Danoprevir is a non-covalent binding macrocyclic carboxypeptide protease inhibitor developed by China Geli Biotechnology Co., Ltd. In vitro studies, danorrevir has a strong inhibitory effect on the genes 1, 4, 5 and 6 hepatitis C viruses [1-4]; in clinical studies, danorrevir has good efficacy in patients with genotype 1 and 4 hepatitis C viruses.
In a phase II clinical study in my country, 69 genotype 1 patients with non-cirrhosis who had been infected with hepatitis C virus were treated with danorrevir combined with polyethylene glycol interferon and ribavirin for 12 weeks (MAKALU study), and the continuous virological response rate reached 96% after 12 weeks of discontinuation of the drug. The safety is good. The only adverse events related to danorrevir are nausea and diarrhea. The adverse reactions of danorrevir combined with polyethylene glycol interferon and ribavirin 3-linked regimen are similar to those of the polyethylene glycol interferon + ribavirin 2-linked regimen. A few patients have mild ALT and AST abnormalities. Three patients (4%) relapsed after stopping the medication. In a study in Taiwan, my country, patients with cirrhosis of genotype 1 were treated with danorevivir combined with interferon and ribavirin for 24 weeks, and the continuous virological response rate after 12 weeks of discontinuation of the drug reached 91% [5]. A few patients may develop drug resistance, and the common drug resistance mutation sites are located at the NS3 protease R155 and D168 sites [6].
Danorrevir has an interaction with ritonavir. Ritonavir can inhibit the enzyme system of drug metabolism of danorrevir, slow down drug metabolism, and improve the efficacy of danorrevir. The 4-pair drug for danorevivir + interferon + ribavirin + ritonavir was treated with 4 drugs for 24 weeks. The continuous virological response of 24% can reach 96.6%, and the continuous virological response of 24 hepatitis C type 4 was as high as 100% [7]. In Taiwan, people with non-cirrhosis hepatitis C virus infection in gene type 1b in my country used this 4-link regimen for 12 weeks, and the continuous virological response rate after stopping the drug reached 100% [5].
References
[1] Tong X, Li L, Haines K, Najera I. Identification of the NS5B S282T resistant variant and two novel amino acid substitutions that affect replication capacity in hepatitis C virus-infected patients treated with mericitabine and danoprevir. Antimicrob Agents Chemother. 2014. 58(6): 3105-14.
[2] Jiang Y, Andrews SW, Condroski KR, et al. Discovery of danoprevir (ITMN-191/R7227), a highly selective and potential inhibitor of hepatitis C virus (HCV) NS3/4A protease. J Med Chem. 2014. 57(5): 1753-69.
[3] Gottwein JM, Scheel TK, Jensen TB, Ghanem L, Bukh J. Differential efficiency of protein inhibitors against HCV genotypes 2a, 3a, 5a, and 6a NS3/4A protease recombinant viruses. Gastroenterology. 2011. 141(3): 1067-79.
[4] Imhof I, Simmonds P. Genotype differences in susceptibility and resistance development of hepatitis C virus to protease inhibitors telaprevir (VX-950) and danoprevir (ITMN-191). Hepatology. 2011. 53(4): 1090-9.
[5] Kao JH, Tung SY, Lee Y, et al. Ritonavir-boosted danoprevir plus peginterferon alfa-2a and ribavirin in Asian chronic hepatitis C patients with or without cirrhosis. J Gastroenterol Hepatol. 2016. 31(10): 1757-1765.
[6] Lim SR, Qin X, Susser S, et al. Virologic escape during danoprevir (ITMN-191/RG7227) monotherapy is hepatitis C virus subtype dependent and associated with R155K substitution. Antimicrob Agents Chemother. 2012. 56(1): 271-9.
[7] Everson G, Cooper C, Hezode C, et al. DAUPHINE: a randomized phase II study of danoprevir/ritonavir plus peginterferon alpha-2a/ribavirin in HCV genotypes 1 or 4. Liver Int. 2015. 35(1): 108-19.
