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  1. Article ; Online: Extensive C->U transition biases in the genomes of a wide range of mammalian RNA viruses; potential associations with transcriptional mutations, damage- or host-mediated editing of viral RNA.

    Peter Simmonds / M Azim Ansari

    PLoS Pathogens, Vol 17, Iss 6, p e

    2021  Volume 1009596

    Abstract: The rapid evolution of RNA viruses has been long considered to result from a combination of high copying error frequencies during RNA replication, short generation times and the consequent extensive fixation of neutral or adaptive changes over short ... ...

    Abstract The rapid evolution of RNA viruses has been long considered to result from a combination of high copying error frequencies during RNA replication, short generation times and the consequent extensive fixation of neutral or adaptive changes over short periods. While both the identities and sites of mutations are typically modelled as being random, recent investigations of sequence diversity of SARS coronavirus 2 (SARS-CoV-2) have identified a preponderance of C->U transitions, proposed to be driven by an APOBEC-like RNA editing process. The current study investigated whether this phenomenon could be observed in datasets of other RNA viruses. Using a 5% divergence filter to infer directionality, 18 from 36 datasets of aligned coding region sequences from a diverse range of mammalian RNA viruses (including Picornaviridae, Flaviviridae, Matonaviridae, Caliciviridae and Coronaviridae) showed a >2-fold base composition normalised excess of C->U transitions compared to U->C (range 2.1x-7.5x), with a consistently observed favoured 5' U upstream context. The presence of genome scale RNA secondary structure (GORS) was the only other genomic or structural parameter significantly associated with C->U/U->C transition asymmetries by multivariable analysis (ANOVA), potentially reflecting RNA structure dependence of sites targeted for C->U mutations. Using the association index metric, C->U changes were specifically over-represented at phylogenetically uninformative sites, potentially paralleling extensive homoplasy of this transition reported in SARS-CoV-2. Although mechanisms remain to be functionally characterised, excess C->U substitutions accounted for 11-14% of standing sequence variability of structured viruses and may therefore represent a potent driver of their sequence diversification and longer-term evolution.
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Subject code 612
    Language English
    Publishing date 2021-06-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: A systematic review of Hepatitis B virus (HBV) prevalence and genotypes in Kenya

    Louise O Downs / Cori Campbell / Paul Yonga / George Githinji / M Azim Ansari / Philippa C Matthews / Anthony O Etyang

    PLOS Global Public Health, Vol 3, Iss 1, p e

    Data to inform clinical care and health policy.

    2023  Volume 0001165

    Abstract: The aim of this systematic review and meta-analysis is to evaluate available prevalence and viral sequencing data representing chronic hepatitis B (CHB) infection in Kenya. More than 20% of the global disease burden from CHB is in Africa, however there ... ...

    Abstract The aim of this systematic review and meta-analysis is to evaluate available prevalence and viral sequencing data representing chronic hepatitis B (CHB) infection in Kenya. More than 20% of the global disease burden from CHB is in Africa, however there is minimal high quality seroprevalence data from individual countries and little viral sequencing data available to represent the continent. We undertook a systematic review of the prevalence and genetic data available for hepatitis B virus (HBV) in Kenya using the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) 2020 checklist. We identified 23 studies reporting HBV prevalence and 8 studies that included HBV genetic data published in English between January 2000 and December 2021. We assessed study quality using the Joanna Briggs Institute critical appraisal checklist. Due to study heterogeneity, we divided the studies to represent low, moderate, high and very high-risk for HBV infection, identifying 8, 7, 5 and 3 studies in these groups, respectively. We calculated pooled HBV prevalence within each group and evaluated available sequencing data. Pooled HBV prevalence was 3.4% (95% CI 2.7-4.2%), 6.1% (95% CI 5.1-7.4%), 6.2% (95% CI 4.64-8.2) and 29.2% (95% CI 12.2-55.1), respectively. Study quality was overall low; only three studies detailed sample size calculation and 17/23 studies were cross sectional. Eight studies included genetic information on HBV, with two undertaking whole genome sequencing. Genotype A accounted for 92% of infections. Other genotypes included genotype D (6%), D/E recombinants (1%) or mixed populations (1%). Drug resistance mutations were reported by two studies. There is an urgent need for more high quality seroprevalence and genetic data to represent HBV in Kenya to underpin improved HBV screening, treatment and prevention in order to support progress towards elimination targets.
    Keywords Public aspects of medicine ; RA1-1270
    Subject code 306
    Language English
    Publishing date 2023-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Risk of Reactivation of Hepatitis B Virus (HBV) and Tuberculosis (TB) and Complications of Hepatitis C Virus (HCV) Following Tocilizumab Therapy

