Agarwal, Kosh

Aldersley, Mark A.

Aranday-Cortes, Elihu

da Silva Filipe, Ana

Foster, Graham R.

Hughes, Joseph

Irving, William L

Macdonald, Douglas

McLauchlan, John

Richardson, Paul

Rosenberg, William

Sreenu, Vattipally

Thomson, Emma C.

Ustianowski, Andrew

Wiselka, Martin

English

Ana da Silva Filipe

Vattipally Sreenu

Joseph Hughes

Elihu Aranday-Cortes

William L. Irving

Graham R. Foster

Kosh Agarwal

William Rosenberg

Douglas Macdonald

Paul Richardson

Mark A. Aldersley

Martin Wiselka

Andrew Ustianowski

John McLauchlan

Emma C. Thomson

Crossref

Journal of Hepatology

Reply to: “Reply to: ‘Response to DAA therapy in the NHS England Early Access Programme for rare HCV subtypes from low and middle income countries’”

da Silva Filipe, A

Sreenu, V

Hughes, J

Aranday-Cortes, E

Irving, WL

Foster, GR

Agarwal, K

Rosenberg, W

Macdonald, D

Richardson, P

Aldersley, MA

Wiselka, M

Ustianowski, A

McLauchlan, J

Thomson, EC

Queen Mary Research Online

Reply to: "Reply to: 'Response to DAA therapy in the NHS England Early Access Programme for rare HCV subtypes from low and middle income countries'".

Irving, William L.

Enlighten: Publications

Reply to: "Reply to: 'Response to DAA therapy in the NHS England Early Access Programme for rare HCV subtypes from low  and middle income countries'"

