Early maternal tenofovir treatment and infant vaccination: a scalable model for hepatitis B virus mother-to-child transmission control in resource-limited areas
Editorial Commentary

Early maternal tenofovir treatment and infant vaccination: a scalable model for hepatitis B virus mother-to-child transmission control in resource-limited areas

Md Deen Islam1,2,3 ORCID logo, Carla S. Coffin1,2,3 ORCID logo

1Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; 2Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; 3The Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

Correspondence to: Carla S. Coffin, MD. Department of Medicine, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB T2N 4Z6, Canada; Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada; The Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada. Email: cscoffin@ucalgary.ca.

Comment on: Pan CQ, Dai E, Mo Z, et al. Tenofovir and Hepatitis B Virus Transmission During Pregnancy: A Randomized Clinical Trial. JAMA 2025;333:390-9.

Keywords: Hepatitis B virus (HBV); mother-to-child transmission (MTCT); tenofovir disoproxil fumarate (TDF); hepatitis B immunoglobulin (HBIG); resource-limited settings (RLS)

Received: 08 May 2025; Accepted: 01 September 2025; Published online: 24 October 2025.

doi: 10.21037/tgh-25-59

Despite the availability of an effective hepatitis B vaccine since 1981, an estimated 254 million individuals remain chronically infected with hepatitis B virus (HBV), and more than 1.2 million new infections occur annually, predominantly through mother-to-child transmission (MTCT) (1). The implementation of robust strategies to prevent MTCT is imperative to mitigating the global burden of chronic hepatitis B. Clinical practice guidelines emphasize universal prenatal screening, timely birth dose vaccination, and adherence to immunization schedules to achieve >95% efficacy in reducing MTCT rates (2). Post-exposure prophylaxis with hepatitis B immunoglobulin (HBIG) for selected neonates are also often recommended (3). Additional strategies to prevent MTCT include antiviral therapy during the third trimester for mothers with high viral loads (HBV DNA >200,000 IU/mL). Moreover, recently published data indicate that vertical transmission risk can be further mitigated if enhanced schedules and/or additional doses of HBV passive-active immunoprophylaxis are offered (Table 1).

Table 1

Comparison of MTCT rates following different intervention strategies for both mothers and infants, or either alone

