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Abstract Details
Understanding early serum hepatitis D virus and HBsAg kinetics during pegylated interferon-alfa therapy via mathematical modeling
Guedj J1, Rotman Y, Cotler SJ, Koh C, Schmid P, Albrecht J, Haynes-Williams V, Liang JT, Hoofnagle JH, Heller T, Dahari H. Hepatology. 2014 Aug 7. doi: 10.1002/hep.27357. [Epub ahead of print]
Author information
1Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, 87545; INSERM UMR 738, University Paris Diderot, F-75018, Paris; University Paris Diderot, Sorbonne Paris Cité, Paris, France.
Abstract
There is little information on the early kinetics of hepatitis delta virus (HDV) and hepatitis B surface antigen (HBsAg) during interferon-αtherapy. 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 to 2.9 days (IQR:[1.5;5.3]) with pretreatment production and clearance of about 1010 (IQR:[107 -1010 ]) virions/day. None of the patients with flat 2nd 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.