山东省艾滋病病毒感染者抗病毒治疗继发性耐药影响因素的病例对照研究
  中华流行病学杂志  2018, Vol. 39 Issue (7): 943-947   PDF    
http://dx.doi.org/10.3760/cma.j.issn.0254-6450.2018.07.015
中华医学会主办。
0

文章信息

单士馨, 孙晓光, 朱晓艳, 张娜, 廖玫珍, 黄涛, 李瑞, 杨特, 段青, 康殿民.
Shan Shixin, Sun Xiaoguang, Zhu Xiaoyan, Zhang Na, Liao Meizhen, Huang Tao, Li Rui, Yang Te, Duan Qing, Kang Dianmin.
山东省艾滋病病毒感染者抗病毒治疗继发性耐药影响因素的病例对照研究
Related factors on secondary drug resistance in HIV infected persons receiving antiretroviral therapy in Shandong province: a case-control study
中华流行病学杂志, 2018, 39(7): 943-947
Chinese Journal of Epidemiology, 2018, 39(7): 943-947
http://dx.doi.org/10.3760/cma.j.issn.0254-6450.2018.07.015

文章历史

收稿日期: 2017-12-13
山东省艾滋病病毒感染者抗病毒治疗继发性耐药影响因素的病例对照研究
单士馨1, 孙晓光1, 朱晓艳1, 张娜1, 廖玫珍1, 黄涛1, 李瑞1, 杨特2, 段青2, 康殿民1,3     
1. 250014 济南, 山东省疾病预防控制中心;
2. 250062 济南大学, 山东省医学科学院医学与生命科学学院;
3. 250012 济南, 山东大学公共卫生学院 山东省传染病预防控制重点实验室
摘要: 目的 了解HIV感染者抗病毒治疗发生继发性耐药的影响因素,为提高山东省抗病毒治疗效果提供依据。方法 按照病例对照研究设计,1:2匹配病例组和对照组,2015年10月进行入户面对面调查。根据山东省级实验室自建的HIV感染者抗病毒治疗耐药数据库和艾滋病综合防治数据信息系统,筛选研究对象。样本量估计为330例(病例110例、对照组220例),研究对象为在山东省存活的HIV感染者、年龄≥15岁、参加抗病毒治疗≥6个月并检测病毒载量(VL)。针对VL>1 000拷贝/ml者进行实验室耐药检测,筛选出继发性耐药者作为病例组,非继发性耐药者为对照组。采用EpiData 3.1软件和SPSS 22.0软件建立数据库,运用非条件逐步logistic回归分析继发性耐药的影响因素。结果 研究对象共288例(病例组103例、对照组185例)。病例组年龄为(37.62±1.06)岁,对照组年龄为(37.90±0.74)岁,以男性、已婚/同居者、高中及以下文化程度、汉族为主。多因素logistic回归分析结果显示,与治疗时间 < 1年相比,治疗时间1~3年和>3年的OR值分别为8.80(95% CI:3.69~21.00)、3.00(95% CI:1.20~7.53);与未漏服相比,漏服比例>25.0%的OR值为15.41(95% CI:4.59~51.71);本人领药OR值为0.22(95% CI:0.07~0.74)。结论 HIV感染者的治疗时间、漏服比例、本人领药为其抗病毒治疗继发性耐药的影响因素。治疗时间≥1年、漏服药物比例>25%为继发性耐药的危险因素,本人领药为继发性耐药的保护因素。应加强治疗优化的干预力度,提高HIV感染者本人对服药的认知水平。
关键词: 艾滋病     抗病毒治疗     继发性耐药     病例对照研究    
Related factors on secondary drug resistance in HIV infected persons receiving antiretroviral therapy in Shandong province: a case-control study
Shan Shixin1, Sun Xiaoguang1, Zhu Xiaoyan1, Zhang Na1, Liao Meizhen1, Huang Tao1, Li Rui1, Yang Te2, Duan Qing2, Kang Dianmin1,3     
1. Shandong Provincial Center for Disease Control and Prevention, Jinan 250014, China;
2. School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan 250062, China;
3. Key Laboratory of Infectious Disease Control and Prevention of Shandong Province, School of Public Health, Shandong University, Jinan 250012, China
Corresponding author: Kang Dianmin, Email:dmkang66@163.com
Fund program: Shandong Province Medical and Health Science and Technology Development Plan (2013WS0161)
Abstract: Objective To explore the causes of secondary drug resistance among HIV infected persons who were receiving antiretroviral therapy in Shandong province, and provide evidence for the improvement of antiretroviral therapy strategy. Methods A case-control study was designed with 1:2 matching on case and control groups. Household and face-to-face interview were conducted in October, 2015. All the study subjects were screened from both the drug resistant database of antiretroviral therapy of Shandong provincial laboratory and national comprehensive HIV/AIDS database in Shandong. The sample size was estimated as 330 cases including 110 drug resistant and 220 non-drug resistant cases. Subjects were people living with HIV/AIDS (PLWHA) aged 15 or older and received antiretroviral therapy for more than 6 months with records of virus load (VL). Subjects who presented VL above 1 000 copies/ml would receive drug resistance testing. Subjects who were confirmed resistant to with secondary drug, were selected as case group, the rest subjects with non-secondary drug resistance would form the control group. EpiData 3.1 software and SPSS 22.0 software were used to establish a database. Related influencing factors were analyzed with non-conditional stepwise logistic regression model. Results A total of 288 cases were enrolled, including 103 in the case and 185 cases in the control groups, with average age as (37.62±1.06) years and (37.90±0.74) years old, respectively. Most of them were male, married/cohabitant, with education level of junior/senior high school or below and under Han nationality. Results from the multivariate logistic regression model showed that ORs (95%CI) of receiving antiretroviral therapy for 1-3 years, or more than 3 years were equal to 8.80 (3.69-21.00), 3.00 (1.20-7.53), compared with receiving antiretroviral therapy less than one year, respectively. OR (95%CI) of Among the PLWHA that with missing rate above 25.0% on medication, the OR appeared as 15.41(4.59-51.71), compared with not missing medication. OR (95%CI) among those who took the medicine themselves was 0.22 (0.07-0.74). Conclusions Factors as duration of treatment, missing rate on medication and taking medicine by oneself were of influence on secondary drug resistance. Other factors as duration on antiretroviral therapy longer than 1 year, missing rate above 25.0% on medication, were related to the risk on secondary drug resistance. However, if the medicine was taken by oneself, it served as a protective factor for secondary drug resistance. It is necessary to strengthen the intervention and health education programs related to antiretroviral therapy.
Key words: AIDS     Antiretroviral therapy     Secondary drug resistance     Case-control study    

