Baseline resistance-associated substitutions may impact DAA response among treatment failure chronic hepatitis C patients with pegylated interferon and ribavirin in real life.

摘要

To evaluate the impact of baseline resistance-associated substitutions (RASs) on direct-acting antiviral (DAA) treatment response among pegylated interferon in combination with ribavirin (PR) failing patients in a real-life setting. Blood samples and clinical data from 171 patients who failed PR treatment were collected. All of them received rescue DAA regimens. RAS identified in the NS3, NS5A and NS5B regions by Sanger sequencing method were compared by DAA regimen and HCV subtypes. We assessed sustained virological response at 12 weeks (SVR12) and evaluated the impact of baseline RASs on the effectiveness of DAA regimens in clinical practice. The overall SVR12 rates were: 89.47% (153/171), 92.1% (117/127) in patients without cirrhosis versus 81.8% (36/44) in those with cirrhosis, without significant difference (χ~(2)=3.69, P=0.08); 87.9% in genotype (GT)1b patients (n=116) versus 93.8% in GT2a (n=32) versus 90.5% in GT3 (n=21) versus 100% in GT6 (n=2), without significant difference (χ~(2)=1.02, P=0.84); 66.7% in asunaprevir (ASV) + daclatasvir (DCV) regimen (n=24) versus 94.0% in sofosbuvir (SOF)-based regimen (n=133), with significant difference (χ~(2)=19.7, P=0.001). Our results showed that the prevalence of NS3, NS5A, NS5B RASs was 45.02%, 39.76% and 71.34%, respectively, and higher incidence of RASs in cirrhosis than without cirrhosis (81.8% versus 63.8%), with a statistically significant difference (χ~(2)=4.92, P=0.03). In the ASV/DCV cohort (n=24), 4 of 11 patients (36.4%) with baseline NS3/NS5A RASs achieved SVR12, whereas 12 of 13 patients (92.3%) without RASs achieved SVR12, with significant difference (χ~(2)=8.39, P=0.008). However, this relationship was not seen in the SOF-based subgroup (94.6% versus 92.7%; χ~(2)=0.18, P=0.7). Treatment failure with DAAs occurred in 10.53% (n=18) of our study population, baseline NS5A substitution including L31M or Y93H (n=13) was the most frequently detected RAS, rescue regimen with velpatasvir (VEL)/SOF + ribavirin (RBV) for 12 weeks or 24 weeks was highly effective in patients who failed previous use of NS5A inhibitors, regardless of GT or cirrhosis. Natural RASs are common in Chinese patients failing with PR treatment. High prevalence of clinically relevant RASs (such as L31M, Y93H) supports the appropriateness of HCV resistance tests to properly guide DAA-based therapy. These findings might be used to select salvage therapies.