基于抗病毒治疗与艾滋病疫情关联的统计模型研究
发布时间：2019-06-12 17:40
【摘要】：艾滋病是全世界广受关注的公共卫生和社会问题,世界各国均不同程度的采用抗病毒治疗来应对艾滋病的危害。当前的治疗工作对艾滋病疫情控制有着较为重要的影响,治疗一方面能降低个体的病毒载量(VL)从而降低了艾滋病病毒传播的机会,艾滋病(AIDS)患者的发病率和死亡率明显下降,患者的免疫功能得到重建,生存质量得到了改善。但另一方面,从长期的效果看,高效逆转录治疗只能控制病毒的活动复制,不能将感染者体内的病毒完全清除,需长期或终身服药。长期或终身服药的药物毒副作用不仅降低病人的生活质量,同时可能产生广泛的耐药性,而且治疗延长了病人的生命并改善了身体健康状况从而增加将艾滋病病毒(HIV)传染给别人的可能性。所以,针对HIV的抗病毒治疗(ART)是否有利于(或不利于)HIV疫情控制,或在什么条件下是有利于疫情的控制是目前关于HIV个体的ART和疫情控制关系方面具有挑战性的研究领域。本研究以既往针对HIV的免疫-病毒动力学和药物动力学模型的研究为基础,引入长期治疗带来的个体VL变化会对治疗效果和疫情造成的影响。抗病毒治疗不仅提高患者的生存时间,同时也降低了诊断后的疾病进展危险,最终对HIV感染的整个自然进程产生显著影响。而在不同的高效抗逆转录病毒治疗(HAART)的长期治疗策略中,如何控制治疗的相关副作用与疾病发生危险的平衡是我们重点关注的。 第一部分,ART的个体VL模型。为了仔细评估治疗的副作用和持续(或间断)性治疗的弊端,模拟和预测感染HIV后疾病的进展,我们改进了传统的HIV动力学模型,引入影响病毒感染进展的期望寿命、治疗效用、耐药和敏感性等变量,利用一系列包括不同迭代动力学模拟的方法来研究最佳的初始治疗时间、更换方案时间、最佳CD4计数阈值、治疗方案的持续、耐药和依从性,拟合治疗情况下病毒载量的进展和不同治疗策略的模型。通过量效关系构造病毒动力学与药物动力学结合的模型,研究不同的用药方式下个体药物浓度与效应的关系,进而分析感染者个体的VL、健康或被感染的CD4+T细胞计数的发展变化,确定模型的关键参数,在此基础上建立微观的病毒动力学和宏观疫情的复合模型,利用理论分析和数值模拟的方法来研究复合模型的动态行为,探讨预防干预措施和不同治疗措施的有效性,预测HIV疫情的发展趋势。 第二部分,AIDS疫情估计宏观统计模型。本部分针对已有的考虑微观的病毒动力学和宏观的传染病动力学的复合模型的研究,重点关注抗病毒治疗对疫情发展的影响,在宏观的动力学模型中引入治疗的起始时刻、抗药性、药效等刻画治疗的因素,并研究他们之间的相互作用。本部分建立了反映微观的病毒动力学和宏观感染模型两类系统的桥梁,通过此桥梁来研究个体水平的抗病毒治疗工作对我国HIV感染率的影响。我们在模型中引入传染力的变化、病程进展变化等新的因子来减少变量数,运用拉丁超立方抽样法(LHS)和部分秩相关系数(PRCCs)来检验再生数R0的独立性和敏感性,发现了对2015年的疫情和R0能产生影响的重要参数。同时根据血液中的CD4水平,我们将感染者和病人分为不同的阶段,并将其抗病毒治疗的过程和结构用数学模型表达出来。可以证明当Rol时,无病的平衡点是全局稳定的,而当Rol时,这个疾病将会持续存在。 我们研究了两种不同情况下ART的效果：一经确诊就立即开展ART和当CD4水平低于350/uL时才开展ART(这是当前的治疗政策)。发现疾病的治疗存在一个关健的阈值,如果疾病的传播力(VL)低于这个值的话,那么就病毒的再生数而言,确诊后立即开展ART的效果会比现在的治疗政策好；然而,如果疾病的VL大于这个关健值的话,当前的治疗政策效果就会优于立即治疗的效果。这个研究结果同时还提示我们新的信息：如果疾病的感染性相对较低的话(即相对较好的治疗效果),扩大ART的覆盖率就会降低病毒的再生数和新发HIV感染率；然而如果疾病的感染性相对较高时,扩大ART的覆盖率反而会导致HIV新发感染数的增加,这和异性传播中的情况是一样的。所以,如果ART效果是相对较好的,那就采取立即治疗的方案,否则还是当前的治疗政策更合理。 利用男男同性性行为人群(MSM)的疫情数据,我们得到再生数估测值、干预参数值以及高危人群数量。本研究得到再生数R0为3.88(95%CI3.69-4.07),可知传播系数β0远大于异性传播与一般高危人群的传播。此外,本研究发现MSM人群HIV诊断率远低于其他高危人群。同时,MSM的治疗覆盖率低于国家调查的平均值,模拟结果显示强化高危人群教育以及增加监测及检测强度可以降低疾病传播速度。根据疾病的感染性及感染者(病人)行为改变,扩大治疗覆盖率可以减少HIV的新发感染。而敏感性分析提示对治疗效果影响最大的参数为感染率β0以及患者疾病相关的死亡率α,。而且,高效的药物可以减少HIV感染者每种高危行为的传播率,且加强教育可以减少与HIV患者的接触率,提高安全套的使用率。意味着高效药物、及时的教育可以有效控制艾滋病病毒的流行。 本研究中,我们还运用时空模型的趋势面分析、空间自相关分析、回归分析等方法对云南省的AIDS疫情进行了分析和预测,很多因素的地理分布不同会导致HIV/AIDS在不同地区有不同分布,比如铁路分布、静脉吸毒人群分布、商业性行为人群分布等,通过模型分析能进一步得出聚集地区发病的诱因所在,为决策提供科学依据。 本文的主要创新点包括：在模型中考虑了长期治疗带来的个体病毒进展对体内药物浓度、治疗效果和疫情造成的影响,创新性的研究了不同的服药方式对HIV病毒演化、耐药产生的影响。探讨抗病毒治疗时机选择、覆盖率、个体／平均病毒载量的变化对HIV感染和病死率的影响；以高危人群队列和全国HIV疫情、实验室检测实际数据为基础,利用Bayes统计推断方法进行模型的参数估计；对我国目前MSM人群的HIV传播基本再生数(R0)做了系统估计,并对其敏感性做了评价,得到了各个参数对R0的影像,可为实施各项干预措施提供依据。
[Abstract]:AIDS is a popular public health and social problem in the world, and all countries in the world use anti-virus therapy to deal with the hazards of AIDS. The current treatment work has an important effect on the control of the AIDS epidemic situation, and the treatment can reduce the viral load (VL) of the individual so as to reduce the chance of the transmission of the AIDS virus, and the morbidity and the mortality of the AIDS patients are obviously reduced, The immune function of the patient was reconstructed and the quality of life was improved. On the other hand, from the long-term effect, high-efficiency reverse transcription can only control the active replication of the virus, and can not completely remove the virus in the infected person, and can take the medicine for a long time or for a long time. The toxic and side effects of long-term or long-term administration not only reduce the quality of life of the patient, but also can produce a wide range of drug resistance, and the treatment prolongs the life of the patient and improves the health condition of the body, thereby increasing the possibility of the transmission of the HIV (HIV) to other people. Therefore, whether the anti-virus therapy (ART) for HIV is in favor of (or