乙肝病毒婴儿的治疗：机会之窗？

StephenW

Treatment of infants with hepatitis B virus: A window of opportunity?
Simon C. Ling1,low asterisk,'Correspondence information about the author Simon C. LingEmail the author Simon C. Ling
, Douglas Mogul2
See Article, pages 871–875
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DOI: https://doi.org/10.1016/j.jhep.2019.08.007 |
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The high global prevalence of chronic hepatitis B infection (3.5%, or 257 million people) is largely sustained by vertical transmission from mother to infant.1 Most infants who acquire hepatitis from their mothers develop chronic infection and face a lifetime risk of early death from hepatocellular carcinoma or the complications of cirrhosis. Although such severe outcomes may occur during childhood, they are rare in the pediatric age range and are further reduced by access to expert medical care and antiviral therapy when needed.2, 3, 4 However, children with chronic hepatitis B often suffer impaired quality of life and stigmatization, may transmit the virus to others, and may develop liver fibrosis during childhood that eventually results in adverse clinical outcomes during adulthood. Effective prevention and treatment of chronic hepatitis B infection in children are therefore important goals.

Strategies to achieve the elimination of hepatitis B infection rely heavily on newborn immunization. When delivered to a newborn within 24 hours of birth and followed by 2 subsequent doses, the hepatitis B vaccine is approximately 90% effective at preventing perinatal hepatitis B infection. Vaccine failure rates can be further reduced by antiviral treatment of HBV-infected pregnant mothers.5 Vertical transmission of hepatitis B infection is therefore largely preventable, but newborn immunization programs often struggle to achieve appropriately high levels of coverage for their at-risk populations, and some countries have yet to implement such programs.6 For now, therefore, large numbers of children continue to acquire new hepatitis B infection every year.

Treatment of hepatitis B infection in these children has mostly been limited to those children with high viral load associated with significant and prolonged elevations of liver enzymes, such that only a small minority of children are treated. Interested in the possibility of widening the eligibility for treatment, several investigators have studied the treatment of children with high viral load, positive hepatitis B e antigen (HBeAg), and normal or near-normal liver enzyme concentrations (e.g. alanine aminotransferase [ALT] less than 60 units/liter). This so called “immune tolerant” hepatitis B accounts for the majority of chronically infected children. Five studies have demonstrated conflicting results when evaluating interferon and a nucleoside antiviral agent combination therapy in this phase of infection. In the first study, 23 immune tolerant children, 3–17 years old, were treated with 8 weeks of lamivudine followed by combination therapy with lamivudine and interferon-α for 10 months.7 Most children (78%) had undetectable HBV DNA levels at end of treatment, 22% seroconverted to anti-HBeAg, and an impressive 17% were negative for antibodies to HBV surface antigen (HBsAg) at end of therapy (far more than expected according to the natural history of the infection). HBV DNA levels rebounded in all individuals that had not seroconverted to anti-HBeAg once therapy was discontinued. The small number of participants limited statistical comparison between responders and non-responders, but there was a suggestion that female, Asian, genotype B, older children were more likely to respond to treatment. Poddar et al. subsequently reported 62 “immune tolerant” children (mean age 7 years, ALT <80 U/L), 28 of whom received lamivudine and interferon-α, while 34 who declined therapy formed a control group.8 In the treatment group, 39% achieved HBeAg seroconversion and 21% became HBsAg undetectable, compared to 6% and 0%, respectively, in the untreated controls. None of the clinical, biochemical or histological variables examined differed between responders and non-responders, although genotype testing was not available.