King's Research Portal

                       King’s Research Portal  DOI:10.1016/j.jhep.2017.11.044Document VersionPeer reviewed versionLink to publication record in King's Research PortalCitation for published version (APA):da Silva Filipe, A., Sreenu, V., Hughes, J., Aranday-Cortes, E., Irving, W. L., Foster, G. R., Agarwal, K.,Rosenberg, W., Macdonald, D., Richardson, P., Aldersley, M. A., Wiselka, M., Ustianowski, A., McLauchlan, J.,& Thomson, E. C. (2018). Reply to: No effect of resistance-associated substitutions in patients with rare HCVsubtypes following treatment with sofosbuvir-containing regimens. Journal of Hepatology.https://doi.org/10.1016/j.jhep.2017.11.044Citing this paperPlease note that where the full-text provided on King's Research Portal is the Author Accepted Manuscript or Post-Print version this maydiffer from the final Published version. If citing, it is advised that you check and use the publisher's definitive version for pagination,volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you areagain advised to check the publisher's website for any subsequent corrections.General rightsCopyright and moral rights for the publications made accessible in the Research Portal are retained by the authors and/or other copyrightowners and it is a condition of accessing publications that users recognize and abide by the legal requirements associated with these rights.•Users may download and print one copy of any publication from the Research Portal for the purpose of private study or research.•You may not further distribute the material or use it for any profit-making activity or commercial gain•You may freely distribute the URL identifying the publication in the Research PortalTake down policyIf you believe that this document breaches copyright please contact librarypure@kcl.ac.uk providing details, and we will remove access tothe work immediately and investigate your claim.Download date: 06. Oct. 2023Accepted ManuscriptLetter to the EditorReply to: No effect of resistance-associated substitutions in patients with rareHCV subtypes following treatment with sofosbuvir-containing regimensAna da Silva Filipe, Vattipally Sreenu, Joseph Hughes, Elihu Aranday-Cortes,William L Irving, Graham R. Foster, Kosh Agarwal, William Rosenberg,Douglas Macdonald, Paul Richardson, Mark A. Aldersley, Martin Wiselka,Andrew Ustianowski, John McLauchlan, Emma C. ThomsonPII: S0168-8278(18)30014-XDOI: https://doi.org/10.1016/j.jhep.2017.11.044Reference: JHEPAT 6821To appear in: Journal of HepatologyReceived Date: 17 November 2017Accepted Date: 22 November 2017Please cite this article as: da Silva Filipe, A., Sreenu, V., Hughes, J., Aranday-Cortes, E., Irving, W.L., Foster, G.R.,Agarwal, K., Rosenberg, W., Macdonald, D., Richardson, P., Aldersley, M.A., Wiselka, M., Ustianowski, A.,McLauchlan, J., Thomson, E.C., Reply to: No effect of resistance-associated substitutions in patients with rare HCVsubtypes following treatment with sofosbuvir-containing regimens, Journal of Hepatology (2018), doi: https://doi.org/10.1016/j.jhep.2017.11.044This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customerswe are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, andreview of the resulting proof before it is published in its final form. Please note that during the production processerrors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.  Reply to: No effect of resistance-associated substitutions in patients with rare HCV subtypes following treatment with sofosbuvir-containing regimens Ana da Silva Filipe1, Vattipally Sreenu1, Joseph Hughes1, Elihu Aranday-Cortes1, William L Irving2, Graham R. Foster3, Kosh Agarwal4, William Rosenberg5, Douglas Macdonald5, Paul Richardson6, Mark A. Aldersley7, Martin Wiselka8, Andrew Ustianowski9, John McLauchlan1, Emma C. Thomson1 1. MRC-University of Glasgow Centre for Virus Research, Glasgow, UK.  2. Gastrointestinal and Liver Disorders Theme, NIHR Nottingham Biomedical Research Centre at  the Nottingham University Hospitals NHS Trust and the University of Nottingham, UK. 3. Blizard Institute, Queen Mary University of London, London, UK.  4. Institute of Liver Studies, King's College Hospital Foundation Trust, London UK.  5. Institute of Liver and Digestive Health, University College of London, London, United Kingdom. 6. Royal Liverpool University NHS Trust, Liverpool, UK.  7. Liver Unit, St James’s University Hospital, Leeds, UK.  8. Infectious Diseases Unit, University Hospitals Leicester NHS Trust, Leicester, UK.  9. Infectious Diseases, North Manchester General Hospital, Manchester, UK.  Financial Support: This work was supported by grants from the Medical Research Foundation to HCV Research UK (C0365) and the UK Medical Research Council (MRC) to the STOP-HCV consortium (MR/K01532X/1). AS, VS, JH, EAC, JM and ECT were also supported by the MRC (MC.UU.12014/1) and ECT was funded by the Wellcome Trust (102789/Z/13/Z). We are also grateful to Gilead Sciences and Bristol Myers Squibb for financial support. Correspondence: Prof J McLauchlan, MRC-University of Glasgow Centre for Virus Research, Sir Michael Stoker Building, Garscube Campus, Glasgow G61 1QH, UK; E-mail,  john.mclauchlan@glasgow.ac.uk; Tel no. +44 141 330 4028.   Conflict of Interest: The authors disclose the following conflicts: WLI has received speaker and consultancy fees from Roche Products, Janssen Cilag and Novartis, educational grants from Boehringer Ingelheim, MSD and Gilead Sciences, and research grant support from GlaxoSmithKline, Pfizer, Gilead Sciences and Janssen Cilag; GRF has received research grants from Roche, Gilead Sciences, Springbank, and received speaker and consultancy fees from AbbVie, Gilead Sciences, MSD, GSK and Janssen Pharmaceuticals; KA has received speaker and consultancy fees from AbbVie, Achillion, Astellas, BMS, Gilead Sciences, GSK, Janssen, MSD, Novartis; WR is among the inventors and patent holders for the ELF® Test and receives consultancy fees from Siemens; MAA has been an advisory board member and in receipt of educational grants from Gilead Sciences; AU has received speaker fees and advisory board fees from Gilead Sciences, ViiV, Abbvie, MSD, Janssen and BMS; JM has received speaker and consultancy fees from Abbvie, Gilead Sciences and BMS. The remaining authors have no conflicts to declare. Author Contributions: The study was designed and led by AS, JM and ECT. EAC, VS and JH formed NGS and host genetic analysis. WLI collated and provided the clinical data from HCV Research UK. GRF, KA, WR, DM, PR, MAA, MW and AU consented the patients, provided clinical data and provided samples. All authors contributed to and commented on the drafting of the final manuscript.   