替诺福韦与安慰剂预防围产期传播乙型肝炎

StephenW

Tenofovir versus Placebo to Prevent Perinatal Transmission of Hepatitis B

    Gonzague Jourdain, M.D., Ph.D., Nicole Ngo-Giang-Huong, Pharm.D., Ph.D., Linda Harrison, M.Sc., Luc Decker, Ph.D., Woottichai Khamduang, Ph.D., Camlin Tierney, Ph.D., Nicolas Salvadori, M.Sc., Tim R. Cressey, Ph.D., Wasna Sirirungsi, Ph.D., Jullapong Achalapong, M.D., Prapap Yuthavisuthi, M.D., Prateep Kanjanavikai, M.D., Orada P. Na Ayudhaya, M.D., Thitiporn Siriwachirachai, M.D., Sinart Prommas, M.D., Prapan Sabsanong, M.D., Aram Limtrakul, M.D., Supang Varadisai, M.D., Chaiwat Putiyanun, M.D., Pornnapa Suriyachai, M.D., Prateung Liampongsabuddhi, M.D., Suraphan Sangsawang, M.D., Wanmanee Matanasarawut, M.D., Sudanee Buranabanjasatean, M.D., Pichit Puernngooluerm, M.D., Chureeratana Bowonwatanuwong, M.D., Thanyawee Puthanakit, M.D., Virat Klinbuayaem, M.D., Satawat Thongsawat, M.D., Sombat Thanprasertsuk, M.D., George K. Siberry, M.D., Diane H. Watts, M.D., Nahida Chakhtoura, M.D., Ms.G.H., Trudy V. Murphy, M.D., Noele P. Nelson, M.D., Ph.D., M.P.H., Raymond T. Chung, M.D., Stanislas Pol, M.D., Ph.D., and Nantasak Chotivanich, M.D.

Abstract
Background

Pregnant women with an elevated viral load of hepatitis B virus (HBV) have a risk of transmitting infection to their infants, despite the infants’ receiving hepatitis B immune globulin.
Methods

In this multicenter, double-blind clinical trial performed in Thailand, we randomly assigned hepatitis B e antigen (HBeAg)–positive pregnant women with an alanine aminotransferase level of 60 IU or less per liter to receive tenofovir disoproxil fumarate (TDF) or placebo from 28 weeks of gestation to 2 months post partum. Infants received hepatitis B immune globulin at birth and hepatitis B vaccine at birth and at 1, 2, 4, and 6 months. The primary end point was a hepatitis B surface antigen (HBsAg)–positive status in the infant, confirmed by the HBV DNA level at 6 months of age. We calculated that a sample of 328 women would provide the trial with 90% power to detect a difference of at least 9 percentage points in the transmission rate (expected rate, 3% in the TDF group vs. 12% in the placebo group).
Results

From January 2013 to August 2015, we enrolled 331 women; 168 women were randomly assigned to the TDF group and 163 to the placebo group. At enrollment, the median gestational age was 28.3 weeks, and the median HBV DNA level was 8.0 log10 IU per milliliter. Among 322 deliveries (97% of the participants), there were 319 singleton births, two twin pairs, and one stillborn infant. The median time from birth to administration of hepatitis B immune globulin was 1.3 hours, and the median time from birth to administration of hepatitis B vaccine was 1.2 hours. In the primary analysis, none of the 147 infants (0%; 95% confidence interval [CI], 0 to 2) in the TDF group were infected, as compared with 3 of 147 (2%; 95% CI, 0 to 6) in the placebo group (P=0.12). The rate of adverse events did not differ significantly between groups. The incidence of a maternal alanine aminotransferase level of more than 300 IU per liter after discontinuation of the trial regimen was 6% in the TDF group and 3% in the placebo group (P=0.29).
Conclusions

In a setting in which the rate of mother-to-child HBV transmission was low with the administration of hepatitis B immune globulin and hepatitis B vaccine in infants born to HBeAg-positive mothers, the additional maternal use of TDF did not result in a significantly lower rate of transmission. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT01745822.)

