Maternal Antiviral Prophylaxis to Prevent Perinatal Transmission of Hepatitis B Virus in Thailand

Condition(s) targeted: Hepatitis B Chronic Infection; Pregnancy

Intervention: tenofovir disoproxil fumarate (Drug); placebo (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Institut de Recherche pour le Developpement

Official(s) and/or principal investigator(s):
Gonzague Jourdain, MD, PhD, Principal Investigator, Affiliation: Institut de Recherche pour le Developpement

Overall contact:
Gonzague Jourdain, MD, PhD, Phone: +66818830065, Email: Gonzague.Jourdain@ird.fr

Chronic hepatitis B (CHB) infection is complicated by cirrhosis and liver cancer. In Thailand, 7% of adults are chronically infected by Hepatitis B virus (HBV). The risk of perinatal transmission of HBV is about 12% when a mother has a high HBV load in her plasma, even if her infant receive specific immunoglobulin and vaccine. The hypothesis of this study is that a potent antiviral, tenofovir, can decrease HBV load in HBV infected pregnant women and therefore reduce the risk of perinatal transmission/ Pregnant women participating in this study will receive tenofovir or placebo during the last trimester of pregnancy and two months postpartum. The risk of perinatal transmission will be compared between the two groups. The results of the study will help define policy to manage HBV infected pregnant women to prevent perinatal transmission.

Official title: Phase 3, Randomized Clinical Trial to Assess the Efficacy and Safety of Tenofovir in Hepatitis B Virus Infected, s and e Antigen Positive, Pregnant Women to Prevent Perinatal Transmission Despite Infant Passive-active HBV Immunization.

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Primary outcome: Infant's Hepatitis B infection status at 6 months of age

Secondary outcome:

Adverse events

Flares after study treatment interruption

Infant's HBV infection status

Infant growth related outcomes, including weight, height and HC Z-scores

Detailed description: This is a phase III, placebo controlled, double blind, randomized clinical trial to assess the efficacy and safety of tenofovir disoproxil fumarate (TDF) given from 28 weeks' gestation until 2 months postpartum to pregnant women with Hepatitis B (HB) virus (HBV) chronic infection and positive for HB s and e antigen to prevent perinatal transmission of HBV to their infants. All infants will receive HBV passive (HB specific immunoglobulin) and active (vaccine) immunization. Chronic hepatitis B (CHB) infection is complicated by cirrhosis and hepatocellular carcinoma (HCC), the 10th leading cause of death worldwide. In 2011, about 7% of adults in Thailand were HBsAg carriers. Infant hepatitis B (HB) immunization and HB immune globulin (HBIg) administered at birth effectively prevent most mother-to-child transmission (MTCT) of HBV. However, about 12% of mothers with high load of HBV transmit the virus to their infants, despite active and passive immunization. Studies have suggested that antiviral treatment at the end of pregnancy and during early postpartum can reduce the risk of transmission to the child. A potential limitation to this approach is the risk of hepatic disease exacerbation following discontinuation of antiviral treatment postpartum, and this risk has not been properly evaluated. No randomized clinical trials have adequately demonstrated the efficacy and safety of maternal antiviral treatment the prevention of mother to child transmission of HBV. This is the reason why this approach is not currently recommended by the Associations for the Study of Liver Diseases. We hypothesize that a potent antiviral, tenofovir, can decrease HBV viral load in HBV infected pregnant women and therefore reduce the risk of perinatal transmission, before infants are definitely protected by passive-active immunization. We also hypothesize that only moderate exacerbations of liver disease will be observed after discontinuation of a short antiviral course (5 months). While the primary objective of the study is to assess the efficacy of tenofovir versus placebo for the prevention of perinatal transmission, an important secondary objective is the assessment of the risk of postpartum hepatic disease exacerbation. Within 2 years, 328 women and their infants will be enrolled from public hospitals in Thailand and randomized to receive either tenofovir disoproxil fumarate or matching placebo from 28 weeks of pregnancy until 2 months postpartum. Mothers and infants will be followed until one year postpartum. The primary endpoint will be the detection of HBsAg and HBV DNA in infants at six months of life. An interim analysis will be conducted when half of the outcomes are available.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Female.

Criteria:

Inclusion Criteria:

- Pregnancy

- At least 18 years of age

- Negative Human Immunodeficiency Virus (HIV) serology

- Positive HBsAg and hepatitis B e antigen (HBeAg) tests

- Gestational age of 28 weeks (+ or - 10 days) as determined by obstetrician

- Alanine Aminotransferase (ALT)≤30 U/L, confirmed ≤60 U/L on a subsequent blood draw

- Agreeing to bring their infants at the planned study visits at one study site until

one year after delivery and to inform the site investigators if they plan to move to another place and not be able to return to the clinic.

