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The following are publications describing outputs from the STOP-HCV programme and work that has been done in collaboration with the consortium.

2020

Impact of virus subtype and host IFNL4 genotype on large-scale RNA structure formation in the genome of hepatitis C virus. Simmonds P, Kuypers L, Irving WL, McLauchlan J, Cooke GS, Barnes E, Ansari MA. August 2020. RNA. DOI: 10.1261/rna.075465.120. PMID: 32747607.

Efficacy of NS5A inhibitors against unusual and potentially difficult-to-treat HCV subtypes. Nguyen D, Smith D, Vaughan-Jackson A, Magri A, Barnes E, Simmonds, STOP-HCV Consortium. Journal of Hepatology, 26thMay 2020. DOI.org/10.1016/j.jhep.2020.05.029. PMID: 32470499.

Consensus recommendations for resistance testing in the management of chronic hepatitis C virus infection: Public Health England HCV Resistance Group. Bradshaw D, Mbisa JL, Geretti AM, Healy BJ, Cooke GS, Foster GR, Thomson EC, McLauchlan J, Agarwal K, Sabin C, Mutimer D, Moss P, Irving WL, Barnes E, Hepatitis C Trust, UK. J Infect. 2019 Dec;79(6):503-512. doi: 10.1016/j.jinf.2019.10.007. PMID: 31629015

2019

Validation of a Model for Identification of Patients With Compensated Cirrhosis at High Risk of Decompensation. Guha IN Harris R, Berhane S, Dillon A, Coffey L, James MW, Cucchetti A, Harman DJ, Aithal GP, Elshaarawy O, Waked I, Stewart S, Johnson PJ. Clinical Gastroenterology Hepatology. 1 February 2019.
Layman summary: We combined data from the ALBI and FIB-4 scoring systems to develop a system to identify patients with compensated cirrhosis (i.e. severe liver scarring but no symptoms) at highest risk for decompensation ( i.e. symptoms of liver failure including fluid, bleeding and confusion).Using a combination of ALBI and FIB-4 scores, we developed and validated a model that identified patients at low vs high risk of decompensation. Implications for patient care - we validated the scoring system in 2 independent international cohorts (Europe and the Middle East), so it might be used worldwide in determining the prognoses of patients with cirrhosis.

Interferon lambda 4 impacts the genetic diversity of hepatitis C virus. Ansari MA, Aranday-Cortes E, Ip CLC, da Silva Filipe A, Hin LS, Bamford CGG, Bonsall D, Trebes A, Piazza P, Sreenu V, Cowton VM, STOP-HCV Consortium, Hudson E, Bowden R, Klenerman K, Patel AH, Foster GR, Irving WL, Agarwal K, Simmonds P, Thomson E, Holmes C, Barnes E, Spencer CCA, McLauchlan J, Pedergnana V. Elife. 3 September 2019.

Impact of IFNL4 genetic variants on sustained virologic response and vireamia in hepatitis C virus genotype 3 patients. Pedergnana V, Irving WL, Barnes E, McLauchlan J, Spencer CCA. J Interferon Cytokine Res. 2019 Jul 1. Doi: 10.1089/jir.2019.0013

A Cost-Effectiveness Analysis of Shortened Direct-Acting Antiviral Treatment in Genotype 1 Noncirrhotic Treatment-Naive Patients With Chronic Hepatitis C Virus. Fawsitt CG, Vickerman P, Cooke G, Welton NJ, STOP-HCV Consortium. Value Health. June 2019.
Layman summary: The cost effectiveness of direct-acting antiviral treatment for chronic hepatitis C virus has been well documented, although the cost of treatment is considerable. Shortened treatment durations have been proposed to reduce costs, albeit at the expense of potentially curing fewer patients. Shortening treatment duration from 12 to 8 weeks using direct-acting antiviral therapy is cost-effective for treatment of mild chronic hepatitis C virus in genotype 1 noncirrhotic treatment-naive patients, provided a re-treatment strategy is adopted for patients who fail first-line treatment. There was considerable uncertainty in the cost-effectiveness estimates for the 6- and 4-week shortened treatments, with some indication that the 6-week treatment may be cost-effective, but the 4-week treatment may not.

