Editor's Note: Antiviral treatment can maximize the long-term suppression of hepatitis B virus (HBV) DNA replication, reducing liver necrosis, fibrosis, cirrhosis, liver cancer, and other complications, thereby improving the quality of life and extending the survival time of hepatitis B patients. Currently, long-acting interferon is recommended as a first-line treatment option by guidelines in Europe, the United States, the Asia-Pacific region, and China. Long-acting interferon treatment for chronic hepatitis B (CHB) offers a greater probability of achieving clinical cure and is also the most effective means of reducing the risk of liver cancer. Recently, at the 17th National Conference on Clinical Liver Diseases in 2024, Professor Qing Xie from Ruijin Hospital presented a report titled "Contributions and Challenges of Long-Acting Interferon in the Clinical Cure of Chronic Hepatitis B." This article from Hepatology Digest summarizes the report for our readers.Current Development Status of Clinical Cure for CHB
Around 2010, China began early explorations into the clinical cure of CHB. Between 2017 and 2018, China’s clinical cure of CHB gained international recognition. From 2019 to 2021, the clinical cure of CHB in China entered a phase of rapid and in-depth development. In 2022, the “Guidelines for the Prevention and Treatment of Chronic Hepatitis B (2022 Edition)” (hereinafter referred to as the “Guidelines”) were published, which suggested that for eligible patients, a clinical cure should be pursued. The guidelines recommend that patients who have advantages from nucleos(t)ide analogs (NAs) treatment should be treated with pegylated interferon alpha (PEG-IFNα) to achieve clinical cure. Consequently, the population eligible for antiviral treatment and clinical cure began to expand.
In August 2022, the National Institutes of Health (NIH) in the United States updated the Trans-NIH Strategic Plan for HBV Cure, reiterating the definition of HBV cure and establishing the vision of eliminating HBV. The mission includes developing strategies for the cure of CHB, enhancing vaccine coverage, and expanding screening and monitoring.
Professor Wen Juei Jeng from Chang Gung Memorial Hospital in Taiwan, China, and former American Association for the Study of Liver Diseases (AASLD) President Professor Anna Lok co-authored a review on HBV cure strategies, emphasizing that clinical cure remains the ideal goal for HBV treatment globally.
Clinical Application of Interferon in CHB Treatment
A meta-analysis encompassing 57 studies, including 2 prospective cohort studies, 22 prospective cohort studies, and 33 retrospective cohort studies, analyzed data from 258,744 HBsAg-positive patients, of whom 63,270 (24.4%) achieved HBsAg clearance. Patients who cleared HBsAg were designated as Group A, while those who did not were designated as Group B. The primary outcome was the difference in hepatocellular carcinoma (HCC) incidence between the two groups, with secondary outcomes including differences in cirrhosis, liver decompensation events, all-cause mortality, and liver-related mortality. The results indicated that the incidence of HCC was 0.84% in Group A and 3.14% in Group B. The incidence of cirrhosis was 2.95% in Group A and 8.18% in Group B. The incidence of liver decompensation was 0.31% in Group A and 2.53% in Group B. The liver-related mortality rate was 0.04% in Group A compared to 1.89% in Group B. These results demonstrate that multiple disease-related risks are significantly reduced after HBsAg clearance.
At the 2020 AASLD annual meeting, a long-term real-world follow-up study of CHB patients treated with NAs was reported. This retrospective study was conducted across 13 centers in eight countries or regions in the United States, Europe, and the Asia-Pacific, involving treatment-naïve CHB patients treated with either entecavir (ETV) or tenofovir disoproxil fumarate (TDF) monotherapy. The study observed the HBsAg clearance rate over a follow-up period of up to 10 years (until patient death, data loss, or March 1, 2020). The adjusted competing risk analysis calculated the HBsAg clearance rate and explored determinants of HBsAg clearance. The results showed a 10-year cumulative HBsAg clearance rate of only 2.29%.
