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A special issue of Microorganisms (ISSN 2076-2607). This special issue belongs to the section "Virology".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 49021

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Dr. Isabelle Chemin

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Centre de Recherche en Cancérologie de Lyon INSERM U1052, CNRS UMR5286, Université de Lyon, Lyon, France
Interests: HBV variants; hepatocellular carcinoma
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Special Issue Information

Dear Colleagues,

Achieving the WHO diagnostic objectives by 2030 of 90% of people with chronic hepatitis B and treating 90% of eligible people to prevent the development of hepatocellular cancer will require a substantial scale-up of tests and treatments. The improvement of the cascade of care will require us to address and overcome the following main current obstacles: diagnosis of populations in different countries including low/middle income groups, the need for confirmation of viral load, the validation of affordable tests, and the stratification of liver disease before treatment. Other limiting factors include a lack of knowledge of infection of the community, stigma and fear of disclosure, distance from care sites, lack or cost of transportation, and long waiting times in health establishments. Therefore, this effort will include an educational valence for awareness on hepatitis B virus (HBV) infection and liver cancer in the targeted population, providing the use of a rapid diagnostic orientation test (TROD) with provision of a rapid test result including confirmation of the viral load, an immediate DNA test following a TROD-positive result, use of non-invasive tests for stratification of liver disease, and viral detection and therefore quick start of treatment.

In this context, this Special Issue aims to decipher the barriers in terms of the prevention, the diagnosis, and access to treatment of patients with viral hepatitis; propose new biomarkers; and explore viral variability in order to help expand access to anti-viral treatments for HBV chronic carriers.

Dr. Isabelle Chemin
Guest Editor

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Published Papers (11 papers)

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Editorial

Jump to: Research, Review, Other

3 pages, 199 KiB

Open AccessEditorial

Special Issue: “Updates on HBV Infection”

by Isabelle Chemin and Flor Helene Pujol

Microorganisms 2022, 10(3), 580; https://doi.org/10.3390/microorganisms10030580 - 7 Mar 2022

Cited by 4 | Viewed by 1787

Abstract

Hepatitis B virus (HBV) infection remains a global public health issue: a number of barriers still hamper the control of the HBV epidemic and in finding a cure for HBV [...] Full article

(This article belongs to the Special Issue Updates on HBV Infection)

Research

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9 pages, 413 KiB

Open AccessCommunication

High Rates of Liver Cirrhosis and Hepatocellular Carcinoma in Chronic Hepatitis B Patients with Metabolic and Cardiovascular Comorbidities

by Jan-Hendrik Bockmann, Matin Kohsar, John M. Murray, Vanessa Hamed, Maura Dandri, Stefan Lüth, Ansgar W. Lohse and Julian Schulze-zur-Wiesch

Microorganisms 2021, 9(5), 968; https://doi.org/10.3390/microorganisms9050968 - 30 Apr 2021

Cited by 8 | Viewed by 2659

Abstract

Background: The prevalence of metabolic and cardiovascular diseases is rising worldwide. However, little is known about the impact of such disorders on hepatic disease progression in chronic hepatitis B (CHB) during the era of potent nucleo(s)tide analogues (NAs). Methods: We retrospectively analyzed a single-center cohort of 602 CHB patients, comparing the frequency of liver cirrhosis at baseline and incidences of liver-related events during follow-up (hepatocellular carcinoma, liver transplantation and liver-related death) between CHB patients with a history of diabetes, obesity, hypertension or coronary heart disease (CHD). Results: Rates of cirrhosis at baseline and liver-related events during follow-up (median follow-up time: 2.51 years; NA-treated: 37%) were substantially higher in CHB patients with diabetes (11/23; 3/23), obesity (6/13; 2/13), CHD (7/11; 2/11) or hypertension (15/43; 4/43) compared to CHB patients without the indicated comorbidities (26/509; 6/509). Multivariate analysis identified diabetes as the most significant predictor for cirrhosis (p = 0.0105), while comorbidities did not correlate with liver-related events in pre-existing cirrhosis. Conclusion: The combination of metabolic diseases and CHB is associated with substantially increased rates of liver cirrhosis and secondary liver-related events compared to CHB alone, indicating that hepatitis B patients with metabolic comorbidities warrant particular attention in disease surveillance and evaluation of treatment indication. Full article