unfavorable to) the control of the HIV epidemic, or under what conditions is the control of the benefit of the epidemic is the current challenging field of research on the relationship between the ART and the epidemic control of the HIV-individual. This study is based on previous studies of HIV-based immune-viral dynamics and pharmacokinetic models, and the introduction of individual VL changes from long-term treatment will have an impact on the therapeutic effect and the epidemic. The antiviral therapy not only improves the survival time of the patient, but also reduces the disease progression risk after the diagnosis, and finally has a significant effect on the whole natural process of the HIV infection. In the long-term treatment strategies of different high-efficiency antiretroviral therapy (HAART), the balance of how to control the associated side effects of treatment and the risk of a disease is our focus. the first part, the individual vl mode of the art, Type. In order to carefully assess the side effects of treatment and the disadvantages of continuous (or intermittent) treatment, we have improved the traditional HIV dynamics model, introducing the desired life, therapeutic utility, drug resistance, and sensitivity to the progress of viral infection. The optimal initial treatment time, the replacement protocol time, the optimal CD4 count threshold, the duration, the resistance and the compliance of the treatment regimen, the progress of the viral load and the model of the different treatment strategies were studied using a series of methods including different iterative dynamics simulations. The relationship between the concentration and effect of the individual drug in different dosage forms was studied by the model of the relationship between the dose-effect relationship and the pharmacokinetics and the pharmacokinetics of the drug, and the development of the number of VL, healthy or infected CD4 + T cells in the infected individuals was analyzed, and the key parameters of the model were determined. On the basis of this, the complex model of the micro-dynamics and the macro-epidemic situation was established, and the dynamic behavior of the composite model was studied by the method of theoretical analysis and numerical simulation. The preventive intervention measures and the effectiveness of different treatment measures were discussed, and the development trend of the HIV epidemic was predicted. The second part, the AIDS epidemic estimating macro-system In this part, we focus on the effects of anti-virus therapy on the development of the epidemic, and introduce the treatment initiation time, drug resistance, drug effect and so on in the macroscopic dynamic model. and to study the phase between them Interaction. This part has set up a bridge that reflects the micro-dynamics of the virus and the macro-infection model, and this bridge is used to study the anti-virus treatment of individual level and the infection rate of HIV in China. The influence of RHS and partial rank correlation coefficient (PRCCs) was used to check the independence of the number of regeneration (R0) and the partial rank correlation coefficient (PRCMs). Sensitivity, it was found that the effects of the epidemic and R0 could have an impact on the year 2015 Parameters. At the same time, according to the level of CD4 in the blood, we divide the infected person and the patient into different stages and use the mathematical model table for the process and structure of the anti-virus treatment It can prove that when Rol is, the equilibrium point of the disease is global and stable, and when Rol, the disease will be held. continued. We have studied the effect of ART in two different cases: ART is performed immediately upon diagnosis and