Impact of ARV Chemoprophylaxis on Emergence and Spread of HIV Drug Resistance

描述(由申请人提供)：暴露前的抗逆转录病毒预防措施对人类免疫缺陷病毒(HIV)耐药性的发展和异性传播的潜在影响尚不清楚，也没有建模。这项提议将使用新一代数学和计算模型来调查抗逆转录病毒化学预防对艾滋病毒耐药性流行病学模式的影响，这些模型代表了构成艾滋病毒耐药性动态基础的现实的生物学、人口学、流行病学和行为异质性。这些创新的模型：i)纳入血浆病毒血症、CD4细胞下降、艾滋病毒疾病进展、传染性、危险行为和抗逆转录病毒化学预防效果在个人内部和之间的变化；ii)模拟不同的化学预防使用策略；iii)在人群水平预测艾滋病毒耐药性结果。我们的长期目标是使用建模和模拟来设计有助于控制全球艾滋病毒流行的公共卫生干预战略。中心假设是，以传播和感染艾滋病毒感染风险最高的特定人群为目标，可以最大限度地减少艾滋病毒耐药性的传播。提出的具体目标是：i)模拟不同抗逆转录病毒化学预防实施情景下的HIV流行，并分析HIV耐药性预测模式；ii)识别HIV耐药性预测模式的关键决定因素，并评估预测不确定性；iii)确定模型预测对建模框架和假设的敏感性。这项研究的新颖之处在于，将使用多种建模方法和建模尺度来模拟在资源有限的情况下，不同的抗逆转录病毒化学预防策略对艾滋病毒耐药性发生率和流行率的影响。我们的发现应该有助于确定艾滋病毒耐药性传播的关键决定因素，以及遏制全球艾滋病毒流行和耐药性的最有效的抗逆转录病毒化学预防策略。 公共卫生相关性：拟议的研究具有创新性，因为我们将使用新开发的数学和计算模型来分析不同抗逆转录病毒化学预防策略下艾滋病毒耐药性传播的模式和决定因素。我们的工作将有助于确定具有最大公共健康利益的抗逆转录病毒化学预防策略，从而指导公共卫生政策。

DESCRIPTION (provided by applicant): The potential impact of antiretroviral pre-exposure prophylaxis on the development and heterosexual transmission of human immunodeficiency virus (HIV) drug resistance is unknown and has not been modeled. This proposal will investigate the effect of antiretroviral chemoprophylaxis on the epidemiologic patterns of HIV drug resistance using a new generation of mathematical and computational models that represent realistic biological, demographic, epidemiologic and behavioral heterogeneities that underlie the dynamics of HIV drug resistance. These innovative models: i) incorporate variation in plasma viremia, CD4 cell decline, HIV disease progression, infectiousness, risk behavior, and effect of antiretroviral chemoprophylaxis both within and among individuals; ii) simulate different strategies of chemoprophylaxis use; and iii) predict HIV drug resistance outcomes at the population level. Our long term goal is to use modeling and simulation to design public health intervention strategies that will help control the global HIV epidemic. The central hypothesis is that targeting specific subpopulations of persons at highest risk for transmitting and acquiring HIV infection can minimize the spread of HIV drug resistance. The specific aims proposed are: i) to simulate an HIV epidemic under different scenarios of antiretroviral chemoprophylaxis implementation and analyze the predicted patterns of HIV drug resistance; ii) to identify the key determinants of the predicted patterns of HIV drug resistance and evaluate the prediction uncertainty; and iii) to determine the sensitivity of the model predictions to modeling framework and assumptions. The proposed research is novel in that multiple modeling approaches and modeling scales will be used to simulate the effect of different antiretroviral chemoprophylaxis strategies on the incidence and prevalence of HIV drug resistance in resource-limited settings. Our findings should help identify the key determinants for spread of HIV drug resistance and the most effective antiretroviral chemoprophylaxis strategies to curb both the global HIV epidemic and drug resistance. PUBLIC HEALTH RELEVANCE: The proposed research is innovative in that we will use newly developed mathematical and computational models to analyze the patterns and determinants of spread of HIV drug resistance under different antiretroviral chemoprophylaxis strategies. Our work will help identify antiretroviral chemoprophylaxis strategies with maximal public health benefit and thereby guide public health policy.