Time association between hepatitis C therapy and hepatocellular carcinoma emergence in cirrhosis: Relevance of non-characterized nodules

Zoe Mariño, Anna Darnell, Sabela Lens, Victor Sapena, Alba Díaz, Ernest Belmonte, Christie Perelló, Jose Luis Calleja, Maria Varela, Manuel Rodriguez, Carlos Rodriguez de Lope, Susana Llerena, Xavier Torras, Adolfo Gallego, Margarita Sala, Rosa María Morillas, Beatriz Minguez, Jordi Llaneras, Susana Coll, José Antonio CarrionMercedes Iñarrairaegui, Bruno Sangro, Ramón Vilana, Manel Sole, Carmen Ayuso, José Ríos, Xavier Forns, Jordi Bruix, María Reig

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47 Citations (Scopus)


© 2019 Background & Aims: Despite direct-acting antivirals being highly effective at eradicating hepatitis C virus infection, their impact on the development of hepatocellular carcinoma (HCC) remains controversial. We analyzed the clinical and radiological outcome of cirrhotic patients treated with interferon-free regimens to estimate the risk of developing HCC. Methods: This was a retrospective multicenter study focusing on cirrhotic patients treated with direct-acting antivirals until December 2016. Clinical and radiologic characteristics were collected before the start of antiviral therapy, at follow-up and at HCC development. Diagnosis of HCC was centrally validated and its incidence was expressed as HCC/100 person-years. Results: A total of 1,123 patients were included (60.6% males, 83.8% Child-Pugh A) and 95.2% achieved a sustained virologic response. Median time of follow-up was 19.6 months. Seventy-two patients developed HCC within a median of 10.3 months after starting antiviral treatment. HCC incidence was 3.73 HCC/100 person-years (95% CI 2.96–4.70). Baseline liver function, alcohol intake and hepatic decompensation were associated with a higher risk of HCC. The relative risk was significantly increased in patients with non-characterized nodules at baseline 2.83 (95% CI 1.55–5.16) vs. absence of non-characterized nodules. When excluding these patients, the risk remained increased. Conclusion: These data expose a clear-cut time association between interferon-free treatment and HCC. The mechanisms involved in the increased risk of HCC emergence in the short term require further investigation. Lay summary: In this cohort of cirrhotic patients, interferon-free therapies achieved a high rate of sustained virologic response (>95%); however, we reported a risk of de novo hepatocellular carcinoma of 3.73 per 100 person-years and a clear-cut time association with antiviral therapy. The time association between starting direct-acting antivirals and developing hepatocellular carcinoma, together with the association with the presence of non-characterized nodules at baseline ultrasound, suggests that antiviral therapy elicits a mechanism (probably immune-related) that primes the growth and clinical recognition of hepatocellular carcinoma early during follow-up. As a result, short-term liver cancer risk is significantly increased.
Original languageEnglish
Pages (from-to)874-884
JournalJournal of Hepatology
Publication statusPublished - 1 May 2019


  • Cirrhosis
  • De novo hepatocellular carcinoma
  • Direct-acting antivirals
  • HCV
  • Incidence


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