Update on combination therapies against HBV in clinical investigations.

Functional cure has been proposed to be the treatment endpoint of cure therapies in chronic hepatitis B (CHB), yet it is rarely achieved with monotherapy of novel virus-targeting agents or immunomodulators. Although translation inhibitors - small interfering RNAs (siRNAs) and antisense oligonucleotides can produce marked decline in hepatitis B surface antigen (HBsAg) levels, the response is often not sustained and HBsAg seroclearance rarely occur after treatment cessation, suggesting that pharmacological reduction in HBsAg level may be insufficient in restoring HBV-specific immune response. Increasing number of studies have adopted the combination approach with virus-directing agent(s) plus immunomodulator(s). To date, the most effective regimen involves the concurrent or sequential use of siRNA with PEG-IFNα for 48 weeks, with resultant off-therapy HBsAg seroclearance rates approaching 30 %, and functional cure rates of up to 10 %. Other immunomodulators studied in combination with siRNA such as toll-like receptor agonists, therapeutic vaccines, monoclonal hepatitis B surface antibodies, and immune checkpoint inhibitors are less effective. Almost all studies included NUC and only a few evaluated protocolized NUC withdrawal; thus, few studies have truly evaluated functional cure. Low baseline HBsAg level is the most reliable predictor of HBsAg seroclearance, with many trials exclusively enrolling patients with HBsAg level <200 to <1000 IU/mL. While recent studies have shown promise, further research is needed to determine the optimal classes of drugs to combine, duration of use for each drug and whether they should be used concurrently or sequentially, to meet the desired goal of 30 % functional cure rate.