儿童和青少年慢性乙肝: 自然史

StephenW

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在儿童和青少年慢性乙肝
http://www.journal-of-hepatology.eu/article/S0168-8278%2812%2900358-3/fulltext#b0265
Natural history

Chronic HBV infection is defined as a positive HBsAg for 6months or longer. Chronic hepatitis B (CHB) in childhood is a mild disease, and infected children are mostly asymptomatic, have normal growth and a normal physical examination [53]. Most perinatally infected subjects present a positive HBeAg and high serum levels of HBV DNA, with normal or minimally elevated serum alanine aminotransferases (ALT). A transplacental transfer of maternal HBeAg has been proved both in mice and in humans, and could elicit HBe/HBcAg-specific Th cell tolerance in utero [40], [54], [55], [56]. Such an induced tolerance could explain the higher chronicity rate in babies born to HBeAg-positive mothers and the different rate of chronicity between neonatal and adult infection. The synthesis of large amounts of HBeAg by the wild type virus could be necessary to maintain the tolerance [57]. This immunotolerant phase is characterized by high viral replication and little liver damage, although in Italian children, after 7years of disease, 7–10% of subjects showed severe hepatitis at liver biopsy and 1.7–4.5% had cirrhosis [53], [58]. It lasts 10–30years when infection is acquired perinatally, whereas it is of minimal duration in subjects infected later in life.

Viral mutants not capable of secreting HBeAg are then slowly selected (pre-core mutants are detected in 89% of HBeAg-positive patients) [59]. Selection seems to be secondary to an advantage of such mutants over wild type HBV, as hepatocytes infected by the latter are more susceptible to cytotoxic T lymphocyte-mediated clearance [60]. Pre-core mutants selection leads to a lower secretion of HBeAg. When the decreased amount of secreted tolerogen is no more sufficient to maintain immunotolerance, the immune system starts attacking infected hepatocytes [56], [57]. ALT levels rise, reflecting the bioptic finding of necroinflammation of liver parenchyma, and HBV DNA levels fluctuate. This phase of active hepatitis leads to seroconversion to anti-HBe antibodies in 60–95% of patients on long-term follow-up [58], [61]. ALT levels significantly increase before HBeAg clearance and may remain elevated for 6months after seroconversion [53], [62], [63], [64]. Up to 20% of spontaneous seroconverters may have ALT flare-ups in the years following seroconversion, which seems to be more likely in subjects carrying a pre-core mutant [63]. Spontaneous seroconversion occurs earlier and more frequently in subjects who have acquired HBV horizontally than in those infected perinatally (14–16% vs. 4–5% per year) [53], [58], [62], [65]. It usually occurs after puberty, with about 90% of children <15years of age still HBeAg positive [65]. It was shown that boys with earlier-onset puberty seroconverted at younger age (13 vs. 22years), suggesting that androgens play a role in this process [64]. Environmental factors, such as nutritional status, have been suggested to influence immune response to HBV, accelerating seroconversion in children after adoption from developing countries [62]. Genotype C and maternal HBeAg-positive status were also associated with delayed spontaneous seroconversion [24], [61], [62], [66], [67], [68].

HBsAg-positive, HBeAg-negative, and anti-HBe-positive patients are considered inactive carriers, express absent or low viral replication, with low or undetectable HBV DNA, and have inactive liver histology, with normal ALT levels. Inactive carriers with no signs of cirrhosis at seroconversion did not show progression to cirrhosis over 24–29year follow-up [53], [58].