StephenW

替诺福韦与安慰剂预防围产期传播乙型肝炎

    Gonzague茹尔丹，医学博士，妮可傲江，梅家，药学博士，博士，琳达·哈里森，硕士，吕克·德克博士，Woottichai Khamduang博士，Camlin尔尼，博士，尼古拉斯萨尔瓦多，硕士，添R.克雷西，博士，Wasna Sirirungsi，博士，Jullapong Achalapong，MD，Prapap Yuthavisuthi，MD，普拉Kanjanavikai，MD， Orada公寓P.娜Ayudhaya的，MD，Thitiporn Siriwachirachai，MD，Sinart Prommas，MD，Prapan Sabsanong，MD，亚兰Limtrakul，MD，Supang Varadisai，MD，Chaiwat Putiyanun，MD，Pornnapa Suriyachai，MD，Prateung Liampongsabuddhi，MD，Suraphan Sangsawang医学博士，医学博士Wanmanee Matanasarawut，医学博士Sudanee Buranabanjasatean，医学博士Pichit Puernngooluerm，医学博士Chureeratana Bowonwatanuwong，医学博士Thanyawee Puthanakit，医学博士Virat Klinbuayaem，医学博士Satawat Thongsawat，医学博士Sombat Thanprasertsuk，医学博士George K. Siberry， Diane H. Watts，医学博士，Nahida Chakhtoura医学博士，GH女士，Trudy V. Murphy博士，Noele P. Nelson博士，MPH博士，Raymond T. Chung博士，斯坦尼斯拉斯Pol，M.D.，Ph.D.和Nantasak Chotivanich，M.D.

抽象
背景

尽管婴儿接受乙肝免疫球蛋白治疗，但乙肝病毒（HBV）病毒载量升高的孕妇有传染给其婴儿的风险。
方法

在泰国进行的这项多中心双盲临床试验中，我们随机分配丙肝丙氨酸转氨酶水平为每公升60 IU或更低的乙肝e抗原（HBeAg）阳性孕妇，以接受替诺福韦二富马酸替诺福韦（TDF）或安慰剂产后28个星期到2个月。婴儿出生时接种乙肝免疫球蛋白，出生时接种乙肝疫苗1,2,4和6个月。主要终点是婴儿乙型肝炎表面抗原（HBsAg）阳性状态，由6个月龄时的HBV DNA水平证实。我们计算，328名妇女的样本将提供90％的权力，以检测传播速率至少9个百分点的差异（预期比率，TDF组为3％，安慰剂组为12％）。
结果

从2013年1月到2015年8月，我们招收了331名女性; 168名妇女被随机分配到TDF组，163名被安排到安慰剂组。入选时，孕龄中位数为28.3周，HBV DNA水平中位数为每毫升8.0 log10 IU。在322次分娩中（97％的参与者），有319名单胎分娩，两对双生子和一名死胎。从乙肝免疫球蛋白出生到接种的中位时间为1.3小时，从乙肝疫苗出生到接种的平均时间为1.2小时。在主要分析中，TDF组中147名婴儿（0％; 95％置信区间[CI]，0至2）中没有一名感染，而147名婴儿中有3名（2％; 95％CI，0至6 ）在安慰剂组（P = 0.12）。不良事件发生率在各组之间没有显着差异。停用试验方案后，母体丙氨酸转氨酶水平超过300 IU /升的发生率在TDF组为6％，安慰剂组为3％（P = 0.29）。
结论

在HBeAg阳性母亲所生婴儿乙型肝炎免疫球蛋白和乙型肝炎疫苗给药时，母婴HBV传播率较低的情况下，额外的母婴使用TDF并没有显着影响较低的传播速度。 （由Eunice Kennedy Shriver国立儿童健康和人类发展研究所资助; ClinicalTrials.gov编号，NCT01745822）。

StephenW

Maternal tenofovir disoproxil fumarate use does not lower HBV transmission

Jourdain G, et al. NEJM. 2018;doi:10.1056/NEJMoa1708131.
March 7, 2018

Pregnant women who received tenofovir disoproxil fumarate and other prevention measures did not experience a significantly lower rate of transmission of hepatitis B compared to pregnant women who received placebo, according to findings recently published in The New England Journal of Medicine.

“Antiviral agents that inhibit HBV replication, such as lamivudine, tenofovir disoproxil fumarate and telbivudine, which have been administered to pregnant women with a high HBV viral load, may reduce the risk of mother-to-child transmission,” Gonzague Jourdain, MD, PhD, the Institut de Recherche pour le Développement Unité Mixte Internationale 174–Program for Health, Prevention, and Treatment, Thailand, and colleagues wrote.

Researchers added that WHO does not recommend this approach due to a lack of high-quality evidence regarding benefits and harms. Conversely, the American Association for the Study of Liver Diseases recommends antiviral therapy in pregnant women who are hepatitis B surface antigen (HBsAg)–positive and have a HBV DNA level of more than 200,000 IU/mL even though the evidence is uncertain and low quality.

