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  4th Intl Lipodystrophy Workshop
San Diego at Coronado Beach, Sept 22-25, 2002
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Nukes, Fat Loss, Mitochondrial Toxicity, Lactate
Reported by Jules Levin
  --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.