Affiliations: Division of Chemical Pathology, Red Cross Children's
Hospital, National Health Laboratory Service and University of Cape Town, Cape
Town, South Africa | Divisions of Pediatric Medicine and Infectious
Diseases, Institute of Child Health and School of Child and Adolescent Health,
Red Cross Children's Hospital, University of Cape Town, Cape Town, South
Africa
Note: [] Correspondence: George F. van der Watt, Red Cross Children's
Hospital, National Health Laboratory Service and University of Cape Town,
Rondebosch, Cape Town, 7700, South Africa. Tel.: +27 216585224/6/0; Fax: +27
216585225; E-mail: george.vanderwatt@uct.ac.za
Abstract: Nucleoside reverse transcriptase inhibitors (NRTIs) affect
mitochondrial DNA polymerase gamma causing significant toxic effects, including
fatal lactic acidosis. Little is known about mitochondrial DNA (mtDNA) in human
immunodeficiency virus (HIV) infected children who face a lifetime exposure to
these agents. We performed a cross sectional observation of mtDNA levels in
whole blood in a pediatric population to ascertain the relationship between
mtDNA, NRTI regimens and parameters of HIV-infection severity. Whole blood
mitochondrial / nuclear DNA (mt:nDNA) ratios were determined by real-time PCR
in three groups: 27 presumed HIV-negative, 89 HIV-infected, NRTI-treated and 62
HIV-infected treatment-naive children. Multivariate analysis was used to
identify variables independently associated with mtDNA depletion. Mean mt:nDNA
ratios were lower (p< 0.001) at 77% of control in the HIV-infected
antiretroviral treatment (ART) naïve group and 73% of control in the ART
group, but not different between the two HIV-infected groups. Mt:nDNA ratios
were negatively associated with age (p=0.029), HIV status (p< 0.0001) and
Log_{10} of the HIV-1 viral load (p=0.035) and positively
associated with CD4% (p= 0.032). A stavudine vs. zidovudine based regimen was
associated with lower but not significant levels of mtDNA (p=0.08). Depletion
of whole blood mtDNA in children is associated independently with HIV-infection
and markers of HIV infection severity, and does not improve with either
stavudine or zidovudine based ART despite virological control, suggesting that
these agents also deplete mtDNA. The long-term consequences of this potentially
toxic effect remain a cause for concern
Keywords: Pediatric HIV, NRTI's, mitochondrial toxicity, mitochondrial DNA depletion, DNA polymerase gamma
