Early initiation of antiviral treatment for two infants with acute HBV infection: Beneficial or unfavorable?

Abstract

Mother-to-child transmission is the major route of hepatitis B virus (HBV) infection in children, and antiviral therapy is generally deferred in infancy due to presumed immune tolerance. Here, we report the clinical course and treatment response of two infants younger than 6 months with HBV infection who initiated antiviral therapy due to elevated serum transaminase levels indicative of an immune-active status. Notably, Case #01 achieved a functional cure after 25 months of antiviral treatment. Case #02 did not achieve a functional cure but attained HBV DNA clearance and HBeAg seroconversion at 12 and 5 months of therapy, respectively. At the last follow-up visit (month 67), the HBsAg level of Case #02 was 10.70 IU/mL. These findings suggest that early antiviral intervention, initiated before 6 months of age, may be beneficial for infants with HBV infection who are in an immune-active status. A potential treatment window may exist even during early infancy; however, treatment strategies should be individualized and guided by careful clinical assessment.

1. Introduction

Mother-to-child transmission (MTCT) is the major route of hepatitis B virus (HBV) infection in children. The risk of chronicity is strongly age-dependent, with perinatal or early infancy infections leading to chronic infection in up to 90% of individuals.^[1] These observations point to the growing interest in early antiviral interventions.

Current guideline^[2] recommend initiating antiviral therapy in children aged ≥1 year with HBeAg-positive chronic hepatitis B (CHB) in the immune-active status but provide no specific guidance for infants younger than 1 year with HBV infection. Exploratory studies have shown that initiating antiviral therapy before 1 year of age can achieve functional cure rates as high as 90%, without serious adverse events.^[3] Previous studies have also reported relatively high clinical cure rates in children, with younger age at treatment initiation associated with better outcomes.^[4] For infants with HBV infection younger than 6 months, who are at an early stage of infection, whether this period represents an optimal therapeutic window remains to be elucidated.

In this case report, we describe two infants with HBV infection who initiated antiviral therapy before 6 months of age (at 3 months and 5 months). We analyzed their baseline characteristics and antiviral treatment responses, focusing particularly on functional cures, to provide therapeutic insights for early decision-making in infants with HBV infection.

2. Case presentation

Two infants with acute HBV infection through MTCT were enrolled in this study and started to receive antiviral therapy within the six months of age. Case #01 and Case #02 were a female and a male infant, respectively, who were admitted to Chinese PLA General Hospital in March 2019 and December 2019. The mothers of both infants were hepatitis B surface antigen (HBsAg) positive and hepatitis B e antigen (HBeAg) positive, with normal alanine aminotransferase (ALT) levels. Neither mother received antiviral prophylaxis during late pregnancy. The maternal HBV DNA levels before delivery were 8.46 log₁₀ IU/mL and 8.86 log₁₀ IU/mL, respectively. Both infants received standard immunoprophylaxis after birth according to current recommendations.^[5]

As shown in Table 1, Case #01 was identified as HBsAg-positive (48,240.00 IU/mL) and HBeAg-positive (1,541.00 COI) during a routine health screening at 5 months of age. HBV DNA was 7.50 log₁₀ IU/mL, and ALT was mildly elevated at 57 U/L, leading to a diagnosis of HBV infection. For Case #02, serological testing for HBV markers was performed at 1 day and 1 month after birth, both testing positive for HBsAg and HBeAg. At 3 months of age, laboratory tests revealed HBV DNA of 7.00 log₁₀ IU/mL, HBeAg of 1,015.00 COI, quantitative HBsAg (qHBsAg) of 27,022.00 IU/mL, and ALT of 151 U/L, confirming HBV infection.

Table 1.

Baseline characteristics and clinical outcomes of two HBV-infected infants receiving antiviral therapy.

Item	Case #01	Case #02
Baseline characteristics
Age (months)	5	3
Sex	girl	boy
Transmission route	MTCT	MTCT
ALT (U/L)	57	151
AST (U/L)	96	100
HBV-DNA (log10 IU/mL)	7.50	7.00
qHBsAg (IU/mL)	48,240.00	27,022.00
Mother’s HBV DNA at delivery (log10 IU/mL)	8.46	8.86
Clinical outcomes
Treatment regimen	LAM + IFN-α	NAs + IFN-α
Treatment duration (months)	28	67
Follow-up duration (months)	35	67
Undetectable HBV DNA	Yes	Yes
Time taken (months)	14	12
HBeAg seroclearance	Yes	Yes
Time taken (months)	10	6
HBeAb positivity	Yes	Yes
Time taken (months)	10	6
HBsAg loss	Yes	No (10.70 IU/mL)
Time taken (months)	25	/
HBsAb positivity	Yes (80 U/L)	No
Time taken (months)	28	/

HBV: Hepatitis B virus; MTCT: Mother-to-child transmission; ALT: Alanine aminotransferase; AST: Aspartate transaminase; qHBsAg: Quantitative hepatitis B surface antigen; HBeAg: Hepatitis B e antigen; HBeAb: Hepatitis B virus e antibody; HBsAg: Hepatitis B surface antigen; HBsAb: Hepatitis B surface antibody; LAM: Lamivudine; IFN-α: Interferon-α; NAs: Nucleos(t)ide analogues.

