Details

Autor(en) / Beteiligte

• Svarovskaia, Evguenia S.
• Dvory-Sobol, Hadas
• Parkin, Neil
• Hebner, Christy
• Gontcharova, Viktoria
• Martin, Ross
• Ouyang, Wen
• Han, Bin
• Xu, Simin
• Ku, Karin
• Chiu, Sophia
• Gane, Edward
• Jacobson, Ira M.
• Nelson, David R.
• Lawitz, Eric
• Wyles, David L.
• Bekele, Neby
• Brainard, Diana
• Symonds, William T.
• McHutchison, John G.
• Miller, Michael D.
• Mo, Hongmei

Titel

Infrequent Development of Resistance in Genotype 1–6 Hepatitis C Virus–Infected Subjects Treated With Sofosbuvir in Phase 2 and 3 Clinical Trials

Ist Teil von

• Clinical infectious diseases, 2014-12, Vol.59 (12), p.1666-1674

Ort / Verlag

Oxford: Oxford University Press

Erscheinungsjahr

2014

Link zum Volltext

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• Background. Sofosbuvir is a chain-terminating nucleotide analogue inhibitor of the hepatitis C virus (HCV) NS5B RNA polymerase that is efficacious in subjects with HCV genotype 1–6 infection. Sofosbuvir resistance is primarily conferred by the S282T substitution in NS5B. Methods. NS5B sequencing and susceptibility testing of HCV from subjects infected with genotypes 1–6 who participated in phase 2 and 3 sofosbuvir clinical trials was performed. Results. No NS5B variants present at baseline among 1645 sofosbuvir-treated subjects were associated with treatment failure; sofosbuvir susceptibility was within 2-fold of reference. Among 282 subjects who did not achieve sustained virologic response, no novel sofosbuvir resistance–associated variants were identified, and the NS5B changes observed did not confer significant reductions in sofosbuvir susceptibility. In 1 subject with S282T observed at relapse 4 weeks after sofosbuvir monotherapy, the resistant variant (13.5-fold reduced sofosbuvir susceptibility, replication capacity <2% of control) became undetectable by deep sequencing 12 weeks after treatment. L159F and V321A were identified as treatment-emergent variants but did not confer resistance to sofosbuvir in the replicon system. Conclusions. These data demonstrate a uniform susceptibility of subject-derived HCV to sofosbuvir, and also show that selection of sofosbuvir-resistant HCV is exceedingly rare and is associated with a significant reduction in viral fitness.