Reducing Vertical Transmission of Hepatitis B in Africa

Study Overview
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Brief Summary
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Hepatitis B virus is an infection that can be easily transmitted from women to newborns at the time of delivery. Our objective is to identify novel options that are effective and safe in preventing perinatal transmission of hepatitis B in Africa. The REVERT-B study (Reducing Vertical Transmission of Hepatitis B in Africa) is a clinical trial designed to test a new strategy of using antiviral medication in high-risk pregnant women and newborns to reduce the risk of hepatitis B transmission. The study will measure efficacy, safety, tolerability and adherence to medication.

Detailed Description
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The REVERT-B trial is a multi-center, phase III, randomized 2x2 factorial study designed to test the efficacy of early maternal TDF vs standard duration and neonatal 3TC prophylaxis compared to matching placebo in preventing HBV MTCT. Eligible pregnant women with HBV in prenatal care (n=450) will be randomized 1:1:1:1 to one of four maternal and neonatal prophylaxis combinations (shown as A-D in the figure below). Women will initiate daily oral TDF early (2nd trimester) or at the standard time per WHO guidelines (3rd trimester) and will continue TDF until delivery. The current WHO standard of care in pregnant women with HBV (EAg+) in Cameroon is TDF prophylaxis from 28 weeks until delivery. Newborns will receive liquid 3TC or matching placebo for the first six months of life to provide coverage until the vaccine series is complete. All infants in the study will be offered the 4-dose HBV vaccine series starting at birth. The 2x2 factorial design allows for two simultaneous studies where we first assess efficacy of early maternal prophylaxis (Aim 1) and secondarily assess efficacy of neonatal prophylaxis (Aim 2). The study endpoint for both aims is the MTCT rate (proportion of infants HBsAg+) at 6-9 months of age. Women and infants will be followed until 6-9 months after delivery and subaims will assess safety and adherence to maternal TDF and neonatal 3TC. Plasma testing will be used to measure medication adherence.

Official Title
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A Phase III, Randomized, 2x2 Factorial Trial to Assess the Efficacy of Antiviral Therapy in Women and Infants in Reducing Vertical Transmission of Hepatitis B in Africa

Conditions
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Hepatitis B Infection

Intervention / Treatment
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* Drug: Tenofovir Disoproxil Fumarate
* Drug: Lamivudine Oral Solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: prenatal clinic patient, age ≥16 years, 14-32 weeks gestational age according to clinic dating based on LMP or ultrasound, active hepatitis B with risk of vertical transmission (HBsAg+ AND HBeAg+ or HBV DNA >1000 IU/ML), plan to receive follow up care and deliver at study facility, capable of providing informed consent. Exclusion Criteria: HIV positive (according to HIV antibody testing performed at the initial prenatal visit) known liver cirrhosis or end-stage liver disease, elevated liver enzymes (ALT >5x upper limit of normal), elevated serum creatinine (>1.4 mg/dl) currently taking tenofovir medication allergy or intolerance to tenofovir study medication, known fetal anomaly in the current pregnancy, clinical illness requiring hospitalization at the time of enrollment evidence of early labor at the time of enrollment.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 50 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
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: 2x2 factorial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pregnant Women - Tenofovir<br>Women will be randomized to early initiation (enrollment at 14-28 weeks pregnant) vs standard initiation (at 28 weeks pregnant) of tenofovir disoproxil fumarate (TDF) 300 mg daily oral medication until delivery. | Drug: Tenofovir Disoproxil Fumarate<br>* oral TDF medication 300 mg daily<br>* Other names: TDF;|
| Placebo Comparator: Newborn Infants - Lamivudine<br>Infants exposed to HBV at birth will be randomized to receive oral lamivudine post-exposure prophylaxis or matching placebo. Medication will be administered twice daily for 6 months. | Drug: Lamivudine Oral Solution<br>* Oral lamivudine with weight-based dosing BID from birth until 6 months of age<br>* Other names: 3TC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vertical Transmission of hepatitis B Infection | The proportion of infants with Hepatitis B surface antigen positivity (SAg+) | 6-9 months of age | 
| Virologic Suppression | The proportion of women with a suppressed HBV DNA viral load (<10 IU/mL). | at delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| In utero HBV infection | HBV infection (SAg+, PCR positive) | at birth | 
| Maternal Adherence to TDF | HPLC measurement of serum | 8 weeks after starting medication | 
| Maternal Adherence to TDF | HPLC measurement of serum | at delivery | 
| Infant Adherence to 3TC | HPLC measurement of serum | 12 weeks after starting 3TC | 
| Infant Adherence to 3TC | HPLC measurement of serum | 24 weeks after starting 3TC | 
| Hepatitis B Flare | Increase in ALT (>2x ULN) after stopping TDF at delivery | 12 weeks after delivery | 
| Hepatitis B Flare | Increase in ALT (>2x ULN) after stopping TDF at delivery | 24 weeks after delivery | 
| Preterm delivery | Delivery <37 weeks gestational age | assessed at delivery | 
| Composite Adverse Birth Outcomes | PTD, SAB, IUFD, neonatal death | during pregnancy or up to 28 days after delivery | 
| Incident HIV infection during pregnancy | Maternal HIV infection with seroconversion to positive test | at delivery | 
| Retention in Prenatal Care | at least 4 ANC visits after 28 weeks GA | assessed at time of delivery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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perinatal infection, hepatitis B in pregnancy