    Cori Campbell / Monique I. Andersson / M. Azim Ansari / Olivia Moswela / Siraj A. Misbah / Paul Klenerman / Philippa C. Matthews

    Frontiers in Medicine, Vol

    A Systematic Review to Inform Risk Assessment in the COVID-19 Era

    2021  Volume 8

    Abstract: Objectives: Tocilizumab (TCZ), an IL-6 receptor antagonist, is used in the treatment of severe COVID-19 caused by infection with SARS-CoV-2. However, unintended consequences of TCZ therapy include reactivation of tuberculosis (TB) or hepatitis B virus ( ... ...

    Abstract Objectives: Tocilizumab (TCZ), an IL-6 receptor antagonist, is used in the treatment of severe COVID-19 caused by infection with SARS-CoV-2. However, unintended consequences of TCZ therapy include reactivation of tuberculosis (TB) or hepatitis B virus (HBV), and worsening of hepatitis C virus (HCV). We set out to assimilate existing data for these complications, in order to help inform evidence-based risk assessments for the use of TCZ, and thus to reduce the risk of serious but preventable complications.Methods: We searched the global WHO database of Individual Case Safety Reports (ICSRs) and adverse drug reactions (ADRs) (“VigiBase”) and undertook a systematic literature review, in accordance with PRISMA guidelines. We generated mean cumulative incidence estimates for infection complications.Results: Mean cumulative incidence of HBV and TB were 3.3 and 4.3%, respectively, in patients receiving TCZ. Insufficient data were available to generate estimates for HCV. These estimates derive from heterogeneous studies pre-dating SARS-CoV-2, with differing epidemiology and varied approaches to screening and prophylaxis, so formal meta-analysis was not possible.Conclusions: We underline the need for careful individual risk assessment prior to TCZ prescription, and present an algorithm to guide clinical stratification. There is an urgent need for ongoing collation of safety data as TCZ therapy is used in COVID.
    Keywords tocilizumab ; biologic ; SARS-CoV-2 ; COVID-19 ; infection ; reactivation ; Medicine (General) ; R5-920
    Subject code 610
    Language English
    Publishing date 2021-08-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Case Report

    Louise O. Downs / Anna L. McNaughton / Mariateresa de Cesare / M. Azim Ansari / Jacqueline Martin / Charles Woodrow / Rory Bowden / Jane Collier / Eleanor Barnes / Philippa C. Matthews

    Wellcome Open Research, Vol

    Application of hepatitis B virus (HBV) deep sequencing to distinguish between acute and chronic infection [version 2; peer review: 2 approved]

    2021  Volume 5

    Abstract: Deep sequencing of the full-length hepatitis B virus (HBV) genome provides the opportunity to determine the extent to which viral diversity, genotype, polymorphisms, insertions and deletions may influence presentation and outcomes of disease. Increasing ... ...

