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Conference
"Mitochondrial Toxicity in the era of HAART" Dr. Julio Montaner (biography) English - 2002-04-26 - 23 minutes
(31 slides)
Summary : Nucleoside analogues can induce mitochodrial toxicity through the inhibition of the human DNA polymerase gamma enzyme. This can lead to a wide range of clinical toxicities, from asymptomatic hyperlactaemia to death. We have recently developed an assay that can monitor changes in mitochondrial DNA(mtDNA) levels in peripheral blood cells. Using this assay, we have characterized changes in mtDNA relative to nuclear DNA (nDNA) in peripheral blood cells of patients with symptomatic nucleoside induced hyperlactataemia. Total DNA was extracted from blood cells derived from buffycoast. A nuclear gene and a mitochondrial gene were quantified by real-time PCR. Three groups of patients were assayed: i)HIV uninfected controls (N=24), ii) HIV infected asymptomatic and antiretroviral naīve (N=47), iii) HIV infected taking antiretroviral with symptomatic hyperlactataemia (N=8). The latter patients were studied longitudinally before, during and after antiretroviral interruption. Selected patients re-introduced antiretroviral therapy with d4T-sparing regimens. The decline in mtDNA preceded the increase in venous lactate levels.
More recentlys, we have evaluated the changes in mtDNA/nDNA in relation to various selected antiretroviral drug regimens in a population setting. To this end, we recently completed a cross-sectional study on a non-random sample of participant within the BC CFE Drug Treatment Program. Eligible patients had continuously received saquinavir plus ritonavir with either nevirapine (N=20), laminadine (N=15), stavudine (d4T)(N=53) or lamivudine plus d4T (N=69), for 4 to 30 months. Participants were included if a buffycoat sample collected between Aug 1998-Sept 2001 was available for testing. The mtDNA/nDNA ratio was measured using real-time PCR on the last sample collected during the observation period. We found that d4T-sparing regimens were associated with a higher median mtDNA/nDNA ratio than d4T-containing regimens (p=0.016). Furthermore, the mtDNA/nDNA ratio were skewed toward lower values for the d4T-containing regimens but normally distributed for the d4T-sparing ones. Of note, this was despite the fact that study patients had received d4T-containing regimens for a shorter median time than patients taking d4T-sparing regimens (13 vs. 25 months, p=0.002).
In conclusion, these results demonstrate that mtDNA levels are significantly decreased among patients who develop symptomatic, nucleoside related hyperlactataemia, an effect that was reversed upon therapy discontinuation. Furthermore, we demonstrated that mtDNA/nDNA ratios are statically significantly lower in d4T-containing regimens then in selected d4T-sparing regimens in a population setting. Of note, the latter results represent a conservative estimate of the magnitude of the effect of d4T-containing regimens on mtDNA/nDNA, due to a survivor bias effect in the d4T-containing cohort.
Learning objectives : The viewer will gain insights into the rapidly evolving field of mitochondrail toxicity research.
Random venous lactic acid (RVLA) as a monitoring tool.
Introduction to the mitochondrial DNA assay.
Mitochondrial toxicity is often associated with NRTI use.
Hyperlactemia is more often associated with d4T and HU, possibly other NRTIs.
Significance of lactic acidsis (LA) in HAART-treated patients.
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