title: TMC435  for the treatment of chronic hepatitis C.
abstract: BACKGROUND
  Chronic hepatitis C (CHC) virus infection affects more than 170 million people globally. The aim of treatment of CHC is to effect sustained elimination of the virus (a sustained virological response, SVR). Prior to the development of direct-acting antiviral (DAA) agents, the standard of care (SOC) for CHC comprised combined treatment with pegylated interferon (PegIFN) and ribavirin (RBV).
  
  
  METHODS
  TMC435 (Tibotec pharmaceuticals) is a macrocyclic non-covalent NS3/NS4A protease inhibitor (DAA) that is currently in Phase III clinical development. TMC435 is being developed in treatment regimens both with and without PegIFN and RBV. In Phase IIb clinical trials, the addition of TMC435 to current SOC significantly increased the SVR rate in both treatment-naive and experienced patients with CHC. It differs, however, from the other first-generation protease inhibitors in that it is administered once daily, has a different tolerability and resistance profile and has activity against CHC genotypes 1 - 6 with the exception of genotype 3. Furthermore, the addition of TMC435 to PegIFN/RBV appears to be able to significantly shorten treatment duration in the majority of patients. This article will review the pharmacology, pharmacodynamics, safety and efficacy of TMC435 by evaluating the preclinical and clinical studies to date.
  
  
  CONCLUSIONS
  TMC435 is a 'second-wave' protease inhibitor that has the potential to play a pivotal role in the next phase of CHC treatment. The forthcoming results of Phase III trials involving TMC435 are awaited with interest.
authors.affiliation: Royal Free Hospital, UCL Medical School, Centre for Hepatology, Rowland Hill Street, London, NW3 2PF, UK. g.dusheiko@ucl.ac.uk
authors.forename: Sudeep
authors.initials: S
authors.lastname: Tanwar
authors.forename: Paul M
authors.initials: PM
authors.lastname: Trembling
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Dusheiko
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D016174:Hepacivirus / Q000187:drug effects; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D007372:Interferons / Q000494:pharmacology / Q000627:therapeutic use; D012254:Ribavirin / Q000494:pharmacology / Q000627:therapeutic use; D000069616:Simeprevir; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D000998:Antiviral Agents; D006575:Heterocyclic Compounds, 3-Ring; D013449:Sulfonamides; D012254:Ribavirin; D007372:Interferons; D000069616:Simeprevir