1185 CHARACTERIZATION OF HCV NS3 VARIANTS THAT EMERGED DURING VIROLOGIC BREAKTHROUGH AND RELAPSE FROM BI 201335 PHASE II SILEN-C2 STUDY IN PEGIFN/RBV TREATMENT-EXPERIENCED PATIENTS

Abstract

ribavirin (TRIPLE) or with peginterferon alfa-2a (P) and ribavirin (R) (QUAD) in chronic HCV genotype 1 treatment-naive patients. Clinical virology analyses are presented from patients with viral breakthrough (vBT) in DUAL arms, which were terminated due to vBT. Methods: Patients were randomized to VX-222 100mg (n =18) or 400mg (n =29) bid with TVR 1125mg bid for 12 weeks. 79% (37/47) of patients were subtype 1a, 21% (10/47) were subtype 1b. Treatment arms were discontinued if vBT rate was >25% with 90% confidence and patients were offered 48 weeks of PR. HCVRNA levels were measured (Roche Taqman HCV assay version 2.0, LLOQ: 25 IU/mL). Population sequence analysis of NS3•4A and NS5B was performed at baseline, vBT, and follow-up time points. Results: All DUAL regimen patients had an initial decline in HCVRNA, with 72% having ≤LLOQ by Week 2. However, both DUAL arms were terminated due to vBT. Of 12 patients with vBT, 11 were subtype 1a and 1 was subtype 1b. Sequencing identified variants resistant to both TVR and VX-222 in all patients at time of vBT: NS3-V36A/L, R155I/T, A156S/T/V, V36A/M+R155K and NS5B-L419S, R422K, M423T. The most common profile was NS3-A156T+NS5BR422K (n =5). Eleven of 12 patients started PR in the extension phase (1 patient declined); HCVRNA levels became undetectable in 7/11 patients. Of 5 patients with detectable HCVRNA (including the patient who declined PR), 4 had only wild-type virus during followup (median time from end of TVR+VX-222 treatment = 24 weeks, range 6–31). Conclusions: The DUAL regimens of telaprevir+VX-222 resulted in rapid initial declines in HCVRNA but were associated with >25% on-treatment vBT. Patients with vBT had variants resistant to both drugs. Resistant variants were suppressed and HCVRNA levels became undetectable in the majority of patients who were subsequently treated with PR. In 4 of the 5 patients with viremia, resistance to both drugs was lost during follow-up, indicating poor fitness of dual-resistant variants. Additional antiviral pressure with PR in QUAD regimens resulted in viral suppression; no patients experienced vBT.