Introduction
Chronic infection with hepatitis C virus (HCV) is a well-recognized risk factor for liver cirrhosis and hepatocellular carcinoma (HCC), which is one of the most common malignancies worldwide (1,2). HCV infection is a leading cause of HCC; the prevalence rate of HCV infection among HCC patients is around 70% in Japan (3,4). The recurrence risk of patients with HCC is extremely high compared to that of other malignancies and this is associated with poor survival (5,6). Therefore, anti-virus therapy for the eradication of HCV is very important to prevent the development and recurrence of HCC and prolong the prognosis of patients with this malignancy (7-10). A meta-analyses including 30 studies analyzing the association between response to HCV interferon (IFN)-based therapy and development of HCC demonstrated that eradication of HCV infection dramatically reduced the risk of HCC (relative risk for all persons 0.24; 95% confidence interval [CI] 0.18 to 0.31) (10).
The recent introduction of IFN-free direct-acting antivirals (DAAs) led to revolutionary progress in HCV treatment because of its higher tolerability and sustained virological response (SVR) rate than conventional IFN-based therapy (11). Therefore, IFN-based therapy has been replaced by DAA therapy and the number of patients who achieved SVR with this therapy is increasing steadily. Several studies suggest that eradication of HCV by DAA therapy is associated with improved liver function and quality of life as well as reduced risk of decompensated liver disease (7,12,13). Moreover, it has gradually been determined that the suppressive effects of DAA therapy on HCC development are similar to those of IFN-based therapy (8,9,14). However, some conflicting data has described unexpected high rates of HCC occurrence and recurrence after successful DAA treatment (15-17). Therefore, it is important to examine whether eradication of HCV by DAA therapy reduces the risk of HCC.
The purpose of the present study was to evaluate the suppressive effect of DAA therapy on the recurrence of HCV-related HCC after curative treatment. The anti-liver tumorigenesis effects in the DAA therapy group were compared not only to a non-antiviral therapy group but also to an IFN-based therapy group.
Discussion
The results of the present study revealed that the patients in whom HCV infection was successfully eradicated by DAAs after curative treatment of initial HCC had a similar recurrence rate as those who underwent IFN-based therapy. Furthermore, compared with the non-treatment group, successful treatment with DAAs reduced the risk of HCC recurrence after curative treatment by about one-fifth, which was almost the same as that reported previously for IFN-based therapy (10). These results strongly encourage us to introduce DAA treatment among patients treated with curative treatment for primary HCV-related HCC.
Recently, DAAs have become the dominant therapy for HCV infection in place of conventional IFN-based therapy because of its higher tolerability and SVR rate (11). In fact, all the patients in the DAA group did not develop serious complications during DAA treatment and achieved SVR. On the other hand, it is reported that patients with HCC had significantly higher DAA failure (19). The presence of active HCC was the primary predictor of DAA failure even after controlling for other variables (19). Therefore, we did not introduce DAA treatment to HCV positive patients with active HCC and this might lead to the achievement of extremely high SVR rate in this study. In order to achieve SVR, it is important to confirm that there is no active HCC before introducing DAA treatment.
Importantly, it is also expected that treatment with DAAs may exert an anti-liver tumorigenesis effect, which was proven by IFN-based therapy in patients with cirrhosis (10). Several studies have revealed the association between successful DAA treatment and the reduction of the risk of HCC (8,9,14). HCV eradication can improve hepatic inflammation and fibrosis, both of which are associated with the progression of precancerous lesions into malignant cell clones (20). Therefore, HCV eradication from the liver exerts a protective effect against HCC development, regardless of the type of antiviral treatment. Importantly, not the type of antiviral treatment (IFN or DAA) but treatment response (SVR or non-SVR) was the only independent predictive factor of HCC recurrence after curative treatment (21).
On the other hand, some studies have indicated that DAAs could instead promote the development of HCC (15-17). To explain these contrasting results, the following hypotheses can be considered: DAAs cause a deregulation of the immune system through an abrupt reduction in the HCV load, leaving immune cells less active against tumor cells already present at the beginning of antiviral treatment (22,23). Moreover, it can persist even after successful DAA treatment, while exogenous IFN used as part of HCV treatment plays a protective role in HCC by switching on inflammatory cells with pro-apoptotic and anti-tumoral activities (24,25).
However, it should be recognized that patients treated with DAAs have a significantly higher risk of HCC occurrence or recurrence than those with IFN-based therapy because of their background factors. Namely, DAA-treated patients have a significantly higher rate of known risk factors for HCC, including cirrhosis, older age, and a higher baseline alpha-fetoprotein (AFP) level (14). Age and serum AFP levels were higher and liver fibrosis was more advanced in patients who achieved SVR with DAA therapy than those in patients who achieved SVR with IFN-based therapy (26). The higher prevalence of underlying HCC risks among DAA-treated individuals could be because patients treated with earlier DAA regimens had previously failed treatment with IFN-based therapy (14). Indeed, patients were significantly older in the DAA group in the present study. Furthermore, two patients had recurrent HCC within a year in the DAA group, while none did in the IFN group.
Another emphasized point of the present study is that even though HCV could be eradicated successfully by either DAA- or IFN-based therapy, the risk of recurrence almost never changes within a year. Because DAAs might not be able to inactivate tumor cells already present at the beginning of antiviral treatment, close follow-up for surveying HCC development is required. All of the guidelines from the American Associated for the Study of Liver Diseases, the European Association for the Study of the Liver, and the Japan Society of Hepatology recommended surveillance every 3-4 months using image examination with or without tumor maker measurements after curative treatment of HCC (27-29). The appropriate surveillance interval also should be determined on the basis of risk factors of HCC recurrence such as male sex, older age, presence of cirrhosis, alcohol consumption, higher AFP levels, and advanced stage of primary HCC (1,27-33).
The main limitation of our study is the small sample size and relatively short follow-up time. Our study is also limited by its study design as a retrospective-cohort study. Further prospective multicenter studies with larger sample sizes and longer follow-up periods are warranted to further verify the anti-liver tumorigenesis effect of DAAs. However, although there are such limitations, the result of the present study indicating the anti-liver tumorigenesis effect of DAAs is extremely important because there is a concern that DAAs might promote HCC (15-17).
In conclusion, SVR by DAAs showed a suppressive effect on HCV-related HCC recurrence after curative treatment, which was almost equal to that obtained by IFN-based therapy. However, the risk of HCC recurrence almost never changes within a year and, therefore, strict surveillance should be performed at least within a year after curative treatment for primary HCC even if successful DAA treatment is achieved.