These encouraging studies from the UK and India contrast with 2 more recent multicenter trials performed by the Hepatitis B Research Network in the United States and Canada.9, 10 Sixty immune tolerant children (age 3–18 years, ALT less than 60 U/L in males and 40 U/L in females) were treated with an initial 8 weeks of entecavir followed by combination of entecavir and peginterferon-α-2a for an additional 40 weeks.9 All children showed an initial reduction in HBV DNA levels while on treatment, which rebounded in all but 4 children after treatment was stopped. Only 2 children (3%, both Asian, 1 genotype B and 1 genotype C) maintained the primary endpoint of HBV DNA level <1,000 IU/ml and seroconversion to anti-HBeAg at post-treatment week 48, and these 2 patients also showed seroconversion to anti-HBs antibody. Feld et al. used a similar regimen in 28 immune tolerant adults and reported that 2% achieved the same primary endpoint 48 weeks after discontinuation of therapy.10

Finally, investigators in Beijing, China studied a different sequence of treatments in children with “immune tolerant” hepatitis B.11 These investigators reversed the order in which the antiviral therapies were introduced. They randomized 69 children (age 1–16 years, ALT less than 60 U/L, genotype B and C) to an untreated control group or a treatment group who initially received 12-weeks of interferon, followed by 60 weeks of combined interferon and lamivudine therapy, followed by 24 weeks of lamivudine monotherapy, to complete a total 96 weeks of therapy. Outcomes were assessed at treatment week 96. In the treatment group, HBeAg seroconversion was noted in 33% and HBsAg loss in 22%, compared to 4% and 0%, respectively, in the control group. Multivariable analysis revealed higher baseline ALT to be predictive of response to therapy.

Taken together, these 5 studies leave significant questions unanswered as we try to understand the optimal approach to management of children with chronic hepatitis B with high viral load, positive HBeAg and normal or near-normal ALT.12 We cannot yet be certain of the effects on treatment efficacy of variables such as drug choice (interferon combined with lamivudine vs. entecavir), sequence of therapy (interferon monotherapy first, or nucleoside analogue first), viral genotype, or patient characteristics (sex, age, race, ALT, etc.). At best, about a third of children with immune tolerant HBV infection may develop a durable response (i.e. seroconversion to anti-HBeAg and low HBV DNA) using existing therapies, although this proportion may be far smaller according to the North American studies. Alternative strategies are therefore needed to achieve effective treatment for the majority of children with chronic hepatitis B infection.

The experience with one such alternative strategy is reported in this edition of the Journal of Hepatology. Zhu et al. compared the outcomes of 18 hepatitis B-infected infants with elevated ALT treated under 1 year of age with lamivudine, to the outcomes of 11 similar infants who waited until more than 1 year of age to receive treatment with interferon (interferon is contraindicated under 1 year of age).13 For infants treated with lamivudine, interferon could be added if HBsAg remained positive after 1 year of age. Similarly, for older infants treated with interferon, lamivudine was added if HBV DNA declined less than 2 logs after 3 months of interferon therapy. Treatment was continued in both groups for 12 months and for those who had not by then achieved HBsAg seroconversion, treatment was continued until HBsAg or HBeAg seroconversion was achieved.

The 2 groups of infants were diagnosed and followed from the same age. Nine of the 18 lamivudine-treated young infants achieved HBsAg loss by 12 months of age, compared to none of the 11 infants who waited until >1 year of age to start interferon treatment. Remarkably, after 12 months of treatment, 83% of lamivudine-treated infants had lost HBsAg and 83% had developed anti-HBs antibody, compared to 36% and 27%, respectively, in the interferon-treated older infants. During longer term follow-up, all participants except 1 interferon-treated infant achieved HBsAg or HBeAg seroconversion and therefore stopped treatment, and none have shown sero-reversion in the median 102-month off-treatment observation period. This treatment response rate is greatly superior to that described in a recent meta-analysis or prior pediatric studies, which found that HBsAg loss occurred in 7–23% of children depending on the duration of follow-up and seroconversion to anti-HBsAg occurred in 5%.14

There are scarce published data describing the natural history of hepatitis B infection during infancy. We know little about changes in ALT during these early months, and it is therefore important to note the significant elevation of ALT in the infants included in the Zhu et al. study at baseline (mean values of 357 and 209 U/L in the 2 groups). This suggests that the investigators included only a select group of infants with very active hepatitis, who may respond differently to those with normal or mildly elevated ALT. Furthermore, we do not have good data describing the likelihood of spontaneous loss of HBsAg and seroconversion to anti-HBs positivity without treatment during infancy. During the initial few months of follow-up, before reaching 12 months of age, Zhu et al.’s delayed interferon treatment group acts as an untreated control group, and during this time (before 12 months of age), HBsAg seroconversion rates are much higher in the lamivudine-treated group. The published literature provides little additional information on events in this very young age group. In a natural history study of children with chronic hepatitis B infection in Taiwan, 72 vertically-infected infants were included among the total cohort of 415 children, and 7 of these 72 (9.7%) developed HBeAg seroconversion in the first 3 years (median age at seroconversion 1.8 years, range 1.0–2.9 years), but no information was provided about HBsAg seroconversion.15

