Hepatology International

, Volume 12, Issue 2, pp 90–93 | Cite as

Early occurrence and recurrence of hepatocellular carcinoma in hepatitis C virus-infected patients after sustained virological response

  • Tatsuo Kanda
  • Shunichi Matsuoka
  • Mitsuhiko Moriyama



Hepatitis C virus


Hepatocellular carcinoma


Direct-acting antiviral agent


Sustained virological response


Chronic hepatitis C virus (HCV) infection is one of the major causes of liver cirrhosis and hepatocellular carcinoma (HCC). Recently, the interferon-free combination of direct-acting antiviral agents (DAAs) against HCV could result in higher sustained virological response (SVR) rates (~ 95%) [1]. In the interferon era, long-term eradication of HCV could lead to the reduction of liver-related complications, including HCC [2]. In the DAA era, achievement of SVR and long-term eradication of HCV can be expected to prevent liver-related complications, including HCC.

SVR is important for the prevention of HCC development

Nishiguchi et al. [3] demonstrated that interferon-α improved liver function and that its use could be associated with a reduction of HCC in patients with chronic HCV infection and cirrhosis. Yoshida et al. [4] retrospectively studied 2890 patients with chronic hepatitis C diagnosed by liver biopsy. Among these, 490 patients did not receive interferon treatment. Of the other 2400 interferon-treated patients, SVR was, and was not achieved in 789 (32.9%) and 1568 (65.3%) patients, respectively. In 43 patients, response was undetermined. They observed that HCC developed in 89 (3.7%) of 2400 interferon-treated patients and in 59 (12.0%) of 490 untreated patients with median follow-up after liver biopsy of 4.3 years for all 2890 patients [4]. In 337 patients with cirrhosis, HCC developed in 33 (14.3%) of 230 interferon-treated patients and in 32 (29.9%) of 107 untreated patients. Of 2400 interferon-treated patients, HCC developed in 10 (1.3%) of 786 patients with SVR and in 76 (4.8%) of 1568 patients without SVR. Of 230 interferon-treated patients with cirrhosis, HCC developed in 1 (1.9%) of 53 patients with SVR, whereas HCC developed in 30 (17.9%) of 168 patients without SVR [4]. They also found, by multivariate analysis, that interferon therapy was associated with a risk ratio for HCC of 0.516 (95% CI 0.358 to 0.742) and especially among patients with SVR (risk ratio, 0.197 [CI 0.099 to 0.392]) [4]. Of interest, the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) cohort showed that maintenance peginterferon did not reduce the incidence of HCC in HCV-positive patients with bridging fibrosis or cirrhosis [5]. These results suggest that it is important for the prevention of HCC to achieve SVR in all HCV-positive patients.

SVR by interferon could reduce recurrence in post-HCC treated patients

As postsurgical recurrence of HCC is frequent and fatal, various adjuvant treatments including interferon should be considered [6]. However, it is difficult to use interferon with or without ribavirin in post-HCC surgical patients due to their relatively poor liver function. Shiratori et al. [7] demonstrated that interferon therapy after the ablation of HCC by ethanol injection improves the prognosis in HCV-positive patients with HCC. This randomized, controlled study included total 74 patients with compensated cirrhosis, 3 or fewer HCCs and lower HCV RNA loads (< or = 2 × 106 copies/mL): 49 patients received interferon for 48 weeks, resulting in 14 with SVR and 35 with non-SVR; and 25 patients did not receive interferon [7]. Of interest, the rate of first recurrence of new HCC lesions was similar in patients treated with or without interferon. However, the rates of second or third recurrence of HCCs seemed to be lower in the interferon group than in the untreated group. Survival rates in patients with and without SVR were 86 and 80% at 3 years, 78 and 65% at 5 years, and 68 and 48% at 7 years, respectively [7]. Meta-analysis also showed that interferon treatment after resection or ablation of HCC could reduce the recurrence of HCC and improve their survival [8].

