The present invention concerns an inhibitor for use for preventing and/or treating an infection with hepatitis B virus (HBV) and an in vitro screening method for the identification of a candidate compound suitable for preventing and/or treating an infection with hepatitis B virus. Inventors show that the knock-down of histone chaperone HIRA before HBV inoculation led to a strong decrease in HBV cccDNA (covalently closed circular DNA) accumulation and stable rcDNA (relaxed circular DNA) levels, in HepG2-NTCP cell line, indicating either a possible incomplete or delayed rcDNA to cccDNA transition. This effect was independent from HBx protein expression in Primary human hepatocytes (PHH). HIRA is able to interact with cccDNA and its recruitment is concomitant with deposition of histone variant H3.3 in HepG2-NTCP cell line. HIRA was able to interact with HBc (HBV capsid protein) in infected hepatocytes and in an HepaRG cell line expressing HBc in an inducible manner.