Treatment With Direct-acting Antivirals for HCV Decreases But Does Not Eliminate the Risk of Hepatocellular Carcinoma

Federico Piñero; Manuel Mendizabal; Ezequiel Ridruejo; Fernando Herz Wolff; Beatriz Ameigeiras; Margarita Anders; María Isabel Schinoni; Virginia Reggiardo; Ana Palazzo; María Videla; Cristina Alonso; Luisa Santos; Adriana Varón; Sebastián Figueroa; Cecilia Vistarini; Raúl Adrover; Nora Fernández; Daniela Perez; Federico Tanno; Nelia Hernández; Marcela Sixto; Silvia Borzi; Andres Bruno; Daniel Cocozzella; Alejandro Soza; Valeria Descalzi; Claudio Estepo; Alina Zerega; Alexandre de Araujo; Hugo Cheinquer; Marcelo Silva; LALREAN


Liver International. 2019;39(6):1033-1043. 

In This Article

Abstract and Introduction


Background & Aims: Data from Europe and North America have been published regarding the risk of developing hepatocellular carcinoma (HCC) after treatment with direct antiviral agents (DAA). We proposed to evaluate cumulative incidence and associated risk factors for de novo HCC.

Methods: This was a prospective multicentre cohort study from Latin America including 1400 F1-F4-treated patients with DAAs (F3-F4 n = 1017). Cox proportional regression models (hazard ratios, HR and 95% CI) were used to evaluate independent associated variables with HCC. Further adjustment with competing risk regression and propensity score matching was carried out.

Results: During a median follow-up of 16 months (IQR 8.9–23.4 months) since DAAs initiation, overall cumulative incidence of HCC was 0.02 (CI 0.01; 0.03) at 12 months and 0.04 (CI 0.03; 0.06) at 24 months. Cumulative incidence of HCC in cirrhotic patients (n = 784) was 0.03 (CI 0.02-0.05) at 12 months and 0.06 (CI 0.04-0.08) at 24 months of follow-up. Failure to achieve SVR was independently associated with de novo HCC with a HR of 4.9 (CI 1.44; 17.32), after adjusting for diabetes mellitus, previous interferon non-responder, Child-Pugh and clinically significant portal hypertension. SVR presented an overall relative risk reduction for de novo HCC of 73% (CI 15%-91%), 17 patients were needed to be treated to prevent one case of de novo HCC in this cohort.

Conclusions: Achieving SVR with DAA regimens was associated with a significant risk reduction in HCC. However, this risk remained high in patients with advanced fibrosis, thus demanding continuous surveillance strategies in this population.


The annual incidence risk of hepatocellular carcinoma (HCC) among patients with chronic hepatitis C virus (HCV) and cirrhosis has been reported between 1.5% and 8%.[1,2] Sustained virologic response (SVR) has been associated with a reduced risk of liver-related and overall mortality rates,[3,4] and in patients with interferon (IFN)-based antiviral treatments a 76% relative risk reduction of developing HCC was observed in this population.[4] High SVR rates with the new direct-acting antiviral (DAA) combinations raised the hope that there would be a significant reduction in HCC incidence, particularly in patients with severe fibrosis.[5]

However, recently published studies from Europe and North America suggested that there is little or no impact of DAA-based regimens on the occurrence of de novo HCC and on the contrary, some authors even described a potential increased risk.[6–8] Following these preliminary reports, larger cohorts and meta-analysis did not describe robust evidence associating DAAs regimens with an increased risk of de novo HCC when compared to IFN-based therapies.[9–15] No evidence has come from other regions of the world, in particular Latin America. Thus, we sought to prospectively evaluate the cumulative incidence of de novo HCC after therapy with DAAs in a large prospective cohort from the Latin American Liver Research, Educational and Awareness Network (LALREAN).