预防乙型肝炎病毒的母婴传播

StephenW

Prevention of the mother‐to‐child transmission of Hepatitis B virus
Stanislas Pol
Gonzague Jourdain
First published: 22 June 2018
https://doi.org/10.1111/liv.13875
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Mother‐to‐child transmission (MTCT) of Hepatitis B virus (HBV) accounts for the majority of HBV chronic infections,1, 2 a leading cause of cirrhosis and hepatocellular carcinoma worldwide.3 Before the universal recommendation of the sero‐vaccination of the infants born to HBV infected mothers, around 40% of newborns were infected,4 among whom 65%‐90% developed chronic infection.5

Over the last two decades, the estimated number of chronic infections worldwide has dropped from 360 to 257 million, as a result of universal immunization in high endemicity countries and sero‐vaccination of infants born to HBV infected mothers: the neonatal HBV immunization with at least three doses by 6 months of age, as well as the additional administration of hepatitis B immunoglobulin (HBIg), have dramatically reduced the prevalence of infection6, 7 in children.8 Some high endemicity countries, such as Alaska, have already achieved the elimination of MTCT of HBV.9 Despite these efficacious prophylaxis tools, mother‐to‐child transmission still occurs in infants born to women with high HBV load (>200 000 IU/mL)10-15 and, usually, detectable HBeAg.16 It is assumed that these transmissions occur in utero or during delivery.

The residual risk of HBV MTCT led to the international recommendation of pre‐emptive antiviral therapy in HBsAg‐positive pregnant women with HBV DNA levels >200 000 IU/mL despite “Low” Quality/Certainty of Evidence13 in contrast with the 2015 World Health Organization (WHO) Hepatitis Guidelines for management of chronic HBV.3 Antiviral therapy (AVT) by nucleos(t)ide analogues, which inhibit HBV replication, such as lamivudine, tenofovir disoproxil fumarate (TDF) and telbivudine, may be administered to pregnant women with high HBV load to reduce HBV MTCT.10-12

In the present issue of Liver International, Thilakanathan and colleagues report the HBV status outcome of a large series of 558 HBsAg positive women and their 642 babies in Australia.16 They report their assessment of: (i) the risk of HBV MTCT according to maternal viral load and AVT uptake; (ii) the accuracy of quantitative HBsAg (cheaper than HBV DNA quantitation) in predicting high viral load; (iii) the infant vaccine response.

In this observational cohort which has been previously reported,17 HBIg was administered to infants within 12 hours of birth and HB vaccine at 0, 2, 4 and 6 months of age. Antiviral treatment was not randomized but offered to women if they agreed. Among the 117 mothers who opted for AVT with viral load ≥6 log10 IU/mL, only one transmission occurred (0.85%) while there were two transmissions (8.7%) among those 23 who opted out, that is, a trend towards a significant efficacy (Fishers's exact P = .07 if a statistical comparison was allowed).

These observations are consistent with the results of our recent randomized, placebo‐controlled, double‐blind clinical trial in Thailand18 assessing the efficacy and safety of TDF from 28 weeks gestation to 2 months postpartum for the prevention of mother‐to‐child HBV transmission. Our study enrolled 331 pregnant women (168 TDF, 163 placebo) with HBeAg and a mean HBV DNA titre of 8.0 log10 IU/mL. Infants received HBIg at birth and HB vaccine at birth, 1, 2, 4 and 6 months. The primary endpoint was HBsAg positivity at 6 months, confirmed by HBV‐DNA. Of 322 (97%) on‐study deliveries, there were 319 singletons, two twin pairs and one stillborn (TDF); 21 newborns (7%) (8 TDF, 13 placebo) were preterm. In the primary analysis, 0/147 (0%, 95% CI 0.0‐2.5%) infants were infected in TDF, vs 3/147 (2.0%, 95% CI 0.4‐5.8%) in placebo (P = .12), a non‐statistically significant reduction in HBV mother‐to‐child transmission. Nevertheless, AVT may prevent in utero and intrapartum transmission of HBV more efficiently than sero‐vaccination alone11-15: no perinatal transmissions were reported in the TDF or telbivudine‐treated groups of previous studies even though up to 25% of pregnant women had HBV DNA levels >200 000 IU/L at time of delivery in these studies.10, 13

We observed a lower percentage of HBV‐infected infants (2%) in the placebo arm, compared to those reported in previous studies (up to 12%), most of them conducted in China.10-15 This discrepancy could be related to the time from birth to first administration of HB vaccine and HBIg. Unfortunately, the timing of the birth dose has usually not been reported in other studies. Interestingly, studies in humans and chimpanzees showed that the timing of vaccination following exposure may be essential.19, 20 In our study, 96% of infants received vaccination <4 hours after birth: the median time of HBIg and vaccine administration was 1.3 and 1.2 hours after birth respectively. In addition, there may have been differences with previous studies in terms of frequency of amniocentesis, C‐sections or prevalence of circulating escape mutants.