To the Editor:  We thank Zeuzem et al for their response to our recently published findings (1, 2). Their data provide a valuable addition to reports describing virological outcomes for patients infected with “rare” subtypes who have received sofosbuvir (SOF)-based therapy but have not been well represented in previous large-scale clinical trials. We agree with the authors that assessing treatment outcome in cohorts infected with poorly characterized or uncharacterized subtypes would ideally be determined from patients who have achieved both SVR and treatment relapse. However, well-defined cohorts do not exist in most low- and middle-income countries (LMICs) where such subtypes are typically found, and consequently the necessary evidence base has been lacking. We wish to comment further on the implications for treatment of patients in LMICs as part of the WHO global elimination plan. Recently, we published a study illustrating the lack of HCV sequence data in LMICs, particularly those in Africa as well as South and Central America (3). We agree that a SVR rate of 100% in 8 gt4r-infected patients treated with SOF/VEL±VOX is reassuring. However, the additional finding of SOF/LDV treatment failure in 2/4 patients with gt4r in Zeuzem et al’s larger analysis (1) is concerning although the authors did not give details of the disease status of these patients. In our study, all EAP patients had cirrhosis, which may well have influenced response to therapy. The apparent lower response of gt4r to SOF/LDV is worth highlighting for countries planning to use generic versions of these DAAs as treatment for gt4 infection where a significant proportion of patients are possibly infected with the gt4r subtype. Although gt4r is uncommon in Europe and the USA, it is not a rare genotype in Central African countries including the Democratic Republic of the Congo, the Republic of Congo, the Central African Republic, Burundi, and Gabon. It will be important for these countries to consider the potential advantage of using SOF/VEL-based treatment versus SOF/LDV to achieve high rates of HCV clearance. Finally, the large dataset provided by Zeuzem et al substantially increases the available data for DAA target genes in subtypes that are rare in high income countries (HICs).   However, there remains a question as to whether the full extent of RAS polymorphisms in such subtypes should be considered as fully documented. Regarding gt1l, also associated with lower SVR rates in our study, we combined the sequence data for gt1l isolates across the HCV NS5A coding region between residues 24-32 where RAS typically occur from Zeuzem et al, our publication (Filipe et al) and available Genbank sequences. Our analysis shows that methionine is dominant at positions 28 and 31 (11/12 sequences). However, position 30 is polymorphic in gt1l (Q, n=7; R, n=5). In the common gt1 subtypes, gt1a and gt1b, position 30 does not show such variability; for gt1a, Q is encoded in 96% of sequences (4801/4983) and for gt1b, R is encoded in 92% of sequences (4328/4705) (McLauchlan, unpublished). The motif consisting of M28R30M31 is found not only in gt1l but also gt4r. The gt1l-infected patients reported by Zeuzem et al who had this motif received VEL and not LDV, which was the prescribed NS5A inhibitor in our EAP cohort. We note that one of the gt4r-infected patients in the Zeuzem et al study with the M28R30M31 motif did receive LDV and relapse occurred, the second patient who received LDV had a V28R30M31 motif. All other gt4r-infected patients who achieved SVR received SOF/VEL±VOX. In the absence of relevant in vitro subgenomic replicons to test gt1l, we agree with Zeuzem et al that patients receiving SOF-based regimens for gt4r should be treated with VEL but this recommendation could be extended to geographic regions where gt1l may circulate to mitigate against possible resistance with strains containing the V/M28R30M31 motif. In summary, the available, modest data suggest that NS5A polymorphisms, which may impact treatment response are common in HCV strains from certain African genotypes. The impact of these polymorphisms appears to be minimal in patients receiving SOF/VEL- based regimens but there are concerns about the efficacy of LDV in these isolates. Further studies examining the effectiveness of current therapies in larger numbers of patients will be required to identify the optimum regimen for these potentially resistant subtypes. REFERENCES  1. Zeuzem S, Dvory-Sobol H, Brainard DM. Reply to: "Response to DAA therapy in the NHS England Early Access Programme for rare HCV subtypes from low and middle income countries": No effect of   resistance-associated substitutions in patients with rare HCV subtypes following treatment with sofosbuvir-containing regimens. J Hepatol 2017; in press. 2. da Silva Filipe A, Sreenu V, Hughes J, Aranday-Cortes E, Irving WL, Foster GR, Agarwal K, et al. Response to DAA therapy in the NHS England Early Access Programme for rare HCV subtypes from low and middle income countries. J Hepatol 2017; in press. 3. Niebel M, Singer JB, Nickbakhsh S, Gifford RJ, Thomson EC. Hepatitis C and the absence of genomic data in low-income countries: a barrier on the road to elimination? Lancet Gastroenterol Hepatol 2017;2:700-701. 

