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

• Published in: Journal of hepatology 2019-05, Vol.70 (5), p.874-884
• Main Authors: Mariño, Zoe, Darnell, Anna, Lens, Sabela, Sapena, Victor, Díaz, Alba, Belmonte, Ernest, Perelló, Christie, Calleja, Jose Luis, Varela, Maria, Rodriguez, Manuel, Rodriguez de Lope, Carlos, Llerena, Susana, Torras, Xavier, Gallego, Adolfo, Sala, Margarita, Morillas, Rosa María, Minguez, Beatriz, Llaneras, Jordi, Coll, Susana, Carrion, José Antonio, Iñarrairaegui, Mercedes, Sangro, Bruno, Vilana, Ramón, Sole, Manel, Ayuso, Carmen, Ríos, José, Forns, Xavier, Bruix, Jordi, Reig, María
• Format: Article
• Language: English
• Subjects: Aged; Alcoholic beverages; Antiviral agents; Antiviral Agents - therapeutic use; Carcinoma, Hepatocellular - epidemiology; Carcinoma, Hepatocellular - etiology; Carcinoma, Hepatocellular - mortality; Carcinoma, Hepatocellular - pathology; Cirrhosis; De novo hepatocellular carcinoma; Direct-acting antivirals; Female; HCV; Hepatitis; Hepatitis C; Hepatitis C - complications; Hepatitis C - drug therapy; Hepatocellular carcinoma; Humans; Incidence; Interferon; Liver cancer; Liver cirrhosis; Liver Cirrhosis - complications; Liver Neoplasms - epidemiology; Liver Neoplasms - etiology; Liver Neoplasms - mortality; Liver Neoplasms - pathology; Male; Middle Aged; Nodules; Patients; Retrospective Studies; Sustained Virologic Response; Time Factors; Ultrasound
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2019.01.005

[Display omitted] •The risk of HCC in patients with HCV cirrhosis treated with DAAs persists despite viral cure.•The presence of indeterminate nodules before starting DAA is associated with a 3 times greater risk of HCC.•A time association between DAA therapy and developing HCC reflects increased short-term HCC risk.•DAA therapy elicits a mechanism that primes the emergence of HCC early during follow-up. 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. 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. 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. 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. 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