Tenofovir in Pregnancy to Prevent Mother to Child Transmission of Hepatitis B.

NCT04114890 | Completed Phase 2

• 1 other identifier: VIR19001
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

Brief Summary

Hepatitis B virus (HBV) can be asymptomatic for years but can also lead to chronic hepatitis, hepatocellular carcinoma, and liver failure and death and cannot be eradicated with the current therapy. Chronic maternal HBV infection is an important source of perinatal transmission in regions of high HBV prevalence. In antenatal clinics at Shoklo Malaria Research Unit (SMRU), the Hepatitis B (HB) surface antigen (sAg) prevalence is 8.3% with a HB e-antigen (HBeAg) prevalence of 32.7% in those positive for HBsAg in 2012-2014. Perinatal infection occurs in 70-90% of women with HBeAg positive chronic HBV compared with 0-30% in those with HBeAg negative chronic HBV (inactive carriers). These infection rates reflect, in part, the failure of maternal and child health programs to prevent perinatal transmission with hepatitis B immunoglobulin (HBIG) and HB vaccines. Prevention of mother to child transmission (PMTCT) fails in an estimated 8-32% of cases with adequate preventive techniques. Antiretrovirals, like tenofovir (TFV) that is administered as the prodrug Tenofovir Disoproxil Fumarate (TDF), are active against HBV and may reduce the risk of HBV transmission at birth if offered at the right time in pregnancy. One of the major gaps in implementing this strategy is adequate pharmacokinetic (PK) data in pregnant women that informs correct dosing. One recently published population PK study in 154 women who provided maternal blood samples (32 and 36 weeks of pregnancy, at delivery, and at 1 and 2 months post-partum) reported a tenofovir area under curve (AUC) 0-24 that was estimated to be 20% (95% CI, 19-21%) lower during pregnancy than during post-partum suggesting no dose adjustments are needed in 3rd trimester. Most PK studies for TDF in pregnancy have been for Human Immunodeficiency Virus type 1 (HIV-1) infections. However, these patients often receive additional antiretroviral medications, preventing conclusions on PK parameters of Tenofovir (TFV) alone. Doses that are optimal for HIV may not be appropriate for HBV. When TDF is administered during pregnancy and potentially during lactation, it is important to establish the infant drug exposure. Previous human studies have shown that antiretrovirals administered to lactating mothers are present in the breast milk and have detected a low TDF breast milk concentration representing 0.03% or less of the proposed infant dosage. However, there is no data on this subject in therapeutic treatment of HBV infected women. In resource poor settings TDF administration will be ceased after 1 month post-partum. While there is some understanding of what happens to viral load post cessation in non-pregnant individuals, post-partum TDF cessation is less well understood and may be affected by differences in immunity. With breastmilk as the primary source of nutrition for babies in resource limited settings, it is important to know the viral exposure from breastmilk, if any, as these settings may also have problems achieving birth dose, HBIG and completion of the recommended three doses of vaccine. The investigators propose a dense PK study of once daily TDF 300 mg during pregnancy given for PMTCT of HBV mono-infection. Tenofovir PK will be measured in maternal blood samples in steady-state, in the 2nd and 3rd trimesters and post-partum. The presence of HBV DNA in blood and breast milk will also be explored in women after cessation of treatment until 6 months post-partum.

Conditions

Hepatitis B; Tenofovir; Pregnancy

Outcome Measures

Primary Outcomes (9)

• Area under the plasma concentration-time curve [AUC]

  At pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post-dose in second trimester between 22-26 weeks gestation, in third trimester between 30-38 weeks gestation, and 4 weeks post-partum.

• Maximum (peak) plasma drug concentration [Cmax]

  At pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post-dose in second trimester between 22-26 weeks gestation, in third trimester between 30-38 weeks gestation, and 4 weeks post-partum.

• Minimum plasma drug concentration [Cmin]

  At pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post-dose in second trimester between 22-26 weeks gestation, in third trimester between 30-38 weeks gestation, and 4 weeks post-partum.

• Initial (fictive) or back-extrapolated plasma drug concentration at time zero [C0]

  At pre-dose (in second trimester between 22-26 weeks gestation, in third trimester between 30-38 weeks gestation, and 4 weeks post-partum.)

• Plasma drug concentration at time 24 [C24]

  At 24 hours post-dose (in second trimester between 22-26 weeks gestation, in third trimester between 30-38 weeks gestation, and 4 weeks post-partum.)

• Trough plasma concentration (measured concentration at the end of a dosing interval at steady state [taken directly before next administration]) [Cthrough]

  At the end of a dosing interval at steady state

• Apparent total clearance of the drug from plasma after oral administration [CL/F]

  At pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post-dose in second trimester between 22-26 weeks gestation, in third trimester between 30-38 weeks gestation, and 4 weeks post-partum.

• Elimination half-life [t½]

  At pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post-dose in second trimester between 22-26 weeks gestation, in third trimester between 30-38 weeks gestation, and 4 weeks post-partum.

• Time to reach maximum (peak) plasma concentration following drug administration [tmax]

  At pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post-dose in second trimester between 22-26 weeks gestation, in third trimester between 30-38 weeks gestation, and 4 weeks post-partum.

Secondary Outcomes (4)

• Maternal breastmilk TFV concentrations

  1 month post-partum

• Milk to maternal plasma concentration ratios (M/P)

  1 month post-partum

• Infant plasma drug concentration

  At 1 month of life

• HBV DNA in blood and breastmilk

  At delivery and 1, 2, 3, 4, 5, and 6 months post-partum

Study Arms (1)

Pregnant woman with second trimester and third trimester

EXPERIMENTAL

Drug: Tenofovir Disoproxil Fumarate

Interventions

Tenofovir Disoproxil Fumarate DRUG

Tenofovir Disoproxil Fumarate 300 mg once daily and will continue until one month after delivery

Pregnant woman with second trimester and third trimester

Eligibility Criteria

• Age: 16 Years - 49 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Single viable pregnancy at enrollment day
• Estimated Gestational Age (EGA) 20-\<24 weeks for 2nd trimester or EGA 28-\<34 for 3rd trimester
• Willing and able to give informed consent for participation in the study
• Hepatitis B infected (HBsAg and HBeAg confirmed positive or HBsAg confirmed positive and HBV DNA detected in HBeAg negative)
• Burmese and Karen female, 16-49 years (inclusive)
• Willing to take TDF daily during pregnancy
• Plans to deliver at SMRU clinics

You may not qualify if:

• Undetectable HBV DNA in HBeAg negative women
• HIV infected or other chronic illness incompatible with the study requirements or receiving Immunosuppressive therapy
• Creatinine at screening \>1 mg/dL
• Serum phosphate \<2.4 mg/dL
• History of chronic kidney disease

Sponsors & Collaborators

• University of Oxford: lead

Study Sites (1)

Shoklo Malaria Research unit (SMRU) clinics

Mae Sot, Changwat Tak, 63110, Thailand

Location

MeSH Terms

Conditions

Hepatitis B

Interventions

Tenofovir

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Hepadnaviridae Infections; DNA Virus Infections; Virus Diseases; Hepatitis, Viral, Human; Hepatitis; Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 18, 2019
• First Posted: October 3, 2019
• Study Start: January 8, 2021
• Primary Completion: September 29, 2023
• Study Completion: September 29, 2023
• Last Updated: March 27, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will share

Locations

TH (1)