Reply to: No effect of resistance-associated substitutions in patients with rare HCV subtypes following treatment with sofosbuvir-containing regimens

Enlighten

     da Silva Filipe, A. et al. (2018) Reply to: "Reply to: 'Response to DAA therapy in the NHS England Early Access Programme for rare HCV subtypes from low and middle income countries'". Journal of Hepatology, 68(4), pp. 864-866. (doi:10.1016/j.jhep.2017.11.044)  This is the author’s final accepted version.  There may be differences between this version and the published version. You are advised to consult the publisher’s version if you wish to cite from it.     http://eprints.gla.ac.uk/162710/            Deposited on:  26 February 2018             Enlighten – Research publications by members of the University of Glasgow http://eprints.gla.ac.uk Reply to: No effect of resistance-associated substitutions in patients with rare HCV subtypes following treatment with sofosbuvir-containing regimens Ana da Silva Filipe1, Vattipally Sreenu1, Joseph Hughes1, Elihu Aranday-Cortes1, William L Irving2, Graham R. Foster3, Kosh Agarwal4, William Rosenberg5, Douglas Macdonald5, Paul Richardson6, Mark A. Aldersley7, Martin Wiselka8, Andrew Ustianowski9, John McLauchlan1, Emma C. Thomson1 1. MRC-University of Glasgow Centre for Virus Research, Glasgow, UK. 2. Gastrointestinal and Liver Disorders Theme, NIHR Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and the University of Nottingham, UK. 3. Blizard Institute, Queen Mary University of London, London, UK. 4. Institute of Liver Studies, King's College Hospital Foundation Trust, London UK. 5. Institute of Liver and Digestive Health, University College of London, London, United Kingdom. 6. Royal Liverpool University NHS Trust, Liverpool, UK. 7. Liver Unit, St James’s University Hospital, Leeds, UK.  8. Infectious Diseases Unit, University Hospitals Leicester NHS Trust, Leicester, UK. 9. Infectious Diseases, North Manchester General Hospital, Manchester, UK. Financial Support: This work was supported by grants from the Medical Research Foundation to HCV Research UK (C0365) and the UK Medical Research Council (MRC) to the STOP-HCV consortium (MR/K01532X/1). AS, VS, JH, EAC, JM and ECT were also supported by the MRC (MC.UU.12014/1) and ECT was funded by the Wellcome Trust (102789/Z/13/Z). We are also grateful to Gilead Sciences and Bristol Myers Squibb for financial support. Correspondence: Prof J McLauchlan, MRC-University of Glasgow Centre for Virus Research, Sir Michael Stoker Building, Garscube Campus, Glasgow G61 1QH, UK; E-mail, john.mclauchlan@glasgow.ac.uk; Tel no. +44 141 330 4028. Conflict of Interest: The authors disclose the following conflicts: WLI has received speaker and consultancy fees from Roche Products, Janssen Cilag and Novartis, educational grants from Boehringer Ingelheim, MSD and Gilead Sciences, and research grant support from GlaxoSmithKline, Pfizer, Gilead Sciences and Janssen Cilag; GRF has received research grants from Roche, Gilead Sciences, Springbank, and received speaker and consultancy fees from AbbVie, Gilead Sciences, MSD, GSK and Janssen Pharmaceuticals; KA has received speaker and consultancy fees from AbbVie, Achillion, Astellas, BMS, Gilead Sciences, GSK, Janssen, MSD, Novartis; WR is among the inventors and patent holders for the ELF® Test and receives consultancy fees from Siemens; MAA has been an advisory board member and in receipt of educational grants from Gilead Sciences; AU has received speaker fees and advisory board fees from Gilead Sciences, ViiV, Abbvie, MSD, Janssen and BMS; JM has received speaker and consultancy fees from Abbvie, Gilead Sciences and BMS. The remaining authors have no conflicts to declare. Author Contributions: The study was designed and led by AS, JM and ECT. EAC, VS and JH formed NGS and host genetic analysis. WLI collated and provided the clinical data from HCV Research UK. GRF, KA, WR, DM, PR, MAA, MW and AU consented the patients, provided clinical data and provided samples. All authors contributed to and commented on the drafting of the final manuscript.   To the Editor: We thank Zeuzem et al for their response to our recently published findings (1, 2). Their data provide a valuable addition to reports describing virological outcomes for patients infected with “rare” subtypes who have received sofosbuvir (SOF)-based therapy but have not been well represented in previous large-scale clinical trials. We agree with the authors that assessing treatment outcome in cohorts infected with poorly characterized or uncharacterized subtypes would ideally be determined from patients who have achieved both SVR and treatment relapse. However, well-defined cohorts do not exist in most low- and middle-income countries (LMICs) where such subtypes are typically found, and consequently the necessary evidence base has been lacking. We