抗病毒治疗是控制艾滋病最有效的方法,不仅能有效抑制HIV复制,重建免疫功能,降低HIV传播风险,而且能延缓艾滋病临床病程,提高HIV感染者的生活质量,降低艾滋病的发病率和死亡率[1-3]。随着抗病毒治疗时间的延长,HIV感染者继发性耐药已成为影响抗病毒治疗效果的主要因素。原发性耐药指在抗病毒治疗前发生的耐药,继发性耐药指抗病毒治疗后在药物压力下诱导产生的耐药。既往调查多研究耐药与依从性的关系,对耐药与周围支持性环境、医疗服务可及性的相关性研究较少[4-5]。本研究旨在分析山东省HIV感染者抗病毒治疗中发生继发性耐药的影响因素,为提高山东省艾滋病抗病毒治疗效果提供参考依据。

对象与方法

1.研究对象:2015年10月根据山东省级实验室直建的HIV-1耐药基因型检测in-house法的耐药数据库,结合艾滋病综合防治数据信息系统,筛选研究对象。研究对象为山东省存活的HIV感染者、年龄≥15岁、参加抗病毒治疗≥6个月并检测病毒载量(viral load,VL),数据库共有2 449例HIV感染者,耐药检测结果筛选出继发性耐药者213例。

