Previous studies have demonstrated that
nucleic acid polymers (
NAPs) have both entry and post-entry inhibitory activity against duck hepatitis B virus (DHBV)
infection. The inhibitory activity exhibited by
NAPs prevented DHBV
infection of primary duck hepatocytes in vitro and protected ducks from DHBV
infection in vivo and did not result from direct activation of the immune response. In the current study treatment of primary human hepatocytes with NAP
REP 2055 did not induce expression of the TNF,
IL6,
IL10, IFNA4 or IFNB1 genes, confirming the lack of direct immunostimulation by
REP 2055. Ducks with persistent DHBV
infection were treated with NAP 2055 to determine if the post-entry inhibitory activity exhibited by
NAPs could provide a
therapeutic effect against established DHBV
infection in vivo. In all REP 2055-treated ducks, 28 days of treatment lead to initial rapid reductions in serum DHBsAg and DHBV
DNA and increases in anti-
DHBs antibodies.
After treatment, 6/11 ducks experienced a sustained virologic response: DHBsAg and DHBV
DNA remained at low or undetectable levels in the serum and no DHBsAg or DHBV core
antigen positive hepatocytes and only trace amounts of DHBV total and covalently closed
circular DNA (cccDNA) were detected in the liver at 9 or 16 weeks of follow-up. In the remaining 5/11 REP 2055-treated ducks, all markers of DHBV
infection rapidly rebounded
after treatment withdrawal: At 9 and 16 weeks of follow-up, levels of DHBsAg and DHBcAg and DHBV total and cccDNA in the liver had rebounded and matched levels observed in the control ducks treated with
normal saline which remained persistently infected with DHBV. These data demonstrate that treatment with the NAP
REP 2055 can lead to sustained control of persistent DHBV
infection. These effects may be related to the unique ability of
REP 2055 to block release of DHBsAg from infected hepatocytes.