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Hepatitis B virus peptide inhibitors: solution structures and interactions with the viral capsid

Muhamad A, Ho KL, Rahman MB, Tejo BA, Uhrín D, Tan WS

Org Biomol Chem, 2015 Jul 28;13(28):7780-9.
PMID: 26100394 DOI: 10.1039/c5ob00449g

Hepatitis B virus (HBV) infection remains a health problem globally despite the availability of effective vaccines. In the assembly of the infectious virion, both the preS and S regions of the HBV large surface antigen (L-HBsAg) interact synergistically with the viral core antigen (HBcAg). Peptides preS and S based on the L-HBsAg were demonstrated as potential inhibitors to block the viral assembly. Therefore, the objectives of this study were to determine the solution structures of these peptides and study their interactions with HBcAg. The solution structures of these peptides were solved using (1)H, (13)C, and (15)N NMR spectroscopy. Peptide preS has several structured regions of β-turns at Ser7-Pro8-Pro9, Arg11-Thr12-Thr13 and Ser22-Thr23-Thr24 sequences whereas peptide S has only one structured region observed at Ser3-Asn4-His5. Both peptides contain bend-like structures surrounding the turn structures. Docking studies revealed that both peptides interacted with the immunodominant region of HBcAg located at the tip of the viral capsid spikes. Saturation Transfer Difference (STD) NMR experiments identified several aromatic residues in peptides preS and S that interact with HBcAg. This study provides insights into the contact regions of L-HBsAg and HBcAg at atomic resolution which can be used to design antiviral agents that inhibit HBV morphogenesis.

Matched MeSH terms: Hepatitis B virus/drug effects
Interpretation and application of virological testing including resistance in chronic hepatitis B

Locarnini S

Med J Malaysia, 2005 Jul;60 Suppl B:41-51.
PMID: 16108173
Matched MeSH terms: Hepatitis B virus/drug effects
Fulltext Doxorubicin Activates Hepatitis B Virus Replication by Elevation of p21 (Waf1/Cip1) and C/EBPα Expression

Chen YF, Chong CL, Wu YC, Wang YL, Tsai KN, Kuo TM, et al.

PLoS One, 2015;10(6):e0131743.
PMID: 26121644 DOI: 10.1371/journal.pone.0131743

Hepatitis B virus reactivation is an important medical issue in cancer patients who undergo systemic chemotherapy. Up to half of CHB carriers receiving chemotherapy develop hepatitis and among these cases a notable proportion are associated with HBV reactivation. However, the molecular mechanism(s) through which various chemotherapeutic agents induce HBV reactivation is not yet fully understood. In this study, we investigated the role of the cell cycle regulator p21 (Waf1/Cip1) in the modulation of HBV replication when a common chemotherapeutic agent, doxorubicin, is present. We showed that p21 expression was increased by doxorubicin treatment. This elevation in p21 expression enhanced the expression of CCAAT/enhancer-binding protein α (C/EBPα); such an increase is likely to promote the binding of C/EBPα to the HBV promoter, which will contribute to the activation of HBV replication. Our current study thus reveals the mechanism underlying doxorubicin modulation of HBV replication and provides an increased understanding of HBV reactivation in CHB patients who are receiving systemic chemotherapy.

Matched MeSH terms: Hepatitis B virus/drug effects*
Inhibition of hepatitis B virus assembly with synthetic peptides derived from the viral surface and core antigens

Tan WS

J Gen Appl Microbiol, 2002 Apr;48(2):103-7.
PMID: 12469306

The long surface antigen (L-HBsAg) of hepatitis B virus (HBV) plays a central role in the production of infectious virions. During HBV morphogenesis, both the PreS and S domains of L-HBsAg form docking sites for the viral nucleocapsids. Thus, a compound that disrupts the interaction between the L-HBsAg and nucleocapsids could serve as a therapeutic agent against the virus based upon inhibition of morphogenesis. Synthetic peptides correspond to the binding sites in L-HBsAg inhibited the association of L-HBsAg with core antigen (HBcAg). A synthetic peptide carrying the epitope for a monoclonal antibody to the PreS1 domain competed weakly with L-HBsAg for HBcAg, but peptides corresponding to a linear sequence at the tip of the nucleocapsid spike did not, showing that the competing peptide does not resemble the tip of the spike.

