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

doi:10.1002/hep.27357

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 journal › Article › peer-review

39 Scopus citations

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 (t_1/2) was estimated as 2.9 days (IQR: 1.5-5.3) corresponding to a pretreatment production and clearance of about 10¹⁰ (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. (Hepatology 2014;60:1901-1909).

Original language	English (US)
Pages (from-to)	1902-1910
Number of pages	9
Journal	Hepatology
Volume	60
Issue number	6
DOIs	https://doi.org/10.1002/hep.27357
State	Published - Dec 1 2014
Externally published	Yes

ASJC Scopus subject areas

Hepatology

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10.1002/hep.27357

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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. (2014). Understanding early serum hepatitis D virus and hepatitis B surface antigen kinetics during pegylated interferon-alpha therapy via mathematical modeling. Hepatology, 60(6), 1902-1910. https://doi.org/10.1002/hep.27357

Guedj, J, Rotman, Y, Cotler, SJ, Koh, C, Schmid, P, Albrecht, J, Haynes-Williams, V, Liang, TJ, Hoofnagle, JH, Heller, T & Dahari, H 2014, 'Understanding early serum hepatitis D virus and hepatitis B surface antigen kinetics during pegylated interferon-alpha therapy via mathematical modeling', Hepatology, vol. 60, no. 6, pp. 1902-1910. https://doi.org/10.1002/hep.27357

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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-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).",

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

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doi = "10.1002/hep.27357",

language = "English (US)",

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T1 - Understanding early serum hepatitis D virus and hepatitis B surface antigen kinetics during pegylated interferon-alpha therapy via mathematical modeling

AU - Guedj, Jeremie

AU - Rotman, Yaron

AU - Cotler, Scott J.

AU - Koh, Christopher

AU - Schmid, Peter

AU - Albrecht, Jeff

AU - Haynes-Williams, Vanessa

AU - Liang, T. Jake

AU - Hoofnagle, Jay H.

AU - Heller, Theo

AU - Dahari, Harel

PY - 2014/12/1

Y1 - 2014/12/1

N2 - 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).

AB - 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).

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

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