Clinical management of drug–drug interactions in HCV therapy: Challenges and solutions

Abstract

Hepatitis C virus (HCV) infected patients often take multiple co-medications to treat adverse events related to HCV therapy, or to manage other co-morbidities. Drug-drug interactions associated with this polypharmacy are relatively new to the field of HCV pharmacotherapy. With the advent of the direct-acting antivirals telaprevir and boceprevir, which are both substrates and inhibitors of the cytochrome P450 (CYP) 3A iso-enzyme, knowledge and awareness of drug-drug interactions have become a cornerstone in the evaluation of patients starting and continuing HCV combination therapy. In our opinion, an overview of conducted drug-drug interaction studies and a list of contraindicated medications is not enough for the clinical management of these drug-drug interactions. Knowledge of pharmacokinetic profiles and concentration-effect relationships is key for the interpretation of these data, and insight into how to manage these interactions (e.g., dose adjustments, safe alternatives and therapeutic drug monitoring) is of equal importance. This review provides a practical overview of the safe and effective management of these clinical challenges.

Direct-Acting Antivirals (DAAs): Drug-Drug Interactions (DDIs) in the Treatment of Hepatitis C Virus (HCV)

“…From the start of combined treatment, therapeutic drug monitoring of immunosuppressants with dose adjustment can solve this problem (about 50% of observed diferences in healthy volunteers) [16].…”

“…Similar situation is for locally applied corticosteroids by inhalation or intranasally such as luticasone and budesonide. According to available data, beclomethasone can be used safely in patients on strong CYP3A inhibitors [16] and represents a corticosteroid of choice in patients with HCV therapy.…”

“…DAAs are expected to increase statin levels and the associated risk of severe toxicity such as rhabdomyolysis [16]. Atorvastatin levels were elevated almost eight times with telaprevir, and this combination is contraindicated.…”

Treatment of chronic hepatitis C in patients with HIV/HCV coinfection

“…These treatments showed higher rates of sustained virological response (SVR) than Peg-IFN + RBV [31][32][33][34][35][36][37][38] but reduced tolerability [39] and adherence due to the high pill burden. At the same time several pharmacokinetic interactions have been appeared between HCV NS3/4A protease inhibitors and antiretroviral drugs [40][41][42][43] . Finally in 2013 a new wave of DAAs arrived, characterized by high efficacy, good tolerability, a low pill burden and shortened treatment duration [44,45] .…”

Oral antiviral therapies for chronic hepatitis C infection

“…In addition, telaprevir and boceprevir are dosed 2 and 3 times daily respectively, and carry a high pill burden (12 per day for boceprevir and 6 for telaprevir in addition of 47 for ribavirin) Poordad et al 2011;Bacon et al 2011;Zeuzem et al 2011a]. CYP3A4 and CYP3A5 metabolism requires drug adaptation and choice due to potential drugdrug interactions [Burger et al 2013]. Finally, both telaprevir and boceprevir are approved only for genotype-1-infected patients even if an antiviral potency has been reported in genotype-2-infected patients (telaprevir) [Foster et al 2011] and to a lesser extent in genotype-4-infected patients (telaprevir and boceprevir).…”