(This article belongs to the Special Issue Updates on HBV Infection)

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20 pages, 4584 KiB

Open AccessArticle

Conformational Plasticity of Hepatitis B Core Protein Spikes Promotes Peptide Binding Independent of the Secretion Phenotype

by Cihan Makbul, Vladimir Khayenko, Hans Michael Maric and Bettina Böttcher

Microorganisms 2021, 9(5), 956; https://doi.org/10.3390/microorganisms9050956 - 29 Apr 2021

Cited by 10 | Viewed by 3200

Abstract

Hepatitis B virus is a major human pathogen, which forms enveloped virus particles. During viral maturation, membrane-bound hepatitis B surface proteins package hepatitis B core protein capsids. This process is intercepted by certain peptides with an “LLGRMKG” motif that binds to the capsids at the tips of dimeric spikes. With microcalorimetry, electron cryo microscopy and peptide microarray-based screens, we have characterized the structural and thermodynamic properties of peptide binding to hepatitis B core protein capsids with different secretion phenotypes. The peptide “GSLLGRMKGA” binds weakly to hepatitis B core protein capsids and mutant capsids with a premature (F97L) or low-secretion phenotype (L60V and P5T). With electron cryo microscopy, we provide novel structures for L60V and P5T and demonstrate that binding occurs at the tips of the spikes at the dimer interface, splaying the helices apart independent of the secretion phenotype. Peptide array screening identifies “SLLGRM” as the core binding motif. This shortened motif binds only to one of the two spikes in the asymmetric unit of the capsid and induces a much smaller conformational change. Altogether, these comprehensive studies suggest that the tips of the spikes act as an autonomous binding platform that is unaffected by mutations that affect secretion phenotypes. Full article

(This article belongs to the Special Issue Updates on HBV Infection)

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10 pages, 966 KiB

Open AccessCommunication

Hepatitis B Virus Genotype Study in West Africa Reveals an Expanding Clade of Subgenotype A4

by Rayana Maryse Toyé, Damien Cohen, Flor Helene Pujol, Amina Sow-Sall, Gora Lô, Kunikazu Hoshino, Masashi Mizokami, Fabien Zoulim, Maud Lemoine, Coumba Touré-Kane and Isabelle Chemin

Microorganisms 2021, 9(3), 623; https://doi.org/10.3390/microorganisms9030623 - 17 Mar 2021

Cited by 6 | Viewed by 2796

Abstract

Hepatitis B virus (HBV) classification comprises up to 10 genotypes with specific geographical distribution worldwide, further subdivided into 40 subgenotypes, which have different impacts on liver disease outcome. Though extensively studied, the classification of subgenotype A sequences remains ambiguous. This study aimed to characterize HBV isolates from West African patients and propose a more advanced classification of subgenotype A. Fourteen HBV full-length genome sequences isolated from patients from The Gambia and Senegal were obtained and phylogenetically analyzed. Phylogenetic analysis of HBV genotype A sequences isolated from Senegalese and Gambian patients exhibited separate clusters from the other known and confirmed subgenotypes A (A1, A2, A6). Most of the sequences (10/14) clustered with an isolate from Cuba, reported as subgenotype A4 (supported by maximal bootstrap value). Four isolates from The Gambia and Senegal clustered separately from all other subgenotypes and samples sequenced in the study. Three of which from The Gambia, designated as an expanding clade of subgenotype A4, exhibited a mean inter-subgenotypic nucleotide divergence over the entire genome sequence higher than 4% in comparison with the other subgenotypes and the other isolates sequenced in the study, except with subgenotype A4 isolates (3.9%), and this was supported by a maximal bootstrap value. The last one from Senegal seemed to be an expanding subgenotype close to the new clade of A4. Amino acid analysis unveiled a novel motif specific to these isolates. This study revealed an expanding evolution of HBV subgenotype A and novel amino acid motifs. It also highlighted the need for a consensus regarding the analysis and classification of HBV sequences. Full article

(This article belongs to the Special Issue Updates on HBV Infection)

