Advertisement

Hepatology International

, Volume 13, Issue 3, pp 293–301 | Cite as

Direct-acting antiviral agents do not increase the incidence of hepatocellular carcinoma development: a prospective, multicenter study

  • Tatsuya Ide
  • Hironori KogaEmail author
  • Masahito Nakano
  • Satoru Hashimoto
  • Hiroshi Yatsuhashi
  • Nobito Higuchi
  • Makoto Nakamuta
  • Satoshi Oeda
  • Yuichiro Eguchi
  • Satoshi Shakado
  • Shotaro Sakisaka
  • Yoko Yoshimaru
  • Yutaka Sasaki
  • Yuichi Honma
  • Masaru Harada
  • Masataka Seike
  • Tatsuji Maeshiro
  • Satoshi Miuma
  • Kazuhiko Nakao
  • Seiichi Mawatari
  • Akio Ido
  • Kenji Nagata
  • Shuichi Matsumoto
  • Yuko Takami
  • Tetsuo Sohda
  • Tatsuyuki Kakuma
  • Takuji Torimura
Original Article
  • 308 Downloads

Abstract

Background

While achieving sustained virological response (SVR) following interferon-based or direct-acting antiviral agent (DAA) treatments reduces the incidence of hepatocellular carcinoma (HCC), an increase in unexpected early occurrence or recurrence of HCC after hepatitis C virus elimination by DAA treatments has been reported. We prospectively investigated the incidence and risk factors of HCC after DAA treatment in a large multicenter cohort in Japan.

Methods

Patients with chronic hepatitis C with or without cirrhosis who were treated with DAAs and obtained SVR were enrolled. DAAs were administered for 3 or 6 months. A total of 2552 patients were enrolled.

Results

Of these, 70 patients (2.7%) developed HCC. The 12-, 24-, and 36-month cumulative HCC incidences were 1.3%, 2.9%, and 4.9% in all patients; 2.5%, 5.2%, and 10.0% in those with cirrhosis; and 0.9%, 2.1%, and 2.9% in those without cirrhosis, respectively. Multivariate analysis revealed age, sex, gamma-glutamyl transpeptidase level, and fibrosis-4 index to be independent factors associated with HCC. Patients with these four factors had an approximately six-to-sevenfold increased risk for HCC development. Five patients with large and early tumor occurrence did not receive contrast imaging examinations before treatment.

Conclusion

Although the results of our prospective study suggested that achieving SVR by DAA treatment reduces the incidence of HCC, HCC development still occurs. Careful follow-up is important in patients with risk factors.

Keywords

Hepatitis C virus Sustained virological response Fibrosis-4 (FIB-4) index Hepatocarcinogenesis 

Abbreviations

HCV

Hepatitis C virus

HCC

Hepatocellular carcinoma

DAA

Direct-acting antiviral

SVR

Sustained virological response

IFN

Interferon

AFP

Alpha-fetoprotein

ASV

Asunaprevir

DCV

Daclatasvir

SOF

Sofosbuvir

AST

Aspartate aminotransferase

ALT

Alanine aminotransferase

GGTP

Gamma-glutamyl transpeptidase

FIB-4

Fibrosis-4

APRI

AST to platelet count ratio index

AUC

Area under the curve

ROC

Receiver-operating characteristics

US

Ultrasonography

CT

Computed tomography

MRI

Magnetic resonance imaging

Vp

Tumor thrombus of the portal vein

Notes

Acknowledgements

We thank Editage (www.editage.jp) for English language editing.

Funding

None.

Compliance with ethical standards

Conflict of interest:

Akio Ido has COI as follows: (1) Speaking fees or honoraria; AbbVie GK, Bristol Myers Squibb Co. Ltd., Gilead Sciences Inc., and Eisai Co. Ltd. (2) Research grants; AbbVie GK, Otsuka Pharmaceutical Co. Ltd., MSD K.K., Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd., Astellas Pharmaceutical Inc., and Takeda Pharmaceutical Co. Ltd. The other authors disclose no conflicts.

Ethical approval

The protocol was approved by all hospital institutional review boards and carried out in compliance with the Declaration of Helsinki.

Informed consent

Written informed consent was obtained from all participating patients.