    Abstract Deep sequencing of the full-length hepatitis B virus (HBV) genome provides the opportunity to determine the extent to which viral diversity, genotype, polymorphisms, insertions and deletions may influence presentation and outcomes of disease. Increasing experience with analysis of HBV genomic data opens up the potential for using these data to inform insights into pathophysiology of infection and to underpin decision making in clinical practice. We here set out to undertake whole genome HBV sequencing from an adult who presented acutely unwell with a new diagnosis of HBV infection, and tested positive for both HBV anti-core IgM and IgG, possibly representing either acute hepatitis B infection (AHB) or chronic hepatitis B with an acute reactivation (CHB-AR). The distinction between these two scenarios may be important in predicting prognosis and underpinning treatment decisions, but can be challenging based on routine laboratory tests. Through application of deep whole-genome sequencing we typed the isolate as genotype-D1, and identified several minority variants including G1764A and G1986A substitutions in the pre-core promoter and pre-core regions, which support CHB-AR rather than AHB. In the longer term, enhanced deep sequencing data for HBV may provide improved evidence to distinguish between acute and chronic infection, to predict outcomes and to stratify treatment.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2021-01-01T00:00:00Z
    Publisher Wellcome
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Case Report

    Louise O. Downs / Anna L. McNaughton / Mariateresa de Cesare / M. Azim Ansari / Jacqueline Martin / Charles Woodrow / Rory Bowden / Jane Collier / Eleanor Barnes / Philippa C. Matthews

    Wellcome Open Research, Vol

    Application of hepatitis B virus (HBV) deep sequencing to distinguish between acute and chronic infection [version 1; peer review: 2 approved]

    2020  Volume 5

    Abstract: Deep sequencing of the full-length hepatitis B virus (HBV) genome provides the opportunity to determine the extent to which viral diversity, genotype, polymorphisms, insertions and deletions may influence presentation and outcomes of disease. Increasing ... ...

    Abstract Deep sequencing of the full-length hepatitis B virus (HBV) genome provides the opportunity to determine the extent to which viral diversity, genotype, polymorphisms, insertions and deletions may influence presentation and outcomes of disease. Increasing experience with analysis of HBV genomic data opens up the potential for using these data to inform insights into pathophysiology of infection and to underpin decision making in clinical practice. We here set out to undertake whole genome HBV sequencing from an adult who presented acutely unwell with a new diagnosis of HBV infection, and tested positive for both HBV anti-core IgM and IgG, possibly representing either acute hepatitis B infection (AHB) or chronic hepatitis B with an acute reactivation (CHB-AR). The distinction between these two scenarios may be important in predicting prognosis and underpinning treatment decisions, but can be challenging based on routine laboratory tests. Through application of deep whole-genome sequencing we typed the isolate as genotype-D1, and identified several minority variants including G1764A and G1986A substitutions in the pre-core promoter and pre-core regions, which support CHB-AR rather than AHB. In the longer term, enhanced deep sequencing data for HBV may provide improved evidence to distinguish between acute and chronic infection, to predict outcomes and to stratify treatment.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2020-10-01T00:00:00Z
    Publisher Wellcome
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: The Design and Development of a Multi-HBV Antigen Encoded in Chimpanzee Adenoviral and Modified Vaccinia Ankara Viral Vectors; A Novel Therapeutic Vaccine Strategy against HBV

    Senthil K. Chinnakannan / Tamsin N. Cargill / Timothy A. Donnison / M. Azim Ansari / Sarah Sebastian / Lian Ni Lee / Claire Hutchings / Paul Klenerman / Mala K. Maini / Tom Evans / Eleanor Barnes

    Vaccines, Vol 8, Iss 184, p

    2020  Volume 184

    Abstract: Chronic hepatitis B virus (HBV) infection affects 257 million people globally. Current therapies suppress HBV but viral rebound occurs on cessation of therapy; novel therapeutic strategies are urgently required. To develop a therapeutic HBV vaccine that ... ...