On the contrary, 1–5% of HBeAg-positive children developed cirrhosis [53], [58], [69]. Between 2% and 5% of children with CHB developed HCC during childhood [24], [58], [70]. Incidence of HCC in high prevalence areas was significantly reduced after the implementation of immunization programs [71]. Children developing HCC are more likely to be males (70%), with cirrhosis (80%) and undergoing early seroconversion, suggesting that necroinflammation during seroconversion to anti-HBe may be severe and lead to cirrhosis and HCC [24], [58], [70]. Long-term risk of both HCC and cirrhosis is directly correlated to viral replication and serum HBV DNA levels [72], [73]. The role of viral genotype on the risk of developing HCC is still to be defined: in children, 80% of HCCs are present in cirrhotic genotype B patients, whereas young adults with HCC are mostly non-cirrhotic [24], [66]. In adults, genotypes C and F increase the risk for HCC [66], [74], [75], [76]. Furthermore, such a risk is higher in persons with a family history of HCC, and a new susceptibility locus has been recently described in 1p36.22 [77], [78]. Seroconversion to anti-HBe reduces the overall risk of developing HCC later in life, but an annual incidence of 0.2% has been described in HBeAg-negative adults (1.6% of asymptomatic HBsAg carriers) [79].

In 5% of anti-HBe-positive children, a pre-core mutant is selected, with persistent viral replication, abnormal ALT levels and histologically active hepatitis (HBeAg-negative chronic hepatitis). The latter progresses slowly in children, whereas adult patients are at increased risk of cirrhosis and HCC [53], [58], [79], [80]. A stronger immune response with a faster turnover of infected cells could account for such an increased severity, and could be secondary to the reduced secretion of the tolerogen HBeAg [55], [81].

In long-term longitudinal studies, it was shown that 7–14% of inactive carriers lost HBsAg and became anti-HBs-positive. Spontaneous seroconversion to anti-HBs is a rare event in childhood (1%/year and 0.6%/year in horizontally and perinatally infected children, respectively) [53], [58], [62], [80]. HBsAg clearance and anti-HBs seroconversion mark the resolution of HBV infection, and are accompanied by improved liver histology. Long-term prognosis after HBsAg seroclearance is excellent if it occurs before the development of cirrhosis or HCC and in the absence of concomitant infections [82]. Nevertheless, cccDNA persists indefinitely in hepatocytes, and low-level viral replication or reactivation upon immunosuppression are still possible

StephenW

自然史

慢性HBV感染的定义为6个月或更长的时间为HBsAg阳性。慢性乙型肝炎（CHB）在童年是一种轻微的疾病，受感染的儿童大多无症状，有正常的生长和体格检查正常[53]。围产期感染的科目提出了HBeAg阳性和血清HBV DNA水平高，与正常或轻度升高的血清丙氨酸转氨酶（ALT）。 à胎盘转移产妇大三阳已经证明，在小鼠和人类，并可能引起HBe阳性/ HBcAg特异性Th细胞公差在子宫内[40]，[54]，[55]，[56]。可以解释这种诱导耐受较高的慢性化率在HBeAg阳性的母亲和新生儿和成人感染慢性之间不同幅度的婴儿出生。 HBeAg的大量的野生型病毒的合成，有必要保持的耐受性[57]。这种免疫耐受阶段的特点是高病毒复制和肝功能损害不大，虽然在意大利的孩子，后疾病7年，7-10％的患者表现为严重肝炎肝活检和1.7-4.5％有肝硬化[53]，[58] 。持续1030年的感染是由于母婴传播而感染者以后的生活中是最小的持续时间。

