title: ITPA deficiency and ribavirin level are still predictive of anaemia in HCV-HIV-coinfected patients receiving ribavirin combined with a first-generation DAA (ANRS HC27 study).
abstract: BACKGROUND
  We aimed to determine the impact of inosine triphosphatase (ITPA) deficiency on ribavirin (RBV)-induced anaemia in HIV-HCV-coinfected patients receiving a triple therapy including the haematotoxic direct-acting antiviral agent boceprevir (BOC).
  
  
  METHODS
  Patients of the ANRS HC27 BocepreVIH study were genotyped for two ITPA single nucleotide polymorphisms involved in ITPA deficiency. RBV trough concentration (Ctrough) was determined at week (W)4 and W8. Impact of ITPA deficiency on anaemia, RBV Ctrough, response and haematotoxicity (grade 3/4 anaemia, erythropoietin [EPO] use, RBV dose reduction or transfusion between day [D]0 and W8) was evaluated. Impact of RBV Ctroughon anaemia was also studied.
  
  
  RESULTS
  Among the 63 genotyped patients, 33% had a predicted ITPA deficiency. ITPA deficiency was associated with a lower haemoglobin (Hb) decline both at W4 (-1.0 g/dl versus -2.1 g/dl; P=0.02) and W8 (-2.7 g/dl versus -4.1 g/dl; P=0.05). None of the patients with ITPA deficiency received EPO between D0-W8 versus 26% of patients without ITPA deficiency (P=0.01). RBV Ctroughwas associated with Hb decrease both at W4 and W8 and an RBV Ctroughcutoff value of 2 µg/ml was significantly associated with a W4 Hb decline >2 g/dl. Haematotoxicity was significantly associated with a lower W4 Hb level (P=0.017), absence of ITPA deficiency (P=0.018) and higher RBV Ctrough(P=0.012). ITPA deficiency, W4 RBV Ctroughand gender were independent predictors of anaemia at W4. ITPA deficiency was not associated with virological response.
  
  
  CONCLUSIONS
  ITPA deficiency and RBV Ctroughare still predictive of RBV-induced anaemia in HIV-HCV-coinfected patients treated with RBV combined with a first-generation direct antiviral agent.
authors: Aix Marseille University, APHM Timone, Service de Pharmacocinétique et Toxicologie, Marseille, France.|CRO2 INSERM U911, Marseille, France.|Centre Régional de Pharmacovigilance Marseille Provence Corse, Service de pharmacologie clinique et pharmacovigilance, APHM Sainte-Marguerite, Marseille, France.
authors: Farid
authors: F
authors: Kheloufi
authors: Aix Marseille University, APHM Sainte-Marguerite, Service d'Immuno-hématologie clinique, Marseille, France.|INSERM, UMR912 (SESSTIM), 13006, Marseille, France.
authors: Isabelle
authors: I
authors: Poizot-Martin
authors: Faculty of Medicine of Nice, Hôpital Pasteur, Laboratoire de Pharmacologie, Nice, France.
authors: Rodolphe
authors: R
authors: Garraffo
authors: Rennes 1 University, Rennes, France.|Rennes University Hospital, Department of Clinical Pharmacology, Rennes, France.|INSERM 1414 CIC-P Clinical Investigation Centre, Rennes, France.
authors: Aude
authors: A
authors: Tavenard
authors: Aix Marseille University, APHM Timone, Service de Pharmacocinétique et Toxicologie, Marseille, France.
authors: Sylvie
authors: S
authors: Quaranta
authors: Rennes 1 University, Rennes, France.|Rennes University Hospital, Department of Clinical Pharmacology, Rennes, France.|INSERM 1414 CIC-P Clinical Investigation Centre, Rennes, France.
authors: Alain
authors: A
authors: Renault
authors: Faculty of Medicine of Nice, Hôpital Pasteur, Laboratoire de Pharmacologie, Nice, France.
authors: Thibault
authors: T
authors: Lavrut
authors: Service d'Hépato-Gastro-Entérologie, Hôpital Saint-Joseph, Marseille, France.
authors: Marc
authors: M
authors: Bourlière
authors: Hôpital Européen, Marseille, France.
authors: Philippe
authors: P
authors: Halfon
authors: Infectious Diseases Department, University Hospital, and UMR 1347, University of Burgundy, Dijon, France.
authors: Lionel
authors: L
authors: Piroth
authors: Rennes 1 University, Rennes, France.|Rennes University Hospital, Department of Clinical Pharmacology, Rennes, France.|INSERM 1414 CIC-P Clinical Investigation Centre, Rennes, France.
authors: Eric
authors: E
authors: Bellissant
authors: Aix Marseille University, APHM Timone, Service de Pharmacocinétique et Toxicologie, Marseille, France.|CRO2 INSERM U911, Marseille, France.
authors: Bruno
authors: B
authors: Lacarelle
authors: Infectious Diseases Unit - INSERM U941, Assistance Publique Hôpitaux de Paris (AP-HP) - Saint-Louis Hospital, Paris, France.|Paris VII - Denis Diderot University, Paris, France.
authors: Jean-Michel
authors: JM
authors: Molina
authors: Aix Marseille University, APHM Timone, Service de Pharmacocinétique et Toxicologie, Marseille, France.|CRO2 INSERM U911, Marseille, France.
authors: Caroline
authors: C
authors: Solas
mesh_terms: D000483:Alleles; D000740:Anemia / Q000175:diagnosis* / Q000209:etiology*; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D060085:Coinfection; D004359:Drug Therapy, Combination; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D008297:Male; D008661:Metabolism, Inborn Errors / Q000150:complications*; D008875:Middle Aged; D009154:Mutation; D011755:Pyrophosphatases / Q000172:deficiency* / Q000235:genetics; D012254:Ribavirin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012307:Risk Factors; D000097630:Inosine Triphosphatase
chemical_list: D000998:Antiviral Agents; D011755:Pyrophosphatases; D012254:Ribavirin; D000097630:Inosine Triphosphatase