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直接抗病毒药物治疗丙型肝炎失败的影响因素分析
DOI: 10.3969/j.issn.1001-5256.2022.05.016
伦理学声明：本研究方案于2017年9月13日经由北京大学第一医院生物医学研究伦理委员会审批，批号: (2017)科研第(02)号。血清样本的采集和临床资料的收集均获得患者知情同意。
利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。
作者贡献声明：杨宇晴负责课题设计，样本收集，资料分析，撰写论文；尚佳、卢诚震、杨松参与样本收集；陈宏宇参与资料分析；潘家莉、韩一凡、席宏丽参与样本处理；亢倩、谭宁参与论文修改；徐小元负责拟定写作思路，指导撰写文章并最后定稿。
Influencing factors for direct-acting antiviral therapy failure in treatment of hepatitis C
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摘要:
目的 从基线临床资料和基因测序寻找耐药相关替代突变(RAS)两个方面将抗病毒药物(DAA)治疗结束后HCV RNA复阳患者与DAA治疗成功的HCV感染者进行对比，旨在分析DAA治疗丙型肝炎失败的影响因素。 方法 纳入2019年11月—2021年10月来自多中心的13例DAA初治失败患者(治疗失败组)并对其复阳血清进行测序，与51例DAA初治成功患者(对照组)的基线临床资料及测序结果进行对比。非正态分布的计量资料组间比较采用Mann-Whitney U检验；计数资料组间比较采用χ2检验，进行单因素和多因素logistic回归分析计算比值比(OR)并分析治疗失败的影响因素。 结果 12例有完整疗程资料的患者全部于用药结束后1年内复发，男性治疗失败患者的基线TBil、DBil、Cr普遍高于女性(Z值分别为-2.517、-2.440、-2.132，P值分别为0.010、0.010、0.038)，年龄在55岁及以下(OR=5.152, 95%CI: 1.116~23.790, P=0.036)、基因型为3b型(OR=9.726, 95%CI: 1.325~71.398, P=0.025)的患者治疗失败可能性更高。3种基因片段上的主要RAS发生率在治疗失败和治疗成功组间不同，治疗失败组检测到的共有RAS均未在治疗成功组检测出。 结论 DAA治疗失败的影响因素有年龄、基因型以及血清病毒基因序列上的RAS种类。 Abstract:Objective To investigate the influencing factors for direct-acting antiviral agent (DAA) therapy failure in the treatment of hepatitis C by comparing baseline clinical data and resistance-associated substitution (RAS) in sequencing data between the patients with HCV RNA reactivation after DAA therapy and the patients with successful DAA treatment. Methods A total of 13 patients from multiple centers who failed DAA therapy from November 2019 to October 2021 were enrolled as treatment failure group, and sequencing was performed for their positive serum samples. A total of 51 patients with successful DAA treatment were enrolled as control group, and baseline clinical data and sequencing results were compared between the treatment failure group and the control group. The Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups, and the chi-square test was used for comparison of categorical data between groups; univariate and multivariate logistic regression analyses were performed to calculate odds ratio (OR) and investigate the influencing factors for treatment failure. Results All 12 patients with complete treatment data experienced recurrence within 1 year after the end of medication. The male patients with treatment failure had significantly higher baseline total bilirubin, direct bilirubin, and creatinine than their female counterparts (Z=-2.517, -2.440, and -2.132, P=0.010, 0.010, and 0.038), and the patients with an age of ≤55 years (OR=5.152, 95% confidence interval [CI]: 1.116-23.790, P=0.036) or genotype 3b (OR=9.726, 95%CI: 1.325-71.398, P=0.025) had a higher probability of treatment failure. There were differences in the incidence rates of major RAS mutations on three gene fragments between the treatment failure group and the treatment success group, and the common RAS mutations detected in the treatment failure group were not detected in the treatment success group. Conclusion Age, genotype, and RAS in serum virus gene sequence are influencing factors for DAA treatment failure. -
