title: Daclatasvir plasma level and resistance selection in HIV patients with hepatitis C virus cirrhosis treated with daclatasvir, sofosbuvir, and ribavirin.
abstract: OBJECTIVE
  Effective treatment with direct-acting antiviral drugs against hepatitis C virus (HCV) is a medical need in cirrhotic HIV-HCV co-infected patients.
  
  
  METHODS
  This study investigated the plasma levels of daclatasvir (DCV) and ribavirin (RBV) in HIV-HCV co-infected subjects treated with DCV, sofosbuvir, and RBV. Drug concentrations were quantified using validated high-performance liquid chromatography methods with ultraviolet detection. The HCV non-structural protein 5A and non-structural protein 5B coding regions were analyzed by population-based sequencing.
  
  
  RESULTS
  DCV was dosed at week 4 and at week 8 of treatment, and RBV at week 8. One patient had the lowest DCV level, corresponding to 32.7% of the overall median value of the other patients at week 4 and about 40% at week 8. The Y93H variant was detected in this subject at weeks 8, 16, and 20 of treatment, but not before treatment or at day 2, and the patient experienced virological failure. Another subject with the Y93H variant at baseline and appropriate DCV levels had HCV RNA <12 IU/ml at week 12 and undetectable at week 16.
  
  
  CONCLUSIONS
  Sub-optimal DCV drug levels allow the selection of resistance-associated variants and fail to contribute to antiviral activity. No definite reason for the low DCV level was found. Quantifying the drug is suggested in difficult-to-treat patients.
authors.affiliation: Department of Molecular Medicine, University of Padova, Via Gabelli 63, 35100 Padova, Italy. Electronic address: saverio.parisi@unipd.it.
authors.forename: Saverio G
authors.initials: SG
authors.lastname: Parisi
authors.affiliation: Department of Molecular Medicine, University of Padova, Via Gabelli 63, 35100 Padova, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Loregian
authors.affiliation: Department of Molecular Medicine, University of Padova, Via Gabelli 63, 35100 Padova, Italy.
authors.forename: Samantha
authors.initials: S
authors.lastname: Andreis
authors.affiliation: Department of Molecular Medicine, University of Padova, Via Gabelli 63, 35100 Padova, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Nannetti
authors.affiliation: Infectious Disease Unit, Padova Hospital, Padova, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Cavinato
authors.affiliation: Department of Molecular Medicine, University of Padova, Via Gabelli 63, 35100 Padova, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Basso
authors.affiliation: Infectious Disease Unit, Padova Hospital, Padova, Italy.
authors.forename: Renzo
authors.initials: R
authors.lastname: Scaggiante
authors.affiliation: Department of Molecular Medicine, University of Padova, Via Gabelli 63, 35100 Padova, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Dal Bello
authors.affiliation: Department of Molecular Medicine, University of Padova, Via Gabelli 63, 35100 Padova, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Messa
authors.affiliation: Infectious Disease Unit, Padova Hospital, Padova, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Cattelan
authors.affiliation: Department of Molecular Medicine, University of Padova, Via Gabelli 63, 35100 Padova, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Palù
mesh_terms: D000998:Antiviral Agents / Q000008:administration & dosage*; D002219:Carbamates; D060085:Coinfection / Q000188:drug therapy*; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000097:blood*; D008103:Liver Cirrhosis / Q000209:etiology; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines; D012254:Ribavirin / Q000008:administration & dosage; D000069474:Sofosbuvir / Q000008:administration & dosage; D014633:Valine / Q000031:analogs & derivatives
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D011759:Pyrrolidines; D012254:Ribavirin; D014633:Valine; C549273:daclatasvir; D000069474:Sofosbuvir
keywords: Daclatasvir; HIV–HCV patients; Mutation; Population-based sequencing; Therapeutic drug monitoring; Virological failure