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12 pages, 275 KiB

Open AccessArticle

Cryptic HBV Replicative Activity Is Frequently Revealed in Anti-HBc-Positive/HBsAg-Negative Patients with HIV Infection by Highly Sensitive Molecular Assays, and Can Be Predicted by Integrating Classical and Novel Serological HBV Markers

by Romina Salpini, Vincenzo Malagnino, Lorenzo Piermatteo, Tiziana Mulas, Mohammad Alkhatib, Rossana Scutari, Elisabetta Teti, Carlotta Cerva, Katia Yu La Rosa, Marta Brugneti, Ada Bertoli, Benedetta Rossi, Vera Holzmayer, Jeffrey Gersch, Mary Kuhns, Gavin Cloherty, Francesca Ceccherini-Silberstein, Carlo-Federico Perno, Marco Iannetta, Massimo Andreoni, Loredana Sarmati and Valentina Svicher Show full author list Hide full author list

Microorganisms 2020, 8(11), 1819; https://doi.org/10.3390/microorganisms8111819 - 18 Nov 2020

Cited by 10 | Viewed by 2686

Abstract

The anti-HBc-positive/HBsAg-negative status is frequent in HIV-infection and correlates with poor survival. Here, by highly-sensitive assays, we evaluate cryptic HBV replication and factors correlated with its detection in 81 anti-HBc-positive/HBsAg-negative HIV-infected patients. Patients were treated for >12 months with HBV-active modern combined antiretroviral-therapy (cART) and had serum HBV-DNA < 20 IU/mL by commercial Real-Time PCR. Serum HBV-DNA was quantified by droplet digital PCR, serum HBV-RNA by an Abbott research assay, and anti-HBc titer (proposed to infer intrahepatic cccDNA) by Lumipulse/Fujirebio. Cryptic serum HBV-DNA was detected in 29.6% of patients (median (IQR): 4(1–15) IU/mL) and serum HBV-RNA in 3.7% of patients despite HBsAg-negativity and HBV-active cART. Notably, cryptic serum HBV-DNA correlated with an advanced CDC-stage (p = 0.01) and a lower anti-HBs titer (p = 0.05), while serum HBV-RNA correlated with lower nadir CD4+ cell-count (p = 0.01). By analyzing serological HBV-markers, the combination of anti-HBs < 50 mIU/mL (indicating lower immune response) plus anti-HBc > 15COI (reflecting higher HBV replicative activity) was predictive of cryptic serum HBV-DNA (OR: 4.7(1.1–21.7), p = 0.046, PPV = 62.5%, and NPV = 72%). In conclusion, cryptic HBV-replication (not detected by classical assays) characterizes a conspicuous set of anti-HBc-positive HIV-infected patients despite HBsAg-negativity and HBV-active combined antiretroviral therapy (cART). The integration of classical and novel markers may help identify patients with cryptic HBV-replication, thus optimizing the monitoring of anti-HBc-positive/HBsAg-negative HIV-infected patients. Full article

(This article belongs to the Special Issue Updates on HBV Infection)

13 pages, 1747 KiB

Open AccessArticle

Clinical, Epidemiological, and Geospatial Characteristics of Patients Infected with Hepatitis C Virus Treated with Second-Generation Direct-Action Antivirals in a Reference Center in a Mesoregion of São Paulo State, Brazil

by Danilo Zangirolami Pena, Murilo Fernandes Anadão, Edilson Ferreira Flores, Mayara Namimatsu Okada, Alexandre Martins Portelinha Filho, Rodrigo Sala Ferro and Luiz Euribel Prestes-Carneiro

Microorganisms 2020, 8(10), 1575; https://doi.org/10.3390/microorganisms8101575 - 13 Oct 2020