ART is performed only when the CD4 level is lower than 350/ uL (this is current Treatment policy). The treatment of a disease is found to have a threshold for health. If the spread force (VL) of the disease is below this value, the effect of ART immediately after the diagnosis is better than the current treatment policy; however, if the VL of the disease is greater than this, The current treatment policy will be better than immediate if you have a good value. The results of the study are also suggestive of new information: if the disease is relatively low in infectivity (i.e., a relatively good therapeutic effect), it is possible to expand the coverage of ART to reduce the number of regenerations of the virus and the new HIV infection rate; however, if the disease is infectious The increase in the coverage of ART, when relatively high, will result in an increase in the number of new HIV infections, as well as in the transmission of the opposite sex It's the same. So, if the ART effect is relatively good, then take immediate treatment, or the current treatment The policy is more reasonable. With the data of the epidemic of MSM, we get the estimated value of the number of regeneration and the value of the intervention parameter. The number of the high-risk population was 3.88 (95% CI 3.69-4.07), and it was found that the propagation coefficient {0} was much higher than that of the opposite sex. The high-risk population was spread. In addition, the study found that the HIV diagnostic rate of the MSM population is much lower At the same time, the treatment coverage of MSM is lower than that of the national survey, and the simulation results show that the strengthening of high-risk population education and the increase of monitoring and detection intensity can be reduced The propagation speed of low disease can be reduced according to the infection of the disease and the behavior of the infected person (the patient), and the treatment coverage rate can be reduced by H. New infections in the IV. The sensitivity analysis indicated that the most important parameters for the effect of treatment were infection rate%0 and the patient's disease phase High-efficiency drugs can reduce the rate of spread of each high-risk behavior of people living with HIV and enhance education to reduce the rate of exposure to HIV patients and to increase The rate of use of condoms means that high-efficiency drugs and timely education can be effectively controlled. In this study, we also analyze and forecast the AIDS epidemic in Yunnan province by using the trend surface analysis, space self-correlation analysis and regression analysis of the space-time model, and the geographical distribution of many factors can lead to different HIV/ AIDS in different areas. The distribution, such as the distribution of the railway, the distribution of the intravenous drug users, the distribution of the commercial sex, and the like, can be further obtained through the model analysis, The main innovative point of this paper is to consider the effect of the progress of the individual viruses brought by the long-term treatment on the drug concentration, the therapeutic effect and the epidemic situation of the body in the model. The effect of the change of the selection, coverage rate and individual/ average viral load on the HIV infection and mortality was discussed. Based on the high-risk population cohort and the national HIV epidemic and the laboratory's actual data, the Bayes statistical inference was used. The parameter estimation of the model is carried out, and the basic regeneration number (R0) of HIV transmission in the current MSM population in China is estimated, and the sensitivity is evaluated. The image of each parameter pair R0 is obtained.
