Hepatitis B Treatment: What We Know Now and What Remains to Be Researched

Abstract

Chronic hepatitis B virus (HBV) infection remains a major global health burden. Currently, two types of treatment, interferons (IFNs) and nucleos(t)ide analogues (NAs), have been approved. These treatments are effective in suppressing HBV replication and in decreasing the risk of developing cirrhosis, liver failure, hepatocellular carcinoma (HCC), and death. However, these treatments do not eliminate the virus, and the risk of HCC remains. This review article summarizes current knowledge about the safety, efficacy, and clinical indications of hepatitis B treatment. It also discusses limitations of existing treatment, gaps in knowledge, and feasibility of a hepatitis B cure.

Figure 1

HBV lifecycle and antiviral targets.3 HBV entry: Lipopeptides mimicking pre‐S1 domain competing with a Dane particle for binding to NTCP (e.g., Myrcludex B); other small molecule inhibitors are in development. Targeting cccDNA: Prevention of cccDNA formation; damage and destruction through cytokines or cccDNA sequence‐specific nucleases; functional silencing through modulation of host cellular epigenetic‐modifying enzymes by cytokines or inhibition of viral protein function. HBV mRNAs: Small interfering RNA approaches or anti‐sense oligonucleotides to block viral replication and viral protein expression. HBV polymerase: Reverse transcriptase inhibitors include approved NAs; RNAse H inhibitors are in preclinical evaluation. Nucleocapsid assembly and pgRNA packaging: Capsid assembly modulators can affect nucleocapsid assembly and pgRNA encapsidation and may affect the nuclear functions of HBc (cccDNA regulation and IFN‐stimulated gene expression). Targeting HBsAg: Phosphorothioate oligonucleotides nucleic acid polymer inhibiting HBsAg release and monoclonal antibodies to decrease circulating HBsAg load are under evaluation. Abbreviations: dslDNA, double‐stranded linear DNA; HBc, hepatitis B core protein; HBe, hepatitis B e protein; HBs, hepatitis B surface antigen; HBx, hepatitis B x protein; mRNA, messenger RNA; MVB, multivesicular body; NTCP, sodium taurocholate cotransporting polypeptide; pgRNA, pregenomic RNA; Pol, polymerase; rcDNA, relaxed circular DNA; RNAse H, ribonuclease H.

Figure 2

Phases of chronic HBV infection.3 Traditionally, phases of chronic HBV infection are defined by HBeAg status, serum HBV DNA, and ALT levels. Quantitative HBsAg levels are different in each phase and are generally highest in the immune tolerant phase and lowest in the inactive carrier phase. Although most patients progress from one phase to the next, not all patients go through each phase; reversion to an earlier phase can occur. Immune tolerant: HBeAg‐positive, high serum HBV DNA but normal ALT levels. Immune clearance/HBeAg‐positive chronic hepatitis: HBeAg‐positive, high serum HBV DNA, and elevated ALT levels; HBeAg seroconversion to anti‐HBe occurs after varying durations. Inactive carrier: HBeAg‐negative, serum HBV DNA low (generally <2,000 IU/mL) or undetectable. Reactivation/HBeAg‐negative chronic hepatitis: HBeAg‐negative, elevated levels of HBV DNA and ALT in serum, HBV precore and/or basal core promoter variant often present. Abbreviation: HBsAg, hepatitis B surface antigen.