Dynamic evolution of the sofosbuvir-associated variant A1343V in HEV-infected patients under concomitant sofosbuvir-ribavirin treatment.

Autor:	Gömer A; Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany., Dinkelborg K; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany.; TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.; German Center for Infectious Disease Research (DZIF); Partner Sites Hannover-Braunschweig, Germany., Klöhn M; Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany., Jagst M; Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany.; Institute of Virology, University of Veterinary Medicine Hannover, Hannover, Germany., Wißing MH; Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany., Frericks N; Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany., Nörenberg P; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany.; TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany., Behrendt P; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany.; TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.; German Center for Infectious Disease Research (DZIF); Partner Sites Hannover-Braunschweig, Germany., Cornberg M; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany.; German Center for Infectious Disease Research (DZIF); Partner Sites Hannover-Braunschweig, Germany.; Excellence Cluster 2155 RESIST, Hannover Medical School, Hannover, Germany., Wedemeyer H; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany.; German Center for Infectious Disease Research (DZIF); Partner Sites Hannover-Braunschweig, Germany.; Excellence Cluster 2155 RESIST, Hannover Medical School, Hannover, Germany., Steinmann E; Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany.; German Centre for Infection Research (DZIF), External Partner Site, Bochum, Germany., Maasoumy B; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany.; German Center for Infectious Disease Research (DZIF); Partner Sites Hannover-Braunschweig, Germany., Todt D; Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany.; European Virus Bioinformatics Center (EVBC), Jena, Germany.
Jazyk:	angličtina
Zdroj:	JHEP reports : innovation in hepatology [JHEP Rep] 2024 Jan 03; Vol. 6 (3), pp. 100989. Date of Electronic Publication: 2024 Jan 03 (Print Publication: 2024).
DOI:	10.1016/j.jhepr.2023.100989
Abstrakt:	Background & Aims: In the absence of a hepatitis E virus (HEV)-specific antiviral treatment, sofosbuvir has recently been shown to have antiviral activity against HEV in vivo . However, a variant, A1343V, that is strongly associated with viral relapse impedes treatment success. In this study, we investigated the occurrence of variants during sofosbuvir and ribavirin treatment in vivo and assessed the sensitivity of resistance-associated variants to concurrent treatment in cell culture. Methods: Two patients with chronic HEV infection that did not clear infection under ribavirin treatment were subsequently treated with a combination of sofosbuvir and ribavirin. We determined response to treatment by measuring liver enzymes and viral load in blood and stool. Moreover, we analyzed viral evolution using polymerase-targeted high-throughput sequencing and assessed replication fitness of resistance-associated variants using a HEV replicon system. Results: Combination treatment was successful in decreasing viral load towards the limit of quantification. However, during treatment sustained virological response was not achieved. Variants associated with sofosbuvir or ribavirin treatment emerged during treatment, including A1343V and G1634R. Moreover, A1343V, as a single or double mutation with G1634R, was associated with sofosbuvir resistance during concomitant treatment in vitro . Conclusions: These results highlight the importance of variant profiling during antiviral treatment of patients with chronic infection. Understanding how intra-host viral evolution impedes treatment success will help guide the design of next-generation antivirals. Impact and Implications: The lack of hepatitis E virus (HEV)-specific antivirals to treat chronic infection remains a serious health burden. Although ribavirin, interferon and sofosbuvir have been reported as anti-HEV drugs, not all patients are eligible for treatment or clear infection, since resistant-associated variants can rapidly emerge. In this study, we analyzed the efficacy of sofosbuvir and ribavirin combination treatment in terms of HEV suppression, the emergence of resistance-associated variants and their ability to escape treatment inhibition in vitro . Our results provide novel insights into evolutionary dynamics of HEV during treatment and thus will help guide the design of next-generation antivirals. Competing Interests: H.W. received grants, consulting feed and honoraria from Abbvie, Aligos, Altimmune, Biotest, BMS, BTG, Dicerna, Enanta, Gilead, Janssen, Merck/MSD, MYR GmbH, Roche, Vri Biotechnology. In addition H.W. served as clinical trial investigator for Abbvie, Altimmune, BMS, Gilead, Jansen, Merck/MSD, MYR GmbH, Novartis, Vri Biotechnology. M.C. received consulting fees, honoraria or travel support by: Abbvie, AiCuris, Gilead, GlaxoSmithKline, Janssen–Cilag, MSD Sharp & Dohme, Spring Bank Pharmaceuticals, Swedish Orphan Biovitrum AB (SOBI) and Falk. Moreover, M.C. is on the board of the German Liver Foundation (GASL: 2017–2020). P.B. received funding from the German Centre for infection research (DZIF). B.M. received grants, consulting feed, honoraria and travel support from: Roche Diagnostics, Fujirebio, EWIMED, AbbVie, Luvos, Norgine and Gilead. In addition, B.M. own Biotech stocks. Please refer to the accompanying ICMJE disclosure forms for further details. (© 2023 The Author(s).)
Databáze:	MEDLINE
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