    Abstract Chronic hepatitis B virus (HBV) infection affects 257 million people globally. Current therapies suppress HBV but viral rebound occurs on cessation of therapy; novel therapeutic strategies are urgently required. To develop a therapeutic HBV vaccine that can induce high magnitude T cells to all major HBV antigens, we have developed a novel HBV vaccine using chimpanzee adenovirus (ChAd) and modified vaccinia Ankara (MVA) viral vectors encoding multiple HBV antigens. ChAd vaccine alone generated very high magnitude HBV specific T cell responses to all HBV major antigens. The inclusion of a shark Invariant (SIi) chain genetic adjuvant significantly enhanced the magnitude of T-cells against HBV antigens. Compared to ChAd alone vaccination, ChAd-prime followed by MVA-boost vaccination further enhanced the magnitude and breadth of the vaccine induced T cell response. Intra-cellular cytokine staining study showed that HBV specific CD8+ and CD4+ T cells were polyfunctional, producing combinations of IFNγ, TNF-α, and IL-2. In summary, we have generated genetically adjuvanted ChAd and MVA vectored HBV vaccines with the potential to induce high-magnitude T cell responses through a prime-boost therapeutic vaccination approach. These pre-clinical studies pave the way for new studies of HBV therapeutic vaccination in humans with chronic hepatitis B infection.
    Keywords Hepatitis B virus (HBV) ; therapeutic HBV vaccine ; T cell vaccine ; chimpanzee adenovirus ; ChAd ; ChAdOx1 ; Medicine ; R
    Subject code 570 ; 610
    Language English
    Publishing date 2020-04-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Viral genome wide association study identifies novel hepatitis C virus polymorphisms associated with sofosbuvir treatment failure

    David A. Smith / Carlota Fernandez-Antunez / Andrea Magri / Rory Bowden / Nimisha Chaturvedi / Jacques Fellay / John McLauchlan / Graham R. Foster / William L. Irving / STOP-HCV Consortium / Peter Simmonds / Vincent Pedergnana / Santseharay Ramirez / Jens Bukh / Eleanor Barnes / M. Azim Ansari

    Nature Communications, Vol 12, Iss 1, Pp 1-

    2021  Volume 11

    Abstract: Sofosbuvir is a common therapy in hepatitis C virus infection, which targets the NS5B polymerase. Here, Smith et al. analyze the association between whole genome HCV polymorphisms and sofosbuvir treatment failure and identify three common polymorphisms ... ...

    Abstract Sofosbuvir is a common therapy in hepatitis C virus infection, which targets the NS5B polymerase. Here, Smith et al. analyze the association between whole genome HCV polymorphisms and sofosbuvir treatment failure and identify three common polymorphisms present in non-targeted NS2 and NS3 proteins associated with reduced treatment response.
    Keywords Science ; Q
    Language English
    Publishing date 2021-10-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Efficacy of ultra-short, response-guided sofosbuvir and daclatasvir therapy for hepatitis C in a single-arm mechanistic pilot study

    Barnaby Flower / Le Manh Hung / Leanne Mccabe / M Azim Ansari / Chau Le Ngoc / Thu Vo Thi / Hang Vu Thi Kim / Phuong Nguyen Thi Ngoc / Le Thanh Phuong / Vo Minh Quang / Thuan Dang Trong / Thao Le Thi / Tran Nguyen Bao / Cherry Kingsley / David Smith / Richard M Hoglund / Joel Tarning / Evelyne Kestelyn / Sarah L Pett /
    Rogier van Doorn / Jennifer Ilo Van Nuil / Hugo Turner / Guy E Thwaites / Eleanor Barnes / Motiur Rahman / Ann Sarah Walker / Jeremy N Day / Nguyen VV Chau / Graham S Cooke

    eLife, Vol

    2023  Volume 12

    Abstract: Background: World Health Organization has called for research into predictive factors for selecting persons who could be successfully treated with shorter durations of direct-acting antiviral (DAA) therapy for hepatitis C. We evaluated early virological ... ...