Cited by 1 | Viewed by 1944

Abstract

Hepatitis virus infection is a major public health problem worldwide. Currently, Brazil has almost 700,000 cases. The Brazilian Unified Health System (SUS) provides therapeutic regimens for people infected with hepatitis C virus (HCV). We determined the clinical, laboratory, epidemiologic, and geospatial characteristics of patients infected with HCV treated with second-generation direct-action antivirals (DAAs) in a hospital reference center in São Paulo state, Brazil, using data from file records. A map was constructed using a geographic information system. From 2015 to 2018, 197 individuals received second-generation DAAs (mean age, 57.68 ± 1.36 years; interquartile range, 56.22–59.14 years; 58.9% male; 41.1% female). Genotypes 1a and 1b accounted for 75.7% of cases and the prevalent therapeutic regimen was sofosbuvir/simeprevir. Sustained viral response accounted for 98.9% and the METAVIR score F3/F4 for 50.8%. Increased alanine transferase was significantly correlated with an increase in α-fetoproteins (p = 0.01), and severe necro-inflammatory activity (p = 0.001). Associated comorbidities were found in 71.6%, mainly coronary artery and gastrointestinal disorders. The cumulative incidence in the region was 2.6 per 10,000 inhabitants. Our data highlight the role of reference hospitals in Brazil’s public health system in the treatment of HCV. Low incidence rates demonstrated the fragility of municipalities in the active search for patients. Full article

(This article belongs to the Special Issue Updates on HBV Infection)

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12 pages, 1607 KiB

Open AccessArticle

A New Method for Next-Generation Sequencing of the Full Hepatitis B Virus Genome from A Clinical Specimen: Impact for Virus Genotyping

by Flavia Hebeler-Barbosa, Ivan Rodrigo Wolf, Guilherme Targino Valente, Francisco Campello do Amaral Mello, Elisabeth Lampe, Maria Inês de Moura Campos Pardini and Rejane Maria Tommasini Grotto

Microorganisms 2020, 8(9), 1391; https://doi.org/10.3390/microorganisms8091391 - 11 Sep 2020

Cited by 7 | Viewed by 3891

Abstract

Hepatitis B virus (HBV) is an enveloped virus that induces chronic liver disease. HBV has been classified into eight genotypes (A–H) according to its genome sequence by using Sanger sequencing or reverse hybridization. Sanger sequencing is often restricted to analyzing the S gene and is inaccurate for detecting minority genetic variants, whereas reverse hybridization detects only known mutations. Next-generation sequencing (NGS) is a robust tool for clinical virology with different protocols available. The objective of this study was to develop a new method for the study of viral genetic polymorphisms or more accurate genotyping using genome amplification followed by NGS. Plasma obtained from five chronically infected HBV individuals was used for viral DNA isolation. HBV full-genome PCR amplification was the enrichment method for NGS. Primers were used to amplify all HBV genotypes in three overlapping amplicons, following a tagmentation step and Illumina NGS. For phylogenetic analysis, sequences were extracted from the HBVdb database. We were able to amplify a full HBV genome; further, NGS was shown to be a robust method and allowed better genotyping, mainly in patients carrying mixed genotypes, classified according to other techniques. This new method may be significant for whole genome analyses, including other viruses. Full article

(This article belongs to the Special Issue Updates on HBV Infection)

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Review

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24 pages, 1151 KiB

Open AccessReview

A New Endemic of Concomitant Nonalcoholic Fatty Liver Disease and Chronic Hepatitis B

by Hira Hanif, Muzammil M. Khan, Mukarram J. Ali, Pir A. Shah, Jinendra Satiya, Daryl T.Y. Lau and Aysha Aslam

Microorganisms 2020, 8(10), 1526; https://doi.org/10.3390/microorganisms8101526 - 4 Oct 2020

Cited by 11 | Viewed by 5341

Abstract

Hepatitis B virus (HBV) infection remains a global public problem despite the availability of an effective vaccine. In the past decades, nonalcoholic fatty liver disease (NAFLD) has surpassed HBV as the most common cause of chronic liver disease worldwide. The prevalence of concomitant chronic hepatitis B (CHB) and NAFLD thus reaches endemic proportions in geographic regions where both conditions are common. Patients with CHB and NAFLD are at increased risk of liver disease progression to cirrhosis and hepatocellular carcinoma. Due to the complexity of the pathogenesis, accurate diagnosis of NAFLD in CHB patients can be challenging. Liver biopsy is considered the gold standard for diagnosing and determining disease severity, but it is an invasive procedure with potential complications. There is a growing body of literature on the application of novel noninvasive serum biomarkers and advanced radiological modalities to diagnose and evaluate NAFLD, but most have not been adequately validated, especially for patients with CHB. Currently, there is no approved therapy for NAFLD, although many new agents are in different phases of development. This review provides a summary of the epidemiology, clinical features, diagnosis, and management of the NAFLD and highlights the unmet needs in the areas of CHB and NAFLD coexistence. Full article