Intervention for mother/infant Intervention strategy Intervention components Mother’s HBV status MTCT rate Key findings and references
Infants only Active immunization alone 3-dose HBV vaccine [at birth (within 24 hours), 1 month, and 6 months] HBsAg+, HBeAg−, VL (<2×105 IU/mL) 0% MTCT rates in infants of HBeAg− mothers receiving either vaccine alone or vaccine + HBIG are the same, suggesting HBIG may not add significant benefit in low-risk cases (4)
Passive-active immunization 3-dose HBV vaccine [at birth (within 24 hours), 1 month, and 6 months] + HBIG (100 IU within 12 hours) HBsAg+, HBeAg−, VL (<2×105 IU/mL) 0%
Active immunization alone 3-dose HBV vaccine [at birth (within 24 hours), 1 month, and 6 months] HBsAg+, HBeAg+, VL (≥6 log10 copies/mL) 16.90% For infants born to HBeAg+ mothers, the immunoprophylaxis failure rate (indicating MTCT) for infants who received HBIG plus vaccine was 7.9% (29/367). The immunoprophylaxis failure rate for infants who received only the vaccine was 16.9% (11/65). This difference was statistically significant (P=0.021) (5)
Passive-active immunization 3-dose HBV vaccine [at birth (within 24 hours), 1 month, and 6 months) + HBIG (within 12 hours) HBsAg+, HBeAg+, VL (>106 IU/mL) 5–10% In infants of HBeAg+ mothers with high HBV DNA (>6 log10 IU/mL), the failure rate of immunoprophylaxis (HBIG + vaccine) remains above 5% [5.6% (27/482)]. Increasing the vaccine dose did not significantly lower the MTCT rate in this high-risk group (6)
Passive-active immunization 3-dose 10 or 20 μg HBV vaccine [at birth (within 24 hours), 1 month, and 6 months] + HBIG (within 12 hours and at 1 month) HBsAg+, HBeAg+, VL (≥5 log10 IU/mL) >3% For infants born to mothers with high HBV DNA levels (≥5 log10 IU/mL), an increased dose (20 μg) of vaccine did not significantly reduce MTCT of HBV compared to the standard dose (10 μg). In both vaccine groups, 32–55% mothers were HBeAg positive, and all mothers were HBsAg positive (7)
Passive-active immunization 3-dose HBV vaccine [at birth (within 2 hours), 1 month, and 6 months] + HBIG (100 IU within 2 hours) HBsAg+, HBeAg+, VL (>2×105 IU/mL) 1.20% Infants that were administered combined immunoprophylaxis within two hours of birth had an MTCT rate of 1.2% (1/83) compared to 9.46% (7/74) in those who received combined immunoprophylaxis between 2 and 12 hours after birth (8)
Passive-active immunization 3-dose HBV vaccine [at birth (within 1 hour), 1 month, and 6 months] + HBIG (100 IU within 1 hour) HBsAg+, HBeAg+, VL (>2.75×106 IU/mL) 2.40% Earlier use (within 1 hour after birth) of HBIG and hepatitis B vaccine can provide better protection efficacy against MTCT of HBV. The overall rate of MTCT was 0.9% (9/982), with none (0%) of the 607 infants of HBeAg− mothers and 9 (2.4%) of 375 infants of HBeAg+ mothers acquiring HBV. All 9 HBV-infected infants were born to mothers with HBV DNA >2.75×106 IU/mL (9)
Both mothers and infants Passive immunization to mothers and passive-active immunization to infants HBIG (200 IU) to mothers during third trimester (28, 32, and 36 weeks of gestation), and HBIG (100 IU) at birth (within 12 hours) + hepatitis B vaccine series 10 µg [at birth (within 24 hours), 1 month, and 6 months] to infants HBsAg+, HBeAg+, VL (≥6 log10 copies/mL) 10.30% There were no significant differences in outcomes for infants who received HBIG plus vaccine based on whether their mothers received antepartum HBIG. For HBeAg+ mothers who received antepartum HBIG, the immunoprophylaxis failure rate in their infants was 10.3% (10/97). For HBeAg+ mothers who did not receive antepartum HBIG, the immunoprophylaxis failure rate in their infants was 9.0% (30/335). The difference between these rates was not statistically significant (P=0.685) (5)
Antivirals to mothers and passive-active immunization to infants TDF to mothers during the third trimester (starting at week 28 of gestation), and HBIG at birth (within 12 hours) + hepatitis B vaccine series [at birth (within 24 hours), 1 month, and 6 months] to infants HBsAg+, HBeAg+, VL (≥5.3 log10 IU/mL) 0% As the standard of care, initiating TDF at week 28 for the HBeAg+ mothers with high viral load and HBV vaccination with HBIG for infants resulted in MTCT rates of 0% (0/142), indicating this regimen is most effective for high-risk mothers (10)
Antivirals to mothers and active immunization to infants TDF to mothers during the second trimester (starting at week 16 of gestation), and hepatitis B vaccine series [at birth (within 24 hours), 1 month, and 6 months] to infants HBsAg+, HBeAg+, VL (≥5.3 log10 IU/mL) 0.76% Initiating TDF at week 16 for the HBeAg+ mothers with high viral load and HBV vaccination for infants resulted in MTCT rates of 0.76% (1/131), suggesting that HBIG might not be crucial in RLS (10)

HBV DNA ≥5.3 log10 IU/mL is equivalent to ≥200,000 IU/mL. HBeAg, hepatitis B e antigen; HBIG, hepatitis B immunoglobulin; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; MTCT, mother-to-child transmission; RLS, resource-limited settings; TDF, tenofovir disoproxil fumarate; VL, viral load.

Numerous observational studies have highlighted the efficacy and safety of nucleos(t)ide analogs [i.e., tenofovir disoproxil fumarate (TDF), lamivudine, or telbivudine] administered in the second to third trimester in reducing maternal viremia and MTCT risk (11). Importantly, there are robust randomized controlled trials demonstrating reduced HBV MTCT with peripartum antiviral prophylaxis (12,13). Although, expert guidelines may vary with respect to the timing of antiviral treatment initiation, most advise between 28 and 32 weeks of pregnancy (2). The safety profile of TDF is well documented (14), showing no significant differences in maternal or fetal complications between treated and untreated patients (15,16). Nonetheless, most studies have recommended starting treatment in the third trimester to balance effectiveness vs. risk of in utero fetal exposure. Based on cumulative evidence, the 2024 World Health Organization (WHO) guidelines recommend TDF therapy by gestational week 28 weeks in highly viremic mothers (HBV DNA >200,000 IU/mL), combined with HBIG and timely birth-dose vaccination within 24 hours, and completed vaccine series before 6 months (17). However, in highly endemic resource-limited settings (RLS), multiple barriers contribute to the inconsistent implementation of the WHO recommendations leading to ongoing MTCT risk (18). A significant proportion of infants are born outside of healthcare facilities, resulting in delays or, in some cases, complete omission of timely vaccination. In many RLS, the standard cold chain (2–8 ℃) is often compromised impacting access to the HBV vaccine and HBIG (19). While cost-saving strategies such as restricting HBIG administration to infants born to mothers with HBV DNA levels >20,000 IU/mL at delivery have been proposed, this approach may be considered ethically problematic and is often impractical in settings where HBV DNA testing is unavailable or inaccessible (20,21).

