Evaluating short-term and long-term liver fibrosis improvement in hepatitis C patients after DAA treatment

Abstract

Despite achieving a high cure rate with the direct-acting antivirals (DAAs) in hepatitis C treatment, further research is needed to identify additional benefits of the DAA therapy. The current study evaluated liver fibrosis improvement in 848 hepatitis C patients treated with DAAs, who also achieved sustained virologic response. By the fibrosis-4 (FIB-4) index, patients were categorized based on their baseline fibrosis levels, and the improvement in fibrosis was analyzed in both short-term (9-26 weeks) and long-term (≥ 36 weeks) follow-up. The results showed a significant decrease in the FIB-4 index, indicating an improvement in liver fibrosis, in 63.0% and 67.6% of the patients during the short-term and long-term follow-up, respectively. Short-term improvement was associated with factors including ribavirin usage, blood cholinesterase levels, alanine transaminase levels, albumin levels, and the baseline FIB-4 index, while long-term improvement was associated with factors such as aspartate transaminase levels, total protein level, and the baseline FIB-4 index. The current study emphasizes the importance of continuous assessment and post-treatment monitoring of liver fibrosis, which will provide crucial insights for enhancing patient care in hepatitis C management.

Keywords

chronic hepatitis C / sustained virologic response / direct-acting antivirals / liver fibrosis

Fundings

The current study was sponsored by the National Natural Science Foundation of China (Grant No. 82273691), the Natural Science Foundation of Jiangsu Province (Grant No. BK20190106), the Nanjing Important Science & Technology Specific Projects (Grant No. 2021-11005), the National Natural Youth Science Foundation of China (Grant No. 81703273), and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

Acknowledgments

The current study is a joint effort of many investigators and staff members, and their contributions are gratefully acknowledged. We especially thank all patients who participated in the study.

References

[1] Devarbhavi H, Asrani SK, Arab JP, et al. Global burden of liver disease: 2023 update[J]. J Hepatol, 2023, 79(2): 516-537. doi: 10.1016/j.jhep.2023.03.017

[2] Lingala S, Ghany MG. Natural history of hepatitis C[J]. Gastroenterol Clin North Am, 2015, 44(4): 717-734. doi: 10.1016/j.gtc.2015.07.003

[3] Martinello M, Solomon SS, Terrault NA, et al. Hepatitis C[J]. Lancet, 2023, 402(10407): 1085-1096. doi: 10.1016/S0140-6736(23)01320-X

[4] Zhu X, Wang M, Liu M, et al. Efficacy and safety of direct-acting antivirals for treatment-naive patients with genotype 1 hepatitis C virus infection[J]. Per Med, 2019, 16(5): 421-429. doi: 10.2217/pme-2018-0121

[5] Marascio N, Quirino A, Barreca GS, et al. Discussion on critical points for a tailored therapy to cure hepatitis C virus infection[J]. Clin Mol Hepatol, 2019, 25(1): 30-36. doi: 10.3350/cmh.2018.0061

[6] Naggie S, Cooper C, Saag M, et al. Ledipasvir and sofosbuvir for HCV in patients coinfected with HIV-1[J]. N Engl J Med, 2015, 373(8): 705-713. doi: 10.1056/NEJMoa1501315

[7] Scaglione V, Mazzitelli M, Costa C, et al. Virological and clinical outcome of DAA containing regimens in a cohort of patients in Calabria Region (Southern Italy)[J]. Medicina (Kaunas), 2020, 56(3): 101. doi: 10.3390/medicina56030101

[8] Carrat F, Fontaine H, Dorival C, et al. Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study[J]. Lancet, 2019, 393(10179): 1453-1464. doi: 10.1016/S0140-6736(18)32111-1

[9] Itakura J, Kurosaki M, Setoyama H, et al. Applicability of APRI and FIB-4 as a transition indicator of liver fibrosis in patients with chronic viral hepatitis[J]. J Gastroenterol, 2021, 56(5): 470-478. doi: 10.1007/s00535-021-01782-3

[10] Yen YH, Kuo FY, Kee KM, et al. APRI and FIB-4 in the evaluation of liver fibrosis in chronic hepatitis C patients stratified by AST level[J]. PLoS One, 2018, 13(6): e0199760. doi: 10.1371/journal.pone.0199760

