Emergence of resistance-associated variants during sofosbuvir treatment in chronically infected hepatitis E patients
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Emergence of resistance-associated variants during sofosbuvir treatment in chronically infected hepatitis E patients. / Gömer, André; Klöhn, Mara; Jagst, Michelle; Nocke, Maximilian; Pischke, Sven; Horvatits, Thomas; Schulze Zur Wiesch, Julian; Müller, Tobias; Hardtke, Svenja; Cornberg, Markus; Wedemeyer, Heiner; Behrendt, Patrick; Steinmann, Eike; Todt, Daniel.
in: HEPATOLOGY, Jahrgang 78, Nr. 6, 01.12.2023, S. 1882-1895.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Emergence of resistance-associated variants during sofosbuvir treatment in chronically infected hepatitis E patients
AU - Gömer, André
AU - Klöhn, Mara
AU - Jagst, Michelle
AU - Nocke, Maximilian
AU - Pischke, Sven
AU - Horvatits, Thomas
AU - Schulze Zur Wiesch, Julian
AU - Müller, Tobias
AU - Hardtke, Svenja
AU - Cornberg, Markus
AU - Wedemeyer, Heiner
AU - Behrendt, Patrick
AU - Steinmann, Eike
AU - Todt, Daniel
N1 - Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.
PY - 2023/12/1
Y1 - 2023/12/1
N2 - BACKGROUND AND AIMS: Chronic HEV infections remain a serious problem in immunocompromised patients, as specifically approved antiviral drugs are unavailable. In 2020, a 24-week multicenter phase II pilot trial was carried out, evaluating the nucleotide analog sofosbuvir by treating nine chronically HEV-infected patients with sofosbuvir (Trial Number NCT03282474). During the study, antiviral therapy reduced virus RNA levels initially but did not lead to a sustained virologic response. Here, we characterize the changes in HEV intrahost populations during sofosbuvir treatment to identify the emergence of treatment-associated variants.APPROACH AND RESULTS: We performed high-throughput sequencing on RNA-dependent RNA polymerase sequences to characterize viral population dynamics in study participants. Subsequently, we used an HEV-based reporter replicon system to investigate sofosbuvir sensitivity in high-frequency variants. Most patients had heterogenous HEV populations, suggesting high adaptability to treatment-related selection pressures. We identified numerous amino acid alterations emerging during treatment and found that the EC 50 of patient-derived replicon constructs was up to ~12-fold higher than the wild-type control, suggesting that variants associated with lower drug sensitivity were selected during sofosbuvir treatment. In particular, a single amino acid substitution (A1343V) in the finger domain of ORF1 could reduce susceptibility to sofosbuvir significantly in 8 of 9 patients.CONCLUSIONS: In conclusion, viral population dynamics played a critical role during antiviral treatment. High population diversity during sofosbuvir treatment led to the selection of variants (especially A1343V) with lower sensitivity to the drug, uncovering a novel mechanism of resistance-associated variants during sofosbuvir treatment.
AB - BACKGROUND AND AIMS: Chronic HEV infections remain a serious problem in immunocompromised patients, as specifically approved antiviral drugs are unavailable. In 2020, a 24-week multicenter phase II pilot trial was carried out, evaluating the nucleotide analog sofosbuvir by treating nine chronically HEV-infected patients with sofosbuvir (Trial Number NCT03282474). During the study, antiviral therapy reduced virus RNA levels initially but did not lead to a sustained virologic response. Here, we characterize the changes in HEV intrahost populations during sofosbuvir treatment to identify the emergence of treatment-associated variants.APPROACH AND RESULTS: We performed high-throughput sequencing on RNA-dependent RNA polymerase sequences to characterize viral population dynamics in study participants. Subsequently, we used an HEV-based reporter replicon system to investigate sofosbuvir sensitivity in high-frequency variants. Most patients had heterogenous HEV populations, suggesting high adaptability to treatment-related selection pressures. We identified numerous amino acid alterations emerging during treatment and found that the EC 50 of patient-derived replicon constructs was up to ~12-fold higher than the wild-type control, suggesting that variants associated with lower drug sensitivity were selected during sofosbuvir treatment. In particular, a single amino acid substitution (A1343V) in the finger domain of ORF1 could reduce susceptibility to sofosbuvir significantly in 8 of 9 patients.CONCLUSIONS: In conclusion, viral population dynamics played a critical role during antiviral treatment. High population diversity during sofosbuvir treatment led to the selection of variants (especially A1343V) with lower sensitivity to the drug, uncovering a novel mechanism of resistance-associated variants during sofosbuvir treatment.
U2 - 10.1097/HEP.0000000000000514
DO - 10.1097/HEP.0000000000000514
M3 - SCORING: Journal article
C2 - 37334496
VL - 78
SP - 1882
EP - 1895
JO - HEPATOLOGY
JF - HEPATOLOGY
SN - 0270-9139
IS - 6
ER -