Background and Aims: Direct-acting antivirals (DAAs) dramatically improve the sustained virological response (SVR) of chronic hepatitis C (CHC) patients. However, continuous liver damage after SVR may be a risk of hepatocellular carcinoma (HCC). We clarified pretreatment characteristics related to sustained liver damage after SVR. Methods: A total of 286 CHC patients were treated with an interferon-free DAA regimen. Among them, 250 patients achieved SVR for 12 weeks after the end of treatment (SVR12); these individuals were classified based on α-fetoprotein (AFP) and alanine transaminase (ALT) levels posttreatment. Baseline characteristics significantly associated with AFP >5 ng/mL and ALT level ≥20 IU/L after SVR were clarified using multivariate analyses. Results: Among the pretreatment factors examined, serum AFP values and the presence of fatty liver (FL) were significantly associated with abnormal AFP (p < 0.0001) and ALT levels 12 weeks after SVR12 (SVR24; p = 0.0109). For 126 patients who showed an increase in baseline AFP level, FL, fibrosis-4 (FIB-4) index, and albumin levels before treatment were related to abnormal AFP at SVR24 (p = 0.0005, 0.0232, and 0.0400 for FL, FIB-4 index, and albumin, respectively). Similarly, for 150 patients with abnormal baseline ALT levels, FL was associated with an ALT level ≥ 30 IU/L after SVR (p = 0.0430). Conclusions: High FIB-4 index, low albumin level, and FL before DAA treatment were associated with a risk of sustained liver damage with AFP and ALT elevation after SVR; patients with these factors should be carefully monitored for emergence of HCC.

Keywords:
Chronic hepatitis C, Direct acting antivirals, Liver damage, Hepatocellular carcinoma
1.
Shire NJ, Sherman KE: Epidemiology of hepatitis C virus: a battle on new frontiers. Gastroenterol Clin North Am 2015;44:699-716.
2.
Singal AG, Volk ML, Jensen D, Di Bisceglie AM, Schoenfeld PS: A sustained viral response is associated with reduced liver-related morbidity and mortality in patients with hepatitis C virus. Clin Gastroenterol Hepatol 2010;8:280-288, 288.e281.
3.
Bruno S, Stroffolini T, Colombo M, Bollani S, Benvegnu L, Mazzella G, Ascione A, Santantonio T, Piccinino F, Andreone P, Mangia A, Gaeta GB, Persico M, Fagiuoli S, Almasio PL: Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study. Hepatology 2007;45:579-587.
4.
George SL, Bacon BR, Brunt EM, Mihindukulasuriya KL, Hoffmann J, Di Bisceglie AM: Clinical, virologic, histologic, and biochemical outcomes after successful HCV therapy: a 5-year follow-up of 150 patients. Hepatology 2009;49:729-738.
5.
Asahina Y, Tsuchiya K, Nishimura T, Muraoka M, Suzuki Y, Tamaki N, Yasui Y, Hosokawa T, Ueda K, Nakanishi H, Itakura J, Takahashi Y, Kurosaki M, Enomoto N, Nakagawa M, Kakinuma S, Watanabe M, Izumi N: α-fetoprotein levels after interferon therapy and risk of hepatocarcinogenesis in chronic hepatitis C. Hepatology 2013;58:1253-1262.
6.
Kudo M: Surveillance, diagnosis, treatment, and outcome of liver cancer in Japan. Liver Cancer 2015;4:39-50.
7.
Clinical practice guidelines for hepatocellular carcinoma differ between Japan, United States, and Europe. Liver Cancer 2015;4:85-95.
8.
Ichikawa S, Ichikawa T, Motosugi U, Sano K, Morisaka H, Enomoto N, Matsuda M, Fujii H: Was hypervascular hepatocellular carcinoma visible on previous gadoxetic acid-enhanced magnetic resonance images? Liver Cancer 2015;4:154-162.
9.
Joo I, Lee JM: Recent advances in the imaging diagnosis of hepatocellular carcinoma: value of gadoxetic acid-enhanced MRI. Liver Cancer 2016;5:67-87.
10.
