Long-Term Hepatic and Extrahepatic Outcomes of Chronic Hepatitis C Patients After Sofosbuvir-Based Treatment (LONGHEAD Study)

Chung-Feng Huang^#¹, Jeong Heo^#², Rong-Nan Chien³, Yang-Hyun Baek⁴, Jia-Horng Kao⁵, Ju-Hyun Kim⁶, Ting-Tsung Chang⁷, Kwan-Soo Byun⁸, Jyh-Jou Chen⁹, Sook-Hyang Jeong¹⁰, Tsung-Hui Hu¹¹, Young-Seok Kim¹², Cheng-Yuan Peng¹³, Won-Young Tak¹⁴, Horng-Yuan Wang¹⁵, Seung-Kew Yoon¹⁶, I-Shyan Sheen³, Youn-Jae Lee¹⁷, Yu-Chun Hsu¹⁸, Hyung-Joon Yim¹⁹, Pei-Chien Tsai¹, Ming-Lun Yeh¹, Sang-Hoon Ahn²⁰, Chia-Yen Dai¹, Seung-Woon Paik²¹, Jee-Fu Huang¹, Yoon-Jun Kim²², Wan-Long Chuang¹, Young-Suk Lim²³, Ming-Lung Yu²⁴

Affiliations

¹ Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou Road, Kaohsiung, 807, Taiwan.
² Department of Internal Medicine, College of Medicine, Pusan National University and Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea.
³ Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan.
⁴ Department of Internal Medicine, Dong-A University College of Medicine, Busan, Republic of Korea.
⁵ Hepatitis Research Center and Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
⁶ Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Republic of Korea.
⁷ Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁸ Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea.
⁹ Liouying Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan.
¹⁰ Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
¹¹ Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan.
¹² Department of Internal Medicine, Bucheon Hospital, Soon Chun Hyang University, Asan, Republic of Korea.
¹³ Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, School of Medicine, China Medical University, Taichung, Taiwan.
¹⁴ Department of Internal Medicine, School of Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea.
¹⁵ Division of Gastroenterology, Department of Internal Medicine, Taipei Mackay Memorial Hospital, Taipei, Taiwan.
¹⁶ Department of Internal Medicine, Seoul St. Mary's Hospital, Seoul, Republic of Korea.
¹⁷ Department of Internal Medicine, Inje University Busan Paik Hospital, Busan, Republic of Korea.
¹⁸ Department of Gastroenterology and Hepatology, Changhua Christian Hospital, Changhua, Taiwan.
¹⁹ Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Republic of Korea.
²⁰ Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea.
²¹ Sungkyunkwan University, Seoul, Republic of Korea.
²² Seoul National University Hospital, Seoul, Republic of Korea.
²³ Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro43-gil, Songpa-gu, Seoul, 05505, Republic of Korea. limys@amc.seoul.kr.
²⁴ Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou Road, Kaohsiung, 807, Taiwan. fish6069@gmail.com.

^# Contributed equally.

PMID: 40205145
PMCID: PMC12084436
DOI: 10.1007/s40121-025-01145-y

Long-Term Hepatic and Extrahepatic Outcomes of Chronic Hepatitis C Patients After Sofosbuvir-Based Treatment (LONGHEAD Study)

Chung-Feng Huang et al. Infect Dis Ther. 2025 May.

. 2025 May;14(5):1089-1101.

doi: 10.1007/s40121-025-01145-y. Epub 2025 Apr 10.