We also understand little about host and hepatitis B virus interactions during infancy. Early suggestions that a “defective” neonatal immune system fails to respond to hepatitis B and thus enables chronic infection have been challenged by evidence that newborn infants mount hepatitis B-specific T-cell responses. The “immune tolerant” phase of hepatitis B (defined by viral markers and ALT level) in older children is characterized by evidence of HBV-specific immune activity, although this activity is weak.16 In general, the newborn immune system differs from older children and adults in its greater production of anti-inflammatory cytokines, lesser production of pro-inflammatory cytokines, its Th2/TReg predominant T-cell responses and differences in innate immune activity mediated by toll-like receptors.17, 18 We must await further studies to determine how this may impact responses to antiviral therapies.

Because the clinical benefit of combination antiviral therapy for children with “immune tolerant” hepatitis B is uncertain and unimpressive, there is a pressing need to identify more widely effective ways to treat children with hepatitis B. The small study by Zhu and colleagues provides hope that novel timing of treatment during infancy may facilitate a far greater likelihood of successful antiviral therapy, including HBsAg seroconversion. Treatment of young infants cannot yet be clinically recommended based on these data, but a potential window of opportunity in early life has been identified for further study, when the relationship between host and hepatitis B virus may be more susceptible to disruption by current antiviral agents.

StephenW

乙肝病毒婴儿的治疗：机会之窗？
Simon C. Ling1，低星号，关于作者Simon C. Ling的通讯信息给作者Simon Simon C. Ling发电子邮件
，道格拉斯·莫古尔2
参见文章，第871–875页
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DOI：https：//doi.org/10.1016/j.jhep.2019.08.007 |
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全球慢性乙型肝炎感染率很高（3.5％，即2.57亿人）在很大程度上是由母亲向婴儿的垂直传播所维持的。1大多数从母亲那里感染肝炎的婴儿都患有慢性感染，终身面临因早逝而死亡的风险。肝细胞癌或肝硬化的并发症。尽管此类严重后果可能会在儿童时期发生，但在儿科年龄范围内很少见，并且在需要时可通过获得专业医疗护理和抗病毒治疗进一步降低。2、3、4然而，慢性乙型肝炎儿童通常会受到以下疾病的影响：生活和污名化，可能会将病毒传播给其他人，并可能在儿童期发展为肝纤维化，最终导致成年期临床不良后果。因此，有效预防和治疗儿童慢性乙型肝炎是重要的目标。

消除乙型肝炎感染的策略在很大程度上依赖于新生儿免疫。当在出生后的24小时内分娩给新生儿，然后再注射2剂，乙型肝炎疫苗在预防围产期乙型肝炎感染方面大约有90％有效。通过对乙肝病毒感染的怀孕母亲进行抗病毒治疗，可以进一步降低疫苗的失败率。5因此，乙型肝炎感染的垂直传播在很大程度上是可以预防的，但是新生儿免疫接种计划通常很难为高危人群实现适当的高水平覆盖率，并且一些国家尚未实施此类计划。6因此，到目前为止，每年仍有大量儿童继续感染新的乙型肝炎。

