Dynamic evolution of the sofosbuvir-associated variant A1343V in HEV-infected patients under concomitant sofosbuvir-ribavirin treatment
André Gömer,
Katja Dinkelborg,
Mara Klöhn,
Michelle Jagst,
Michael Hermann Wißing,
Nicola Frericks,
Pia Nörenberg,
Patrick Behrendt,
Markus Cornberg,
Heiner Wedemeyer,
Eike Steinmann,
Benjamin Maasoumy,
Daniel Todt
Affiliations
André Gömer
Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
Katja Dinkelborg
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
Mara Klöhn
Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
Michelle Jagst
Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany; Institute of Virology, University of Veterinary Medicine Hannover, Hannover, Germany
Michael Hermann Wißing
Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
Nicola Frericks
Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
Pia Nörenberg
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
Patrick Behrendt
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
Markus Cornberg
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
Heiner Wedemeyer
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
Eike Steinmann
Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany; German Centre for Infection Research (DZIF), External Partner Site, Bochum, Germany; Corresponding authors. Addresses: Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Universitätsstr. 150, 44801 Bochum, Germany; Tel.: +49 234 32 22463, fax: +49 234 32 14352; (E. Steinmann), or (D. Todt), or Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany; (B. Maasoumy)
Benjamin Maasoumy
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany; German Center for Infectious Disease Research (DZIF); Partner Sites Hannover-Braunschweig, Germany; Corresponding authors. Addresses: Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Universitätsstr. 150, 44801 Bochum, Germany; Tel.: +49 234 32 22463, fax: +49 234 32 14352; (E. Steinmann), or (D. Todt), or Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany; (B. Maasoumy)
Daniel Todt
Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany; European Virus Bioinformatics Center (EVBC), Jena, Germany; Corresponding authors. Addresses: Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Universitätsstr. 150, 44801 Bochum, Germany; Tel.: +49 234 32 22463, fax: +49 234 32 14352; (E. Steinmann), or (D. Todt), or Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany; (B. Maasoumy)
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.
