Inter-individual variability in pharmacokinetics and response to protease inhibitor-based antiretroviral therapy

艾滋病毒治疗明显提高了生存率。然而，一些患者由于毒性或病毒变异而无法治疗，即使在药物存在的情况下，病毒也会繁殖。这两个因素都受到进入患者体内的药物量的强烈影响。血液中。例如，药物过多，病人就会出现某些类型的毒性，而药物过少，病毒就能尝试不同的突变，最终找到那些能让它存活下来的突变。我们对影响血液中药物浓度的因素的了解正在迅速发展。我们最近的工作表明，SLCO转运蛋白是一种将抗hiv药物转移到肠道和肝细胞的分子泵，它可以影响体内某些药物的吸收和清除。这些转运蛋白是由人类基因组编码的，这些基因存在差异，这意味着在一些个体中它们的活性与在另一些个体中不同。因此，本研究的目的是评估SLCO转运体基因的差异是否能够解释一些药物浓度的差异以及对抗hiv药物毒性和失败的易感性。最终，如果这个项目取得成功，它将有助于开发测试方法，帮助艾滋病医生以正确的剂量给正确的病人提供正确的药物。

Treatment for HIV clearly improves survival. However, some patients fail therapy either because of toxicity or because the virus mutates, allowing it to multiply even in the presence of the drug. Both of these factors are strongly influenced by the amount of drug that enters a patient?s bloodstream. For example, too much drug and the patient will experience some types of toxicity and too little drug and the virus is able to try out different mutations, eventually finding those which allow it to survive. Our knowledge of the factors that influence drug concentrations in the blood is rapidly developing. Our recent work has shown that SLCO transporters, which are molecular pumps that transfer anti-HIV drugs into gut and liver cells can influence the absorption and clearance of some drugs from the body. These transporters are encoded by the human genome and there are differences in these genes meaning that in some individuals they have different activity than in others. Therefore, the reason for this research is to assess whether differences in SLCO transporter genes are able to explain some of the differences in drug concentrations and susceptibility to toxicity and failure of anti-HIV drugs. Ultimately, if this project is successful it will aid the development of tests that help HIV doctors to give the right drug, at the right dose to the right patient.