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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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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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Article ; Online: Comprehensive Comparative Analysis of Standard Validated, Genetic, and Novel Biomarkers to Enhance Prognostic Risk-Stratification in Patients With Hepatitis C Virus Cirrhosis.

Innes, Hamish / Walker, Alex J / Benselin, Jennifer / Grove, Jane I / Pedergnana, Vincent / Azim Ansari, M / Lin, Shang-Kuan / McLauchlan, John / Hutchinson, Sharon J / Barnes, Eleanor / Irving, William L / Guha, Indra Neil

Clinical and translational gastroenterology

2022 Volume 13, Issue 3, Page(s) e00462

Abstract: Introduction: Risk-stratifying patients with hepatitis C virus (HCV) cirrhosis according to medium-term prognosis will inform clinical decision-making. It is unclear which biomarkers/models are optimal for this purpose. We quantified the discriminative ... ...

Abstract	Introduction: Risk-stratifying patients with hepatitis C virus (HCV) cirrhosis according to medium-term prognosis will inform clinical decision-making. It is unclear which biomarkers/models are optimal for this purpose. We quantified the discriminative ability of 14 diverse biomarkers for prognosis prediction over a 4-year time. Methods: We recruited 1196 patients with HCV cirrhosis from the United Kingdom for a prospective study. Genetic risk score, collagen (e.g., PROC3), comorbidity (e.g., CirCom), and validated biomarkers from routine data were measured at enrollment. Participants were linked to UK hospital admission, cancer, and mortality registries. Primary endpoints were (i) liver-related outcomes for patients with compensated cirrhosis and (ii) all-cause mortality for decompensated cirrhosis. The discriminative ability of all biomarkers was quantified individually and also by the fraction of new prognostic information provided. Results: At enrollment, 289 (24%) and 907 (76%) had decompensated and compensated cirrhosis, respectively. Participants were followed for 3-4 years on average, with >70% of the follow-up time occurring post-HCV cure. Seventy-five deaths in the decompensated subgroup and 98 liver-related outcomes in the compensated subgroup were reported. The discriminative ability of the albumin-bilirubin-fibrosis-4 index (C-index: 0.71-0.72) was superior to collagen biomarkers (C-index = 0.58-0.67), genetic risk scores (C-index = 0.50-0.57), and comorbidity markers (0.53-0.60). Validated biomarkers showed the greatest prognostic improvement when combined with a comorbidity or a collagen biomarker (generally >30% of new prognostic information added). Discussion: Inexpensive biomarkers such as the albumin-bilirubin-fibrosis-4 index predict medium-term cirrhosis prognosis moderately well and outperform collagen, genetic, and comorbidity biomarkers. Improvement of performance was greatest when a validated test was combined with comorbidity or collagen biomarker.
MeSH term(s)	Biomarkers ; Hepacivirus/genetics ; Hepatitis C ; Humans ; Liver Cirrhosis/diagnosis ; Liver Cirrhosis/genetics ; Prognosis ; Prospective Studies
Chemical Substances	Biomarkers
Language	English
Publishing date	2022-02-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2581516-7
ISSN	2155-384X ; 2155-384X
ISSN (online)	2155-384X
ISSN	2155-384X
DOI	10.14309/ctg.0000000000000462
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Comparative Computational Studies on Selective CytochromeP450 1B1 Inhibitors

Mohd Usman Mohd Siddique / Azim Ansari / Barij Nayan Sinha / Venkatesan Jayaprakash

International Journal Bioautomation, Vol 24, Iss 3, Pp 213-

2020 Volume 224

Abstract: Selective inhibitors of CYP isoforms gaining importance in the treatment of cancers caused by hormonal imbalance. Metabolites of estradiol and polyaromatic hydrocarbons generated due to CYP1B1 activity were reported to be oncogenic. The selective CYP1B1 ... ...

Abstract	Selective inhibitors of CYP isoforms gaining importance in the treatment of cancers caused by hormonal imbalance. Metabolites of estradiol and polyaromatic hydrocarbons generated due to CYP1B1 activity were reported to be oncogenic. The selective CYP1B1 inhibitors could have the potential therapeutic utility in controlling the cancer due to these oncogens. Due to the CYP isoforms high sequence similarity the design of selective CYP inhibitor is difficult. Recently our group has reported two novel chemical classes (scaffolds) that are specific towards CYP1B1. The chemical architecture of these compounds should give valuable information for its selectivity and potency against CYP1B1. Overlay of our compounds and ANF by Shape and electrostatic based similarity and molecular docking displayed different orientations. Moreover the study has shown the overlay of three atom bridge of selective inhibitor superimposed on -O-CH- linking aryl groups rather than -CO-CH=CH- of ANF. Molecular docking simulation revealed that the selective inhibitors are either establishing H-bonding interaction with Asp333 or π-π staking interaction Phe231 and Phe268. Molecular docking simulation has provided much more information rather than simple shape and electrostatic based similarity study. Crucial H-bonding interactions and π-π staking interactions responsible for selectivity towards CYP1B1 were identified. Two atom linker between the aryl groups matter, cyclization simply ensures the planarity of ANF and quinazolines.
Keywords	cyp1b1 ; selective inhibitors ; similarity search ; docking ; druggability ; adme ; Biology (General) ; QH301-705.5
Subject code	540
Language	English
Publishing date	2020-09-01T00:00:00Z
Publisher	Bulgarian Academy of Sciences
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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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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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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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 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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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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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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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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