title: HCV kinetic and modeling analyses indicate similar time to cure among sofosbuvir combination regimens with daclatasvir, simeprevir or ledipasvir.
abstract: Recent clinical trials of direct-acting-antiviral agents (DAAs) against hepatitis C virus (HCV) achieved >90% sustained virological response (SVR) rates, suggesting that cure often took place before the end of treatment (EOT). We sought to evaluate retrospectively whether early response kinetics can provide the basis to individualize therapy to achieve optimal results while reducing duration and cost.
  
  
  
  58 chronic HCV patients were treated with 12-week sofosbuvir+simeprevir (n=19), sofosbuvir+daclatasvir (n=19), or sofosbuvir+ledipasvir in three French referral centers. HCV was measured at baseline, day 2, every other week, EOT and 12weeks post EOT. Mathematical modeling was used to predict the time to cure, i.e., <1 virus copy in the entire extracellular body fluid.
  
  
  
  All but one patient who relapsed achieved SVR. Mean age was 60±11years, 53% were male, 86% HCV genotype-1, 9% HIV coinfected, 43% advanced fibrosis (F3), and 57% had cirrhosis. At weeks 2, 4 and 6, 48%, 88% and 100% of patients had HCV<15IU/ml, with 27%, 74% and 91% of observations having target not detected, respectively. Modeling results predicted that 23 (43%), 16 (30%), 7 (13%), 5 (9%) and 3 (5%) subjects were predicted to reach cure within 6, 8, 10, 12 and 13weeks of therapy, respectively. The modeling suggested that the patient who relapsed would have benefitted from an additional week of sofosbuvir+ledipasvir. Adjusting duration of treatment according to the modeling predicts reduced medication costs of 43-45% and 17-30% in subjects who had HCV<15IU/ml at weeks 2 and 4, respectively.
  
  
  
  The use of early viral kinetic analysis has the potential to individualize duration of DAA therapy with a projected average cost saving of 16-20% per 100-treated persons.
authors.affiliation: The Program for Experimental & Theoretical Modeling, Division of Hepatology, Loyola University Medical Center, Maywood, IL, USA; Theoretical Biology & Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM, USA. Electronic address: harel.dahari@gmail.com.
authors.forename: Harel
authors.initials: H
authors.lastname: Dahari
authors.affiliation: The Program for Experimental & Theoretical Modeling, Division of Hepatology, Loyola University Medical Center, Maywood, IL, USA; Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Canini
authors.affiliation: Center for Modeling and Simulation in the Biosciences, BioQuant Center, Heidelberg University, Heidelberg, Germany.
authors.forename: Frederik
authors.initials: F
authors.lastname: Graw
authors.affiliation: The Program for Experimental & Theoretical Modeling, Division of Hepatology, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Uprichard
authors.affiliation: University of Sao Paulo Hospital das Clınicas, Sao Paulo, Brazil.
authors.forename: Evaldo S A
authors.initials: ES
authors.lastname: Araújo
authors.affiliation: Laboratoire Alphabio, Marseille, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Penaranda
authors.affiliation: Internal Medicine and Infectious Disease, Hôpital Européen, Marseille, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Coquet
authors.affiliation: Internal Medicine and Infectious Disease, Hôpital Européen, Marseille, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Chiche
authors.affiliation: Division of Hepatology, Hôpital Saint Joseph, Marseille, France.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Riso
authors.affiliation: Division of Hepatology, CH Hyères, Hyères, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Renou
authors.affiliation: Division of Hepatology, Hôpital Saint Joseph, Marseille, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Bourliere
authors.affiliation: The Program for Experimental & Theoretical Modeling, Division of Hepatology, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Cotler
authors.affiliation: Laboratoire Alphabio, Marseille, France; Internal Medicine and Infectious Disease, Hôpital Européen, Marseille, France. Electronic address: philippe.halfon@alphabio.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Halfon
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage*; D001562:Benzimidazoles / Q000008:administration & dosage; D002219:Carbamates; D004359:Drug Therapy, Combination; D005260:Female; D005449:Fluorenes / Q000008:administration & dosage; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D011759:Pyrrolidines; D012367:RNA, Viral / Q000097:blood; D012189:Retrospective Studies; D000069616:Simeprevir / Q000008:administration & dosage; D000069474:Sofosbuvir / Q000008:administration & dosage; D013997:Time Factors; D014633:Valine / Q000031:analogs & derivatives
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D002219:Carbamates; D005449:Fluorenes; D007093:Imidazoles; D011759:Pyrrolidines; D012367:RNA, Viral; C586541:ledipasvir; D000069616:Simeprevir; D014633:Valine; C549273:daclatasvir; D000069474:Sofosbuvir
keywords: Duration of therapy; HCV; Mathematical modeling; SVR; Viral kinetics