References

  1. 1.
    Gower E, Estes C, Blach S, Razavi-Shearer K, Razavi H. Global epidemiology and genotype distribution of the hepatitis C virus infection. J Hepatol. 2014;61:S45–S57.CrossRefGoogle Scholar
  2. 2.
    Hiramatsu N, Oze T, Takehara T. Suppression of hepatocellular carcinoma development in hepatitis C patients given interferon-based antiviral therapy. Hepatol Res. 2015;45:152–161.CrossRefGoogle Scholar
  3. 3.
    Tanaka Y, Nishida N, Sugiyama M. Safety and tolerability of ledipasvir/sofosbuvir with and without ribavirin in patients with chronic hepatitis C virus genotype 1 infection: Analysis of phase III ION trials. Hepatology. 2015;62:25–30.CrossRefGoogle Scholar
  4. 4.
    Kwo P, Gitlin N, Nahass R, Bernstein D, Etzkorn K, Rojter S, et al. Simeprevir plus sofosbuvir (12 and 8 weeks) in HCV genotype 1-infected patients without cirrhosis: OPTIMIST-1, a phase 3, randomized study. Hepatology. 2016;64:370–380.CrossRefGoogle Scholar
  5. 5.
    Pol S, Lucier S, de Lédinghen V, Zoulim F, Dorival-Mouly C, et al. Safety and efficacy of the combination daclatasvir-sofosbuvir in HCV genotype 1-monoinfected patients. J Hepatol. 2017;66:39–47.CrossRefGoogle Scholar
  6. 6.
    Calvaruso V, Cabibbo G, Cacciola I, Petta S, Madonia S, Bellia A, Tinè F, et al. Incidence of Hepatocellular carcinoma in patients with HCV-associated cirrhosis treated with direct-acting antiviral agents. Gastroenterology. 2018;155:411–421.CrossRefGoogle Scholar
  7. 7.
    Reig M, Mariño Z, Perelló C, Iñarrairaegui M, Ribeiro A, Lens S, et al. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. J Hepatol. 2016;65:719–726.CrossRefGoogle Scholar
  8. 8.
    Conti F, Buonfiglioli F, Scuteri A, Crespi C, Bolondi L, Caraceni P, et al. Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals. J Hepatol. 2016;65:727–733.CrossRefGoogle Scholar
  9. 9.
    Nakao Y, Hashimoto S, Abiru S, Komori A, Yamasaki K, Nagaoka S, et al. Rapidly growing, moderately differentiated HCC: A clinicopathological characteristic of HCC occurrence after IFN-free DAA therapy? J Hepatol. 2017;68:854–855.CrossRefGoogle Scholar
  10. 10.
    Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 2003;38:518-526.CrossRefGoogle Scholar
  11. 11.
    Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43:1317–1325.CrossRefGoogle Scholar
  12. 12.
    Kuzuya T, Nakagawa S, Satoh J, Kanazawa Y, Iwamoto Y, Kobayashi M, et al. Committee of the Japan Diabetes Society on the diagnostic criteria of diabetes mellitus. Report of the committee on the classification and diagnostic criteria of diabetes mellitus. Diabetes Res Clin Pract 2002;55:65-85.CrossRefGoogle Scholar
  13. 13.
    Roche B, Coilly A, Duclos-Vallee JC, Samuel D. The impact of treatment of hepatitis C with DAAs on the occurrence of HCC. Liver Int. 2018;38(Suppl. 1):139–145.CrossRefGoogle Scholar
  14. 14.
    Waziry R, Hajarizadeh B, Grebely J, Amin J, Law M, Danta M, et al. Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: A systematic review, meta-analyses, and meta-regression. J Hepatol. 2017;67:1204–1212.CrossRefGoogle Scholar
  15. 15.
    Kanwal F, Kramer J, Asch SM, Chayanupatkul M, Cao Y, El-Serag HB, et al. Risk of Hepatocellular Cancer in HCV Patients Treated With Direct-Acting Antiviral Agents. Gastroenterology. 2017;153:996–1005.CrossRefGoogle Scholar
  16. 16.
    Ioannou GN, Green PK, Berry K. HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma. J Hepatol. 2018;68:25–322.CrossRefGoogle Scholar
  17. 17.
    Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127(Suppl 1):S35–50.CrossRefGoogle Scholar
  18. 18.
    Ikeda K, Saitoh S, Arase Y, Chayama K, Suzuki Y, Kobayashi M, et al. Effect of interferon therapy on hepatocellular carcinogenesis in patients with chronic hepatitis type C: a long-term observation study of 1,643 patients using statistical bias correction with proportional hazard analysis. Hepatology. 1999;29:1124–1130.CrossRefGoogle Scholar
  19. 19.
    Kasahara A, Hayashi N, Mochizuki K, Takayanagi M, Yoshioka K, Kakumu S, et al. Risk factors for hepatocellular carcinoma and its incidence after interferon treatment in patients with chronic hepatitis C. Osaka Liver Disease Study Group. Hepatology. 1998;27:1394–1402.CrossRefGoogle Scholar
  20. 20.
    Yoshida H, Shiratori Y, Moriyama M, Arakawa Y, Ide T, Sata M, et al. Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. IHIT Study Group. Inhibition of hepatocarcinogenesis by interferon therapy. Ann Intern Med 1999;131:174-181.CrossRefGoogle Scholar
  21. 21.
    Doi Y, Kubo M, Yonemoto K, Ninomiya T, Iwase M, Tanizaki Y, et al. Liver enzymes as a predictor for incident diabetes in a Japanese population: the Hisayama study. Obesity 2007;15:1841–1850.CrossRefGoogle Scholar
  22. 22.
    Wang Z, Song P, Xia J, Inagaki Y, Tang W, Kokudo N. Can gamma-glutamyl transferase levels contribute to a better prognosis for patients with hepatocellular carcinoma? Drug Discov Ther. 2014;8:134–138.CrossRefGoogle Scholar