This multicenter, randomized clinical trial, “Tenofovir and hepatitis B virus transmission during pregnancy”, re-evaluates the accepted treatment strategies to reduce MTCT (10). The study authors demonstrated that timely initiation of TDF therapy reduces maternal viral loads to <20,000 IU/mL at delivery and MTCT rates to 2% or lower. Importantly, the study challenges the necessity of HBIG if early antiviral therapy is initiated, potentially reducing costs and logistical barriers. In this study, 280 hepatitis B e antigen (HBeAg)-positive pregnant individuals with HBV DNA >200,000 IU/mL were enrolled across seven tertiary hospitals in China (June 2018–February 2021). Participants were randomized to receive TDF starting either at gestational week 16 (experimental group) or week 28 (standard care). Infants in the experimental group received HBV vaccination alone (at birth, 1 month, and 6 months), while those in the standard group received both vaccination and HBIG at birth. A salvage strategy was used in the experimental group, with HBIG administered if maternal HBV DNA remained >200,000 IU/mL before delivery. The primary outcome was MTCT at 28 weeks, defined as infants being hepatitis B surface antigen (HBsAg)-negative and/or HBV DNA <20 IU/mL. Mothers were followed every 4 weeks until delivery and postpartum through week 28; infants were evaluated at birth and at 12, 24, and 28 weeks. Methodological strengths include rigorous ethical review, approval with an independent Data and Safety Monitoring Committee (DSMC), and robust non-inferiority study design.

The study found that initiating TDF at week 16 with vaccination alone resulted in a non-inferior MTCT rate of 0.76% by intention-to-treat (ITT) and 0% by per-protocol analyses compared to standard care (0%), both meeting the 3% non-inferiority margin. Importantly, a higher proportion of participants in the early-TDF group achieved HBV DNA levels <20,000 IU/mL compared to the standard group (94.7% vs. 65.9%). All participants received some form of intervention to prevent MTCT of HBV given the high-risk group (i.e., mothers enrolled in the study had HBV DNA levels of >200,000 IU/mL). It is worth noting that five infants in the experimental group also received HBIG as a salvage measure. Despite four of their mothers having low pre-delivery HBV DNA levels (35–1,190 IU/mL), HBIG was given due to protocol violations during the coronavirus disease 2019 (COVID-19) lockdown. All five infants had undetectable HBV DNA (<20 IU/mL) prior to HBIG administration. Four were HBsAg-negative, while one tested HBsAg-positive. HBIG was administered only to this infant, who was born prematurely at 35 weeks to a mother with high HBV DNA (303,000 IU/mL).

TDF is associated with potential effects on fetal bone development, and given the longer in utero exposure (24 vs. 12 weeks), the clinical significance remains unclear (22). For example, in the experimental group, no twins and three stillbirths were reported, whereas the standard care group had four sets of twins and no stillbirths. Overall, the study found no statistically significant differences in congenital anomalies, rates of adverse perinatal outcomes, infant growth parameters, and bone mineral density, supporting the short-term safety profile. However, it could be due to the small sample size and lack of enough statistical power. Additional data and longer-term follow-up are needed to evaluate the risk of breakthrough HBV infection, sustained immune protection, and the safety of early TDF exposure.

In summary, by demonstrating the non-inferiority of earlier TDF initiation without the use of HBIG, this study challenges current paradigms and offers a potentially scalable strategy for preventing MTCT of HBV in low-resource settings. While the findings are promising, replication in diverse populations with varying HBV epidemiology and healthcare infrastructures is necessary before broad implementation can be recommended. This study provides emerging evidence that challenges standard practices for preventing MTCT of HBV, viewed through the lens of cost-effectiveness and ethical feasibility, and may represent a significant step forward in global HBV elimination efforts.

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-25-59/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-25-59/coif). C.S.C. reports fees for consulting and research grants paid to the University of Calgary. 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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doi: 10.21037/tgh-25-59
Cite this article as: Islam MD, Coffin CS. Early maternal tenofovir treatment and infant vaccination: a scalable model for hepatitis B virus mother-to-child transmission control in resource-limited areas. Transl Gastroenterol Hepatol 2025;10:58.

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