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Understanding early serum hepatitis D virus and hepatitis B surface antigen kinetics during pegylated interferon‐alpha therapy via mathematical modeling
Author(s) -
Guedj Jeremie,
Rotman Yaron,
Cotler Scott J.,
Koh Christopher,
Schmid Peter,
Albrecht Jeff,
HaynesWilliams Vanessa,
Liang T. Jake,
Hoofnagle Jay H.,
Heller Theo,
Dahari Harel
Publication year - 2014
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.27357
Subject(s) - hbsag , medicine , pegylated interferon , hepatitis d virus , gastroenterology , seroconversion , hepatitis b virus , interquartile range , interferon , alpha interferon , virology , immunology , virus , ribavirin , hepatitis c virus
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 (t 1/2 ) 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 t 1/2 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. (H epatology 2014;60:1901–1909)