Therapeutic strategies for hepatitis B virus infection: towards a cure

Fanning, Gregory; Zoulim, Fabien; Hou, Jinlin; Bertoletti, Antonio

doi:10.1038/s41573-019-0037-0

Cited by 409 publications

(439 citation statements)

References 174 publications

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“…Novel therapeutics targets in the HBV Life Cycle (adapted from ref. 8 ). cccDNA direct-acting drugs are shown in red.…”

Section: F I G U R Ementioning

confidence: 99%

“…RNAseH inhibitors causes the accumulation of long RNA:DNA heteroduplexes and blocks the plus-polarity DNA strand production. CAMs, capsid assembly modulators; cccDNA, covalently closed circular DNA; CRISPR-Cas9, clustered regularly interspaced short palindromic repeats associated protein 9; DNA, deoxyribonucleic acid; HBV, hepatitis B virus; HDACs, histone deacetylases; KDMs, lysine demethylases; LNA, locked nucleic acid; NA, nucleoside analogue; NAPs, nucleic acid polymers; NTCP, sodium-taurocholate cotransporting polypeptide; pgRNA, pregenomic RNA; rcDNA, relaxed-circular DNA; RNA, ribonucleic acid; siRNA, small interfering RNA; SSOs, single-stranded oligonucleotides; TALENs, transcription activator-like effector nucleases; ZFNs, zinc finger nucleus TA B L E 1 Clinical trials with novels therapeutics in pipeline for chronic hepatitis B 8,15…”

Section: F I G U R Ementioning

confidence: 99%

“…Several chemical classes of capsid allosteric modulators (CAMs) have been described to target the interdimer interphase of HBc, destabilizing its assembly rate. 8 Depending on their chemical structure CAMs lead to the formation of either aberrant or morphologically normal capsids lacking genetic material, both preventing the release of viral genetic material into newly infected cells and blocking the transport of incoming NC to the nucleus, thereby affecting cccDNA levels (Figure 1). In addition, some CAMs present secondary effects that prevent NC disassembly and inhibit the formation of cccDNA in de novo-infected cells or directly reduce HBe secretion [9][10][11] (Figure 1).…”

Section: Nucleocapsid Assembly Modulatorsmentioning

confidence: 99%

“…Changing the strength or association rate could affect production of the normal NC. Several chemical classes of capsid allosteric modulators (CAMs) have been described to target the interdimer interphase of HBc, destabilizing its assembly rate . Depending on their chemical structure CAMs lead to the formation of either aberrant or morphologically normal capsids lacking genetic material, both preventing the release of viral genetic material into newly infected cells and blocking the transport of incoming NC to the nucleus, thereby affecting cccDNA levels (Figure ).…”

Section: Introductionmentioning

confidence: 99%

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Can we cure hepatitis B virus with novel direct‐acting antivirals?

Martínez

Villeret

Testoni

et al. 2020

Liver International

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Current treatments against chronic hepatitis B (CHB) include pegylated interferon alpha (Peg‐IFNα) and nucleos(t)ide analogs (NAs), the latter targeting the viral retrotranscriptase, thus inhibiting de novo viral production. Although these therapies control infection and improve the patient's quality of life, they do not cure HBV‐infected hepatocytes. A complete HBV cure is currently not possible because of the presence of the stable DNA intermediate covalently closed circular DNA (cccDNA). Current efforts are focused on achieving a functional cure, defined by the loss of Hepatitis B surface antigen (HBsAg) and undetectable HBV DNA levels in serum, and on exploring novel targets and molecules that are in the pipeline for early clinical trials. The likelihood of achieving a long‐lasting functional cure, with no rebound after therapy cessation, is higher using combination therapies targeting different steps in the hepatitis B virus (HBV) replication cycle. Novel treatments and their combinations are discussed for their potential to cure HBV infection, as well as exciting new technologies that could directly target cccDNA and cure without killing the infected cells.

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“…Novel therapeutics targets in the HBV Life Cycle (adapted from ref. 8 ). cccDNA direct-acting drugs are shown in red.…”

Section: F I G U R Ementioning

confidence: 99%

Section: F I G U R Ementioning

confidence: 99%

Section: Nucleocapsid Assembly Modulatorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Can we cure hepatitis B virus with novel direct‐acting antivirals?

Martínez

Villeret

Testoni

et al. 2020

Liver International

Self Cite

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“…In a woodchuck model blocking PD‐L1 together with HBV therapeutic vaccination reduced HBV DNA concentrations . Unfortunately it has proven more difficult to validate the efficacy of immunomodulator therapies in human studies . A recent combination of a TLR7 agonist RO7011785 in 3 cohorts of chronic hepatitis B patients, including virologically suppressed patients has been primarily designed to show the safety of the combination.…”

Section: Current Studies Of Combination Antiviral Therapymentioning

confidence: 99%

Will we need novel combinations to cure HBV infection?

Dusheiko

2020

Liver International

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Chronic hepatitis B is a numerically important cause of cirrhosis and hepatocellular carcinoma. Nucleoside analogue therapy may modify the risk. However, maintenance suppressive therapy is required, as a functional cure (generally defined as loss of HBsAg off treatment) is an uncommon outcome of antiviral treatment. Chronic hepatitis B is a numerically important cause of cirrhosis and hepatocellular carcinoma. Nucleoside analogue therapy may modify the risk. However, maintenance suppressive therapy is required, as a functional cure (generally defined as loss of HBsAg off treatment) is an uncommon outcome of antiviral treatment. Currently numerous investigational agents being developed to either interfere with specific steps in HBV replication or as host cellular targeting agents, that inhibit viral replication, and deplete or inactivate cccDNA, or as immune modulators. Synergistic mechanisms will be needed to incorporate a decrease in HBV transcription, impairment of transcription from HBV genomes, loss of cccDNA or altered epigenetic regulation of cccDNA transcription, and immune modulation or immunologically stimulated hepatocyte cell turnover. Nucleoside analogue suppressed patients are being included in many current trials. Trials are progressing to combination therapy as additive or synergistic effects are sought. These trials will provide important insights into the biology of HBV and perturbations of the immune response, required to effect HBsAg loss at different stages of the disease. The prospect of cures of hepatitis B would ensure that a wide range of patients could be deemed candidates for treatment with new compounds if these were highly effective, finite and safe. Withdrawal of therapy in short‐term trials is challenging because short‐term therapies may risk severe hepatitis flares, and hepatic decompensation. The limited clinical trial data to date suggest that combination therapy is inevitable.

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Combination treatment of pegylated interferon and tenofovir versus tenofovir for people with chronic hepatitis B

Wang

Chai

et al. 2023

Cochrane Database of Systematic Reviews

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Therapeutic strategies for hepatitis B virus infection: towards a cure

Cited by 409 publications

References 174 publications

Can we cure hepatitis B virus with novel direct‐acting antivirals?

Can we cure hepatitis B virus with novel direct‐acting antivirals?

Will we need novel combinations to cure HBV infection?

Combination treatment of pegylated interferon and tenofovir versus tenofovir for people with chronic hepatitis B

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