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• W2811167011 abstract "Treatment with direct-acting antiviral agents (DAAs) for chronic hepatitis C virus (HCV) infection is very effective and well tolerated.[1]Falade-Nwulia O. Suarez-Cuervo C. Nelson D.R. Fried M.W. Segal J.B. Sulkowski M.S. Oral direct-acting agent therapy for hepatitis C virus infection: a systematic review.Ann Intern Med. 2017; 166: 637-648Crossref PubMed Scopus (441) Google Scholar Nevertheless, resistance-associated substitutions (RAS) have been described, including the nonstructural protein 5B (NS5B) S282T substitution which confers major resistance to sofosbuvir in vitro.2Lam A.M. Espiritu C. Bansal S. Micolochick Steuer H.M. Niu C. Zennou V. et al.Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis C virus.Antimicrob Agents Chemother. 2012; 56: 3359-3368Crossref PubMed Scopus (216) Google Scholar, 3Xu S. Doehle B. Rajyaguru S. Han B. Barauskas O. Feng J. et al.In vitro selection of resistance to sofosbuvir in HCV replicons of genotype-1 to -6.Antivir Ther. 2017; Crossref Scopus (22) Google Scholar The presence of this substitution in treatment-naïve patients has never been described, presumably because it severely impairs viral replicative fitness and therefore usually does not persist after treatment cessation.[4]Sarrazin C. The importance of resistance to direct antiviral drugs in HCV infection in clinical practice.J Hepatol. 2016; 64: 486-504Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar Herein, we report a case of S282T persistence for 21 weeks upon DAA treatment failure. A 66-year-old man who has sex with men (MSM) was diagnosed with a human-immunodeficiency virus-1 (HIV) infection in 1996, and has since then been successfully treated with antiretroviral therapy. He reported an active sex life with condomless anal intercourse and active and passive fisting with several different male partners at different locations across Europe and the USA. His medical history included three acute HCV infections, which were all successfully treated with diverse antiviral regimens shortly following acute infection (Fig. 1). In September 2016, he acquired his fourth HCV infection (genotype 4d), for which treatment was initiated in November 2016 with sofosbuvir and ledipasvir for 12 weeks. At treatment initiation (t0 in Fig. 1), Sanger sequencing showed no RAS in NS5B (nucleotide 7953–9293 from start of H77 reference genome), but P/T58L in NS5A. Shortly following treatment initiation, HCV RNA (COBAS® AmpliPrep/COBAS® TaqMan® HCV Test v2.0 [CAP/CTM; Roche Diagnostics, Mannheim, Germany]) decreased (Fig. 1). However, in February 2017, twelve weeks after treatment initiation (t1 in Fig. 1), HCV RNA load was 7,570,000 IU/mL, and sequence analysis showed the S282T substitution in NS5B (Fig. 1). In NS5A, 58L was still present. Hereafter, HCV RNA levels declined rapidly, but increased again over time (t2 in Fig. 1), which in retrospect could be explained by the fact that the patient, as he later reported, had decided to interrupt sofosbuvir/ledipasvir at week 8 and restarted two to four weeks afterwards. Remarkably, even when HCV RNA levels were high, the S282T substitution persisted over time (Fig. 1). While analyzing persistence of the NS5B-S282T substitution by Sanger sequencing, a genotype 1a superinfection was found. This superinfection was confirmed with clonal analysis of this NS5B fragment. This genotype was not detectable in earlier samples, using a subtype specific NS5A-PCR. Sequence analysis did not show any RAS in genotype 1a. In July 2017, the patient initiated treatment with sofosbuvir, elbasvir/grazoprevir and ribavirin for 24 weeks. HCV RNA levels decreased rapidly and in April 2018 he achieved a sustained virological response. The patient gave his consent for participation in the MOSAIC (MSM Observational Study of Acute Infection with hepatitis C) study. This study was approved by the Institutional Review Board of the Academic Medical Center at the University of Amsterdam. Sequences were submitted to GenBank (accession numbers MH380035 to MH380048). In this sexually active HIV-infected MSM who acquired his fourth HCV infection, the key sofosbuvir RAS NS5B-S282T remained present as the major viral variant for 21 weeks, even when HCV RNA levels were high, demonstrating that viral fitness was not compromised. This finding is remarkable, as this substitution is rarely found among patients with DAA failure.5Donaldson E.F. Harrington P.R. O'Rear J.J. Naeger L.K. Clinical evidence and bioinformatics characterization of potential hepatitis C virus resistance pathways for sofosbuvir.Hepatology. 2015; 61: 56-65Crossref PubMed Scopus (141) Google Scholar, 6Dietz J. Susser S. Vermehren J. Peiffer K.H. Grammatikos G. Berger A. et al.Patterns of resistance-associated substitutions in patients with chronic HCV infection following treatment with direct-acting antivirals.Gastroenterology. 2017; Google Scholar, 7Svarovskaia E.S. Dvory-Sobol H. Parkin N. Hebner C. Gontcharova V. Martin R. et al.Infrequent development of resistance in genotype 1–6 hepatitis C virus-infected subjects treated with sofosbuvir in phase 2 and 3 clinical trials.Clin Infect Dis. 2014; 59: 1666-1674Crossref PubMed Scopus (169) Google Scholar, 8Wyles D. Dvory-Sobol H. Svarovskaia E.S. Doehle B.P. Martin R. Afdhal N.H. et al.Post-treatment resistance analysis of hepatitis C virus from phase II and III clinical trials of ledipasvir/sofosbuvir.J Hepatol. 