Tenofovir in Early Pregnancy to Prevent Mother-to-child Transmission of Hepatitis B Virus

Study Overview
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Brief Summary
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Mother-to-child transmission (MTCT) of hepatitis B virus (HBV) remains the major mode of transmission in most high and intermediate HBV endemic areas, despite existing WHO immunoprophylaxis recommendations. This immunoprophylaxis regimen, if given optimally, can prevent 75-80% of HBV MTCT, but optimal implementation is difficult because it requires administering monovalent HBV vaccine and hepatitis B immunoglobulin (HBIg) within 24 hours of birth. Due to the barriers of giving HBIg, the World Health Organization (WHO) states, …owing to concerns related to supply, safety and cost, the use of HBIg is not feasible in most settings. Clearly, global control of HBV transmission will require improved MTCT prevention. Therefore, the investigators hypothesize that treating HBV early in pregnancy will lead to undetectable HBV DNA levels at delivery and prevention of MTCT of HBV without HBIg; a concept that has already been proven with HIV. Tenofovir disoproxil fumarate (TDF), an approved anti-HBV drug, is promising to prevent MTCT of HBV due to its high potency against hepatitis B and its safety record in pregnant women. A randomized, controlled clinical trial (RCT) will be necessary to determine if TDF given to HBV-infected pregnant women early in pregnancy plus vaccine to the newborn can decrease MTCT of HBV without HBIg. However, before embarking on a RCT, several critical knowledge gaps need to be addressed including the ideal timing for TDF initiation. The purpose of this proposal is to address these knowledge gaps.

Detailed Description
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The investigators hypothesize that anti-HBV therapy given in the late first or early second trimester achieves undetectable HBV DNA at delivery in >=95% of pregnant women with chronic hepatitis B. The one-arm, open-label, interventional study aims: 1, To estimate the time to complete HBV DNA suppression (<100 IU/ml) in 170 HBV DNA positive women who start TDF in the late first or early second trimester; and to estimate the proportion of women with HBV DNA <100 IU/ml at delivery. 2, To address potential barriers to and the efficacy of implementing TDF in early pregnancy to prevent mother-to-child transmission of hepatitis B. The investigators will measure potential barriers to acceptability and effectiveness of this intervention: adherence, potential hepatitis B flares in mothers (safety), and the proportion of hepatitis B infections in the offspring at 1 year of age (efficacy).

Official Title
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Prevention of Mother-to-child Transmission of Hepatitis B Virus: a One Arm, Open Label Intervention Study to Estimate the Optimal Timing of Tenofovir (TDF) in Pregnancy

Conditions
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Hepatitis B

Intervention / Treatment
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* Drug: Tenofovir Disoproxil Fumarate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pregnant women aged 18 and over HBsAg positive In the 12th-20th week of pregnancy Willing to take TDF daily during pregnancy Providing written informed consent Plans to deliver at Shoklo Malaria Research Unit (SMRU) Able and willing to comply with study requirements Exclusion Criteria: Anti-HIV positive Negative qualitative HBV DNA if HBeAg negative On immunosuppressive therapy Elevated creatinine History of kidney disease Short cervix History of pregnancy complications or prior pre-term labor

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 49 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Interventional Model Description: Single group study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tenofovir Disoproxil Fumarate<br>Women early in pregnancy (end of first or beginning second trimester) will be treated with TDF to determine the efficacy of this strategy to bring >=95% of women to undetectable HBV DNA levels at delivery. | Drug: Tenofovir Disoproxil Fumarate<br>* 300 mg daily<br>* Other names: Viread;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The time (from inclusion through delivery; up to 6 months) to HBV DNA suppression (<100 IU/ml) | HBV DNA will be monitored every month | Up to 9 months | 
| The proportion of women with undetectable HBV DNA at delivery | HBV DNA will be monitored at delivery. | At delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of hepatitis B flares in mothers postpartum | All women will continue on study for 3 months after stopping TDF to measure their alanine aminotransferase (ALT) and aspartate aminotransferase (AST) monthly to detect a flare, which will be defined as >5x baseline or >10x the upper limit of normal. If at the end of the 3 months, there has been no change in ALT and AST, then the mothers will be discharged from the study. If there is an increase in liver enzymes but not a true flare, they will be followed for an additional 3 months with monthly ALT testing. | Monthly measured for 3 months after stopping TDF. | 
| The proportion of women who adhered to TDF treatment during the course of the study (from inclusion through 1 month after delivery; up to 7 months; drug levels) | Measurement of tenofovir drug levels | Up to 9 months | 
| The proportion of women who adhered to TDF treatment during the course of the study (from inclusion through 1 month after delivery; up to 7 months; drug accountability) | Drug accountability using standard methods (subtracting the number of tablets left from the number of tablets distributed). | Up to 9 months | 
| The proportion of women who adhered to TDF treatment during the course of the study (from inclusion through 1 month after delivery; up to 7 months; questionnaire) | All women will be surveyed at monthly visits and at birth to measure adherence including actionable barriers. | Up to 9 months | 
| The proportion of hepatitis B infections in the offspring at 1 year of age | Testing for HBsAg in children between 2 and 12 months of age. | Between month 2 and 12 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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mother to child transmission, hepatitis B, tenofovir