[11] Cholankeril G, Kramer JR, Chu J, et al. Longitudinal changes in fibrosis markers are associated with risk of cirrhosis and hepatocellular carcinoma in non-alcoholic fatty liver disease[J]. J Hepatol, 2023, 78(3): 493-500. doi: 10.1016/j.jhep.2022.10.035

[12] Tamaki N, Kurosaki M, Tanaka K, et al. Noninvasive estimation of fibrosis progression overtime using the FIB-4 index in chronic hepatitis C[J]. J Viral Hepat, 2013, 20(1): 72-76. doi: 10.1111/j.1365-2893.2012.01635.x

[13] Monto A. Steatosis in chronic hepatitis C: relative contributions of obesity, diabetes mellitus, and alcohol[J]. Hepatology, 2002, 36(3): 729-736. doi: 10.1053/jhep.2002.35064

[14] Hui JM, Sud A, Farrell GC, et al. Insulin resistance is associated with chronic hepatitis C and virus infection fibrosis progression[J]. Gastroenterology, 2003, 125(6): 1695-1704. doi: 10.1053/j.gastro.2003.08.032

[15] Afsari A, Lee E, Shokrani B, et al. Clinical and pathological risk factors associated with liver fibrosis and steatosis in African-Americans with chronic hepatitis C[J]. Dig Dis Sci, 2017, 62(8): 2159-2165. doi: 10.1007/s10620-017-4626-7

[16] Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection[J]. Hepatology, 2006, 43(6): 1317-1325. doi: 10.1002/hep.21178

[17] Pawlotsky JM, Negro F, Aghemo A, et al. EASL recommendations on treatment of hepatitis C: final update of the series[J]. J Hepatol, 2020, 73(5): 1170-1218. doi: 10.1016/j.jhep.2020.08.018

[18] Hagström H, Talbäck M, Andreasson A, et al. Repeated FIB-4 measurements may help identify individuals at risk of severe liver disease[J]. J Hepatol, 2020, 73(5): 1023-1029. doi: 10.1016/j.jhep.2020.06.007

[19] Trifan A, Stanciu C. Checkmate to liver biopsy in chronic hepatitis C?[J]. World J Gastroenterol, 2012, 18(39): 5514-5520. doi: 10.3748/wjg.v18.i39.5514

[20] Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the study of liver diseases[J]. Hepatology, 2018, 68(2): 723-750. doi: 10.1002/hep.29913

[21] El-Sherif O, Jiang ZG, Tapper EB, et al. Baseline factors associated with improvements in decompensated cirrhosis after direct-acting antiviral therapy for hepatitis C virus infection[J]. Gastroenterology, 2018, 154(8): 2111-2121.e8. doi: 10.1053/j.gastro.2018.03.022

[22] R Core Team. The R project for statistical computing[EB/OL]. [2023-10-01]. https://www.R-project.org/.

[23] Hu SX, Kyulo NL, Xia VW, et al. Factors associated with hepatic fibrosis in patients with chronic hepatitis C: a retrospective study of a large cohort of U.S. patients[J]. J Clin Gastroenterol, 2009, 43(8): 758-764. doi: 10.1097/MCG.0b013e31818be17c

[24] Nahon P, Bourcier V, Layese R, et al. Eradication of hepatitis C virus infection in patients with cirrhosis reduces risk of liver and non-liver complications[J]. Gastroenterology, 2017, 152(1): 142-156.e2. doi: 10.1053/j.gastro.2016.09.009

[25] Feng L, Sun K, Zhang J, et al. A novel non-invasive index using AFP and APTT is associated with liver fibrosis in patients with chronic hepatitis B infection: a retrospective cohort study[J]. BMJ Open, 2015, 5(9): e008032. doi: 10.1136/bmjopen-2015-008032

[26] Ferra-Murcia S, Collado-Romacho AR, Nievas-Soriano BJ, et al. Real-life early anthropometric, lipid and liver changes after direct-acting antiviral therapy in PLWHIV with HCV co-infection[J]. J Clin Med, 2022, 11(9): 2639. doi: 10.3390/jcm11092639

[27] Serfaty L, Andreani T, Giral P, et al. Hepatitis C virus induced hypobetalipoproteinemia: a possible mechanism for steatosis in chronic hepatitis C[J]. J Hepatol, 2001, 34(3): 428-434. doi: 10.1016/S0168-8278(00)00036-2

