PMID- 25098971
OWN - NLM
STAT- MEDLINE
DCOM- 20150211
LR  - 20211021
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 60
IP  - 6
DP  - 2014 Dec
TI  - Understanding early serum hepatitis D virus and hepatitis B surface antigen 
      kinetics during pegylated interferon-alpha therapy via mathematical modeling.
PG  - 1902-10
LID - 10.1002/hep.27357 [doi]
AB  - There is little information on the early kinetics of hepatitis delta virus (HDV) 
      and hepatitis B surface antigen (HBsAg) during interferon-alpha 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-alpha2a 
      (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. 
      CONCLUSION: 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.
CI  - (c) 2014 by the American Association for the Study of Liver Diseases. This article 
      has been contributed to by U.S. Government employees and their work is in the 
      public domain in the USA.
FAU - Guedj, Jeremie
AU  - Guedj J
AD  - 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 Cite, F-75018, Paris, France.
FAU - Rotman, Yaron
AU  - Rotman Y
FAU - Cotler, Scott J
AU  - Cotler SJ
FAU - Koh, Christopher
AU  - Koh C
FAU - Schmid, Peter
AU  - Schmid P
FAU - Albrecht, Jeff
AU  - Albrecht J
FAU - Haynes-Williams, Vanessa
AU  - Haynes-Williams V
FAU - Liang, T Jake
AU  - Liang TJ
FAU - Hoofnagle, Jay H
AU  - Hoofnagle JH
FAU - Heller, Theo
AU  - Heller T
FAU - Dahari, Harel
AU  - Dahari H
LA  - eng
GR  - P20 GM103452/GM/NIGMS NIH HHS/United States
GR  - P30 GM110907/GM/NIGMS NIH HHS/United States
GR  - P20-GM103452/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20141027
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Antiviral Agents)
RN  - 0 (Hepatitis B Surface Antigens)
RN  - 0 (Interferon-alpha)
RN  - 0 (RNA, Viral)
RN  - 0 (Recombinant Proteins)
RN  - 3WJQ0SDW1A (Polyethylene Glycols)
RN  - Q46947FE7K (peginterferon alfa-2a)
SB  - IM
CIN - Hepatology. 2015 Jun;61(6):2118-9. PMID: 25363327
CIN - Hepatology. 2015 Jun;61(6):2117-8. PMID: 25363368
MH  - Adolescent
MH  - Adult
MH  - Antiviral Agents/*pharmacology/therapeutic use
MH  - Clinical Trials as Topic
MH  - Female
MH  - Hepatitis B Surface Antigens/*blood
MH  - Hepatitis B, Chronic/complications/drug therapy
MH  - Hepatitis D, Chronic/complications/drug therapy
MH  - Hepatitis Delta Virus/*drug effects
MH  - Humans
MH  - Interferon-alpha/*pharmacology/therapeutic use
MH  - Male
MH  - Middle Aged
MH  - *Models, Biological
MH  - Polyethylene Glycols/*pharmacology/therapeutic use
MH  - RNA, Viral/*blood
MH  - Recombinant Proteins/pharmacology/therapeutic use
MH  - Treatment Outcome
MH  - Virus Release/drug effects
MH  - Virus Replication/drug effects
MH  - Young Adult
PMC - PMC4245461
MID - NIHMS622381
EDAT- 2014/08/08 06:00
MHDA- 2015/02/12 06:00
PMCR- 2015/12/01
CRDT- 2014/08/08 06:00
PHST- 2014/02/07 00:00 [received]
PHST- 2014/08/05 00:00 [accepted]
PHST- 2014/08/08 06:00 [entrez]
PHST- 2014/08/08 06:00 [pubmed]
PHST- 2015/02/12 06:00 [medline]
PHST- 2015/12/01 00:00 [pmc-release]
AID - 10.1002/hep.27357 [doi]
PST - ppublish
SO  - Hepatology. 2014 Dec;60(6):1902-10. doi: 10.1002/hep.27357. Epub 2014 Oct 27.