Clinical evaluation of sofosbuvir/ledipasvir in patients with chronic hepatitis C genotype 1 with and without prior daclatasvir/asunaprevir therapy

Aim This study explored treatment outcomes of sofosbuvir (SOF)/ledipasvir (LDV) therapy for chronic hepatitis C patients with and without prior daclatasvir (DCV)/asunaprevir (ASV) therapy. Methods Overall, 530 Japanese patients who were infected with hepatitis C virus genotype 1 received SOF/LDV therapy for 12 weeks, and resistance-associated variants (RAVs) in the hepatitis C virus non-structural protein (NS)5A and NS5B regions were assessed at baseline and virological relapse by direct sequencing. Results Sustained virological response (SVR) rates did not significantly differ between patients with and without NS5A Y93H/N (94.2% [113/120] vs. 97.7% [345/353]), but the SVR rate was significantly lower in patients with prior DCV/ASV therapy compared to those without (69.2% [18/26] vs. 98.4% [496/504], P < 0.001). Among 26 patients with prior DCV/ASV therapy, the prevalence of NS5A multi-RAVs (≥2) was similar between responders and non-responders (61% [11/18] vs. 75% [5/8]), but all patients without RAVs achieved SVR. Multivariate analysis showed that prior DCV/ASV therapy and history of hepatocellular carcinoma were independently associated with treatment failure (odds ratio, 37.55; 95% confidence interval, 10.78–130.76; P < 0.001 for prior DCV/ASV therapy; odds ratio, 4.42; 95% confidence interval, 1.09–18.04; P = 0.03 for the history of HCC). All SOF/LDV failure patients (n = 8) with prior DCV/ASV treatment had two or more factors of cirrhosis, IL28B unfavorable genotype, and baseline NS5A multi-RAVs. The multiple NS5A RAVs had increased but NS5B substitutions, C316N/A207T/A218S or L159F, had not changed at the time of relapse. Conclusions Prior DCV/ASV therapy is associated with failure of SOF/LDV therapy due to multiple RAVs.