- Understanding the need for adequate infant immunization and agreeing to the blood

draws from their infants and the need for close follow up to manage possible exacerbation of hepatitis. Exclusion Criteria:

- History of tenofovir treatment at any time, or any other anti-HBV treatment during

the current pregnancy

- Creatinine clearance <50 ml/min, calculated using the Cockcroft-Gault formula

- Dipstick proteinuria>1+ (>30 mg/dL) or normoglycemic glucosuria confirmed on two

separate occasions

- Positive serology for Hepatitis C infection less than 12 months prior to enrollment

- Evidence of pre-existing fetal anomalies incompatible with life

- Any concomitant condition or treatment that, in the view of the clinical site

investigator, would contraindicate participation or satisfactory follow up in the study.

- Concurrent participation in any other clinical trial without written agreement of the

two study teams

Gonzague Jourdain, MD, PhD, Phone: +66818830065, Email: Gonzague.Jourdain@ird.fr

Bhumibol Adulyadej Hospital, Bangkok 10220, Thailand; Recruiting
Sinart Prommas, MD, Phone: +6625347317, Email: n_prommas@hotmail.com
Prapaisri Layangool, MD, Phone: +6625347306, Email: p_layangool@yahoo.com
Sinart Prommas, MD, Principal Investigator
Prapaisri Layangool, MD, Sub-Investigator

Nopparat Rajathanee Hospital, Bangkok 10230, Thailand; Recruiting
Orada Patamasingh Na Ayudhaya, MD, Phone: +6625174270-9, Email: oradaaom@hotmail.com
Anita Luvira, MD, Phone: +6625174270-9, Email: aluvira@yahoo.com
Orada Patamasingh Na Ayudhaya, MD, Principal Investigator
Anita Luvira, MD, Sub-Investigator

Prapokklao Hospital, Chantaburi 22000, Thailand; Recruiting
Prapap Yuthavisuthi, MD, Phone: +6639324975, Ext: 5253, Email: yuthavisuthi@gmail.com
Chaiwat Ngampiyasakul, MD, Phone: +6639324975, Ext: 5253, Email: chaiwat008@gmail.com
Prapap Yuthavisuthi, MD, Principal Investigator
Chaiwat Ngampiyasakul, MD, Sub-Investigator

Health Promotion Center Region 10, Chiang Mai 50100, Thailand; Recruiting
Suraphan Sangsawang, Phone: +6653272740, Email: suraphan@anamai.moph.go.th
Kanokwan Jittayanun, Phone: +6653272740, Email: kkulsawad@yahoo.co.th
Suraphan Sangsawang, MD, Principal Investigator
Kanokwan Jittayanun, MD, Sub-Investigator

Nakornping Hospital, Chiang Mai 50180, Thailand; Recruiting
Aram Limtrakul, MD, Phone: +6653999200, Email: aramlim@hotmail.com
Arunrat Suwannarat, MD, Phone: +6653999200, Email: arunrat11@yahoo.com
Aram Limtrakul, MD, Principal Investigator
Arunrat Suwannarat, MD, Sub-Investigator

Chiangrai Prachanukroh Hospital, Chiang Rai 57000, Thailand; Recruiting
Jullapong Achalapong, MD, Phone: +6653711300, Ext: 1217, Email: drjullapong@gmail.com
Chulapong Chanta, MD, Phone: +6653711300, Ext: 1274, Email: Chul_chan@yahoo.com
Jullapong Achalapong, MD, Principal Investigator
Chulapong Chanta, MD, Sub-Investigator

Chonburi Regional Hospital, Chonburi 20000, Thailand; Recruiting
Nantasak Chotivanich, MD, Phone: +6638931390, Email: nantasak.cho@gmail.com
Chureeratana Bowonwatanuwong, MD, Phone: +6638274200, Email: c.bowon@gmail.com
Nantasak Chotivanich, MD, Principal Investigator
Suchat Hongsiriwon, MD, Sub-Investigator
Chureeratana Bowonwatanuwong, MD, Sub-Investigator

Khon Kaen Hospital, Khon Kaen 40000, Thailand; Recruiting
Thitiporn Siriwachirachai, MD, Phone: +6643336789, Email: siriwachirachai@hotmail.com
Ussanee Srirompotong, MD, Phone: +6643336789
Thitiporn Siriwachirachai, MD, Principal Investigator
Ussanee Srirompotong, MD, Sub-Investigator

Lampang Hospital, Lampang 52000, Thailand; Recruiting
Prateung Liampongsabuddhi, MD, Phone: +6654223623-7, Email: prateung@yahoo.com
Kultida Pongdetudom, MD, Phone: +6654223623-7, Email: pongdetudom@yahoo.com
Prateung Liampongsabuddhi, MD, Principal Investigator
Kultida Pongdetudom, MD, Sub-Investigator

