抗病毒治疗及中止治疗患者HIV耐药性研究

发布时间：2018-06-06 03:41

本文选题：HIV + ART　；参考：《中国疾病预防控制中心》2017年硕士论文

【摘要】：目的:本研究通过开展两个横断面调查,分别观察:1、部分地区接受艾滋病抗病毒治疗12个月左右患者的HIV (Human Immunodeficiency Virus)耐药情况及其影响因素;2、部分地区中止抗病毒治疗患者HIV耐药情况及其影响因素。方法:1、本研究的调查方案按照全国艾滋病病毒耐药性监测指南(2012版)中获得性HIV耐药横断面研究方案进行。在北京、吉林、湖南、广西、四川、贵州、新疆和云南8个监测地区开展相关调查。本研究的目标人群纳入标准为:(1)HIV阳性患者;(2)年龄≥18岁;(3)接受免费艾滋病抗病毒治疗(Antiretroviral Therapy, ART) 9-18个月;(4)自愿参加调查并愿意提供知情同意书。2、在四川、重庆、云南、广西、河南和湖南6个地区,对上述省中止抗病毒治疗的部分患者展开相关调查。本研究的目标人群纳入标准为:(1) HIV阳性患者;(2)年龄≥18岁;(3)中止治疗1个月及以上;(4)自愿参加调查并愿意提供知情同意书。结果:1、2014年在8个地区共调查了 765名接受9-18个月抗病毒治疗的成人,平均年龄是44.7岁。男性546 (71.4%)人,女性219 (28.6%)人;汉族607 (79.3%)人,少数民族158 (20.7%)人;已婚325 (42.5%)人,未婚440 (57.5%)人;67.6%的患者通过异性途径感染艾滋病病毒。多数病人(56.0%)初始治疗方案使用的是AZT/3TC/EFV或NVP,其次就是TDF/3TC/EFV或NVP (29.9%),二线方案使用者有50 (6.5%)人。经过13.9个月的中位治疗时间后,CD4细胞计数≥350组的患者比例从抗病毒治疗前的17.2%提高到调查时的37.4%,同时CD4细胞计数中位数从抗病毒治疗开始前的222cells/ul升高到调查时的303cells/ul。765位接受调查的患者中,65 (8.5%)位患者在调查时病毒载量抑制失败(病毒载量≥1000 copies/ml)。对这65位病毒抑制失败患者进行扩增,64位患者成功得到合格的pol基因序列,有33位患者出现耐药突变位点,耐药率为4.3%。33位耐药患者中,所有人都出现了对 NNRTIs (non-nucleoside reverse transcriptase inhibitors)药物的耐药,81.8%的患者对 NRTIs (nucleoside reverse transcriptase inhibitors)药物耐药,而 3%的患者出现了对 PIs(protease inhibitors)药物的耐药。NNRTIs最常出现的耐药突变位点是K103N(54.5%,18/33),G190A/S/R/(27.3%,9/33),和 Y181C (24.2%,8/33); NRTIs 最常出现的是位于 RT 区的M184I/V (66.7%,22/33)和 K65R (39.4%,13/33),而 Pis 突变位点仅在 M46L 这个位点出现。多因素统计中发现两个变量与耐药发生有关:过去一个月服药比例在90%以下的患者发生耐药的风险是服药比例在90%以上的患者的6倍(95%CI:1.7-20.7;P=0.005);四川和贵州的患者发生耐药的风险是其他省份的7.3倍(95%CI:3.6-15.2;P0.0001)。2、本次共调查了 481位中止抗病毒治疗患者,所有的患者均采集全血样本并进行实验室检测,其中365人接受问卷调查。对接受问卷调查的365人分析显示,男性258 (70.7%)人,女性107 (29.3%)人;汉族222 (60.8%)人,其他民族143 (39.2%)人;农村户口291 (79.7%)人,城镇户口 74(20.3%)人;221 (60.5%)人感染途径为异性传播,17(4.7%)人为同性传播,100 (27.4%)人通过吸毒传播,27 (7.4%)人通过其他途径传播。中止治疗 1-6 个月患者有 86 (23.6%)人,6-12 个月 75 (20.6%)人,12-24 个月 85 (23.3%)人,24-36个月36 (9.7%)人,≥36个月42 (11.5%)人。在所调查对象中,52人(10.8%)因治疗失败中止治疗,124人(25.8%)因副反应中止治疗,177人(36.8%)因依从性问题中止治疗。481位采集到样本的中止治疗患者中,337 (70.1%)位患者在调查时病毒载量≥1000 copies/ml。对这337位患者进行基因扩增,336 (99.7%,336/337)位患者成功得到序列,其中有65位患者至少携带一个耐药突变,耐药率为13.5%。65位耐药患者中,57 (87.7%,57/65)例患者出现了对NNRTIs药物的耐药,4.6% (3,3/65)的患者对NRTIs药物耐药,而10.8% (7,7/65)的患者出现了对Pis药物的耐药。NNRTIs最常出现的耐药突变位点是K103N(56.9%,37/65); NRTIs 最常出现的是位于 RT 区的 M184I/V (3.1%, 2/65),而 Pis 突变位点仅在I54V这个位点出现。多因素统计中发现两个变量与耐药发生有关:没有医疗保险的中止治疗患者发生耐药的风险是有医疗保险患者的2.8倍(95%CI:1.2-6.6;P=0.02);调查时CD4细胞计数0-199 copies/ml的中止治疗患者发生耐药的风险是CD4细胞计数≥350 copies/ml的患者的3.6倍(95%CI:1.4-8.9;P=0.006),调查时CD4细胞计数200-350 copies/ml的患者发生耐药的风险是CD4细胞计数≥350 copies/ml的患者的3.5倍(95%CI:1.4-8.4;P=0.006)。多因素统计中发现两个变量与病毒未抑制有关:病人在抗病毒治疗时从县或市医院领取药物发生病毒未抑制(病毒载量≥1000 copies/ml)的风险是患者从村、镇卫生院领药的2.9倍(95%CI:1.6-5.3;P=0.0003);调查时CD4细胞计数0-199 copies/ml的患者发生病毒载量未抑制的风险是 CD4 细胞计数≥350 copies/ml 的患者的 10.3 倍(95%CI:4.9-21.7;P0.0001),调查时CD4细胞计数200-350 copies/ml的中止治疗患者发生病毒载量未抑制的风险是CD4细胞计数≥350 copies/ml的患者的 4.6 倍(95%CI:2.6-8.3;P0.0001)。结论:综上所述,本研究表明现阶段一直持续服用免费抗病毒治疗药物9-18个月患者病毒抑制率已达到WHO提出的90%的病毒抑制标准,治疗后患者的CD4细胞计数值明显升高,耐药发生率为4.3%,但是四川和贵州耐药发生较高。在中止抗病毒治疗患者中病毒未抑制率和耐药比例均较高,其中耐药率达到13.5%,调查时CD4细胞计数低的患者发生耐药和病毒未抑制的风险大,患者中止抗病毒治疗原因主要是药物副反应和依从性不好,应针对患者退出的原因,制定相应措施降低退出的比例,同时需进一步加强中止治疗人群的耐药监测。虽然坚持服药患者的耐药流行较低,但本研究中发现仍有一定比例中止抗病毒治疗的患者中并有较高的耐药发生,如不尽早采取措施,这将成为保持我国长期抗病毒治疗效果的一个重要的制约因素。