2017; 66: 703-710Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 9Di Maio V.C. Cento V. Lenci I. Aragri M. Rossi P. Barbaliscia S. et al.Multiclass HCV resistance to direct-acting antiviral failure in real-life patients advocates for tailored second-line therapies.Liver Int. 2017; 37: 514-528Crossref PubMed Scopus (76) Google Scholar, 10Gane E.J. Metivier S. Nahass R. Ryan M. Stedman C.A. Svarovskaia E.S. et al.The emergence of NS5B resistance associated substitution S282T after sofosbuvir-based treatment.Hepatol Commun. 2017; 1: 538-549Crossref PubMed Scopus (28) Google Scholar Furthermore, in the few cases with S282T that have been described, S282T is known to disappear completely by 12 weeks following treatment cessation.7Svarovskaia E.S. Dvory-Sobol H. Parkin N. Hebner C. Gontcharova V. Martin R. et al.Infrequent development of resistance in genotype 1–6 hepatitis C virus-infected subjects treated with sofosbuvir in phase 2 and 3 clinical trials.Clin Infect Dis. 2014; 59: 1666-1674Crossref PubMed Scopus (169) Google Scholar, 11Hedskog C. Dvory-Sobol H. Gontcharova V. Martin R. Ouyang W. Han B. et al.Evolution of the HCV viral population from a patient with S282T detected at relapse after sofosbuvir monotherapy.J Viral Hepat. 2015; 22: 871-881Crossref PubMed Scopus (56) Google Scholar This is explained by the fact that S282T is located at the active site of the NS5B polymerase, and has been shown to severely affect the replicative fitness of a wide range of HCV genotypes, as evidenced by low replication capacity in HCV replicons (3.2% to 22% compared to the wildtype).[3]Xu S. Doehle B. Rajyaguru S. Han B. Barauskas O. Feng J. et al.In vitro selection of resistance to sofosbuvir in HCV replicons of genotype-1 to -6.Antivir Ther. 2017; Crossref Scopus (22) Google Scholar It is unclear why S282T persisted in our patient. Possibly, the effect of S282T on HCV replication capacity might be smaller in genotype 4d, as this effect is known to differ by HCV genotype.[3]Xu S. Doehle B. Rajyaguru S. Han B. Barauskas O. Feng J. et al.In vitro selection of resistance to sofosbuvir in HCV replicons of genotype-1 to -6.Antivir Ther. 2017; Crossref Scopus (22) Google Scholar However, to the best of our knowledge, data for genotype 4d have never been published. The possibility that S282T does not necessarily impair viral fitness is supported by the fact that we identified a genotype 4a sequence in GenBank (Y11604) with S282T in a treatment-naïve patient.[12]Chamberlain R.W. Adams N. Saeed A.A. Simmonds P. Elliott R.M. Complete nucleotide sequence of a type 4 hepatitis C virus variant, the predominant genotype in the Middle East.J Gen Virol. 1997; 78: 1341-1347Crossref PubMed Scopus (176) Google Scholar Alternatively, additional compensatory substitutions could restore the lack of viral fitness due to the presence of S282T. In our patient, several substitutions relative to the genotype 4d reference strain DQ418786 were identified (N120S, E128D, T130N, D189A, K231R, K270R, I276T, D327G, R334C and K517R), none of which have been associated with fitness restoration thus far. Furthermore, all of these substitutions were already present before treatment initiation. It is possible that other compensatory mutations outside the sequenced domain may have contributed to fitness restoration. In NS5A, the T/P58L substitution was found, both at treatment initiation and treatment failure. However, we are unable to draw a definite conclusion about the role of T/P58L in the sofosbuvir/ledipasvir treatment failure of our patient, as there is no specific data for genotype 4d on the role of this substitution in the susceptibility to ledipasvir. Finally, onward transmission of the HCV strain containing the S282T substitution in our patient does not seem to be an unlikely scenario. After treatment failure, the patient acquired a superinfection with another HCV genotype, which confirms ongoing sexual risk behavior. At the time of the superinfection HCV RNA levels of the S282T-strain were very high (16,800,000 IU/ml). As this patient reported sexual risk behavior with several partners in large cities across Europe and the USA, international spread of this genotype 4d variant with the NS5B-S282T RAS cannot be excluded. Therefore, in case of DAA failure with a sofosbuvir containing regimen in an MSM infected with genotype 4d, we strongly advise clinicians to perform a resistance analysis, which includes the NS5B gene. A.N. was financially supported by the “Aidsfonds” Netherlands (grant 2013.037). The funding source had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. Marc van der Valk: through his institution has received independent scientific grant support from Gilead Sciences, Janssen Pharmaceuticals Inc, Merck & Co and ViiV Healthcare, has served on scientific advisory boards for Abbvie, BMS, Gilead Sciences, MSD and ViiV Healthcare, and has received speakers fees from Gilead Sciences. Janke Schinkel: through her institution has received independent scientific grant support from Abbvie, Gilead and MSD and Roche diagnostics, served on consultancy board of Gilead. All others have no conflicts of interest to declare. Please refer to the accompanying ICMJE disclosure forms for further details. A.N. drafted the manuscript. J.M. and M.V. are physicians treating the patient in this case report. R.M., S.R. and J.S. were responsible for laboratory analysis, and together with M.P., they also contributed to the intellectual content of the manuscript. All authors critically revised the manuscript. Download .pdf (.16 MB) Help with pdf files Supplementary data" @default.
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• W2811167011 title "Persistence of NS5B-S282T, a sofosbuvir resistance-associated substitution, in a HIV/HCV-coinfected MSM with risk of onward transmission" @default.
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