[28] Wawrzynowicz-Syczewska M. Ribavirin--pharmacological features, antiviral effects against hepatitis C virus (HCV) and other viruses and side effects during treatment[J]. Przegl Epidemiol (in Polish), 2002, 56 Suppl 5: 35-40. https://pubmed.ncbi.nlm.nih.gov/15553070/

[29] Bacon BR. Managing hepatitis C[J]. Am J Manag Care, 2004, 10(2S): S30-S40. https://pubmed.ncbi.nlm.nih.gov/15084065/

[30] Verna EC, Morelli G, Terrault NA, et al. DAA therapy and long-term hepatic function in advanced/decompensated cirrhosis: real-world experience from HCV-TARGET cohort[J]. J Hepatol, 2020, 73(3): 540-548. doi: 10.1016/j.jhep.2020.03.031

[31] Jing J, Liu C, Zhu S, et al. Pathological and ultrastructural observations and liver function analysis of Eimeria stiedai-infected rabbits[J]. Vet Parasitol, 2016, 223: 165-172. doi: 10.1016/j.vetpar.2016.04.020

[32] Chalouni M, Wittkop L, Bani-Sadr F, et al. Risk of severe clinical events after sustained virological response following direct-acting antiviral therapy in HIV and hepatitis C virus coinfected participants[J]. HIV Med, 2021, 22(9): 791-804. doi: 10.1111/hiv.13127

[33] Everhart JE, Wright EC. Association of γ-glutamyl transferase (GGT) activity with treatment and clinical outcomes in chronic hepatitis C (HCV)[J]. Hepatol Baltim Md, 2013, 57(5): 1725-1733. doi: 10.1002/hep.26203

[34] Toyoda H, Tada T, Yasuda S, et al. Dynamic evaluation of liver fibrosis to assess the risk of hepatocellular carcinoma in patients with chronic Hepatitis C who achieved sustained virologic response[J]. Clin Infect Dis, 2020, 70(6): 1208-1214. doi: 10.1093/cid/ciz359

[35] Strazzulla A, Iemmolo RMR, Carbone E, et al. The risk of hepatocellular carcinoma after directly acting antivirals for hepatitis C virus treatment in liver transplanted patients: is it real?[J]. Hepat Mon, 2016, 16(11): e41933. doi: 10.5812/hepatmon.41933

[36] Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma[J]. Hepatology, 2018, 67(1): 358-380. doi: 10.1002/hep.29086

[37] European Association for Study of Liver, European Organisation for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma[J]. Eur J Cancer, 2012, 48(5): 599-641. doi: 10.1016/j.ejca.2011.12.021

[38] Santi V, Trevisani F, Gramenzi A, et al. Semiannual surveillance is superior to annual surveillance for the detection of early hepatocellular carcinoma and patient survival[J]. J Hepatol, 2010, 53(2): 291-297. doi: 10.1016/j.jhep.2010.03.010

[39] Strazzulla A, Coppolino G, Barreca GS, et al. Evolution of glomerular filtration rates and neutrophil gelatinase-associated lipocalin during treatment with direct acting antivirals[J]. Clin Mol Hepatol, 2018, 24(2): 151-162. doi: 10.3350/cmh.2017.0059

[40] Mazzitelli M, Torti C, Sabatino J, et al. Evaluation of cardiac function by global longitudinal strain before and after treatment with sofosbuvir-based regimens in HCV infected patients[J]. BMC Infect Dis, 2018, 18(1): 518. doi: 10.1186/s12879-018-3426-9

[41] Leuştean A, Popescu C, Nichita L, et al. Dynamics of APRI and FIB-4 in HCV cirrhotic patients who achieved SVR after DAA therapy[J]. Exp Ther Med, 2021, 21(1): 99. doi: 10.3892/etm.2020.9531

[42] Montasser MF, Zaky S, Salaheldin M, et al. Fib-4 predicts early hematological adverse events induced by interferon-based triple therapy in chronic hepatitis C virus patients[J]. J Interferon Cytokine Res, 2019, 39(2): 85-94. doi: 10.1089/jir.2018.0131

[43] Yaraş S, Sezgin O, Üçbilek E, et al. Significant decrease in liver stiffness detected by two dimensional shear-wave elastography after treatment with direct-acting antiviral agents in patients with chronic hepatitis C[J]. Turk J Gastroenterol, 2020, 31(2): 142-147. doi: 10.5152/tjg.2020.19418