Understanding the antiviral effects of RNAi-based therapy on chronic hepatitis B infection

Abstract

AbstractReaching hepatitis B surface antigen (HBsAg) loss (called functional cure) with approved treatment with pegylated interferon-α(IFN) and/or nucleos(t)ide analogues (NAs) in chronic hepatitis B virus (HBV) infected patients is suboptimal. The RNA interference (RNAi) drug ARC-520 was shown to be effective in reducing serum HBV DNA, HBsAg and hepatitis B e antigen (HBeAg) in chimpanzees and small animals. A recent clinical study (Heparc-2001) showed reduction of serum HBV DNA, HBeAg and HBsAg in HBeAg-positive patients treated with a single dose of ARC-520 and daily NA (entecavir). To provide insights into HBV dynamics under ARC-520 treatment and its efficacy in blocking HBV DNA, HBsAg, and HBeAg production we developed a a multi-compartmental pharmacokinetic-pharamacodynamic model and calibrated it with measured HBV data. We showed that the time-dependent ARC-520 efficacies in blocking HBsAg and HBeAg are more than 96% effective around day 1, and slowly wane to 50% in 1-4 months. The combined ARC-520 and entecavir effect on HBV DNA is constant over time, with efficacy of more than 99.8%. HBV DNA loss is entecavir mediated and the strong but transient HBsAg and HBeAg decays are solely ARC-520 mediated. We added complexity to the model in order to reproduce current long-term therapy outcomes with NAs by considering the tradeoff between hepatocyte loss and hepatocyte division, and used it to makein-silicolong-term predictions for virus, HBsAg and HBeAg titer dynamics. These results may help assess ongoing RNAi drug development for hepatitis B virus infection.Author summaryWith about 300 million persons infected worldwide and 800,000 deaths annually, chronic infection with hepatitis B virus (HBV) is a major public health burden with high endemic areas around the world. Current treatment options focus on removing circulating HBV DNA but are suboptimal in removing hepatitis B s- and e-antigens. ARC-520, a RNA interference drug, had induced substantial hepatitis B s- and e- antigen reductions in animals and patients receiving therapy. We study the effect of ARC-520 on hepatitis B s- and e-antigen decline by developing mathematical models for the dynamics of intracellular and serum viral replication, and compare it to patient HBV DNA, hepatitis B s- and e-antigen data from a clinical trial with one ARC-520 injection and daily nucleoside analogue therapy. We examine biological parameters describing the different phases of HBV DNA, s-antigen and e-antigen decline and rebound after treatment initiation, and estimate treatment effectiveness. Such approach can inform the RNA interference drug therapy.