Direct-Acting Antiviral Therapy and Risk of Hepatocellular Carcinoma Recurrence in Patients with Chronic Hepatitis C

Direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection showed high rates (>95%) of sustained virologic response (SVR) with good safety. SVR after DAA therapy may result in improved liver dysfunction in patients with hepatocellular carcinoma (HCC), but its impact on the risk of HCC recurrence has been the subject of controversy. In this issue of Gut and Liver, Ahn et al.¹reported that HCV-related HCC patients with complete response (CR) to treatment achieved acceptable SVR (88%) with DAA therapy, and 37% experienced HCC recurrence during the median follow-up period of 15.8 months (range, 4.4 to 29.9 months). Unfortunately, this study did not include a control group, which made it difficult to ascertain whether DAA therapy itself could increase or decrease the risk of HCC recurrence.

In 2016, Reig et al.²sparked a debate by reporting an unexpectedly high HCC recurrence rate in HCV-infected patients following DAA therapy. Since then, studies evaluating the impact of DAA therapy on the risk of HCC recurrence after CR have produced conflicting data, and some studies have suggested a decreased risk of HCC recurrence, while others have shown the opposite results. A meta-analysis also showed that the use of DAA therapy was associated with a >60% lower risk of HCC recurrence compared to patients without DAA treatment (odds ratio, 0.36; 95% confidence interval, 0.27 to 0.47; p<0.001).³However, most relevant studies had several limitations including heterogeneity between the cohorts in terms of stage of HCC, different HCC treatment options, multiple HCC treatments, the time interval between CR to HCC treatment and the initiation of DAA therapy, surveillance protocols after DAA therapy, the duration of follow-up, and variability in the analytical methods used. Therefore, there are still no conclusive data that DAA therapy is associated with the risk of recurrent HCC in patients with CR to HCC treatment and the controversy continues.

Apart from these debates, it is evident that the risk of recurrent HCC continues in HCV-infected patients with CR to HCC treatment after DAA therapy even achieving an SVR. The major risk factors for HCC recurrence are male gender, older age, non-SVR, advanced liver fibrosis, cirrhosis, and higher posttreatment alpha-fetoprotein levels. The time interval between curative therapy and DAA therapy has been suggested as a risk factor for HCC recurrence after HCC CR.⁴Tsai et al.⁵found that the recurrence rate was significantly higher among patients with a timespan of <4 months (54.6%) between HCC treatment and DAA therapy compared to those with a timespan of >4 months (21.3%, p=0.026). Singal et al.⁶revealed that the risk of early recurrence could differ according to the initiation time of DAA therapy. The proportion of patients with HCC recurrence was 44.0% for those with a duration from HCC CR to DAA initiation of fewer than 3 months, 50.0% for those with a duration from HCC CR to DAA initiation of 4 to 6 months, and 36.9% for those with a duration of more than 6 months. However, these values did not achieve statistical significance. In multivariate analysis, Ogawa et al.⁷reported that the time between previous HCC treatment and DAA exposure within 1 year (hazard ratio, 3.20; 95% confidence interval, 1.29 to 9.65; p=0.0011) was significantly associated with HCC recurrence. In this issue of Gut and Liver, Ahn et al.¹also reported that a short last HCC treatment durability before DAA therapy (<12 months) was an independent risk factor of HCC recurrence in both a multicenter Korean cohort and a nationwide cohort from the Korean Health Insurance Review and Assessment Service database. The authors defined last HCC treatment durability as the time between the final HCC treatment and the start of DAA therapy.

The delay of DAA therapy can provide a longer time for immune surveillance to work and allow a longer time to verify HCC CR, thereby minimizing the chance of misclassification bias.⁴Meanwhile, SVR with DAA therapy can result in fibrosis regression and improvements in portal hypertension and liver dysfunction, which is the major cause of mortality in patients with HCC CR and untreated HCV infections. Singal et al.⁸reported that patients with prior HCC had a median time from HCC CR to DAA initiation of 7.7 months, and DAA therapy was associated with a significant reduction in the risk of death (hazard ratio, 0.54; 95% confidence interval, 0.33 to 0.90). In a systematic review with a meta-analysis, Saraiya et al.⁹suggested an acceptable HCC recurrence rate after DAA therapy that was delayed at least 6 months after the HCC CR. However, the appropriate timing of DAA initiation after CR in HCV-related HCC patients remains controversial. The American Gastroenterological Association expert review suggested that DAA therapy should not be withheld from patients with CR to HCC therapy, but DAA therapy can be deferred 4 to 6 months to confirm response to HCC therapy.¹⁰However, even after SVR with DAA therapy in patients with HCC CR, clinicians and patients should be vigilant for HCC recurrence and require regular surveillance.