Zoe Mariño1, Anna Darnell2, Sabela Lens1, Victor Sapena3, Alba Díaz4, Ernest Belmonte2, Christie Perelló5, Jose Luis Calleja5, Maria Varela6, Manuel Rodriguez6, Carlos Rodriguez de Lope7, Susana Llerena7, Xavier Torras8, Adolfo Gallego9, Margarita Sala10, Rosa María Morillas10, Beatriz Minguez11, Jordi Llaneras12, Susana Coll13, José Antonio Carrion13, Mercedes Iñarrairaegui14, Bruno Sangro14, Ramón Vilana2, Manel Sole4, Carmen Ayuso15, José Ríos16, Xavier Forns1, Jordi Bruix3, María Reig17. 1. Liver Unit, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain. 2. Barcelona Clinic Liver Cancer (BCLC) Group, Radiology Department, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Spain. 3. Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain. 4. Barcelona Clinic Liver Cancer (BCLC) Group, Pathology Department, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Spain. 5. Liver Unit, Hospital Universitario Puerta de Hierro IDIPHIM, Universidad Autónoma de Madrid, Madrid, Spain. 6. Liver Unit, Gastroenterology Department, Hospital Universitario Central de Asturias, Universidad de Oviedo, Oviedo, Spain. 7. Gastroenterology Department, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain. 8. Gastroenterology and Hepatology Department, Hospital de la Santa Creu i Sant Pau, CIBERehd, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain. 9. Gastroenterology and Hepatology Department, Hospital de la Santa Creu i Sant Pau, CIBERehd, Barcelona, Spain. 10. Liver Unit, Gastroenterology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain. 11. Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Universitat Autónoma de Barcelona, Vall d'Hebron Institute of Research (VHIR), Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain. 12. Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Universitat Autónoma de Barcelona, Vall d'Hebron Institute of Research (VHIR), Spain. 13. Liver Section, Gastroenterology Department, Hospital del Mar, IMIM (Hospital del Mar Medical Research Institute), UAB (Universitat Autonoma de Barcelona) Barcelona, Spain. 14. Liver Unit, Clínica Universidad de Navarra, IDISNA, Pamplona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain. 15. Barcelona Clinic Liver Cancer (BCLC) Group, Radiology Department, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain. 16. Medical Statistics Core Facility, IDIBAPS, Hospital Clinic Barcelona, Spain; Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain. 17. Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain. Electronic address: mreig1@clinic.ub.es.
Abstract
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.
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.
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Authors: Amit G Singal; Nicole E Rich; Neil Mehta; Andrea D Branch; Anjana Pillai; Maarouf Hoteit; Michael Volk; Mobolaji Odewole; Steven Scaglione; Jennifer Guy; Adnan Said; Jordan J Feld; Binu V John; Catherine Frenette; Parvez Mantry; Amol S Rangnekar; Omobonike Oloruntoba; Michael Leise; Janice H Jou; Kalyan Ram Bhamidimarri; Laura Kulik; George N Ioannou; Annsa Huang; Tram Tran; Hrishikesh Samant; Renumathy Dhanasekaran; Andres Duarte-Rojo; Reena Salgia; Sheila Eswaran; Prasun Jalal; Avegail Flores; Sanjaya K Satapathy; Sofia Kagan; Purva Gopal; Robert Wong; Neehar D Parikh; Caitlin C Murphy Journal: Gastroenterology Date: 2019-07-30 Impact factor: 22.682
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