Emerging antivirals for the treatment of hepatitis B

Abstract

Chronic infection with hepatitis B virus (HBV) constitutes a major global public health threat, causing substantial disease burdens such as liver cirrhosis and hepatocellular carcinoma, thus representing high unmet medical needs. Currently available therapies are safe, well tolerated, and highly effective in decreasing viremia and improving measured clinical outcomes with low rates of antiviral resistance. However, long-term management remains a clinical challenge, mainly due to the slow kinetics of HBV surface antigen clearance. In this article, we review emerging antivirals directed at novel targets derived from mechanisms of viral cellular entry, viral replication, viral assembly, and the host immune response, leading to preclinical and clinical trials for possible future therapeutic intervention. The recent therapeutic advances in the development of all categories of HBV inhibitors may pave the way for regimens of finite duration that result in long-lasting control of chronic hepatitis B infection.

Current and future antiviral drug therapies of hepatitis B chronic infection

“…Adefovir, an acyclic NA, is a potent inhibitor of viral patients should be closely monitored [55] . Treatment with IFN-α has been shown to modulate the epigenetic repression of cccDNA activity and its potential role in antiviral treatment is discussed later.…”

“…A few non-nucleocapsid molecules have been shown to inhibit the replication of both the wild type virus and of drug resistant variants [78] . These include compounds that belong either to the family of phenylpropenamide (AT-61 and AT-130) and have been reported to prevent RNA encapsidation or to the family of heteroaryldihydropyrimidines (BAY41-4109) that can destabilize nucleocapsids [55,79] . In addition to their impact on replication cycle, these agents can inhibit cccDNA intracellular amplification by inhibiting nucleocapsid recycling to the nucleus in woodchuck animal model [80] .…”

“…TLR7 and TLR9 ligands or agonists have been shown to inhibit viral replication by the production of vast amounts of type Ⅰ and Ⅲ IFNs via the activation of plasmacytoid dendritic cells (pDCs) [83] . Experiments in chimpanzee and woodchucks have shown that a synthetic TLR-7 agonist reduced serum and liver viremia as well as HBsAg and increased the expression of IFN-α and interferon stimulated genes [55] . This compound has reached Phase Ⅰ clinical trials [84] .…”

“…The dysfunction of viral specific T cells has been associated with defects in co-stimulatory pathways. The negative regulation of T cell function associates with defects in co-stimulatory pathways and in particular with the increased expression of inhibitory receptors programmed cell death 1 (PD-1) and its ligand 1, T-cell immunoglobulin domain, mucin domain-containing molecule-3 (TIM3) and CD244 as well as the impairment of DCs and the increased frequencies of T regulatory cells (Tregs) [55,88,89] . Restoration of T cell function could, at least partially, be achieved by the blockage of the negative regulatory pathways including inhibitors of such receptors, e.g., anti-PD-1 mAb, and anti-apoptotic drugs that block TIM3 [13] .…”

809 Reversal of Proximal Renal Tubular Dysfunction After Nucleotide Analogue Withdrawal in Chronic Hepatitis B

“…The next challenging task is to find new antiviral therapies that can replace ADV or TDF for long-term suppression of HBV replication with high efficacy without causing adverse effects of PRTD and nephrotoxicity. The benefit of tenofovir alafenamide for the reduction of nucleotide analogue-related nephrotoxicity remains to be proven [20,39].…”