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Antimicrob. Agents Chemother. doi:10.1128/AAC.00893-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Impact of Nucleoside Reverse Transcriptase Inhibitors on Mitochondria in HIV-1 Infected Children Receiving HAART

Division of Infectious Diseases, Department of Pediatrics, University of California San Diego, La Jolla, CA, Center for Molecular Genetics and Center for AIDS Research, Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, MA, Department of Clinical Pharmacy, University of Colorado Health Science Center, Denver, CO

^* To whom correspondence should be addressed. Email: asaitoh{at}ucsd.edu.

	Abstract

Background: Mitochondrial toxicity induced by nucleoside reverse transcriptase inhibitors (NRTI) has been reported to be responsible for various adverse effects. The relative impact of NRTI on mitochondria of HIV-1 infected children receiving highly active antiretroviral therapy (HAART) is unknown.

Methods: Mitochondrial DNA (mtDNA) levels were quantified longitudinally from peripheral blood mononuclear cells (PBMC) in 31 HIV-1-infected children from PACTG 382 receiving HAART including nelfinavir, efavirenz, and different NRTI with undetectable plasma HIV-1 RNA >2 years.

Results: The median mtDNA levels in PBMC increased from 137 copies/cell at baseline to 179 copies/cell at week 48 (P = 0.01) and 198 copies/cell at week 104 (P < 0.001). Before initiation of HAART, children who received regimens containing didanosine had persistently lower mtDNA levels compared to those in children without didanosine (106 vs. 140 copies/cell, P = 0.008). During HAART, the median mtDNA increase from baseline to week 104 was the lowest in children who received regimens containing didanosine (+26 copies/cell) compared to other regimens (+79 copies/cell) (P = 0.02). A multivariate analysis also demonstrated that the use of ddI during HAART was the only NRTI associated with the change in mtDNA levels (P = 0.007).

Conclusion: Children receiving didanosine containing antiretroviral regimens have the lowest mtDNA in PBMC and may be at greater risk for long-term adverse effects due to mitochondrial toxicity. This may be of particular importance in resource-limited countries where didanosine is widely used for treatment of HIV-infected children.

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