Foster Caroline, Lyall Hermione
The Family Clinic and Imperial College, St Mary's Hospital, Praed Street, London W2 1NY, UK.
J Antimicrob Chemother. 2008 Jan;61(1):8-12. doi: 10.1093/jac/dkm411. Epub 2007 Nov 13.
In the last 10 years, the enormous impact of combination antiretroviral (ARV) therapy on paediatric HIV-associated mortality and morbidity in well-resourced settings and its role in the prevention of mother-to-child transmission (MTCT) of HIV cannot be underestimated. However, it is thus inevitable that children with HIV-1 infection will be exposed to ARVs for an ever-increasing length of time throughout post-natal growth and development, and the cumulative toxicities are becoming progressively apparent. Evidence for nucleoside reverse transcriptase inhibitor (NRTI)-associated mitochondrial toxicity is seen in vitro, in animal models and in NRTI-exposed adults and children. Proposed mechanisms of NRTI mitochondrial toxicity include, among others, impairment of mitochondrial DNA (mtDNA) replication and acquisition of mtDNA point mutations. Alterations in the mtDNA synthesis potentially reduce the production of mtDNA-encoded respiratory chain subunits, resulting in impaired oxidative phosphorylation and mitochondrial dysfunction. NRTI-associated mitochondrial toxicity in children has varied presentations including lactic acidosis, pancreatitis, cardiomyopathy and neuropathy, which are comparable to NRTI-exposed adults and children with congenital mitochondrial disorders. In the prevention of MTCT, uninfected infants are exposed to an ever-widening range of ARVs, often from conception and throughout fetal life. Animal models demonstrate evidence of mitochondrial toxicity from perinatal NRTI exposure, but controversy continues as to the extent of mitochondrial effects in NRTI-exposed children. Paediatric studies assessing the impact of reduced exposure to NRTIs or the use of NRTIs with lower mitochondrial toxicity are urgently required. In an era of expanding treatment options, minimizing toxicities becomes an increasing possibility, indeed a necessity.
在过去十年中，联合抗逆转录病毒（ARV）疗法对资源丰富地区儿童HIV相关死亡率和发病率产生了巨大影响，其在预防HIV母婴传播（MTCT）中的作用不可低估。然而，HIV-1感染儿童在出生后的生长发育过程中不可避免地会接触ARV的时间越来越长，累积毒性也日益明显。核苷类逆转录酶抑制剂（NRTI）相关的线粒体毒性在体外、动物模型以及接触NRTI的成人和儿童中均有证据。NRTI线粒体毒性的潜在机制包括线粒体DNA（mtDNA）复制受损和mtDNA点突变的获得等。mtDNA合成的改变可能会减少mtDNA编码的呼吸链亚基的产生，导致氧化磷酸化受损和线粒体功能障碍。儿童中NRTI相关的线粒体毒性表现多样，包括乳酸酸中毒、胰腺炎、心肌病和神经病变，这与接触NRTI的成人以及患有先天性线粒体疾病的儿童相似。在预防MTCT方面，未感染的婴儿会接触到越来越多的ARV，通常从受孕开始直至整个胎儿期。动物模型显示围产期接触NRTI存在线粒体毒性的证据，但对于接触NRTI的儿童中线粒体影响的程度仍存在争议。迫切需要开展儿科研究，评估减少NRTI暴露或使用线粒体毒性较低的NRTI的影响。在治疗选择不断扩大的时代，将毒性降至最低不仅越来越有可能，而且确实是必要的。