对VL>1 000拷贝/ml的感染者进行实验室耐药检测,结果为耐药定义为继发性耐药,不耐药定义为非继发性耐药[6]。采用单纯随机抽样法抽取110例继发性耐药的感染者作为病例组。对照组选择标准是来自于相同县(区)、同性别、年龄差距≤5岁的非继发性耐药的感染者。

2.研究设计:采用病例对照研究方法,按照1 : 2匹配病例组和对照组。样本量估算为330例(病例组110例、对照组220例)。样本量估算公式:

按照漏服者预期耐药的RR=3.9,α=0.05,β=0.10,病例组和对照组的预期漏服率分别为26.2%和13.4%[7]P1=0.376,失访率为10%~15%。

3.调查内容:自行设计调查问卷,进行预调查完善问卷内容。调查方式为入户面对面调查。问卷内容包括吸烟、饮酒等生活习惯、抗病毒治疗情况和不良反应等。

4.实验室检测:①耐药检测:采用雅培Abbott Real Time HIV-1 Kit(M2000)全自动病毒载量检测系统(美国Abbott Molecular公司)。标本采集后2周内全部完成VL检测,对VL>1 000拷贝数/ml的标本提取核酸、扩增和测序,获得核酸序列,采用in-house法进行耐药性检测,将获得的基因序列提交至斯坦福大学耐药数据库(https://hivdb.stanford.edu/),进行耐药位点分析。②CD4+T淋巴细胞计数(CD4)检测:采用FACS Canto Ⅱ流式细胞仪(美国BD医疗器械有限公司),对研究对象的新鲜EDTA抗凝全血检测CD4

5.统计学分析:利用EpiData 3.1软件建立数据库,双录入数据,利用SPSS 22.0软件进行数据分析。单因素分析采用χ2检验,比较病例组和对照组的一般情况和服药相关特征。单因素分析筛选有统计学意义的自变量,进行非条件逐步logistic回归多因素分析,自变量纳入标准=0.05,剔除标准=0.10。检验水准α=0.05,双侧检验。

结果

1.人口学特征:病例组实际调查103人;对照组实际调查185人。病例组年龄为(37.62±1.06)岁,对照组年龄为(37.90±0.74)岁,两组的年龄差异无统计学意义(χ2=3.909,P=0.271)。研究对象以男性(占80.6%,232/288)、已婚/同居者(占52.8%,152/288)、高中及以下文化程度(占80.9%,233/288)、汉族(占95.1%,274/288)为主,两组的年龄、性别、婚姻状况、民族、文化程度方面具有可比性,差异均无统计学意义(P>0.05)。见表 1

表 1 山东省艾滋病病毒感染者抗病毒治疗继发性耐药影响因素的病例对照研究分组比较

2.继发性耐药单因素分析:家庭人均月收入、基线CD4、治疗时间、治疗中途换药、取药点距离、漏服比例>25.0%是继发性耐药的影响因素(P<0.05)。见表 1

3. logistic回归多因素分析:治疗时间、漏服比例>25.0%、本人领药是抗病毒治疗继发性耐药的影响因素。治疗时间≥1年、漏服比例>25.0%是继发性耐药的危险因素。与治疗时间<1年相比,治疗时间1~3年和>3年的OR值为8.80(95%CI:3.69~21.00)和3.00(95%CI:1.20~7.53);与未漏服的相比,漏服比例>25.0%的OR值为15.41(95%CI:4.59~51.71)。本人领药是继发性耐药的保护性因素(OR=0.22,95%CI:0.07~0.74)。见表 2

表 2 山东省艾滋病病毒感染者继发性耐药logistic回归多因素分析
讨论

山东省启动免费抗病毒治疗工作以来,参加抗病毒治疗的感染者由2003年的20余例上升到2015年的5 659例,2011年开始抗病毒治疗耐药率从3.1%上升到2015年的5.3%[8],耐药问题严重影响抗病毒治疗效果。既往研究显示CD4是判断抗病毒治疗的直接生物学指标,基线CD4较高的感染者免疫功能重建效果更好[9-10]。本研究感染者CD4较低,免疫重建功能较差,更易发生继发性耐药。因此,及时甄别易发生继发性耐药的感染者,尽早针对性治疗,对提高抗病毒治疗效果意义重大。

