Mitochondrial Toxicogenomics for Antiretroviral Management: HIV Post-exposure Prophylaxis in Uninfected Patients
Mitochondrial Toxicogenomics for Antiretroviral Management: HIV Post-exposure Prophylaxis in Uninfected Patients
复制标题
DOI：
10.3389/fgene.2020.00497
复制
发表时间：
2020-05-26
影响因子：
3.7
通讯作者：
Garrabou, Gloria
中科院分区：
文献类型：
--
作者：
Bano, Maria;Moren, Constanza;Garrabou, Gloria
背景：线粒体基因组已被用于研究、诊断和毒理基因组学的多个领域。几种化合物损害线粒体DNA（mtDNA），包括生物和治疗剂，如人类免疫缺陷病毒（HIV），但也包括其抗逆转录病毒治疗，导致不良的临床表现。HIV感染和治疗的患者可能表现出线粒体和代谢谱受损，但病毒或治疗毒性的具体贡献仍然难以捉摸。HIV的后果没有治疗干扰的评价已在幼稚（非治疗）的患者，但治疗毒性的评估没有病毒干扰通常仅限于在体外assessment.Objective：本研究的目的是确定是否抗逆转录病毒治疗没有HIV干扰可能导致mtDNA的干扰。我们研究了接受HIV暴露后预防（PEP）以防止进一步感染的未感染健康患者的临床、线粒体和代谢毒性。我们评估了两种不同的PEP方案，根据其组成，以确定他们是否是耐受性问题和衍生toxic.Methods的原因：我们分析了PEP停药的原因和主要的治疗退出，从外周血单核细胞和代谢谱，线粒体DNA含量的次要影响，前和后28天的PEP，在23名患者根据PEP组成分类：一种蛋白酶抑制剂（PI）+齐多夫定/拉米夫定（PI + AZT +3TC; n = 9）或PI+替诺福韦/恩曲他滨结果：含齐多夫定的治疗方案增加了停药的风险（RR = 9.33; 95%CI = 1.34-65.23）与胃肠道并发症相关的药物不良反应有关。在没有代谢紊乱的情况下，4周PEP（含PI + AZT +3TC）导致的线粒体毒性（mtDNA/nDNA水平降低-17.9 +/-25.8）高于PI + TDF + FTC（增加43.2 +/-24.3单位mtDNA/nDNA;组间p <0.05）。线粒体DNA变化与基线丙氨酸转氨酶水平呈显著负相关（p <0.05），提示适当的肝功能可以保护抗逆转录病毒毒性。在没有HIV感染的情况下，预防性短期抗逆转录病毒治疗可引起继发性效应，导致治疗中断和亚临床线粒体损伤，特别是嘧啶类似物，如AZT，在某些人群中，它仍然是PEP的替代选择和首选。今后的努力应侧重于推出具有更安全的临床和有丝分裂毒性特征的新策略。
Background: Mitochondrial genome has been used across multiple fields in research, diagnosis, and toxicogenomics. Several compounds damage mitochondrial DNA (mtDNA), including biological and therapeutic agents like the human immunodeficiency virus (HIV) but also its antiretroviral treatment, leading to adverse clinical manifestations. HIV-infected and treated patients may show impaired mitochondrial and metabolic profile, but specific contribution of viral or treatment toxicity remains elusive. The evaluation of HIV consequences without treatment interference has been performed in naive (non-treated) patients, but assessment of treatment toxicity without viral interference is usually restricted to in vitro assays.Objective: The objective of the present study is to determine whether antiretroviral treatment without HIV interference can lead to mtDNA disturbances. We studied clinical, mitochondrial, and metabolic toxicity in non-infected healthy patients who received HIV post-exposure prophylaxis (PEP) to prevent further infection. We assessed two different PEP regimens according to their composition to ascertain if they were the cause of tolerability issues and derived toxicity.Methods: We analyzed reasons for PEP discontinuation and main secondary effects of treatment withdrawal, mtDNA content from peripheral blood mononuclear cells and metabolic profile, before and after 28 days of PEP, in 23 patients classified depending on PEP composition: one protease inhibitor (PI) plus Zidovudine/Lamivudine (PI plus AZT + 3TC; n = 9) or PI plus Tenofovir/Emtricitabine (PI plus TDF + FTC; n = 14).Results: Zidovudine-containing-regimens showed an increased risk for drug discontinuation (RR = 9.33; 95% CI = 1.34-65.23) due to adverse effects of medication related to gastrointestinal complications. In the absence of metabolic disturbances, 4-week PEP containing PI plus AZT + 3TC led to higher mitochondrial toxicity (-17.9 +/- 25.8 decrease in mtDNA/nDNA levels) than PI plus TDF + FTC (which increased by 43.2 +/- 24.3 units mtDNA/nDNA; p < 0.05 between groups). MtDNA changes showed a significant and negative correlation with baseline alanine transaminase levels (p < 0.05), suggesting that a proper hepatic function may protect from antiretroviral toxicity.Conclusions: In absence of HIV infection, preventive short antiretroviral treatment can cause secondary effects responsible for treatment discontinuation and subclinical mitochondrial damage, especially pyrimidine analogs such as AZT, which still rank as the alternative option and first choice in certain cohorts for PEP. Forthcoming efforts should be focused on launching new strategies with safer clinical and mitotoxic profile.