The co-existence of NS5A and NS5B resistance-associated substitutions is associated with virologic failure in Hepatitis C Virus genotype 1 patients treated with sofosbuvir and ledipasvir

<div><p>Objective</p><p>The present study aimed to reveal the factors associated with virologic failure in sofosbuvir and ledipasvir (SOF/LDV)-treated patients, and identify baseline NS5A or NS5B resistance-associated substitutions (RASs).</p><p>Methods</p><p>Four hundred ninety-three patients with Hepatitis C Virus (HCV) genotype 1b infection were treated with SOF/LDV; 31 had a history of interferon (IFN)-free treatment with daclatasvir and asunaprevir. The effect of baseline RASs on the response to SOF/LDV therapy was analyzed.</p><p>Results</p><p>Overall, a sustained virologic response at 12 weeks (SVR12) was achieved in 476 patients (96.6%). The SVR12 rates in the patients with IFN-free treatment-naïve and retreatment were 97.6% and 80.6%, respectively. HCV elimination was not achieved in 17 patients, 11 (including 5 with IFN-free retreatment) of whom had virologic failure. Eight patients had coexisting NS5A RASs of Q24, L28 and/or R30, L31, or Y93 and one patient had coexisting NS5A RASs of P32L and A92K. Interestingly, 10 and 8 patients had NS5B A218S and C316N RAS respectively. According to a multivariate analysis, coexisting NS5A RASs, NS5A P32 RAS, NS5B A218 and/or C316 RASs, and γ-glutamyltranspeptidase were associated with virologic failure. In the naïve patients, all patients without NS5B A218 and/or C316 RAS achieved an SVR12. Notably, the SVR12 rates of patients with coexisting NS5A and NS5B RASs were significantly lower (83.3%).</p><p>Conclusions</p><p>Although SOF/LDV therapy resulted in a high SVR12 rate, coexisting NS5A and NS5B RASs were associated with virologic failure. These results might indicate that the coexisting baseline RASs influence the therapeutic effects of SOF/LDV.</p></div

The virologic response rates (intention-to-treat analysis).

<p>The sustained virologic response (SVR) 12 rates of the IFN-free treatment-naïve patients and IFN-free retreatment patients were 97.6% and 80.6% respectively.</p

The baseline resistance-associated substitutions (RASs) and virologic failure in patients treated with sofosbuvir and ledipasvir.

<p>The baseline resistance-associated substitutions (RASs) and virologic failure in patients treated with sofosbuvir and ledipasvir.</p

The reasons for the discontinuation of sofosbuvir/lediprevir.

<p>The reasons for the discontinuation of sofosbuvir/lediprevir.</p

The sustained virologic response (SVR) 12 rate in the patients with co-existing NS5A and NS5B RASs.

<p>The interferon (IFN) free-naïve patients with coexisting resistance-associated substitutions (RASs) of Q24, L28, and/or R30, L31, or Y93 and NS5B A218 and/or C316 had a significantly lower sustained virologic response (SVR) 12 rate in comparison to the patients without these RASs.</p

The multivariate logistic regression analysis of factors associated with virologic failure in patients treated with sofosbuvir and ledipasvir.

<p>The multivariate logistic regression analysis of factors associated with virologic failure in patients treated with sofosbuvir and ledipasvir.</p