没有能力的分泌HBeAg的病毒突变体，然后慢慢地选择（HBeAg阳性患者中检测到89％的预核突变体）[59]。选择似乎是继发于这些突变体比野生型HBV的优点，后者感染的肝细胞的细胞毒性T淋巴细胞介导的​​间隙[60]更容易受到。前核突变体的选择到一个较低的HBeAg的分泌。当减少量分泌tolerogen是没有更足以维持免疫耐受，免疫系统开始攻击感染的肝细胞[56]，[57]。 ALT水平上升，反映肝实质坏死性炎症活检发现，HBV DNA水平波动。这一阶段的活动性肝炎抗-HBe抗体的血清转换导致60-95％的患者长期随访升[58]，[61]。前ALT水平显着提高HBeAg清除，并且可能会继续升高血清转换后6个月[53]，[62]，[63]，[64]。最多可能有20％自发血清转化后的几年里ALT耀斑起坐血清学转换，这似乎更有可能携带预核心突变[63]。自发血清转换更早，更频繁地发生在谁收购HBV水平比在围产期感染者（14-16％与每年的4-5％）[53]，[58]，[62]，[65]。它通常发生在青春期后，约90％的儿童<年龄15年仍然e抗原阳性[65]。结果表明，与早发性青春期的男孩血清转换在低龄（13主场迎战22年的），表明雄激素在这个过程中发挥作用[64]。环境因素，如营养状况，已经提出来影响对HBV的免疫应答，加快收养孩子后，来自发展中国家的血清转换的[62]。 C基因型和自发血清转换延迟也与母亲HBeAg阳性状态[24]，[61]，[62]，[66]，[67]，[68]。

HBsAg阳性，HBeAg阴性，抗-HBe阳性的患者被认为是不活动的载体，表达缺失或低，低或检测不到的HBV DNA病毒复制，有不活泼的肝脏组织学，ALT水平正常。肝硬化血清转换没有任何迹象显示非活动性携带者没有表现出超过2429年进展为肝硬化随访[53]，[58]。

相反，有1-5％的HBeAg阳性的儿童发展肝硬化[53]，[58]，[69]。 2％和5％的慢性乙型肝炎的儿童在童年开发肝癌[24]，[58]，[70]。实施免疫规划后，在高流行地区的肝癌发病率明显降低[71]。肝细胞癌是儿童更可能是男性（70％），肝硬化（80％），可能是严重的，并导致肝硬化和肝癌发生早期的血清转化，表明抗-HBe血清转化过程中的坏死性炎症[24]，[58] [70]。肝癌和肝硬化的长期风险是直接相关的病毒复制和血清HBV DNA水平[72]，[73]。发展为HCC的危险病毒基因型的作用仍是被定义为：在儿童中，80％的肝癌是目前在肝硬化B基因型，而肝癌大多是青壮年非肝硬化性[24]，[66]。在成人中，基因型C和F提高肝癌的风险[66]，[74]，[75]，[76]。此外，这样的风险是在有HCC家族史的，一个新的易感基因最近已描述在1p36.22高[77]，[78]。抗-HBe血清转换在以后的生活发展为HCC的整体风险降低，但0.2％的年发病率已经HBeAg阴性的成年人无症状HBsAg携带者（1.6％）[79]。

在5％抗-HBe阳性的儿童，选择预先核心的突变体，持续的病毒复制，ALT水平异常和（HBeAg阴性慢性肝炎组织学活动性肝炎）。后者的进展缓慢的儿童，而成人患者在肝硬化和肝癌的风险增加[53]，[58]，[79]，[80]。更强的免疫反应可以解释这样一个日益严重感染的细胞具有更快的营业额，可能是继发的的tolerogen HBeAg的分泌减少[55]，[81]。

在长期的纵向研究中，它被证明是7-14％的非活动性携带者成为失去HBsAg和抗-HBs阳性。自发抗-HBs血清转换是一个罕见的事件（1％/年和0.6％/年的水平和围产期感染的儿童，分别在童年）[53]，[58]，[62]，[80]。 HBsAg清除和抗-HBs血清转换标志乙肝病毒​​感染的分辨率，都伴随着改善肝脏组织学。乙肝表面抗原转阴后的长期预后是优秀的，如果它之前发生肝硬化或肝癌的发展和并发感染的情况下[82]。然而，cccDNA的持续存在是在肝细胞中，仍然是可能的低级别的免疫抑制病毒的复制或再活化后

StephenW

"Tenofovir disoproxil fumarate is a nucleos(t)ide analogue originally licensed for treatment of HIV infection, which is structurally similar to adefovir and of equal antiviral activity. Nevertheless, as it proved to be less nephrotoxic than adefovir, the approved dose for adults is higher than that of adefovir (300mg/day). For such a reason, tenofovir was shown to have a greater antiviral activity than adefovir in clinical trials (undetectable HBV DNA in 76% of patients vs. 13% of adefovir-receiving subjects after 48weeks of treatment) [142]. After three years of treatment, 72% of HBeAg-positive and 87% of HBeAg-negative patients have HBV DNA levels <400copies/ml [143]."