Key words:
- Hepatitis C /
- Antiviral Agents /
- Resistance-associated Substitution
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表 1 治疗失败患者性别与部分生化指标的关系
Table 1. Relationship between gender and some biochemical indicators in patients with DAAs treatment failure
项目 男(n=5) 女(n=7) Z值 P值 TBil(μmol/L) 16.00(11.35~19.95) 8.20(6.90~10.40) -2.517 0.010 DBil(μmol/L) 4.57(3.10~7.52) 2.60(1.60~3.10) -2.440 0.010 Cr(μmol/L) 83.94(61.47~189.75) 44.50(39.85~63.00) -2.132 0.038 GGT(U/L) 37.00(30.50~152.00) 26.00(14.80~46.10) -1.714 0.106 AST(U/L) 54.00(32.50~87.50) 24.60(16.00~57.20) -1.139 0.268 ALT(U/L) 83.00(38.50~131.00) 24.20(13.00~64.70) -1.543 0.149 
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表 2 治疗失败组与对照组患者基线特征对比
Table 2. Baseline characteristics of patients with DAAs treatment failure compared with patients with DAAs treatment success
项目 治疗失败组(n=13) 对照组(n=51) 统计值 P值 男/女(例) 6/7 19/29 χ2=0.183 0.452 年龄≤55岁/年龄＞55岁(例) 10/3 17/30 χ2=6.833 0.010 PLT(109/L) 142.00(96.25~272.75) 150.00(109.50~215.00) Z=-0.034 0.987 Cr(μmol/L) 58.00(40.95~85.50) 67.50(55.73~82.50) Z=-1.163 0.257 TBil(μmol/L) 9.65(7.98~15.45) 12.30(9.10~17.20) Z=-1.814 0.071 DBil(μmol/L) 3.00(2.00~4.25) 2.90(1.71~4.83) Z=-0.292 0.773 AST(U/L) 47.50(23.25~66.05) 28.50(23.00~56.30) Z=-0.568 0.570 ALT(U/L) 45.00(15.75~85.25) 28.00(18.00~64.70) Z=-0.544 0.586 基因3b型/非3b型(例) 4/8 2/48 χ2=9.526 0.011
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表 3 基线logistic回归分析DAA初治失败的独立影响因素
Table 3. Baseline logistic regression analysis of independent predictors of DAAs treatment failure
参数 P值 OR 95%CI 单因素logistic回归分析 性别 0.670 1.308 0.381~4.495 年龄≤55岁/年龄＞55岁 0.015 5.882 1.421~24.355 基因型3b型/非3b型 0.009 12.000 1.801~71.315 PLT 0.896 1.000 0.993~1.006 Cr 0.947 0.999 0.979~1.020 TBil 0.137 1.115 0.966~1.287 DBil 0.539 1.064 0.873~1.296 AST 0.686 0.996 0.977~1.015 ALT 0.590 0.997 0.986~1.008 多因素logistic回归分析 年龄≤55岁/年龄＞55岁 0.036 5.152 1.116~23.790 基因型3b型/非3b型 0.025 9.726 1.325~71.398
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表 4 治疗失败组RAS分布情况
Table 4. RAS patterns in the treatment failure group
编号 基因型 用药 NS3 RAS NS5A RAS NS5B RAS 1 1b DAC+ASV S7A、T46S、V48I、Y56H、A66G、P86Q、K87A、P89S、S122G、F147S、D168A、V170I、S181T Q24、K26、L31V、L34V、K78R、T83M、H85S、Y93H、V164A、K166R、V174T A25P、Q47L、M57L、D62N、R65Q、Q90K、R98K、K114R、Q127L、A218S 2 2a SOF/VEL+RBV Q24、K26、R30Q、L34V、L37F、T55A、S101T、T135N、V138L、V153L、V164P、E171D、V174T、V196T、A197V、L199V A25P、Q47L、M57L、R65Q、K81R、V85I、Q90M、R98K、N117D、K124E、Q127L、T132S、M173R、N206K、A218S、I262V 3 1b 仿制药 Q24、K26、R30Q、L31M、L34V、L37F、I74L、H85R、Y93H、C98S、V124I、138L、A146T、V164A、V174T Q47L、D62N、R65Q、V85L、Q90K、R98K、K124E、Q127L、T130S、E131V、T137V、A218S、S231N、R254K、I262V、N273 4 1b EBR/GZR V48I、A66G、P86Q、K87S、F147S、A150V、V151A、V170I、M179T Q24、K26、L31F、L34V、T56I、Y93H、R108K、A115P、V121I、V164A、A197T A25P、Q47L、K81R、V85I、Q90K、R98K、K100Q、N110S、V116T、K124E、Q127L、E131Q、D135N、N206K、C213S、A218S、S231N、R254K、N273 5 1b DAC+ASV A66G、K87A、S122C、F147S W22、Q24、K26、R30Q、L31M、L34V、T83M、H85C、Y93H、V164A、K166R、V174T A25P、S46G、Q47L、M57L、Q90K、R98K、K114R、Q127L、A218S、S231N、V235I、Q251R、R254T
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