Toward a Functional Cure for Hepatitis B

Abstract

Current treatment of chronic hepatitis B virus (HBV) infection, pegylated interferon-α (pegIFN-α) and nucleos(t)ide analogue (NA), can suppress HBV replication, reverse liver inflammation and fibrosis, and decrease risks of cirrhosis and hepatocellular carcinoma, but hepatitis B surface antigen (HBsAg) loss is rare. Functional HBV cure is defined as undetectable HBsAg and unquantifiable serum HBV DNA for at least 24 weeks after a finite course of therapy. This requires suppression of HBV replication and viral protein production as well as restoration of immune response to HBV. Direct-acting antivirals targeting virus entry, capsid assembly, viral protein production and secretion are in clinical trials. In parallel, immune modulatory therapies to stimulate HBV-specific immune response and to remove immune blockade are being tested. Clinical trials of direct-acting antivirals alone or immune modulatory therapies alone have not been successful in achieving HBV cure. Recent combinations of direct-acting antivirals and immune modulatory therapies have shown promising results particularly with combinations that included pegIFN-α. These results need to be confirmed in larger studies with longer follow-up, and further work is needed to develop simpler regimens with fewer drugs that can be administered orally and safely. While there is a strong desire to develop finite therapies that can achieve HBV cure, safety is paramount and new therapies must provide incremental value compared to standard of care, which is predominantly long-term NA therapy.

Keywords: Direct-acting antivirals; Hepatitis B surface antigen loss; Immune modulatory therapies; Nucleos(t)ide analogues; Pegylated interferon-α.

Fig. 1

Steps toward achieving hepatitis B virus (HBV) cure. HBV cure requires suppression of HBV DNA replication and HBV protein particularly hepatitis B surface antigen (HBsAg) production, and stimulation or revival of HBV-specific immune response. Several classes of drugs targeting each step are in clinical trials. pegIFN-α, pegylated interferon-α; siRNA, short interfering RNA; ASO, antisense oligonucleotides; TLR7, Toll-like receptor 7; TLR8, Toll-like receptor 8.

Fig. 2

Hepatitis B virus (HBV) lifecycle and targets for direct-acting antiviral drugs. Sodium taurocholate co-transporting polypeptide (NTCP) receptor blocker inhibits HBV entrance into hepatocyte. Short interfering RNAs (siRNA) and antisense oligonucleotides (ASO) interferes with translation of RNA transcribed from covalently circular DNA: messenger RNA and/or pregenomic RNA, and RNA transcribed from integrated HBV DNA. Capsid assembly modulators (CAM) interfere with capsid formation resulting in empty or aberrant capsids, decreasing pregenomic RNA packaging and HBV DNA replication. Nucleic acid polymer blocks subviral hepatitis B surface antigen (HBsAg) assembly and secretion, leading to HBsAg reduction. Vaccinal antibodies bind and neutralize circulating HBsAg and potentially restore exhausted HBV-specific immune response. Anti-HBs, hepatitis B surface antibody; rcDNA, relaxed circular DNA; cccDNA, covalently closed circular DNA; pgRNA, pregenomic RNA; mRNA, messenger RNA; HBe, hepatitis B e protein; HBx, hepatitis B X protein.

Fig. 3

Success in achieving off-treatment hepatitis B surface antigen (HBsAg) loss in clinical trials of hepatitis B virus (HBV) cure therapies. Highest rates of sustained HBsAg loss have been achieved with combination therapies of 3 to 4 drugs that include nucleos(t)ide analogue (NA) and pegIFN-α, plus additional direct-acting antiviral and/or immune modulatory therapy. All but one trial* included NA. Some trials used concurrent therapies while others used sequential therapies. FU, follow-up; CAM, capsid assembly modulator; siRNA, small interfering RNA; pegIFN-α, pegylated interferon-α; TLR7, Toll-like receptor 7; Ab, antibody; ASO, antisense oligonucleotide; NAP, nucleic acid polymer.

Fig. 4

Challenges in developing hepatitis B virus (HBV) cure therapies. HBV cure therapies need to be efficacious, safe, simple, and provide incremental value compared to currently available treatment. HBsAg, hepatitis B surface antigen; HDV, hepatitis delta virus; HIV, human immunodeficiency virus.