Novel and Emerging Therapies
Heteroaryldihydropyrimidines. Heteroaryldihydropyrimidines (HAPs) are antiviral compounds that have been shown to inhibit HBV replication in isolated cells and animal models. In contrast to nucleotide and nucleoside analogs, which interfere with the replication of the viral genome, HAPs prevent the proper assembly of the protein capsule that surrounds the mature virus and serves as the site of DNA replication (Deres 2003; Stray 2005). They are effective against HBV mutant strains resistant to nucleotide/nucleoside analog drugs (Billioud 2011). Bay 41-4109, the best studied HAP, reduced HBV viral load by about 2 to 3-fold in a humanized mouse model (mice with livers that contain human liver cells) (Billioud 2011; Weber 2002). These compounds await human trials.
RNA interference (RNAi) is a cellular mechanism for controlling gene expression; it is used by cells to regulate cell development and metabolism, but can also be used to turn off the expression of foreign genes, such as those of an invading virus. Since the life cycle of HBV relies on RNA intermediates for its replication, it is sensitive to inhibition by RNAi (Grimm 2011). Therapeutic RNA inhibitors have been designed to interrupt HBV DNA replication, and turn off the genes that produce the structural and regulatory proteins required for assembly of infectious HBV particles. They have shown success in decreasing virus replication in cell cultures (Wilson 2009). Early results of a safety trial of the small interfering RNA NUC B1000 appear promising (Gish 2011).
Thymosin α1. Thymosin α1 (Tα1) is an immunomodulatory peptide derived from the thymus that stimulates T-cells (one of the principle immune cells) to mature and produce cytokines, as well as increases the ability of the immune system to recognize invading pathogens (Delaney 2002; Yang 2008). In several studies of Tα1 therapy in chronic, HBeAg-negative (low-infectivity) HBV patients, thymosin lowered the liver enzyme ALT and increased the rate of HBV DNA clearance (Yang 2008). It is better tolerated than IFN-α. While treatment with Tα1 alone does not appear to be superior to current HBV therapies (Grimm 2011), it may enhance the effectiveness of antivirals and IFN when used as a combination therapy (Mao 2011; Zhang 2009), especially in difficult-to-treat HBeAg-positive patients. Tα1 is approved for use as a hepatitis B treatment in 30 countries, but is not yet available in the U.S. (SciClone 2012).