Mathematical Modeling of Triphasic Viral Dynamics in Patients with HBeAg-Positive Chronic Hepatitis B Showing Response to 24-Week Clevudine Therapy

Abstract

BackgroundModeling of short-term viral dynamics of hepatitis B with traditional biphasic model might be insufficient to explain long-term viral dynamics. The aim was to develop a novel method of mathematical modeling to shed light on the dissociation between early and long-term dynamics in previous studies.MethodsWe investigated the viral decay pattern in 50 patients from the phase III clinical trial of 24-week clevudine therapy, who showed virological response and HBsAg decline. Immune effectors were added as a new compartment in the model equations. We determined some parameter values in the model using the non-linear least square minimization method.ResultsMedian baseline viral load was 8.526 Log10copies/mL, and on-treatment viral load decline was 5.683 Log10copies/mL. The median half-life of free virus was 24.89 hours. The median half-life of infected hepatocytes was 7.39 days. The viral decay patterns were visualized as triphasic curves with decreasing slopes over time: fastest decay in the first phase; slowest in the third phase; the second phase in between.ConclusionsIn the present study, mathematical modeling of hepatitis B in patients with virological response and HBsAg decline during 24-week antiviral therapy showed triphasic viral dynamics with direct introduction of immune effectors as a new compartment, which was thought to reflect the reduction of clearance rate of infected cells over time. This modeling method seems more appropriate to describe long-term viral dynamics compared to the biphasic model, and needs further validation.

Understanding the Complex Patterns Observed during Hepatitis B Virus Therapy

“…Assume the flat phase starts at $t_1$ and ends at $t_2$, then the length of the flat phase is $L=t_2-t_1$, while $L=0$ for bi-phasic virus dynamics $V\left(t\right)$. Note that we define tri-phasic dynamics based on $V\left(t\right)$ being concave and that a convex function that has three slopes of decay (as in [19]) will be called bi-phasic in our study.…”

Feedback control of an HBV model based on ensemble kalman filter and differential evolution

“…Eighty percent of all liver cancer is caused by chronic hepatitis B, resulting in half a million fatalities annually [22]. Several therapeutic agents have been approved by the Food and Drug Administration, including interferon and nucleosides/nucleotides analogues (NUCs) such as lamivudine, adefovir, entecavir, telbivudine and tenofovir [1,2,13]. These agents fall into one of two categories: inhibiting de novo infection and inhibiting viral production.…”

“…The effectiveness of HBV therapy may be improved by developing dynamic drug strategies, where the treatment schedule changes over time in response to the individual's disease progression. The model we use to derive the optimal drug treatment strategies for HBV infection is originally developed in [13], although the paper did not provide a mathematical analysis of the model. The authors introduced immune effectors as a new compartment in the model to show triphasic viral dynamics since traditional biphasic models is not sufficient to explain long-term viral dynamics of hepatitis B.…”

“…The descriptions and values for the parameters are summarized in Table 1. For a more detailed discussion of this model and parameter values, see [13]. Table 1.…”

Ultradeep Pyrosequencing and Molecular Modeling Identify Key Structural Features of Hepatitis B Virus RNase H, a Putative Target for Antiviral Intervention

“…Attempts to experimentally determine the 3-dimensional (3-D) structure of the HBV DNA polymerase or its RNase H domain have been unsuccessful thus far. Experimentally solved RNase H structures from various organisms have been reported (12)(13)(14)(15)(16)(17)(18)(19)(20)(21). The catalytic activity of type 1 RNases H has been shown to depend on a conserved tetrad of residues (DEDD), likely through a two-metal-ion-dependent mechanism (22)(23)(24).…”