wish to comment further on the implications for treatment of patients in LMICs as part of the WHO global elimination plan. Recently, we published a study illustrating the lack of HCV sequence data in LMICs, particularly those in Africa as well as South and Central America (3). We agree that a SVR rate of 100% in 8 gt4r-infected patients treated with SOF/VEL±VOX is reassuring. However, the additional finding of SOF/LDV treatment failure in 2/4 patients with gt4r in Zeuzem et al’s larger analysis (1) is concerning although the authors did not give details of the disease status of these patients. In our study, all EAP patients had cirrhosis, which may well have influenced response to therapy. The apparent lower response of gt4r to SOF/LDV is worth highlighting for countries planning to use generic versions of these DAAs as treatment for gt4 infection where a significant proportion of patients are possibly infected with the gt4r subtype. Although gt4r is uncommon in Europe and the USA, it is not a rare genotype in Central African countries including the Democratic Republic of the Congo, the Republic of Congo, the Central African Republic, Burundi, and Gabon. It will be important for these countries to consider the potential advantage of using SOF/VEL-based treatment versus SOF/LDV to achieve high rates of HCV clearance.   Finally, the large dataset provided by Zeuzem et al substantially increases the available data for DAA target genes in subtypes that are rare in high income countries (HICs). However, there remains a question as to whether the full extent of RAS polymorphisms in such subtypes should be considered as fully documented. Regarding gt1l, also associated with lower SVR rates in our study, we combined the sequence data for gt1l isolates across the HCV NS5A coding region between residues 24-32 where RAS typically occur from Zeuzem et al, our publication (Filipe et al) and available Genbank sequences. Our analysis shows that methionine is dominant at positions 28 and 31 (11/12 sequences). However, position 30 is polymorphic in gt1l (Q, n=7; R, n=5). In the common gt1 subtypes, gt1a and gt1b, position 30 does not show such variability; for gt1a, Q is encoded in 96% of sequences (4801/4983) and for gt1b, R is encoded in 92% of sequences (4328/4705) (McLauchlan, unpublished). The motif consisting of M28R30M31 is found not only in gt1l but also gt4r. The gt1l-infected patients reported by Zeuzem et al who had this motif received VEL and not LDV, which was the prescribed NS5A inhibitor in our EAP cohort. We note that one of the gt4r-infected patients in the Zeuzem et al study with the M28R30M31 motif did receive LDV and relapse occurred, the second patient who received LDV had a V28R30M31 motif. All other gt4r-infected patients who achieved SVR received SOF/VEL±VOX. In the absence of relevant in vitro subgenomic replicons to test gt1l, we agree with Zeuzem et al that patients receiving SOF-based regimens for gt4r should be treated with VEL but this recommendation could be extended to geographic regions where gt1l may circulate to mitigate against possible resistance with strains containing the V/M28R30M31 motif.  In summary, the available, modest data suggest that NS5A polymorphisms, which may impact treatment response are common in HCV strains from certain African genotypes. The impact of these polymorphisms appears to be minimal in patients receiving SOF/VEL-based regimens but there are concerns about the efficacy of LDV in these isolates. Further studies examining the effectiveness of current therapies in larger numbers of patients will be required to identify the optimum regimen for these potentially resistant subtypes. REFERENCES 1. Zeuzem S, Dvory-Sobol H, Brainard DM. Reply to: "Response to DAA therapy in the NHS England Early Access Programme for rare HCV subtypes from low and middle income countries": No effect of resistance-associated substitutions in patients with rare HCV subtypes following treatment with sofosbuvir-containing regimens. J Hepatol 2017; in press. 2. da Silva Filipe A, Sreenu V, Hughes J, Aranday-Cortes E, Irving WL, Foster GR, Agarwal K, et al. Response to DAA therapy in the NHS England Early Access Programme for rare HCV subtypes from low and middle income countries. J Hepatol 2017; in press. 3. Niebel M, Singer JB, Nickbakhsh S, Gifford RJ, Thomson EC. Hepatitis C and the absence of genomic data in low-income countries: a barrier on the road to elimination? Lancet Gastroenterol Hepatol 2017;2:700-701.  

https://eprints.gla.ac.uk/162710/7/162710.pdf

Reply to: No effect of resistance-associated substitutions in patients with rare HCV subtypes following treatment with sofosbuvir-containing regimens

Abstract

Similar works

Full text

Available Versions

Crossref

Queen Mary Research Online

Enlighten: Publications

King's Research Portal

Enlighten