HCV resistance compartmentalization within tumoral and non-tumoral liver in transplanted patients with hepatocellular carcinoma

Liver Int. 2019 Oct;39(10):1986-1998. doi: 10.1111/liv.14168. Epub 2019 Jul 16.

Abstract

Background & aims: We investigated the HCV-RNA amount, variability and prevalence of resistance-associated substitutions (RASs), in plasma, hepatic tumoral and non-tumoral tissue samples in patients undergoing liver-transplant/hepatic-resection (LT/HR), because of hepatocellular carcinoma and/or cirrhosis.

Methods: Eighteen HCV-infected patients undergoing LT/HR, 94.0% naïve to direct-acting antivirals (DAAs), were analysed. HCV-RNA was quantified in all compartments. NS3/NS5A/NS5B in plasma and/or in tumoral/non-tumoral tissues were analysed using Sanger and Ultra-deep pyrosequencing (UDPS, 9/18 patients). RASs prevalence, genetic-variability and phylogenetic analysis were evaluated.

Results: At the time of LT/HR, HCV-RNA was quantifiable in all compartments of DAA-naïve patients and was generally lower in tumoral than in non-tumoral tissues (median [IQR] = 4.0 [1.2-4.3] vs 4.3[3.1-4.9] LogIU/µg RNA; P = 0.193). The one patient treated with sofosbuvir + ribavirin represented an exception with HCV-RNA quantifiable exclusively in the liver, but with higher level in tumoral than in non-tumoral tissues (51 vs 7 IU/µg RNA). RASs compartmentalization was found by Sanger in 4/18 infected-patients, and by UDPS in other two patients. HCV-compartmentalization resulted to be associated with HBcAb-positivity (P = 0.013). UDPS showed approximately higher genetic-variability in NS3/NS5A sequences in all compartments. Phylogenetic-analysis showed defined and intermixed HCV-clusters among/within all compartments, and were strongly evident in the only non-cirrhotic patient, with plasma and non-tumoral sequences generally more closely related.

Conclusions: Hepatic compartments showed differences in HCV-RNA amount, RASs and genetic variability, with a higher segregation within the tumoral compartment. HBV coinfection influenced the HCV compartmentalization. These results highlight HCV-strain diversifications within the liver, which could explain some of the failures occurring even today in the era of DAAs.

Keywords: Compartmentalization; HBV-coinfection; HCV; Hepatocellular carcinoma; Liver transplantation; Resistance-associated substitutions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antiviral Agents / therapeutic use*
  • Carcinoma, Hepatocellular / surgery
  • Coinfection / drug therapy
  • Drug Resistance, Viral / genetics*
  • Drug Therapy, Combination
  • Genotype
  • Hepacivirus / drug effects
  • Hepacivirus / genetics*
  • Hepatitis B, Chronic / drug therapy
  • Hepatitis C, Chronic / drug therapy*
  • Humans
  • Liver Neoplasms / surgery
  • Liver Transplantation*
  • Male
  • Middle Aged
  • Phylogeny
  • Ribavirin / therapeutic use
  • Sofosbuvir / therapeutic use
  • Sustained Virologic Response
  • Treatment Failure
  • Viral Nonstructural Proteins / genetics*

Substances

  • Antiviral Agents
  • Viral Nonstructural Proteins
  • Ribavirin
  • Sofosbuvir