Understanding Hepatitis B Virus Dynamics and the Antiviral Effect of Interferon Alpha Treatment in Humanized Chimeric Mice.

Whereas the mode of action of lamivudine (LAM) against hepatitis B virus (HBV) is well established, the inhibition mechanism(s) of interferon alpha (IFN-α) is less completely defined. To advance our understanding, we mathematically modeled HBV kinetics during 14-day pegylated IFN-α-2a (pegIFN), LAM, or pegIFN-plus-LAM (pegIFN+LAM) treatment of 39 chronically HBV-infected humanized uPA/SCID chimeric mice. Serum HBV DNA and intracellular HBV DNA were measured frequently. We developed a multicompartmental mathematical model and simultaneously fit it to the serum and intracellular HBV DNA data. Unexpectedly, even in the absence of an adaptive immune response, a biphasic decline in serum HBV DNA and intracellular HBV DNA was observed in response to all treatments. Kinetic analysis and modeling indicate that the first phase represents inhibition of intracellular HBV DNA synthesis and secretion, which was similar under all treatments with an overall mean efficacy of 98%. In contrast, there were distinct differences in HBV decline during the second phase, which was accounted for in the model by a time-dependent inhibition of intracellular HBV DNA synthesis, with the steepest decline observed during pegIFN+LAM treatment (1.28/day) and the slowest (0.1/day) during pegIFN monotherapy. Reminiscent of observations in patients treated with pegIFN and/or LAM, a biphasic HBV decline was observed in treated humanized mice in the absence of an adaptive immune response. Interestingly, combination treatment did not increase the initial inhibition of HBV production but rather enhanced second-phase decline, providing insight into the dynamics of HBV treatment response and the mode of action of IFN-α against HBV.