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

Jeremie Guedj, Yaron Rotman, Scott J. Cotler, Christopher Koh, Peter Schmid, Jeff Albrecht, Vanessa Haynes-Williams, T. Jake Liang, Jay H. Hoofnagle, Theo Heller, Harel Dahari

Research output: Contribution to journalArticlepeer-review

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 1010 (IQR: 109.7-1010.7) 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. (Hepatology 2014;60:1901-1909).

Original languageEnglish (US)
Pages (from-to)1902-1910
Number of pages9
JournalHepatology
Volume60
Issue number6
DOIs
StatePublished - Dec 1 2014
Externally publishedYes

ASJC Scopus subject areas

  • Hepatology

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