Kudo M: Breakthrough imaging in hepatocellular carcinoma. Liver Cancer 2016;5:47-54.
11.
Toyoda H, Kumada T, Tada T, Sone Y, Kaneoka Y, Maeda A: Tumor markers for hepatocellular carcinoma: simple and significant predictors of outcome in patients with HCC. Liver Cancer 2015;4:126-136.
12.
Kudo M: Risk of hepatocellular carcinoma in patients with hepatitis C virus who achieved sustained virological response. Liver Cancer 2016;5:155-161.
13.
Kudo M, Izumi N, Sakamoto M, Matsuyama Y, Ichida T, Nakashima O, Matsui O, Ku Y, Kokudo N, Makuuchi M: Survival analysis over 28 years of 173,378 patients with hepatocellular carcinoma in Japan. Liver Cancer 2016;5:190-197.
14.
Ho MC, Hasegawa K, Chen XP, Nagano H, Lee YJ, Chau GY, Zhou J, Wang CC, Choi YR, Poon RT, Kokudo N: Surgery for intermediate and advanced hepatocellular carcinoma: a consensus report from the 5th Asia-Pacific primary liver cancer expert meeting (APPLE 2014). Liver Cancer 2016;5:245-256.
15.
Kudo M: Locoregional therapy for hepatocellular carcinoma. Liver Cancer 2015;4:163-164.
16.
Kang TW, Rhim H: Recent advances in tumor ablation for hepatocellular carcinoma. Liver Cancer 2015;4:176-187.
17.
Teng W, Liu KW, Lin CC, Jeng WJ, Chen WT, Sheen IS, Lin CY, Lin SM: Insufficient ablative margin determined by early computed tomography may predict the recurrence of hepatocellular carcinoma after radiofrequency ablation. Liver Cancer 2015;4:26-38.
18.
Lin CC, Cheng YT, Chen MW, Lin SM: The effectiveness of multiple electrode radiofrequency ablation in patients with hepatocellular carcinoma with lesions more than 3 cm in size and barcelona clinic liver cancer stage A to B2. Liver Cancer 2016;5:8-20.
19.
Tsurusaki M, Murakami T: Surgical and locoregional therapy of HCC: TACE. Liver Cancer 2015;4:165-175.
20.
Arizumi T, Ueshima K, Minami T, Kono M, Chishina H, Takita M, Kitai S, Inoue T, Yada N, Hagiwara S, Minami Y, Sakurai T, Nishida N, Kudo M: Effectiveness of Sorafenib in patients with transcatheter arterial chemoembolization (TACE) refractory and intermediate-stage hepatocellular carcinoma. Liver Cancer 2015;4:253-262.
21.
Geschwind JF, Gholam PM, Goldenberg A, Mantry P, Martin RC, Piperdi B, Zigmont E, Imperial J, Babajanyan S, Foreman PK, Cohn A: Use of transarterial chemoembolization (TACE) and sorafenib in patients with unresectable hepatocellular carcinoma: US regional analysis of the GIDEON registry. Liver Cancer 2016;5:37-46.
22.
Obi S, Sato S, Kawai T: Current status of hepatic arterial infusion chemotherapy. Liver Cancer 2015;4:188-199.
23.
Lin CC, Hung CF, Chen WT, Lin SM: Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with portal vein thrombosis: impact of early response to 4 weeks of treatment. Liver Cancer 2015;4:228-240.
24.
Kudo M: Molecular targeted therapy for hepatocellular carcinoma: where are we now? Liver Cancer 2015;4:I-VII.
25.
Zhang B, Finn RS: Personalized clinical trials in hepatocellular carcinoma based on biomarker selection. Liver Cancer 2016;5:221-232.
26.
Kudo M: Immune checkpoint blockade in hepatocellular carcinoma. Liver Cancer 2015;4:201-207.
27.
Tateyama M, Yatsuhashi H, Taura N, Motoyoshi Y, Nagaoka S, Yanagi K, Abiru S, Yano K, Komori A, Migita K, Nakamura M, Nagahama H, Sasaki Y, Miyakawa Y, Ishibashi H: Alpha-fetoprotein above normal levels as a risk factor for the development of hepatocellular carcinoma in patients infected with hepatitis C virus. J Gastroenterol 2011;46:92-100.
