Depletion of mitochondrial DNA in liver under antiretroviral therapy with didanosine, stavudine, or zalcitabine
Depletion of mitochondrial DNA in liver under antiretroviral therapy with didanosine, stavudine, or zalcitabine
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DOI：
10.1002/hep.20074
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发表时间：
2004-02
期刊：
影响因子：
13.5
通讯作者：
U. Walker;J. Bäuerle;M. Laguno;J. Murillas;S. Mauss;G. Schmutz;B. Setzer;R. Miquel;J. Gatell;J. Mallolas
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文献类型：
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作者：
U. Walker;J. Bäuerle;M. Laguno;J. Murillas;S. Mauss;G. Schmutz;B. Setzer;R. Miquel;J. Gatell;J. Mallolas
与“非 D 药”齐多夫定、拉米夫定和阿巴卡韦相比，“D 药”HIV 逆转录酶抑制剂扎西他滨、去羟肌苷和司他夫定是相对较强的聚合酶 γ 抑制剂。 D 药物会消耗培养肝细胞中的线粒体 DNA (mtDNA)。这种 mtDNA 的消耗与体外乳酸产量的增加有关。为了研究 HIV 感染者高乳酸血症的起源以及抗逆转录病毒治疗对肝脏 mtDNA 的影响，我们对 94 名慢性丙型肝炎病毒 (HCV) 感染者的肝组织进行了活检。八十名受试者同时感染艾滋病毒。在活检时测量血清乳酸。对肝脏 mtDNA 和肝脏组织学进行集中评估。与未使用 D 药物的患者 (n = 35) 相比，活检时接受 D 药物的 HIV 感染患者 (n = 34) 的肝脏 mtDNA 含量降低了 47% (P<.0001)。除了多变量分析中 HCV 基因型 I 状态与 mtDNA 耗竭之间可能存在关联外，没有其他病毒学、免疫学、组织学、人口统计学或治疗相关变量可以解释 mtDNA 耗竭。只有三名患者的乳酸高于正常上限，所有患者均接受 D 类药物治疗。他们每个人的 mtDNA 均低于任何非 D 类药物患者，并且与乳酸正常的 D 类药物患者相比显着减少 (P = .017)。总之，D 药物治疗与慢性 HCV 感染的 HIV 感染患者的肝脏 mtDNA 减少有关。肝脏中线粒体 DNA 的中度消耗并不一定会导致高乳酸血症，但肝脏线粒体 DNA 的更明显减少可能是导致乳酸升高的重要因素。 （肝病学 2004 年；39：311-317。）
The “D drug” HIV reverse‐transcriptase inhibitors zalcitabine, didanosine, and stavudine are relatively strong inhibitors of polymerase‐gamma compared with the “non–D drugs” zidovudine, lamivudine, and abacavir. D drugs deplete mitochondrial DNA (mtDNA) in cultured hepatocytes. This mtDNA depletion is associated with an increased in vitro production of lactate. To investigate the origin of hyperlactatemia in HIV‐infected patients and the effects of antiretroviral therapy on liver mtDNA, we biopsied liver tissue from 94 individuals with chronic hepatitis C virus (HCV) infection. Eighty subjects were coinfected with HIV. Serum lactate was measured at the time of biopsy. Hepatic mtDNA and liver histology were centrally assessed. Liver mtDNA content of HIV‐infected patients receiving D drugs at the time of biopsy (n = 34) was decreased by 47% (P<.0001) compared with those without D drugs (n = 35). Aside from a possible association between HCV genotype I status and mtDNA depletion in multivariate analysis, there were no other virologic, immunologic, histologic, demographic or treatment‐related variables that could explain the mtDNA depletion. Lactate was above the upper limit of normal in only three patients, all of whom were treated with D drugs. The mtDNA in each of them was lower than in any non–D drug patient and significantly (P = .017) depleted compared with D drug patients with normal lactate. In conclusion, D drug treatment is associated with decreased hepatic mtDNA in HIV‐infected patients with chronic HCV infection. Moderate mtDNA depletion in liver does not necessarily lead to hyperlactatemia, but more pronounced decreases in hepatic mtDNA may be an important contributor to lactate elevation. (HEPATOLOGY 2004;39:311–317.)