Peginterferon plus ribavirin could also reduce the occurrence and recurrence of HCC and improve the survival as well [9, 10, 11]. Huang et al. [9] observed that, after the end of treatment, 43 (41%) of 105 patients developed HCC recurrence, and that, of interest, 24 (56%) of these 43 patients had their recurrence within 6 months after the end of treatment and that 33 (77%) of the patients with HCC recurrence were of de novo pattern. These results indicated that peginterferon plus ribavirin therapy had a limited effect in the tertiary prevention of HCC.

Ryu et al. [12] also examined the effects of SVR by interferon therapy before HCC occurrence on recurrence and survival after curative surgical microwave ablation. This retrospective study included 518 HCV-associated HCC patients: 34 patients with SVR before HCC occurrence and 484 control patients without SVR before or after surgery. They found that survival rates of patients with and without SVR were 100 and 94.8% at 1 year, 100 and 74.6% at 3 years, 95.8 and 50.7% at 5 years, and 80.4 and 23.4% at 10 years, respectively [12]. They also found that the recurrence-free survival rates were significantly higher in patients with SVR by interferon therapy before HCC occurrence.

Will DAAs have the same effects for secondary prevention as interferon treatment?

Interferon-including regimens have been effective for only HCV-positive patients with a mild stage of cirrhosis and interleukin 28B (IL28B) major type [13]. Interferon-free combination of DAAs could be used in HCV-positive patients even if they have decompensated cirrhosis [14], as well as aged patients. We also reported that the occurrence of HCC was not a rare event during and immediately after peginterferon with ribavirin therapy in HCV-positive patients because HCV-associated HCC patients were getting progressively older than before in Japan [15]. Clinicians should regularly check for the possible occurrence or recurrence of HCC during or after antiviral treatments even in patients with SVR.

According to these reasons, DAAs could be used in patients after surgery for HCC. Will DAAs have the same effects for secondary prevention as interferon treatment? There are several articles debating this issue [16, 17, 18, 19, 20, 21]. Although Reig et al. [16] observed a high rate of HCC recurrence after DAA treatment in patients with prior HCC, almost studies demonstrated that SVR was associated with a reduction in the risk of HCC among patients treated with DAAs and that DAA treatment did not promote HCC [17, 18, 19]. Meta-analyses including a total of 41 studies (n = 13,875 patients) demonstrated that there was no different HCC occurrence or recurrence following SVR between DAA and interferon-based treatment [18]. A recent prospective population study demonstrated that, among patients with advanced hepatitis C (fibrosis stage =>F3) receiving DAAs, the risk of “de novo” HCC during the first year is not higher, and might be lower, than that of untreated patients and that early HCC appearance may reflect pre-existing, microscopic, or undetectable tumors [20].

Ryu et al. [12] also demonstrated that patients with HCC occurring more than 5 years after achieving SVR by interferon had longer recurrence-free survival, supporting the fact that DAA-induced SVR does not seem to reduce occurrence in patients with HCV-associated cirrhosis and recurrence in patients previously treated for HCC in the short term [22]. Ioannou et al. [19] also reported DAA-induced SVR is associated with a 71% reduction in HCC risk, although they diagnosed HCC at least 180 days after the initiation of antiviral treatment. SVR by peginterferon and ribavirin could not prevent early HCC recurrence within 6 months after the end of treatment in some patients [9], although there are contrary opinions [21, 23]. SVR achieved by peginterferon and ribavirin markedly improved survival in intermediate stage HCC patients receiving transarterial chemoembolization (TACE) [24]. This effect of SVR should be addressed since some patients with intermediate stage HCC were not considered to receive antiviral treatment for their assumption to be shorter survival.


