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Nukes, Fat Loss, Mitochondrial Toxicity, Lactate
Reported by Jules Levin
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--Switch Study From Nelfinavir to Atazanavir - (9/24/02)
--Atazanavir: preliminary week 24 study results show no increase in glucose,
cholesterol and triglycerides - (9/24/02)
--Liopdystrophy pre-conference day 1 report
From Jules Levin:
I'm at this year's conference as I've attended every one since the inception
of this meeting. I'm a bit disappointed in the overall collection of studies
this year. There are few clinically relevant studies of much interest. There
are a number of basic science studies presented related to insulin
resistance, mitochondrail toxicity, cardiovascular risk, fat cells and
protease inhibitors. The quality of the studies submitted this year is not up
to par from previous conference. So why is the level down this year? My
feelings are the progress in research & understanding in this area has been
very slow, in fact not much progress has been made clinically in treating
body changes. Treating abnormal metabolics has en more progress but is still
not a mystery & has not been controlled. This year there are a lot of
conferences bunched together: Barcelona, Lipodystrophy & ICAAC. So abstract
may get submitted to other conferences. There was a meeting here two nights
ago organized by the Forum For HIV Collaborative Researcher were about 30
researchers and several community were invited to discuss the preliminary
results from Carl Grunfeld's FRAM study he reported at Barcelona and to
compare them to the Lipodystrophy Definition Study reported on by Andrew Carr
at the past Retrovirus Conference. There was much discussion about Grunfeld's
preliminary finding that fat accumulation in the belly occurs but not as much
as expected in his study so he suggested it should not be included in the
"definition" of lipodystrophy although we really do not have an officially
accepted definition. Personally, I think this reflects what I think are the
reasons littlle real clinical progress has been made in this area. I don't
think we can clearly define lipodystrophy. I'm not comvinced we will design a
study that succeeds in doing this, just like neuropathy is not clearly
defined. You know lipodystrophy when you see it, that is what many docs &
researchers say & I agree. It consists of a combination of body changes and
metabolic abnormalities. Of interest was a discussion yesterday at the
workshop on trying to establish a lab test or assay to detect mitochondrial
toxicity & depletion that will correlate test results with fat loss. First of
all, we have not yet clearly established a correlation between mitochondrial
toxicity & fat loss. There is adequate research data to support that nukes
contribute to mitochondrial toxicity & mitochondrial depletion but how much
of it do you need to establish real damage & clinically relevant body changes
& damage? We don't know the answers to that. The question debated by
researchers yesterday is whether the assay should be taking test samples from
the blood (PBMCs) or tissue by biopsy from the affected sites like leg
muscles, belly tissue, the arms, legs, etc. There are some assays but it
appear that samples should not be taken from PBMCs but from affected tissue
areas. Study results on going with tissue samples are being conducted and
perhaps there will be a reliable assay that can detect accumulated toxicity i
n the near future but the key for us clinically will be to correlate the
depletion with fat changes. There are two studies here linking d4T with fat
loss.
Lactate, nukes, mitochondrial toxicity & fat loss
Lonergan and others including GlaxoSmithKline reported (abstract 21) on the
changes in lactate levels seen in 118 patients who were on d4T and had
elevated lactate (>2.1mmol/l) or lipoatrophy - fat loss- or both. 86 patients
replaced D4T with abacavir and 32/118 replaced d4T with AZT. 16 patients had
lactate >2.1 mmol/l. 12 of 16 patients replaced d4T with abacavir and 4 of 16
replaced d4T with AZT. Elevated lactate decreased lactate levels by over 50%
by week 48 on abacavir. Sympotomatic lactate is uncommon and we are not sure
what mildly elevated lactate without symptoms means clinically and if
anything should be done about it. Clinical testing for lactate is a blood
test but results are unreliable, inconsistent, and its hard to perform the
test well. 52/116 patients reported at baseline at least 1 clinical symptom.
10-12 of 100 patients reported a reduction in symptoms in
nausea/vomiting/anorexia. 1 patient reported improved abdominal
pain/bloating. 17 serious adverse events and 8 cases of abacavir hyper
sensitivity were reported. The authors concluded that NRTI-induced
hyperlactatemia showed early and sustained improvements in lab markers,
without recurrence, when d4T was replaced by either abacavir or AZT. But the
link between lactate increases and fat loss are not adequate. Several studies
find slowing or slight improvements in fat loss after switching from d4T to
abacavir and that elevated lactate might reflect mitochondrial toxicity &
perhaps fat loss. A number of studies find d4T more associated with fat loss
or lipoatrophy than other nukes expect perhaps ddI. These studies have been
of short duration and found small improvements in fat loss. The long term
benefits in fat loss are yet to be identified. If fat loss is stopped or
slowed that's a benefit. Furthe studies to confirm this are needed. But the
link of elevated lactate to fat loss is weak & the link of reversing elevated
lactate & improving fat loss is weak.
David Nolan and the Australian mitochondrial researchers from Australia will
report today on a study looking at the various nukes and their effects on fat
loss in sucutaneous fat tissue in the leg in patients on either AZT OR D4T
regimens. Patients had DEXA scans to detect fat loss. Today they will report
results after following patients for 2 years and I'll report results later as
I'm restricted from reporting results until after the presentations.
On the other hand Graeme Moyle reported a poster study on the results of
subcutaneous fat biopsies taken from the left buttock to see evaluate the
extent of fat loss and mitochondrial depletion in 42 male patients. He
reported finding that both d4T and AZT based ART are associated with
significant fat tissue depletion. Is mitochondrial depletion in fat tissue in
buttock refelective of the arm, leg, face, and other areas? The findings in
this study is somewhat at odds with findings of other studies where d4T is
linked to fat loss, elevated lactate, or mitochondrial depletion.
There are studies here linking nukes to lipid abnormalities, not just linking
the abnormalities to PIs. There are studies here suggesting that PI therapy
in combination with nukes create a synergy in accelerating fat loss that PI
therapy or nuke therapy separately do not cause. In other words combining a
Pi with nukes accelerates fat loss, so some have jumped to the conclusion,
based on limited study data, that nuke sparing regimens will not lead to fat
loss or not as quickly. The ACTG is studying this with a nuke sparing
regimen. You could do this with double PIs like ritonavir-saquinavir,
Kaletra-saquinavir, a PI+NRTI combination. But there are also studies,
including here, suggesting that PIS can contribute to fat loss. So its
preliminary and not established that nuke sparing will not lead to fat loss
or it will appreciably slow it down, and its preliminary to conclude such a
combination will not have other safety concerns or implications regarding
body changes & metabolic abnormalities.
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