No Association Between Direct‐Acting Antivirals and Hepatocellular Carcinoma Progression on the Waiting List: Time to Put This Controversy to Rest?

Abstract

The potential association between the receipt of direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV ) infection and the development of de novo or aggressive progression of hepatocellular carcinoma (HCC), surprisingly, continues to be debated, more than 3 years after first being raised in small single-center observational studies. (1)(2)(3) After initial studies without a concurrent control group described both an increased incidence of de novo HCC as well as more aggressive recurrence after curative anticancer therapy in patients with HCV who received DAAs compared with historic controls, several groups have explored this association in different populations across the world. (2,3) A review of the data shows that DAA therapy is not associated with the development of de novo HCC or aggressive progression of HCC after locoregional therapy, and follow-up studies have failed to corroborate the initial findings. (4) In a well-designed study, Singal et al. retrospectively analyzed a cohort of 793 patients with HCV-related HCC who achieved a complete radiological response following surgical resection, local ablation, transarterial chemoembolization or radioembolization, or radiation therapy across 31 North American centers. (5) They compared the incidence of posttreatment recurrence of HCC after complete radiological response between HCV-HCC patients who received DAA therapy and those who did not. The authors found that DAA therapy was not associated with an increased incidence of HCC recurrence and that HCC recurrence patterns were similar in DAA-treated and DAA-untreated patients. (5) A follow-up publication showed that the receipt of DAA therapy after the documentation of a complete response of HCC was associated with a 46% decrease in the hazard of death (hazard ratio, 0.54; 95% confidence interval, 0.33-0.90). (6) In this issue, Piñero et al. explore the association between DAA treatment and progression of HCC while on the transplant waiting list among 994 patients listed for transplantation across 20 centers in Latin America. (7) In addition to wait-list progression, they also looked at posttransplant recurrence of HCC. The authors compared 3 cohorts of patients with HCC listed for transplantation: those with HCC unrelated to HCV (n = 503), patients with HCV and HCC who did not receive DAAs (n = 327), and those with HCV and HCC treated with DAAs either before (n = 66) or after (n = 98) transplantation. A total of 81.9% were within Milan criteria, and the median time from listing to transplantation was between 6 and 9 months. The authors found that receipt of pretransplant DAA therapy was not associated with dropout from the transplant list or posttransplant recurrence of HCC.Why is this topic of interest to clinicians managing patients with HCC on the transplant waiting list? Transplant hepatologists have to consider a number of factors while deciding on the optimal timing of DAA therapy in HCV-HCC patients listed for transplantation. The benefits of treating HCV in patients on the waiting li...