# CLINICAL and MOLECULAR HEPATOLOGY The forum for latest knowledge of hepatobiliary diseases ## Bacteroides eggerthii for MASLD Infiltrative HCC as an immunotherapy-resistant subtype SGLT2 inhibitors and liver fibrosis progression Aspirin and HCC risk in MASLD Hypothyroidism and liver-related events ![](https://assets.reachrx.ai/images/10.3350%E2%98%8Dcmh.2025.0379/_page_0_Picture_6.jpeg) ### CLINICAL and MOLECULAR HEPATOLOGY #### Correspondence https://doi.org/10.3350/cmh.2025.0379 Clinical and Molecular Hepatology 2026;32:e55-e57 ## Correspondence to editorial on "Switching to besifovir in patients with chronic hepatitis B receiving tenofovir disoproxil fumarate: A randomized trial" Hyung Joon $Yim^{1,*}$ , Seong Hee $Kang^{1,*}$ , Young Kul Jung¹, and Jin Mo $Yang^2$ ¹Department of Internal Medicine, Korea University Ansan Hospital, Ansan; ²Department of Internal Medicine, St. Vincent's Hospital, The Catholic University of Korea, Suwon, Korea Keywords: Chronic hepatitis; Hepatitis B; Besifovir; Tenofovir; Treatment Dear Editor. We thank Professor Seto for his comprehensive review and comments on our paper.^1,2 As he mentioned, besifovir maleate (BSV) showed non-inferior virological responses compared to tenofovir disoproxil fumarate (TDF) in the phase 3 clinical trial with lower drug-related adverse events in treatment-naïve patients with chronic hepatitis B (CHB) after 48-week administration of either antiviral agent.³ During the double-blind period, paired liver biopsy was performed, and necroinflammatory activity was significantly improved more in the BSV arm compared with the TDF arm.⁴ Extension of the phase 3 study showed no emergence of antiviral resistance and maintained safety after long-term therapy.^5,6 Recently, BSV was shown to decrease the risk of developing hepatocellu- lar carcinoma.7 However, previous studies included only treatment-naïve patients with CHB. In the present study, we investigated whether switching to BSV can exhibit comparable efficacy and better safety in patients with CHB under long-term TDF therapy compared with maintaining TDF.¹ As reported, BSV was shown to be non-inferior to TDF in maintaining the virologic response achieved by TDF. Statistical analyses were performed using the per-protocol set as well as the full analysis set (FAS) in which seven patients were excluded from each group due to violation of exclusion criteria (history of antiviral resistance, prior exposure to BSV, or positive antibody to human immunodeficiency virus), withdrawal of consent to the trial, pregnancy or follow-up loss. Of note, the FAS included all patients who had taken the study medication at least once or more if they fulfilled the #### **Corresponding author:** Hyung Joon Yim Department of Internal Medicine, Korea University Ansan Hospital, 123 Jeokgeum-ro, Danwon-gu, Ansan 15355, Korea Tel: +82-31-412-6565, Fax: +82-31-412-5582, E-mail: gudwns21@korea.ac.kr https://orcid.org/0000-0002-6036-2754 #### Jin Mo Yang Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, 93 Jungbu-daero, Paldal-gu, Suwon 16247, Korea Tel: +82-31-249-8211, Fax: +82-31-253-8898, E-mail: jmyangdr@catholic.ac.kr https://orcid.org/0000-0002-8339-4716 \*Equally contributed to this work. Editor: Han Ah Lee, Chung-Ang University College of Medicine, Korea Received: Apr. 7, 2025 / Accepted: Apr. 8, 2025 enrollment criteria. Hence, those with low compliance with the study protocol were not excluded from this set. A modified intention to treat (mITT) analysis was performed with FAS, and the results are shown in the supplementary tables in detail.1 Briefly, a total of 139 patients were included, and the virologic response rate at week 48 was 100% (69/69) and 98.6% (69/70) in the BSV and the TDF groups, respectively (*P*=1.00). The rate of normal alanine aminotransferase was 89.9% (62/69) and 85.7% (60/70) (*P*=0.456), and the HBeAg seroconversion rate among the HBeAg positive subjects was 14.3% (4/28) and 10.7% (3/28) (*P*=1.000) in each group, respectively, at week 48. Only one patient achieved HBsAg seroconversion, suggesting a functional cure in the BSV group while no one was in the TDF group (*P*=0.43). Overall, the results of the mITT