[Abstract]:Objective: in this study, two cross-sectional investigations were carried out to observe: 1, in some areas, the drug resistance of HIV (Human Immunodeficiency Virus) and its influencing factors for patients with AIDS antiviral therapy for about 12 months and so on; 2, HIV resistance of patients with antiviral treatment in some areas and its influencing factors. Methods: 1. The scheme was conducted in 8 monitoring areas in Beijing, Jilin, Hunan, Guangxi, Sichuan, Guizhou, Xinjiang and Yunnan in Beijing, Jilin, Hunan, Guangxi, Guizhou, Xinjiang and Yunnan, in accordance with the National AIDS drug resistance monitoring Guide (2012 Edition). The target population of this study was included (1) HIV positive patients; (2) age more than 18 years; (3) accepted free of charge AIDS antiviral treatment (Antiretroviral Therapy, ART) 9-18 months; (4) voluntary participation in the survey and willing to provide the informed consent.2, in Sichuan, Chongqing, Yunnan, Guangxi, Henan and Hunan, 6 areas of the above-mentioned provinces to suspend antiviral treatment are investigated. The target population of this study is: (1) HIV positive patients (2) age more than 18 years old; (3) suspension of treatment for 1 months and more; (4) voluntary participation in the investigation and willing to provide informed consent. Results: 765 adults with 9-18 months of antiviral treatment were investigated in 8 regions for 12014 years, the average age was 44.7 years, 546 (71.4%) men, female 219 (28.6%) people, Han people, minority nationalities. 0.7%) people; married 325 (42.5%), unmarried 440 (57.5%); 67.6% of the patients infected with HIV through heterosexual pathways. Most patients (56%) were treated with AZT/3TC/EFV or NVP, followed by TDF/3TC/EFV or NVP (29.9%), and the second line scheme made the use of 50 (6.5%) people. After a median of 13.9 months of treatment, CD4 cells The proportion of patients who counted more than 350 groups increased from 17.2% before antiviral therapy to 37.4% in the survey, while the median of CD4 cell counts increased from 222cells/ul before the beginning of antiviral therapy to the 303cells/ul.765 position in the survey, and 65 (8.5%) patients failed to suppress viral load (viral load > 1000 COP) during the investigation. Ies/ml). To amplify the 65 patients with the failure of the virus, 64 patients successfully got a qualified pol gene sequence, 33 patients had resistance mutation sites, the drug resistance rate was 4.3%.33 resistant, all of them were resistant to NNRTIs (non-nucleoside reverse transcriptase inhibitors), and 81.8% of the patients were to NRT. Is (nucleoside reverse transcriptase inhibitors) drug resistance, and 3% of patients with PIs (protease inhibitors) drug resistant.NNRTIs most often appear the most common resistance mutation loci are K103N (54.5%, 18/33), G190A/S/R/ (24.2%, 66.7%). And K65R (39.4%, 13/33), and Pis mutation site only at the M46L site. Multifactor statistics found that two variables were associated with drug resistance: the risk of drug resistance in patients with less than 90% over the past month was 6 times as much as 90% of patients (95% CI:1.7-20.7; P=0.005); patients in Sichuan and Guizhou occurred. The risk of resistance was 7.3 times (95%CI:3.6-15.2; P0.0001).2 in other provinces. The total of 481 cases of antiviral treatment were investigated. All the patients collected whole blood samples and carried out laboratory tests. 365 of them were investigated by questionnaire. 258 (70.7%) men, 107 (29.3%) women, and 107 (29.3%) men were analyzed. 