Hepatitis B Chronic Infection, Pregnancy
Conditions
Keywords
Hepatitis B, Hepatitis B sAg, Hepatitis B eAg, pregnancy
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.
Interventions
DRUGtenofovir disoproxil fumarate
administration: tablet 300 mg, once a day, from enrollment at 28 weeks' gestation until 2 months postpartum
DRUGplacebo
administration: one tablet, once a day, from enrollment at 28 weeks' gestation until 2 months postpartum
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Centers for Disease Control and Prevention
Gilead Sciences
Institut de Recherche pour le Developpement
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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 |
| 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 |
| 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. |
Countries
Thailand
Participant flow
Recruitment details
Study Enrollment Dates: January 8, 2013 to August 19, 2015 in 17 hospital based antenatal care and pediatrics departments in Thailand
Participants by arm
| Arm | Count |
|---|---|
| Tenofovir Disoproxil Fumarate tenofovir disoproxil fumarate, 300 mg tablets
tenofovir disoproxil fumarate: administration: tablet 300 mg, once a day, from enrollment at 28 weeks' gestation until 2 months postpartum | 168 |
| Placebo matching placebo (of tenofovir disoproxil fumarate)
placebo: administration: one tablet, once a day, from enrollment at 28 weeks' gestation until 2 months postpartum | 163 |
| Total | 331 |
Baseline characteristics
| Characteristic | Tenofovir Disoproxil Fumarate | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 25.5 years | 26.7 years | 26.1 years |
| Gestational age at enrollment | 28.3 weeks | 28.1 weeks | 28.3 weeks |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 168 Participants | 163 Participants | 331 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 168 Participants | 163 Participants | 331 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 331 | 0 / 323 |
| other Total, other adverse events | 42 / 331 | 31 / 323 |
| serious Total, serious adverse events | 62 / 331 | 66 / 323 |
Outcome results
Primary
Percentage of Infants With Hepatitis B Infection at 6 Months of Age
Infection is defined as a HBsAg positive test confirmed by detectable HBV DNA
Time frame: 6 months of age
Population: Participants in the primary analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tenofovir Disoproxil Fumarate | Percentage of Infants With Hepatitis B Infection at 6 Months of Age | 0 Participants |
| Placebo | Percentage of Infants With Hepatitis B Infection at 6 Months of Age | 3 Participants |
Secondary
Percentage of Infants With Hepatitis B Infection 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
Time frame: at or after 6 months through 12 months of age
Population: infants until 12 months of age
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tenofovir Disoproxil Fumarate | Percentage of Infants With Hepatitis B Infection at or After 6 Months Through 12 Months of Age | 0 Participants |
| Placebo | Percentage of Infants With Hepatitis B Infection at or After 6 Months Through 12 Months of Age | 3 Participants |
Secondary
Percentage of Participants With Adverse Events
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.
Time frame: from enrollment (28 weeks' gestation) to 12 months postpartum
Population: Mother-infant pairs
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tenofovir Disoproxil Fumarate | Percentage of Participants With Adverse Events | Maternal | 41 Participants |
| Tenofovir Disoproxil Fumarate | Percentage of Participants With Adverse Events | Infant | 43 Participants |
| Placebo | Percentage of Participants With Adverse Events | Maternal | 44 Participants |
| Placebo | Percentage of Participants With Adverse Events | Infant | 38 Participants |
Secondary
Percentage of Participants With Flares After Study Treatment Interruption
Flare, or acute exacerbation of hepatitis B, after study treatment interruption is defined as an Alanine Aminotransferase plasma level above 300 IU/mL
Time frame: Following planned discontinuation of study treatment up to 12 months postpartum
Population: Women who had delivered
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tenofovir Disoproxil Fumarate | Percentage of Participants With Flares After Study Treatment Interruption | 9 Participants |
| Placebo | Percentage of Participants With Flares After Study Treatment Interruption | 5 Participants |
Secondary
Weight, Height and Head Circumference for Age
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.
Time frame: assessed at 6 months and 12 months of age, 6 months reported
Population: infants at 6 months of age
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tenofovir Disoproxil Fumarate | Weight, Height and Head Circumference for Age | Weight for age | -0.4 Z-score | Standard Deviation 1.1 |
| Tenofovir Disoproxil Fumarate | Weight, Height and Head Circumference for Age | Length for age | -0.2 Z-score | Standard Deviation 1.2 |
| Tenofovir Disoproxil Fumarate | Weight, Height and Head Circumference for Age | Head circumference for age | -0.6 Z-score | Standard Deviation 1.1 |
| Placebo | Weight, Height and Head Circumference for Age | Weight for age | -0.2 Z-score | Standard Deviation 1.1 |
| Placebo | Weight, Height and Head Circumference for Age | Length for age | -0.2 Z-score | Standard Deviation 1.2 |
| Placebo | Weight, Height and Head Circumference for Age | Head circumference for age | -0.6 Z-score | Standard Deviation 0.9 |