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© 2017. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

S282T in NS5B is the primary amino acid substitution associated with resistance to sofosbuvir (SOF) but has rarely been detected in patients treated with a SOF‐based regimen. Here, the emergence and fitness of the S282T substitution in virologic failure patients administered SOF‐based regimens across the SOF and ledipasvir (LDV)/SOF phase 2 and 3 programs was evaluated. Plasma samples collected at baseline and at virologic failure were amplified and deep sequenced (1% cutoff). To date, over 12,000 patients have been treated in SOF or LDV/SOF phase 2 and 3 studies. Of these, deep sequencing was available at baseline in 8598 patients (62.4% genotype [GT] 1, 10.7% GT2, 20.9% GT3, and 6.0% GT4‐6) and at virologic failure in 901 patients. In the 8598 patients, no S282T substitution was detected at baseline; at virologic failure, 10 of the 901 (1%) patients had S282T detected. The SOF‐based regimen associated with treatment‐emergent S282T was SOF monotherapy in two patients, retreatment with LDV/SOF in prior LDV/SOF failures in three patients, LDV/SOF for 8 weeks in 1 GT1 patient, LDV/SOF for 12 weeks in 1 patient each with GT3, GT4, and GT5, and LDV/SOF + ribavirin for 12 weeks in 1 GT6 patient. Nine of 10 patients with emergent S282T received an SOF‐based retreatment regimen, eight of whom achieved sustained virologic response 12 weeks after treatment and one of whom failed retreatment. Conclusion: The emergence of S282T substitution was rare in patients who fail SOF‐based regimens. Successful retreatment of prior SOF failure patients is possible in the presence of S282T substitution with SOF in combination with various direct‐acting antiviral agents. (Hepatology Communications 2017;1:538–549)

Details

Title
The emergence of NS5B resistance associated substitution S282T after sofosbuvir‐based treatment
Author
Gane, Edward J 1 ; Metivier, Sophie 2 ; Nahass, Ronald 3 ; Ryan, Michael 4 ; Stedman, Catherine A 5 ; Svarovskaia, Evguenia S 6 ; Mo, Hongmei 6 ; Doehle, Brian 6 ; Hadas Dvory‐Sobol 6 ; Hedskog, Charlotte 6 ; Lin, Ming 6 ; Brainard, Diana M 6 ; Yang, Jenny C 6 ; McHutchison, John G 6 ; Sulkowski, Mark 7 ; Younes, Ziad 8 ; Lawitz, Eric 9 

 Auckland Clinical Studies, Auckland, New Zealand 
 Centre Hospitalier Universitaire‐Purpan, Toulouse, France 
 ID Care, Inc, Hillsborough, NJ 
 Digestive and Liver Disease Specialists, Norfolk, VA 
 Christchurch Hospital and University of Otago, Christchurch, New Zealand 
 Gilead Sciences, Inc, Foster City, CA 
 Johns Hopkins University School of Medicine, Baltimore, MD 
 Gastro One, Germantown, TN 
 Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX 
Pages
538-549
Section
Original Articles
Publication year
2017
Publication date
Aug 2017
Publisher
Wolters Kluwer Health Medical Research, Lippincott Williams & Wilkins
e-ISSN
2471254X
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2289813441
Copyright
© 2017. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.