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Biomedicines
Special Issues
Novel Biomarkers and Mechanisms Underlying HBV and HDV Infection
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Novel Biomarkers and Mechanisms Underlying HBV and HDV Infection

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 10532

Special Issue Editor

Dr. Romina Salpini

E-Mail Website
Guest Editor
Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
Interests: HBV; HDV; HIV; SARS-CoV-2; diagnostics of viral diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Hepatitis B virus (HBV) cannot be eliminated completely from infected hepatocytes since intrahepatic covalently closed circular DNA (cccDNA) persists in the liver of infected people. Unfortunately, estimation of the HBV intrahepatic reservoir is strongly limited by the need of liver biopsy.

In recent years, multiple novel non-invasive HBV have been emerging as affordable surrogate markers of the pool and activity of the HBV intrahepatic reservoir and could also reflect the extent of HBV–DNA integration within the DNA of infected hepatocytes. Indeed, these aspects are crucial to elucidate still the undefined pathogenic mechanisms that underly HBV and HDV infection and to assess properly the therapeutic response, also considering the upcoming introduction of novel anti-HBV therapies aimed to achieve functional HBV cure.

Innovative HBV biomarkers also represent promising tools for improved disease staging, HCC-risk stratification and anti-HBV therapy optimization in the setting of both HBV mono-infection and HBV co-infection with hepatitis delta virus (HDV).

In this light, this Special Issue aims to collect research articles and reviews on the pathogenic mechanisms that underly HBV and HDV infections and on innovative HBV biomarkers, with a special focus on the role of novel HBV biomarkers in reflecting viral intrahepatic reservoir characteristics and dynamics, as well as in predicting disease outcome in the setting of both HBV infection and HBV/HDV co-infection.

Dr. Romina Salpini
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • hepatitis B
  • hepatitis delta
  • HBV novel markers
  • cccDNA
  • intrahepatic HBV reservoir
  • HBV integration

Published Papers (4 papers)