Although interferon-free regimens could result in higher SVR rates in HCV patients even with advanced liver fibrosis and after HCC surgery, this treatment may also affect hepatic immunity and activity [25, 26, 27]. These regimens might also have an effect on tumor immunity, which is especially important for short-term occurrence and recurrence. Recently, it was reported that the levels of cytokines in serum before DAA treatment correlate with the later development of HCC [28]. Debes et al. [28] investigated 13 patients who developed HCC within 18 months after DAA treatment and 10 patients who did not develop HCC, and they evaluated their serum cytokines before, during and after DAA treatment. They concluded that a set of immune markers could predict HCC development following DAA treatment in HCV-positive patients [28]. Further studies will be needed regarding this issue. Both short-term and long-term incidences of HCC during and after interferon-free combinations of DAA therapy should be focused upon in clinical practice.



This work was partially supported by JSPS KAKENHI [Grant number 17K09404] and Japan Agency for Medical Research and Development (AMED) [Grant Number JP16jk0210014].

Compliance with ethical standards

Conflict of interest

Dr. Tatsuo Kanda received research grants from Merck Sharp and Dohme (MSD), Chugai Pharm and AbbVie. The founding sponsors played no role in the study design, data collection, analyses, interpretation, writing of the manuscript, or in the decision to publish the results. Shunichi Matsuoka and Mitsuhiko Moriyama have declared that there are no conflicts of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of authors.

Informed consent

Not necessary, see above.


