title: Ribavirin dose reduction during telaprevir/ribavirin/peg-interferon therapy overcomes the effect of the ITPA gene polymorphism.
abstract: Treatment success of chronic hepatitis C virus genotype 1 infection has improved with the advent of telaprevir plus peg-interferon/ribavirin triple combination therapy. However, the effect of inosine triphosphatase (ITPA) polymorphism on dose reduction during triple therapy, especially during the postmarketing phase, has not been sufficiently evaluated. We analysed 273 patients with genotype 1 infection who were treated with triple therapy and assessed the effect of the ITPA polymorphism on dose reduction. ITPA and IFNL4 SNP genotypes were determined by the Invader assay. A stepwise multivariate regression analysis was performed to identify factors associated with outcome of the therapy. The overall sustained viral response (SVR) rate 12 weeks after the end of therapy was 80.2% (219/273). Decline of haemoglobin was significantly faster, and ribavirin was more extensively reduced in patients with ITPA SNP rs1127354 genotype CC than CA/AA. Extensive reduction of ribavirin resulted in mild reduction of telaprevir and peg-interferon, but no significant increase in viral breakthrough. Although the amount of telaprevir given was slightly higher in CA/AA patients, the total dose of peg-interferon and the SVR rate did not differ between the two groups. Multivariate analysis showed that IFNL4 but not ITPA SNP genotype, platelet count and peg-interferon adherence were significantly associated with outcome of therapy. Postmarketing-phase triple therapy resulted in a high SVR rate in spite of extensive ribavirin dose reduction in a diverse patient population, indicating the importance of treatment continuation and appropriate management of adverse events.
authors.affiliation: Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Akamatsu
authors.forename: C N
authors.initials: CN
authors.lastname: Hayes
authors.forename: M
authors.initials: M
authors.lastname: Tsuge
authors.forename: E
authors.initials: E
authors.lastname: Murakami
authors.forename: N
authors.initials: N
authors.lastname: Hiraga
authors.forename: H
authors.initials: H
authors.lastname: Abe
authors.forename: D
authors.initials: D
authors.lastname: Miki
authors.forename: M
authors.initials: M
authors.lastname: Imamura
authors.forename: H
authors.initials: H
authors.lastname: Ochi
authors.forename: K
authors.initials: K
authors.lastname: Chayama
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage*; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D005838:Genotype; D060005:Genotyping Techniques; D016174:Hepacivirus / Q000145:classification / Q000235:genetics / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage*; D007378:Interleukins / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000008:administration & dosage*; D020641:Polymorphism, Single Nucleotide; D011755:Pyrophosphatases / Q000235:genetics*; D012254:Ribavirin / Q000008:administration & dosage*; D016896:Treatment Outcome; D055815:Young Adult; D000095022:Interferon Lambda; D000097630:Inosine Triphosphatase
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D007378:Interleukins; D009842:Oligopeptides; D011755:Pyrophosphatases; D012254:Ribavirin; C579163:IFNL4 protein, human; D000095022:Interferon Lambda; C486464:telaprevir; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase
keywords: anaemia; dose reduction; haemoglobin; hepatitis C virus; sustained viral response