Hepatitis C virus NS5A inhibitors and drug resistance mutations

Abstract

Some direct-acting antiviral agents for hepatitis C virus (HCV), such as telaprevir and boceprevir have been available since 2011. It was reported that HCV NS5A is associated with interferon signaling related to HCV replication and hepatocarcinogenesis. HCV NS5A inhibitors efficiently inhibited HCV replication in vitro. Human studies showed that dual, triple and quad regimens with HCV NS5A inhibitors, such as daclatasvir and ledipasvir, in combination with other direct-acting antiviral agents against other regions of HCV with or without peginterferon/ribavirin, could efficiently inhibit HCV replication according to HCV genotypes. These combinations might be a powerful tool for "difficult-to-treat" HCV-infected patients. "First generation" HCV NS5A inhibitors such as daclatasvir, ledipasvir and ABT-267, which are now in phase III clinical trials, could result in resistance mutations. "Second generation" NS5A inhibitors such as GS-5816, ACH-3102, and MK-8742, have displayed improvements in the genetic barrier while maintaining potency. HCV NS5A inhibitors are safe at low concentrations, which make them attractive for use despite low genetic barriers, although, in fact, HCV NS5A inhibitors should be used with HCV NS3/4A inhibitors, HCV NS5B inhibitors or peginterferon plus ribavirin. This review article describes HCV NS5A inhibitor resistance mutations and recommends that HCV NS5A inhibitors be used in combination regimens potent enough to prevent the emergence of resistant variants.

Increased Replicative Fitness Can Lead to Decreased Drug Sensitivity of Hepatitis C Virus

“…(i) Several wellcharacterized inhibitor resistance mutations of HCV were not detected in the mutant spectra of HCV p45 and HCV p100 (see Tables S8 and S9 [http://www2.cbm.uam.es:8080/cv-303/Suppl MatSheldon.pdf]). Substitution F28I in NS5A affected the same amino acid of the F28S daclatasvir resistance mutation (73). UDPS identified F28I as present at a 0.75% frequency in the mutant spectrum of HCV p100.…”

Direct acting anti-hepatitis C virus drugs: Clinical pharmacology and future direction

“…[15] Patients with mutation in Y93H and Q30K are typically more susceptible to develop such resistance, a condition that may be minimized by the use of a combination treatment. [16] Ledipasvir undergoes oxidative metabolism by unknown mechanism, and is excreted mainly through the biliary tract (86%), while less than 1% in the urine.…”

Management of Chronic Hepatitis C Virus Infection: A Consensus Report of the Study Group for Viral Hepatitis of the Turkish Society of Clinical Microbiology and Infectious Diseases-2017 Update

“…Tedavi sırasında ya da doğal olarak gelişen NS3/4 mutasyonlarına örnek olarak 36., 54., 55., 80., 155., 156., 168. ve 170. aminoasid pozisyonları verilebilir (132,133). NS5A'nın birinci kangalında yer alan 28., 30., 31., 32., 92. ve 93. aminoasid pozisyonları NS5A inhibitörleri için, NS5B böl-gesindeki 282., 321.,419.-499. ve 556. aminoasid pozisyonları ise NS5B inhibitörleri için anahtar mutasyon bölgeleridir (134,135).…”