替诺福韦与安慰剂预防乙型肝炎围产期传播的比较
Tenofovir versus Placebo to Prevent Perinatal Transmission of Hepatitis B.
作者信息
Jourdain Gonzague, Ngo-Giang-Huong Nicole, Harrison Linda, Decker Luc, Khamduang Woottichai, Tierney Camlin, Salvadori Nicolas, Cressey Tim R, Sirirungsi Wasna, Achalapong Jullapong, Yuthavisuthi Prapap, Kanjanavikai Prateep, Na Ayudhaya Orada P, Siriwachirachai Thitiporn, Prommas Sinart, Sabsanong Prapan, Limtrakul Aram, Varadisai Supang, Putiyanun Chaiwat, Suriyachai Pornnapa, Liampongsabuddhi Prateung, Sangsawang Suraphan, Matanasarawut Wanmanee, Buranabanjasatean Sudanee, Puernngooluerm Pichit, Bowonwatanuwong Chureeratana, Puthanakit Thanyawee, Klinbuayaem Virat, Thongsawat Satawat, Thanprasertsuk Sombat, Siberry George K, Watts Diane H, Chakhtoura Nahida, Murphy Trudy V, Nelson Noele P, Chung Raymond T, Pol Stanislas, Chotivanich Nantasak
机构信息
From the Institut de Recherche pour le Développement Unité Mixte Internationale 174-Program for Health, Prevention, and Treatment (PHPT) (G.J., N.N.-G.-H., L.D., N.S., T.R.C.), the Faculty of Associated Medical Sciences, Chiang Mai University (G.J., N.N.-G.-H., L.D., W.K., N.S., T.R.C., W.S.), Nakornping Hospital (A.L.), Health Promotion Center Region 1 (S.S.), the Medical Department, Sanpatong Hospital (V.K.), and the Department of Internal Medicine, Faculty of Medicine, Chiang Mai University (S. Thongsawat), Chiang Mai, the Obstetrics and Gynecology Department, Chiangrai Prachanukroh Hospital (J.A.), and Mae Chan Hospital (S.B.), Chiang Rai, Prapokklao Hospital, Chantaburi (P.Y.), Banglamung Hospital (P.K.) and Chonburi Hospital (C.B., N. Chotivanich), Chonburi, Nopparat Rajathanee Hospital (O.P.N.A.), Bhumibol Adulyadej Hospital (S. Prommas), and the Faculty of Medicine, Chulalongkorn University (T.P.), Bangkok, Khon Kaen Hospital, Khon Kaen (T.S.), Samutprakarn Hospital, Samutprakarn (P. Sabsanong), Samutsakhon Hospital, Samutsakorn (S.V.), Chiang Kham Hospital (C.P.) and Phayao Hospital (P. Suriyachai), Phayao, Lampang Hospital, Lampang (P.L.), Lamphun Hospital, Lamphun (W.M.), Maharaj Nakornratchasrima Hospital, Nakornratchasrima (P.P.), and the Department of Disease Control, Ministry of Public Health, Nonthaburi (S. Thanprasertsuk) - all in Thailand; the Department of Immunology and Infectious Diseases (G.J., N.N.-G.-H., T.R.C.) and the Center for Biostatistics in AIDS Research (L.H., C.T.), Harvard T.H. Chan School of Public Health, and the Gastrointestinal Unit, Massachusetts General Hospital (R.T.C.) - both in Boston; the Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom (T.R.C.); the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (G.K.S., N. Chakhtoura); the Office of the Global AIDS Coordinator, Department of State, Washington, DC (D.H.W.); the Centers for Disease Control and Prevention, Atlanta (T.V.M., N.P.N.); and Université Paris Descartes, INSERM Unité 1223, Institut Pasteur, the Department of Hepato-Gastroenterology, Cochin University Hospital, Paris (S. Pol).
出版信息
N Engl J Med. 2018 Mar 8;378(10):911-923. doi: 10.1056/NEJMoa1708131.
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 log 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 .).
背景
尽管婴儿接受了乙型肝炎免疫球蛋白，但乙肝病毒（HBV）病毒载量升高的孕妇仍有将感染传播给其婴儿的风险。
方法
在泰国进行的这项多中心、双盲临床试验中，我们将丙氨酸转氨酶水平每升60国际单位或更低的乙肝e抗原（HBeAg）阳性孕妇，从妊娠28周随机分配至产后2个月接受替诺福韦酯（TDF）或安慰剂治疗。婴儿在出生时接受乙型肝炎免疫球蛋白，并在出生时、1、2、4和6个月时接种乙肝疫苗。主要终点是婴儿乙肝表面抗原（HBsAg）阳性状态，通过6月龄时的HBV DNA水平确认。我们计算得出，328名女性的样本量将使该试验有90%的把握检测到传播率至少相差9个百分点（预期率，TDF组为3%，安慰剂组为12%）。
结果
从2013年1月至2015年8月，我们纳入了331名女性；168名女性被随机分配至TDF组，163名被分配至安慰剂组。入组时，中位孕周为28.3周，中位HBV DNA水平为每毫升8.0 log IU。在322例分娩（97%的参与者）中，有319例单胎分娩、2对双胞胎和1例死产婴儿。从出生到给予乙型肝炎免疫球蛋白的中位时间为1.3小时，从出生到给予乙肝疫苗的中位时间为1.2小时。在初步分析中，TDF组的147名婴儿中无一例感染（0%；95%置信区间[CI]，0至2），而安慰剂组的147名婴儿中有3例感染（2%；95%CI，0至6）（P = 0.12）。两组不良事件发生率无显著差异。试验方案停药后，TDF组母亲丙氨酸转氨酶水平超过每升300国际单位的发生率为6%，安慰剂组为3%（P = 0.29）。
结论
在HBeAg阳性母亲所生婴儿中，通过给予乙型肝炎免疫球蛋白和乙肝疫苗，母婴HBV传播率较低的情况下，母亲额外使用TDF并未导致传播率显著降低。（由尤妮斯·肯尼迪·施赖弗国家儿童健康与人类发展研究所资助；ClinicalTrials.gov编号，NCT01745822。）
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