LAUSR

HBV is a hepatotropic DNA virus that replicates by reverse transcription [1]. The virus is genetically diverse, with at least 8 genotypes that differ by ~8% at the amino acid level. It chronically infects about 290 million people worldwide, causing hepatitis, hepatic fibrosis, and cirrhosis that lead to the death of >850,000 patients annually via liver failure or hepatocellular carcinoma [2]. Therapy primarily employs nucleos(t)ide analog drugs that can drive HBV below the detection limit, but interferon α is used in some patients [3]. The ideal goal of therapy would be a complete cure, in which no trace of the virus remains in the body and HBV-induced disease is eliminated. Unfortunately, extremely low levels of replication-competent HBV can persist in patients even after they have appeared to resolve an acute infection. Therefore, the consensus is that the goal of HBV treatment, at least for the foreseeable future, will be a ‘functional cure’. The clinical definition of a functional cure is still being debated, but it essentially means attaining a stable state where there is no detectable virus in the body after drug withdrawal and disease progression has been halted [4]. Current therapies achieve a functional cure in only a few percent of patients [5] because viral replication is not completely suppressed and HBV titers resurge if the nucleos(t)ide analogs are withdrawn. Furthermore, the overall chances of death from liver failure and hepatocellular carcinoma induced by chronic HBV infection are reduced by only twoto four-fold [3]. Reverse transcription is catalyzed by the coordinate action of the viral reverse transcriptase (RT) and ribonuclease H (RNaseH) activities located on adjacent domains of the viral polymerase protein [1]. RNaseHs cleave RNA within an RNA:DNA heteroduplex, and the role of the HBV RNaseH is to degrade the viral RNA after it has been copied into DNA by the RT to permit synthesis of the second DNA strand. Inhibiting the RNaseH causes synthesis of the viral minus-polarity DNA strand to stall and blocks synthesis of the plus-polarity strand. This fatally damages the viral DNA. No drugs have been developed against the RNaseH despite its essential function, primarily due to lack of suitable screening assays. 2. Prospects for HBV RNaseH drugs