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

Phase 3

Completed

Conditions: Hepatitis B Chronic Infection
Pregnancy

Interventions: Drug: placebo
Drug: tenofovir disoproxil fumarate

Registration Number: NCT01745822

Lead Sponsor: Institut de Recherche pour le Developpement

Brief Summary: 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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 654

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	placebo	matching placebo (of tenofovir disoproxil fumarate)
Tenofovir disoproxil fumarate	tenofovir disoproxil fumarate	tenofovir disoproxil fumarate, 300 mg tablets

Primary Outcome Measures

Name	Time	Method
Percentage of Infants With Hepatitis B Infection at 6 Months of Age	6 months of age	Infection is defined as a HBsAg positive test confirmed by detectable HBV DNA

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Adverse Events	from enrollment (28 weeks' gestation) to 12 months postpartum	Occurrence of maternal and infant adverse events, including maternal and infants Serious Adverse Events (as defined by the International Conference on Harmonization Good Clinical Practice) and NIH Division of AIDS grade 3/4 signs and symptoms, regardless of their relatedness to the study treatment.
Percentage of Infants With Hepatitis B Infection at or After 6 Months Through 12 Months of Age	at or after 6 months through 12 months of age	Infants will be considered HBV infected if at any time point at or after 6 months through 12 months of age, a sample tests positive for HBsAg and HBV DNA
Percentage of Participants With Flares After Study Treatment Interruption	Following planned discontinuation of study treatment up to 12 months postpartum	Flare, or acute exacerbation of hepatitis B, after study treatment interruption is defined as an Alanine Aminotransferase plasma level above 300 IU/mL
Weight, Height and Head Circumference for Age	assessed at 6 months and 12 months of age, 6 months reported	Weight, length/height and head circumference WHO Z scores are measures of relative weight, height and head circumference adjusted for child age and sex. The Z-score indicates the number of standard deviations away from a reference population in the same age range and with the same sex. A Z-score of 0 is equal to the mean. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean.

Trial Locations

Locations (17): Bhumibol Adulyadej Hospital
🇹🇭
Bangkok, Thailand
Prapokklao Hospital
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Chanthaburi, Thailand
Maharat Nakhon Ratchasima Hospital
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Nakhon Ratchasima, Nakhon Ratchasrima, Thailand
Nopparat Rajathanee Hospital
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Bangkok, Thailand
Chiangrai Prachanukroh Hospital
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Chiang Rai, Thailand
Nakornping Hospital
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Chiang Mai, Thailand
Lamphun Hospital
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Lamphun, Thailand
Phayao Provincial Hospital
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Phayao, Thailand
Samutsakhon Hospital
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Samut Sakhon, Thailand
Mae Chan Hospital
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Mae Chan, Chiangrai, Thailand
Chonburi Regional Hospital
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Chon Buri, Thailand
Lampang Hospital
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Lampang, Thailand
Samutprakarn Hospital
🇹🇭
Samut Prakan, Thailand
Health Promotion Center Region 10
🇹🇭
Chiang Mai, Thailand
Banglamung Hospital
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Bang Lamung, Chon Buri, Thailand
Chiang Kham Hospital
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Chiang Kham, Phayao, Thailand
Khon Kaen Hospital
🇹🇭
Khon Kaen, Thailand