The second message of the Australian study is that quantitative HBsAg may not be useful for the detection of high maternal viral loads (weak correlation between the two measures, R = .536). The detection of HBeAg was more predictive of high viral loads, though 6.6% of women with high risk of transmission were misclassified.21 Access to rapid and cheap virological assays at the point‐of‐care may be essential to identify mothers at high risk of mother‐to‐child transmission and maximize cost‐effectiveness.

The third message is that the infant vaccine response was 98.7% overall (457/463, including the 3 infected infants), which supports the lack of specific recommendations from the World Health Organization for infant testing. Of note, the US CDC recommends that all children born to HBsAg‐positive mothers be tested for HBsAg at 9‐12 months of age.22 The effectiveness of sero‐vaccination or at least of systematic vaccination of infants born to HBV infected mothers in addition to vaccination of all children and adolescents not previously immunized, as implemented in Alaska, Singapore and Taiwan, yielded to: (i) a major reduction in HBs antigen carrier rates between 1989 (when more than 10% of citizens were infected) and 1993 (less than 2% of citizens)9; (ii) a significant reduction in chronic hepatitis cases9; (iii) a reduction in mortality, mostly by reduction in HCC rate both in adults and children,23, 24 documenting the dramatic effectiveness of immunization for the prevention of liver cancer. Lastly, many studies have demonstrated the economic benefit of systemic HBV vaccination.

In conclusion, several studies have demonstrated the benefit of newborn sero‐vaccination in reducing HBV MTCT. From a public health perspective, the first priority should be the strict implementation of the immunization recommendations, including the birth dose, which can be safely administered in the immediate hours after birth. Data available since a vaccine exists suggest that the protection conferred by HB immunization persists for decades and, likely, lifelong. When HBV DNA (or HBe serology) testing are available, a pre‐emptive therapy should be offered to all pregnant women with high viral load for HBV elimination in combination with the earliest newborn sero‐vaccination.
CONFLICT OF INTEREST

Dr S Pol has received consulting and lecturing fees from Bristol‐Myers Squibb, Janssen, Gilead, Roche, MSD and Abbvie and grants from Bristol‐Myers Squibb, Gilead, Roche and MSD; Dr G Jourdain has no conflict to declare.

StephenW

预防乙型肝炎病毒的母婴传播
斯坦尼斯拉波尔
Gonzague Jourdain
首次发布：2018年6月22日
https://doi.org/10.1111/liv.13875
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请参阅第1212页上的文章

乙型肝炎病毒（HBV）的母婴传播（MTCT）占HBV慢性感染的大部分，1,2是世界范围内肝硬化和肝细胞癌的主要原因[3]。在血清接种HBV感染母亲所生的婴儿中，约有40％的新生儿感染，其中4例65％-90％发生慢性感染.5

在过去的二十年中，由于高流行国家的普遍免疫和HBV感染母亲所生婴儿的血清接种疫苗，全球慢性感染人数估计从360万下降到2.57亿：新生儿HBV免疫至少6个月大的三个剂量以及乙肝免疫球蛋白（HBIg）的额外施用已经显着降低了儿童感染的患病率[6,7] [8]。一些高流行国家，如阿拉斯加，已经取消了HBV的MTCT。尽管采用了这些有效的预防措施，但母婴传播仍然存在于HBV高负荷（> 200 000 IU / mL）妇女所生的婴儿中，并且通常可检测到HBeAg。[16]这些传播发生在子宫内或分娩过程中。

尽管“低”的质量/证据确凿13，与2015年世界卫生组织（WHO）相比，HBV MTCT的残留风险导致了国际推荐的HBsAg阳性孕妇中HBV DNA水平> 200 000 IU / mL的预防性抗病毒治疗（WHO）慢性乙型肝炎治疗的肝炎指南.3可通过核苷（酸）类似物抑制HBV复制的抗病毒治疗（AVT），如拉米夫定，富马酸替诺福韦酯（TDF）和替比夫定，高乙肝病毒载量降低HBV MTCT.10-12

在本期“国际肝病”杂志上，Thilakanathan及其同事报道了澳大利亚558名HBsAg阳性女性及其642名婴儿的HBV状况结果[16]。他们报告了以下评估：（i）根据母亲感染HBV MTCT的风险病毒载量和AVT吸收; （ii）定量HBsAg（比HBV DNA定量更便宜）在预测高病毒载量中的准确性; （iii）婴儿疫苗应答。

