[pronut-hiv] Severity of NRTI-mediated mitochondrial toxicity differs in blood and fat cells

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Severity of NRTI-mediated mitochondrial toxicity differs in blood and
fat cells 

Chris Gadd, Tuesday, August 01, 2006 

Damage to the mitochondria caused by the nucleoside reverse
transcriptase inhibitors (NRTIs) varies according to tissue type,
Australian researchers report in the 1st August edition of The Journal
of Acquired Immune Deficiency Syndromes. While both ddI (didanosine,
Videx / VidexEC) and d4T (stavudine, Zerit) cause mitochondrial toxicity
in fat tissue, only ddI is linked to the side-effect in white blood
cells. 

Mitochondria are cellular components that produce energy for the cell
by breaking down food molecules. Damage to the mitochondria is caused by
some NRTIs, leading to symptoms such as fat loss, damage to the
peripheral nerves and elevations of lactic acid levels in the blood.
Studies have reached divergent conclusions regarding the relative risk
of mitochondrial toxicity with different NRTIs. This may be due to their
analysis of different tissue samples. 

To clarify the relationship between NRTI use and damage to the
mitochondria in different tissues, investigators took blood samples and
fat specimens from the thighs of 61 adult HIV-positive patients
attending a clinic in Melbourne. They then compared the levels of
mitochondrial DNA, a measure of how many mitochondria are in each cell,
between patients taking different combinations of NRTIs. 

Almost all of the study participants were white men. On average, they
had been taking their current antiretroviral therapy treatment regimen
for 16.5 months, although 14 of the participants were not taking any
anti-HIV drugs at the start of the study. 

There was no association between mitochondrial DNA levels and the
patients' age, CD4 percentage, use of protease inhibitors or duration
of NRTI exposure in either the fat tissue, or in the peripheral blood
mononuclear cells (PBMCs) extracted from the patients' blood samples.


However, mitochondrial DNA levels were significantly reduced in
patients taking either ddI or d4T (p < 0.001). In contrast, patients
taking AZT (zidovudine, Retrovir) without ddI or d4T had similar levels
of mitochondrial DNA to the patients taking no anti-HIV therapy. 

When they examined the mitochondrial levels in the patients'
PBMC's, the investigators found a similar reduction in
mitochondrial DNA with the use of ddI (p = 0.003). However, the patients
taking d4T without ddI had similar levels of mitochondrial DNA to the
patients taking no anti-HIV therapy (p = 0.5). 

"Current NRTI exposure is the major determinant of mitochondrial DNA
levels in fat and PBMCs, but the precise associations are different in
each tissue," the investigators conclude. "Both ddI and d4T exposure
are associated with fat mitochondrial DNA depletion, whereas ddI
exposure was the only observed association with mitochondrial DNA
depletion in PBMCs." 

The investigators speculate that mitochondria in PBMCs are less
susceptible to d4T, as these cells may lack the enzyme thymidine
kinase-1, which is required to convert d4T into its active form. 

Importantly, however, this suggests that analysing mitochondrial damage
in cells from blood samples may not produce a representative picture of
the effects occurring in other tissues in the body. "Although blood is
easily sampled, it is unlikely to be an appropriate tissue for
understanding the events occurring in tissues where problematic NRTI
toxicities occur, including fat and neurones," they warn. They also
point out that AZT can cause damage to muscle cells, which may not be
reflected in analysis of blood cells. 

However, their results could explain why improvements in fat levels
under the skin after switching from d4T to abacavir (Ziagen) were not
mirrored by improvements in mitochondrial DNA levels in blood cells in
clinical studies. 

Although they could not detect a link between mitochondrial toxicity
and symptoms in their relatively small sample, the investigators suggest
that NRTI use could cause damage to the mitochondria soon after a
patient starts to take the drugs, since they saw no association between
time on therapy and mitochondrial toxicity. 

Conversely, they saw no differences in mitochondrial levels between
patients who had never taken NRTIs, and those who had stopped taking
them an average of 21 months earlier. "This suggests that
mitochondrial DNA depletion reverses when NRTIs are ceased, whereas
clinical toxicities, such as lipoatrophy and neuropathy, do not reverse
rapidly," they write. 

Reference 

Cherry CL et al. Tissue-specific associations between mitochondrial DNA
levels and current treatment status in HIV-infected individuals. J
Acquir Immune Defic Syndr 42: 435-440, 2006.