(This article belongs to the Special Issue Updates on HBV Infection)

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20 pages, 1932 KiB

Open AccessReview

Impact of Hepatitis B Virus Genetic Variation, Integration, and Lymphotropism in Antiviral Treatment and Oncogenesis

by Keith C.K. Lau, Kelly W. Burak and Carla S. Coffin

Microorganisms 2020, 8(10), 1470; https://doi.org/10.3390/microorganisms8101470 - 24 Sep 2020

Cited by 18 | Viewed by 11630

Abstract

Chronic Hepatitis B Virus (HBV) infection poses a significant global health burden. Although, effective treatment and vaccinations against HBV are available, challenges still exist, particularly in the development of curative therapies. The dynamic nature and unique features of HBV such as viral variants, integration of HBV DNA into host chromosomes, and extrahepatic reservoirs are considerations towards understanding the virus biology and developing improved anti-HBV treatments. In this review, we highlight the importance of these viral characteristics in the context of treatment and oncogenesis. Viral genotype and genetic variants can serve as important predictive factors for therapeutic response and outcomes in addition to oncogenic risk. HBV integration, particularly in coding genes, is implicated in the development of hepatocellular carcinoma. Furthermore, we will discuss emerging research that has identified various HBV nucleic acids and infection markers within extrahepatic sites (lymphoid cells). Intriguingly, the presence of hepatocellular carcinoma (HCC)-associated HBV variants and viral integration within the lymphoid cells may contribute towards the development of extrahepatic malignancies. Improved understanding of these HBV characteristics will enhance the development of a cure for chronic HBV infection. Full article

(This article belongs to the Special Issue Updates on HBV Infection)

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29 pages, 787 KiB

Open AccessReview

Recent Advances in Understanding, Diagnosing, and Treating Hepatitis B Virus Infection

by Magda Rybicka and Krzysztof Piotr Bielawski

Microorganisms 2020, 8(9), 1416; https://doi.org/10.3390/microorganisms8091416 - 15 Sep 2020

Cited by 30 | Viewed by 9352

Abstract

Chronic hepatitis B virus (HBV) infection affects 292 million people worldwide and is associated with a broad range of clinical manifestations including cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Despite the availability of an effective vaccine HBV still causes nearly 900,000 deaths every year. Current treatment options keep HBV under control, but they do not offer a cure as they cannot completely clear HBV from infected hepatocytes. The recent development of reliable cell culture systems allowed for a better understanding of the host and viral mechanisms affecting HBV replication and persistence. Recent advances into the understanding of HBV biology, new potential diagnostic markers of hepatitis B infection, as well as novel antivirals targeting different steps in the HBV replication cycle are summarized in this review article. Full article

(This article belongs to the Special Issue Updates on HBV Infection)

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Other

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8 pages, 2358 KiB

Open AccessOpinion

Contribution of HIV/AIDS-Related Human and Social Sciences Research to a Better Understanding of the Challenges of Hepatitis B Prevention, Diagnosis and Care

by Charlotte Bauquier and Marie Préau

Microorganisms 2021, 9(6), 1166; https://doi.org/10.3390/microorganisms9061166 - 28 May 2021

Cited by 1 | Viewed by 2397

Abstract

Recent scientific advances in hepatitis B virus research hint at the possibility of finding a cure in the medium term. In this context, the characterization of infected persons constitutes a major public health issue in terms of implementing adapted screening and prevention strategies. Overcoming the current challenges national health systems face in hepatitis B diagnosis is essential if the World Health Organization’s target of treating 80% of infected patients by 2030 is to be reached. These challenges reflect those previously faced in the fight against HIV/AIDS. Using the knowledge produced to date in Human and Social Sciences research in the fight against HIV/AIDS, we propose avenues of reflection to support and guide the development of research in the diagnosis of hepatitis B infection. More specifically, we present theoretical, methodological and epistemological considerations for how HSS research can be optimized in the following three HBV diagnosis-related areas: (i) access to screening; (ii) retention in care; and (iii) the integration of quality of life measurement in clinical trials. Full article

(This article belongs to the Special Issue Updates on HBV Infection)

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