Summarized by / Author: Rooma Nankani MD (1), Rohini Manaktala MD (1)
Summary Reviewer: Paul Robert Anthony Jr. MD (2)
Contribution To Literature:
This trial showed that the maternal use of tenofovir in hepatitis B positive mothers did not result in significantly lower rate of perinatal hepatitis B transmission. However, it is known that the rate of mother to child HBV transmission is low with the use of hepatitis B immune globulin and hepatitis B vaccine in infants from hepatitis B positive mothers.
The goal of the trial was to determine the effect of tenofovir in preventing hepatitis B transmission from mother to infant. The trial was an effort to explore other alternatives besides hepatitis B immunoglobulin administration and hepatitis B vaccine in infants as the risk of transmission of hepatitis B remains elevated despite these measures.
It was a multicenter, randomized, double-blind, placebo-controlled, parallel group clinical trial performed at 17 public hospitals in Thailand from January 2013 to August 2015.
Patients enrolled in the study were hepatitis B e antigen (HBeAg) positive pregnant women with an ALT level of 60 IU/L or less who were randomly assigned in 1:1 ratio to receive 300 mg of tenofovir disoproxil fumarate (TDF) daily (n=168) or matching placebo (n=163) which involved taking similar tablets but without the active pharmaceutical ingredient. Both group were received their respective medication from 28 weeks of gestation to 2 months post partum. Infants of both groups received hepatitis B immune globulin at birth and hepatitis B vaccine at birth as well as at 1, 2, 4, and 6 months.
- Total number of patients: 331
- Duration of follow-up (maternal visits): 28, 32 and 36 weeks of gestation, at delivery and at 1, 2, 3, 4, 6 and 12 months post partum
- Duration of follow-up (infant visits): birth and 1, 2, 4, 6, 9 and 12 months of age for physical examination and blood work for determination of HBV infection status; and for recording of vaccinations until 6 months of age; and for signs/conditions suggestive of possible mitochondrial dysfunction at 6 and 12 months of age
- Median gestational age: 28.3 weeks
- Median HBV DNA level: 8log (10) IU/mL
- Median time from birth to administration of hepatitis B immune globulin: 1.3 hours
- Median time from birth to administration of hepatitis B vaccine: 1.2 hours
- Mode of infant delivery: 26% were Cesarean sections
- Pregnant women (from age 18 years or older) at 28 weeks of gestational age (within a window of +/- 10 days)
- Positive HbsAg and HBeAg tests
- ALT level of 30 IU/L or less at screening and 60 IU/L or less at trial entry
- Positive serologic test for HIV or hepatitis C virus
- Received TDF at any time
- Received any other anti-HBV treatment during the current pregnancy
- Estimated creatinine clearance of less than 50 mL per minute or had confirmed proteinuria or normoglycemic glycosuria
- Evidence of fetal anomaly that was incompatible with life
Other salient features/characteristics:
- Women with an elevated ALT level (>60 IU/L) at any trial visit had their level tested again within 2 weeks
- Pregnancies that resulted in multiple births were counted as one mother-infant pair and were counted as having HBV infection if at least one infant was infected
- Amniocentesis and Cesarean section delivery may be associated with increased risk of HBV transmission
- The positive status of hepatitis B surface antigen (HBsAg) in the infant confirmed by the HBV DNA level at 6 months of age. Results found that none of the 147 infants in the TDF group were infected (0%, [CI] 0 to 2) as compared with three of 147 (2%, [CI] 0 to 6) in the placebo group (p=0.12).
- At 6 months follow up, 99% of the TDF and placebo groups had an HbsAg antibody level of at least 10 IU/L.
- Adverse events that were measured included: maternal hepatic flares (ALT level of >300 IU/L) after discontinuation of the trial regimen, and infant growth at 6 months.
- The incidence of maternal ALT level of more than 300 IU/L after discontinuation of the trial regimen was 6% in the TDF group and 3% in the placebo group (p=0.29).
- Overall, the rate of adverse events did not differ significantly between the two groups.
Findings from this trial did not reach statistical significance with regards to detection of HBV infection in infants whose mothers received TDF. Although the observed rate of mother to child transmission in the TDF group was not statistically significant at short term follow up, the long-term risk of transmission among these infants was predicted to be less than 2.5%.
With regards to safety concerns of TDF, there was no significant maternal or infant safety incidence reported. Only notable events reported were maternal asymptomatic hepatic flares.
Moreover, prior to the completion of the trial it was expected in general that the rate of HBV transmission would be 7% or more among infants who received HBV vaccine, hepatitis B immune globulin and had been born to mothers with higher HBV DNA levels. Surprisingly, this trial found an overall lower rate of HBV transmission. This difference could be due to sampling variations (for example: sample size, differences in population baseline characteristics and duration of time between infant birth and first administration of the hepatitis B vaccine) compared to other similar studies.
Overall, this trial did not show a lower rate of HBV transmission from mother to infant with the administration of TDF in addition to hepatitis B immune globulin and vaccine to infant compared to placebo.
Jourdain G., Ngo-Giang-Huong, L., Harrison, L, et al. Tenofovir versus Placebo to Prevent Perinatal Transmission of Hepatitis B. NEJM. 2018, 378 (10): 911-923. Source
1. Department of Internal Medicine, University of Connecticut Health Center
2. Department of Infectious Disease, Saint Francis Hospital, Hartford, Connecticut