在这些儿童中，乙型肝炎感染的治疗主要限于那些病毒载量高，肝酶显着和长期升高相关的儿童，因此只有一小部分儿童得到治疗。对扩大治疗资格的可能性感兴趣，一些研究者已经研究了病毒载量高，乙型肝炎e抗原（HBeAg）阳性，肝酶浓度正常或接近正常（例如，丙氨酸转氨酶[ALT]少）的儿童的治疗方法。超过60个单位/升）。这种所谓的“免疫耐受”乙型肝炎占慢性感染儿童的大多数。五项研究表明，在感染的这一阶段评估干扰素和核苷类抗病毒药物联合治疗时，结果矛盾。在第一个研究中，对23例3至17岁的免疫耐受儿童进行了8周的拉米夫定治疗，随后联合拉米夫定和干扰素-α进行了10个月的治疗。7大多数儿童（78％）的HBV DNA水平未检测到在治疗结束时，有22％的患者血清转化为抗HBeAg，在治疗结束时，有令人印象深刻的17％的HBV表面抗原（HBsAg）抗体阴性（根据感染的自然病程远超出预期）。一旦停止治疗，所有未血清转化为抗HBeAg的个体中HBV DNA水平反弹。少数参与者限制了有反应者和无反应者之间的统计比较，但是有人建议，女性，亚洲人，基因型B，年龄较大的儿童更可能对治疗产生反应。 Poddar等。随后报告了62名“免疫耐受”儿童（平均年龄7岁，ALT <80％U / L），其中28名接受了拉米夫定和干扰素-α，而拒绝治疗的34名则成为对照组。8在治疗组中，有39％达到HBeAg血清转换，未检测到21％的HBsAg，相比之下，未经治疗的对照组分别为6％和0％。尽管无法进行基因型检测，但应答者与非应答者之间所检查的临床，生化或组织学变量均无差异。
这些来自英国和印度的令人鼓舞的研究与美国和加拿大的乙型肝炎研究网络最近进行的2项多中心试验形成对照。9，10名60免疫耐受的儿童（年龄3-18岁，ALT低于60 U / L）男性接受40 U / L治疗，女性接受40 teU / L的治疗，最初是用恩替卡韦治疗8周，然后联合恩替卡韦和聚乙二醇干扰素-α-2a再治疗40周。9所有儿童在治疗期间均表现出HBV DNA含量最初降低停止治疗后，除4名儿童外，其余所有儿童均反弹。在治疗后第48周，只有2名儿童（3％，亚洲人，1名B型基因型和1名C型基因型）维持HBV DNA水平<1,000 IU / ml和血清转化为抗HBeAg的主要终点，这2名患者还显示血清转化为抗HBs抗体。费尔德等。在28位免疫耐受的成年人中使用了相似的治疗方案，并报道2％的患者在停止治疗后48周达到了相同的主要终点指标10。

最后，中国北京的研究人员研究了“免疫耐受”乙型肝炎儿童的不同治疗顺序。11这些研究人员颠倒了抗病毒治疗的引入顺序。他们将69名儿童（年龄1-16岁，ALT低于60 U / L，基因型B和C）随机分配至未经治疗的对照组或治疗组，这些组最初接受12周的干扰素治疗，随后接受60周的干扰素联合治疗。拉米夫定治疗，然后进行24周的拉米夫定单药治疗，以完成总共96周的治疗。在治疗的第96周评估了结局。在治疗组中，HBeAg血清转化率为33％，HBsAg丢失为22％，而对照组分别为4％和0％。多变量分析显示较高的基线ALT可预测对治疗的反应。

综上所述，这5项研究仍悬而未决，因为我们试图了解治疗病毒载量高，HBeAg阳性，ALT正常或接近正常的慢性乙型肝炎儿童的最佳方法。12我们尚不能确定其影响诸如药物选择（干扰素联合拉米夫定与恩替卡韦），治疗顺序（干扰素单药治疗或核苷类似物治疗），病毒基因型或患者特征（性别，年龄，种族，ALT等）的变量对治疗效果的影响。 ）。最佳情况下，约有三分之一的具有免疫耐受性HBV感染的儿童使用现有疗法可能会产生持久反应（即血清转化为抗HBeAg和低HBV DNA），尽管根据北美的研究，这一比例可能要小得多。因此，需要采取其他对策，以对大多数患有慢性乙型肝炎感染的儿童取得有效的治疗。