本研究结果显示,家庭人均月收入、治疗时间、中途换药、漏服比例、感染途径、不良反应、外出、取药点距离等因素对继发性耐药有一定影响,与以往研究基本一致[11-12]。但是,吸烟、饮酒对于继发性耐药发生未构成明显影响,与文献报道[13-14]存在差异。本研究发现医生主动提供咨询服务、服药督导员监督与继发性耐药无关,与文献报道结论相同[15]。漏服原因主要有遗忘、不良反应等,与其他研究结果相似[16]。感染者本人领药是保持较好治疗效果、不易发生继发性耐药的保护因素,在今后工作中应加强对感染者的服药依从性管理和心理疏导,提高感染者主动服药意识,力求发挥感染者自身的积极作用[11, 17-18]。多因素分析结果显示,服药时间长和漏服是继发性耐药的重要危险因素,随着抗病毒治疗时间的延长,感染者依从性变差[19-20],依从性较差的感染者,其耐药率是依从性较好感染者的3.14倍[21],治疗期间有药物漏服现象的感染者病毒抑制失败风险是无药物漏服感染者的2~3倍[22],漏服比例>25.0%是继发性耐药的重要危险因素。治疗时间1~3年的感染者继发性耐药风险高于治疗时间>3年的感染者。可能与治疗1~3年是控制继发性耐药的关键期、感染者面临药物不良反应的影响有关,需开展进一步研究。

本研究存在不足。病例组研究对象中途换药的比例较高,部分研究对象可能不是当年首次做耐药检测,而对耐药检测结果造成影响;另外,难免出现选择性偏倚和回忆性偏倚。

综上所述,治疗时间≥1年、漏服药物比例>25.0%是抗病毒治疗继发性耐药的危险因素,本人领药是抗病毒治疗继发性耐药的保护性因素。应加强治疗优化的干预力度,提高HIV感染者的服药认知水平,严格控制药物漏服比例,争取提供更便捷的治疗服务,从而提高抗病毒治疗的可及性。