富马酸替诺福韦酯是一种核苷（酸）类似物最初许可用于治疗艾滋病毒感染，是结构相似，阿德福韦和平等的抗病毒活性。然而，它被证明是比阿德福韦的肾毒性较少，获批准的成人剂量为高于阿德福韦300mg/day。由于这样的理由，替诺福韦结果表明，以具有更大的抗病毒活性，在临床试验中比阿德福韦（试验不到HBV DNA在76％的患者，对13％的阿德福韦酯接收主体治疗48周后）[142]。经过三年的治疗，72％的HBeAg阳性和HBeAg阴性患者有87％的HBV DNA水平<400copies/ml[143]。

StephenW

Who and when to treat

Need for treatment should be evaluated at each follow-up visit, in order to treat as soon as early signs of liver damage are detected. Children with CHB should undergo physical examination and measurement of serum ALT, HBeAg/anti-HBe, and alpha-fetoprotein levels every 6months. ALT should be monitored every 3months at diagnosis (for 1year) and if persistently elevated, and every 12months in HBeAg-negative patients with low viral load (<2000IU/ml). HBV DNA levels should be assessed every 12months, along with a complete blood count, a full liver panel and a liver ultrasound [83], [85], [88]. Lifetime follow-up is warranted even for inactive carriers, because of the risk of cirrhosis (7.8% of patients at 25years), HCC (2.2%) and reactivation of HBV infection, with seroreversion to HBeAg positivity (1–4% of patients) or progression to HBeAg-negative hepatitis (15–24%) [79], [89].

Decision to treat should be based on the following parameters: ALT levels, HBeAg positivity, HBV DNA levels, liver histology, family history of cirrhosis, and/or HCC, co-existing liver diseases, and patient’s treatment history. Serum ALT level is the most useful marker of liver damage and should be used to identify patients who could be considered for possible antiviral therapy. Published evidence suggests that patients with normal or mildly elevated ALT respond poorly to available treatments [90], [91]. Benefit of treating children with normal ALT has not been established, and the risk of developing antiviral resistance could turn it deleterious when considering the future of these patients [92]. Therefore, children in the immunotolerant phase should not be treated outside of clinical trials, and should be monitored and treated when the increase of ALT levels reveals immune activation. The three largest clinical trials of antiviral drugs in children used ALT levels higher than 1.5 times the laboratory ULN or more than 60IU/L, whichever was lower, as inclusion criteria [90], [91], [93]. Unfortunately, the upper limit of normal (ULN) for ALT levels has not yet been established for children [94].

Serum ALT level has to be elevated for at least 6months (12months if HBeAg-negative), in order to avoid treating patients who are undergoing spontaneous HBeAg seroconversion. Persistent ALT elevation mandates assessment of serum HBV DNA levels. High HBV DNA values warrant treatment, whereas low HBV DNA levels should lead to the exclusion of other causes of liver disease. The cut-off value for HBV DNA has not been defined, and arbitrary values are used in clinical trials and guidelines. As children have a higher HBV replication rate, a value of 20,000IU/ml has been chosen by different authors [85], [95]. However, lower values have been associated with progressive liver disease in adults and latest management guidelines identified 2.000IU/ml to be a good cut-off [83].