Matched MeSH terms: Hepatitis B virus/drug effects*
Fulltext Willingness to pay for hepatitis B vaccination in Selangor, Malaysia: A cross-sectional household survey

Rajamoorthy Y, Radam A, Taib NM, Rahim KA, Munusamy S, Wagner AL, et al.

PLoS One, 2019;14(4):e0215125.
PMID: 30964934 DOI: 10.1371/journal.pone.0215125

BACKGROUND: In Malaysia, one million individuals are estimated to be infected with the hepatitis B virus. A vaccine for infants has been compulsory since 1989, whereas those born before 1989 need to spend their own money to be vaccinated in private clinics or hospitals. The aim of this study was to investigate and ascertain the determinants of willingness to pay (WTP) for adult hepatitis B vaccine in Selangor, Malaysia.
METHODS: In 2016, 728 households were selected through a stratified, two stage cluster sample and interviewed. Willingness to pay for hepatitis B vaccine was estimated using the Contingent Valuation Method, and factors affecting WTP were modelled with logit regression.
RESULTS: We found that 273 (37.5%) of the households were willing to pay for hepatitis B vaccination. The mean and median of WTP was estimated at Ringgit Malaysia (RM)303 (approximately US$73) for the three dose series. The estimated WTP was significantly greater in those with higher levels of education, among Malays and Chinese (compared to others, predominantly Indians), and for those with greater perceived susceptibility to hepatitis B virus infection. Other factors-perceived severity, barriers, benefits and cues to action-were not significantly associated with WTP for adult hepatitis B vaccination.
CONCLUSION: Additional resources are needed to cover the households that are not willing to pay for hepatitis B vaccination. More awareness (particularly in regards to hepatitis B virus susceptibility) could change the national perception towards self-paid hepatitis B virus vaccination and increase hepatitis B vaccine coverage.

Matched MeSH terms: Hepatitis B virus/drug effects*
Fulltext Practical approach in hepatitis B e antigen-negative individuals to identify treatment candidates

Azmi AN, Tan SS, Mohamed R

World J Gastroenterol, 2014 Sep 14;20(34):12045-55.
PMID: 25232242 DOI: 10.3748/wjg.v20.i34.12045

The natural history of chronic hepatitis B is characterized by different phases of infection, and patients may evolve from one phase to another or may revert to a previous phase. The hepatitis B e antigen (HBeAg)-negative form is the predominant infection worldwide, which consists of individuals with a range of viral replication and liver disease severity. Although alanine transaminase (ALT) remains the most accessible test available to clinicians for monitoring the liver disease status, further evaluations are required for some patients to assess if treatment is warranted. Guidance from practice guidelines together with thorough investigations and classifications of patients ensure recognition of who needs which level of care. This article aims to assist physicians in the assessment of HBeAg-negative individuals using liver biopsy or non-invasive tools such as hepatitis B s antigen quantification and transient elastography in addition to ALT and hepatitis B virus DNA, to identify who will remain stable, who will reactivate or at risk of disease progression hence will benefit from timely initiation of anti-viral therapy.

Matched MeSH terms: Hepatitis B virus/drug effects*
Fulltext Phage display creates innovative applications to combat hepatitis B virus

Tan WS, Ho KL

World J Gastroenterol, 2014 Sep 7;20(33):11650-70.
PMID: 25206271 DOI: 10.3748/wjg.v20.i33.11650

Hepatitis B virus (HBV) has killed countless lives in human history. The invention of HBV vaccines in the 20(th) century has reduced significantly the rate of the viral infection. However, currently there is no effective treatment for chronic HBV carriers. Newly emerging vaccine escape mutants and drug resistant strains have complicated the viral eradication program. The entire world is now facing a new threat of HBV and human immunodeficiency virus co-infection. Could phage display provide solutions to these life-threatening problems? This article reviews critically and comprehensively the innovative and potential applications of phage display in the development of vaccines, therapeutic agents, diagnostic reagents, as well as gene and drug delivery systems to combat HBV. The application of phage display in epitope mapping of HBV antigens is also discussed in detail. Although this review mainly focuses on HBV, the innovative applications of phage display could also be extended to other infectious diseases.

