title: Telaprevir-S isomer enhances ribavirin exposure and the ribavirin-related haemolytic anaemia in a concentration-dependent manner.
abstract: The standard-of-care for the treatment of genotype-1 chronic hepatitis C is based on the combination of direct acting antivirals, such as boceprevir and telaprevir, with ribavirin and pegylated-interferon alfa. These triple regimens give a higher response rate than dual therapy, but on the other hand show a more than 10% higher rate of anaemia. Not enough focus has been given to the interaction between telaprevir and RBV. In this work, we aimed to study and deepen this relationship by comparing ribavirin plasma and intra-erythrocytic concentrations at one month of triple and dual therapy (17 vs. 119 patients). Moreover, we determined telaprevir isomers concentrations and tested them for correlation with ribavirin concentrations and haemoglobin loss at one month of treatment. Finally, all drugs concentration data were tested for their correlation with the renal function during treatment. The comparisons of ribavirin concentration and toxicity data were repeated on a sub-group of 9 patients who had been treated 1 year before with dual therapy and then re-treated with triple therapy. The observed ribavirin plasma and intra-erythrocytic concentrations in triple therapy were significantly higher compared to dual therapy, both in whole group and sub-group comparison. Ribavirin concentrations were significantly correlated to the haemoglobin loss and telaprevir-S isomer concentrations (r(2)=0.317 P(value)=0.023 and r(2)=0.388 P(value)=0.008, respectively). Renal function had a significant decrease from the baseline value, but was not significantly correlated with drugs concentrations. These results highlight for the first time that, in the context of triple therapy with telaprevir, ribavirin exposure is related to the telaprevir-S isomer plasma concentration. We conclude that the addition of telaprevir to the dual therapy increases ribavirin exposure and haemoglobin loss: this effect could probably be managed through the therapeutic drug monitoring of ribavirin and telaprevir-S concentrations.
authors: Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy. Electronic address: amedeo.denicolo@unito.it.
authors: Amedeo
authors: A
authors: De Nicolò
authors: Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy.
authors: Lucio
authors: L
authors: Boglione
authors: Unit of Gastroenterology, University of Turin, Department of Medical Sciences, S. Giovanni Battista (Molinette) Hospital, Turin, Italy.
authors: Alessia
authors: A
authors: Ciancio
authors: Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy.
authors: Jessica
authors: J
authors: Cusato
authors: Unit of Gastroenterology, University of Turin, Department of Medical Sciences, S. Giovanni Battista (Molinette) Hospital, Turin, Italy.
authors: Silvia
authors: S
authors: Strona
authors: Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy.
authors: Chiara Simona
authors: CS
authors: Cardellino
authors: Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy.
authors: Adnan Mohamed
authors: AM
authors: Abdi
authors: Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy.
authors: Giuseppe
authors: G
authors: Cariti
authors: Unit of Gastroenterology, University of Turin, Department of Medical Sciences, S. Giovanni Battista (Molinette) Hospital, Turin, Italy.
authors: Giulia
authors: G
authors: Troshina
authors: Unit of Gastroenterology, University of Turin, Department of Medical Sciences, S. Giovanni Battista (Molinette) Hospital, Turin, Italy.
authors: Gian Paolo
authors: GP
authors: Caviglia
authors: Unit of Gastroenterology, University of Turin, Department of Medical Sciences, S. Giovanni Battista (Molinette) Hospital, Turin, Italy.
authors: Antonina
authors: A
authors: Smedile
authors: Unit of Gastroenterology, University of Turin, Department of Medical Sciences, S. Giovanni Battista (Molinette) Hospital, Turin, Italy.
authors: Mario
authors: M
authors: Rizzetto
authors: Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy.
authors: Giovanni
authors: G
authors: Di Perri
authors: Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy.
authors: Antonio
authors: A
authors: D'Avolio
mesh_terms: D000328:Adult; D000743:Anemia, Hemolytic / Q000139:chemically induced*; D000998:Antiviral Agents / Q000009:adverse effects* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D016174:Hepacivirus / Q000187:drug effects / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use; D007536:Isomerism; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000009:adverse effects* / Q000737:chemistry / Q000627:therapeutic use; D012254:Ribavirin / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D009842:Oligopeptides; D012254:Ribavirin; C486464:telaprevir
keywords: Anaemia; HCV-1; Interaction; Ribavirin; Telaprevir