  1. 1.
    Omata M, Kanda T, Wei L, Yu ML, Chuang WL, Ibrahim A, et al. APASL consensus statements and recommendation on treatment of hepatitis C. Hepatol Int 2016;10:702–726Google Scholar
  2. 2.
    Omata M, Kanda T, Yu ML, Yokosuka O, Lim SG, Jafri W, et al. APASL consensus statements and management algorithms for hepatitis C virus infection. Hepatol Int 2012;6:409–435Google Scholar
  3. 3.
    Nishiguchi S, Kuroki T, Nakatani S, Morimoto H, Takeda T, Nakajima S, et al. Randomised trial of effects of interferon-alpha on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet 1995;346:1051–1055Google Scholar
  4. 4.
    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;131:174–181Google Scholar
  5. 5.
    Di Bisceglie AM, Shiffman ML, Everson GT, Lindsay KL, Everhart JE, Wright EC, et al. Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon. N Engl J Med 2008;359:2429–2441Google Scholar
  6. 6.
    Takayama T, Makuuchi M. Prevention of hepatocellular carcinoma recurrence: actuality and perspectives. Hepatogastroenterology 2002;49:87–90Google Scholar
  7. 7.
    Shiratori Y, Shiina S, Teratani T, Imamura M, Obi S, Sato S, et al. Interferon therapy after tumor ablation improves prognosis in patients with hepatocellular carcinoma associated with hepatitis C virus. Ann Intern Med 2003;138:299–306Google Scholar
  8. 8.
    Singal AK, Freeman DH Jr, Anand BS. Meta-analysis: interferon improves outcomes following ablation or resection of hepatocellular carcinoma. Aliment Pharmacol Ther 2010;32:851–858Google Scholar
  9. 9.
    Huang JF, Yeh ML, Yu ML, Dai CY, Huang CF, Huang CI, et al. The tertiary prevention of hepatocellular carcinoma in chronic hepatitis C patients. J Gastroenterol Hepatol 2015;30:1768–774Google Scholar
  10. 10.
    Lee SH, Jin YJ, Shin JY, Lee JW. Assessment of hepatocellular carcinoma risk based on peg-interferon plus ribavirin treatment experience in this new era of highly effective oral antiviral drugs. Medicine (Baltimore) 2017;96:e5321Google Scholar
  11. 11.
    Nirei K, Kanda T, Nakamura H, Matsuoka S, Takayama T, Sugitani M, et al. Persistent hepatic inflammation plays a role in hepatocellular carcinoma after sustained virological response in patients with HCV infection. Int J Med Sci 2018;15:466–474Google Scholar
  12. 12.
    Ryu T, Takami Y, Wada Y, Tateishi M, Matsushima H, Yoshitomi M, et al. Effect of achieving sustained virological response before hepatitis C virus-related hepatocellular carcinoma occurrence on survival and recurrence after curative surgical microwave ablation. Hepatol Int 2018.
  13. 13.
    Kanda T, Imazeki F, Yokosuka O. New antiviral therapies for chronic hepatitis C. Hepatol Int 2010;4:548–561Google Scholar
  14. 14.
    Kanda T. Interferon-free treatment for HCV-infected patients with decompensated cirrhosis. Hepatol Int 2017;11:38–44Google Scholar
  15. 15.
    Kanda T, Imazeki F, Mikami S, Kato K, Shimada N, Yonemitsu Y, et al. Occurrence of hepatocellular carcinoma was not a rare event during and immediately after antiviral treatment in Japanese HCV-positive patients. Oncology 2011;80:366–372Google Scholar
  16. 16.
    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;65:719–726Google Scholar
  17. 17.
    Kanwal F, Kramer J, Asch SM, Chayanupatkul M, Cao Y, El-Serag HB. Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents. Gastroenterology 2017;153(996–1005):e1Google Scholar
  18. 18.
    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;67:1204–1212Google Scholar
  19. 19.
    Ioannou GN, Green PK, Berry K. HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma. J Hepatol 2017. (Epub ahead of print)
  20. 20.
    Romano A, Angeli P, Piovesan S, Noventa F, Anastassopoulos G, Chemello L, et al. Newly diagnosed Hepatocellular Carcinoma in patients with advanced hepatitis C treated with DAAs: a prospective population study. J Hepatol 2018. (Epub ahead of print)
  21. 21.
    Li DK, Ren Y, Fierer DS, Rutledge S, Shaikh OS, Lo Re V, et al. The short-term incidence of hepatocellular carcinoma is not increased after hepatitis C treatment with direct-acting antivirals: an ERCHIVES study. Hepatology 2017. (Epub ahead of print)
  22. 22.
    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;65:727–733Google Scholar
  23. 23.
    Huang AC, Mehta N, Dodge JL, Yao FY, Terrault NA. Direct-acting antivirals do not increase the risk of hepatocellular carcinoma recurrence after local-regional therapy or liver transplant waitlist dropout. Hepatology 2018. (Epub ahead of print)
  24. 24.
    Teng W, Hsieh YC, Lui KW, Chen WT, Hung CF, Huang CH, et al. Eradication of hepatitis C virus profoundly prolongs survival in hepatocellular carcinoma patients receiving transarterial chemoembolization. J Viral Hepat 2017;24:1160–1167Google Scholar
  25. 25.
    Martin B, Hennecke N, Lohmann V, Kayser A, Neumann-Haefelin C, Kukolj G, et al. Restoration of HCV-specific CD8 + T cell function by interferon-free therapy. J Hepatol 2014;61:538–543Google Scholar
  26. 26.
    Hengst J, Falk CS, Schlaphoff V, Deterding K, Manns MP, Cornberg M, et al. Direct-acting antiviral-induced hepatitis C virus clearance does not completely restore the altered cytokine and chemokine milieu in patients with chronic hepatitis C. J Infect Dis 2016;214:1965–1974Google Scholar
  27. 27.
    Kanda T, Yasui S, Nakamura M, Nakamoto S, Takahashi K, Wu S, et al. Interferon-free treatment for patients with chronic hepatitis C and autoimmune liver disease: higher SVR rates with special precautions for deterioration of autoimmune hepatitis. Oncotarget 2018;9:11631–11637Google Scholar
  28. 28.
    Debes JD, van Tilborg M, Groothuismink ZMA, Hansen BE, Schulze Zur Wiesch J, von Felden J, et al. Levels of cytokines in serum associate with development of hepatocellular carcinoma in patients with HCV infection treated with direct-acting antivirals. Gastroenterology 2018;154(515–517):e3Google Scholar

Copyright information

© Asian Pacific Association for the Study of the Liver 2018

Authors and Affiliations

  1. 1.Division of Gastroenterology and Hepatology, Department of MedicineNihon University School of MedicineTokyoJapan

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