The Safety of Anti-viral Therapy in Preventing HBV MTCT in Pregnant Women After Discontinuation

The Safety of Anti-viral Therapy in Preventing Mother-to-child Transmission of Hepatitis B Virus in Pregnant Women After Discontinuation

Mother-to-child transmission (MTCT) is the most common mode of perpetuating chronic hepatitis B virus (HBV) infection in endemic countries. Many studies have demonstrated antepartum anti-viral therapy (AVT) is a advisable option to reduce mother-to-child transmission and the risk of vaccination breakthrough in infants who received passive-active immunoprophylaxis. However, several controversies over antiviral treatment have not been resolved, that is, optimal duration, effect of postpartum therapy, and risk of postpartum alanine aminotransferase (ALT) flare after withdrawal. Will the risk of postpartum hepatitis flares increase after short-term AVT in late pregnancy for maternal HBV infection is discontinued? Is there any correlation between postpartum hepatitis flares and withdrawal time? Will the proportion of postpartum flares be reduced if extending the duration of AVT after delivery? There is an urgent need in this area. This study mainly investigated the safety of antiviral therapy in preventing HBV mother-to-child transmission in pregnant women after discontinuation.

Study Overview

• Status: Completed
• Conditions: Hepatitis B, Chronic
• Intervention / Treatment: Drug: Telbivudine 600mg; Drug: Tenofovir disoproxil fumarate 300mg

Detailed Description

Between June 2015 and December 2017, 111 mothers were enrolled during their visit to the Department of Gynecology and Obstetrics or the Department of Infectious Diseases of the Third Affiliated Hospital of Sun Yat-Sen University in Guangzhou, Guangdong province, China. Pregnant women fulfilling the inclusion and exclusion criteria were offered participation in the study. All pregnant women who opted for AVT need to sign a consent form and started on oral telbivudine (LDT) 600 mg or tenofovir disoproxil fumarate (TDF) 300 mg (as per patients' wishes) daily between gestational weeks 24 and 28. Serum levels of HBV DNA, HBsAg, HBsAb, HBeAg, HBeAb, liver function tests, haematology and renal biochemistry were measured at baseline(i.e. at screening), every 4 weeks after treatment begins, at the time of delivery, and at 1, 2, 3, 6, 12 month postpartum. After delivery, treatment with LDT or TDF was immediately withdrew to the patients with an intention of breastfeeding, while the other patients, without desire of breastfeeding, would subsequently extend antiviral treatment duration to postpartum 6 weeks. All infants were vaccinated with genetically engineered HBV vaccine 20 ug according to a standard vaccination regimen (i.e. within 12h of birth, at week 4 and at week 24) and 200 IU doses of hepatitis B immunoglobulin immediately (within 2h) after birth and at day 15. The infant's HBV serologic status and HBV DNA were tested at birth (before immunization) and again at 7 months. The investigators discussed the postpartum liver function after withdrawal and evaluated the impact of extending the postpartum duration of AVT administered for the prevention of perinatal transmission.

• Study Type: Interventional
• Enrollment (Actual): 111
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Gestational age between 24 and 28 weeks
• Detectable serum HBsAg at the Screening visit and at least 6 months prior
• Serum HBV DNA level >1,000,000 IU/mL at Screening visit
• Alanine aminotransferase (ALT) below the upper limit of normal (ULN; 40 IU/mL)

Exclusion Criteria:

