Entecavir Add-on Peg-Interferon Therapy Plays a Positive Role in Reversing Hepatic Fibrosis in Treatment-Naïve Chronic Hepatitis B Patients: A Prospective and Randomized Controlled Trial
Chronic hepatitis B (CHB) is a significant global health challenge, with approximately 257 million people infected worldwide. Despite the availability of effective vaccines and antiviral therapies, achieving a functional cure—defined as the loss of hepatitis B surface antigen (HBsAg) with or without the presence of hepatitis B surface antibody (HBsAb)—remains elusive for many patients. Nucleos(t)ide analogs (NAs), such as entecavir (ETV), are widely used due to their ability to suppress hepatitis B virus (HBV) DNA replication, improve liver function, and enhance histology. However, the addition of pegylated interferon (Peg-IFN) to NA therapy has been explored to enhance therapeutic outcomes, though the results have been controversial. This study aimed to evaluate the efficacy of ETV monotherapy versus ETV combined with Peg-IFN in treatment-naïve CHB patients, focusing on HBsAg seroconversion, sustained virologic response, and hepatic fibrosis reversal.
Study Design and Methodology
This prospective, randomized controlled trial was conducted between August 2013 and January 2015 at the Shanghai Public Health Clinical Center and Zhongshan Hospital in China. A total of 144 treatment-naïve CHB patients were enrolled and randomly assigned to two groups in a 1:1 ratio. The first group received ETV monotherapy (n = 70), while the second group received ETV with Peg-IFN add-on therapy from week 26 to week 52 (n = 74). Both groups were followed up for at least 2 years. Key endpoints included HBsAg and hepatitis B e antigen (HBeAg) seroconversion rates, sustained virologic response, transient elastography values, and histological scores. These parameters were assessed every 3 months until the study’s conclusion. The primary endpoint was the rate of HBsAg loss.
Baseline Characteristics
The baseline characteristics of the two groups were comparable. All patients were HBsAg-positive with an HBV viral load exceeding 500 IU/mL. None of the participants had decompensated liver cirrhosis. Some patients exhibited elevated alpha-fetoprotein (AFP) levels at baseline, but imaging studies ruled out liver cancer or abnormal masses.
Clinical Efficacy
The study revealed differences in clinical efficacy between the two groups at various time points. At week 52, the ETV monotherapy group demonstrated better liver function recovery compared to the combination therapy group, as evidenced by lower alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. However, by week 104, there was no significant difference in ALT and AST levels between the two groups. The monotherapy group also showed a more favorable decrease in AFP levels compared to the combination therapy group. Despite these differences, both groups exhibited significant improvements in liver function and transient elastography values over the 2-year study period.
HBsAg and HBeAg Seroconversion
At week 26, no patients in either group achieved HBsAg seroconversion. By week 52, one patient in the monotherapy group had lost HBsAg, while none in the combination group achieved this milestone. At week 78, one patient in the combination group achieved HBsAg seroconversion. By the end of the study (week 104), three patients in the combination group and one in the monotherapy group were HBsAg-negative. There was no significant difference in the HBsAg seroconversion rate between the two groups (1.8% vs. 4.1%, P = 0.809). Similarly, the HBeAg seroconversion rates were comparable (12.5% vs. 11.0%, P = 0.787).
Histological Improvement
Both groups showed significant improvements in liver histology over the study period. The combination therapy group demonstrated a greater reduction in transient elastography values compared to the monotherapy group (mean liver stiffness value: 6.6 kPa vs. 7.8 kPa, P = 0.028). Liver biopsy results also indicated better histological improvement in the combination therapy group, particularly in fibrosis stage and inflammation grade. The Ishak fibrosis score decreased more significantly in the combination therapy group compared to the monotherapy group.
Adverse Events
The combination therapy group experienced more adverse events, consistent with the known side effects of Peg-IFN. These included thyroid dysfunction, granulopenia, fever, and fatigue. In contrast, the monotherapy group had fewer adverse events, with only one case of thyroid dysfunction and one case of fatigue reported.
Discussion
The study’s findings suggest that while both ETV monotherapy and ETV combined with Peg-IFN are effective in improving liver function and histology, the addition of Peg-IFN did not significantly enhance HBsAg or HBeAg seroconversion rates. However, the combination therapy showed a more pronounced improvement in hepatic fibrosis, as evidenced by transient elastography and liver biopsy results. This aligns with previous research indicating that Peg-IFN’s immunomodulatory effects may contribute to fibrosis regression by enhancing cytotoxic T-cell activity.
The lack of significant differences in virologic response and seroconversion rates between the two groups may be attributed to the relatively short duration of Peg-IFN administration (26 weeks). Longer treatment periods or different dosing schedules might yield different outcomes, as suggested by other studies. Additionally, the small sample size and patient dropout rate may have limited the study’s ability to detect significant differences in certain endpoints.
Conclusion
In treatment-naïve CHB patients, both ETV monotherapy and ETV combined with Peg-IFN effectively improved liver function and histology. However, the addition of Peg-IFN did not significantly enhance HBsAg or HBeAg seroconversion rates or sustained virologic suppression. Nonetheless, combination therapy demonstrated a more positive role in reversing hepatic fibrosis compared to monotherapy. These findings highlight the potential benefits of combination therapy in managing hepatic fibrosis, though further research is needed to optimize treatment regimens and minimize adverse effects.
doi.org/10.1097/CM9.0000000000000857
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