Review Article

The Efficacy and Safety of Daclatasvir in the Treatment of Chronic Hepatitis C Virus Infection

C. Bunchorntavakul; K. R. Reddy

Disclosures

Aliment Pharmacol Ther. 2015;42(3):258-272. 

In This Article

Abstract and Introduction

Abstract

Background The treatment of hepatitis C virus (HCV) has evolved dramatically after the introduction of direct acting anti-virals. NS5A protein plays an important role in HCV replication and is an attractive target for drug development.

Aim To review clinical studies on the efficacy and safety of direct-acting anti-virals regimens containing daclastavir, an NS5A inhibitor, in the treatment of chronic hepatitis C.

Methods A Medline search was undertaken to identify relevant literature using search terms including 'daclatasvir', 'HCV treatment' and 'NS5A inhibitors'. Furthermore, we scanned abstracts presented at the recent international meetings in liver disease, viral hepatitis and infectious disease, as well as the reference lists of the review articles to identify publications not retrieved by electronic searches.

Results Daclatasvir is the first-in-class HCV NS5A inhibitor that has been demonstrated in Phase I-III trials to have a potent anti-viral effect and clinical efficacy across multiple HCV genotypes (GT). Daclastavir is generally safe and well tolerated, with a low barrier to resistance and low potential for drug–drug interaction. When Daclastavir is added to PEG-IFN/RBV platform, sustained virological response (SVR) rates are increased significantly compared with PEG-IFN/RBV alone. The all-oral combination of Daclastavir/asunaprevir (ASV; protease inhibitor) has high SVR rates against GT1b, but less activity against GT1a. Dual combination of Daclastavir/Sofosbuvir (SOF; nucleotide polymerase inhibitor) and triple combination of Daclastavir/ASV/beclabuvir (BCV; non-nucleoside polymerase inhibitor) have demonstrated >90% SVR rates in both treatment naïve and treatment-experienced patients with GT1. Furthermore, Daclastavir/SOF combination has also demonstrated up to 90% SVR rates in patients with GT3, and in those with human immunodeficiency virus coinfection, cirrhosis and post-transplant HCV recurrence with any GT. Daclastavir/ASV/BCV has primarily demonstrated near 100% SVR rates in patients with GT4.

Conclusion Daclastavir-containing regimens, with or without PEG-IFN, have shown promising results in clinical trials, and present an excellent treatment option for those with chronic HCV and for multiple genotypes.

Introduction

Worldwide, chronic hepatitis C virus (HCV) infection is a leading cause of chronic liver disease and hepatocellular carcinoma. Treatment with pegylated interferon (PEG-IFN) and ribavirin (RBV) had been the standard of care for HCV patients for a decade, until the development of several direct-acting antivirals (DAA), that are in three main classes; NS3/4A inhibitors [e.g. boceprevir (BOC), telaprevir (TPV), simeprevir, asunaprevir (ASV), and paritaprevir boosted by ritonavir], NS5A inhibitors [e.g. daclatasvir (DCV), ledipasvir, and ombitasvir], and NS5B nucleotide [sofosbuvir (SOF)] and non-nucleoside (e.g. dasabuvir) polymerase inhibitors. These DAAs have been approved variably in various parts of the World as either along with PEG-IFN and RBV, or with RBV, or in combination as multiple all oral DAAs with or without RBV, while new DAAs particularly of a pangenotypic nature are being developed. DCV have been approved for the treatment of HCV genotype (GT) 1 as part of three-drug combination with PEG-IFN and RBV, and along with ASV in certain regions of the World. In addition, the recent European Association of the Study of the Liver (EASL) recommendations have suggested the use of DCV-containing regimens as an option for all HCV GTs in various groups patients, including treatment-naïve, treatment-experienced, compensated and decompensated cirrhosis, chronic kidney disease, post-liver transplantation (LT) and human immunodeficiency virus (HIV) coinfection.[1]

The excellent tolerability and high sustained virological response (SVR) rates with all oral therapy for HCV infection in the clinic could signal the end of the need for IFN as an integral component of the standard of care. This transition would reduce the burden of treatment in all HCV patients and allow more individuals to be treated including those who are intolerant of interferon or are unresponsive, and further have contraindications to IFN-based therapy.

This review will walk you through the development of the first-in-class NS5A inhibitor, DCV, from the in vitro and clinical phase study stages to an official approval. In addition, the safety and efficacy of DCV in various treatment regimens and patient populations will also be discussed.

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