Daclatasvir plus asunaprevir in treatment-naïve patients with hepatitis C virus genotype 1b infection

Abstract

Aim: To assess daclatasvir plus asunaprevir (DUAL) in treatment-naïve patients from mainland China, Russia and South Korea with hepatitis C virus (HCV) genotype 1b infection.

Methods: Patients were randomly assigned (3:1) to receive 24 wk of treatment with DUAL (daclatasvir 60 mg once daily and asunaprevir 100 mg twice daily) beginning on day 1 of the treatment period (immediate treatment arm) or following 12 wk of matching placebo (placebo-deferred treatment arm). The primary endpoint was a comparison of sustained virologic response at posttreatment week 12 (SVR12) compared with the historical SVR rate for peg-interferon plus ribavirin (70%) among patients in the immediate treatment arm. The first 12 wk of the study were blinded. Safety was assessed in DUAL-treated patients compared with placebo patients during the first 12 wk (double-blind phase), and during 24 wk of DUAL in both arms combined.

Results: In total, 207 patients were randomly assigned to immediate (n = 155) or placebo-deferred (n = 52) treatment. Most patients were Asian (86%), female (59%) and aged < 65 years (90%). Among them, 13% had cirrhosis, 32% had IL28B non-CC genotypes and 53% had baseline HCV RNA levels of ≥ 6 million IU/mL. Among patients in the immediate treatment arm, SVR12 was achieved by 92% (95% confidence interval: 87.2-96.0), which was significantly higher than the historical comparator rate (70%). SVR12 was largely unaffected by cirrhosis (89%), age ≥ 65 years (92%), male sex (90%), baseline HCV RNA ≥ 6 million (89%) or IL28B non-CC genotypes (96%), although SVR12 was higher among patients without (96%) than among those with (53%) baseline NS5A resistance-associated polymorphisms (at L31 or Y93H). During the double-blind phase, aminotransferase elevations were more common among placebo recipients than among patients receiving DUAL. During 24 wk of DUAL therapy (combined arms), the most common adverse events (≥ 10%) were elevated alanine aminotransferase and upper respiratory tract infection; emergent grade 3-4 laboratory abnormalities were infrequently observed, and all grade 3-4 aminotransferase abnormalities (alanine aminotransferase, n = 9; aspartate transaminase, n = 6) reversed within 8-11 d. Two patients discontinued DUAL treatment; one due to aminotransferase elevations, nausea, and jaundice and the other due to a fatal adverse event unrelated to treatment. There were no treatment-related deaths.

Conclusion: DUAL was well-tolerated during this phase 3 study, and SVR12 with DUAL treatment (92%) exceeded the historical SVR rate for peg-interferon plus ribavirin of 70%.

Keywords: Asunaprevir; Chronic hepatitis C; Daclatasvir; Direct-acting antiviral; Genotype 1b; Liver disease; NS3; NS5A.

Figure 1

SVR12 in the immediate treatment arm. ¹Includes the patient with genotype 1a infection; ²On-treatment HCV RNA ≥ LLOQ after < LLOQ, or increased > 1 log₁₀ over nadir; ³Posttreatment HCV RNA ≥ LLOQ after < LLOQ without detectable target at EOT. EOT: End of treatment; HCV: Hepatitis C virus; LLOQ: Lower limit of quantitation; SVR12: Sustained virologic response at post-treatment week 12.

Figure 2

SVR12 according to selected baseline characteristics in the immediate treatment arm. HCV: Hepatitis C virus; SVR12: Sustained virologic response at posttreatment week 12.

Figure 3

SVR12 in the placebo-deferred treatment arm. ¹On-treatment HCV RNA ≥ LLOQ after < LLOQ, or increased >1 log₁₀ over nadir; ²HCV RNA < LLOQ (TND) at EOT followed by HCV RNA ≥ LLOQ at any follow-up visit; ³Other nonresponders included patients who had HCV RNA < LLOQ (TND) at EOT, but with missing posttreatment week 12 data; ⁴Death, not considered related to study therapy (stab wound). EOT: End of treatment; HCV: Hepatitis C virus; LLOQ: Lower limit of quantitation; SVR12, Sustained virologic response at post-treatment week 12.

Figure 4

SVR12 according to selected baseline characteristics in the placebo-deferred treatment arm¹. ¹Reasons for patients not achieving SVR12 included virologic breakthrough (n = 7), relapse (n = 1) or other (n = 1; death, not considered related to study therapy). HCV: Hepatitis C virus; SVR12: Sustained virologic response at post-treatment week 12.