Danoprevir for the Treatment of Hepatitis C Virus Infection: Design, Development, and Place in Therapy

Abstract

On June 8, 2018, an NS3/4A protease inhibitor called danoprevir was approved in China to treat the infections of HCV genotype (GT) 1b – the most common HCV genotype worldwide. Based on phase 2 and 3 clinical trials, the 12-week regimen of ritonavir-boosted danoprevir (danoprevir/r) plus peginterferon alpha-2a and ribavirin offered 97.1% (200/206) of sustained virologic response at post-treatment week 12 (SVR12) in treatment-naïve non-cirrhotic patients infected with HCV genotype 1b. Adverse events such as anemia, fatigue, fever, and headache were associated with the inclusion of peginterferon alpha-2a and ribavirin in the danoprevir-based regimen. Moreover, drug resistance to danoprevir could be traced to amino acid substitutions (Q80K/R, R155K, D168A/E/H/N/T/V) near the drug-binding pocket of HCV NS3 protease. Despite its approval, the clinical use of danoprevir is currently limited to its combination with peginterferon alpha-2a and ribavirin, thereby driving its development towards interferon-free, ribavirin-free regimens with improved tolerability and adherence. In the foreseeable future, pan-genotypic direct-acting antivirals with better clinical efficacy and less adverse events will be available to treat HCV infections worldwide.

Keywords:

• danoprevir
• ITMN-191
• R7227
• HCV NS3/4A inhibitor
• HCV genotype

Acknowledgments

We are grateful for Prof. Lai Wei who shared with us the SVR12 data from the MANASA and MAKALU studies. This work was supported by the National Nature Science Foundation of China (grant numbers 31871324, 81730064, 31571368), Natural Science Foundation of Hunan Province (grant number 2018JJ3713), Hunan Youth Elite Project (grant number 2018RS3006), and National Science and Technology Major Project (grant number 2018ZX10715004).

Abbreviations

ATP, adenosine triphosphate; AUC, area under the plasma concentration-time curve; BID, twice daily; C_max, maximum plasma concentration; C_max,ss, observed maximum plasma concentration at steady state; C_trough,ss, observed trough concentration at steady state; CYP, cytochrome P450; DAA, direct-acting antiviral; Danoprevir/r, ritonavir-boosted danoprevir; EC_50, half-maximal effective concentration; GT, genotype; HCV, hepatitis C virus; IC_50, half maximal inhibitory concentration; SVR, sustained virologic response; T_1/2, elimination half-life; T_max, time to maximum plasma concentration; UK, United Kingdom; USA or US, United States of America; V_d, apparent volume of distribution.

Disclosure

The authors declare no conflicts of interest in this work.