Authors

Affiliations

¹ Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou Road, Kaohsiung, 807, Taiwan.
² Department of Internal Medicine, College of Medicine, Pusan National University and Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea.
³ Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan.
⁴ Department of Internal Medicine, Dong-A University College of Medicine, Busan, Republic of Korea.
⁵ Hepatitis Research Center and Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
⁶ Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Republic of Korea.
⁷ Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁸ Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea.
⁹ Liouying Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan.
¹⁰ Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
¹¹ Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan.
¹² Department of Internal Medicine, Bucheon Hospital, Soon Chun Hyang University, Asan, Republic of Korea.
¹³ Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, School of Medicine, China Medical University, Taichung, Taiwan.
¹⁴ Department of Internal Medicine, School of Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea.
¹⁵ Division of Gastroenterology, Department of Internal Medicine, Taipei Mackay Memorial Hospital, Taipei, Taiwan.
¹⁶ Department of Internal Medicine, Seoul St. Mary's Hospital, Seoul, Republic of Korea.
¹⁷ Department of Internal Medicine, Inje University Busan Paik Hospital, Busan, Republic of Korea.
¹⁸ Department of Gastroenterology and Hepatology, Changhua Christian Hospital, Changhua, Taiwan.
¹⁹ Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Republic of Korea.
²⁰ Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea.
²¹ Sungkyunkwan University, Seoul, Republic of Korea.
²² Seoul National University Hospital, Seoul, Republic of Korea.
²³ Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro43-gil, Songpa-gu, Seoul, 05505, Republic of Korea. limys@amc.seoul.kr.
²⁴ Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou Road, Kaohsiung, 807, Taiwan. fish6069@gmail.com.

^# Contributed equally.

PMID: 40205145
PMCID: PMC12084436
DOI: 10.1007/s40121-025-01145-y

Abstract

Background/aims: Direct-acting antivirals (DAAs) are highly effective in treating hepatitis C virus (HCV) infection. The long-term hepatic and extrahepatic outcomes of DAAs in chronic hepatitis C (CHC) patients receiving curative antivirals are elusive.

Methods: CHC patients were retrieved from two phase III sofosbuvir-based clinical trials conducted from 2013-2014. Patients who achieved a sustained virological response have been followed prospectively for 5 years since 2016. A propensity score-matched interferon-based historical control with a 1:3 ratio was used for comparison. Quality of life (QoL) was measured by the SF-36, liver fibrosis was measured by electrography, and fibrosis-related markers were followed annually in the prospective cohort.

Results: A total of 160 DAA- and 480 interferon-treated patients were enrolled. Twenty-eight patients developed hepatocellular carcinoma (HCC) over a follow-up period of 4424 person-years (annual incidence: 0.6%). The incidence of HCC did not differ significantly between the DAA cohort and interferon-treated patients (P = 0.07). Cox regression analysis revealed that FIB-4 was the only factor independently associated with HCC development (hazard ratio [HR]: 95% confidence interval [CI] 3.59/1.68-7.66, P = 0.001). The incidence of newly developed cardio-cerebrovascular disease was 13.8 per 1000 person-years and 0.9 per 1000 person-years in interferon-treated patients and the DAA cohort, respectively (P < 0.001). Interferon-based patients had a significantly greater incidence of cardio-cerebrovascular disease (HR/CI 3.39/1.28-8.96, P = 0.014). There was a substantial decrease in liver stiffness (P_trend = 0.08) and M2BPGi (P_trend = 0.05) and a significant reduction in LOXL2 (P_trend = 0.02) over 5 years. A significant decrease in QoL was observed in role limitations due to physical health and emotional problems, whereas the other parameters were maintained consistently throughout the 5 years of follow-up.

Conclusions: HCV eradication by DAAs improved liver- and non-liver-related outcomes, constantly promoted liver fibrosis regression, and maintained quality of life after HCV cure.

Clinical trial number: NCT03042520.

Keywords: DAA; HCV; Long-term outcome; SVR.

