奈韦拉平治疗获得性免疫缺陷综合征导致肝损伤的危险因素分析

Risk factors for liver injury in patients with acquired immunodeficiency syndrome treated with nevirapine

目的分析获得性免疫缺陷综合征患者使用包含奈韦拉平（NVP）方案进行联合抗反转录病毒治疗（c-ART）引起超敏反应肝损伤的相关危险因素。方法收集2008年6月-2015年10月武汉大学中南医院接受包含NVP联合治疗方案的患者临床资料及血液标本共132例,采用PCR-SSP技术检测人类白细胞抗原（HLA）DRB1及HLA-Cw基因型。开始c-ART治疗6周内出现NVP超敏反应相关肝损伤者列为肝损伤组（n=41）,未发生肝损伤者为对照组（n=91）,分析NVP超敏反应引起肝损伤的相关危险因素。计量资料组间比较采用t检验;计数资料组间比较采用χ^2检验。采用单因素Logistic回归法分析NVP超敏反应相关肝损伤的危险因素,将P〈0.10的单因素分析变量纳入多因素Logistic回归模型进行逐步回归分析。用Spearman相关系数分析发生超敏反应相关肝损患者中CD4细胞数与ALT值的相关性。结果多因素Logistic回归分析显示男性[P=0.002,比值比（OR）=12.297,95%可信区间（95%CI）：2.467-61.300]、基线CD4细胞计数高（P=0.023,OR=1.010,95%CI：1.001-1.018）、合并HCV感染（P=0.022,OR=10.598,95%CI：1.411-79.613）、HLA-Cw＊03基因携带（P〈0.001,OR=34.119,95%CI：5.543-210.023）为NVP超敏反应相关肝损伤的危险因素。在合并HCV感染或高CD4细胞数（≥200个/μl）或携带HLA-Cw＊03等位基因患者中男性肝损伤发生率（63.9%）高于女性（11.6%）,差异有统计学意义（χ^2=23.390,P〈0.001）。患者基线CD4细胞计数与ALT水平呈正相关（r=0.583,P〈0.001）。结论男性、合并HCV感染、基线CD4细胞数高的人类免疫缺陷病毒感染者应尽量避免使用NVP,HLA-CW＊03基因筛查对于预测NVP超敏反应相关肝毒性的价值有待进一步研究。

Objective To investigate the risk factors for hypersensitivity- associated liver injury induced by the combined antiretroviral therapy（ c- ART） including nevirapine（ NVP） in patients with acquired immunodeficiency syndrome. Methods The clinical data and blood samples of 132 patients who received the combined therapy including NVP in Zhongnan Hospital of Wuhan University from June 2008 to October 2015 were collected,and PCR- SSP was used to determine the genotypes of human leukocyte antigen（ HLA） DRB1 and HLA-Cw. The patients who experienced hypersensitivity- associated liver injury induced by NVP within 6 weeks of c- ART were enrolled in the liver injury group（ 41 patients）,and those who did not experience liver injury were enrolled in the control group（ 91 patients）. The risk factors for liver injury induced by NVP hypersensitivity were analyzed. The t- test was used for comparison of continuous data between groups; the chi- square test was used for comparison of categorical data between groups. The univariate logistic regression method was used to analyze the risk factors for liver injury associated with NVP hypersensitivity,and the variables with P〈0. 10 were included in the multivariate logistic regression model to perform stepwise regression analysis. The Spearman correlation coefficient was used to analyze the correlation between the number of CD4 cells and alanine aminotransferase（ ALT） level in patients experiencing hypersensitivity- associated liver injury. Results The results of the multivariate logistic regression analysis showed that male sex（ OR = 12. 297,95% CI： 2. 467- 61. 300,P = 0. 002）,a high CD4 cell count at baseline（ OR = 1. 010,95% CI： 1. 001- 1. 018,P = 0. 022）,HCV co- infection（ OR = 10. 598,95%CI： 1. 411- 79. 613,P = 0. 022）,and a HLA- Cw＊03 carrier（ OR = 34. 119,95% CI： 5. 543- 210. 023,P〈0. 001） were risk factors for liver injury associated with NVP hypersensitivity. In the patients with HCV co- infection or a high CD4 cell count（ ≥200 / μl） or carrying HLA- Cw＊03 allele,male patients had a significantly higher incidence rate of liver injury than female patients（ 63. 9% vs 11. 6%,χ^2= 23. 390,P〈0. 001）. Baseline CD4 cell count was positively correlated with ALT level（ r = 0. 583,P〈0. 001）. Conclusion Male patients infected with human immunodeficiency virus who are co- infected with HCV and have a high CD4 cell count at baseline should avoid using NVP.The value of HLA- Cw＊03 gene screening in predicting hepatotoxicity associated with NVP hypersensitivity awaits further investigation.