Clinical and Molecular Hepatology

"Combination therapy"

Original Article

RNAi-mediated HBV antigen shutdown enhances the antiviral immune effects of PEGIFNα via T and B cell crosstalk remodeling: Wenjing Zai, Kongying Hu, Mengying He, Ziyang Song, Pan Gao, Chen Luo, Minxiang Xie, Asha Ashuo, Min Yang, Jieliang Chen, Zhenghong Yuan; Received April 17, 2026 Accepted September 3, 2026 Published online September 11, 2026; DOI: https://doi.org/10.3350/cmh.2026.0385 [Accepted]

Abstract
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Backgrounds/Aims
PEGylated interferon-α (PEGIFNα) shows promise in treating chronic hepatitis B (CHB), yet patient response remains suboptimal. While suppressing hepatitis B virus (HBV) antigens by RNA interference (RNAi) could enhance PEGIFNα efficacy in CHB patients, the underlying immunological mechanisms remain obscure.
Methods
Using our newly established extracellular humanized IFNAR (IFNAR-hEC) mouse model of chronic HBV infection, we evaluated the efficacy of a GalNac-conjugated siRNA (GalNac-siHBV) alone or in combination with PEGIFNα. Phenotypic and functional characteristics of immune cells were assessed by flow cytometry, ELISpot, and single-cell RNA sequencing (scRNA-seq).
Results
High circulating HBsAg reduced antiviral effects and immune responsiveness of PEGIFNα. Combined PEGIFNα and RNAi therapy synergistically and durably suppressed HBsAg (~4log10 IU/mL, vs PBS) and achieved HBsAg seroconversion in ~30% of mice, outperforming either monotherapy. Mechanistically, PEGIFNα enhanced global T and B cell function, whereas combined therapy further amplified HBV-specific T and B cell responses. scRNA-seq analysis indicated that combined therapy attenuated inhibitory B cell-B cell interactions, strengthened MHC-I-mediated T cell crosstalk, and enhanced MHC-II signaling networks across B cells and hepatocytes/Cd8+ T cells, collectively improving the lymphocyte functionality and facilitating HBsAg seroconversion. Reinforcing MHC-I/II signaling with agonistic antibodies (α4-1BB, αCD40) or IL-2-Fc further potentiated antiviral immune responses of combinational regimen.
Conclusions
Combined RNAi and PEGIFNα therapy exerts synergistic antiviral effects by relieving HBV antigen-induced immune tolerance and orchestrating a functional T cell-B cell crosstalk network centered on MHC-I/II signaling. Enhancing antigen presentation pathways represents a promising adjunctive strategy to improve functional cure rate of CHB.

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Research Letter

Noncanonical EZH2 activity cooperates with FOXM1 to drive tumorigenesis and advanced progression in HCC: Sungju Jung, Hyun Jin Bang, Myong-Suk Park, Kyung Hwa Lee, Lothar Hennighausen, Kyung Hyun Yoo, Woo Kyun Bae; Clin Mol Hepatol 2026;32(2):e179-e184.
Published online February 2, 2026; DOI: https://doi.org/10.3350/cmh.2025.1379

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Original Articles

Viral hepatitis

Entecavir plus tenofovir versus entecavir plus adefovir in chronic hepatitis B patients with a suboptimal response to lamivudine and adefovir combination therapy: Jung Gil Park, Soo Young Park; Clin Mol Hepatol 2015;21(3):242-248.
Published online September 30, 2015; DOI: https://doi.org/10.3350/cmh.2015.21.3.242

Abstract
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Background/Aims

We compared the efficacies of entecavir (ETV) plus tenofovir (TDF) and ETV plus adefovir (ADV) in chronic hepatitis B (CHB) patients with genotypic resistance to lamivudine (LAM) who showed a suboptimal response to LAM and ADV combination therapy.

Methods

We reviewed 63 CHB patients with genotypic resistance to LAM who showed a suboptimal response to LAM and ADV combination therapy. Among these patients, 30 were treated with ETV + ADV and 33 were treated with ETV + TDF for 12 months.

Results

The only baseline characteristic that differed significantly between the two groups was the ETV resistance profile. The rate of a virologic response [serum hepatitis B virus (HBV) DNA level of <20 IU/mL] was significant higher for ETV+TDF than for ETV+ADV over 12 months (57.6% vs. 23.3%, P=0.006, at 6 months; 84.8% vs. 26.7%, P<0.001, at 12 months). The probability of a virologic response was significantly increased in ETV+TDF (P<0.001, OR=54.78, 95% CI=7.15-419.54) and decreased in patients with higher baseline viral loads (P=0.001, OR=0.18, 95% CI=0.07-0.50) in multivariate analysis. No serious adverse event occurred during the study period.

Conclusions

In patients with CHB who showed a suboptimal response to LAM and ADV combination therapy, ETV+TDF was superior to ETV+ADV in achieving a virologic response regardless of the HBV resistance profile. Further large-scale and long-term follow-up prospective studies are needed to explain these results.

