Real-world efficacy of daclatasvir and asunaprevir with respect to resistance-associated substitutions

Abstract

Aim: To investigate daclatasvir (DCV) and asunaprevir (ASV) efficacy in hepatitis C (HCV) patients, with respect to resistance-associated substitutions (RASs).

Methods: A total of 392 HCV-infected patients from multiple centers were included in this study. We evaluated their clinical courses and sustained virologic responses (SVR) according to pretreatment factors (gender, age, history of interferon-based regimens, platelet counts, level of viremia, pretreatment NA5A:L31, and Y93 substitutions). We also analyzed the pretreatment and post-treatment major RASs of NS3:D168, NS5A:L31 and Y93 substitutions using a direct-sequencing method in 17 patients who were unable to achieve SVR at 12 wk after treatment completion (SVR12).

Results: The overall SVR12 rate was 88.3%. Thirty-one patients discontinued treatment before 24 wk because of adverse events, 23 of whom achieved SVR12. There were no significant differences in SVR12 rates with respect to gender, age, history of interferon-based regimens, and platelet counts. The SVR12 rate in patients with viral loads of ≥ 6.0 log IU/mL was significantly lower than those with viral loads of < 6.0 log IU/mL (P < 0.001). The SVR12 rate in patients with Y93 substitution-positive was significantly lower than those with Y93 substitution-negative (P < 0.001). The L31 substitution-positive group showed a lower SVR12 rate than the L31 substitution-negative group, but the difference was not statistically significant. Seventeen patients who did not achieve SVR12 and had available pretreatment and post-treatment sera had additional RASs in NS3:D168, NS5:L31, and Y93 substitution at treatment failure.

Conclusion: Combination of DCV and ASV is associated with a high SVR rate. Baseline RASs should be thoroughly assessed to avoid additional RASs after treatment failure.

Keywords: Asunaprevir; Combination therapy; Daclatasvir; Hepatitis C; Resistance-associated substitutions.

Figure 1

Virological response and treatment outcomes. Black closed squares indicate the proportion of patients who discontinued treatment because of adverse events and unachieved SVR12. Non-response (NR), where HCV RNA remained detectable during treatment, prompting treatment discontinuation. Breakthrough (BT), where HCV RNA was undetectable but reappeared during treatment. Relapse (REL), where HCV RNA was undetectable at the end of the treatment but became quantifiable again during follow-up. Gray closed squares indicate the proportion of patients with HCV RNA detected at the time of measurement. Light gray square indicate the proportion of patients who discontinued treatment because of adverse events but nevertheless achieved SVR12. White closed squares indicate the proportion of patients whose HCV RNA viral loads were undetected at the time of measurement. The Post 12 wk bar indicates the number of patients in each square.

Figure 2

Bars in this graph indicate SVR12 rates according to gender (male, female), age (< 65 year vs ≥ 65 year), history of interferon-based regimen treatment (+ vs -), level of viremia (< 6.0 logIU/mL vs ≥ 6.0 logIU/mL), platelet counts (< 10 × 10⁴/mm³ vs ≥ 10 × 10⁴/mm³), pretreatment existing L31 substitution [(-): substitution negative, (+): substitution positive], pretreatment existing Y93 substitution [(-): substitution negative, (+): substitution positive], and Y93 and/or L31 [(-): both L31 and Y93 substitution negative, (+): either L31 or Y93 substitution positive, or both L31 and Y93 substitution positive]. M: Male; F: Female; IFN: Interferon.