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.)
作者: StephenW 时间: 2018-3-8 13:52
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.
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 作者: StephenW 时间: 2018-3-8 14:00
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。