PEG-IFNα has a dual mechanism of direct antiviral and immune modulation effects, achieving persistent immune control over HBV, accelerating the decline of viral antigens in blood and liver, and promoting NK cell proliferation. NAs can strongly inhibit viral replication and assist in the functional reconstruction of HBV-specific CD8+ T cells. Combining PEG-IFNα with NAs aids in the reconstruction of immune response.
Recent AASLD data and other published studies indicate that PEG-IFNα combined with NAs can enhance the clinical cure rate of CHB compared to monotherapy.
The “Everest Project” included CHB patients treated with NAs for more than one year, with HBsAg ≤ 1500 IU/mL, HBeAg negative, and HBV DNA < 100 IU/mL. These patients received sequential/combination PEG-IFNα treatment for 48 weeks, or up to 96 weeks. In the 3.5-year interim analysis, 3988 people were included in the per-protocol (PP) analysis set. The results showed a 48-week HBsAg clearance rate of 33.2%. Among those who did not achieve HBsAg clearance at 48 weeks, 66.6% achieved HBsAg < 100 IU/mL. These results indicate that sequential/combination PEG-IFNα significantly improves the clinical cure rate for patients with NAs advantages.
A meta-analysis showed that the HBsAg clearance rate in inactive HBsAg carrier patients treated with PEG-IFNα for 48 weeks was 47%. Additionally, the lower the baseline HBsAg level, the higher the HBsAg clearance rate, which further increases with prolonged PEG-IFNα treatment.
A study found that postpartum CHB patients treated with PEG-IFNα-2b and TDF achieved an HBsAg clearance rate of over 40%. The study included NAs-treated postpartum women aged 25-41 years with HBsAg ≤ 3000 IU/mL at 6-48 weeks postpartum. All patients received combined PEG-IFNα-2b and TDF treatment for 48 weeks, with early achievers of HBsAg clearance stopping treatment. Among the 12 patients who completed treatment, 9 were HBeAg positive. The HBsAg clearance rate was 41.7%, HBsAg seroconversion rate was 33.3%, HBeAg seroconversion rate was 100%, and HBV DNA negativity (< 20 IU/mL) was 58.3%. The median treatment duration for HBsAg clearance was 37.4 weeks. Patients who achieved HBsAg clearance started combination treatment earlier postpartum and had a greater HBsAg decline at 12 or 24 weeks.
Notably, a study reported at the 2013 EASL meeting mentioned that the absolute number of CD8+ T cells significantly decreased (P < 0.001) during long-term PEG-IFNα treatment. PEG-IFNα exerts different effects on innate and adaptive immune systems, and its efficacy may be limited by its depletion of CD8+ T cells.
In 2021, Academician Fusheng Wang and other experts proposed the concept and application strategy of intermittent treatment. Intermittent treatment refers to PEG-IFNα being administered in a “treatment-intermission-retreatment” manner on the basis of continuous NAs treatment. Intermittent treatment helps restore immune function and increases the chance of clinical cure for CHB patients.
The Need for New Drug Development for CHB Cure
Professor Qing Xie stated that currently, we have drugs targeting the HBV life cycle and those modulating host immune response. However, the cure for CHB still anticipates the development of new drugs.
Professor Xie introduced three major challenges faced in the development of new drugs for clinical cure of CHB.
First, what is the best combination therapy? For example, the dual therapy of EYP001 + PEG-IFNα showed more significant HBsAg reduction compared to the triple therapy of EYP001 + PEG-IFNα + ETV.
Second, new clinical studies seldom use HBsAg clearance as the primary efficacy endpoint. For instance, phase III trials of GLS4 and NASVAC mainly focus on HBV DNA suppression as the primary endpoint. Some new drugs show good efficacy during treatment but lack durability, such as GSK836, where the proportion of patients achieving HBsAg clearance dropped from nearly 30% at the end of treatment to about 10% after 24 weeks of follow-up.
Third, gene-editing drugs are progressing slowly and currently are in preclinical stages, with issues such as low editing efficiency. For example, cytosine base editors can effectively reduce viral biomarkers, but their editing rate is only 50%-80%, not achieving 100% editing or complete HBsAg clearance.
