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Study
Finds mtDNA in Blood Is Not a Reliable Marker of Clinical Mitochondrial
Diseases and Cannot Be Used in the Place of Tissue Biopsies
Therapy
with nucleoside
reverse transcriptase inhibitor (NRTI) agents has been associated
with lipoatrophy
and lactic
acidosis, presumably through inhibition of DNA polymerase-[gamma]
and resultant mitochondrial
DNA (mtDNA) depletion.
In
past investigations, studies have looked at mtDNA depletion and
a few specific mutations but not at the entire mtDNA genome to correlate
with clinical toxicity.
This
is the largest prospective longitudinal study to date that has performed
a complete analysis of the entire mtDNA genome in addition to mtDNA
depletion.
The
study population included 54 HIV-infected NRTI-treated patients
with or without clinical mitochondrial toxicities, 33 HIV-infected
NRTI-naive patients, and 48 age-matched healthy volunteers.
Data
on demographics, treatment, and clinical characteristics were collected,
and blood was drawn for mtDNA analysis, serum fasting lipids, and
lactate.
Results
·
No
depletion was found in blood mtDNA levels of subjects with clinical
mitochondrial toxicities;
·
Duration
of NRTI therapy was the only predictor of mtDNA levels.
·
After
complete analysis of the mtDNA genome, only 2 subjects showed development
of mutations during the study period, after 14 and 52 months of
antiretroviral therapy.
Based
on these results, the authors concluded the following:
·
Blood
mtDNA content is not associated with the use of specific NRTIs,
nor does it predict clinical symptoms such as lipoatrophy.
·
The
only factor associated with mtDNA depletion was duration
of NRTI use.
·
Complete
mutational analysis of the mitochondrial genome revealed mtDNA mutations
in 2 patients.
·
More
extensive studies of mtDNA mutation at the single molecule level
are required to correlate mitochondrial dysfunction with NRTI-caused
molecular defects in mtDNA.
Discussion
In
contrast to other studies, the researchers did not find mtDNA depletion
in HIV-infected subjects who are naive to ARV therapy. Indeed, on
multivariate analysis, mtDNA levels were only associated with duration
of NRTI therapy. These observations argue against a role for HIV
itself in mtDNA depletion.
In
this study, the only factor associated with mtDNA depletion was
duration of NRTI use in general. This is consistent with prior clinical
observations that linked the duration of ARV therapy to the advent
of clinical mitochondrial toxicities.
The
use of a specific ARV drug, particularly stavudine/d4T
(Zerit), zidovudine/ZDV
(Retrovir), or didanosine/ddI
(Videx), was not specifically associated with such depletion.
This is in contrast to fat tissue data, where mtDNA was significantly
lower in subjects treated with thymidine analogues (d4T > ZDV)
when compared with thymidine-sparing regimens.
“In
conclusion,” write the authors, “blood mtDNA is not a good marker
of clinical mitochondrial diseases and cannot obviate the need for
tissue biopsies.”
They
continue, “In contrast to the association between fat mtDNA depletion
and lipoatrophy found in other studies, we found no evidence of
blood mtDNA depletion in such cases. Depletion of mtDNA was only
related to a longer duration of NRTI therapy. \”
Finally,
they note, “Future studies with larger number of subjects are required
to determine whether the few point mutations in the mitochondrial
genome seen in this study are indeed correlated with clinical NRTI
toxicities.’
06/01/05
Reference
G McComsey and others. Extensive Investigations of Mitochondrial DNA Genome in Treated HIV-Infected
Subjects: Beyond Mitochondrial DNA Depletion. Journal of Acquired Immune Deficiency
Syndromes 39(2):181-188, June 1, 2005.
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