Lonafarnib (LNF) is an investigational drug targeting hepatitis delta virus (HDV) but not hepatitis B virus (HBV), providing a unique opportunity to model HDV kinetics and how changes in HDV affect HBV. We performed a detailed kinetic analysis and developed a mathematical model to explain serum HBV DNA, HDV RNA and hepatitis B surface antigen (HBsAg) kinetics in 15 HBV/HDV coinfected patients receiving LNF-based treatment. After a delay of 0-2 days, patients experienced a rapid 1st-phase HDV-decline followed by either a viral plateau, 2nd slower-decline phase, or viral breakthrough (VB). LNF monotherapy led to a flat-partial-response (often followed by VB), while LNF combination therapy with ritonavir or pegylated interferon-$α$ (PEG-IFN$α$) was associated with a biphasic HDV decline (without VB). All treatments except LNF+PEG-IFN$α$ had at least one patient experiencing an increase in HBV on-treatment. Our model successfully reproduced the observed HDV and HBV kinetics. We estimated an HDV RNA half-life of 1.26 days [95% confidence interval, CI: 1.05--1.47] in serum and treatment efficacy of 94% in inhibiting HDV RNA production across all treatments [95% CI: 89%--97%], as reflected by the 1st phase HDV decline. The 2nd phase of HDV decline was explained by a time-dependent increase in efficacy, reaching a maximum of 98.9%. The model explained the increase in serum HBV DNA by a median 4-fold [interquartile range, IQR: 1--28] increase in HBV DNA production rate when HDV declined below an inhibitory threshold. The stability of serum HBsAg was explained by a constant number of HBsAg-producing cells.