The parents of both infants expressed a strong willingness to initiate antiviral therapy. After detailed discussion and written informed consent, antiviral therapy was initiated at 5 months of age for Case #01 and at 3 months for Case #02. Both infants initially received oral lamivudine (LAM) at a dose of 4 mg·kg^–1·day^–1, with treatment regimens adjusted according to age and treatment response: interferon-alpha (IFN-α) could be added after 1 year of age, LAM could be switched to entecavir (ETV) after 2 years, and IFN-α could be replaced by pegylated interferon-alpha (Peg-IFN-α) after 3 years.^[5]

As shown in Figure 1A and 1B, both infants demonstrated favorable antiviral responses following individualized combination therapy.

Figure 1.

Dynamic changes in plasma ALT, HBV DNA, HBeAg, and qHBsAg levels in two HBV-infected infants during antiviral therapy. (A) Case #01 and (B) Case #02, respectively, showing longitudinal profiles of the four biomarkers over time. Treatment regimens and durations are annotated for each case. ALT: Alanine aminotransferase; HBV: Hepatitis B virus; DNA: Deoxyribonucleic acid; HBeAg: Hepatitis B e antigen; qHBsAg: Quantitative hepatitis B surface antigen; anti-HBe: Hepatitis B virus e antibody; anti-HBs: Hepatitis B surface antibody; LAM: Lamivudine; IFN-α: Interferon-α; ETV: Entecavir; Peg-IFN-α: Pegylated interferon-α.

Case #01: The infant initially received LAM monotherapy. After 7 months, the levels of HBV DNA, HBeAg, and qHBsAg declined to 3.19 log₁₀ IU/mL, 837.60 COI, and 4683.00 IU/mL, respectively. At 12 months of age, interferon alpha-2b (IFN-α-2b, 3 MU/m², subcutaneously or intramuscularly, every other day) was added to increase antiviral efficacy. After 10 months of therapy, the patient achieved HBeAg seroclearance (0.62 COI, <1.00 COI considered negative) and developed anti-HBe, with HBV DNA 2.64 log₁₀ IU/mL and qHBsAg 825.00 IU/mL. At month 14 of treatment, HBV DNA became undetectable (<40.00 IU/mL) and qHBsAg further declined to 133.60 IU/mL. By month 25, HBsAg loss was achieved (<0.05 IU/mL), while anti-HBs remained negative. IFN-α-2b was then discontinued, and LAM was continued for 3 additional months as consolidation therapy. At treatment month 28, anti-HBs appeared (80 U/L). The patient remained HBsAg negative during follow-up at month 35, with anti-HBs levels reaching 316 U/L. No significant adverse events were observed throughout the treatment and follow-up.

Case #02: Following initiation of LAM monotherapy, the patient exhibited an early virological and biochemical response, with ALT peaking at 596 U/L after 4 months of therapy. At month 6, HBeAg seroclearance (0.47 COI) and anti-HBe appearance were achieved, accompanied by a decline in HBV DNA to 3.00 log₁₀ IU/mL and qHBsAg to 2930.00 IU/mL. At treatment month 12, HBV DNA became undetectable (<40.00 IU/mL) and qHBsAg decreased to 1549.00 IU/mL. At this time (15 months of age), IFN-α-2b (3 MU/m², every other day) was added. After 11 months of IFN-α therapy (treatment month 23), qHBsAg further decreased to 459.10 IU/mL; however, the treatment effect plateaued, and IFN-α-2b was discontinued. Entecavir (ETV, 0.015 mg·kg^–1·day^–1, orally) was then initiated as monotherapy. At treatment month 33 (3 years of age), qHBsAg rebounded to 639.40 IU/mL, prompting the addition of pegylated interferon alpha-2b (Peg-IFN-α-2b, 90−120 µg/m², subcutaneously, once weekly). After 15 months of Peg-IFN-α-2b and ETV combinational therapy (treatment month 48), qHBsAg decreased to 211.10 IU/mL and Peg-IFN-α-2b was discontinued, while ETV monotherapy continued. When qHBsAg rose again to 573.00 IU/mL at month 52 of treatment, Peg-IFN-α-2b was reintroduced, leading to a gradual and sustained decline in qHBsAg to 10.70 IU/mL by month 67. The patient maintained good adherence and experienced no significant adverse reactions during therapy.

Overall, both cases showed viral suppression and either HBsAg clearance or a marked decline following early sequential combination antiviral therapy, with excellent tolerance and safety.

Written informed consent for the publication of case details and related laboratory test results was provided by the parents or legal guardians of the patients.

