Tenofovir and Hepatitis B Virus Transmission During Pregnancy: A Randomized Clinical Trial

Abstract

Importance: Standard care for preventing mother-to-child transmission (MTCT) of hepatitis B virus (HBV) in highly viremic mothers consists of maternal antiviral prophylaxis beginning at gestational week 28 combined with an HBV vaccine series and HBV immune globulin (HBIG) at birth. However, HBIG is unavailable in some resource-limited areas.

Objective: To determine whether initiating tenofovir disoproxil fumarate (TDF) at gestational week 16 combined with HBV vaccinations for infants is noninferior to the standard care of TDF at gestational week 28 combined with HBV vaccinations and HBIG for infants in preventing MTCT in mothers with HBV and high levels of viremia.

Design, setting, and participants: An unblinded, 2-group, randomized, noninferiority clinical trial was conducted in 7 tertiary care hospitals in China. A total of 280 pregnant individuals (who all identified as women) with HBV DNA levels greater than 200 000 IU/mL were enrolled between June 4, 2018, and February 8, 2021. The final follow-up occurred on March 1, 2022.

Interventions: Pregnant individuals were randomly assigned to receive either TDF starting at gestational week 16 with HBV vaccinations for the infant or TDF starting at gestational week 28 with HBV vaccinations and HBIG administered to the infant.

Main outcomes and measures: The primary outcome was the MTCT rate, defined as detectable HBV DNA greater than 20 IU/mL or hepatitis B surface antigen positivity in infants at age 28 weeks. Noninferiority was established if the MTCT rate in the experimental group did not increase by more than an absolute difference of 3% compared with the standard care group, as measured by the upper limit of the 2-sided 90% CI.

Results: Among 280 pregnant individuals who enrolled in the trial (mean age, 28 years; mean gestational age at enrollment, 16 weeks), 265 (95%) completed the study. Among all live-born infants, using the last observation carried forward, the MTCT rate was 0.76% (1/131) in the experimental group and 0% (0/142) in the standard care group. In the per-protocol analysis, the MTCT rate was 0% (0/124) in the experimental group and 0% (0/141) in the standard care group. The between-group difference was 0.76% (upper limit of the 2-sided 90% CI, 1.74%) in all live-born infants and 0% (upper limit of the 2-sided 90% CI, 1.43%) in the per-protocol analysis. Both comparisons met the criterion for noninferiority. Rates of congenital defects and malformations were 2.3% (3/131) in the experimental group and 6.3% (9/142) in the standard care group (difference, 4% [2-sided 95% CI, -8.8% to 0.7%]).

Conclusions and relevance: Among pregnant women with HBV and high levels of viremia, TDF beginning at gestational week 16 combined with HBV vaccination for infants was noninferior to the standard care of TDF beginning at gestational week 28 combined with HBIG and HBV vaccination for infants. These results support beginning TDF at gestational week 16 combined with infant HBV vaccine to prevent MTCT of HBV in geographic areas where HBIG is not available.

Trial registration: ClinicalTrials.gov Identifier: NCT03476083.

Figure 1.. Flowchart of Patient Enrollment in the Trial

Out of the 281 mothers randomized, 280 were enrolled (1 in the experimental group dropped out before enrollment), resulting in 140 mothers in each group. In the experimental group, 128 mothers with 128 infants completed the study, while in the standard care group, 137 mothers with 141 infants completed the study. HBeAg indicates hepatitis B e-antigen; HBIG, hepatitis B immune globulin; HBV, hepatitis B virus; HCV, hepatitis C virus; and TDF, tenofovir disoproxil fumarate. ^aDropouts and consent withdrawals were mainly due to the COVID-19 pandemic lockdowns and patients changing care facilities. ^bAll mothers in the experimental group had singleton births. ^cFive infants received HBIG at birth, but only 4 completed the study. All 5 infants who received HBIG were excluded from the per-protocol analysis.

Figure 2.. Assessment of Outcome Difference Between Groups and Noninferiority

The plot illustrates the between-group difference in mother-to child transmission rates and the 2 analyses’ upper 1-sided 90% CI. The dashed line indicates the noninferiority margin. The intention-to-treat analysis was based on all live-born infants, including those who withdrew from the study, with missing data imputed using the last observation carried forward approach. The per-protocol analysis was based on the dataset comprising all infants who completed the study at age 28 weeks with protocol adherence. The upper 1-sided 90% CI was used to determine the primary outcome.