Amino Acid Substitutions in Genotype 3a Hepatitis C Virus Polymerase Protein Affect Responses to Sofosbuvir. Wing Peter, Jones M, Cheung M, DaSilva S, Bamford C, Jason Lee WY, Aranday-Cortes E, Da Silva Filipe A, McLauchlan J, Smith D, Irving W, Cunningham M, Ansari A, Barnes E, Foster GR. Gastroenterology. 9 May 2019.
Layman summary: Sofosbuvir is a pan-genotype inhibitor of the hepatitis C virus (HCV) polymerase and eliminates most chronic HCV infections. However, HCV genotype 3 responds less well to sofosbuvir-based therapies than other genotypes. We identified a mutation in the HCV genotype 3 viral polymerase that combined with other variants reduces response to Sofosbuvir. Clinically, infection with HCV genotype 3 containing this variant reduces the likelihood of achieving a sustained virological response.

Interpreting Viral Deep Sequencing Data with GLUE. Singer JB, Thomson EC, Hughes J, Aranday-Cortes E, McLauchlan J, da Silva Filipe A, Tong L, Manso CF, Gifford RJ, Robertson DL, Barnes E, Ansari MA, Mbisa JL, Bibby DF, Bradshaw D, Smith D. Viruses. 3 April .
Layman summary: Computer methods can be used to analyse a hepatitis C virus infection for drug resistance. We analysed the virus in patients who had been given drugs but where this treatment did not clear the virus; these patients often have a virus with significant resistance. Within any infected patient, there is a population of slightly different viruses. We found that in a small number of cases, the computer method which carefully accounted for the variation in the virus population was able to identify drug resistance better than a more simplistic method.

2018

Characterization of hepatitis C virus resistance to grazoprevir reveals complex patterns of mutations following on-treatment breakthrough that are not observed at relapse. Bonsall D, Black S, Howe AYM, Chase R, Ingravallo P, Pak I, Brown A, Smith D, Bowden R, Barnes E, and the STOP HCV Consortium. Infection and Drug Resistance, 2018 Aug 8

Evidence of CD4+ T cell-mediated immune pressure on the Hepatitis C virus genome. Lucas M, Deshpande P, James I, Rauch A, Pfafferott K, Gaylard E, Shahzma Merani S, Plauzolles A, Lucas A, McDonnell W, Kalams S, Pilkinton M, Chastain C, Barnett L, Prosser A, Mallal S, Fitzmaurice K, Drummer H, Ansari A, Pedergnana V, Barnes E, John M, Kelleher D, Klenerman P, Gaudieri S. ‘Evidence of CD4+ T cell-mediated immune pressure on the Hepatitis C virus genome’ Sci Rep. 8 May 2018.
Layman summary: We studied the virus in patients and tried to relate how the virus changes in relation to the immune response. This gives some indication of how “strong” the immune response is. This study showed that the “helper” T cell response provides important pressure on the virus and is useful evidence in designing vaccines against HCV.

Impact of IFNL4 genotype on Interferon-stimulated Gene Expression during DAA therapy for Hepatitis C. Ramamurthy N, Marchi E, Ansar MA, Pedergnana V, Mclean A, Hudson E, STOP HCV consortium, Bowden R, Spencer CCA, Barnes E, Klenerman P. Hepatology. 13 March 2018.
Layman summary: This study looked at what happened to the immune response in patients who receive oral antiviral treatments for HCV in the BOSON study. We saw that patients with a so-called “favourable” interferon genotype i.e their DNA produces a particular type of interferon (called lambda 3), had a better clearance of virus with the medication (sofosbuvir and ribavirin). This was accompanied by a “boost” in their immune response during therapy. We concluded that this boost in immunity was important in helping clear the last few viruses from the liver.

Resistance analysis of genotype 3 HCV reveals subtypes inherently resistant to NS5A inhibitors. Smith D, Magri A, Bonsall D, Ip C, Trebes A, Brown A, Piazza P, Bowden R, STOP-HCV Consortium, Ansari MA, Simmonds P, Barnes E. Hepatology. February 2018.
Layman summary: In this work we sequenced the Hepatitis C Virus (HCV) from 496 patients infected with genotype 3 HCV. We detected resistance to an antiviral drug called daclatasvir in 22% of the viral sequences. We also identified a pattern of resistance in the less common genotype 3b and genotype 3g viruses, which we tested in a cell culture model this showed they were not only highly resistant to daclatasvir but also all other approved drugs in the same class (NS5A Inhibitors). This work suggests that these less common subtypes are inherently resistant to this class of drugs.

