【摘要】：艾滋病是全世界廣受關(guān)注的公共衛(wèi)生和社會問題,世界各國均不同程度的采用抗病毒治療來應(yīng)對艾滋病的危害。當(dāng)前的治療工作對艾滋病疫情控制有著較為重要的影響,治療一方面能降低個體的病毒載量(VL)從而降低了艾滋病病毒傳播的機(jī)會,艾滋病(AIDS)患者的發(fā)病率和死亡率明顯下降,患者的免疫功能得到重建,生存質(zhì)量得到了改善。但另一方面,從長期的效果看,高效逆轉(zhuǎn)錄治療只能控制病毒的活動復(fù)制,不能將感染者體內(nèi)的病毒完全清除,需長期或終身服藥。長期或終身服藥的藥物毒副作用不僅降低病人的生活質(zhì)量,同時可能產(chǎn)生廣泛的耐藥性,而且治療延長了病人的生命并改善了身體健康狀況從而增加將艾滋病病毒(HIV)傳染給別人的可能性。所以,針對HIV的抗病毒治療(ART)是否有利于(或不利于)HIV疫情控制,或在什么條件下是有利于疫情的控制是目前關(guān)于HIV個體的ART和疫情控制關(guān)系方面具有挑戰(zhàn)性的研究領(lǐng)域。本研究以既往針對HIV的免疫-病毒動力學(xué)和藥物動力學(xué)模型的研究為基礎(chǔ),引入長期治療帶來的個體VL變化會對治療效果和疫情造成的影響�？共《局委煵粌H提高患者的生存時間,同時也降低了診斷后的疾病進(jìn)展危險,最終對HIV感染的整個自然進(jìn)程產(chǎn)生顯著影響。而在不同的高效抗逆轉(zhuǎn)錄病毒治療(HAART)的長期治療策略中,如何控制治療的相關(guān)副作用與疾病發(fā)生危險的平衡是我們重點關(guān)注的。 第一部分,ART的個體VL模型。為了仔細(xì)評估治療的副作用和持續(xù)(或間斷)性治療的弊端,模擬和預(yù)測感染HIV后疾病的進(jìn)展,我們改進(jìn)了傳統(tǒng)的HIV動力學(xué)模型,引入影響病毒感染進(jìn)展的期望壽命、治療效用、耐藥和敏感性等變量,利用一系列包括不同迭代動力學(xué)模擬的方法來研究最佳的初始治療時間、更換方案時間、最佳CD4計數(shù)閾值、治療方案的持續(xù)、耐藥和依從性,擬合治療情況下病毒載量的進(jìn)展和不同治療策略的模型。通過量效關(guān)系構(gòu)造病毒動力學(xué)與藥物動力學(xué)結(jié)合的模型,研究不同的用藥方式下個體藥物濃度與效應(yīng)的關(guān)系,進(jìn)而分析感染者個體的VL、健康或被感染的CD4+T細(xì)胞計數(shù)的發(fā)展變化,確定模型的關(guān)鍵參數(shù),在此基礎(chǔ)上建立微觀的病毒動力學(xué)和宏觀疫情的復(fù)合模型,利用理論分析和數(shù)值模擬的方法來研究復(fù)合模型的動態(tài)行為,探討預(yù)防干預(yù)措施和不同治療措施的有效性,預(yù)測HIV疫情的發(fā)展趨勢。 第二部分,AIDS疫情估計宏觀統(tǒng)計模型。本部分針對已有的考慮微觀的病毒動力學(xué)和宏觀的傳染病動力學(xué)的復(fù)合模型的研究,重點關(guān)注抗病毒治療對疫情發(fā)展的影響,在宏觀的動力學(xué)模型中引入治療的起始時刻、抗藥性、藥效等刻畫治療的因素,并研究他們之間的相互作用。本部分建立了反映微觀的病毒動力學(xué)和宏觀感染模型兩類系統(tǒng)的橋梁,通過此橋梁來研究個體水平的抗病毒治療工作對我國HIV感染率的影響。我們在模型中引入傳染力的變化、病程進(jìn)展變化等新的因子來減少變量數(shù),運用拉丁超立方抽樣法(LHS)和部分秩相關(guān)系數(shù)(PRCCs)來檢驗再生數(shù)R0的獨立性和敏感性,發(fā)現(xiàn)了對2015年的疫情和R0能產(chǎn)生影響的重要參數(shù)。同時根據(jù)血液中的CD4水平,我們將感染者和病人分為不同的階段,并將其抗病毒治療的過程和結(jié)構(gòu)用數(shù)學(xué)模型表達(dá)出來�？