222 (60.8%) people and 143 (39.2%) people of other nationalities; 291 (79.7%) in rural areas and 74 (20.3%) in urban areas; 221 (60.5%) is transmitted by the opposite sex, 17 (4.7%) is transmitted by the same sex, 100 (27.4%) people spread through drug use, and people are transmitted through other ways. (20.6%) people, 12-24 months 85 (23.3%), 24-36 months 36 (9.7%), and 36 months 42 (11.5%). Among the subjects, 52 (10.8%) were discontinued for treatment failure, 124 (25.8%) was discontinued for side effects, and the patient was discontinued for the discontinuation treatment of the.481 position. In the survey, the 337 patients were amplified by viral load more than 1000 copies/ml., and 336 (99.7%, 336/337) patients succeeded in getting the sequence, of which 65 patients carried at least one drug resistance mutation, and the resistance rate was 13.5%.65 resistant, 57 (87.7%, 57/65) patients were resistant to NNRTIs drugs and 4.6% (3,3/65) patients. Drug resistance to NRTIs, and 10.8% (7,7/65) patients appeared the most frequently occurring resistance mutation loci of drug resistant.NNRTIs to Pis drugs (56.9%, 37/65); NRTIs most frequently appeared in M184I/V (3.1%, 2/65) located in RT region, while Pis mutation site appeared only at the I54V this site. Two variables were found in multifactor statistics and drug-resistant hair. Life - related: the risk of drug resistance in patients without medical insurance is 2.8 times as high as those with medical insurance (95%CI:1.2-6.6; P=0.02); the risk of drug resistance in patients with CD4 cell counts of 0-199 copies/ml at the time of investigation is 3.6 times (95%CI:1.4-8.9; P=0.006) in patients with CD4 cell counts more than 350 copies/ml. The risk of drug resistance in a cell count of 200-350 copies/ml was 3.5 times (95%CI:1.4-8.4; P=0.006) of the CD4 cell count of more than 350 copies/ml. The multifactor statistics found that two variables were not associated with the virus inhibition: the patients received drugs from the county or the city hospital during antiviral treatment (viral load > 1000 copies/). The risk of ML) was 2.9 times (95%CI:1.6-5.3; P=0.0003) from the village and the Town Health Hospital; the risk of uninhibited viral load in the CD4 cell count of 0-199 copies/ml was 10.3 times (95%CI:4.9-21.7; P0.0001) of the patients with CD4 cell counts more than 350 copies/ml, and the suspension of the CD4 cell count 200-350 copies/ml in the investigation. The risk of uninhibited viral load in the treatment patients was 4.6 times (95%CI:2.6-8.3; P0.0001) in patients with CD4 cell counts more than 350 copies/ml. Conclusion: To sum up, this study showed that the rate of virus inhibition in patients who had been taking free antiviral therapy at the present stage for 9-18 months had reached 90% of the virus inhibition standard proposed by WHO. The CD4 cell count of the patients was significantly higher, the incidence of drug resistance was 4.3%, but the drug resistance in Sichuan and Guizhou was higher. The rate of uninhibited virus and the drug resistance were higher in the patients who stopped the antiviral treatment, and the drug resistance rate reached 13.5%. The risk of drug resistance and the uninhibited virus was high in the patients with low CD4 cell count. The main reason for antiviral treatment is the adverse drug reaction and poor compliance. We should formulate corresponding measures to reduce the proportion of withdrawal, and further strengthen the drug resistance monitoring of the discontinued people. Although the prevalence of drug resistance in patients taking medicine is low, it is found that there is still a certain proportion of the discontinuation of antiviral treatment in this study. There is a high level of resistance in patients who are treated. If not taken early, it will become an important constraint to maintain the long-term efficacy of antiviral therapy in China.
【学位授予单位】：中国疾病预防控制中心
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R512.91

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