• Patient is co-infected with hepatitis A virus, hepatitis C virus, hepatitis delta virus, hepatitis E virus or HIV.
• Patient has a history of antiviral treatment or concurrent treatment with immunomodulators, cytotoxic drugs, or steroids.
• Patient has clinical signs of threatened miscarriage in early pregnancy.
• Patient has evidence of hepatocellular carcinoma or cirrhosis.
• Patient has evidence of fetal deformity by 3-dimensional ultrasound examination.
• Patient has a husband infected with HBV.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Early cessation; Pregnant mothers who opted for antiviral therapy would start on oral LDT 600 mg or TDF 300 mg (as per patients' wishes) daily between gestational weeks 24 and 28. Antiviral therapy was discontinued in intrapartum.	Drug: Telbivudine 600mg; Pregnant mothers who opted for antiviral therapy would start on oral LDT 600 mg daily between gestational weeks 24 and 28.; Other Names: Sebivo; Drug: Tenofovir disoproxil fumarate 300mg; Pregnant mothers who opted for antiviral therapy would start on oral TDF 300 mg daily between gestational weeks 24 and 28.; Other Names: Viread
Experimental: Late cessation; Pregnant mothers who opted for antiviral therapy would start on oral LDT 600 mg or TDF 300 mg (as per patients' wishes) daily between gestational weeks 24 and 28. After delivery, mothers ceased antiviral treatment at postpartum 6 weeks.	Drug: Telbivudine 600mg; Pregnant mothers who opted for antiviral therapy would start on oral LDT 600 mg daily between gestational weeks 24 and 28.; Other Names: Sebivo; Drug: Tenofovir disoproxil fumarate 300mg; Pregnant mothers who opted for antiviral therapy would start on oral TDF 300 mg daily between gestational weeks 24 and 28.; Other Names: Viread
No Intervention: Control; Eligible patients who refused antiviral therapy but consented to the study were assigned to the control arm.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postpartum flare incidence	Time-to-event measures. Postpartum flare was defined as an alanine aminotransferase (ALT) rise to three times baseline level or five times ULN (40U/L) within 12 months post-delivery. Maternal would be recorded if postpartum flare occured. At the end of postpartum 12-month follow-up period, postpartum flare incidence was measured.	From baseline to postpartum 12 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time of flare onset	Time-to-event measures. Time of the onset of postpartum liver damage.	Baseline (i.e. at screening); at the time of delivery; at 1,2,3,6,12 month postpartum.
Proportion of severe flares	As per protocol, ALT flares (>5 times baseline level or >10 times ULN) were considered severe adverse events (SAEs).	Baseline (i.e. at screening); at the time of delivery; at 1,2,3,6,12 month postpartum.
Peak ALT during flare	Peak ALT during postpartum flare.	Baseline (i.e. at screening); at the time of delivery; at 1,2,3,6,12 month postpartum.
The rate of perinatal transmission	Perinatal transmission was established by detectable HBV DNA and HBsAg levels in the peripheral blood of infants at 7 months.	7 months after birth.
HBV kinetics in patients	Changes of HBV viral load in patients treated and not treated with antiviral agents.	Baseline (i.e. at screening); at 4-week intervals after treatment was begun up to delivery; at the time of delivery; at 1,2,3,6,12 month postpartum.
The liver function normalization rate	Normal liver function was defined as the value of ALT level lower 40U/L.	Baseline (i.e. at screening); at 4-week intervals after treatment was begun up to delivery; at the time of delivery; at 1,2,3,6,12 month postpartum.
Maternal HBsAg loss/seroconversion rate	Measurement of the proportion of maternal hepatitis B surface antigen loss and seroconversion.	Baseline (i.e. at screening); at 4-week intervals after treatment was begun up to delivery; at the time of delivery; at 1,2,3,6,12 month postpartum.
Incidence of perinatal and partum complications	Perinatal and partum complications included hypertensive disorders in pregnancy, gestational diabetes mellitus, fetal growth retardation, premature delivery, premature rupture of membrane, and postpartum hemorrhage.	Baseline (i.e. at screening); at 4-week intervals after treatment was begun up to delivery; at the time of delivery; at 1,2,3,6,12 month postpartum.
Birth height	Measurement of infants' height at the time of delivery.	At the time of delivery.
Birth weight	Measurement of infants' weight at the time of delivery.	At the time of delivery.
Neonate apgar score at 1 minute	Apgar scores of neonates included activity, pulse, grimace, appearance and respiration.	At 1 minute after birth.
Neonate apgar score at 5 minutes	Apgar scores of neonates included activity, pulse, grimace, appearance and respiration.	At 5 minutes after birth.
Incidence of deformity	The incidence of baby deformity was recorded during the postpartum follow-up period.	At the time of delivery; at 1, 7, 12 month postpartum.
Breastfeeding rate	Breast feeding status was assessed in all infants during the postpartum follow-up period.	At birth, at 1 and 7 month follow-up.

Collaborators and Investigators

• Sponsor: Third Affiliated Hospital, Sun Yat-Sen University
• Investigators: Study Chair: Zhi-liang Gao, PhD, Third Affiliated Hospital, Sun Yat-Sen University

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2015
• Primary Completion (Actual): December 31, 2017
• Study Completion (Actual): December 31, 2017

Study Registration Dates

• First Submitted: January 21, 2018
• First Submitted That Met QC Criteria: March 12, 2018
• First Posted (Actual): March 19, 2018

Study Record Updates

• Last Update Posted (Actual): August 29, 2018
• Last Update Submitted That Met QC Criteria: August 27, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: exacerbation; pregnancy; hepatitis B virus; flare; antiviral agents
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Enterovirus Infections; Picornaviridae Infections; Hepatitis, Chronic; Hepatitis B; Hepatitis; Hepatitis A; Hepatitis B, Chronic; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Tenofovir; Telbivudine
• Other Study ID Numbers: Safety of anti-viral agents

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data (IPD) is not available to other researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No