Understanding the antiviral effects of RNAi-based therapy in HBeAg-positive chronic hepatitis B infection

The RNA interference (RNAi) drug ARC-520 was shown to be effective in reducing serum hepatitis B virus (HBV) DNA, hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) in HBeAg-positive patients treated with a single dose of ARC-520 and daily nucleosidic analogue (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 multi-compartmental pharmacokinetic-pharamacodynamic model and calibrated it with frequent measured HBV kinetic data. We showed that the time-dependent single dose 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 single dose ARC-520 and entecavir effect on HBV DNA was constant over time, with efficacy of more than 99.8%. The observed continuous HBV DNA decline is entecavir mediated, the strong but transient HBsAg and HBeAg decays are ARC-520 mediated. The modeling framework may help assess ongoing RNAi drug development for hepatitis B virus infection.

Automated summary

The RNA interference drug ARC-520 has shown significant efficacy in reducing HBV DNA, HBeAg, and HBsAg levels in patients, with a more than 96% efficacy in blocking HBsAg and HBeAg at the start of treatment, gradually decreasing to around 50% within 1-4 months. The combined use of ARC-520 and entecavir maintained a consistent efficacy of over 99.8% in reducing HBV DNA levels, with entecavir mediating continuous decline in HBV DNA and ARC-520 mediating strong but temporary reductions in HBsAg and HBeAg. The developed modeling framework could aid in assessing the development of RNAi drugs for HBV infection.