了替诺福韦单药治疗和恩替卡韦单药治疗韩国儿童的抗病毒疗效。考虑到过去20年来儿科乙型肝炎的患病率从2％-3％下降到0.1％-0.2％，这些多中心研究的结果值得注意，尽管入选儿童人数不多。这些研究的回顾性设计造成了局限性，这导致难以精确比较非并行组之间病毒学抑制的截止值。同时，一个积极的方面是，替诺福韦有望在2岁以上的儿童中接受国家医疗保险覆盖，方式与恩替卡韦相同。

恩替卡韦已于2014年获得美国食品及药物管理局批准，用于2岁以上的CHB儿童。 2012年，替诺福韦被批准用于12岁或12岁以上的CHB儿童。然而，直到2015年，这两种药物都被韩国儿童的国家医疗保险覆盖。替诺福韦和替诺福韦艾拉酚胺目前正在进行第3阶段全球临床试验研究，以批准分别用于2岁和12岁儿童。目前，由于抗病毒药物耐药率较高，拉米夫定已不再是一线药物，尽管据估计在引入恩替卡韦之前6岁或以下的韩国儿童是有效的.5 Choe等报道了5例与用干扰素-α治疗6个月相比，2年拉米夫定治疗对于达到HBeAg血清转换和HBsAg清除显着有效。尽管事实上它们都是垂直感染的，但在6岁以下的儿童中尤其观察到这种效力优势。
医生的另一个误解是，尽管肝酶水平正常，应该治疗HBV DNA水平高和HBeAg滴度阳性的患者。慢性乙型肝炎患儿应仔细评估治疗指征。免疫耐受期患者不应考虑治疗。治疗前血清丙氨酸氨基转移酶（ALT）水平必须超过正常值上限的两倍才能获得更好的临床反应。如果符合条件的患者的ALT水平持续升高，应排除其他与肝脏相关的可能导致该海拔升高的情况。一个例子是反应性肝炎，可能与肺炎或尿路感染有关。对于有CHB的肥胖儿童，鉴别肝酶升高的原因是否归因于HBV相关的活动性肝炎或脂肪肝病是非常困难的。因此，如果这些患者不能减少体重，应进行肝活检以确定是否开始抗病毒治疗。

治疗策略对预防治疗失败也很重要。药物依从性不足是儿童治疗失败的主要原因之一。医生应该教育患者和家长，每天服用药物很重要。医生应该记住的另一个关键点是在达到临床反应和HBeAg血清学转换后几个月不要停药。作为巩固治疗的一部分，在HBeAg血清转换后需要额外的治疗时间以防止复发[1]。完成缓解（HBeAg血清学转换和HBV DNA清除）后，需要继续使用核苷（酸）类似物两年。此外，如果HBeAg血清学转换延迟或再次检测到HBV DNA并在完全缓解后仍然保持阳性，可能需要较长的巩固周期6

StephenW

https://jkms.org/DOIx.php?id=10.3346/jkms.2018.33.e69