梢宰C明當(dāng)Rol時,無病的平衡點是全局穩(wěn)定的,而當(dāng)Rol時,這個疾病將會持續(xù)存在。 我們研究了兩種不同情況下ART的效果：一經(jīng)確診就立即開展ART和當(dāng)CD4水平低于350/uL時才開展ART(這是當(dāng)前的治療政策)。發(fā)現(xiàn)疾病的治療存在一個關(guān)健的閾值,如果疾病的傳播力(VL)低于這個值的話,那么就病毒的再生數(shù)而言,確診后立即開展ART的效果會比現(xiàn)在的治療政策好；然而,如果疾病的VL大于這個關(guān)健值的話,當(dāng)前的治療政策效果就會優(yōu)于立即治療的效果。這個研究結(jié)果同時還提示我們新的信息：如果疾病的感染性相對較低的話(即相對較好的治療效果),擴(kuò)大ART的覆蓋率就會降低病毒的再生數(shù)和新發(fā)HIV感染率；然而如果疾病的感染性相對較高時,擴(kuò)大ART的覆蓋率反而會導(dǎo)致HIV新發(fā)感染數(shù)的增加,這和異性傳播中的情況是一樣的。所以,如果ART效果是相對較好的,那就采取立即治療的方案,否則還是當(dāng)前的治療政策更合理。 利用男男同性性行為人群(MSM)的疫情數(shù)據(jù),我們得到再生數(shù)估測值、干預(yù)參數(shù)值以及高危人群數(shù)量。本研究得到再生數(shù)R0為3.88(95%CI3.69-4.07),可知傳播系數(shù)β0遠(yuǎn)大于異性傳播與一般高危人群的傳播。此外,本研究發(fā)現(xiàn)MSM人群HIV診斷率遠(yuǎn)低于其他高危人群。同時,MSM的治療覆蓋率低于國家調(diào)查的平均值,模擬結(jié)果顯示強化高危人群教育以及增加監(jiān)測及檢測強度可以降低疾病傳播速度。根據(jù)疾病的感染性及感染者(病人)行為改變,擴(kuò)大治療覆蓋率可以減少HIV的新發(fā)感染。而敏感性分析提示對治療效果影響最大的參數(shù)為感染率β0以及患者疾病相關(guān)的死亡率α,。而且,高效的藥物可以減少HIV感染者每種高危行為的傳播率,且加強教育可以減少與HIV患者的接觸率,提高安全套的使用率。意味著高效藥物、及時的教育可以有效控制艾滋病病毒的流行。 本研究中,我們還運用時空模型的趨勢面分析、空間自相關(guān)分析、回歸分析等方法對云南省的AIDS疫情進(jìn)行了分析和預(yù)測,很多因素的地理分布不同會導(dǎo)致HIV/AIDS在不同地區(qū)有不同分布,比如鐵路分布、靜脈吸毒人群分布、商業(yè)性行為人群分布等,通過模型分析能進(jìn)一步得出聚集地區(qū)發(fā)病的誘因所在,為決策提供科學(xué)依據(jù)。 本文的主要創(chuàng)新點包括：在模型中考慮了長期治療帶來的個體病毒進(jìn)展對體內(nèi)藥物濃度、治療效果和疫情造成的影響,創(chuàng)新性的研究了不同的服藥方式對HIV病毒演化、耐藥產(chǎn)生的影響。探討抗病毒治療時機(jī)選擇、覆蓋率、個體／平均病毒載量的變化對HIV感染和病死率的影響；以高危人群隊列和全國HIV疫情、實驗室檢測實際數(shù)據(jù)為基礎(chǔ),利用Bayes統(tǒng)計推斷方法進(jìn)行模型的參數(shù)估計；對我國目前MSM人群的HIV傳播基本再生數(shù)(R0)做了系統(tǒng)估計,并對其敏感性做了評價,得到了各個參數(shù)對R0的影像,可為實施各項干預(yù)措施提供依據(jù)。
[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.
【學(xué)位授予單位】：南京醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2013
【分類號】：R512.91

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