Burnet Institute, Centre for Virology, Melbourne, Victoria, Australia.
Expert Opin Drug Metab Toxicol. 2009 Dec;5(12):1543-53. doi: 10.1517/17425250903282781.
Antiretroviral therapy (ART) has improved life expectancy with HIV infection, but long-term toxicities associated with these medications are now a major global disease burden. There is a clear need to develop useful methods for monitoring patients on antiretroviral drugs for early signs of toxicity. Assays with predictive utility -- allowing therapy to be changed before serious end organ damage occurs -- would be ideal. Attempts to develop biochemical methods of monitoring ART toxicity have concentrated on the mitochondrial toxicity of nucleoside analogue reverse transcriptase inhibitors and have not generally lead to assays with widespread clinical applications. For example, plasma lactate and peripheral blood measurements of mitochondrial DNA associate with exposure to potentially toxic nucleoside analogue reverse transcriptase inhibitors but have not reliably predicted clinical toxicity. Better assays are needed, including markers of toxicity from additional drug classes. Apoptosis may be a potential marker of ART toxicity. Increased apoptosis has been demonstrated both in vitro and in vivo in association with various antiretroviral drug classes and a range of clinical toxicities. However, quantifying apoptosis on biopsy specimens of tissue (such as adipose tissue) is impractical for patient monitoring. Novel assays have been described that can quantify apoptosis using minute tissue samples and initial results from clinical samples suggest peripheral blood may have utility in predicting ART toxicities. The limitations and potential of such techniques for monitoring patients for drug side effects will be discussed.
抗逆转录病毒疗法 (ART) 提高了 HIV 感染患者的预期寿命，但这些药物的长期毒性现在是一个主要的全球疾病负担。显然需要开发有用的方法来监测接受抗逆转录病毒药物治疗的患者，以早期发现毒性迹象。具有预测效用的检测方法（允许在严重终末器官损伤发生之前改变治疗方法）将是理想的。开发监测 ART 毒性的生化方法的尝试集中在核苷类似物逆转录酶抑制剂的线粒体毒性上，但通常没有导致具有广泛临床应用的检测方法。例如，血浆乳酸和外周血线粒体 DNA 测量与潜在毒性的核苷类似物逆转录酶抑制剂的暴露有关，但不能可靠地预测临床毒性。需要更好的检测方法，包括来自其他药物类别的毒性标志物。细胞凋亡可能是 ART 毒性的一个潜在标志物。已经在体外和体内证明，与各种抗逆转录病毒药物类别和一系列临床毒性相关联，细胞凋亡增加。然而，对组织（如脂肪组织）活检标本进行凋亡定量是不切实际的，不适合患者监测。已经描述了可以使用微小组织样本定量凋亡的新检测方法，并且来自临床样本的初步结果表明，外周血可能具有预测 ART 毒性的效用。将讨论这些技术用于监测患者药物副作用的局限性和潜力。
