Daclatasvir dihydrochloride/Asunaprevir/Beclabuvir hydrochloride

Many reports have evaluated the clinical efficacy and safety of the fixed-dose all-oral combination of daclatasvir, asunaprevir, and beclabuvir (DCV-TRIO), which was approved in Japan in December 2016 for the treatment of hepatitis C genotype (GT)-1 infection. Areas covered: This article reviews the pharmacodynamic and pharmacokinetic properties of the DCV-TRIO combination. The topics covered include data regarding the drug's absorption, distribution, metabolism, excretion, and antiviral activity strategies. Its therapeutic efficacy and safety in GT-1 infection from phase 2/3 clinical trials are also discussed. Expert opinion: The ideal regimen for the treatment of Hepatitis C virus infection should be potent, pangenotypic, Ribavirin-free, safe, co-formulated, and affordable. Considering these characteristics, DCV-TRIO is neither pangenotypic nor potent enough against GT-1a, regardless of the presence or absence of cirrhosis. Other potential limitations of this regimen are its dosification (twice-daily), and the fact that since it includes a protease inhibitor, it is contraindicated in decompensated cirrhosis. For these reasons, it has only been approved in Japan, where more than 70% of the patients are infected with GT-1b. However, this co-formulation might still have a place in the treatment of non-cirrhotic patients infected with GT-1b provided that massive access to treatment is facilitated.

This multinational (Taiwan, South Korea, Russia) phase 3 study evaluated the all‐oral, ribavirin‐free, fixed‐dose combination (DCV‐TRIO) of daclatasvir (NS5A inhibitor) 30 mg, asunaprevir (NS3 inhibitor) 200 mg, and beclabuvir (NS5B inhibitor) 75 mg, in patients with chronic hepatitis C virus genotype‐1 infection, with or without compensated cirrhosis.

UNITY‐4 (NCT02170727) was an open‐label, two‐cohort study in which 169 patients, treatment‐naive (n = 138) or treatment‐experienced (n = 31), received twice‐daily DCV‐TRIO for 12 weeks with 24 weeks of post‐treatment follow‐up. The primary efficacy end point was sustained virologic response at post‐treatment week 12 (SVR12) in treatment‐naive patients.

Eighty‐eight (52%) patients were men, 81 (48%) Taiwanese, 78 (46%) Korean, and 10 (6%) Russian; 23 (14%) had compensated cirrhosis, and 52 (31%) were IL28B (rs1297860) non‐CC genotype. Baseline resistance‐associated NS5A polymorphisms (L31 and/or Y93) were detected in 25/165 (15%) patients with available genotype‐1 sequencing data. SVR12 was achieved by 98.6% (136/138; 95% confidence interval: 94.9–99.8%) of treatment‐naive and 100% (31/31; 95% confidence interval: 88.8–100%) of treatment‐experienced patients. Both virologic failures were found to be infected with hepatitis C virus genotype‐6g; 100% SVR12 was observed for genotype‐1a (n = 8) and genotype‐1b (n = 157). Two patients experienced serious adverse events. Eight (5%) patients experienced reversible grade 3/4 alanine aminotransferase or aspartate aminotransferase elevations, leading to discontinuation in four (2%); all achieved SVR12. There were no grade 3/4 total bilirubin increases and no deaths.

Twelve weeks of DCV‐TRIO was well tolerated and provided 100% SVR12 in treatment‐naive and treatment‐experienced patients with genotype‐1 infection, with or without cirrhosis, including those with baseline NS5A‐L31 or NS5A‐Y93 resistance‐associated substitutions.