Dasabuvir (ABT333) for the treatment of chronic HCV genotype I: a new face of cure, an expert review

ABSTRACT

Hepatitis C virus (HCV) affects nearly 1.3% of US population and around 2% of people worldwide. It is associated with serious complication of Cirrhosis and Hepatocellular carcinoma leading to significant morbidity and mortality. Until now the only treatment option for this serious disease was interferon based therapy which had poor tolerance and at best SVR (Sustained virological response) in only 50% of cases. With the introduction of other direct – acting antiviral agents the treatment of HCV has been revolutionized with significantly high rates of cure. Among novel Direct acting antivirals are non-nucleoside inhibitor NS5B which is highly effective in treatment of HCV genotype 1 a and 1b including those with compensated cirrhosis achieving high cure rates with SVR more than 97 % in pooled analysis from six different phase 3 trials. This review will discuss the DAA – Dasabuvir, a non – nucleoside NS5B inhibitor, its mechanism of action, efficacy, safety & tolerance, and drug resistance. Dasabuvir is approved by FDA in combination with other DAA agents called as the 3D(Viekira Pak) in various interferon free regimens achieving high cure rates (SVR >95%) with low adverse effects. In Europe, it is approved by European medicines agency for use in combination with Ombitasvir, Paritaprevir, and ritonavir with or without ribavirin. The drug is used in treatment naive as well as previously treated patient with high success rates. It is also approved in patients with compensated cirrhosis, patients with HIV co-infection and liver transplant recipients which were in the past were excluded from treatment with interferon based therapy. Dasabuvir is extensively evaluated in large clinical trials and shown excellent SVR among HCV genotype1 patient population in combination with other oral DAAs, with good safety profile and tolerance. Its drawback is its genotype restriction, need for ribavirin (RBV) for 1a genotype, low resistance barrier and high cost. It is well tolerated with less than 1 % of patients permanently discontinuing treatment and 2% of patient experiencing a serious adverse reaction. It is contraindicated in patients with known hypersensitivity to ritonavir (e.g. Steven – Johnson syndrome) and strong inducers of CYP3A and CYP2CB.

KEYWORDS:

• Dasabuvir
• ABT 333
• HCV
• polymerase inhibitor
• sustained virological response (SVR)
• direct antiviral agents (DAA)
• ABT-450
• 3D

Financial & competing interests disclosure

PS Mantry has received grants and received payment for research and consulting from Merck, Abbvie, Gilead, Intercept, Saliz, BMS, Tavere, Shinosi and Mass Biolosum. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• This review discusses the direct antiviral agent (DAA) – dasabuvir, its mechanism of action, efficacy, safety & tolerance, and drug resistance.

• Dasabuvir is an NS5B non-nucleoside polymerase inhibitor effective in genotype 1 patients with chronic HCV infection.

• It is approved in combination with two other DAAs: paritaprevir (boosted with low-dose ritonavir) and ombitasvir with or without ribavirin to treat HCV patients with genotype 1 infection including patients with compensated cirrhosis, post–liver transplant and HIV-coinfected patients.

• Dasabuvir is extremely well tolerated and has a very favorable side effect profile.

• Dasabuvir as a part of the above combination regimen has an overall SVR rate of 97% across different patient populations with an on treatment failure rate of 0.5% and a relapse rate of 1%.

• Its major limitation is its genotype restricted activity, need to include ribavirin for genotype 1a, low resistance barrier and its inability to treat patients with advance cirrhosis (Child–Pugh class B & C