Cressey Tim R, Lallemant Marc
Harvard School of Public Health, Boston, MA, USA.
Infect Genet Evol. 2007 Mar;7(2):333-42. doi: 10.1016/j.meegid.2006.08.004. Epub 2006 Oct 11.
Highly active antiretroviral therapy (HAART), a combination of at least three antiretroviral drugs, has dramatically improved the prognosis of HIV/AIDS. However, viral replication under therapy can lead to the selection of drug resistant viruses and subsequent virologic failure. While poor adherence is likely to be the main cause of treatment failure, individual pharmacokinetic variability can also play an important role. Drug-drug interactions, drug-food interactions, sex, age, renal/hepatic function and pregnancy are all sources of pharmacokinetic variability. Recent pharmacogenetic studies of antiretroviral drugs reported the influence of several genetic polymorphisms on antiretroviral drug exposure, toxicity and response to treatment. Initially, a single nucleotide polymorphism (SNP) in exon 26 (C3435T) of the multi-drug transporter gene (MDR1) was reported to be associated with low antiretroviral plasma drug levels but good initial immunological response; however, conflicting results have since been reported. Several studies on efavirenz, a commonly used antiretroviral drug, have reported higher plasma exposure and early side effects with the homozygous variant of the hepatic cytochrome P450 enzyme CYP2B6 G516T polymorphism, which are more frequently found in African-American subjects. However, despite its association with efavirenz exposure this polymorphism was not associated with time to virologic or toxicity-related failure. Genetic analysis has also proven to be a valuable predictor of antiretroviral drug hypersensitivity reactions; genetic screening of patients prior to initiation of specific antiretrovirals has proven to reduce the incidence of drug hypersensitivity in certain settings. The reasons for antiretroviral treatment failure are multi-factorial but as the individualization of HAART increases understanding the influence of specific genotypes on treatment success and toxicity could further optimize these life-saving treatments.
高效抗逆转录病毒疗法（HAART），即至少三种抗逆转录病毒药物的联合使用，极大地改善了HIV/AIDS的预后。然而，治疗期间的病毒复制会导致耐药病毒的产生以及随后的病毒学治疗失败。虽然依从性差可能是治疗失败的主要原因，但个体药代动力学变异性也可能起重要作用。药物-药物相互作用、药物-食物相互作用、性别、年龄、肾/肝功能和妊娠都是药代动力学变异性的来源。近期对抗逆转录病毒药物的药物遗传学研究报道了几种基因多态性对抗逆转录病毒药物暴露、毒性及治疗反应的影响。最初，多药转运蛋白基因（MDR1）外显子26（C3435T）中的单核苷酸多态性（SNP）被报道与抗逆转录病毒血浆药物水平低但初始免疫反应良好有关；然而，此后有相互矛盾的结果报道。几项关于常用抗逆转录病毒药物依非韦伦的研究报道，肝细胞色素P450酶CYP2B6 G516T多态性的纯合变体与更高的血浆暴露及早期副作用有关，这种情况在非裔美国受试者中更常见。然而，尽管该多态性与依非韦伦暴露有关，但它与病毒学失败或毒性相关失败的时间无关。基因分析也已被证明是抗逆转录病毒药物超敏反应的有价值预测指标；在开始使用特定抗逆转录病毒药物之前对患者进行基因筛查已被证明在某些情况下可降低药物超敏反应发生率。抗逆转录病毒治疗失败的原因是多方面的，但随着HAART个体化程度的提高，了解特定基因型对治疗成功和毒性的影响可能会进一步优化这些挽救生命的治疗方法。