在此前已报道的观察队列中，17例HBIg在出生后12小时内给予婴儿，在0,2,4和6月龄时给予HB疫苗。如果他们同意，抗病毒治疗不是随机的，而是提供给女性的。在选择病毒载量≥6log10IU / mL的117名母亲中，仅有一次传播发生（0.85％），而在23名选择出来的人中有两次传播（8.7％），即趋势显着疗效（如果允许进行统计比较，Fishers准确的P = 0.07）。

这些观察结果与我们最近在泰国进行的一项随机安慰剂对照双盲临床试验的结果18一致，评估了TDF从妊娠28周至产后2个月预防母婴HBV传播的有效性和安全性。我们的研究纳入了331例孕妇（168例TDF，163例安慰剂），其中HBeAg和平均HBV DNA滴度为8.0 log10 IU / mL。新生儿出生时接受HBIg，出生时接种乙肝疫苗1,2,4和6个月。主要终点是6个月时HBsAg阳性，由HBV-DNA证实。在322次（97％）的在学交付中，有319个单身人士，两对双胞胎和一个死胎（TDF）; 21名新生儿（7％）（8名TDF，13名安慰剂）是早产儿。在初步分析中，TDF感染0/147（0％，95％CI 0.0-2.5％）婴儿，安慰剂组为3/147（2.0％，95％CI 0.4-5.8％）（P = .12） ，HBV母婴传播的非统计学显着降低。尽管如此，AVT可以比单独使用血清接种疫苗更有效地预防宫内和产道内HBV传播11-15：尽管高达25％的孕妇患有HBV DNA，但TDF或替比夫定治疗组在以前的研究中没有报道围产期传播在这些研究中分娩时的水平> 200 000 IU / L [10,13]
我们观察到安慰剂组中HBV感染婴儿比例较低（2％），与先前研究报道的相比（高达12％），大部分在中国进行.10-15这种差异可能与从出生到首次给予乙肝疫苗和HBIg的时间。不幸的是，在其他研究中通常没有报道出生剂量的时间。有趣的是，对人类和黑猩猩的研究表明，暴露后接种疫苗的时机可能是必不可少的.19,20在我们的研究中，96％的婴儿在出生后4小时内接种疫苗：HBIg和疫苗给药的中位时间分别为1.3和1.2分别在出生后数小时。此外，在羊膜穿刺术的频率，C节或循环逃逸突变体的流行方面，与以前的研究可能存在差异。

澳大利亚研究的第二个信息是定量HBsAg可能无法用于检测高母体病毒载量（两种测量之间的相关性较弱，R = 0.536）。 HBeAg的检测对高病毒载量有更高的预测性，但传播风险高的妇女有6.6％被错误分类[21]。在护理点进行快速和廉价的病毒学检测对于识别高风险母亲母婴传播并最大限度地提高成本效益。

第三个信息是婴儿疫苗应答总体为98.7％（457/463，包括3名感染的婴儿），这支持了世界卫生组织缺乏婴儿测试的具体建议。值得注意的是，美国疾病预防控制中心建议所有HBsAg阳性母亲所生的孩子在9-12个月大时进行乙肝表面抗原检测[22]。除此之外，乙型肝炎病毒感染母亲所生婴儿的血清接种或至少有系统的疫苗接种的有效性接种阿拉斯加，新加坡和台湾实施的所有未经过免疫接种的儿童和青少年，其结果是：（i）1989年（当超过10％的公民被感染时）和1993年（不到2％的公民）9; （ii）慢性肝炎病例的显着减少9; （3）降低死亡率，主要是通过降低成人和儿童的HCC率[23,24]，记录免疫对预防肝癌的显着效果。最后，许多研究证明了系统性HBV疫苗的经济效益。

总之，一些研究已经证明新生儿血清接种疫苗在减少HBV MTCT方面的益处。从公共卫生角度来看，首要任务应该是严格执行免疫接种建议，包括出生剂量，可以在出生后的几个小时内安全给药。自从存在疫苗后可得到的数据表明，由乙肝疫苗接种所提供的保护持续数十年，并且可能终生存在。当HBV DNA（或HBe血清学）检测可用时，应该为所有高病毒载量的孕妇提供一种先发制人的治疗方法，以结合最早的新生儿血清接种疫苗。
利益冲突

S Pol博士已收到Bristol-Myers Squibb，Janssen，Gilead，Roche，MSD和Abbvie的咨询和演讲费以及Bristol-Myers Squibb，Gilead，Roche和MSD的拨款; G Jourdain博士没有冲突要声明。