Host genetic factors associated with hepatocellular carcinoma: a systematic review. Walker AJ, Peacock C, Pedergnana V, STOP-HCV Consortium, Irving WL. Journal of Viral Hepatatis. 3 February 2018.
Layman summary: Hepatitis C virus (HCV)-infected patients are at risk of developing hepatocellular carcinoma (HCC). There are a large number of studies which have investigated whether the genetic make-up of infected individuals may contribute to the risk of HCC development. The rationale for these studies is that if it was possible to identify individuals at higher risk of HCC development because of their genetic make-up, then it would be possible to institute enhanced surveillance for HCC in those patients, resulting in earlier diagnosis and better outcomes. This review article summarises the published evidence on this subject.

2017

PHYLOSCANNER: Analysing Within- and Between-Host Pathogen Genetic Diversity to Identify Transmission, Multiple Infection, Recombination and Contamination. Wymant C, Hall M, Ratmann O, Bonsall D, Golubchik T, Cesare M, Gall A, Cornelissen M, Fraser C, The Stop-HCV Consortium, The Maela Pneumococcal Collaboration, and The BEEHIVE Collaboration. Infection and Drug Resistance. Mol Biol Evol. 2017 Nov 23.

STOP-HCV - Stratified Medicine to Optimise Treatment for Hepatitis C Virus Infection. Barnes E and Hudson E. Impact, 6: 81-83(3)

A genome-to-genome analysis shows the impact of the innate and adaptive immune system on the hepatitis C virus. Ansari MA, Pedergnana V, Ip C, Magri A, von Delft A, Bonsall D, Chaturvedi N, Bartha I, Smith D, McVean G, Trebes A, Piazza P, Fellay J, Cooke G, Foster G, STOP-HCV Consortium, Hudson E, McLauchlan J, Simmonds P, Bowden R, Klenerman P, Barnes E, Spencer CA. Nature Genetics. 49: 666–673. 2017.

HCV has to escape the immune system to be able to chronically infect humans. In this study we showed that an individuals HLA genes alleles drive changes in the virus genetic material. These changes in the HCV genetics allows it to escape the immune system and carry on replicating. We also showed that individuals who carry different versions of interferon lambda 4 gene carry HCV that are different genetically.

2016

Comparison of next generation sequencing technologies for the comprehensive assessment of full-length hepatitis C viral genomes. Thomson E, Ip C, Badhan A, Christiansen M, Adamson W, Ansari MA, Bibby D, Bonsall D, Bowden R, Breuer J, Brown A, Da Silva Filipe A, Hinds C, Hudson E, Klenerman P, Lythgow K, Mbisa J, McLauchlan J, Myers R, Piazza P, Trebes A, Vattipally S, Witteveldt J, STOP-HCV Consortium, Simmonds P, Barnes E. Journal of Clinical Microbiology 54 (10): 2470-84. 2016.

MAIT cells are activated during human viral infections. van Wilgenburg B, Scherwitzl I, Hutchinson E, Ramamurthy N, de Lara C, Kurioka A, Leng T, Kulicke C, Cole S, Vasanawathana S, Limpitikul W, Malasit P, Young D, Denney L, STOP-HCV Consortium, Fabris P, Giordani MT, Oo YH, Ho L-P, Thompson F, Mongkolsapaya J, Willberg C, Screaton G, Klenerman P. Nature Communications 23 (7):11653. 2016.
Layman summary: This study looked at a newly described cell - the MAIT cell - which is highly abundant in the liver. We showed that these cells can be activated by different virus infections - including HCV. Once activated the cells can release interferon (a small antiviral chemical messenger) and this can suppress HCV growth in a test tube. We think this shows that MAIT cells are an important part of the immune response against HCV.

Evaluation of Viremia Frequencies of a Novel Human Pegivirus by Using Bioinformatic Screening and PCR. Bonsall D Gregory WF, Ip CL, Donfield S, Iles J, Ansari MA, Piazza P, Trebes A, Brown A, Frater J, Pybus OG, Goulder P, Klenerman P, Bowden R, Gomperts ED, Barnes E, Kapoor A, Sharp CP, Simmonds P. Emerging Infectious Diseases. 22(4): 671-678. 2016.

Enhancement of the Replication of Hepatitis C Virus Replicons of Genotypes 1 to 4 by Manipulation of CpG and UpA Dinucleotide Frequencies and Use of Cell Lines Expressing SECL14L2 for Antiviral Resistance Testing Witteveldt J, Martin-Gans M, Simmonds P. Antimicrobial Agents & Chemotherapy 60 (5): 2981-92. 2016.