In adult patients older than 40years of age, treatment can be started solely upon detection of a high viral load, as it is an independent risk factor of cirrhosis and HCC [72], [73]. No data exist in children to support such an approach. Therefore, as response to currently available treatments for children is partial and limited to specific subgroups, histologic assessment of the grade of inflammation and the stage of fibrosis remains recommended before treating a child. Response to both interferon(IFN)-alfa and nucleos(t)ide analogues is more likely when at least moderate necroinflammation or moderate fibrosis are found at liver histology [90], [96]. Although the benefit of treatment has not been established for children with mild inflammation or fibrosis, a family history of HCC may warrant treatment even in children with mild histological changes, as they are at increased risk of developing HCC [77].

StephenW

谁和什么时候治疗

需要治疗，应该在每个随访评估，以治疗尽快发现早期肝损伤的迹象。慢性乙型肝炎的儿童应进行体检和血清ALT，e抗原/抗-HBe和甲胎蛋白水平每6个月的的测量。 ALT应监测，每3个月，诊断（1年）和HBeAg阴性患者的病毒载量低（<2000IU/ml），如果持续升高，每12个月在。 HBV DNA水平，应评估每12个月，随着一个完整的血球计数，一个完整的肝功能和肝脏超声[83]，[85]，[88]。终身随访是必要的，即使对于非活动性携带者，因为肝硬化的风险（7.8％患者在25年），肝癌（2.2％）和HBV感染的活化，与seroreversion HBeAg阳性率（1-4％的患者） HBeAg阴性肝炎或进展（15-24％）[79]，[89]。

决定治疗，应根据以下参数：ALT水平，HBeAg阳性的HBV DNA水平，肝组织学检查，肝硬化家族史的，和/或肝癌，共存的肝脏疾病，患者的治疗史。血清ALT水平是最有用的标记的肝损害和应该被使用，以确定可考虑为可能的抗病毒治疗的患者。发布的证据表明，ALT正常或轻度升高的患者不良反应，现有的治疗方法[90]，[91]。的治疗ALT正常儿童的福利还没有被建立，并考虑未来时，这些患者中[92]，开发抗病毒药物耐药的风险，可以把它有害。因此，不应该被视为孩子的免疫耐受阶段临床试验外，并应监测和治疗时增加ALT水平揭示免疫激活。三个最大的抗病毒药物的临床试验在儿童使用ALT水平高于1.5倍的实验室ULN或超过60IU / L，以较低者为准，作为纳入标准[90]，[91]，[93]。 [94]不幸的是，ALT水平的正常上限（ULN）尚未建立儿童。

血清ALT水平升高至少6个月（12个月，如果HBeAg阴性），以避免治疗谁正在发生自发性HBeAg血清转换的患者。持续ALT升高血清HBV DNA水平的任务评估。高HBV DNA值认股权证治疗，而低HBV DNA水平应排除其他原因引起的肝脏疾病导致。为HBV DNA的cut-off值没有被定义，任意的值用在临床试验和指引。随着孩子有较高的HBV的复制率，值20000 IU / ml的由不同的作者已被选定，[85]，[95]。然而，较低的值已伴有渐进性肝病，在成人和最新的管理准则确定2.000IU/ml的是一个很好的切断[83]。

在成年患者中超过年龄40年的，治疗可以开始完全依赖高病毒载量的检测，因为它是一个独立的危险因素，肝硬化和肝癌[72]，[73]。无数据存在于儿童支持这样的做法。因此，作为响应，目前可用的治疗儿童是局部的和有限的特定亚群，病理评估的炎症的档次和纤维化分期治疗孩子之前，仍建议。当至少有适度的坏死性炎症或中等程度的纤维化肝组织学检查发现，同时干扰素（IFN）-α和核苷（酸）类似物的反应更容易[90]，[96]。虽然尚未建立儿童轻度炎症或纤维化治疗的好处，有家族史的肝癌可以保证即使在治疗儿童轻度病理变化，因为他们是在发展为HCC的风险增加[77]。