Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • There are several limitations in our

    2021-09-11

    There are several limitations in our study. First, only the naturally occurring resistance-associated mutations in patients coinfected with HIV/HCV NCT-503 1b were analyzed. The result was only applicable to HCV genotype 1b, but not the HCV genotype 1a patients. We did not analyze the effect of genotype on the pre-existing resistance-associated mutations. Second, the NS3 region was not analyzed by deep sequencing. Therefore, the presence of the minority variants<20% cannot be excluded due to the low sensitivity of Sanger sequencing technology. Despite these limitations, the results of this study are important in helping raise awareness of pre-existing resistance among Chinese HIV/HCV coinfected, treatment-naïve patients.
    Authors’ contributions
    Disclosure of interest
    Acknowledgments
    Introduction Chronic hepatitis C virus (HCV) infection is a major health problem, with an estimated 170 million individuals infected worldwide (Alter and Seeff, 2000, Leone and Rizzetto, 2005). HCV is a heterogeneous virus composed of at least six major genotypes further divided into individual subtypes (Kuiken and Simmonds, 2009). In addition, the viral polymerase of HCV is highly error-prone, resulting in the existence of a quasispecies of virus within an infected patient, making the discovery of an effective, broad-genotypic treatment suitable for all HCV-infected individuals challenging (Simmonds, 1999, Simmonds, 2004). HCV-associated end-stage liver disease is currently the primary reason for liver transplantation in the United States, and the number of patients with serious liver impairment or hepatocelluar carcinoma resulting from chronic HCV infection is projected to increase (Kim et al., 2013, Selimovic et al., 2012a, Selimovic et al., 2012b). Despite the challenges, tremendous resources have been directed toward discovering and developing novel therapies to treat HCV infection (De Francesco and Carfi, 2007, Hebner et al., 2012, Lam et al., 2012, Lam et al., 2011, Lam et al., 2010, Manns et al., 2011a, Manns et al., 2011b). In addition to ribavirin (RBV) and pegylated interferon alfa (PEG) that were the previous standard of care for HCV treatment (Foster, 2010, Manns et al., 2001, McHutchison et al., 1998, Poynard et al., 1998), five direct-acting antiviral agents (DAAs) have been approved for the treatment of HCV infection: telaprevir (Jacobson et al., 2010, McHutchison et al., 2010), boceprevir (Bacon et al., 2011, Poordad et al., 2011), simeprevir (Jacobson et al., 2013a, Manns et al., 2013), sofosbuvir (Jacobson et al., 2013b, Kowdley et al., 2013, Lawitz et al., 2013), and daclatasvir (Hezode et al., 2012, Sulkowski et al., 2012). Each of these approved DAAs requires coadministration with RBV or PEG/RBV to provide effective antiviral activity against certain HCV genotypes or in hard-to-treat patient subpopulations. Considering the adverse effects of PEG/RBV therapy and the restricted genotype coverage of many approved and investigational drugs, new DAA therapies are needed that possess broad-genotypic coverage in a highly effective regimen without the use of PEG and RBV. The HCV NS3 protein contains two distinct domains that each performs a unique function—a serine protease domain responsible for polyprotein cleavage and an RNA helicase domain that unwinds nascent HCV RNA from its template. The NS3 protease domain is composed of 181 amino acids located at the N-terminus of NS3 and, together with the NS4A co-factor, has the primary function of cleaving the HCV polyprotein junctions between the NS3-4A, NS4A-4B, NS4B-5A, and NS5A-5B proteins (Bartenschlager et al., 1993, Grakoui et al., 1993a, Grakoui et al., 1993b, Tomei et al., 1993). The NS3 protease function is essential to HCV viral replication, and NS3 is considered one of the drugable targets of the virus. Thus, many HCV NS3 protease inhibitors (PIs), including BI 201335 (Bacon et al., 2011), GS-9256 (Zeuzem et al., 2012), GS-9451 (Sheng et al., 2011), and MK-5172 (Lahser et al., 2012, Petry et al., 2010), have recently been or are currently being studied in clinical trials for the treatment of chronic HCV infection. NS3 mutants conferring reduced susceptibility to PIs have been shown to exist at relatively high frequencies within the treatment-naïve HCV quasispecies population. The NS3 PIs historically as a class have a lower barrier to resistance than nucleoside inhibitors, and resistance-associated mutations can be rapidly selected with monotherapy treatment in vivo and in vitro (Robinson et al., 2011). For PIs in development, characterization of activity against known PI mutants, genotype-dependent susceptibility, and phenotyping and cross-resistance analysis of patient sequences are important components of the development process.