Kampira Elizabeth, Dzobo Kevin, Kumwenda Johnstone, van Oosterhout Joep J, Parker M Iqbal, Dandara Collet
1 Division of Human Genetics, University of Cape Town , Cape Town, South Africa .
OMICS. 2014 Jul;18(7):438-45. doi: 10.1089/omi.2014.0026. Epub 2014 May 9.
Mitochondrial toxicity is a major concern related to nucleoside reverse transcriptase inhibitors. Common manifestations are peripheral neuropathy and lipodystrophy. Depletion of mitochondria has been associated with mitochondrial dysfunction. We investigated whether mitochondria DNA (mtDNA) levels in peripheral blood can be used as biomarker of stavudine-associated mitochondrial toxicities. We enrolled 203 HIV-infected Malawian adult patients on stavudine-containing ART and 64 healthy controls of Bantu origin in a cross-sectional study. Total DNA was extracted from whole blood.The glyceraldehyde-3-phosphate dehydrogenase gene was used to estimate nuclear DNA (nDNA) levels and the ATP synthase-8 mitochondrial DNA gene to estimate mtDNA levels, from which mtDNA/nDNA ratios were determined. MtDNA subhaplogroups were established by sequencing. Among patients, peripheral neuropathy was present in 21% (43/203), lipodystrophy in 18% (20/112), elevated lactate level (>2.5 mmol/L) in 17% (19/113). Healthy controls had a higher median mtDNA/nDNA ratio when compared to HIV/AIDS patients (6.64 vs. 5.08; p=0.05), patients presenting with peripheral neuropathy (6.64 vs. 3.40, p=0.039), and patients with high lactate levels (6.64 vs. 0.68, p=0.024), respectively. Significant differences in median mtDNA/nDNA ratios were observed between patients with high and normal lactate levels (5.88 vs. 0.68, p=0.018). The median mtDNA/nDNA ratio of patients in subhaplogroup L0a2 was much lower (0.62 vs. 8.50, p=0.01) than that of those in subhaplogroup L2a. Our data indicate that peripheral blood mtDNA/nDNA ratio is a marker of mitochondrial toxicities of stavudine and is associated with elevated lactate levels and mtDNA subhaplogroups. This could open the prospect to select a substantial group of patients who will not have problematic side effects from stavudine, an affordable and effective antiretroviral drug that is being phased out in Africa due to its toxicity.
线粒体毒性是与核苷类逆转录酶抑制剂相关的一个主要问题。常见表现为周围神经病变和脂肪代谢障碍。线粒体耗竭与线粒体功能障碍有关。我们调查了外周血中的线粒体DNA（mtDNA）水平是否可作为司他夫定相关线粒体毒性的生物标志物。在一项横断面研究中，我们纳入了203名接受含司他夫定抗逆转录病毒治疗的感染HIV的马拉维成年患者以及64名班图族裔健康对照者。从全血中提取总DNA。使用甘油醛-3-磷酸脱氢酶基因来估计核DNA（nDNA）水平，使用ATP合酶-8线粒体DNA基因来估计mtDNA水平，并由此确定mtDNA/nDNA比值。通过测序确定mtDNA亚单倍群。在患者中，21%（43/203）存在周围神经病变，18%（20/112）存在脂肪代谢障碍，17%（19/113）乳酸水平升高（>2.5 mmol/L）。与HIV/AIDS患者相比（6.64对5.08；p=0.05）、与存在周围神经病变的患者相比（6.64对3.40，p=0.039）以及与乳酸水平高的患者相比（6.64对0.68，p=0.024），健康对照者的mtDNA/nDNA比值中位数更高。在乳酸水平高的患者与正常乳酸水平的患者之间观察到mtDNA/nDNA比值中位数存在显著差异（5.88对0.68，p=0.018）。L0a2亚单倍群患者的mtDNA/nDNA比值中位数（0.62对8.50，p=0.01）远低于L2a亚单倍群患者。我们的数据表明，外周血mtDNA/nDNA比值是司他夫定线粒体毒性的一个标志物，并且与乳酸水平升高和mtDNA亚单倍群相关。这可能为选择一大批不会因司他夫定产生不良副作用的患者开辟前景，司他夫定是一种价格低廉且有效的抗逆转录病毒药物，因其毒性正在非洲逐步淘汰。
