Earlier initiation of tenofovir in pregnancy with infant hepatitis B vaccination obviates the need for hepatitis B immune globulin

Chronic hepatitis B (CHB) remains a significant and burdensome health problem throughout the world. In 2022, the estimated number of people living with CHB worldwide was 254 million (1). Globally, it is the leading cause of cirrhosis and liver cancer (2). These complications are the main drivers of death in this population; in 2022, there were an estimated 1.1 million deaths (1). Unfortunately, the annual global deaths from CHB are projected to increase by 39% from 2015 to 2030 (2). As is well known, in 2016, the World Health Organization (WHO) set the goal of eliminating viral hepatitis worldwide by 2030 (3). In the WHO’s updated Global Health Sector Strategies [2022], authors recognize that an integral strategic component is the prevention of hepatitis B virus (HBV) vertical transmission, which is also known as “mother-to-child transmission” (MTCT) (4). This is grounded by the fact that more than 90% of perinatally infected people will develop CHB (2,5). It is estimated that about 4–5 million infants are infected with CHB via MTCT every year (5). Thus, although there are many ongoing efforts focusing on direct treatment of hepatitis B (6), prevention of MTCT remains a strategic imperative from a global perspective.

All three of the major societal guidelines—Asian Pacific Association for the Study of the Liver (APASL) [2016], European Association for the Study of the Liver (EASL) [2017], and American Association for the Study of Liver Diseases (AASLD) [2018]—acknowledged the importance of immediate administration of hepatitis B immune globulin (HBIG) in addition to HBV vaccination to the newborn after delivery (Table 1), ideally within 12 hours (7-9). However, timely administration of HBIG is not possible in low-income and middle-income countries (10,11). One of the explanations for its high cost is that it is a cold chain product; HBIG needs to be kept refrigerated, has a limited shelf life, and must be used timely (10,12,13). Thus, if HBIG is not universally available but there is evidence to support its utility in combination with HBV vaccination in preventing MTCT (13), is there an alternative solution? The authors of “Tenofovir and Hepatitis B Virus Transmission During Pregnancy: A Randomized Clinical Trial”, which was recently published in The Journal of the American Medical Association (JAMA), set out to seek one potential solution to this concerning problem. Specifically, they wanted to see if initiation of tenofovir disoproxil fumarate (TDF) at 16 weeks of gestation with newborn HBV vaccination is noninferior to the currently widely accepted strategy of starting TDF at 28 weeks of gestation with newborn HBV vaccination plus HBIG administration.

Pan et al. conducted an unblinded, randomized, noninferiority trial across seven tertiary hospitals in China from June 2018 to February 2021. The study included hepatitis B e antigen (HBeAg) positive CHB pregnant women (age 20–35 years) with HBV DNA >200,000 IU/mL. Patients with coinfections were excluded, as were those with a history of fetal abnormalities in prior pregnancies, those who exhibited signs of miscarriage, and ultrasonographic evidence of fetal abnormalities. Mothers received 300 mg of TDF, and medication adherence was monitored via pill counts. Infants in both the experimental and standard group received the HBV vaccine (10 µg) within 12 hours of birth. Infants in the standard group also received 100 IU of HBIG at birth. However, infants in the experimental group would also receive HBIG if the maternal HBV DNA level were >200,000 IU/mL at delivery or at the last measurement prior. The primary outcome was the MTCT rate, which was the number of infants with HBV DNA levels >20 IU/mL or hepatitis B surface antigen (HBsAg) positive at age 28 weeks reported as a percentage. The prespecified noninferiority margin for this study was 3% (12). In total, there were 280 mothers who were enrolled in the study (mean age 28 years); however, 265 mothers completed the study. There was a total of 273 infants born: 131 infants in the experimental group and 142 infants in the standard group and these infants were included in the intention-to-treat (ITT) analysis. The median HBV DNA level was 8.23 log₁₀ IU/mL. Notably, the standard group had four pairs of twins which accounted for more infants, but otherwise the mothers and infants in the experimental group had similar characteristics to their counterparts in the standard group. Notably, there were five infants in the experimental group that received HBIG—four of these cases were situations where the infant was given HBIG by a non-research staff during the coronavirus disease 2019 (COVID-19) lockdown. HBIG was used in one case as a salvage attempt for an infant who was born preterm at 35 weeks with a maternal HBV DNA of 303,000 IU/mL. Among these infants, those that completed the trial (4 infants) were excluded in the per protocol analysis. Three infants in the experimental group and one in the standard group were not able to complete the study. Thus, the per protocol analysis had 124 infants in the experimental group and 141 infants in the standard group.

In the ITT analysis, all 273 infants had undetectable HBV DNA levels at birth. One infant in the experimental group was HBsAg positive at birth with undetectable HBV DNA. This infant was lost to follow up and thus removed from the per protocol analysis. From the ITT analysis, the MTCT rates were 0.76% (1/131) in the experimental group and 0% (0/142) in the standard group (12). The difference between the two groups was 0.76% and the upper limit of the 2-sided 90% confidence interval (CI) was 1.74%. Thus, based on the threshold for noninferiority of within 3%, the primary outcome deemed the experimental intervention to be noninferior (12). Per protocol analysis (n=265 infants) MTCT rates were 0% for both groups: 0/124 for the experimental group and 0/141 for the standard group (12). The difference between these two groups were 0% and the upper limit of the 2-sided 90% CI was 1.43% which confirms noninferiority of the experimental intervention (12). The authors also re-evaluated the primary outcome using the upper limits of 2-sided 95% CI. In the post hoc efficacy outcomes, the ITT difference had an upper limit of 2.23% and the per-protocol analysis difference had an upper limit of 2.15% using the 95% CI, but still within the 3% noninferiority margin (12).