Lamphun Hospital, Lamphun 51000, Thailand; Recruiting
Wanmanee Matanasarawut, MD, Phone: +6653569100, Ext: 2150, Email: obgyn.lph@gmail.com
Rosalin Somsamai, MD, Phone: +6653569100, Email: sukannika_waan@hotmail.com
Wanmanee Matanasarawut, MD, Principal Investigator
Rosalin Somsamai, MD, Sub-Investigator

Phayao Provincial Hospital, Phayao 56000, Thailand; Recruiting
Pornnapa Suriyachai, MD, Phone: +6654431209, Email: whan76_1@hotmail.com
Pornchai Techakunakorn, MD, Phone: +6654431169, Email: pcaipyhos@gmail.com
Pornnapa Suriyachai, MD, Principal Investigator
Pornchai Techakunakorn, MD, Sub-Investigator
Guttiga Halue, MD, Sub-Investigator

Samutprakarn Hospital, Samutprakarn 10280, Thailand; Recruiting
Prapan Sabsanong, MD, Phone: +6627018132-9, Email: prapandr@hotmail.com
Parichart Wongngam, MD, Phone: +6627018132-9
Prapan Sabsanong, MD, Principal Investigator
Parichart Wongngam, MD, Sub-Investigator

Samutsakhon Hospital, Samutsakorn 74000, Thailand; Recruiting
Supang Varadisai, MD, Phone: +6634427099-104, Email: supang_vara@hotmail.com
Sawitree Krikajornkitti, MD, Phone: +6634427099-104, Email: yuiwitree@gmail.com
Supang Varadisai, MD, Principal Investigator
Sawitree Krikajornkitti, MD, Sub-Investigator

Mae Chan Hospital, Mae Chan, Chiangrai 57110, Thailand; Recruiting
Sudanee Buranabanjasatean, MD, Phone: +6653771056, Email: sudanee2011@windowslive.com
Sudanee Buranabanjasatean, MD, Principal Investigator

Banglamung Hospital, Banglamung, Chonburi 20150, Thailand; Recruiting
Prateep Kanjanavikai, MD, Phone: +6638411551-2, Email: prateep48@hotmail.com
Siriluk Phanomcheong, MD, Phone: +6638411551-2, Email: siriluk_lukk@yahoo.com
Prateep Kanjanavikai, MD, Principal Investigator
Siriluk Phanomcheong, MD, Sub-Investigator

Maharat Nakhon Ratchasima Hospital, Nakhon Ratchasima, Nakhon Ratchasrima 30000, Thailand; Recruiting
Pichit Puernngoluerm, MD, Phone: +6644235000, Email: bank.pichit26@gmail.com
Anucha Saeresjittima, MD, Phone: +6644235000, Email: anuchasae@gmail.com
Pichit Puernngoluerm, MD, Principal Investigator
Anucha Saeresjittima, MD, Sub-Investigator

Chiang Kham Hospital, Chiang Kham, Phayao 56110, Thailand; Recruiting
Chaiwat Putiyanun, MD, Phone: +6654451300-1, Email: putiyanun@hotmail.com
Chaiwat Putiyanun, MD, Principal Investigator

Related publications:

Xu WM, Cui YT, Wang L, Yang H, Liang ZQ, Li XM, Zhang SL, Qiao FY, Campbell F, Chang CN, Gardner S, Atkins M. Lamivudine in late pregnancy to prevent perinatal transmission of hepatitis B virus infection: a multicentre, randomized, double-blind, placebo-controlled study. J Viral Hepat. 2009 Feb;16(2):94-103. doi: 10.1111/j.1365-2893.2008.01056.x. Epub 2008 Oct 8.

van Zonneveld M, van Nunen AB, Niesters HG, de Man RA, Schalm SW, Janssen HL. Lamivudine treatment during pregnancy to prevent perinatal transmission of hepatitis B virus infection. J Viral Hepat. 2003 Jul;10(4):294-7.

Han GR, Cao MK, Zhao W, Jiang HX, Wang CM, Bai SF, Yue X, Wang GJ, Tang X, Fang ZX. A prospective and open-label study for the efficacy and safety of telbivudine in pregnancy for the prevention of perinatal transmission of hepatitis B virus infection. J Hepatol. 2011 Dec;55(6):1215-21. doi: 10.1016/j.jhep.2011.02.032. Epub 2011 Apr 15.

Colbers AP, Hawkins DA, Gingelmaier A, Kabeya K, Rockstroh JK, Wyen C, Weizsäcker K, Sadiq ST, Ivanovic J, Giaquinto C, Taylor GP, Moltó J, Burger DM; PANNA network. The pharmacokinetics, safety and efficacy of tenofovir and emtricitabine in HIV-1-infected pregnant women. AIDS. 2013 Mar 13;27(5):739-48. doi: 10.1097/QAD.0b013e32835c208b.

Starting date: January 2013
Last updated: June 18, 2015