Researchers randomly grouped 168 pregnant women in Thailand who were hepatitis B e antigen positive with an alanine aminotransferase level lower than 60 IU per liter to receive tenofovir disoproxil fumarate. Another 163 women who met these same criteria received placebo. Both groups of women received their respective medication from the time they were 28 weeks pregnant until 2 months after they gave birth. Offspring were given the hepatitis B immune globulin and HBV vaccine at birth, and the HBV vaccine again at 1, 2, 4, and 6 months.

Jourdain and colleagues reported that none of the 147 infants (0%; 95% CI, 0–2) in the tenofovir disoproxil fumarate group were infected while three of the 147 infants (2%; 95% CI, 0–6) in the placebo group were (P = .12). Maternal alanine aminotransferase levels greater than 300 IU per liter after stopping the trial regimen occurred in 6% in the tenofovir disoproxil fumarate group and 3% in the placebo group (P = .29). The rate of adverse events did not differ significantly between groups.

“A limitation of recent perinatal HBV infection–prevention studies has been the assumptions that were used to calculate the sample size. We calculated the sample size to provide the trial with more than 90% power to detect a difference of 9 percentage points in the rate of transmission (expected rate, 3% in the TDF group vs. 12% in the placebo group),” researchers wrote. “A superiority trial assessing a difference of 1.9 percentage points (0.1% vs. 2%) with 90% power would require a sample of more than 1600 mother–infant pairs, but feasibility might be limited as the use of antiviral treatment in this context increases.” – by Janel Miller

StephenW

母体替诺福韦二吡呋酯富马酸盐使用不会降低HBV传播

Jourdain G等人。 NEJM。 2018; DOI：10.1056 / NEJMoa1708131。
2018年3月7日

根据最近在“新英格兰医学杂志”上发表的研究结果，接受替诺福韦酯的富马酸酯和其他预防措施的孕妇与接受安慰剂的孕妇相比，乙型肝炎的传播率没有显着降低。

Gonzague Jourdain医师表示，抗HBV病毒复制的抗病毒药物，如拉米夫定，替诺福韦酯，延胡索酸富马酸酯和替比夫定，这些药物已经用于高HBV病毒载量的孕妇，可能会降低母婴传播的风险。泰国卫生，预防和治疗计划174国际合作研究所博士及其同事写道。

研究人员补充说，由于缺乏有关益处和危害的高质量证据，WHO不建议采用这种方法。相反，美国肝病研究协会建议对乙型肝炎表面抗原（HBsAg）阳性并且HBV DNA水平超过200,000 IU / mL的孕妇进行抗病毒治疗，即使证据不确定且质量低下。

研究人员将泰国的168名孕妇随机分组，乙型肝炎e抗原阳性，丙氨酸转氨酶水平低于60 IU /升，接受替诺福韦酯类富马酸酯治疗。另有163名符合这些相同标准的女性接受安慰剂。两组妇女在怀孕28周至产后2个月内接受了相应的药物治疗。后代在出生时给予乙型肝炎免疫球蛋白和乙型肝炎疫苗，在1,2,4和6个月再次给予乙肝疫苗。

Jourdain及其同事报道，富马酸替诺福韦酯组147名婴儿（0％; 95％CI，0-2）均未感染，147名婴儿中有3名（2％; 95％CI，0-6）安慰剂组为（P = .12）。停用试验方案后母体丙氨酸转氨酶水平高于300IU / L的发生率为富马酸替诺福韦二吡呋酯组为6％，安慰剂组为3％（P = 0.29）。不良事件发生率在各组之间没有显着差异。

“最近围产期HBV感染预防研究的局限性是用于计算样本量的假设。我们计算了样本量，为90％以上的试验提供了传播速度的9个百分点的差异（预期比率，TDF组为3％，安慰剂组为12％），“研究人员中写道。 “一项评估差异1.9个百分点（0.1％对2％）和90％权力的优势试验需要1600多对母婴配对样本，但可行性可能有限，因为在此情况下使用抗病毒治疗增加。“ - 由Janel米勒

antiHBVren

回复 StephenW 的帖子

有点迷惑

这是同一组试验，最后得到两个不同的结论吗？

StephenW

回复 antiHBVren 的帖子

正确，不同的结果，对照组3例感染.但他们认为这并不是什么不同 - 统计上(statistically).

这项研究的结果与所有其他研究结果不同，特别是来自中国的研究结果. 需要谨慎.

antiHBVren

回复 StephenW 的帖子

是的，国内很多论文造假很严重
绝对不止一个韩春雨！去年撤回很多论文；

学术越顶端，越是真本事，这一点中国也在进步，但是也是厚积薄发