Recent Advances in Hepatitis B Treatment

Abstract

Hepatitis B virus infection affects over 250 million chronic carriers, causing more than 800,000 deaths annually, although a safe and effective vaccine is available. Currently used antiviral agents, pegylated interferon and nucleos(t)ide analogues, have major drawbacks and fail to completely eradicate the virus from infected cells. Thus, achieving a "functional cure" of the infection remains a real challenge. Recent findings concerning the viral replication cycle have led to development of novel therapeutic approaches including viral entry inhibitors, epigenetic control of cccDNA, immune modulators, RNA interference techniques, ribonuclease H inhibitors, and capsid assembly modulators. Promising preclinical results have been obtained, and the leading molecules under development have entered clinical evaluation. This review summarizes the key steps of the HBV life cycle, examines the currently approved anti-HBV drugs, and analyzes novel HBV treatment regimens.

Keywords: HBV; HBV inhibitors; HBV life cycle; HBV treatment; antiviral agents; antiviral therapy; cccDNA; hepatitis B; hepatitis B virus; nucleoside analogues.

Figure 6

Innate immunity modulators; (i) Selective TLR7 agonist [163] (ii) TLR7/8 dual agonist [157] (iii) Dual TLR7/8 agonist. (R) isomer results in selective TLR8 agonist [158] (iv) Selective TLR8 agonist [159].

Figure 8

Nucleocapsid assembly modulators or inhibitors [201,205,206,207,208].

Figure 1

Hepatitis B Virus particles. (A) Infectious HBV virion (Dane particle). The lipid envelope, bearing three types of surface proteins—small (S-HBs), middle (M-HBs) and large (L-HBs)—surrounds the nucleocapsid, consisting of HBV relaxed circular DNA (rcDNA), the viral DNA polymerase (P), and the core protein (HBcAg). (B) Non-infectious HBV particles; enveloped nucleocapsids containing immature or defective DNA/RNA, subviral particles, and naked nucleocapsids.

Figure 2

Hepatitis B Virus genome. Partially double-stranded, relaxed circular DNA (rcDNA) with four overlapping open reading frames (ORFs).

Figure 3

Main features of the hepatitis B virus replication cycle and potential therapeutic targets. (1) HBV entry inhibitors. Lipopeptides mimicking the pre-S1 region of HBV, monoclonal antibodies, and other small molecules under evaluation. (2) Targeting cccDNA. Damage and destruction of cccDNA via sequence-specific nucleases. Direct targeting of the HBx protein. (3) RNA interference. Small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs). (4) HBV polymerase inhibitors. Reverse transcriptase inhibitors (nucleos(t)ide analogues) are part of the current treatment. RNaseH inhibitors are in preclinical evaluation. (5) Nucleocapsid assembly inhibitors or modulators can affect HBV capsid formation, reverse transcription, and pgRNA encapsidation. NTCP; Na(+) taurocholate co-transporting polypeptide, HSPG; heparan sulfate proteoglycan, rc-DNA; relaxed circular DNA, PF-rcDNA; protein-free rcDNA, cccDNA; covalently closed circular DNA, pgRNA; pregenomic RNA, preC; precore, mRNA; messenger RNA, P; polymerase, L-HBs; large hepatitis B surface protein, M-HBs; middle hepatitis B surface protein, S-HBs; small hepatitis B surface protein, HBx; hepatitis B X protein, HBsAg; hepatitis B surface antigen, HBeAg; hepatitis B e antigen, dslDNA; double-stranded linear DNA.

Figure 4

Nucleos(t)ide Analogues (NAs) approved for the treatment of hepatitis B [28,73].

Figure 5

Disubstituted Sulfonamides (DSS) [144].

Figure 7

HBV transcription inhibitor [176].