在《肝病学杂志》的这一版中报道了使用这种替代策略的经验。朱等。比较了在1岁以下接受拉米夫定治疗的ALT升高的18例乙型肝炎感染婴儿的结局，与等到1岁以上接受干扰素治疗的11例类似婴儿的结局（干扰素在1岁以下禁忌） 13）对于接受拉米夫定治疗的婴儿，如果HBsAg在1岁后仍保持阳性，则可以添加干扰素。同样，对于接受干扰素治疗的较大婴儿，如果干扰素治疗3个月后HBV DNA下降少于2 log，则添加拉米夫定。两组均继续治疗12个月，对于尚未达到HBsAg血清转化的患者，继续治疗直至达到HBsAg或HBeAg血清转化。

对两组婴儿进行了诊断，并从同一年龄开始随访。在接受拉米夫定治疗的18个婴儿中，有9个在12周龄时达到了HBsAg降低的水平，而等到1周岁以上才开始干扰素治疗的11个婴儿中，没有一个。值得注意的是，在接受治疗12个月后，接受拉米夫定治疗的婴儿中83％的患者失去了HBsAg，而产生抗HBs抗体的患者为83％，而接受干扰素治疗的较大婴儿分别为36％和27％。在长期随访中，除1名接受干扰素治疗的婴儿外，所有参与者均达到HBsAg或HBeAg血清转化，因此停止治疗，并且在中位102个月的非治疗观察期中均未显示血清转化。这种治疗反应率大大优于最近的荟萃分析或先前的儿科研究中所描述的，后者发现7％至23％的儿童发生HBsAg丢失，这取决于后续治疗的持续时间和血清中抗HBsAg的转换。 5％.14
很少有公开的数据描述婴儿期乙型肝炎感染的自然史。我们对这些早期几个月中ALT的变化知之甚少，因此重要的是要注意Zhu等人所包括的婴儿中ALT的显着升高。在基线进行研究（两组均值分别为357和209 U / L）。这表明研究者只包括了一组极活跃的肝炎婴儿，这些婴儿对ALT正常或轻度升高的婴儿可能有不同的反应。此外，我们没有足够的数据来描述婴儿期未经治疗而自发丧失HBsAg和血清转化为抗HBs阳性的可能性。在随访的最初几个月中，Zhu等人的延迟干扰素治疗组在未达到12周龄之前作为未治疗的对照组，在此期间（12周龄之前），HBsAg血清转化率为在拉米夫定治疗组中更高。出版的文献几乎没有提供有关这个很小年龄段事件的更多信息。在一项针对台湾慢性乙型肝炎感染儿童的自然史研究中，总共415名儿童中包括72例垂直感染婴儿，其中72例中有7例（9.7％）在头3年（中位年龄）出现了HBeAg血清转化血清转化率为1.8年，范围为1.0-2.9年），但未提供有关HBsAg血清转化的信息。15

我们也对婴儿期宿主和乙型肝炎病毒的相互作用了解甚少。早期关于“免疫缺陷”的新生儿免疫系统无法对乙型肝炎做出反应，从而能够进行慢性感染的早期建议受到了新生婴儿发生乙型肝炎特异性T细胞应答的证据的挑战。年龄较大的儿童中乙型肝炎的“免疫耐受”阶段（由病毒标志物和ALT水平定义）以HBV特异性免疫活性的证据为特征，尽管这种活性很弱。16通常，新生儿免疫系统与年龄较大的儿童不同和成年人，其抗炎细胞因子的产量较高，促炎细胞因子的产量较低，其主要的Th2 / TReg T细胞反应以及由Toll样受体介导的先天免疫活性的差异。17，18我们必须等待进一步的研究确定这可能如何影响对抗病毒治疗的反应。

由于联合抗病毒治疗对“免疫耐受”乙型肝炎的儿童的临床益处尚不确定且令人印象深刻，因此迫切需要找到更广泛有效的治疗乙型肝炎儿童的方法。朱及其同事的这项小型研究提供了希望婴儿期新的治疗时机可能会增加成功的抗病毒治疗（包括HBsAg血清转化）的可能性。根据这些数据，尚不能在临床上建议对婴儿进行治疗，但是当宿主与乙型肝炎病毒之间的关系可能更容易受到当前抗病毒药物的干扰时，已经确定了早期生命的机会之窗有待进一步研究。

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