The Impact of HCV Eradication by Direct-acting Antivirals on the Transition of Precancerous Hepatic Nodules to HCC

A Prospective Observational Study

Hidenori Toyoda; Takashi Kumada; Toshifumi Tada; Kazuyuki Mizuno; Yasuhiro Sone; Tomoyuki Akita; Junko Tanaka; Philip J. Johnson


Liver International. 2019;39(3):448-454. 

In This Article

Abstract and Introduction


Background & Aims: It remains controversial whether the eradication of hepatitis C virus (HCV) by interferon (IFN)-free anti-HCV therapy using direct-acting antivirals (DAAs) suppresses or promotes hepatocellular carcinoma (HCC) development. We investigated the influence of HCV eradication by DAA therapy on HCC development, by observing changes of non-hypervascular hypointense nodules (NHHNs) by gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI).

Methods: A total of 401 patients treated with DAA therapy who did not have a history of HCC were enrolled in this prospective cohort study. All patients underwent EOB-MRI prior to the start of DAA therapy and were followed up periodically after therapy. The progression of NHHNs detected at baseline to typical HCC, as indicated by hypervascularization and the incidence of newly emergent NHHNs, was analyzed.

Results: In comparison of patients who achieved sustained virologic response (SVR) with propensity score-matched patients with persistent HCV infection, there was no difference in the incidence of hypervascularization of NHHNs to typical HCC among patients who had NHHNs at baseline. Among patients who did not have NHHNs at baseline, the incidence of the new emergence of NHHNs did not differ between study patients and propensity score–matched patients with persistent HCV infection.

Conclusions: During a 2-year observation period after SVR, the eradication of HCV by IFN-free DAA therapy did not suppress or enhance HCC development. (UMIN000017020).


Hepatocellular carcinoma (HCC) is one of the most important complications of chronic HCV infection.[1–3] A paradigm shift in HCV treatment occurred with the introduction of interferon (IFN)-free therapy using direct-acting antiviral agents (DAAs). These agents have an excellent safety profile and more than 90% of patients with HCV undergoing DAA therapy achieved sustained virologic response (SVR). Achievement of SVR with IFN-based anti-HCV therapy reportedly resulted in a marked decrease in the incidence of HCC.[4–7] However, the effectiveness of HCV eradication by DAA therapy in preventing the development of HCC after SVR remains controversial.[8–16] In particular, recent studies have suggested that HCV eradication by DAA therapy might enhance the risk of HCC development or, after resection, recurrence.[8,9,17] There is thus an urgent need to determine whether HCV eradication by DAA therapy will prevent or enhance HCC development in patients with chronic HCV infection.

Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) is currently the most sensitive imaging modality to detect liver nodules.[18] Non-hypervascular hypointense nodules (NHHNs) are hepatic nodules that are detected during the hepatobiliary phase of EOB-MRI but lack enhancement during its arterial phase. The precise histological/pathological correlates of NHHNs, as detected by EOB-MRI, remain controversial. Where histological examination has been undertaken, they are reported variously as "dysplastic nodules" or "very early HCC".[19] In any case, NHHNs would not fit a clinical diagnosis of HCC according to current AASLD/EASL guidelines and, to this extent, we believe that such lesions most likely represent a "pre-clinical" stage of HCC. Resected specimens examined after EOB-MRI evidence of hypervascularization are usually reported as well-or moderately differentiated HCC and, as such represent a further step in the development of HCC.[20,21] Such lesions would be classified as HCC according to AASLD/EASL guidelines.[22,23]

In this prospective study, we have applied this most sensitive method for the detection of preclinical HCC to examine the impact of HCV eradication on the transition of pre-clinical to clinical HCC. We have also examined the impact of HCV eradication on the emergence of new such lesions in patients without these nodules before therapy.