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J Hepatol. 2019 Jan 23. pii: S0168-8278(19)30015-7. doi: 10.1016/j.jhep.2019.01.005. [Epub ahead of print]

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

Author information

1
Liver Unit, Hospital Clinic, IDIBAPS, University of Barcelona. CIBERehd, 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 the very high efficacy of direct acting antivirals (DAA) to eradicate hepatitis C virus infection, the impact on hepatocellular carcinoma development remains controversial. We analyzed the clinical and radiological outcome of cirrhotic patients treated with interferon-free regimens to estimate the risk of developing hepatocellular carcinoma.

METHODS:

Retrospective, multicenter study focusing on cirrhotic patients treated with direct acting antivirals until December 2016. Clinical and radiologic characteristics before starting antiviral therapy, at follow-up and at hepatocellular carcinoma development were collected. Diagnosis of hepatocellular carcinoma was centrally validated and its incidence was expressed as HCC/100 patients-year.

RESULTS:

1,123 patients were included (60.6% males, 83.8% Child-Pugh A) and 95.2% achieved sustained virological response. Median time of follow-up was 19.6 months. Seventy-two patients developed hepatocellular carcinoma within a median of 10.3 months after starting antiviral treatment. HCC incidence was 3.73 HCC/100 patients-year (95% CI 2.96;4.70). Baseline liver function, alcohol intake and hepatic decompensation were associated to higher risk. 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. There is need to further investigate the mechanisms involved in the increased risk of hepatocellular carcinoma emergence at short term.

LAY SUMMARY:

In this cohort of cirrhotic patients, interferon-free therapies achieved a high rate of sustained virological response (>95%); however, a 3.73% risk of developing de novo hepatocellular carcinoma per 100 persons/year with a clear-cut time association with antiviral therapy was registered. The presence of non-characterized nodules in radiologic assessments before starting DAA was associated to a 9.6% risk of developing hepatocellular carcinoma per 100 persons/year among cirrhotic patients treated with DAA. Thus, patients who started DAA and had indeterminate nodules have up to almost 3 times higher risk of developing HCC than those patients without or with well-defined benign nodules. The time association between starting DAA and developing HCC, together with the association with the presence of non-characterized nodules at the 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, liver cancer risk at short term is significantly increased.

KEYWORDS:

HCV; cirrhosis; de novo hepatocellular carcinoma; direct-acting antivirals; incidence

PMID:
30684506
DOI:
10.1016/j.jhep.2019.01.005

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