@article{PAR00015083,
  title = {{H}epatitis {E} virus mutations associated with ribavirin treatment failure result in altered viral fitness and ribavirin sensitivity},
  author = {{D}ebing, {Y}. and {R}amiere, {C}. and {D}allmeier, {K}. and {P}iorkowski, {G}. and {T}rabaud, {M}. {A}. and {L}ebosse, {F}. and {S}choltes, {C}. and {R}oche, {M}. and {L}egras-{L}achuer, {C}. and de {L}amballerie, {X}avier and {A}ndre, {P}. and {N}eyts, {J}.},
  editor = {},
  language = {{ENG}},
  abstract = {{B}ackground & {A}ims: {R}ibavirin monotherapy is the preferred treatment for chronic hepatitis {E}, although occasional treatment failure occurs. {W}e present a patient with chronic hepatitis {E} experiencing ribavirin treatment failure with a completely resistant phenotype. {W}e aimed to identify viral mutations associated with treatment failure and explore the underlying mechanisms. {M}ethods: {V}iral genomes were deep-sequenced at different time points and the role of identified mutations was assessed in vitro using mutant replicons, antiviral assays, cell culture of patientderived virus and deep-sequencing. {R}esults: {R}ibavirin resistance was associated with {Y}1320{H}, {K}1383{N} and {G}1634{R} mutations in the viral polymerase, but also an insertion in the hypervariable region comprising a duplication and a polymerase-derived fragment. {A}nalysis of these genome alterations in vitro revealed replication-increasing roles for {Y}1320{H} and {G}1634{R} mutations and the hypervariable region insertion. {I}n contrast, the {K}1383{N} mutation in the polymerase {F}1-motif suppressed viral replication and increased the in vitro sensitivity to ribavirin, contrary to the clinical phenotype. {A}naly- sis of the replication of mutant full-length virus and in vitro culturing of patient-derived virus confirmed that sensitivity to ribavirin was retained. {F}inally, deep-sequencing of hepatitis {E} virus genomes revealed that ribavirin is mutagenic to viral replication in vitro and in vivo. {C}onclusions: {M}utations {Y}1320{H}, {G}1634{R} and the hypervariable region insertion compensated for {K}1383{N}-associated replication defects. {T}he specific role of the {K}1383{N} mutation remains enigmatic, but it appears to be of importance for the ribavirin resistant phenotype in this patient. {L}ay summary: {R}ibavirin is the most common treatment for chronic hepatitis {E} and is mostly effective, although some cases of ribavirin treatment failure have been described. {H}ere, we report on a particular case of ribavirin resistance and investigate the underlying causes of treatment failure. {M}utations in the viral polymerase, an essential enzyme for viral replication, appear to be responsible.},
  keywords = {{H}epatitis {E} virus ; {C}hronic hepatitis {E} ; {R}ibavirin ; {R}esistance ; {G}1634{R} ; {F}idelity ; {RNA}-dependent {RNA} polymerase ; {H}ypervariable region},
  booktitle = {},
  journal = {{J}ournal of {H}epatology},
  volume = {65},
  numero = {3},
  pages = {499--508},
  ISSN = {0168-8278},
  year = {2016},
  URL = {https://www.documentation.ird.fr/hor/{PAR}00015083},
}