3. Discussion

This report describes two infant cases of acute HBV infection who initiated antiviral therapy before 6 months of age, at a very early stage of infection. Both patients showed favorable antiviral responses: Case #01 achieved a functional cure, while Case #02 attained HBV DNA loss, HBeAg seroconversion, and a substantial decline in HBsAg levels to 10.70 IU/mL at the last follow-up. These findings suggest that initiating antiviral therapy before 6 months of age is safe and may offer meaningful clinical benefits in HBV-infected infants.

Traditionally, early antiviral intervention has not been recommended in infants, as HBV infection during this period has long been regarded as an immune-tolerant status.^[2] However, emerging evidence indicates that some infants may exhibit immune activation during early infection.^[3,6] In this study, both patients showed indications of immune activation at baseline, such as elevated ALT levels, which prompted therapy. Given the absence of approved antiviral drugs for HBV-infected infants under one year, LAM was chosen for initial monotherapy despite being considered a second-line agent, based on its well-established safety profile in HIV-infected infants.^[7]

The potential clinical benefits of antiviral therapy during infancy have been suggested, but the underlying immunological mechanisms remain largely unexplored. Previous studies have shown that HBV-infected infants may retain HBV-specific immune cells capable of mediating effective antiviral responses.^[8] The observed clinical benefits of early treatment may relate to the incomplete establishment of immune tolerance during infancy. In addition, individual differences likely contribute to treatment outcomes: Case #01 exhibited a classic response pattern characterized by ALT elevation, HBV DNA decline, and eventual HBsAg clearance—suggesting robust HBV-specific T-cell activity capable of coordinated viral clearance. In contrast, Case #02 showed an initial virological and serological response but did not achieve HBsAg clearance, possibly reflecting differences in immune system maturity. Notably, The ALT kinetics differed markedly between the two cases. Case #01 presented with only mildly elevated baseline ALT (57 U/L), whereas Case #02 had a higher baseline ALT (151 U/L) and experienced a significant ALT flare (596 U/L) during treatment. Although elevated ALT is generally considered a surrogate marker of active immune-mediated liver injury and has been associated with favorable treatment responses, Case #01—with lower baseline ALT—achieved a functional cure. This finding suggests that the magnitude of ALT elevation alone is not a definitive predictor of treatment response, and its clinical significance should be interpreted in conjunction with virological, immunological, and other host-related parameters. Moreover, initiating therapy during even mild ALT elevation may capture a favorable window for an effective immune response. Nevertheless, prior studies have identified HBeAg seroconversion combined with HBsAg <1000 IU/mL as a strong predictor of a clinical cure in pediatric CHB patients under 18 years of age,^[9] implying that Case #02 may still achieve a functional cure over time.

Although the two cases suggest potential clinical benefits of antiviral therapy in very young infants, the safety profile requires careful evaluation. In particular, the possible impact of IFN-α on infant growth remains an important clinical concern. IFN-α therapy has been reported to induce transient growth retardation, with such adverse reactions generally reversible after treatment withdrawal.^[10] Given the small sample size and limited follow-up in our study, the long-term developmental outcomes cannot be fully characterized. Moreover, the overall long-term risk–benefit profile of initiating antiviral therapy before six months of age remains unclear. It is not yet established whether short-term serological responses translate into sustained clinical benefit, the potential long-term harms and benefits should be evaluated in larger cohorts with extended follow-up. Therefore, early intervention in very young infants should be approached with caution, with close safety monitoring and prolonged follow-up to achieve a more balanced assessment of potential risks and benefits.

As an exploratory case report, this study has certain limitations. First, it included only two cases, and as with all case reports, the findings are preliminary and require validation in larger cohorts. Second, systematic immunological testing was not performed, preventing clarification of the mechanisms underlying early treatment benefits. Future large-scale prospective studies are needed to define the optimal therapeutic window and antiviral regimen for infants with HBV infection and to explain the immunological mechanisms of early treatment responses. Such evidence is essential for establishing evidence-based, precise treatment strategies for infants with HBV infection.

Acknowledgments

We would like to express our thanks to the patients that participated in this study.

Author Contributions

Fu-Sheng Wang and Shishu Zhu designed and supervised the study; Shishu Zhu was responsible for management of enrolled infants with CHB; Shishu Zhu, Peiyao Fan and Jing Li participated in data acquisition and initial analysis; Peiyao Fan, Jing Li, Shishu Zhu and Fu-Sheng Wang performed data analyses and interpretation, drew all the figures, organized the data in all tables, and drafted the manuscript; Fu-Sheng Wang and Peiyao Fan finalized the manuscript. All authors approved the final manuscript for its publication.

Conflicts of Interest

None.

Editor note: Fu-Sheng Wang is the Editor-in-Chief of Infectious Diseases & Immunity. The article was subject to the journal’s standard procedures, with peer review handled independently by this editor and his research group.

Data Availability Statement

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Funding Statement

This study was supported by the National Key Research and Development Project (2023YFC2308100), and the China National Natural Science Foundation (82130019).