    Abstract Background: World Health Organization has called for research into predictive factors for selecting persons who could be successfully treated with shorter durations of direct-acting antiviral (DAA) therapy for hepatitis C. We evaluated early virological response as a means of shortening treatment and explored host, viral and pharmacokinetic contributors to treatment outcome. Methods: Duration of sofosbuvir and daclatasvir (SOF/DCV) was determined according to day 2 (D2) virologic response for HCV genotype (gt) 1- or 6-infected adults in Vietnam with mild liver disease. Participants received 4- or 8-week treatment according to whether D2 HCV RNA was above or below 500 IU/ml (standard duration is 12 weeks). Primary endpoint was sustained virological response (SVR12). Those failing therapy were retreated with 12 weeks SOF/DCV. Host IFNL4 genotype and viral sequencing was performed at baseline, with repeat viral sequencing if virological rebound was observed. Levels of SOF, its inactive metabolite GS-331007 and DCV were measured on days 0 and 28. Results: Of 52 adults enrolled, 34 received 4 weeks SOF/DCV, 17 got 8 weeks and 1 withdrew. SVR12 was achieved in 21/34 (62%) treated for 4 weeks, and 17/17 (100%) treated for 8 weeks. Overall, 38/51 (75%) were cured with first-line treatment (mean duration 37 days). Despite a high prevalence of putative NS5A-inhibitor resistance-associated substitutions (RASs), all first-line treatment failures cured after retreatment (13/13). We found no evidence treatment failure was associated with host IFNL4 genotype, viral subtype, baseline RAS, SOF or DCV levels. Conclusions: Shortened SOF/DCV therapy, with retreatment if needed, reduces DAA use in patients with mild liver disease, while maintaining high cure rates. D2 virologic response alone does not adequately predict SVR12 with 4-week treatment. Funding: Funded by the Medical Research Council (Grant MR/P025064/1) and The Global Challenges Research 70 Fund (Wellcome Trust Grant 206/296/Z/17/Z).
    Keywords Hepatitis C ; genotype 6 ; response guided therapy ; sofosbuvir ; daclatasvir ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2023-01-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Distinct patterns of within-host virus populations between two subgroups of human respiratory syncytial virus

    Gu-Lung Lin / Simon B. Drysdale / Matthew D. Snape / Daniel O’Connor / Anthony Brown / George MacIntyre-Cockett / Esther Mellado-Gomez / Mariateresa de Cesare / David Bonsall / M. Azim Ansari / Deniz Öner / Jeroen Aerssens / Christopher Butler / Louis Bont / Peter Openshaw / Federico Martinón-Torres / Harish Nair / Rory Bowden / RESCEU Investigators /
    Tanya Golubchik / Andrew J. Pollard

    Nature Communications, Vol 12, Iss 1, Pp 1-

    2021  Volume 11

    Abstract: Respiratory syncytial virus (RSV) is a common infection in children and older adults but little is known about within-host viral population diversity. Here, the authors perform deep sequencing and find that RSV subgroup B exhibited more diversity than ... ...

    Abstract Respiratory syncytial virus (RSV) is a common infection in children and older adults but little is known about within-host viral population diversity. Here, the authors perform deep sequencing and find that RSV subgroup B exhibited more diversity than subgroup A, with implications for development of therapeutics and vaccines.
    Keywords Science ; Q
    Language English
    Publishing date 2021-08-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Publisher Correction

    Gu-Lung Lin / Simon B. Drysdale / Matthew D. Snape / Daniel O’Connor / Anthony Brown / George MacIntyre-Cockett / Esther Mellado-Gomez / Mariateresa de Cesare / David Bonsall / M. Azim Ansari / Deniz Öner / Jeroen Aerssens / Christopher Butler / Louis Bont / Peter Openshaw / Federico Martinón-Torres / Harish Nair / Rory Bowden / RESCEU Investigators /
    Tanya Golubchik / Andrew J. Pollard

    Nature Communications, Vol 12, Iss 1, Pp 1-

    Distinct patterns of within-host virus populations between two subgroups of human respiratory syncytial virus

    2021  Volume 1

    Keywords Science ; Q
    Language English
    Publishing date 2021-10-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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