Unsatisfying Antiviral Therapeutic Effect in Patients with Mother-to-Child Transmitted Chronic Hepatitis B Virus Infection: A Prospective Multi-Center Clinical Study
Introduction
Hepatitis B virus (HBV) is a hepatotropic virus that can cause both acute and chronic liver disease. Chronic HBV infection can lead to severe complications such as cirrhosis and hepatocellular carcinoma (HCC). Globally, an estimated 257 million people are living with chronic HBV infection, resulting in nearly one million deaths annually. The likelihood of an HBV infection becoming chronic depends on the age at which the infection occurs. While less than 5% of healthy adults infected with HBV develop chronic infection, the risk increases significantly in children, particularly those infected before the age of six, with up to 90% of infants developing chronic infection. Mother-to-child transmission (MTCT) is the most critical mode of transmission leading to chronic HBV infection. Despite postnatal active immunization in 94% of children, MTCT remains a major route of new HBV infections, accounting for 36% to 45% of chronic HBV cases in China.
The natural history of chronic HBV infection is divided into several phases, including immune tolerance (IT), immune clearance, low replicative, reactivation, and occult HBV infection. The IT phase, traditionally considered a disease-free period, has been challenged by recent studies suggesting that it may not be entirely asymptomatic. This study aimed to investigate the progression of liver disease and the therapeutic efficacy of antiviral treatment in adult chronic HBV carriers infected via MTCT compared to those infected through horizontal transmission.
Methods
This multi-center, prospective, longitudinal study was conducted across 24 teaching hospitals in mainland China from October 2013 to May 2016. A total of 770 treatment-naïve adult patients with chronic HBV infection were enrolled. Patients with other forms of chronic liver disease, heavy alcohol consumption, previous antiviral treatment, decompensated liver cirrhosis, HCC, or incomplete data were excluded. Ultimately, 683 patients, including 191 with MTCT and 492 with horizontal transmission, were included in the analysis.
Liver biopsies were performed at baseline and after 78 weeks of antiviral therapy to assess liver fibrosis and necro-inflammation using the Ishak scoring system. Significant fibrosis (SF) was defined as an Ishak fibrosis score (F) ≥3, and moderate to severe inflammation was defined as a histology activity index (HAI) ≥5. Non-invasive markers of liver fibrosis and inflammation, including laminin (LN), hyaluronic acid (HA), N-terminal propeptide of Type III procollagen (PIIINP), and matrix metalloproteinase-3 (MMP-3), were also measured. Liver stiffness measurement (LSM) was evaluated using transient elastography (FibroScan).
Results
Baseline Characteristics
Patients infected via MTCT were more likely to be hepatitis B e antigen (HBeAg) positive (68.6% vs. 58.2%, P = 0.012) compared to those with horizontal transmission. Although not statistically significant, MTCT patients had slightly higher levels of hepatitis B surface antigen (HBsAg) and HBV DNA. MTCT patients also exhibited higher levels of alkaline phosphatase (ALP) and lower levels of albumin (ALB), indicating more severe liver damage. Additionally, MTCT patients had higher levels of non-invasive markers such as PIIINP and LN, reflecting increased liver fibrosis.
Histological Findings
At baseline, 47.2% of MTCT patients had significant liver fibrosis (Ishak F ≥3) compared to 36.8% of horizontal transmission patients (P = 0.013). Moderate to severe inflammation (HAI ≥5) was observed in 60.7% of MTCT patients and 57.3% of horizontal transmission patients. Overall, 71.7% of MTCT patients and 65.9% of horizontal transmission patients required antiviral therapy based on their fibrosis and inflammation scores.
Antiviral Treatment Response
After 78 weeks of antiviral therapy, 21.2% of MTCT patients achieved HBeAg clearance compared to 38.0% of horizontal transmission patients (P = 0.043). The virological response rate (HBV DNA <20 IU/mL) was significantly lower in MTCT patients (54.7% vs. 74.1%, P = 0.005). HBeAg seroconversion rates were 13.5% and 26.6% in MTCT and horizontal transmission groups, respectively. No significant differences were observed in histological response or fibrosis stabilization between the two groups.
Risk Factors for Treatment Response
Multivariate analysis identified MTCT as an independent risk factor for both HBeAg clearance (P = 0.028) and virological response (P = 0.038). Other predictors of poor treatment response included higher baseline Ishak fibrosis scores and higher HBV DNA levels.
Discussion
This study highlights the challenges in managing chronic HBV infection in patients infected via MTCT. Despite the traditional view that MTCT leads to a prolonged immune-tolerant phase with minimal liver damage, our findings suggest that these patients are more prone to severe liver disease, including significant fibrosis and inflammation. The poor therapeutic efficacy observed in MTCT patients underscores the need for earlier and longer-term antiviral treatment strategies.
The higher levels of non-invasive markers such as PIIINP and LN in MTCT patients indicate active fibrogenesis, even in the absence of significant clinical symptoms. The lower levels of MMP-3, a key enzyme in extracellular matrix turnover, further suggest impaired fibrolysis in these patients. These findings challenge the notion that the IT phase is entirely asymptomatic and disease-free.
The study also emphasizes the importance of interrupting perinatal transmission to reduce the burden of chronic HBV infection. Despite high vaccination coverage, MTCT remains a significant contributor to new HBV infections, particularly in endemic regions.
Limitations
This study has several limitations. The mode of transmission was based on patient-reported family history, which may introduce recall bias. Additionally, only 217 patients had paired liver biopsies for antiviral efficacy analysis, limiting the generalizability of the findings. Future studies with larger sample sizes are needed to confirm these results.
Conclusion
Adult patients with chronic HBV infection acquired via MTCT are more likely to have severe liver disease and poorer responses to antiviral therapy compared to those infected through horizontal transmission. These findings highlight the importance of earlier and longer-term treatment in MTCT patients and the need for strategies to interrupt perinatal transmission.
doi.org/10.1097/CM9.0000000000000522
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