Ritonavir-boosted protease inhibitor based therapy: a new strategy in chronic hepatitis C therapy

Abstract

Chronic hepatitis C virus (HCV) infection is a worldwide health issue. All oral therapies are quickly replacing peg-interferon-based treatment regimens. Developing effective, well tolerated, treatments accessible for difficult to treat populations remains an unmet need. Ritonavir, an HIV-1 protease inhibitor, has pharmacokinetic properties that enhance the activity of concomitantly administered direct acting antivirals against HCV. Ritonavir inhibits Cytochrome P450 isozyme 3A4, diminishing first pass effect and hepatic metabolism, changing the pharmacokinetic parameters of Cytochrome P450 isozyme 3A4 substrates. When combined with the HCV protease inhibitor paritaprevir, ritonavir increases mean area under the curve, allowing once daily dosing. While Phase II and III clinical trials with ritonavir-boosted paritaprevir, ombitasvir, and dasabuvir demonstrated high efficacy in those with HCV infection, drug–drug interactions warrant cautious use of ritonavir in specific patient populations. Consideration of the patients’ full medication list is imperative due to the ubiquitous nature of the Cytochrome P450 isozyme 3A4 system.

Keywords:

• CYP3A4
• direct-acting antiviral
• hepatitis C
• protease inhibitor
• ritonavir

Financial & competing interests disclosure

KR Reddy is an Ad-Hoc Advisory Board member of and provides research support for Merck, Abbvie, BMS, Gilead and Janssen. 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

• Interferon-based therapies are no longer recommended for the treatment of HCV due to suboptimal outcomes and undesirable side effects. All-oral combinations (e.g., paritaprevir/ritonavir/ombitasvir/dasabuvir) of direct-acting antivirals, with or without ribavirin, represent the new standard of care.

• Ritonavir has no inherent anti-HCV activity. Instead, it has unique pharmacokinetic properties (hepatic and intestinal CYP3A4 inhibitor, intestinal P-glycoprotein/multidrug resistance-associated protein efflux channel modulator) used to boost the efficacy of the concomitantly administered direct-acting antiviral paritaprevir.

• Due to the ubiquitous nature of the CYP3A4 pathway in metabolizing clinically relevant compounds, the potential for drug–drug interactions with ritonavir-boosted therapy is high.

• High rates of SVR were achieved in Phase II and Phase III clinical trials examining the safety and efficacy of fixed-dose combination paritaprevir, ombitasvir, low-dose-ritonavir, with dasabuvir, with or without ribavirin. This regimen was tolerated well, with generally mild side effects and laboratory abnormalities.

• The use of ritonavir-boosted HCV therapy has been shown to be safe and effective in specific patient populations (e.g., post-liver transplant, HIV/HCV co-infected), but dose modifications and contraindications may be considered (see text section 9 and Table 3 for further details). A careful consideration of patients’ full medication list and all possible interactions is strongly suggested.

• Paritaprevir/ritonavir/ombitasvir, dasabuvir and ribavirin therapy provides an option for patients who have failed previous peg-interferon/ribavirin therapy.

• More work needs to be done to evaluate the safety and efficacy of ritonavir-boosted HCV therapy in patients with decompensated cirrhosis and renal impairment.