Mitochondrial toxicity in the era of HAART:: Evaluating venous lactate and peripheral blood mitochondrial DNA in HIV-infected patients taking antiretroviral therapy
Mitochondrial toxicity in the era of HAART:: Evaluating venous lactate and peripheral blood mitochondrial DNA in HIV-infected patients taking antiretroviral therapy
复制标题
DOI：
10.1097/00126334-200309011-00013
复制
发表时间：
2003-09-01
影响因子：
3.6
通讯作者：
O'Shaughnessy, MV
中科院分区：
文献类型：
--
作者：
Montaner, JSG;Côté, HCF;O'Shaughnessy, MV
核苷类似物可以通过抑制人类DNA聚合酶γ来诱导线粒体毒性。这可能导致广泛的临床毒性，从无症状的高乳酸血症到死亡。尽管他们的技术和生理变异，我们建议，随机静脉乳酸测量可以是有用的，以监测核苷相关的线粒体毒性的发展。最近，我们开发了一种检测方法，可以测量外周血细胞中线粒体DNA水平的变化。使用这种检测方法，我们的特点是在线粒体DNA（mtDNA）相对于核DNA（nDNA）的外周血细胞中的症状性核苷诱导的高乳酸血症患者的变化。我们的研究结果表明，有症状的高乳酸血症与显著低的mtDNA/nDNA比值相关，其平均比未感染HIV的对照组低69%，比感染HIV的无症状/抗逆转录病毒初治对照组低45%。在抗逆转录病毒治疗停止后，观察到mtDNA/nDNA比值有统计学显著性（p = 0.016）增加。在重新引入司他夫定（d4 T）保留方案抗逆转录病毒治疗的选定患者中，mtDNA/nDNA比值保持稳定。值得注意的是，在静脉乳酸水平的增加之前，在mtDNA的下降最近，我们已经评估了mtDNA/nDNA比例的变化与选定的抗逆转录病毒药物治疗方案在一项横断面研究中的非随机样本的参与者在不列颠哥伦比亚省卓越中心的艾滋病毒/艾滋病药物治疗计划。符合条件的患者连续接受沙奎那韦+利托那韦+奈韦拉平（n = 20）、拉米夫定（n = 15）、d4 T（n = 53）或拉米夫定+d4 T（n = 69）治疗4 - 30个月。与含d4 T方案相比，保留d4 T方案与较高的中位mtDNA/nDNA比值相关（p = .016），尽管研究患者接受含d4 T方案的中位时间短于接受保留d4 T方案的患者，（13个月对25个月，p = 0.002）。总之，在发生有症状的核苷相关高乳酸血症的患者中，在治疗停止时逆转的效果。此外，mtDNA/nDNA比值在统计学上显着低于患者服用含d4 T的方案比那些选择的d4 T保留方案的人口设置。这些结果表明，测量该参数应作为一种潜在的临床管理工具进行研究。
Nucleoside analogs can induce mitochondrial toxicity by inhibiting the human DNA polymerase gamma. This can lead to a wide range of clinical toxicities, from asymptomatic hyperlactatemia to death. Despite their technical and physiological variability, we propose that random venous lactate measurements can be useful to monitor the development of nucleoside-related mitochondrial toxicity. Recently, we have developed an assay that can measure changes in mitochondrial DNA levels in peripheral blood cells. Using this assay we have characterized changes in mitochondrial DNA (mtDNA) relative to nuclear DNA (nDNA) in peripheral blood cells of patients with symptomatic nucleoside-induced hyperlactatemia. Our results demonstrate that symptomatic hyperlactatemia was associated with markedly low mtDNA/nDNA ratios, which were on average 69% lower than HIV-uninfected controls and 45% lower than HIV-infected asymptomatic/antiretroviral naive controls. A statistically significant (p = .016) increase in mtDNA/nDNA ratio was observed following discontinuation of antiretroviral therapy. The mtDNA/nDNA ratio remained stable among selected patients who reintroduced antiretroviral therapy with stavudine (d4T)-sparing regimens. Of note, the decline in mtDNA preceded the increase in venous lactate levels.More recently we have evaluated changes in the mtDNA/nDNA ratio in relation to selected antiretroviral drug regimens in a cross-sectional study on a non-random sample of participants within the British Columbia Centre for Excellence in HIV/AIDS Drug Treatment Program. Eligible patients had continuously received saquinavir plus ritonavir with either nevirapine (n = 20), lamivudine (n = 15), d4T (n = 53) or lamivudine + d4T (n = 69), for 4 to 30 months. d4T-sparing regimens were associated with a higher median mtDNA/nDNA ratio than d4T-containing regimens (p = .016), despite the fact that study patients had received d4T-containing regimens for a shorter median time than patients taking d4T-sparing regimens (13 versus 25 months, p = .002).In summary, mtDNA levels are significantly decreased among patients who develop symptomatic, nucleoside-related hyperlactatemia, an effect reversed upon therapy discontinuation. Furthermore, mtDNA/nDNA ratios were statistically significantly lower in patients taking d4T-containing regimens than in those taking selected d4T-sparing regimens in a population setting. These results suggest that measurement of this parameter should be investigated as a potential clinical management tool.