Copyright information

© Asian Pacific Association for the Study of the Liver 2019

Authors and Affiliations

  • Tatsuya Ide
    • 1
  • Hironori Koga
    • 1
    Email author
  • Masahito Nakano
    • 1
  • Satoru Hashimoto
    • 2
  • Hiroshi Yatsuhashi
    • 2
  • Nobito Higuchi
    • 3
  • Makoto Nakamuta
    • 3
  • Satoshi Oeda
    • 4
  • Yuichiro Eguchi
    • 4
  • Satoshi Shakado
    • 5
  • Shotaro Sakisaka
    • 5
  • Yoko Yoshimaru
    • 6
  • Yutaka Sasaki
    • 6
  • Yuichi Honma
    • 7
  • Masaru Harada
    • 7
  • Masataka Seike
    • 8
  • Tatsuji Maeshiro
    • 9
  • Satoshi Miuma
    • 10
  • Kazuhiko Nakao
    • 10
  • Seiichi Mawatari
    • 11
  • Akio Ido
    • 11
  • Kenji Nagata
    • 12
  • Shuichi Matsumoto
    • 13
  • Yuko Takami
    • 14
  • Tetsuo Sohda
    • 15
  • Tatsuyuki Kakuma
    • 16
  • Takuji Torimura
    • 1
  1. 1.Division of Gastroenterology, Department of MedicineKurume University School of MedicineKurumeJapan
  2. 2.Clinical Research CenterNational Hospital Organization Nagasaki Medical CenterOmuraJapan
  3. 3.Division of GastroenterologyNational Kyusyu Medical Center HospitalFukuokaJapan
  4. 4.Liver CenterSaga University HospitalSagaJapan
  5. 5.Department of Gastroenterology and Medicine, Faculty of MedicineFukuoka UniversityFukuokaJapan
  6. 6.Department of Gastroenterology and Hepatology, Graduate School of Medical SciencesKumamoto UniversityKumamotoJapan
  7. 7.Third Department of Internal MedicineUniversity of Occupational and Environmental HealthKitakyushuJapan
  8. 8.Department of Gastroenterology, Faculty of MedicineOita UniversityYufuJapan
  9. 9.First Department of Internal Medicine, Faculty of MedicineUniversity of the RyukyusNakagashira-gunJapan
  10. 10.Department of Gastroenterology and HepatologyNagasaki University HospitalNagasakiJapan
  11. 11.Digestive and Lifestyle DiseasesKagoshima University Graduate School of Medical and Dental SciencesSakuragaokaJapan
  12. 12.Department of Liver DiseaseUniversity of Miyazaki HospitalMiyazakiJapan
  13. 13.Fukuoka Tokushukai Medical CenterKasugaJapan
  14. 14.Department of Hepato-Biliary-Pancreatic Surgery and Clinical Research InstituteNational Kyushu Medical Center HospitalFukuokaJapan
  15. 15.Hepatology DivisionJapanese Red Cross Fukuoka HospitalFukuokaJapan
  16. 16.Biostatistics CenterKurume UniversityKurumeJapan

Personalised recommendations