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Conflict of interest statement

Declarations. Conflict of Interests: Ming-Lung Yu: Research support from AbbVie, Abbott, BMS, Gilead, Merck and Roche. Consultant for AbbVie, Abbott, Ascletis, BMS, Gilead Sciences, J&J, Merck, Novartis, Pharmaessential and Roche. Speaker for AbbVie, Abbott, Ascletis, BMS, Gilead Sciences, Merck, Pharmaessential and Roche. Chung-Feng Huang: Speaker for AbbVie, BMS, Gilead Sciences, Merck, and Roche. Young-Suk Lim: Research support and consultant for Gilead Sciences. Young-Seok Kim: Speaker, consultant and grant support for Gilead Sciences. Jeong Huo, Rong-Nan Chien, Yang-Hyun Baek, Jia-Horng Kao, Ju-Hyun Kim, Ting-Tsang Chang, Kwan-Soo Byun, Jyh-Jou Chen, Sook-Hyang Jeong, Tsung-Hui Hu, Cheng-Yuan Peng, Won-Young Tak, Hrong-Yuan Wang, Seung-Kew Yoon, I-Shyan Sheen, Youn-Jae Lee, Yu-Chun Hsu, Pei-Chien Tsai, Ming-Lun Yeh, Sang-Hoon Ahn, Chai-Yen Dai, Seung-Woon Paik, Jee-Fu Huang, Yoon-Jun Kim, and Wan-Long Chuang have nothing to disclose. Ethical Approval: The study was approved by the institutional review board of Kaohsiung Medical University Hospital (KMUHIRB-F(I)-20160082), which conforms to the guidelines of the International Conference on Harmonization for Good Clinical Practice and was performed in accordance with the Helsinki Declaration of 1964 and its later amendments. All patients provided written informed consent.

Figures

**Fig. 1**
A Incidence and risk of newly developed diabetes in DAA- and interferon-treated patients. *Adjusted for age, sex, body mass index, hypertension, dyslipidemia, HCV genotype, HCV viral loads, aspartate aminotransferase, alanine transaminase, platelet counts, and FIB-4. *IFN* interferon-based patients, *DAA* direct-acting antivirals, HR hazard ratio. B Incidence and risk of newly developed cardio-cerebrovascular disease between DAA- and interferon-treated patients. **Adjusted for age, sex, body mass index, diabetes, hypertension, dyslipidemia, HCV genotype, HCV viral loads, aspartate aminotransferase, alanine transaminase, platelet counts, and FIB-4. *IFN* interferon-based patients, *DAA* direct-acting antivirals, HR hazard ratio

See this image and copyright information in PMC

References

1. Interim guidance for country validation of viral hepatitis elimination. https://www.whoint/publications/i/item/9789240028395. Accessed 08 Oct 2024. - PubMed
1. Polaris Observatory HCV Collaborators. Global change in hepatitis C virus prevalence and cascade of care between 2015 and 2020: a modelling study. Lancet Gastroenterol Hepatol. 2022;7(5):396–415. - PubMed
1. Huang CF, Tseng KC, Cheng PN, Hung CH, Lo CC, Peng CY, et al. Impact of sofosbuvir-based direct-acting antivirals on renal function in chronic hepatitis C patients with impaired renal function: a large cohort study from the nationwide HCV registry program (TACR). Clin Gastroenterol Hepatol. 2022;20(5):1151-1162.e1156. - PubMed
1. Huang CF, Lai HC, Chen CY, Tseng KC, Kuo HT, Hung CH, et al. Extrahepatic malignancy among patients with chronic hepatitis C after antiviral therapy: a real-world nationwide study on Taiwanese Chronic Hepatitis C Cohort (T-COACH). Am J Gastroenterol. 2020;115(8):1226–35. - PubMed
1. Huang CF, Yeh ML, Huang CI, Liang PC, Lin YH, Lin ZY, et al. Post-treatment fibrotic modifications overwhelm pretreatment liver fibrosis in predicting HCC in CHC patients with curative antivirals. Hep Intl. 2018;12(6):544–51. - PubMed

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Long-Term Hepatic and Extrahepatic Outcomes of Chronic Hepatitis C Patients After Sofosbuvir-Based Treatment (LONGHEAD Study)

Affiliations

Long-Term Hepatic and Extrahepatic Outcomes of Chronic Hepatitis C Patients After Sofosbuvir-Based Treatment (LONGHEAD Study)

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Associated data

LinkOut - more resources

Full Text Sources