analysis were similar to those of per-protocol analysis, suggesting comparable antiviral efficacy of BSV to TDF in patients who received long-term TDF therapy. Furthermore, data from the mITT analysis using FAS is close to real-life experiences. Hence, as reported, improved bone and renal safety profiles assessed by bone mineral density and estimated glomerular filtration rate propose the rationale for switching TDF to BSV in TDF-experienced patients. A comparison of antiviral efficacy and safety between switching to BSV and to tenofovir alafenamide (TAF) would be necessary for CHB patients receiving TDF, as Dr. Seto mentioned in the Editorial.² Recently, a comparison of BSV and TAF has been performed in treatment-naïve CHB patients by our study group.8 The clinical outcomes, such as the virologic response and incidence of liver-related complications, were not significantly different between the groups. We expect the results of the comparison between BSV and TAF in TDF-experienced patients would be similar. However, the rate of functional cure is still low with current antiviral agents, so combination with emerging therapeutics would be needed.9,10 In conclusion, BSV is a promising alternative to TDF in treatment-naïve as well as TDF-experienced patients with CHB. In the future, we hope BSV will be available worldwide soon to conquer the chronic HBV infection globally. #### **Authors' contribution** H.J.Y. and S.H.K. drafted and finalized the manuscript, and Y.K.J., and J.M.Y. revised the manuscript. All authors reviewed the manuscript. #### **Acknowledgements** This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (RS-2023-00217123). #### **Conflicts of Interest** The authors have no conflicts to disclose. #### **REFERENCES** - 1. Yim HJ, Seo YS, Kim JH, Kim W, Jung YK, Jang JY, et al. Switching to besifovir in patients with chronic hepatitis B receiving tenofovir disoproxil fumarate: A randomized trial. Clin Mol Hepatol 2025;31:810-822. - 2. Seto WK. Besifovir: a viable option for long-term disease control in chronic hepatitis B: Editorial on "Switching to besifovir in patients with chronic hepatitis B receiving tenofovir disoproxil fumarate: A randomized trial". Clin Mol Hepatol 2026;32:374- 376. - 3. Ahn SH, Kim W, Jung YK, Yang JM, Jang JY, Kweon YO, et al. Efficacy and Safety of besifovir dipivoxil maleate compared with tenofovir disoproxil fumarate in treatment of chronic hepatitis B virus infection. Clin Gastroenterol Hepatol 2019;17:1850- 1859.e4. - 4. Yim HJ, Kim W, Ahn SH, Jung YK, Um SH, Sohn JH, et al. Besifovir therapy improves hepatic histology and reduces covalently closed circular DNA in chronic hepatitis B patients. J Gastroenterol Hepatol 2022;37:378-386. - 5. Yim HJ, Kim W, Ahn SH, Yang JM, Jang JY, Kweon YO, et al. Besifovir dipivoxil maleate 144-week treatment of chronic hepatitis B: an open-label extensional study of a phase 3 trial. Am J Gastroenterol 2020;115:1217-1225. - 6. Song DS, Kim W, Ahn SH, Yim HJ, Jang JY, Kweon YO, et al. Continuing besifovir dipivoxil maleate versus switching from tenofovir disoproxil fumarate for treatment of chronic hepa- #### **Abbreviations:** BSV, besifovir; CHB, chronic hepatitis B; FAS, full analysis set; mITT, modified intention-to-treat analysis; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate - titis B: results of 192-week phase 3 trial. Clin Mol Hepatol 2021;27:346-359. - 7. Yim HJ, Kang SH, Jung YK, Ahn SH, Kim W, Yang JM, et al. Reduced risk of hepatocellular carcinoma in patients with chronic hepatitis B receiving long-term besifovir therapy. Cancers (Basel) 2024;16:887. - 8. Kim TH, Kim JH, Yim HJ, Seo YS, Yim SY, Lee YS, et al. Noninferiority outcomes of besifovir compared to tenofovir alafenamide in treatment-naïve patients with chronic hepatitis B. Gut - Liver 2024;18:305-315. - 9. Hui RW, Mak LY, Fung J, Seto WK, Yuen MF. Prospect of emerging treatments for hepatitis B virus functional cure. Clin Mol Hepatol 2025;31(Suppl):S165-S181. - 10. Wu D, Kao JH, Piratvisuth T, Wang X, Kennedy PTF, Otsuka M, et al. Update on the treatment navigation for functional cure of chronic hepatitis B: expert consensus 2.0. Clin Mol Hepatol 2025;31(Suppl):S134-S164.