Matched MeSH terms: Hepatitis B virus/drug effects*
Fulltext Comparative effectiveness of anti-viral drugs with dual activity for treating hepatitis B and HIV co-infected patients: a network meta-analysis

Naing C, Poovorawan Y, Tong KS

BMC Infect Dis, 2018 Nov 14;18(1):564.
PMID: 30428847 DOI: 10.1186/s12879-018-3506-x

BACKGROUND: There are randomized trials assessing a variety of antiviral drugs for hepatitis B virus (HBV), but the relative effectiveness of these drugs in the treatment of patients co-infected with human immunodeficiency virus (HIV) remains unclear. The objectives of the current study were to estimate and rank the relative effectiveness of antiviral drugs for treating HBV and HIV co-infected patients.
METHODS: Randomized trials, assessing the efficacy of antiviral drugs for HBV and HIV co-infected patients were searched in health-related databases. The methodological quality of the included trials was evaluated using the Cochrane risk of bias tool. Main outcome in this meta-analysis study was the success of treatment by antivirals as determined by virologic response. We performed pairwise and network meta-analysis of these trials and assessed the quality of evidence using the GRADE approach.
RESULTS: Seven randomized trials (329 participants) were included in this network meta-analysis study. A network geometry was formed with six treatment options including four antiviral drugs, adefovir (ADV), emtricitabine (FTC), lamivudine (LMV) and tenofovir disoproxil fumarate (TDF), combination treatment of TDF plus LMV, and placebo. The weighted percentage contributions of each comparison distributed fairly equally in the entire network of evidence. An assumption of consistency required for network meta-analysis was not violated (the global Wald test for inconsistency: Chi2(4) = 3.63, p = 0.46). The results of estimates showed no differences between the treatment regimens in terms of viral response for treating HBV and HIV co-infected patients, which spanned both benefit and harm (e.g. LMV vs TDF plus LMV: OR: 0.37, 95%CI: 0.06-2.41). Overall, the certainty of evidence was very low in all comparisons (e.g. LMV vs TDF plus LMV: 218 fewer per 1000,121 more to 602 fewer, very low certainty). Therefore, we remained uncertain to the true ranking of the antiviral treatments in HBV/ HIV co-infected patients.
CONCLUSIONS: The findings suggest that the evidence is insufficient to provide guidance to the relative effectiveness of currently available antiviral drugs with dual activity in treating co-infection of HBV/HIV. Well-designed, large clinical trials in this field to address other important outcomes from different epidemiological settings are recommended.

Matched MeSH terms: Hepatitis B virus/drug effects
Chronic hepatitis B virus infection

Seto WK, Lo YR, Pawlotsky JM, Yuen MF

Lancet, 2018 11 24;392(10161):2313-2324.
PMID: 30496122 DOI: 10.1016/S0140-6736(18)31865-8

Chronic hepatitis B virus infection is a global public health threat that causes considerable liver-related morbidity and mortality. It is acquired at birth or later via person-to-person transmission. Vaccination effectively prevents infection and chronic hepatitis B virus carriage. In chronically infected patients, an elevated serum hepatitis B virus DNA concentration is the main risk factor for disease progression, although there are other clinical and viral parameters that influence disease outcomes. In addition to liver biochemistry, virological markers, and abdominal ultrasonography, non-invasive assessment of liver fibrosis is emerging as an important assessment modality. Long-term nucleos(t)ide-analogue therapy is safe and well tolerated, achieves potent viral suppression, and reduces the incidence of liver-related complications. However, a need to optimise management remains. Promising novel therapies are at the developmental stage. With current vaccines, therapies, and an emphasis on improving linkage to care, WHO's goal of eliminating hepatitis B virus as a global health threat by 2030 is achievable.

Matched MeSH terms: Hepatitis B virus/drug effects*