New Agents for Treatment of HBV Infection: Targeting the Virus Man-Fung Yuen, DSc, MD, PhD In the past 2 decades, nucleos(t)ide analogues are the mainstay treatment for CHB. Their main mode of action is mainly mediated through the inhibitory effects on the viral reverse transcription activity, one of the major steps in the life cycle of hepatitis B virus (HBV). Total serum HBV DNA suppression associated with clinical benefits have already been demonstrated by many long-term follow-up studies. Nevertheless, to suppress the virus with maximal potency, other potential inhibitory steps in the virus life cycle are good targets for new agents. The technical aim is to enhance the rate of HBsAg seroclearance. In addition to the achievement of better disease control and outcome, cessation of therapy may also be possible once HBsAg seroclearance is achieved. At present, there are several new groups of antiviral agents carrying different modes of action being intensively studied in phase I/ II trials. Knocking down the viral mRNA transcriptional activities can be achieved by short interfering RNAs (siRNA) or anti-sense oligonucleotides (ASO). Rapid, profound and sustained suppression of HBV DNA levels, HBV RNA levels and HBsAg, HBeAg, HBcrAg levels are observed in patients receiving different regimens of these agents. Cases of HBsAg seroclearance have also been observed. Another group of new agents is Core protein allosteric modulators (CpAM)/ core inhibitors. These compounds are aimed to inhibit the HBV encapsidation process and hence attenuate the multiple important functions of the HBV core protein including intranuclear cccDNA replenishment. Four-week treatment of these compounds is able to reduce the HBV DNA by 2-3 logs with a similar magnitude of reduction of HBV RNA levels. New data has shown that longer treatment duration have started to observe some declines in viral antigens. Direct targeting for HBsAg is another way to control viral activity. HBsAg release inhibitors blocking the exit of the subviral particles have been shown to achieve a high rate of HBsAg seroclearance and a good chance of achieving positive antibody against HBsAg (anti-HBs), although more evidence is awaited from the on-going studies. In conclusion, many new agents have shown initial promising antiviral effects by acting through different steps of the HBV life cycle. They are well tolerated according from the initial trials. The on-going challenge would be on the design of treatment strategy for HBV with these new agents once their longer term efficacy and safety are established. The treatment aspects for consideration include patient selection, different drug combinations, sequences of administration and duration of treatment.