Daclatasvir vs telaprevir plus peginterferon alfa/ribavirin for hepatitis C virus genotype 1

Abstract

Aim: To evaluate daclatasvir vs telaprevir, each combined with peginterferon alfa-2a/ribavirin (pegIFN/RBV), in treatment-naive hepatitis C virus (HCV) genotype (GT) 1-infected patients.

Methods: In this phase 3, randomized, open-label, noninferiority study, 602 patients were randomly assigned (2:1) to daclatasvir vs telaprevir, stratified by IL28B rs12979860 host genotype (CC vs non-CC), cirrhosis status (compensated cirrhosis vs no cirrhosis), and HCV GT1 subtype (GT1a vs GT1b). Patients were selected by study inclusion criteria from a total of 793 enrolled patients. Patients received daclatasvir 60 mg once daily or telaprevir 750 mg 3 times daily plus pegIFN/RBV. Daclatasvir recipients received 24 wk of daclatasvir plus pegIFN/RBV; those without an extended rapid virologic response (eRVR; undetectable HCV-RNA at weeks 4 and 12) received an additional 24 wk of pegIFN/RBV. Telaprevir-treated patients received 12 wk of telaprevir plus pegIFN/RBV followed by 12 (with eRVR) or 36 (no eRVR) wk of pegIFN/RBV. The primary objective was to compare for noninferiority of sustained virologic response rates at posttreatment week 12 (SVR12) in GT1b-infected patients. Key secondary objectives were to demonstrate that the rates of anemia (hemoglobin < 10 g/dL) and rash-related events, through week 12, were lower with daclatasvir + pegIFN/RBV than with telaprevir + pegIFN/RBV among GT1b-infected patients. Resistance testing was performed using population-based sequencing of the NS5A region for all patients at baseline, and for patients with virologic failure or relapse and HCV-RNA ≥ 1000 IU/mL, to investigate any link between NS5A polymorphisms associated with daclatasvir resistance and virologic outcome.

Results: Patient demographics and disease characteristics were generally balanced across treatment arms; however, there was a higher proportion of black/African Americans in the daclatasvir groups (6.0% and 8.2% in the GT1b and GT1a groups, respectively) than in the telaprevir groups (2.2% and 3.0%). Among GT1b-infected patients, daclatasvir plus pegIFN/RBV was noninferior to telaprevir plus pegIFN/RBV for SVR12 [85% (228/268) vs 81% (109/134); difference, 4.3% (95%CI: -3.3% to 11.9%)]. Anemia (hemoglobin < 10 g/dL) was significantly less frequent with daclatasvir than with telaprevir [difference, -29.1% (95%CI: -38.8% to -19.4%)]. Rash-related events were also less common with daclatasvir than with telaprevir, but the difference was not statistically significant. In GT1a-infected patients, SVR12 was 64.9% with daclatasvir and 69.7% with telaprevir. Among both daclatasvir and telaprevir treatment groups, across GT1b- or GT1a-infected patients, lower response rates were observed in patients with IL28B non-CC and cirrhosis - factors known to affect response to pegIFN/RBV. Consistent with these observations, a multivariate logistic regression analysis in GT1b-infected patients demonstrated that SVR12 was associated with IL28B host genotype (CC vs non-CC, P = 0.011) and cirrhosis status (absent vs present, P = 0.031). NS5A polymorphisms associated with daclatasvir resistance (at L28, R30, L31, or Y93) were observed in 17.3% of GT1b-infected patients at baseline; such variants did not appear to be absolute predictors of failure since 72.1% of these patients achieved SVR12 compared with 86.9% without these polymorphisms. Among GT1b-infected patients, treatment was completed by 85.4% (229/268) in the daclatasvir group, and by 85.1% (114/134) in the telaprevir group, and among GT1a-infected patients, by 67.2% (90/134) and 69.7% (46/66), respectively. Discontinuations (of all 3 agents) due to an AE were more frequent with telaprevir than with daclatasvir, whereas discontinuations due to lack of efficacy were more frequent with daclatasvir, due, in part, to differences in futility criteria.

Conclusion: Daclatasvir plus pegIFN/RBV demonstrated noninferiority to telaprevir plus pegIFN/RBV for SVR12 and was well-tolerated in treatment-naive GT1b-infected patients, supporting the use of daclatasvir with other direct-acting antivirals.

Keywords: Chronic hepatitis C; Daclatasvir; Direct-acting antiviral; Genotype 1b; Liver disease; NS5A inhibitor.

Figure 1

Patient disposition. Efficacy analyses were based on a modified intent-to-treat analysis (included all randomized and treated patients who had received ≥ 1 dose of study medication; patients with missing HCV RNA measurements were considered failures). ¹No longer met study entry criteria during the screening period (n = 139), withdrew consent (n = 28), administrative reason by sponsor (n = 5), lost to follow-up (n = 3), pretreatment AE (n = 2), or other reasons (n = 11); ²All 3 study drugs discontinued; ³Lack of efficacy (n = 15; 11 virologic breakthroughs, 3 futility, and 1 other), AE (n = 14), patient request (n = 6), lost to follow-up (n = 3), and withdrew consent (n = 1); ⁴AE (n = 17), withdrew consent (n = 2), and lost to follow-up (n = 1); ⁵Lack of efficacy (n = 23; 11 virologic breakthroughs, 4 futility, 8 other), adverse event (n = 11), lost to follow-up (n = 6), patient request (n = 1), and other (n = 3); ⁶Lack of efficacy (n = 5; 3 futility, 2 other), AE (n = 8), patient request (n = 3), lost to follow-up (n = 3), and death (n = 1; the death occurred in a patient who had discontinued treatment at week 16 due to bacteremia and died at posttreatment week 4 due to sepsis secondary to HCV-related cirrhosis). DCV: Daclatasvir; GT: Genotype; SVR12: Sustained virologic response (HCV-RNA < LLOQ) at posttreatment week 12; TVR: Telaprevir.

Figure 2

Safety secondary endpoints in GT1b-infected patients (first 12 wk). mITT analysis (patients with missing data at posttreatment week 12 were considered failures). ¹Superior at the 5% significance level; upper bound of the 95%CI was 0%; ²One patient in the TVR arm had no measurement due to discontinuation prior to on-treatment laboratory assessment; ³Includes rash-related SAEs, AEs leading to discontinuation, and grade 3 or 4 AEs. AE: Adverse event; CI: Confidence interval; DCV: Daclatasvir; GT: Genotype; Hgb: Hemoglobin; pegIFN: Peginterferon alfa-2a; RBV: Ribavirin; SAE: Serious adverse event; TVR: Telaprevir.