title: Understanding early serum hepatitis D virus and hepatitis B surface antigen kinetics during pegylated interferon-alpha therapy via mathematical modeling.
abstract: There is little information on the early kinetics of hepatitis delta virus (HDV) and hepatitis B surface antigen (HBsAg) during interferon-α therapy. Here a mathematical model was developed and fitted to frequent HDV and HBsAg kinetic data from 10 patients during the first 28 weeks of pegylated-interferon-α2a (peg-IFN) therapy. Three patients achieved a complete virological response (CVR), defined as undetectable HDV 6 months after treatment stopped with loss of HBsAg and anti-HBsAg seroconversion. After initiation of therapy, a median delay of 9 days (interquartile range [IQR]: 5-15) was observed with no significant changes in HDV level. Thereafter, HDV declined in a biphasic manner, where a rapid first phase lasting for 25 days (IQR: 23-58) was followed by a slower or plateau second phase. The model predicts that the main effect of peg-IFN is to reduce HDV production/release with a median effectiveness of 96% (IQR: 93-99.8). Median serum HDV half-life (t1/2 ) was estimated as 2.9 days (IQR: 1.5-5.3) corresponding to a pretreatment production and clearance of about 10(10) (IQR: 10(9.7) -10(10.7) ) virions/day. None of the patients with flat second phase in HDV achieved CVR. HBsAg kinetics of decline paralleled the second phase of HDV decline consistent with HBsAg-productive-infected cells being the main source of production of HDV, with a median t1/2 of 135 days (IQR: 20-460). The interferon lambda-3 polymorphism (rs12979860) was not associated with kinetic parameters.
  
  
  CONCLUSIONS
  Modeling results provide insights into HDV-host dynamics, the relationship between serum HBsAg levels and HBsAg-infected cells, IFN's mode of action, and its effectiveness. The observation that a flat second phase in HDV and HBsAg kinetics was associated with failure to achieve CVR provides the basis to develop early stopping rules during peg-IFN treatment in HDV-infected patients.
authors.affiliation: Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA; IAME, UMR 1137, INSERM, F-75018, Paris, France; IAME, UMR 1137, Univ Paris 7, Diderot, Sorbonne Paris Cité, F-75018, Paris, France.
authors.forename: Jeremie
authors.initials: J
authors.lastname: Guedj
authors.forename: Yaron
authors.initials: Y
authors.lastname: Rotman
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Cotler
authors.forename: Christopher
authors.initials: C
authors.lastname: Koh
authors.forename: Peter
authors.initials: P
authors.lastname: Schmid
authors.forename: Jeff
authors.initials: J
authors.lastname: Albrecht
authors.forename: Vanessa
authors.initials: V
authors.lastname: Haynes-Williams
authors.forename: T Jake
authors.initials: TJ
authors.lastname: Liang
authors.forename: Jay H
authors.initials: JH
authors.lastname: Hoofnagle
authors.forename: Theo
authors.initials: T
authors.lastname: Heller
authors.forename: Harel
authors.initials: H
authors.lastname: Dahari
mesh_terms: D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D005260:Female; D006514:Hepatitis B Surface Antigens / Q000097:blood*; D019694:Hepatitis B, Chronic / Q000150:complications / Q000188:drug therapy; D019701:Hepatitis D, Chronic / Q000150:complications / Q000188:drug therapy; D003698:Hepatitis Delta Virus / Q000187:drug effects*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011092:Polyethylene Glycols / Q000494:pharmacology* / Q000627:therapeutic use; D012367:RNA, Viral / Q000097:blood*; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D057074:Virus Release / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D006514:Hepatitis B Surface Antigens; D016898:Interferon-alpha; D012367:RNA, Viral; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C100416:peginterferon alfa-2a
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