Interferon Lambda 4 variant rs12979860 is not associated with RAV NS5A Y93H in Hepatitis C Virus Genotype 3a. Pedergnana V Smith D, STOP-HCV Consortium, Klenerman P, Barnes E, Spencer C, Ansari MA. Hepatology. 64 (4):1377-8. 2016.
Layman summary: Viruses can be resistant to certain drugs and this can be determined using their genetic material. Additionally a mutation in a human gene (Interferon Lambda 4) is shown to be associated with HCV genetic diversity. A previous study had shown that a specific mutation in HCV genotype 1 (NS5A Y93H) which resulted in resistance to certain DAAs, was also associated with the mutation in the human gene (Interferon Lambda 4) in HCV genotype 1. In this paper we used our data to show that the in HCV genotype 3 the specific mutation in the HCV (NS5A Y93H), was not associated with the mutation in the human gene (Interferon Lambda 4).

Prioritization of HCV treatment in the direct-acting antiviral era: An economic evaluation. Martin N Vickerman P, Dore G, Grebley J, Miners A, Cairns J, Foster GR, Hutchinson SJ, Goldberg DJ, Martin TCS, Ramsay M, STOP-HCV Consortium, Hickman M. Journal of Hepatology. 65(1):17-25. 2016.
Layman summary: HCV treatment used to be prioritised for those with more advanced liver disease. Using an economic model we showed that in the UK and many other sites elsewhere early treatment of people who inject drugs (PWID) at a mild or moderate stage is highly cost-effective and should be prioritised. Delaying treatment for PWID with mild disease fails to account for the prevention benefits of treatment. The exception is sites with very high prevalence and incidence of HCV in PWID where the benefits of early treatment may be reduced because of high rates of reinfection.

2015

ve-SEQ: Robust, unbiased enrichment for streamlined detection and whole-genome sequencing of HCV and other highly diverse pathogens Bonsall D, Ansari M, Ip C, Trebes A, Brown A, Klenerman P, Buck D, Piazza P, Barnes E, Bowden R. F1000Research 4:1062. 2015.

Efficacy of sofosbuvir plus ribavirin with or without peginterferon-alfa in patients with hepatitis C virus genotype 3 infection and treatment-experienced patients with cirrhosis and hepatitis C virus genotype 2 infection

Foster GR Pianko S, Brown A, Forton D, Nahass RG, George J, Barnes E, Brainard DM, Massetto B, Lin M, Han B, McHutchison JG, Subramanian GM, Cooper C, Agarwal K; BOSON Study Group. Gastroenterology 149(6): 1462-70. 2015

Publications associated with work from the STOP-HCV Consortium:

The harmonic mean p-value for combining dependent tests. Wilson D. Proceedings of the National Academy of Science USA. 22;116(4):1195-1200. January 2019.
Layman summary: The widespread use of Bonferroni correction encumbers the scientific process and wastes opportunities for discovery presented by big data, because it discourages exploratory analyses by overpenalizing the total number of statistical tests performed. In this paper, I introduce the harmonic mean p-value (HMP), a simple to use and widely applicable alternative to Bonferroni correction motivated by Bayesian model averaging that greatly improves statistical power while maintaining control of the gold standard false positive rate. The HMP has a range of desirable properties and offers a different way to think about large-scale exploratory data analysis in classical statistics.

Hepatitis virus (HCV) diagnosis and access to treatment in a UK cohort. Adland E, Jesuthasan G, Downs L, Wharton V, Wilde G, McNaughton AL, Collier J, Barnes E, Klenerman P, Andersson M, Jeffery K, Matthews PC. BMC Infectious Diseases. 14;18(1):461. September 2018.
Layman summary: In this study, we looked at the different laboratory tests that can be used to diagnose infection with hepatitis C virus (HCV), and found that testing for one of the viral proteins ('antigens') in blood is a reliable way to make the diagnosis, and performs much better than older tests which detected just the presence of an antibody. We then studied our local patient population with HCV infection, demonstrating that those who had received treatment had a high rate of successful cure, but also highlighting the need to make treatment accessible to a wider number of patients.

Pretreatment Lesions on Magnetic Resonance Imaging inPatients With Hepatitis C Virus Infection Diagnosed With Hepatocellular Carcinoma After Initiating Direct-Acting Antiviral Therapy. Scott RA, Aithal GP, Francis ST, Irving WL. Gastroenterology. 154 (6) : 1848 - 1850. May 2018.
Layman summary:
In this short letter, we report findings from 7 HCV-infected patients with advanced liver disease who were treated with directly acting antiviral agents (DAAs) and who were diagnosed with liver cancer (HCC) some time after starting their DAA therapy. These patients underwent specialised imaging of their livers using MRI scans before they started their DAAs as part of a broader study looking at the effects of HCV cure on liver structure. On review of their pretreatment MRI scans using a different analytical process, it was possible to identify lesions in all 7 patients occurring in the same anatomical region where the HCC was subsequently diagnosed, strongly suggesting that these patients already had HCC before they started their DAA therapy.