利益冲突:
参考文献
[1] Cohen MS, Smith MK, Muessig KE, et al. Antiretroviral treatment of HIV-1 prevents transmission of HIV-1:where do we go from here[J]. Lancet, 2013, 382(9903): 1515–1524. DOI:10.1016/S0140-6736(13)61998-4
[2] 孙燕, 陈昭云, 赵清霞, 等. 郑州市2004-2015年HIV/AIDS病人抗病毒治疗效果评价[J]. 中国艾滋病性病, 2017(10): 887–889.
Sun Y, Chen ZY, Zhao QX, et al. Effect evaluation of HIV/AIDS patients receiving anti-retroviral treatment during 2004-2015 in Zhengzhou[J]. Chin J AIDS STD, 2017(10): 887–889. DOI:10.13419/j.cnki.aids.2017.10.04
[3] 彭志行, 鲁佳菲, 王岚, 等. 中国艾滋病抗病毒治疗的流行病学研究[J]. 中华流行病学杂志, 2012, 33(9): 977–982.
Peng ZH, Lu JF, Wang L, et al. Epidemiological studies on HIV/AIDS antiretroviral therapy in China[J]. Chin J Epidemiol, 2012, 33(9): 977–982. DOI:10.3760/cma.j.issn.0254-6450.2012.09.023
[4] 赵文宇, 俞海亮, 叶少东, 等. 中国三省386例HIV感染者和艾滋病患者抗病毒治疗服药依从性及其影响因素分析[J]. 中华预防医学杂志, 2016, 50(4): 334–338.
Zhao QY, Yu HL, Ye SD, et al. Factors associated with adherence of highly active antiretroviral therapy among 386 HIV/AIDS patients in 3 provinces of China[J]. Chin Prev Med, 2016, 50(4): 334–338. DOI:10.3760/cma.j.issn.0253-9624.2016.04.010
[5] 孙晓光, 林彬, 苏生利, 等. 2011年山东省抗病毒治疗艾滋病患者中HIV毒株耐药基因变异情况[J]. 中华预防医学杂志, 2012, 46(11): 982–986.
Sun XG, Lin B, Su SL, et al. Mutation of drug resistant gene in HIV/AIDS patients with antiretroviral therapy in Shandong province in 2011[J]. Chin Prev Med, 2012, 46(11): 982–986. DOI:10.3760/cma.j.issn.0253-9624.2012.11.005
[6] 中国疾病预防控制中心性病艾滋病预防控制中心. 国家免费艾滋病抗病毒药物治疗手册(第4版)[M]. 北京: 人民卫生出版社, 2016: 54–56.
National Center for AIDS/STD Control Prevention, Chinese Center for Disease Control and Prevention.Manual of National Free Antiretroviral Treatment(4th ed)[M]. Beijing: People's Medical Publishing House, 2016: 54–56.
[7] 朱晓艳, 王国永, 孙晓光, 等. 山东省抗病毒治疗的HIV/AIDS病人的耐药调查结果分析[J]. 中国艾滋病性病, 2017, 23(2): 107–111.
Zhu XY, Wang GY, Sun XG, et al. Analysis of drug resistance among HIV/AIDS receiving antiretroviral treatment in Shandong province[J]. Chin J AIDS STD, 2017, 23(2): 107–111. DOI:10.13419/j.cnki.aids.2017.02.05
[8] 林彬, 孙晓光, 苏生利, 等. HIV耐药毒株在山东省艾滋病抗病毒治疗人群中的流行及演变[J]. 中华预防医学杂志, 2011, 45(11): 995–998.
Lin B, Sun XG, Su SL, et al. The prevalence and evolution of HIV drug-resistant strains in people who live with HIV/AIDS during HIV antiretroviral therapy in Shandong province[J]. Chin Prev Med, 2011, 45(11): 995–998. DOI:10.3760/cma.j.issn.0253-9624.2011.11.009
[9] 姚仕堂, 姚媛, 时允, 等. 云南省德宏州2012-2014年成年艾滋病患者抗病毒治疗耐药发生及影响因素研究[J]. 中华流行病学杂志, 2016, 37(7): 949–954.
Yao ST, Yao Y, Shi Y, et al. Drug resistance and influencing factors in adult AIDS patients receiving antiretroviral treatment in Dehong, Yunnan province[J]. Chin J Epidemiol, 2016, 37(7): 949–954. DOI:10.3760/cma.j.issn.0254-6450.2016.07.009
[10] 姚仕堂, 时允, 李品银, 等. 云南省德宏州成年艾滋病患者抗病毒治疗脱失情况及其原因分析[J]. 中华流行病学杂志, 2015, 36(7): 667–671.
Yao ST, Shi Y, Li PY, et al. Study on drop-out from antiretroviral therapy among adult HIV-infected individuals in Dehong prefecture, Yunnan province[J]. Chin J Epidemiol, 2015, 36(7): 667–671. DOI:10.3760/cma.j.issn.0254-6450.2015.07.001
[11] Gebrezgabher BB, Kebede Y, Kindie M, et al. Determinants to antiretroviral treatment non-adherence among adult HIV/AIDS patients in northern Ethiopia[J]. AIDS Res Ther, 2017, 14: 16. DOI:10.1186/s12981-017-0143-1
