Pharmacogenetics and HIV treatment outcomes

描述(由申请人提供)：药物遗传学研究加深了对药物代谢和反应变异的病因学的理解，包括艾滋病毒中的抗逆转录病毒药物。尽管基因对药物清除率(药代动力学)的影响在少数情况下已经明确，但基因和治疗反应(药效学)之间的关系还不太清楚。这项建议的目的是确定与抗逆转录病毒药物代谢较慢相关的基因多态是否会导致更好的或更差的治疗结果。考虑到临床环境中不同个体之间的依从性不同，个别药物的药物代谢较慢可能会使这些药物对这些个体较低的依从性更宽容，从而导致更大的治疗成功。或者，较高浓度的慢代谢物可能会导致无法忍受的毒性、不依从性，从而导致治疗失败。或者，在暂时停止所有药物的缓慢代谢者中，延长的半衰期可能会导致接触到单独的缓慢代谢药物--功能性单一疗法--这可能会导致耐药性的出现和治疗的失败。我们的目标是确定药物代谢缓慢的受试者是否有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，我们的目标是确定个体的用药依从性是否改变了基因型和两种治疗结果之间的关系。我们将在博茨瓦纳哈博罗内世界上最大的艾滋病毒治疗地点之一，对艾滋病毒感染者进行两项研究，研究对象是含有Eefavirenz的方案。主要暴露于细胞色素P450 2B6酶的基因型，该酶可代谢依法韦仑。第一项研究将是一组接受治疗的受试者，他们在6个月后开始接受含法那韦仑的治疗方案，结果是病毒载量。第二项研究将是一项病例对照研究，病例是在服用Eefavirenz 6个月后获得无法检测到的病毒载量，但随后出现病毒学失败的个人。病例将是同一临床队列中的个人，他们在实现无法检测到的病毒载量后没有病毒学突破。我们将通过测试基因x依从性统计交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与基因的关系，并测试利用人类基因测试进行定制治疗选择的策略是否会产生更好的艾滋病毒治疗结果。考虑到抗逆转录病毒治疗的救命性质，如果结果得到改善，这项研究既有可能延长个体的生存时间，也有可能延长药物对世界上艾滋病毒感染者的疗效。公共卫生相关性：这项研究旨在确定艾滋病毒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新陈代谢酶之间的关系。归根结底，目标是根据个别患者的代谢状况定制艾滋病毒药物方案，结果是改善艾滋病毒疾病的结果，并最终改善公共健康。

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.