Understanding early serum hepatitis D virus and hepatitis B surface antigen kinetics during pegylated interferon-alpha therapy via mathematical modeling Journal Article

Authors: Guedj, J; Rotman, Y.; Cotler, S. J.; Koh, C; Schmid, P.; Albrecht, J.; Haynes-Williams, V.; Liang, T. J.; Hoofnagle, J. H.; Heller, T; Dahari, H
Article 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-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.
Journal Title: Hepatology (Baltimore, Md.)
Volume: 60
Issue: 6
ISSN: 1527-3350; 0270-9139
Publisher: 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  
Journal Place: United States
Date Published: 2014
Start Page: 1902
End Page: 1910
Language: eng
Notes: LR: 20150719; CI: (c) 2014; GR: P20 GM103452/GM/NIGMS NIH HHS/United States; GR: P20-GM103452/GM/NIGMS NIH HHS/United States; GR: P30 GM110907/GM/NIGMS NIH HHS/United States; JID: 8302946; 0 (Antiviral Agents); 0 (Hepatitis B Surface Antigens); 0 (Interferon-alpha); 0 (Polyethylene Glycols); 0 (RNA, Viral); 0 (Recombinant Proteins); 0 (peginterferon alfa-2a); CIN: Hepatology. 2015 Jun;61(6):2118-9. PMID: 25363327; CIN: Hepatology. 2015 Jun;61(6):2117-8. PMID: 25363368; NIHMS622381; OID: NLM: NIHMS622381 [Available on 12/01/15]; OID: NLM: PMC4245461 [Available on 12/01/15]; PMCR: 2015/12/01 00:00; 2014/02/07 [received]; 2014/08/05 [accepted]; 2014/10/27 [aheadofprint]; ppublish