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Research

12 pages, 1606 KiB  
Article
Susceptibility of Drug Resistant Hepatitis B Virus Mutants to Besifovir
by Juhee Won, Ah Ram Lee, Mehrangiz Dezhbord, Da Rae Lee, Seong Ho Kim, Jong Chul Kim, Soree Park, Nayeon Kim, Byengjune Jae and Kyun-Hwan Kim
Biomedicines 2022, 10(7), 1637; https://doi.org/10.3390/biomedicines10071637 - 07 Jul 2022
Cited by 1 | Viewed by 1802
Abstract
Currently, interferon alpha and nucleos(t)ide analogues (NAs) are clinically available to treat hepatitis B virus (HBV) infection. Several NAs, including lamivudine (LMV), adefovir (ADV), entecavir (ETV) and tenofovir (TDF or TAF) have been approved and administered to chronic hepatitis B (CHB) patients. NAs [...] Read more.
Currently, interferon alpha and nucleos(t)ide analogues (NAs) are clinically available to treat hepatitis B virus (HBV) infection. Several NAs, including lamivudine (LMV), adefovir (ADV), entecavir (ETV) and tenofovir (TDF or TAF) have been approved and administered to chronic hepatitis B (CHB) patients. NAs inhibit HBV DNA synthesis by targeting the reverse transcriptase (RT) domain of HBV polymerase. Several mutations in the RT domain which lead to drug resistance against NAs have been reported, even for TDF and TAF which are highly potent with very low resistance rate. Besifovir (BFV) is a new antiviral dGMP analogue able to be used as a new NA drug for the control of CHB infection. Drug resistance to BFV is not well known due to its shorter duration of clinical use. Recently, we reported that rtL180M (M) and rtM204V (V) mutations, already resistant to LMV, are associated with BFV resistance. However, the susceptibility to BFV of previously known HBV mutants resistant to various drugs has not been studied. To investigate this, we performed in vitro drug susceptibility assays using natural and artificial mutants that are associated with resistance to LMV, ADV, ETV or TDF. As a result, LMV-resistant mutants were not susceptible to BFV and ETV-resistant clones showed partial resistance against BFV as well. However, ADV-resistant mutants were highly sensitive to BFV. In case of tenofovir-resistant mutations, the HBV mutants harboring primary mutations to tenofovir resistance were susceptible to BFV. Therefore, our study revealed that BSV may serve as an alternative drug for patients with ADV-, ETV-, TDF- or TAF-resistance. Full article
(This article belongs to the Special Issue Novel Biomarkers and Mechanisms Underlying HBV and HDV Infection)
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16 pages, 4464 KiB  
Article
Clinical Application of Droplet Digital PCR for Hepatitis Delta Virus Quantification
by Antonella Olivero, Chiara Rosso, Alessia Ciancio, Maria Lorena Abate, Aurora Nicolosi, Giulia Troshina, Angelo Armandi, Davide Giuseppe Ribaldone, Giorgio Maria Saracco, Elisabetta Bugianesi, Mario Rizzetto and Gian Paolo Caviglia
Biomedicines 2022, 10(4), 792; https://doi.org/10.3390/biomedicines10040792 - 29 Mar 2022
Cited by 5 | Viewed by 2632
Abstract
Droplet digital PCR (ddPCR) is a novel developed PCR technology providing the absolute quantification of target nucleic acid molecules without the need for a standard curve and regardless PCR amplification efficiency. Our aim was to develop a ddPCR assay for Hepatitis Delta virus [...] Read more.
Droplet digital PCR (ddPCR) is a novel developed PCR technology providing the absolute quantification of target nucleic acid molecules without the need for a standard curve and regardless PCR amplification efficiency. Our aim was to develop a ddPCR assay for Hepatitis Delta virus (HDV)-RNA viremia quantification and then evaluate its performance in relation to real-time PCR methods. Primers and probe were designed from conserved regions of HDV genome to detect all the 8 HDV genotypes; the World Health Organization (WHO)-HDV international standard was used to calculate the conversion factor transforming results from copies/mL to IU/mL. To evaluate the clinical performance of ddPCR assay, plasma specimens of HDV-infected patients were tested and results were compared with data obtained with two real-time quantitative PCR (RT-qPCR) assays (i.e., in-house assay and commercial RoboGene assay). Analyzing by linear regression a series of 10-fold dilutions of the WHO-HDV International Standard, ddPCR assay showed good linearity with a slope coefficient of 0.966 and R2 value of 0.980. The conversion factor from copies to international units was 0.97 and the quantitative linear dynamic range was from 10 to 1 × 106 IU/mL. Probit analysis estimated at 95% an LOD of 9.2 IU/mL. Data from the evaluation of HDV-RNA in routine clinical specimen of HDV patients exhibited strong agreement with results obtained by RT-qPCR showing a concordance correlation coefficient of 0.95. Overall ddPCR and RT-qPCR showed highly comparable technical performance. Moreover, ddPCR providing an absolute quantification method may allow the standardization of HDV-RNA measurement thus improving the clinical and diagnostic management of delta hepatitis. Full article
(This article belongs to the Special Issue Novel Biomarkers and Mechanisms Underlying HBV and HDV Infection)
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11 pages, 4741 KiB  
Article
Highly Sensitive HBsAg, Anti-HBc and Anti HBsAg Titres in Early Diagnosis of HBV Reactivation in Anti-HBc-Positive Onco-Haematological Patients
