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)

Management of patients with chronic hepatitis C failing repeated courses of interferon‐free direct acting antiviral combination therapy

“…27,28 NS5B nucleotide RASs are detected only in about 1% of failures to nucleotide containing DAA therapies and thus can be re-used for retreatments after DAA failure. 29 However, no correlation between RAS and SVR could be found in our study.…”

“…Similar to other studies the most frequent NS5A RASs were found at amino acid positions 28, 30, 31 and 93, against which the efficacy of NS5A inhibitors varies . NS5B nucleotide RASs are detected only in about 1% of failures to nucleotide containing DAA therapies and thus can be re‐used for retreatments after DAA failure . However, no correlation between RAS and SVR could be found in our study.…”

Efficacy and safety of sofosbuvir/simeprevir plus flat dose ribavirin in genotype 1 elderly cirrhotic patients: A real‐life study

“…Overall, RAVs were found in 6/10 SOF/SMV/RBV failing patients. SOF RAVs at virological failure were low (2/10, 20%), though one patient showed the major S282T mutation, reported in literature with an extremely rare prevalence (around 1%) at SOF failure . Simeprevir RAVs were more frequently at failure (5/10, 50%).…”

“…SOF RAVs at virological failure were low (2/10, 20%), though one patient showed the major S282T mutation, reported in literature with an extremely rare prevalence (around 1%) at SOF failure. 27 Simeprevir RAVs were more frequently at failure (5/10, 50% Of the AEs, only anaemia was more frequent among the elderly vs the younger patients. Grade 2 anaemia was identified in 35.3% of elderly patients in the current work and grade 3 anaemia was observed in 7 (5.3%).…”

From current status to optimization of HCV treatment: Recommendations from an expert panel

“…Due to the high conservation of RNA polymerase catalytic site, aminoacid substitutions in this region result in viral strains with extremely low replicative fitness, so that the most commonly described RAV to SOF, the S282T, is rapidly no longer detectable (84). As a consequence, retreatment of SOF-failed patients with SOF-containing regimens yields optimal efficacy, resulting in same SVR as naïve patients (85,86).…”