title: Effect of Peginterferon or Ribavirin Dosing on Efficacy of Therapy With Telaprevir in Treatment-Experienced Patients With Chronic Hepatitis C and Advanced Liver Fibrosis: A Multicenter Cohort Study.
abstract: We investigated the safety, efficacy, and impact of ribavirin and peginterferon dose reduction on complete early virologic response and sustained virologic response (SVR) to triple therapy with telaprevir in treatment-experienced patients with advanced liver fibrosis.Treatment was initiated for 211 patients who failed treatment with peginterferon and ribavirin, with bridging fibrosis (F3, n = 68) or cirrhosis (F4, n = 143), including 103 (49%) null-responders (NR), 30 (14%) partial responders (PR), and 78 (37%) relapsers (REL). Impaired liver function (ILF) platelets <100,000/mm or albumin <35 g/L were present in 40 patients. The distribution of hepatitis C virus subtypes was: 1a, 1b, or 1, with undetermined subtype for 10 (5%), 187 (89%), and 14 (6%) patients, respectively. Treatment was started with peginterferon alpha-2a or alpha-2b, ribavirin, and telaprevir at standard doses.The overall SVR24 rate was 56% and was lower in cirrhotic patients (NR: 35%, PR: 40%, and REL: 63%, respectively) than in patients with bridging fibrosis (NR: 50%, PR: 75%, and REL: 75%, respectively). The lowest probability of SVR24 was in NRs with ILF (26%). The SVR24 rate significantly decreased in NRs receiving <60% vs >60% of the total ribavirin dose (23% vs 44%, respectively) or <80% vs >80% of the total ribavirin dose (33% vs 48%, respectively). A significant SVR24 decrease was noted subsequent to a total peginterferon dose reduction, both when comparing patients who received <60% vs >60% of the total dose (NR: 0% vs 44%; REL: 33% vs 68%) and patients who received <80% vs >80% of the total dose (NR: 17% vs 50%; REL: 46% vs 71%).Serious adverse events were observed in 31 patients (15%). Deaths occurred in 4 patients. All of the deceased subjects were cirrhotic members of the ILF (baseline serum albumin level <35 g/L and/or platelet count <100,000/mm) group.Ribavirin dose reduction did not affect efficacy in REL but did in NR. Peginterferon dose reduction decreased the SVR24 rate for all groups, particularly in prior NR. ILF increased the risk of fatal complications with a low probability to achieve SVR24. One solution might be to provide wide and early access to novel, efficient, and safe interferon-free combinations to treatment-experienced patients, particularly those with liver cirrhosis.
authors.affiliation: From the ID Clinic, Myslowice, Poland (EJ, AP); Klinika Chorob Zakaznych i Hepatologii, Uniwersytet Medyczny, Białystok, Poland (RF, TL); Uniwersytet J. Kochanowskiego i Wojewodzki Szpital Zespolony, Kielce, Poland (DZ-M, WK); Department of Infectious Diseases and Hepatology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland (DK); Hospital of Infectious Diseases, Warsaw, Poland (HB); Infectious Diseases Clinic, Wroclaw, Poland (BD, WD); Poradnia Wirusowych Zapalen Watroby SU, Kraków, Poland (ML-S); NZOZ Poradnia Chorob Watroby, Zielona Gora, Poland (WL); Department of Infectious Diseases, Hepatology, and Liver Transplantation, Pomeranian Medical University, Szczecin, Poland (KJ); Department of Gastroenterology and Hepatology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland (JM); Department of Basic Biomedical Science, School of Pharmacy, Division of Laboratory, Medicine in Sosnowiec, Medical University of Silesia, Katowice, Poland (JM); Oddzial Obserwacyjno-Zakazny, Szpital im. Zeromskiego, Kraków, Poland (BP-K); Oddzial Obserwacyjno-Zakazny, Szpital Wojewodzki, Koszalin, Poland (JW); Oddzial Chorób Zakaznych, Walbrzych, Poland (KA); Klinika Chorob Infekcyjnych i Alergologii WIM, Warsaw, Poland (MD); Oddzial Obserwacyjno-Zakazny, Szpital Rejonowy, Raciborz, Poland (IO); Ośrodek Leczenia WZW, Centrum Medyczne, Lancut, Poland (AR); Warsaw Medical University and Hospital of Infectious Diseases, Warsaw, Poland (AH); and Faculty of Health Science, Medical University, Wroclaw, Poland (WD).
authors.forename: Ewa
authors.initials: E
authors.lastname: Janczewska
authors.forename: Robert
authors.initials: R
authors.lastname: Flisiak
authors.forename: Dorota
authors.initials: D
authors.lastname: Zarebska-Michaluk
authors.forename: Dorota
authors.initials: D
authors.lastname: Kozielewicz
authors.forename: Hanna
authors.initials: H
authors.lastname: Berak
authors.forename: Beata
authors.initials: B
authors.lastname: Dobracka
authors.forename: Marta
authors.initials: M
authors.lastname: Librant-Suska
authors.forename: Wladyslaw
authors.initials: W
authors.lastname: Lojewski
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Jurczyk
authors.forename: Joanna
authors.initials: J
authors.lastname: Musialik
authors.forename: Barbara
authors.initials: B
authors.lastname: Postawa-Klosińska
authors.forename: Jacek
authors.initials: J
authors.lastname: Wroblewski
authors.forename: Krystyna
authors.initials: K
authors.lastname: Augustyniak
authors.forename: Marek
authors.initials: M
authors.lastname: Dudziak
authors.forename: Iwona
authors.initials: I
authors.lastname: Olszok
authors.forename: Agata
authors.initials: A
authors.lastname: Ruszala
authors.forename: Arkadiusz
authors.initials: A
authors.lastname: Pisula
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Lapinski
authors.forename: Wieslaw
authors.initials: W
authors.lastname: Kryczka
authors.forename: Andrzej
authors.initials: A
authors.lastname: Horban
authors.forename: Witold
authors.initials: W
authors.lastname: Dobracki
mesh_terms: D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D016903:Drug Monitoring; D057915:Drug Substitution / Q000379:methods; D004359:Drug Therapy, Combination; D005260:Female; D019698:Hepatitis C, Chronic / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects; D008103:Liver Cirrhosis / Q000209:etiology / Q000473:pathology; D008111:Liver Function Tests / Q000379:methods; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000008:administration & dosage / Q000009:adverse effects; D062072:Patient Acuity; D011044:Poland / Q000453:epidemiology; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D012254:Ribavirin / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D004337:Drug Carriers; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D009842:Oligopeptides; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C486464:telaprevir; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a