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


In our cohort, we found a cumulative incidence of de novo HCC of 2% and 4% at 12 and 24 months of follow-up in patients who received all-oral direct-acting antiviral therapies for HCV. This cumulative incidence of HCC was higher among cirrhotic patients even after SVR achievement, particularly in those presenting with CSPH. Moreover, CSPH was the strongest independent predictor associated with HCC development. After controlling for confounding variables, patients not achieving SVR presented a five-fold increased risk of HCC. This fold increase in non-responders implies a 73% relative risk reduction for de novo HCC incidence in SVR, with 17 patients requiring treatment to prevent one case of de novo HCC. This effect was specific when evaluated among cirrhotic patients.

Since the introduction of all-oral IFN-free regimens, high cure rates of these new therapies raised the hope that natural history of HCV-related cirrhosis could be modified, including a reduced incidence of HCC. However, several studies suggested an increased risk of HCC after DAA therapy.[8–14] This initial alarm was postulated prior to the full introduction of DAAs in Latin America.[6,7] Approval of DAA regimens in Latin America occurred 18 to 24 months after their approval in Europe and the USA. This allowed us to prospectively evaluate the incidence of de novo HCC following DAAs regimens. To our knowledge, this is the largest to-date prospective cohort study evaluating de novo HCC in Latin America, a region with wide socio-cultural and racial heterogeneity and different spectrum of barriers to access DAA therapies.

Several studies including patients treated with IFN-based therapies described that the risk of HCC was markedly lower in patients achieving SVR.[3] This has been postulated to be the consequence of IFN's immune modulating and antitumour properties rather than its antiviral activity alone. This issue has been a matter of debate. The biological plausibility that sustained this hypothesis is the loss of the anti-oncologic surveillance after the accelerated viral eradication obtained with DAA treatment.[24] Small studies with heterogeneous populations reported a high incidence of HCC following DAA therapy, whereas larger retrospective studies described a HCC risk reduction on achieving SVR.[25] Their retrospective nature and comparison with IFN-treated historical cohorts with less advanced liver disease than DAA cohorts led to important selection biases.

More recently, two large prospective Italian studies reported interesting results that are in line with ours.[26,27] Authors described a similar HCC incidence following DAA therapy and risk factors for HCC development such as diabetes, HBV co-infection,[26] low platelet count and serum albumin.[27] Although SVR was associated with a lower risk of de novo HCC, a persistent risk of HCC development after SVR was observed in cirrhotic patients in both studies. Thus, maintenance of cancer surveillance is still recommended.[26,28] Similar to what was reported by other groups, in our study, the risk of de novo HCC was inversely associated with antiviral therapy response.[8,26–30] In addition, we did not find any association with more aggressive tumour presentation at HCC diagnosis and SVR, in line with other groups' findings.[26,27]

A significant strength of our study is the prospective and multicentre design that allowed us to analyse well-documented variables associated with de novo HCC. However, we faced some limitations. First, our study has a relatively short follow-up time, as a consequence of the recent introduction of DAAs in Latin America. Nevertheless, in most published series, the diagnosis of de novo HCC was done during the first year of initiating DAA therapy. Second, neither do we include a historical nor a control group without antiviral therapy due to ethical restraints. Third, a potential selection bias could have been avoided if HCC had been excluded with contrast-enhanced imaging methods prior to DAAs initiation, differentiating de novo from pre-existing HCC. However, this would be very costly. Nevertheless, in our cohort, six monthly abdominal ultrasound examinations were rigorously indicated before, during and after DAA treatment. This issue has not been correctly assessed in previous studies using ICD codes, in that misclassification of patients might have led to a risk of bias.

In conclusion, our study demonstrates that achieving SVR with DAA regimens was associated with a significant risk reduction in HCC. However, this risk remains high in patients with advanced fibrosis even after achieving viral eradication, thus demanding proper and continuous surveillance strategies in this population.[31,32] Early treatment to prevent cirrhosis is the preferred strategy to avoid liver cancer development. Consequently, in our region we should implement strong public health strategies to provide treatment of HCV infection in early stages of liver disease if our goal is to further diminish de novo incidence of HCC. A lot still needs to be done in our region to overcome barriers to access treatment. On the other hand, health providers should maintain close surveillance of HCC development even in patients achieving viral clearance, with particular focus in those with CSPH.