【学位授予单位】：南京医科大学
【学位级别】：博士
【学位授予年份】：2013
【分类号】：R512.91
本文编号：2498185
[Abstract]:AIDS is a popular public health and social problem in the world, and all countries in the world use anti-virus therapy to deal with the hazards of AIDS. The current treatment work has an important effect on the control of the AIDS epidemic situation, and the treatment can reduce the viral load (VL) of the individual so as to reduce the chance of the transmission of the AIDS virus, and the morbidity and the mortality of the AIDS patients are obviously reduced, The immune function of the patient was reconstructed and the quality of life was improved. On the other hand, from the long-term effect, high-efficiency reverse transcription can only control the active replication of the virus, and can not completely remove the virus in the infected person, and can take the medicine for a long time or for a long time. The toxic and side effects of long-term or long-term administration not only reduce the quality of life of the patient, but also can produce a wide range of drug resistance, and the treatment prolongs the life of the patient and improves the health condition of the body, thereby increasing the possibility of the transmission of the HIV (HIV) to other people. Therefore, whether the anti-virus therapy (ART) for HIV is in favor of (or unfavorable to) the control of the HIV epidemic, or under what conditions is the control of the benefit of the epidemic is the current challenging field of research on the relationship between the ART and the epidemic control of the HIV-individual. This study is based on previous studies of HIV-based immune-viral dynamics and pharmacokinetic models, and the introduction of individual VL changes from long-term treatment will have an impact on the therapeutic effect and the epidemic. The antiviral therapy not only improves the survival time of the patient, but also reduces the disease progression risk after the diagnosis, and finally has a significant effect on the whole natural process of the HIV infection. In the long-term treatment strategies of different high-efficiency antiretroviral therapy (HAART), the balance of how to control the associated side effects of treatment and the risk of a disease is our focus. the first part, the individual vl mode of the art, Type. In order to carefully assess the side effects of treatment and the disadvantages of continuous (or intermittent) treatment, we have improved the traditional HIV dynamics model, introducing the desired life, therapeutic utility, drug resistance, and sensitivity to the progress of viral infection. The optimal initial treatment time, the replacement protocol time, the optimal CD4 count threshold, the duration, the resistance and the compliance of the treatment regimen, the progress of the viral load and the model of the different treatment strategies were studied using a series of methods including different iterative dynamics simulations. The relationship between the concentration and effect of the individual drug in different dosage forms was studied by the model of the relationship between the dose-effect relationship and the pharmacokinetics and the pharmacokinetics of the drug, and the development of the number of VL, healthy or infected CD4 + T cells in the infected individuals was analyzed, and the key parameters of the model were determined. On the basis of this, the complex model of the micro-dynamics and the macro-epidemic situation was established, and the dynamic behavior of the composite model was studied by the method of theoretical analysis and numerical simulation. The preventive intervention measures and the effectiveness of different treatment measures were discussed, and the development trend of the HIV epidemic was predicted. The second part, the AIDS epidemic estimating macro-system In this part, we focus on the effects of anti-virus therapy on the development of the epidemic, and introduce the treatment initiation time, drug resistance, drug effect and so on in the macroscopic dynamic model. and to study the phase between them Interaction. This part has set up a bridge that reflects the micro-dynamics of the virus and the macro-infection model, and this bridge is used to study the anti-virus treatment of individual level and the infection rate of HIV in China. The influence of RHS and partial rank correlation coefficient (PRCCs) was used to check the independence of the number of regeneration (R0) and the partial rank correlation