Molecular Virology of Hepatitis B Virus and Targets for Antiviral Intervention

Glebe, Dieter; König, Alexander

doi:10.1159/000360946

Cited by 22 publications

(17 citation statements)

References 64 publications

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“…Hepatitis B virus (HBV) infection causes 70% of the viral hepatitis-related mortality [ 2 ]. Global estimates suggest that 3.6% of the world’s population is infected with HBV [ 3 ], with the highest burden in Asia and sub-Saharan Africa [ 4 , 5 ]. Human immunodeficiency virus (HIV) and HBV are significant public health threats in sub-Saharan Africa.…”

Section: Introductionmentioning

confidence: 99%

Chronic and Occult Hepatitis B Virus Infection in Pregnant Women in Botswana

Mbangiwa

Kasvosve

Anderson

et al. 2018

Genes

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The hepatitis B virus (HBV) is a global problem; however, the burden of HBV infection in pregnant women in Botswana is unknown. We sought to determine the prevalence of chronic and occult HBV infection in human immunodeficiency virus (HIV)-infected and -uninfected pregnant women in Botswana. Samples from 752 pregnant women were tested for hepatitis B surface antigen (HBsAg), and HBsAg-positive samples were tested for hepatitis B e antigen (HBeAg) and HBV DNA load. Samples that were HBsAg negative were screened for occult HBV infection by determining the HBV DNA load. HBV genotypes were determined based on a 415-base-pair fragment of the surface gene. Among the 752 women tested during pregnancy or early postpartum, 16 (2.1%) (95% confidence interval (CI): 2.0–2.2) were HBsAg-positive. The prevalence of chronic HBV infection was higher (3.1%) among HIV-infected (95% CI: 3.0–3.2) compared with HIV-uninfected women (1.1%) (95% CI: 1.07–1.1, p = 0.057). Among the 622 HBsAg-negative women, the prevalence of occult HBV infection was 6.6% (95% CI: 6.5–6.7). Three of thirteen HBsAg-positive participants were HBeAg-positive, and all were HIV-negative. Of the 11 maternal samples successfully genotyped, five (45.5%) were genotype D3, five (45.5%) were genotype A1, and one was genotype E (9%). Low and similar proportions of HIV-infected and -uninfected pregnant women in Botswana had occult or chronic HBV infection. We identified a subset of HIV-negative pregnant women who had high HBV DNA levels and were HBeAg-positive, and thus likely to transmit HBV to their infants.

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Section: Introductionmentioning

confidence: 99%

Chronic and Occult Hepatitis B Virus Infection in Pregnant Women in Botswana

Mbangiwa

Kasvosve

Anderson

et al. 2018

Genes

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“…Only one subject sample (1/14) returned a positive epitope ‘hit’ by peptide chip screening in the cyclic peptide chip, which comprised 15mer cyclic peptides from genotype A‐D. This reactivity was directed to the continuous cyclic epitope within the HBsAg L domain, residues 20‐32 (NPLGFFPDHQLDP), associated with the essential domain for NTCP receptor binding . The peptide screening also failed to identify any consistent continuous epitopes within the HBsAg, including the HBsAg S antigenic domain (HBsAg S residues 99‐169), which were the target of the anti‐HBs response developed post‐HBsAg clearance in this cohort of CHB functional cure patients.…”

Section: Resultsmentioning

confidence: 99%

Predicting HBsAg clearance in genotype A chronic hepatitis B using HBsAg epitope profiling: A biomarker for functional cure

Walsh

Hammond

Yuen

et al. 2019

Liver International

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Background and Aim Functional cure is the major goal of chronic hepatitis B (CHB) therapy though few biomarkers predict this outcome. HBsAg epitope occupancy can be influenced by therapeutic and immune pressure. The aim of this study was to map the HBsAg epitope profiles during long‐term nucleos(t)ide analogue therapy in patients with genotype A CHB, in the context of HBsAg loss (SL)/seroconversion. Methods We evaluated 25 genotype A CHB patients in the GS‐US‐174‐0103 trial of HBeAg‐positive CHB patients treated with tenofovir or adefovir for 4 years, 14 who achieved SL whilst 11 had no change. We epitope mapped the major domains of HBsAg to identify those patients with HBsAg clearance profile (CP) (loss of binding at both loops 1 and 2 epitopes of the ‘a’ determinant) vs non‐clearance profile (no change in epitope recognition, or loss of epitope binding at one loop only), correlating this to on‐treatment HBsAg responses. Complexed anti‐HBs was also measured. Results Analysis of the HBsAg epitope profiles of the 25 patients at baseline identified no predictive correlation with SL. In contrast, analysis at week 48 and end of study (week 192) or prior to SL identified significant predictive associations between development of HBsAg CPs and outcome of functional cure. The detection of a CP also correlated with the development of an alanine aminotransferase flare and detection of anti‐HBs complexed with HBsAg. Conclusion The detection of HBsAg CPs by epitope mapping represents a novel viral biomarker, reflecting an emerging anti‐HBs selection pressure prior to functional cure.

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“…One of the reasons is that HBV reverse transcription occurs after infection has been developed with formation of HBV cccDNA in the infected nuclei of hepatocytes, in contrast to HIV where reverse transcription occurs after the infection but before the integration of DNA into the host genome [88]. It is encouraging that it has recently been shown that with many years of NUC treatment (median period 126 months) there is marked depletion of cccDNA in the majority of patients, but it was also shown that although serum HBsAg levels were reduced, they remained detectable in 42 of 43 patients [89].…”

Section: Direct-acting Antiviralsmentioning

confidence: 99%

Drugs in Development for Hepatitis B

Dawood

Basit

Jayaraj

et al. 2017

Drugs

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With high morbidity and mortality worldwide, there is great interest in effective therapies for chronic hepatitis B (CHB) virus. There are currently several dozen investigational agents being developed for treatment of CHB. They can be broadly divided into two categories: (1) direct-acting antivirals (DAAs) that interfere with a specific step in viral replication; and (2) host-targeting agents that inhibit viral replication by modifying host cell function, with the latter group further divided into the subcategories of immune modulators and agents that target other host functions. Included among the DAAs being developed are RNA interference therapies, covalently closed circular DNA (cccDNA) formation and transcription inhibitors, core/capsid inhibitors, reverse transcriptase inhibitors, hepatitis B surface antigen (HBsAg) release inhibitors, antisense oligonucleotides, and helioxanthin analogues. Included among the host-targeting agents are entry inhibitors, cyclophilin inhibitors, and multiple immunomodulatory agents, including Toll-like receptor agonists, immune checkpoint inhibitors, therapeutic vaccines, engineered T cells, and several cytokine agents, including recombinant human interleukin-7 (CYT107) and SB 9200, a novel therapy that is believed to both have direct antiviral properties and to induce endogenous interferon. In this review we discuss agents that are currently in the clinical stage of development for CHB treatment as well as strategies and agents currently at the evaluation and discovery phase and potential future targets. Effective approaches to CHB may require suppression of viral replication combined with one or more host-targeting agents. Some of the recent research advances have led to the hope that with such a combined approach we may have a functional cure for CHB in the not distant future.

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Molecular Virology of Hepatitis B Virus and Targets for Antiviral Intervention

Cited by 22 publications

References 64 publications

Chronic and Occult Hepatitis B Virus Infection in Pregnant Women in Botswana

Chronic and Occult Hepatitis B Virus Infection in Pregnant Women in Botswana

Predicting HBsAg clearance in genotype A chronic hepatitis B using HBsAg epitope profiling: A biomarker for functional cure

Drugs in Development for Hepatitis B

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