Citations

Citations to this article as recorded by

Tenofovir plus entecavir combination therapy for chronic hepatitis B with nucleos(t)ide analogue failure
Bengü Tatar, Şükran Köse
The European Research Journal.2020; 6(4): 270. CrossRef
Entecavir+tenofovir vs. lamivudine/telbivudine+adefovir in chronic hepatitis B patients with prior suboptimal response
Hyun Young Woo, Jun Yong Park, Si Hyun Bae, Chang Wook Kim, Jae Young Jang, Won Young Tak, Dong Joon Kim, In Hee Kim, Jeong Heo, Sang Hoon Ahn
Clinical and Molecular Hepatology.2020; 26(3): 352. CrossRef
Is the tenofovir based therapy almighty for previous treatment failure in chronic hepatitis B?
Hyung Joon Yim
Clinical and Molecular Hepatology.2016; 22(2): 238. CrossRef
Biological Antivirals for Treatment of Adenovirus Infections
Katrin Schaar, Carsten Röger, Tanja Pozzuto, Jens Kurreck, Sandra Pinkert, Henry Fechner
Antiviral Therapy.2016; 21(7): 559. CrossRef

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Crossref

Clinical efficacy and safety of the combination therapy of peginterferon alpha and ribavirin in cirrhotic patients with HCV infection: Hong Ryeol Cheong, M.D., Hyun Young Woo, M.D., Jeong Heo, M.D., Ki Tae Yoon, M.D., Dong Uk Kim, M.D., Gwang Ha Kim, M.D., Dae Hwan Kang, M.D., Geun Am Song, M.D., Mong Cho, M.D.; Korean J Hepatol 2010;16(1):38-48.
Published online March 26, 2010; DOI: https://doi.org/10.3350/kjhep.2010.16.1.38

Abstract
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Background/Aims
The combination therapy of peginterferon (PEG-IFN) and ribavirin is the standard treatment for hepatitis C virus (HCV) infection. However, few trials have involved patients with cirrhosis. The purpose of this study was to elucidate the efficacy and safety of treatment with PEG-IFN and ribavirin in patients with cirrhosis associated with HCV infection. Method: A total of 65 patients were treated with PEG-IFN alpha-2a/ribavirin (n=32) or PEG-IFN alpha-2b/ribavirin (n=33). PEG-IFN alpha-2a and PEG-IFN alpha-2b were administered at doses of 180 μg/week and 1.5 μg/kg/week, respectively, and ribavirin was administered orally at doses of 800-1200 mg. Patients with HCV genotype 1 and genotype non-1 were treated for 48 and 24 weeks, respectively. The treatment response was assessed based on the sustained virologic response (SVR). Results: The early virologic response (EVR), end-of-treatment response (ETR), and SVR were 70.0%, 52.0%, and 24.0%, respectively, in genotype 1 (n=50). In genotype non-1 (n=15), the ETR was 53.3% and the SVR was 33.3%. The overall SVR did not differ with genotype (1vs non-1, 24.0%vs.33.3%; P=0.471) or between decompensated cirrhosis and compensated cirrhosis (20.0%vs.27.3%, P=0.630). Ten patients developed cirrhotic complications during the treatment, and 11 stopped treatment due to treatment -related adverse events. Conclusion: The combination therapy of PEG-IFN and ribavirin exhibited a low efficacy in cirrhotic patients with HCV infection and was associated with frequent serious complications. However, with careful management of complications, the therapy may have a considerable efficacy in some patients with cirrhosis and HCV infection. (Korean J Hepatol 2010;16:38-48

Citations

Citations to this article as recorded by

Favorable Outcomes of Chinese HCV-Related Cirrhotic Patients with Sustained Virological Response after Pegylated Interferon Plus Ribavirin Treatment
Geng-lin Zhang, You-ming Chen, Ting Zhang, Qing-xian Cai, Xiao-hong Zhang, Zhi-xing Zhao, Chao-shuang Lin, Zhi-liang Gao
BioMed Research International.2017; 2017: 1. CrossRef
Renewed 2015 Clinical Practice Guidelines for Management of Hepatitis C by Korean Association for the Study of the Liver; What Has Been Changed? - Treatment of Patients with Decompensated Cirrhosis
Geum-Youn Gwak
The Korean Journal of Gastroenterology.2016; 67(3): 137. CrossRef
KASL clinical practice guidelines: management of hepatitis C

Clinical and Molecular Hepatology.2016; 22(1): 76. CrossRef
Treatment Response and Long-Term Outcome of Peginterferon α and Ribavirin Therapy in Korean Patients with Chronic Hepatitis C
Chang Ho Jung, Soon Ho Um, Tae Hyung Kim, Sun Young Yim, Sang Jun Suh, Hyung Joon Yim, Yeon Seok Seo, Hyuk Soon Choi, Hoon Jai Chun
Gut and Liver.2016; 10(5): 808. CrossRef
Treatment of Hepatitis C in Special Conditions: Liver Cirrhosis
Geum-Youn Gwak
Korean Journal of Medicine.2015; 88(6): 643. CrossRef
Pegylated interferon α‐2a plus ribavirin for decompensated hepatitis C virus‐related cirrhosis: relationship between efficacy and cumulative dose
Yan Xu, Wenqian Qi, Xu Wang, Ping Zhao, Yonggui Zhang, Qian Zhang, Shaoyou Qin, Jiangbin Wang
Liver International.2014; 34(10): 1522. CrossRef
KASL clinical practice guidelines: Management of Hepatitis C

Clinical and Molecular Hepatology.2014; 20(2): 89. CrossRef
Clinical and epidemiological features of hepatitis C virus infection in South Korea: A prospective, multicenter cohort study
Mun Hyuk Seong, Ho Kil, Young Seok Kim, Si Hyun Bae, Youn Jae Lee, Han Chu Lee, Byung Hak Kang, Sook-Hyang Jeong
Journal of Medical Virology.2013; 85(10): 1724. CrossRef
A Case of Interstitial Pneumonitis and Pancytopenia Following the Combination Therapy of Pegylated Interferon and Ribavirin
Ji-Hyun Suh, Sung Hwahn Hahn, Ji Eun Lee, Jin Hyung Han, Kyung-Mook Kim, Doh-Hyung Kim, Yon-Seop Kim, Jae-Suk Park, Young-Koo Jee
Tuberculosis and Respiratory Diseases.2011; 70(1): 69. CrossRef