Secondary outcomes included the percentage of mothers whose HBV DNA level at delivery was <200,000 IU/mL, seroconversion and seronegative rates of maternal HBeAg at postpartum week 28, elevations in postpartum ALT levels, and rates of congenital defects or newborn abnormalities. There was a statistically significant greater number of mothers in the experimental group who achieved HBV DNA <200,000 IU/mL compared to those in the standard group. There were no statistically significant differences between groups regarding negative HBeAg serologies at week 28, HBeAg seroconversion at week 28, postpartum ALT level elevations (both more than 5 times and 10 times the upper limit of normal), and rates of congenital defects or newborn abnormalities. As can be deduced, there was a statistically significant higher percentage of mothers who had HBV DNA levels <20,000 IU/mL in the experimental group. Regarding safety analysis, there were four fetal losses including three stillbirths and one miscarriage. These occurred in the experimental group. There was also one case of pregnancy termination for tetralogy of Fallot in the experimental group. According to the authors, these fatalities were determined to be unrelated to TDF except for one, but reportedly the association was inconclusive (12). Obstetric complications were similar between the experimental and standard groups, as were the rates of grade III or grade IV adverse events among the infants. Physical growth parameters and bone mineral density were similar between the two groups as well. Overall, TDF was well-tolerated and only one mother stopped therapy due to nausea. The most common adverse events throughout the entire cohort were elevations in ALT (25%), upper respiratory infections (14.6%), and vomiting (12.9%) (12).

The authors’ findings in this randomized clinical trial are indeed promising. Their findings herald the potential push to no longer require HBIG for infants born to mothers with CHB. The combination of HBIG and HBV vaccination at birth has been shown to reduce the MTCT rate from >90% to <10% (8). From this context, the noninferiority outcome of early maternal TDF initiation followed by HBV vaccination of the newborn alone versus the standard of care with combination of the HBV vaccination plus HBIG is a powerful observation that underscores the role of antiviral therapy and HBV viral load in these cases. Indeed, maternal viral load is an important risk factor for MTCT and, in one meta-analysis, HBV viral load was dose-dependent with MTCT incidence (14). MTCT rates are as high as 10% in mothers with HBV DNA >200,000 IU/mL (15). Interestingly, the MTCT rates of infants whose mothers were HBeAg negative with an HBV viral load of <20,000 IU/mL and who received only the HBV vaccine were ≤2% (12). Consequently, the authors hoped to utilize the viral load of <20,000 IU/mL as the aspirational marker of prevention and they hypothesized that a longer course of TDF therapy would be the primary means of arriving there (12). The next question then becomes what is the optimal duration of therapy? Standard duration of TDF therapy in pregnant women requiring prophylaxis is presumed to be 12 weeks—with treatment initiation recommended at 28–32 weeks. Pan et al. conducted a kinetic analysis of TDF in women of childbearing potential with virologic responses for 12 weeks duration and 24 weeks duration of therapy (16). Among HBeAg positive patients, HBV DNA <200,000 IU/mL was achieved in 90% of patients receiving TDF after 12 weeks and in 93% of patients after 24 weeks (16). Additionally, 75% of patients achieved HBV DNA <20,000 IU/mL after 12 weeks and 86% after 24 weeks (16). Given better results with the 24-week duration, it is reasonable the treatment initiation was at 16 weeks in this trial. In the discussed randomized trial, there was a statistically significant difference in the percentage of mothers achieving HBV DNA <20,000 IU/mL at delivery: 94.7% in the experimental group versus 65.9% in the standard group. In addition to its efficacy, TDF has also been shown to be safe throughout pregnancy (13,17,18)—even as early as within 12 weeks of gestation (19), as well as during breastfeeding (20).

Overall, this is an important study that attempts to change the status quo with respect to previous societal guidelines recommending administration of both HBIG and HBV vaccine to the newborn. Findings from this study support the notion that HBIG is not essential to preventing MTCT, which is particularly unfettering as many low-income countries cannot readily use HBIG. Of note, the new WHO 2024 guidelines for hepatitis B do not explicitly recommend administration of HBIG after delivery (Table 1) (21). These guidelines also recommend offering TDF to all HBsAg positive women if viral load or HBeAg testing is not available (21). Future studies exploring outcomes of different lengths of treatment are needed to determine the optimal duration. Societal guidelines have recommended the use of TDF in pregnancy (Table 1) (7-9); however, there have been several studies that have investigated the use of tenofovir alafenamide (TAF) for prevention of MTCT (15,22,23). In a recent systematic review and meta-analysis, Pan et al. sought to compare the efficacy of TAF and TDF for MTCT reduction as well as safety (15). In their analysis of 31 studies with 4,468 pregnant patients with CHB, the authors found that both TDF and TAF demonstrated equal effectiveness for MTCT reduction in both randomized controlled trial (RCT) and non-RCT studies (15). Additionally, there were no negative fetal or infant outcomes (15). A recent RCT comparing the safety of an 8- vs. 12-week regimen of TAF for MTCT prevention also demonstrated that TAF was safe, well tolerated, and effective (23). Results from the aforementioned analyses will likely be an important point of discussion for future societal guideline updates with respect to utilization of TAF for MTCT prevention. Consequently, another area of investigation would be the necessity for HBIG in settings where TAF is utilized instead of TDF for MTCT prevention.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Gastroenterology and Hepatology. The article has undergone external peer review.

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-14/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-14/coif). S.S. reports that he received support from Kezar; consulting fees from Gilead, Salix, Kezar, Orphalan, Intercept, Eisai, Madrigal, Mallincrodkt, and Sequana; and honoraria from Gilead, Salix, Kezar, Orphalan, Intercept, Eisai, Madrigal, AbbVie, Mallincrodkt, and Sequana. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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