The emergence of NS5B resistance associated substitution S282T after sofosbuvir-based treatment

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).

Figure 1

RNA dynamics and S282T emergence in SOF‐ or LDV/SOF‐treated patients. (A) Emergent S282T substitution in patient 1 (GT2b infection) and patient 2 (GT1b infection), who were treated with SOF monotherapy. (B) Emergent S282T substitution in patient 3 (GT1a infection) treated with LDV/SOF. (C) Emergent S282T substitution in three patients with GT1a infection (patients 4, 5, and 6) retreated with LDV/SOF. (D) Emergent S282T substitution in patients infected with non‐GT1 HCV (patients 7, 8, 9, and 10) who were treated with LDV/SOF.

Figure 2

SOF susceptibility and replication capacity of S282T alone and in combination with L159F. EC₅₀ fold change and replication capacity were calculated using GT1a replicon values. WT, wild type.

Figure 3

Evolution of NS5B 282 codons usage in patient who developed S282T. WT, wild type.