Response to DAA Therapy in the NHS England Early Access Programme for Rare HCV Subtypes from Low and Middle Income Countries. Filipe A, Sreenu V, Hughes J, Aranday-Cortes e, Irving WL, Foster GR, Agarwal K, Rosenberg W, McDonald D, Richardson P, Aldersley MA, Wiselka M, Ustianowski A, McLauchlan J, Thomson E. Journal of Hepatolpgy. 67(6):1348-1350. December 2017.
Layman summary: In this study, we examined the genetic makeup of the hepatitis C virus in patients who had advanced liver disease and who were not cured after treatment for hepatitis C (with the direct-acting antiviral medicines sofosbuvir and ledipasvir or sofosbuvir and daclatasvir). We found a high rate of treatment failure in people who were infected with types of hepatitis C that are rare in Europe but common in Africa. In particular, genotype 4r and 1l viruses were difficult to treat. Subsequently, a low treatment response rate has been found in the same subtypes in other studies in the UK, France and in a large study in Rwanda (the SHARED study).

Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis. Cheung MC Walker AJ, Hudson BE, Verma S, McLauchlan J, Mutimer DJ, Brown A, Gelson WT, MacDonald DC, Agarwal K, Foster GR, Irving WL, HCV Research UK. Journal of Hepatology. 65 (4): 741-7. October 2016.
Layman summary: Our previous study showed that it is possible to cure most patients with very advanced HCV-related liver disease (decompensated cirrhosis) of their HCV infection by treatment with directly acting antiviral agents. This study examined the effect of HCV cure in these patients a year following treatment, in terms of deaths, cancers and other complications of advanced liver disease. We conclude that successful anti-HCV treatment improves the short-to-mid-term patient outcomes even in advanced liver disease.

Prevalence and burden of HCV co-infection in people living with HIV: a global systematic review and meta-analysis. Platt L, Easterbrook P, Gower E, McDonald B, Sabin K, McGowan C, Yanny I, Razavi H, Vickerman P. Lancet Infectious Diseases. 16(7): 797-80. July 2016.

Impact of direct acting antiviral therapy in patients with chronic hepatitis C and decompensated cirrhosis. Foster GR Irving WL, Cheung MC, Walker AJ, Hudson BE, Verma S, McLauchlan J, Mutimer DJ, Brown A, Gelson WT, MacDonald DC, Agarwal K; HCV Research, UK. Journal of Hepatology. 64 (6): 1224-31. June 2016.
Layman summary: In this study, we assessed the ability of the new all oral directly acting antiviral agents (DAAs) to cure HCV infection in patients with advanced liver disease. The trial results were extremely encouraging – over 80% of the 467 treated patients were cured, more so if the infection was with genotype 1 HCV (90.5%) rather than genotype 3 (68.8%). This was one of the first demonstrations of the utility of DAAs in this particular type of patient with immediately life-threatening liver disease (known as decompensated liver cirrhosis).

Characterization of Hepatitis C Virus Recombination in Cameroon by Use of Nonspecific Next-Generation Sequencing. Iles JC, Njouom R, Foupouapouognigni Y, Bonsall D, Bowden R, Trebes A, Piazza P, Barnes E, Pépin J, Klenerman P, Pybus OG. Journal of Clinical Microbiology. 53 (10):3155-6. October 2015.

Minimum target prices for production of direct-acting antivirals and associated diagnostics to combat hepatitis C virus. van de Ven N Fortunak J, Simmons B, Ford N, Cooke GS, Khoo S, Hill A. Hepatology. 61(4):1174-82. April 2015.

Screening and treatment for hepatitis C: a balanced perspective. Matthews PC, Jeffery K, Klenerman P, Barnes E, Cooke G. British Medical Journal. 24;350. February 2015.

Global distribution and prevalence of hepatitis C virus genotypes. Messina JP Humphreys I, Flaxman A, Brown A, Cooke GS, Pybus OG, Barnes E. Hepatology. 61(1):77-87. January 2015.
Layman summary: HCV exists throughout the world as distinct viral genotypes (different strains). We analysed over 1000 previously published papers to properly document which HCV genotypes are found in which countries. This data is urgently needed to guide national health strategies in the treatment of HCV. This paper has been very highly cited and used by other researchers since publication.