In this review we will focus on host factors known to impact hepatitis B virus (HBV) replication as current or potential targets for therapeutic intervention. Some immunotherapeutic strategies will be discussed because they have the potential to activate interferon-mediated clearance of HBV, but attention will also be paid to host machinery and proteins that silence covalently closed circular DNA, destabilize viral RNA, or disrupt entry and trafficking of HBV virions. Many of these are in the early stages of development, but may represent novel avenues to reduce HBV burden when combined with nucleos(t)ide analogues.

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