coefficient (PRCMs). Sensitivity, it was found that the effects of the epidemic and R0 could have an impact on the year 2015 Parameters. At the same time, according to the level of CD4 in the blood, we divide the infected person and the patient into different stages and use the mathematical model table for the process and structure of the anti-virus treatment It can prove that when Rol is, the equilibrium point of the disease is global and stable, and when Rol, the disease will be held. continued. We have studied the effect of ART in two different cases: ART is performed immediately upon diagnosis and ART is performed only when the CD4 level is lower than 350/ uL (this is current Treatment policy). The treatment of a disease is found to have a threshold for health. If the spread force (VL) of the disease is below this value, the effect of ART immediately after the diagnosis is better than the current treatment policy; however, if the VL of the disease is greater than this, The current treatment policy will be better than immediate if you have a good value. The results of the study are also suggestive of new information: if the disease is relatively low in infectivity (i.e., a relatively good therapeutic effect), it is possible to expand the coverage of ART to reduce the number of regenerations of the virus and the new HIV infection rate; however, if the disease is infectious The increase in the coverage of ART, when relatively high, will result in an increase in the number of new HIV infections, as well as in the transmission of the opposite sex It's the same. So, if the ART effect is relatively good, then take immediate treatment, or the current treatment The policy is more reasonable. With the data of the epidemic of MSM, we get the estimated value of the number of regeneration and the value of the intervention parameter. The number of the high-risk population was 3.88 (95% CI 3.69-4.07), and it was found that the propagation coefficient {0} was much higher than that of the opposite sex. The high-risk population was spread. In addition, the study found that the HIV diagnostic rate of the MSM population is much lower At the same time, the treatment coverage of MSM is lower than that of the national survey, and the simulation results show that the strengthening of high-risk population education and the increase of monitoring and detection intensity can be reduced The propagation speed of low disease can be reduced according to the infection of the disease and the behavior of the infected person (the patient), and the treatment coverage rate can be reduced by H. New infections in the IV. The sensitivity analysis indicated that the most important parameters for the effect of treatment were infection rate%0 and the patient's disease phase High-efficiency drugs can reduce the rate of spread of each high-risk behavior of people living with HIV and enhance education to reduce the rate of exposure to HIV patients and to increase The rate of use of condoms means that high-efficiency drugs and timely education can be effectively controlled. In this study, we also analyze and forecast the AIDS epidemic in Yunnan province by using the trend surface analysis, space self-correlation analysis and regression analysis of the space-time model, and the geographical distribution of many factors can lead to different HIV/ AIDS in different areas. The distribution, such as the distribution of the railway, the distribution of the intravenous drug users, the distribution of the commercial sex, and the like, can be further obtained through the model analysis, The main innovative point of this paper is to consider the effect of the progress of the individual viruses brought by the long-term treatment on the drug concentration, the therapeutic effect and the epidemic situation of the body in the model. The effect of the change of the selection, coverage rate and individual/ average viral load on the HIV infection and mortality was discussed. Based on the high-risk population cohort and the national HIV epidemic and the laboratory's actual data, the Bayes statistical inference was used. The parameter estimation of the model is carried out, and the basic regeneration number (R0) of HIV transmission in the current MSM population in China is estimated, and the sensitivity is evaluated. The image of each parameter pair R0 is obtained.
【学位授予单位】：南京医科大学
【学位级别】：博士
【学位授予年份】：2013
【分类号】：R512.91
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