[12] 唐德谊, 聂欢, 蒋平, 等. 重庆市艾滋病抗病毒治疗效果及其影响因素分析[J]. 中国艾滋病性病, 2017, 23(6): 492–495.
Tang DY, Nie H, Jiang P, et al. Therapeutic effect and associated factors of HIV/AIDS patients receiving highly active antiretroviral therapy in Chongqing[J]. Chin J AIDS STD, 2017, 23(6): 492–495. DOI:10.13419/j.cnki.aids.2017.06.07
[13] 张晓菲, 吕翠霞, 董蕾, 等. 山东部分地区社会组织参与艾滋病防治能力现状及提升需求的定性研究[J]. 中国艾滋病性病, 2014, 20(10): 771–773.
Zhang XF, Lyu CX, Dong L, et al. Qualitative study on the situation and enhancement requirement of AIDS prevention ability of social organizations in some areas of Shandong Province[J]. Chin J AIDS STD, 2014, 20(10): 771–773. DOI:10.13419/j.cnki.aids.2014.10.049
[14] 张广, 龚煜汉, 王启兴, 等. 四川省凉山彝族自治州8310例首次接受抗病毒治疗的成年艾滋病患者生存时间及其影响因素[J]. 中华预防医学杂志, 2015, 49(11): 967–972.
Zhang G, Gong YH, Wang QX, et al. Survival time and associated factors of 8310 AIDS patients initially receiving antiretroviral treatment of Liangshan Yi autonomous prefecture, Sichuan province of China[J]. Chin Prev Med, 2015, 49(11): 967–972. DOI:10.3760/cma.j.issn.0253-9624.2015.11.008
[15] 王威, 刘伟, 陈涛, 等. 伊犁哈萨克自治州乡级艾滋病治疗机构内HIV感染者和艾滋病患者抗病毒治疗依从性及影响因素[J]. 中华预防医学杂志, 2017, 51(2): 160–164.
Wang W, Liu W, Chen T, et al. Factors influencing antiretroviral therapy adherence among HIV-infected people on antiretroviral therapy in Ili Kazakh autonomous prefecture[J]. Chin Prev Med, 2017, 51(2): 160–164. DOI:10.3760/cma.j.issn.0253-9624.2017.02.012
[16] Hosseinipour MC, Kumwenda JJ, Weigel R, et al. Second-line treatment in the Malawi antiretroviral programme:high early mortality, but good outcomes in survivors, despite extensive drug resistance at baseline[J]. HIV Med, 2010, 11(8): 510–518. DOI:10.1111/j.1468-1293.2010.00825.x
[17] Yadav DK, Karki P, Yadav S, et al. Adherence to antiretroviral drug treatment ARV among people living with HIV/AIDS:a study from Eastern Nepal[J]. Int J Infect Dis, 2016, 45(1): 124. DOI:10.1016/j.ijid.2016.02.309
[18] Molassiotis A, Nahas-Lopez V, Chung WYR, et al. Factors associated with adherence to antiretroviral medication in HIV-infected patients[J]. Int J STD AIDS, 2002, 13(5): 301–310. DOI:10.1258/0956462021925117
[19] 郑锦雷, 徐云, 何林, 等. 浙江省2009-2014年艾滋病抗病毒治疗效果分析[J]. 中华流行病学杂志, 2016, 37(5): 673–677.
Zheng JL, Xu Y, He L, et al. Analysis on antiretroviral therapy efficacy for HIV/AIDS in Zhejiang province, 2009-2014[J]. Chin J Epidemiol, 2016, 37(5): 673–677. DOI:10.3760/cma.j.issn.0254-6450.2016.05.017
[20] Ajose O, Mookerjee S, Mills EJ, et al. Treatment outcomes of patients on second-line antiretroviral therapy in resource-limited settings:a systematic review and Meta-analysis[J]. AIDS, 2012, 26(8): 929–938. DOI:10.1097/QAD.0b013e328351f5b2
[21] Tadesse WT, Mekonnen AB, Tesfaye WH, et al. Self-reported adverse drug reactions and their influence on highly active antiretroviral therapy in HIV infected patients:a cross sectional study[J]. BMC Pharmacol Toxicol, 2014, 15: 32. DOI:10.1186/2050-6511-15-32
[22] 张继红, 张幼萍, 洪航, 等. 宁波市HIV/AIDS病人的抗病毒治疗依从性及影响因素[J]. 中国艾滋病性病, 2017, 23(5): 393–396.
Zhang JH, Zhang YP, Hong H, et al. Factors associated with adherence to ART for HIV/AIDS patients in Ningbo[J]. Chin J AIDS STD, 2017, 23(5): 393–396. DOI:10.13419/j.cnki.aids.2017.05.07