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  • br Introduction Chronic hepatitis C CHC


    Introduction Chronic hepatitis C (CHC) caused by hepatitis C virus (HCV) infection affects approximately 170 million individuals worldwide [1]. HCV and human immunodeficiency virus (HIV) have similar routes of transmission, including blood-to-blood contact, sharing of injection equipment, and sexual contact, and therefore coinfection of HCV and HIV is very common. In China, the HCV coinfection rate ranges from 85.0 to 97.0% in the HIV-positive populations who acquired HIV-1 infection through intravenous drug use or blood transfusion [2], [3]. HIV/HCV coinfection causes a high level of HCV viral load due to the HIV-related immunosuppression, consequently leading to more rapid fibrosis progression and higher rates of hepatic decompensation [4]. Additional study showed that HIV infection has a deleterious effect on HCV-related liver disease, and such liver disease has become the leading cause of death among HIV-infected patients in the HAART era since the mortality rates directly associated with AIDS have fallen [5]. Therefore, an effective HCV treatment is necessary and urgent for patients with HIV/HCV coinfection. Recently, rapid progresses have been achieved on direct-acting antiviral agents (DAAs) for HCV [6], [7], [8]. The first wave of NS3/4A protease inhibitors (PIs) includes telaprevir (TVR) and boceprevir (BOC), while simeprevir and faldaprevir are the second wave. Paritaprevir (ABT 450) and asunaprevir are also PIs, which have been approved by the US Food and Drug Administration (FDA) in 2014. Several HCV PIs, including danoprevir, vaniprevir and grazoprevir (MK 5172), are currently being licensed or in late-stage clinical trials. The next generation of HCV PIs is of short duration, good tolerability and improved sustained virological response (SVR). Therefore, HCV therapy is entering a new era. However, the rapid replication rate of HCV, along with the error-prone polymerase activity, leads to a high genetic carboxypeptidase a among HCV virions. Some studies have reported that natural drug-resistant HCV variants pre-exist in HCV-infected patients carboxypeptidase a who had never received antiviral therapy [9], [10], [11], [12], [13]. In clinical trials, sequence analysis among the patients with failed treatment has identified variants resistant to the first generation of PIs (BOC and TVR) and those variants involving amino acid positions V36, T54, R155 and A156 [14], [15], [16]. The Q80R may be associated with almost 6-fold resistance to simeprevir, and Q80K mutation may result in lower chances of achieving SVR after simeprevir treatment [17], [18]. The substitutions at amino acids R155 and A168 have been shown to reduce the activities of more recently developed PIs, such as simeprevir, asunaprevir, paritaprevir and vaniprevir [19], [20], [21]. The I/V170A mutation has been clearly associated with resistance to BOC and asunaprevir [22], [23].
    Materials and methods
    Discussion The prevalence of HCV infection varies with HIV transmission mode [33]. In the present study, two HCV subtypes, 1b and 2a, were identified. As the studies carried out by Zhang et al. and Shang et al. [34], [35], subtype 1b (97.14%) apparently predominated in patients coinfected with HIV/HCV in this study. In the present study, 30.88% of patients coinfected with HIV/HCV genotype 1b showed at least one amino acid substitutions associated with the NS3 PI resistance. As different mutations had different sensitivities to anti-HCV PI, the rate of substitutions associated with anti-HCV PI resistance was different (Table 4). We noticed that approximately 30% of strains were not sensitive to the first generation of PIs, such as the BOC and TVR, while more than 98% of the strains remained perfectly sensitive to the second generation of PIs, such as the grazoprevir. Wu et al. [36] found that the prevalence of naturally occurring pre-existing resistance mutations in Japanese HCV monoinfected, genotype 1b patients is 39% (34/88), which is similar to our findings. In contrast, Trimoulet et al. [37] reported that the natural prevalence of HCV PI resistance mutations in patients coinfected with HIV/HCV genotype 1 (58 genotype 1a and 18 genotype 1b) is only 7.9% (6/76). HCV PI resistance mutations were found in 6.5% (31/476) HCV monoinfected genotype 1 patients. Only mutations 36, 54, 155 were detected in patients coinfected with HIV/HCV genotype 1 in their study. The occurrence rate of the pre-existing NS3/4A PI resistance mutations was higher in our population. The differences could be explained by the type of mutations in each study and the differences in the genotype repartition.