Emergence of resistance-associated variants during sofosbuvir treatment in chronically infected hepatitis E patients
Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:78 |
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| Enthalten in: |
Hepatology (Baltimore, Md.) - 78(2023), 6 vom: 01. Dez., Seite 1882-1895 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Gömer, André [VerfasserIn] |
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| Links: |
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| Themen: |
Antiviral Agents |
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| Anmerkungen: |
Date Completed 16.11.2023 Date Revised 16.01.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1097/HEP.0000000000000514 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM358360501 |
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| 520 | |a Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
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| 700 | 1 | |a Pischke, Sven |e verfasserin |4 aut | |
| 700 | 1 | |a Horvatits, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Schulze Zur Wiesch, Julian |e verfasserin |4 aut | |
| 700 | 1 | |a Müller, Tobias |e verfasserin |4 aut | |
| 700 | 1 | |a Hardtke, Svenja |e verfasserin |4 aut | |
| 700 | 1 | |a Cornberg, Markus |e verfasserin |4 aut | |
| 700 | 1 | |a Wedemeyer, Heiner |e verfasserin |4 aut | |
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| 700 | 1 | |a Steinmann, Eike |e verfasserin |4 aut | |
| 700 | 1 | |a Todt, Daniel |e verfasserin |4 aut | |
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