Mitochondrial Research Laboratory, Internal Medicine Department, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
J Acquir Immune Defic Syndr. 2012 Jun 1;60(2):111-6. doi: 10.1097/QAI.0b013e318250455e.
Highly active antiretroviral therapy (HAART) and HIV-related mitochondrial toxicity lead to several adverse effects and have become a major issue, especially in children. The main goal in the treatment of HIV-infected children is to maximize cost-effectiveness while minimizing toxicity. We aimed to study the evolution of mitochondrial parameters over time in children receiving different types antiretroviral regimens.
We followed-up 28 HIV-infected children receiving HAART including either first-generation nucleoside reverse transcriptase inhibitors (1gNRTIs; didanosine, zidovudine, or stavudine; n = 15) or second-generation NRTIs (2gNRTIs; the remaining drugs; n = 13) for a period of 2 years for their immunovirological and mitochondrial status, and compared these subjects with a group of untreated HIV-infected patients (n = 10) and uninfected controls (n = 27). We measured T-lymphocyte CD4+ content (flow cytometry), viral load (real-time polymerase chain reaction), and lactate levels (spectrophotometry); we assessed mtDNA content (real-time polymerase chain reaction), mitochondrial protein levels (Western blot), oxidative stress, mitochondrial mass, and electron transport chain function (spectrophotometry) in peripheral blood mononuclear cells.
At the second time point, lactate levels were significantly higher in children on 1gNRTIs compared with those receiving 2gNRTIs (1.28 ± 0.08 vs. 1.00 ± 0.07 mmol/L, respectively; P = 0.022). MtDNA content was similar among all HIV-infected groups and significantly lower than in healthy controls at baseline. Oxidative stress tended to increase over time in all the groups, with no differences among them. However, a significant decrease in cytochrome c oxidase activity was found over time in HIV-infected patients; this decline was greater in the 1gNRTIs group.
HIV infection and the use of 1gNRTIs caused greater mitochondrial damage than 2gNRTIs over time. The higher lactate levels and the significant decrease observed in cytochrome c oxidase activity argue against the use of 1gNRTIs in HIV-infected children when an alternative is available, in accordance with international recommendations.
高效抗逆转录病毒疗法（HAART）和与 HIV 相关的线粒体毒性导致了多种不良反应，这已成为一个主要问题，尤其是在儿童中。治疗 HIV 感染儿童的主要目标是在最大程度降低毒性的同时实现成本效益最大化。我们旨在研究不同类型抗逆转录病毒方案治疗的儿童中线粒体参数随时间的变化。
我们对 28 名接受 HAART 的 HIV 感染儿童进行了随访，其中包括第一代核苷逆转录酶抑制剂（1gNRTIs；司他夫定、齐多夫定或去羟肌苷；n=15）或第二代 NRTIs（2gNRTIs；其余药物；n=13），为期 2 年，以评估他们的免疫病毒学和线粒体状况，并将这些患者与一组未经治疗的 HIV 感染患者（n=10）和未感染对照者（n=27）进行比较。我们通过流式细胞术测量 T 淋巴细胞 CD4+含量，通过实时聚合酶链反应测量病毒载量，通过分光光度法测量乳酸水平；我们通过实时聚合酶链反应评估 mtDNA 含量，通过 Western blot 评估线粒体蛋白水平，通过分光光度法评估氧化应激、线粒体质量和电子传递链功能。
在第二次时间点，接受 1gNRTIs 的儿童的乳酸水平明显高于接受 2gNRTIs 的儿童（分别为 1.28±0.08 与 1.00±0.07mmol/L，P=0.022）。在所有 HIV 感染组中，mtDNA 含量相似，且与健康对照组相比在基线时明显较低。氧化应激在所有组中随时间呈上升趋势，但无差异。然而，在 HIV 感染患者中，细胞色素 c 氧化酶活性随时间呈显著下降，在 1gNRTIs 组中下降更为明显。
与 2gNRTIs 相比，HIV 感染和使用 1gNRTIs 随时间推移造成更大的线粒体损伤。较高的乳酸水平和观察到的细胞色素 c 氧化酶活性显著下降表明，在有替代方案的情况下，不建议 HIV 感染儿童使用 1gNRTIs，这符合国际建议。
