Abstract
We present a comprehensive within‐host mathematical model to quantify long‐term hepatitis B virus (HBV) dynamics under pharmacological immune suppression and subsequent immune recovery. The model integrates nonlinear intracellular cccDNA production, ALT release, and both cytolytic and noncytolytic CD8
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T‐cell responses within an eight‐dimensional ODE framework. Using longitudinal HBV DNA, HBsAg, ALT, cccDNA, and CD8
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T‐cell activation data from immunosuppressed rhesus macaques, parameters were estimated via the SAEM algorithm, yielding simulations that accurately reproduced prolonged viremia and cccDNA accumulation during immune suppression, followed by rapid viral decline after drug withdrawal. Long‐term simulations revealed two distinct dynamical outcomes, viral clearance or persistent infection, emerging from variations in immune activation and killing efficacy. These results demonstrate how nonlinear intracellular regulation and immune‐driven feedback collectively determine infection fate and establish a modeling framework applicable to broader classes of host–virus systems involving immune suppression and recovery.