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Conference
"Mitochondrial Toxicity" Dr. Marianne Harris (biography) English - 2002-04-15 - 33 minutes
Summary : Nucleoside analogues compete with nucleosides, the natural substrate of human DNA polymerase gamma, which is the only enzyme responsible for the synthesis of mitochondrial DNA (mtDNA). The inhibition of this enzyme leads to depletion of mtDNA and thus of the proteins it encodes, including those involved in oxidative phosphorylation, resulting in impaired cellular energy production. This is the putative mechanism of several known toxicities of nucleoside analogues: myopathy, cardiomyopathy, peripheral neuropathy, pancreatitis, hepatic steatosis and lactic acidosis. In fact, it has been hypothesized that mitochondrial toxicity plays a role in virtually all nucleoside-related toxicities, including bone marrow suppression and lipodystrophy.
The most potentially serious of the nucleoside-related side effects attributed to mitochondrial toxicity is acute lactic acidosis with hepatic steatosis, which is often fatal. Milder increases in lactate levels have been observed chronically in approximately 10-20% of HIV patients receiving nucleoside analogues, and may be accompanied by symptoms such as fatigue, weakness, and weight loss. Chronic hyperlactataemia is seen more often in association with d4T and hydroxyurea; however, the relationship of this clinical syndrome to the fulminant form of lactic acidosis is unclear. The laboratory of the B.C. Centre for Excellence in HIV/AIDS (B.C. CfE) has recently developed an assay to measure the ratio of mitochondrial DNA (mtDNA) to nuclear DNA (nDNA) in peripheral blood cells. This assay was applied to three groups of patients: I) HIV uninfected controls (N=24), II) HIV infected asymptomatic, antiretroviral naive (N=47), and III) HIV infected taking antiretrovirals with symptomatic hyperlactataemia (N=8). The latter patients were studied longitudinally before, during and after interruption of antiretroviral therapy. Symptomatic hyperlactataemia was associated with markedly low mtDNA/nDNA ratios, on average 69% lower than HIV uninfected controls and 45% lower than HIV infected asymptomatic/antiretroviral naive controls. The decline in mtDNA preceded the increase in venous lactate levels. A significant increase in mtDNA/nDNA ratio was observed following discontinuation of antiretroviral therapy. The mtDNA/nDNA ratio remained stable in patients who re-introduced antiretroviral therapy with d4T-sparing regimens.
In order to evaluate differences in mtDNA/nDNA in relation to specific antiretroviral drug regimens, a cross-sectional study was performed using a non-random sample of B.C. CFE Drug Treatment Program participants. Eligible patients had continuously received saquinavir plus ritonavir with either nevirapine (N=20), 3TC (N=15), d4T (N=53) or 3TC plus d4T (N=69), for 4 -30 months. The mtDNA/nDNA ratio was measured from the last buffycoat sample collected between August 1998 and September 2001. Median mtDNA/nDNA ratios were significantly lower in patients receiving d4T- containing regimens than in those receiving d4T- sparing regimens, despite the fact that the median duration of the d4T-containing regimens was shorter than that of the d4T-sparing regimens (13 vs. 25 months, p=0.002).
In summary, mtDNA/nDNA ratios are significantly decreased in patients who develop symptomatic, nucleoside-related hyperlactataemia, and increase when antiretroviral therapy is interrupted. Furthermore, in a cross-sectional study, mtDNA/nDNA ratios are significantly lower in patients receiving d4T-containing regimens than in those receiving selected d4T-sparing regimens. This assay is being evaluated as a tool to monitor mitochondrial toxicity in HIV infected patients receiving nucleoside analogue-based antiretroviral therapy.
(Marianne Harris, Julio Montaner, Helene Côté, St. Paul's Hospital AIDS Research Program, Vancouver, B.C.)
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