Intrahepatic immune changes after hepatitis c virus eradication by direct-acting antiviral therapy

Liver Int. 2020 Jan;40(1):74-82. doi: 10.1111/liv.14226. Epub 2019 Sep 4.


Background & aims: The recent approval of direct acting anti-virals (DAA) has dramatically changed the landscape of hepatitis C virus (HCV) therapy. Whether viral clearance could promote liver carcinogenesis is debated. It has been hypothesized that changes in intrahepatic immune surveillance following viral cure could favour tumour growth. This study aimed at characterizing the intrahepatic immune changes induced by HCV cure following DAA therapy.

Methods: Patients with compensated cirrhosis who underwent surgical resection for hepatocellular carcinoma (HCC) after sustained virological response (SVR) to DAA therapy were included. A control group of untreated HCV-infected patients with compensated cirrhosis was selected. RNA was extracted from tumoral and non-tumoral tissues and analysed using the Nanostring Immuno-Oncology-360 panel. Immune cells were quantified by immunohistochemistry.

Results: Twenty patients were included: 10 patients with a DAA-induced SVR and 10 untreated controls. All of them had a de novo BCLC 0/A HCC. Non-tumoral tissue profiling showed down-regulation of interferon-related genes (including MX1, ISG15 and IFIT1) after DAA therapy. No other differences in immune profiles/immune cell densities were identified between the two groups. The intra-tumoral immune profiles of HCCs that occurred after DAA therapy were not qualitatively or quantitatively different from those of tumours occurring in untreated patients.

Conclusion: In conclusion, removal of HCV infection after DAA-based therapy results only in a down-regulation of interferon-stimulated genes in non-tumoral tissues from patients with cirrhosis who develop HCC. These minor changes in the liver immune microenvironment are unlikely to favour HCC occurrence or recurrence after DAA-induced SVR.

Keywords: direct acting antivirals; hepatitis c virus; hepatocellular carcinoma; immunity.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Aged
  • Aged, 80 and over
  • Antiviral Agents / therapeutic use*
  • Carcinogenesis
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / pathology*
  • Carcinoma, Hepatocellular / surgery
  • Cytokines / genetics
  • Female
  • Gene Expression Profiling
  • Hepacivirus / genetics
  • Hepacivirus / immunology
  • Hepatitis C, Chronic / complications
  • Hepatitis C, Chronic / drug therapy*
  • Humans
  • Immunohistochemistry
  • Liver Cirrhosis / virology
  • Liver Neoplasms / genetics
  • Liver Neoplasms / pathology*
  • Liver Neoplasms / surgery
  • Male
  • Middle Aged
  • Myxovirus Resistance Proteins / genetics
  • RNA, Viral / genetics
  • RNA-Binding Proteins / genetics
  • Sustained Virologic Response
  • Tumor Microenvironment
  • Ubiquitins / genetics


  • Adaptor Proteins, Signal Transducing
  • Antiviral Agents
  • Cytokines
  • IFIT1 protein, human
  • MX1 protein, human
  • Myxovirus Resistance Proteins
  • RNA, Viral
  • RNA-Binding Proteins
  • Ubiquitins
  • ISG15 protein, human