Emergence of resistance-associated variants during sofosbuvir treatment in chronically infected hepatitis E patients

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 -