Early occurrence and recurrence of hepatocellular carcinoma in hepatitis C virus-infected patients after sustained virological response
Hepatitis C virus
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%) . In the interferon era, long-term eradication of HCV could lead to the reduction of liver-related complications, including HCC . 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.  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.  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 . 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 . 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]) . 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 . 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 . 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.  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 . 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 . Meta-analysis also showed that interferon treatment after resection or ablation of HCC could reduce the recurrence of HCC and improve their survival .
Peginterferon plus ribavirin could also reduce the occurrence and recurrence of HCC and improve the survival as well [9, 10, 11]. Huang et al.  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.  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 . 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 . Interferon-free combination of DAAs could be used in HCV-positive patients even if they have decompensated cirrhosis , 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 . 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.  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 . 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 .
Ryu et al.  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 . Ioannou et al.  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 , 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) . 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 . Debes et al.  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 . 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.
This article does not contain any studies with human participants or animals performed by any of authors.
Not necessary, see above.
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