【作者】 彭志行；

【导师】 陈峰；

【作者基本信息】 南京医科大学 ， 流行病与卫生统计学， 2013， 博士

【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Ro<l时,无病的平衡点是全局稳定的,而当Ro>l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。更多还原

【Abstract】 As AIDS epidemic has become one of the most serious global public health and social event, HAART was used in AIDS patients in various degree for every country in the world. The present treatment policy can effectively suppress virus replication and rebuild the immune function of HIV-infected people, and also can improve quality of life and reduce morbidity and mortality of patients, however, HAART can not clear the virus completely. Patients need to take medicine for life. Drug adverse effects and resistance may appear with the long-term medicine-taking, which could reduce the living quality. Moreover, antiviral therapy can prolong the lifespan of HIV infected individuals, which consequently make them have more opportunities to infect others. So in terms of individual therapy and epidemic control, whether antiviral therapy is effective for infection control, or in what circumstance antiviral therapy is effective for infection control is still controversial and need a further study. Based on previous immune-virus dynamics and pharmacokinetic modeling,this study introduces the influence of virologic load variation on treatment effect and HIV epidemic with long-term treatment. Antiviral therapy can extend the life expectancy of HIV infected individuals, reduce the risk of clinical progression of disease, and ultimately produce a significant influence on the whole natural progression. In different long-term policies of HAART, what we focus on is how to keep the balance between drug adverse effects and the risk of HIV new infection.Section1:a virologic load model with individual antiviral therapy. In order to estimate side effect of antiviral therapy, disadvantages of continuous(or discontinuous) therapy, and simulate and predict the progression of disease, we improve the traditional virus dynamic model and introduce several variations like the life expectancy, treatment effect, drug resistance and sensibility. We use a series of ways, including different iterative dynamic models, to investigate optimal initial treatment time, the optimal time to switch therapy, the optimal CD4cell threshold value, the continuity, drug resistance and adherence of treatment policy, and simulate the model of the progression of virologic load under antiviral therapy and the model of different therapy policies. We study the relationship between individual drug concentration and effect in different medications through formulating the model combined virus dynamic model with pharmacokinetic model. Then we can analyze individual virus load, the change of well or infected CD4cell counts, and confirm pivotal parameters, finally on the base of which we formulate the complex model about microscopic virus dynamic model and macroscopical HIV epidemic. We use the way of theoretical analysis and numerical modeling to investigate dynamics of the complex model, the effectiveness of intervening measures and different therapy policies and predict the development tendency of HIV epidemic.Section2:The statistic model for estimating AIDS epidemic. This section mainly focused on the development of the epidemic of AIDS by a composite model, combining micro virus dynamics models with macro infectious disease dynamics models. In the macro dynamic modes, we introduced starting time, resistance, efficacy of the treatment and analyzed relations among them. This study established a bridge between these two modeling system, which is helpful to investigate the impact that antiviral therapy based on individuals has on HIV infected rate of China.In order to reduce the number of variables we introduced two factors to describe variation rate in infectiousness and disease progression rates respectively, used Latin Hypercube Sampling (LHS) and partial rank correlation coefficients (PRCCs) to examine the dependence and sensitivity of the reproduction number RO and the expected number of HIV-positive individuals in2015and got important influencing parameters. Meanwhile, according to the CD4+T cell counts in the blood, we divided the HIV-positive individuals to several stages and formulated a mathematical model with antiviral therapy. It proved that the disease-free equilibrium is globally asymptotically stable when Ro<1, whilst the system is uniformly persistence when R0>1.We studied the effect of antiviral therapy in two situations:antiviral therapy started immediately once diagnosed and started when CD4+T count is less than350cells per μL. There exists a critical value for the infectiousness below which immediate treatment once diagnosed is better than the current policy in terms of the reproduction number. Whereas, current policy exhibits better than immediate treatment if the infectiousness is greater than the critical level. The result also indicated when the infectiousness is relatively low (relatively good treatment efficacy) increasing treatment coverage will decrease the reproduction number and lead to new HIV infection decline, whilst increasing treatment coverage will result in an increase in new HIV infection for the relatively great infectiousness, which is in agreement with that for heterogeneous transmission. This indicates that if treatment efficacy is relatively good our conclusions suggest immediate treatment with high uptake rate, otherwise the current policy is reasonable.Using the data on the number of individuals living with HIV (not AIDS) or AIDS by year among MSM, we obtained estimates of the reproduction number, intervention parameter values and the high-risk population size. Our estimated reproduction number Ro is3.88(95%CI3.69-4.07). From the estimated parameters we know that the transmission coefficient β0is much larger than the estimation for heterosexual transmission and general high-risk population. Our estimation also shows that the diagnose rate among MSM is much lower than that for other high-risk population. Meanwhile, we estimated that the antiviral therapy coverage rate among MSM in2011is less than the estimation by China. Simulation results show that strengthening education to high-risk population and increasing surveillance and testing can slow down the spread of disease. Increasing treatment uptake rate may lead to HIV new infection decline, depending on infectiousness and behavior changes. Further, sensitivity analysis implies the most influential parameters are infection rate β0and disease related death rate for HIV-positive individuals α1. Note that high efficacy drug can reduce the transmission probability of HIV per high-risk behavior, and the education may reduce the contact rate and increase the condom use rate. This means that a high effective drug and timely education may effectively control HIV epidemic.In this study, we also applied trend surface analysis, spatial autocorrelation analysis and regression analysis to analysis and predict the epidemic of AIDS in Yunnan province, China, and found that many factors, such as the geographical distribution of railways, drug of abuse and commercial sexual actor, could contribute to different distribution of AIDS in different areas. Our modeling provided a further study to find the inducement of illness onset for gathering areas.The main original points in this study:First, in our statistic model we took into account the influence of individual virus progression with long-term therapy on the drug concentration, treatment effect and AIDS epidemic. Meanwhile, we tried to figure out the effect taking drugs in different ways on the evolution of HIV and the generation of resistance. Second, what influences the optimal initial treatment time, treatment courage, the change of individual or average virologic load have on the morbidity and mortality of patients were also discussed. Third, based on the data of high-risk groups queue, national AIDS epidemic and lab testing, Bayes statistic method was used to estimate the parameters of the model. At last, we estimated the HIV reproduction number(R0) of MSM systemically, evaluated the sensibility of Ro and got the influence that each parameter had on Ro, which could help us to make interventions.更多还原