Pharmacogenetics and HIV treatment outcomes

描述（由申请人提供）：药物遗传学研究已导致对药物代谢和反应（包括HIV中的抗逆转录病毒药物）变异性的病因学有了更深入的了解。虽然在少数情况下已明确确定了遗传对药物清除率（药代动力学）的影响，但基因与治疗反应（药效学）之间的关系尚不明确。本提案的目的是确定与抗逆转录病毒药物代谢较慢相关的多态性是否会导致更好或更差的治疗结果。考虑到临床环境中个体之间的依从性可变，个体药物的较慢药物代谢可能使这些药物对这些个体的较低依从性更宽容，因此导致更大的治疗成功。或者，慢代谢者中的较高浓度可能导致不可耐受的毒性、不依从性，从而导致治疗失败。或者，暂时停止所有药物的慢代谢者的半衰期延长可能导致单独暴露于慢代谢药物-功能性单药治疗-这可能导致耐药性的出现和治疗失败。我们的目的是确定具有慢药物代谢基因型的受试者与具有其他基因型的受试者相比是否具有1）更高或更低的病毒学抑制率和2）更低或更高的病毒学突破率。此外，我们的目的是确定基因型和2个治疗结果之间的关系是否被个体的药物依从性所改变。我们将在位于博茨瓦纳哈博罗内的世界上最大的艾滋病毒治疗中心之一的艾滋病毒感染者中进行两项含依法韦仑方案的研究。主要暴露是代谢依法韦仑的细胞色素P450 2B 6酶的基因型。第一项研究将是一个前瞻性队列，研究对象是开始含依法韦仑治疗方案的初治个体，结果是6个月时的病毒载量。第二项研究将是一项病例对照研究，病例是在6个月时接受依法韦仑治疗达到不可检测的病毒载量，但随后病毒学失败的个体。病例将是同一临床队列中在达到不可检测的病毒载量后未发生病毒学突破的个体。我们将通过测试基因型x统计依从性相互作用来评估依从性的影响。如果这些假设得到证实，未来的工作将评估其他药物-基因型关系，并测试利用人类基因检测来定制治疗选择的策略是否会导致更好的艾滋病毒治疗结果。如果结果得到改善，鉴于抗逆转录病毒疗法的拯救生命性质，这项研究有可能延长个人的生存时间，并延长世界艾滋病毒感染人口的药物疗效。公共卫生相关性：本研究旨在确定HIV药物代谢率的差异是否可以解释治疗反应的差异。如果得到证实，未来的工作将评估不同药物和代谢酶之间的关系。最终，目标是根据个体患者的代谢情况调整艾滋病毒药物治疗方案，从而改善艾滋病毒疾病的结果，并最终改善公共卫生。

DESCRIPTION (provided by applicant): Pharmacogenetics research has resulted in deeper understanding of the etiology of variability in drug metabolism and response, including antiretroviral drugs in HIV. Although genetic influences on drug clearance rates (pharmacokinetics) have been established clearly in a few circumstances, the relationship between genes and treatment response (pharmacodynamics) has been less clear-cut. The objective of this proposal is to determine if polymorphisms associated with slower metabolism of antiretroviral drugs result in better or worse treatment outcomes. Given variable adherence amongst individuals in clinical settings, slower drug metabolism of individual drugs may make those drugs more forgiving of lower adherence for those individuals and therefore result in greater treatment success. Alternatively, the higher concentrations in slow metabolizers may result in intolerable toxicity, non-adherence, and thus treatment failure. Or, the prolonged half-life in slow metabolizers who temporarily stop all of their medications may result in exposure to the slowly metabolized drug alone- functional monotherapy- which may cause emergence of resistance, and treatment failure. We aim to determine whether subjects with slow drug metabolizing genotypes have 1) higher or lower rates of virological suppression and 2) lower or higher rates of virological breakthrough than those with other genotypes. In addition, we aim to determine if the relation between genotype and the 2 treatment outcomes is modified by the individual's medication adherence. We will conduct two studies in HIV infected individuals on efavirenz-containing regimens in one of the largest HIV treatment sites in the world in Gaborone, Botswana. The primary exposure will be the genotype of the cytochrome P450 2B6 enzyme, which metabolizes efavirenz. The first study will be a prospective cohort of treatment naove individuals initiating efavirenz-containing regimens with the outcome being viral load at 6 months. The second study will be a case-control study with cases being individuals who had achieved undetectable viral loads on efavirenz at 6 months, but subsequently had virological failure. Cases will be individuals in the same clinical cohort who do not have virological breakthrough after achieving undetectable viral loads. We will assess the effect of adherence by testing for a genotype x adherence statistical interaction. If the hypotheses are confirmed, future work will assess other drug-genotype relations and test whether strategies utilizing human genetic testing for tailoring treatment choices would result in better HIV treatment outcomes. If outcomes are improved, given the life-saving nature of antiretroviral therapy, this research has the potential both to prolong survival of individuals and prolong the efficacy of medications for the HIV infected population of the world. PUBLIC HEALTH RELEVANCE: This study aims to determine if differences in the rate of HIV drug metabolism account for differences in treatment response. If proven, future work will assess relations between different drugs and metabolism enzymes. Ultimately, the goal is to tailor HIV drug regimens to individual patients' metabolic profile with the result being improved outcomes in HIV disease, and ultimately, improved public health.