Dynamic evolution of the sofosbuvir-associated variant A1343V in HEV-infected patients under concomitant sofosbuvir-ribavirin treatment.
Viral RNA-directed RNA polymerase inhibitors
high-throughput sequencing
intra-host evolution
resistance profiling
Journal
JHEP reports : innovation in hepatology
ISSN: 2589-5559
Titre abrégé: JHEP Rep
Pays: Netherlands
ID NLM: 101761237
Informations de publication
Date de publication:
Mar 2024
Mar 2024
Historique:
received:
12
07
2023
revised:
14
11
2023
accepted:
11
12
2023
medline:
4
3
2024
pubmed:
4
3
2024
entrez:
4
3
2024
Statut:
epublish
Résumé
In the absence of a hepatitis E virus (HEV)-specific antiviral treatment, sofosbuvir has recently been shown to have antiviral activity against HEV 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. 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 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. 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
Sections du résumé
Background & Aims
UNASSIGNED
In the absence of a hepatitis E virus (HEV)-specific antiviral treatment, sofosbuvir has recently been shown to have antiviral activity against HEV
Methods
UNASSIGNED
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
UNASSIGNED
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
Conclusions
UNASSIGNED
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
UNASSIGNED
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
Identifiants
pubmed: 38434938
doi: 10.1016/j.jhepr.2023.100989
pii: S2589-5559(23)00320-8
pmc: PMC10906529
doi:
Types de publication
Journal Article
Langues
eng
Pagination
100989Informations de copyright
© 2023 The Author(s).
Déclaration de conflit d'intérêts
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.