28.
Tarao K, Rino Y, Ohkawa S, Tamai S, Miyakawa K, Takakura H, Endo O, Yoshitsugu M, Watanabe N, Matsuzaki S: Close association between high serum alanine aminotransferase levels and multicentric hepatocarcinogenesis in patients with hepatitis C virus-associated cirrhosis. Cancer 2002;94:1787-1795.
29.
Okanoue T, Itoh Y, Minami M, Sakamoto S, Yasui K, Sakamoto M, Nishioji K, Murakami Y, Kashima K: Interferon therapy lowers the rate of progression to hepatocellular carcinoma in chronic hepatitis C but not significantly in an advanced stage: a retrospective study in 1148 patients. Viral Hepatitis Therapy Study Group. J Hepatol 1999;30:653-659.
30.
Iwasaki Y, Takaguchi K, Ikeda H, Makino Y, Araki Y, Ando M, Kobashi H, Kobatake T, Tanaka R, Tomita M, Senoh T, Kawaguchi M, Shimoe T, Manabe K, Kita K, Shimamura J, Sakaguchi K, Shiratori Y: Risk factors for hepatocellular carcinoma in Hepatitis C patients with sustained virologic response to interferon therapy. Liver Int 2004;24:603-610.
31.
Tanaka H, Tsukuma H, Kasahara A, Hayashi N, Yoshihara H, Masuzawa M, Kanda T, Kashiwagi T, Inoue A, Kato M, Oshima A, Kinoshita Y, Kamada T: Effect of interferon therapy on the incidence of hepatocellular carcinoma and mortality of patients with chronic hepatitis C: a retrospective cohort study of 738 patients. Int J Cancer 2000;87:741-749.
32.
EASL recommendations on treatment of hepatitis C 2015. J Hepatol 2015;63:199-236.
33.
Okamura Y, Ashida R, Yamamoto Y, Ito T, Sugiura T, Uesaka K: FIB-4 index is a predictor of background liver fibrosis and long-term outcomes after curative resection of hepatocellular carcinoma. Ann Surg Oncol 2016;23:467-474.
34.
Oze T, Hiramatsu N, Yakushijin T, Miyazaki M, Yamada A, Oshita M, Hagiwara H, Mita E, Ito T, Fukui H, Inui Y, Hijioka T, Inada M, Katayama K, Tamura S, Yoshihara H, Inoue A, Imai Y, Hayashi E, Kato M, Miyagi T, Yoshida Y, Tatsumi T, Kasahara A, Hamasaki T, Hayashi N, Takehara T: Post-treatment levels of α-fetoprotein predict incidence of hepatocellular carcinoma after interferon therapy. Clin Gastroenterol Hepatol 2014;12:1186-1195.
35.
Nishida N, Yada N, Hagiwara S, Sakurai T, Kitano M, Kudo M: Unique features associated with hepatic oxidative DNA damage and DNA methylation in non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2016;31:1646-1653.
36.
Nahon P, Bourcier V, Layese R, Audureau E, Cagnot C, Marcellin P, Guyader D, Fontaine H, Larrey D, De Ledinghen V, Ouzan D, Zoulim F, Roulot D, Tran A, Bronowicki JP, Zarski JP, Leroy V, Riachi G, Cales P, Peron JM, Alric L, Bourliere M, Mathurin P, Dharancy S, Blanc JF, Abergel A, Serfaty L, Mallat A, Grange JD, Attali P, Bacq Y, Wartelle C, Dao T, Benhamou Y, Pilette C, Silvain C, Christidis C, Capron D, Bernard-Chabert B, Zucman D, Di Martino V, Thibaut V, Salmon D, Ziol M, Sutton A, Pol S, Roudot-Thoraval F: Eradication of hepatitis C virus infection in patients with cirrhosis reduces risk of liver and non-liver complications. Gastroenterology 2017;152:142-156.e142.
© 2017 S. Karger AG, Basel
2017
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.