HCV耐药突变在三个Ib期临床试验中对DAA单药给药后短期疗效影响的分析

doi:10.5246/jcps.2021.02.011

摘要/Abstract

摘要：

耐药相关突变(Resistance-associated substitutions, RASs)是丙型肝炎病毒(Hepatitis C virus, HCV)治疗的关键因素, 并与一些直接抗病毒药物(Direct acting antivirals, DAAs)为基础的治疗方案的治疗结果相关。在本研究中, 我们主要分析了三个Ib期临床试验(磷酸依米他韦、KW-136和福比他韦)中, 基线Y93H或Y93Y/H耐药突变对NS5A抑制剂单药给药后短期疗效的影响, 并且分析了基线RASs、给药后出现的RASs的发生率。共94例HCV基因型(Genotype, GT)1b (n = 63)和HCV GT-2a (n = 31)的中国初治慢性丙型肝炎(Chronic hepatitis c, CHC)患者被纳入三个Ib期临床试验。本研究中使用Sanger测序法(Sanger sequencing)和二代测序法(Next generation sequencing, NGS)检测了77例患者的耐药突变情况。磷酸依米他韦7天给药试验中, 在30和200 mg剂量组中, 存在基线期Y93H或Y93Y/H突变的患者, 平均最大HCV RNA下降值低于无该突变的患者, 分别为0.83 vs. 2.45 log₁₀ IU/mL和1.92 vs. 2.63 log₁₀ IU/mL。在KW-136 3天给药试验中, 在30、60和120 mg剂量组中, 存在基线期Y93H或Y93Y/H突变的患者, 平均最大HCV RNA下降值低于无该突变的患者, 分别为1.58 vs. 2.89 log₁₀ IU/mL、3.16 vs. 4.09 log₁₀ IU/mL和3.00 vs. 5.04 log₁₀ IU/mL。在福比他韦3天单药给药试验中, 只有30 mg剂量组存在基线期Y93H或Y93Y/H突变, 其中存在基线期Y93H或Y93Y/H突变的患者, 平均最大HCV RNA下降值低于无该突变的患者, 为1.45 vs. 3.59 log₁₀IU/mL。三个试验中, 共54例(70.1%; 54/77)患者被检测到了基线期RASs。最普遍的基线RASs是Y93H和Y93Y/H, 为18.2% (14/77), 其次为L31M (16.9%; 13/77)。DAA单药给药后最普遍出现的RASs是Y93H和Y93Y/H。我们的数据可为以后的临床治疗及临床试验提供参考。

Abstract:

As crucial factors in hepatitis C virus (HCV) management, resistance-associated substitutions (RASs) are associated with the treatment outcome of some direct-acting antiviral (DAA)-based regimens. In this study, we mainly analyzed the impact of baseline Y93H or Y93Y/H on the short-term efficacy after single administration of NS5A inhibitors in three phase Ib clinical trials (yimitasvir phosphate, KW-136 and fopitasvir), and analyzed the prevalence of baseline RASs and treatment-emergent RASs. A total of 94 treatment-na?ve HCV genotype (GT)-1b (n = 63) and GT-2a (n = 31) Chinese patients were enrolled in three phase 1b clinical trials. We investigated RASs in 77 patients with next generation or Sanger sequencing. In the 7-day trial of yimitasvir phosphate, the mean maximum HCV RNA decrease of patients with baseline Y93H or Y93Y/H was lower than that of patients without the mutation in the 30 mg and 200 mg cohorts (0.83 vs. 2.45 log₁₀ IU/mL and 1.92 vs. 2.63 log₁₀ IU/mL). In the 3-day trial of KW-136, the mean maximum HCV RNA decrease in patients with baseline Y93H or Y93Y/H was lower than that of patients without the mutation in the 30, 60 and 120 mg cohorts (1.58 vs. 2.89 log₁₀IU/mL, 3.16 vs. 4.09 log₁₀IU/mL and 3.00 vs. 5.04 log₁₀IU/mL, respectively). In the 3-day trial of fopitasvir, only 30 mg group had baseline Y93H or Y93Y/H, and the average maximum HCV RNA decrease of patients with baseline Y93H or Y93Y/H was lower than that of patients without the mutation (1.45 vs. 3.59 log₁₀IU/mL). In the three trials, baseline RASs were observed in 54 patients (70.1%; 54/77). The most prevalent baseline RASs were Y93H and Y93Y/H (18.2%; 14/77), followed by L31M (16.9%; 13/77). The most common RASs after single administration of DAA were Y93H and Y93Y/H. Our data could provide reference for future clinical treatment and clinical trial.

Key words: Direct acting antiviral agents, Resistance-associated substitutions, HCV sequencing, Genotype 1b and 2a, HCV NS5A inhibitors

Supporting:

周景, 张洪, 李晓娇, 宋相仕, 张萌萌, 丁艳华. HCV耐药突变在三个Ib期临床试验中对DAA单药给药后短期疗效影响的分析[J]. 中国药学(英文版), 2021, 30(2): 133-145.

Jing Zhou, Hong Zhang, Xiaojiao Li, Xiangshi Song, Mengmeng Zhang, Yanhua Ding. Analysis of the effect of HCV resistance-associated substitutions on the short-term efficacy of DAA after single administration in three phase Ib clinical trials[J]. Journal of Chinese Pharmaceutical Sciences, 2021, 30(2): 133-145.

图/表 7

Table 1. Demographics and baseline characteristics among patients participating in the three clinical trials.

Figure 1. Prevalence of resistance associated variants at baseline in 77 individuals (a) and in patients with HCV genotype (GT)-1b (b) and HCV GT-2a (c).

Table 2. List of multiple resistance mutations at baseline.

Table 3. Treatment-emergent NS5A RASs for yimitasvir phosphate, KW-136 and fopitasvir in HCV GT-1b and GT-2a patients.

Figure 2. Prevalence of NS5A RASs-Y93H or Y93Y/H over time in different cohorts with HCV GT-1b for the yimitasvir phosphate (a), KW-136 (b) and fopitasvir (c) clinical trials.

Figure 3. Maximum reduction of HCV RNA loads and HCV RNA changes in log10 from baseline over time in various trials and cohorts. The mean ± standard deviation of the maximum viral load reductions of patients in yimitasvir trial (a), KW-136 trial (c) and fopitasvir trial (e), respectively. HCV RNA changes in log10 from baseline over time in various cohorts of yimitasvir (b), KW-136 (d) and fopitasvir (f), respectively. The baseline RASs of all GT-1b patients are shown. HCV GT-2a patients receiving KW-136 fopitasvir were not included because of poor efficacy.

Table 4. HCV RNA reduction, mutation rate of baseline Y93H or Y93Y/H and exposure of yimitasvir phosphate, KW-136 and fopitasvir.

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