by Carlotta Cerva, Romina Salpini, Mohammad Alkhatib, Vincenzo Malagnino, Lorenzo Piermatteo, Arianna Battisti, Ada Bertoli, Jeff Gersch, Vera Holzmayer, Mary Kuhns, Gavin Cloherty, Ludovica Ferrari, Campogiani Laura, Elisabetta Teti, Maria Cantonetti, William Arcese, Francesca Ceccherini-Silberstein, Carlo-Federico Perno, Massimo Andreoni, Valentina Svicher and Loredana Sarmatiadd Show full author list remove Hide full author list
Biomedicines 2022, 10(2), 443; https://doi.org/10.3390/biomedicines10020443 - 14 Feb 2022
Cited by 5 | Viewed by 2342
Abstract
The role of novel HBV markers in predicting Hepatitis B virus reactivation (HBV-R) in HBsAg-negative/anti-HBc-positive oncohaematological patients was examined. One hundred and seven HBsAg-negative/anti-HBc-positive oncohaematological patients, receiving anti-HBV prophylaxis for >18 months, were included. At baseline, all patients had undetectable HBV DNA, and [...] Read more.
The role of novel HBV markers in predicting Hepatitis B virus reactivation (HBV-R) in HBsAg-negative/anti-HBc-positive oncohaematological patients was examined. One hundred and seven HBsAg-negative/anti-HBc-positive oncohaematological patients, receiving anti-HBV prophylaxis for >18 months, were included. At baseline, all patients had undetectable HBV DNA, and 67.3% were anti-HBs positive. HBV-R occurred in 17 (15.9%) patients: 6 during and 11 after the prophylaxis period. At HBV-R, the median (IQR) HBV-DNA was 44 (27–40509) IU/mL, and the alanine aminotransferase upper limit of normal (ULN) was 44% (median (IQR): 81 (49–541) U/L). An anti-HBc > 3 cut-off index (COI) plus anti-HBs persistently/declining to <50 mIU/mL was predictive for HBV-R (OR (95% CI): 9.1 (2.7–30.2); 63% of patients with vs. 15% without this combination experienced HBV-R (p < 0.001)). The detection of highly sensitive (HS) HBsAg and/or HBV-DNA confirmed at >2 time points, also predicts HBV-R (OR (95% CI): 13.8 (3.6–52.6); 50% of positive vs. 7% of negative patients to these markers experienced HBV-R (p = 0.001)). HS-HBs and anti-HBc titration proved to be useful early markers of HBV-R. The use of these markers demonstrated that HBV-R frequently occurs in oncohaematological patients with signs of resolved HBV infection, raising issues of proper HBV-R monitoring. Full article
(This article belongs to the Special Issue Novel Biomarkers and Mechanisms Underlying HBV and HDV Infection)
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12 pages, 857 KiB  
Article
HBeAg Levels Vary across the Different Stages of HBV Infection According to the Extent of Immunological Pressure and Are Associated with Therapeutic Outcome in the Setting of Immunosuppression-Driven HBV Reactivation
by Lorenzo Piermatteo, Mohammad Alkhatib, Stefano D’Anna, Vincenzo Malagnino, Ada Bertoli, Eleonora Andreassi, Elisa Basile, Alessandra Iuvara, Maria De Cristofaro, Giuseppina Cappiello, Carlotta Cerva, Carmine Minichini, Mariantonietta Pisaturo, Mario Starace, Nicola Coppola, Carla Fontana, Sandro Grelli, Francesca Ceccherini-Silberstein, Massimo Andreoni, Upkar S. Gill, Patrick T. F. Kennedy, Loredana Sarmati, Romina Salpini and Valentina Svicheradd Show full author list remove Hide full author list
Biomedicines 2021, 9(10), 1352; https://doi.org/10.3390/biomedicines9101352 - 29 Sep 2021
Cited by 1 | Viewed by 2579
Abstract
HBeAg is a marker of HBV-activity, and HBeAg-loss predicts a favorable clinical outcome. Here, we characterize HBeAg-levels across different phases of HBV infection, their correlation with virological/biochemical markers and the virological response to anti-HBV therapy. Quantitative HBeAg (qHBeAg, DiaSorin) is assessed in 101 [...] Read more.
HBeAg is a marker of HBV-activity, and HBeAg-loss predicts a favorable clinical outcome. Here, we characterize HBeAg-levels across different phases of HBV infection, their correlation with virological/biochemical markers and the virological response to anti-HBV therapy. Quantitative HBeAg (qHBeAg, DiaSorin) is assessed in 101 HBeAg+ patients: 20 with acute-infection, 20 with chronic infection, 32 with chronic hepatitis and 29 with immunosuppression-driven HBV-reactivation (HBV-R). A total of 15/29 patients with HBV-R are monitored for >12 months after starting TDF/ETV. qHBeAg is higher in immunosuppression-driven HBV-R (median[IQR]:930[206–1945]PEIU/mL) and declines in chronic hepatitis (481[28–1393]PEIU/mL, p = 0.03), suggesting HBeAg production, modulated by the extent of immunological pressure. This is reinforced by the negative correlation between qHBeAg and ALT in acute infection (Rho = −0.66, p = 0.006) and chronic hepatitis (Rho = −0.35; p = 0.05). Interestingly, qHBeAg strongly and positively correlates with qHBsAg across the study groups, suggesting cccDNA as a major source of both proteins in the setting of HBeAg positivity (with limited contribution of integrated HBV-DNA to HBsAg production). Focusing on 15 patients with HBV-R starting TDF/ETV, virological suppression and HBeAg-loss are achieved in 60% and 53.3%. Notably, the combination of qHBeAg > 2000 PEIU/mL + qHBsAg > 52,000 IU/mL at HBV-R is the only factor predicting no HBeAg loss (HBeAg loss: 0% with vs. 72.7% without qHBeAg > 2000 PEIU/mL + qHBsAg > 52,000 IU/mL, p = 0.03). In conclusion, qHBeAg varies over the natural course of HBV infection, according to the extent of immunological pressure. In the setting of HBV-R, qHBeAg could be useful in predicting the treatment response under immunosuppression. Full article
(This article belongs to the Special Issue Novel Biomarkers and Mechanisms Underlying HBV and HDV Infection)
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