Improvement of ALT decay kinetics by all-oral HCV treatment: Role of NS5A inhibitors and differences with IFN-based regimens

PLoS One. 2017 May 18;12(5):e0177352. doi: 10.1371/journal.pone.0177352. eCollection 2017.

Abstract

Background: Intracellular HCV-RNA reduction is a proposed mechanism of action of direct-acting antivirals (DAAs), alternative to hepatocytes elimination by pegylated-interferon plus ribavirin (PR). We modeled ALT and HCV-RNA kinetics in cirrhotic patients treated with currently-used all-DAA combinations to evaluate their mode of action and cytotoxicity compared with telaprevir (TVR)+PR.

Study design: Mathematical modeling of ALT and HCV-RNA kinetics was performed in 111 HCV-1 cirrhotic patients, 81 treated with all-DAA regimens and 30 with TVR+PR. Kinetic-models and Cox-analysis were used to assess determinants of ALT-decay and normalization.

Results: HCV-RNA kinetics was biphasic, reflecting a mean effectiveness in blocking viral production >99.8%. The first-phase of viral-decline was faster in patients receiving NS5A-inhibitors compared to TVR+PR or sofosbuvir+simeprevir (p<0.001), reflecting higher efficacy in blocking assembly/secretion. The second-phase, noted δ and attributed to infected-cell loss, was faster in patients receiving TVR+PR or sofosbuvir+simeprevir compared to NS5A-inhibitors (0.27 vs 0.21 d-1, respectively, p = 0.0012). In contrast the rate of ALT-normalization, noted λ, was slower in patients receiving TVR+PR or sofosbuvir+simeprevir compared to NS5A-inhibitors (0.17 vs 0.27 d-1, respectively, p<0.001). There was no significant association between the second-phase of viral-decline and ALT normalization rate and, for a given level of viral reduction, ALT-normalization was more profound in patients receiving DAA, and NS5A in particular, than TVR+PR.

Conclusions: Our data support a process of HCV-clearance by all-DAA regimens potentiated by NS5A-inhibitor, and less relying upon hepatocyte death than IFN-containing regimens. This may underline a process of "cell-cure" by DAAs, leading to a fast improvement of liver homeostasis.

Publication types

  • Clinical Trial

MeSH terms

  • Administration, Oral
  • Aged
  • Alanine Transaminase / blood*
  • Alanine Transaminase / metabolism
  • Antiviral Agents / administration & dosage
  • Antiviral Agents / pharmacology*
  • Drug Therapy, Combination
  • Female
  • Hepacivirus / genetics
  • Hepatitis C / drug therapy*
  • Humans
  • Interferons / pharmacology
  • Kinetics
  • Male
  • Middle Aged
  • Oligopeptides / administration & dosage
  • Oligopeptides / pharmacology
  • RNA, Viral / blood
  • Ribavirin / administration & dosage
  • Ribavirin / pharmacology
  • Simeprevir / administration & dosage
  • Simeprevir / pharmacology
  • Sofosbuvir / administration & dosage
  • Sofosbuvir / pharmacology
  • Treatment Outcome
  • Viral Nonstructural Proteins / antagonists & inhibitors*

Substances

  • Antiviral Agents
  • NS-5 protein, hepatitis C virus
  • Oligopeptides
  • RNA, Viral
  • Viral Nonstructural Proteins
  • Ribavirin
  • telaprevir
  • Interferons
  • Simeprevir
  • Alanine Transaminase
  • Sofosbuvir

Grant support

This study was funded in part by the Italian Ministry of Instruction, University and Research (MIUR) (Accordi di Programma 2011: RBAP11YS7K_001 [HIRMA], Bandiera InterOmics Protocollo PB05 1°), and by Aviralia Foundation. Abbott molecular (Abbott Park, Illinois, U.S.A.) provided part of the laboratory material for HCV-RNA determination. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.