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JAC Advance Access originally published online on November 13, 2007
Journal of Antimicrobial Chemotherapy 2008 61(1):8-12; doi:10.1093/jac/dkm411
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Leading articles

HIV and mitochondrial toxicity in children

Caroline Foster and Hermione Lyall*

The Family Clinic and Imperial College, St Mary's Hospital, Praed Street, London W2 1NY, UK

* Corresponding author. Tel: +44-207-886-6349; Fax: +44-207-886-7644; E-mail: hermione.lyall{at}st-marys.nhs.uk

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.

Keywords: nucleoside reverse transcriptase inhibitors , mitochondrial DNA , DNA polymerase {gamma} , HIV , children


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