Abstract - Dasabuvir (Exviera°). Only assessed as part of a difficult-to-manage combination in hepatitis C 

• In late 2015, the first-choice treatment for patients with chronic hepatitis C due to a genotype 1 virus (HCV- 1) was the combination of ledipasvir (an NS5A protein inhibitor) + sofosbuvir (a nucleotide inhibitor of NS5B RNA polymerase), despite major uncertainties regarding its adverse effects. This combination is almost always virologically effective.
  
  
• Dasabuvir is a non-nucleoside inhibitor of the viral RNA polymerase NS5B. It is authorised in the EU for the treatment of patients with chronic hepatitis C due to HCV-1, usually combined with the fixed-dose combination (Viekirax°) of ombitasvir (an HCV NS5A protein inhibitor) + paritaprevir (an HCV protease inhibitor) + ritonavir (to enhance paritaprevir bioavailability).
   
• The dasabuvir + ombitasvir + ritonavir-boosted paritaprevir combination has not been compared directly with the ledipasvir + sofosbuvir combination.
   
• In six trials including a total of 2315 HCV-1-infected patients who had no cirrhosis or compensated cirrhosis, treatment with this combination for 12 or 24 weeks, usually combined with ribavirin, led to sustained undetectable viraemia in almost every case. Ribavirin did not appear beneficial in patients with HCV genotype 1b infection.
   
• Data on the adverse effects of dasabuvir are weak, as they are mainly based on an unblinded trial in about 250 patients. The main adverse effects of dasabuvir in this trial were nausea, diarrhoea, insomnia, rash, and anaemia.
   
• The role of dasabuvir in cases of life-threatening liver injury among patients receiving the dasabuvir + ombitasvir + ritonavir-boosted paritaprevir combination is unclear. Dasabuvir overdose can occur in patients with severe liver failure.
   
• Dasabuvir is mainly metabolised by cytochrome P450 isoenzyme CYP2C8. Given the metabolic characteristics of the other drugs included in the combination, this creates a very high risk of pharmacokinetic interactions with drugs belonging to numerous therapeutic classes and makes treatment particularly difficult to manage.
   
• In practice, there is no evidence that the harm-benefit balance of combination therapy with dasabuvir is better than that of the ledipasvir + sofosbuvir combination. Postmarketing reports of serious liver injury highlight the many unknowns in terms of adverse effects and interactions. Particularly active pharmacovigilance is warranted.

Abstract - Ombitasvir + paritaprevir + ritonavir (Viekirax°).
Hepatitis C: high risk of interactions and serious liver injury 

• In patients with HCV genotype 4 (HCV-4) infection, initial assessment of ombitasvir + ritonavir-boosted paritaprevir + ribavirin combination therapy for 12 weeks is based primarily on an unblinded trial in 135 patients without cirrhosis. Virological efficacy was achieved in every case. In early 2016, this combination is the peginterferon alfa-sparing antiviral regimen with the least weak evidence of virological efficacy in HCV-4 infection.
   
• In HCV-1 infection, clinical trials of this regimen combined with dasabuvir showed no improvement over the ledipasvir + sofosbuvir combination.
   
• Paritaprevir is hepatotoxic. Cases of liver failure leading to liver transplantation or death have been attributed to the ombitasvir + ritonavir-boosted paritaprevir combination, given with or without dasabuvir.
   
• This combination carries a high risk of pharmacokinetic interactions, making it very difficult to use.

©Prescrire 1 May 2016

"Dasabuvir (Exviera°). Only assessed as part of a difficult-to-manage combination" Prescrire Int 2016; 25 (171): 117-120. (Pdf, subscribers only)

"Ombitasvir + paritaprevir + ritonavir (Viekirax°). Hepatitis C: high risk of interactions and serious liver injury" Prescrire Int 2016; 25 (171): 124-125. (Pdf, subscribers only)