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Switch to Abacavir Improves Fat Loss; Experimental Uridine Study Improves Mitochondrial Toxicity in Vitro
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There were several interesting studies presented today. Perhaps the most clinically relevant study was a follow-up on the MITOX Study, which examines patients for 2 years after switching to abacavir from 6 years on a d4T-based regimen. The new data follows patients out as long as 2 years and reports gain in peripheral fat after switching to abacavir. German researcher Ulrich Walker presented a study today showing that uridine, a pre-curser for special DNA components, in a supplement form, improves mitochondrial toxicity in vitro.
David Nolan gave a talk discussing how AZT and d4T can reduce fat cell mitochondrial DNA. He and other researchers maintain that mitochondrial toxicity (reduced mtDNA) in fat cells are associated with and plays an important contributing role in the development of lipoatrophy (fat loss in the periphery). He presented data from a study showing that compared with HIV+ ART-naive patients (n=24, 1349) copies/cell), median mtDNA copies/cell was reduced by 80% in d4T recipients (n=23, 240 copies/cell) and by 44% in AZT recipients (n=28, 726 copies/cell). Regimens without d4T/AZT (n=24, 1349 copies/cell) had similar levels to HIV-negative individuals. Switching patients from d4T to AZT based regimens showed improvements in mtDNA values within 2-12 months. There was a panel discussion about the role of mitochondrial toxicity and mtDNA loss in the development of lipoatrophy, which is controversial.
There is no direct evidence that mtDNA loss or mitochondrial toxicity directly leads to fat loss. But there is an association between the two. Patients with fat loss do show mtDNA loss which appears to reverse when d4T is substituted by abacavir. As you can see from the data reported below from the MITOX Study lipoatrophy improved continually over the course of 2 years after switching from d4T or AZT to abacavir. In addition to NRTI use and mitochondrial toxicities, studies have shown a number of additional factors that are associated with fat loss including genetic predisposition, insulin resistance, and having low body weight before starting ART. We certainly do not clearly understand what causes lipoatrophy and I think the consensus opinion remains that the cause appears to be multi-factorial based on what we so far know. Numerous factors may play a role in an individual developing fat loss. And in a given individual perhaps one factor may be more influential. While in another individual another factor may be more individual. It may take years to figure the causes out or perhaps we will not figure this out. We still donÕt know what causes diabetes. But we have a therapy for diabetesÑinsulin. At the Workshop today two studies were presented addressing the possibility for successful intervention. Immediately below the results of the MITOX Study report what happens to limb fat in patients with lipoatrophy two years after substituting abacavir for d4T or AZT. Ulrich WalkerÕs presentation on the possibility of using uridine as an intervention is discussed below. And yesterday early study results were reported on using rosiglitazone, an anti-diabetic drug, as a potential intervention were reported. You can read the rosiglitazone report on the NATAP website.
MITOX Study Shows Steady Increase in Limb Fat Over 2 years in Patients with Lipoatrophy After Switching from d4T or AZT to Abacavir
Brief summary: Patients in this study had been on d4T (85%) or AZT (15%) for 6 years and saw 50% loss in limb fat. Two years after switching to abacavir limb fat increased 36% from the amount it was at the time of the switch to abacavir. Over the course of the two years the graph presented by Carr showed a continuing steady increase of limb fat, suggesting that if limb fat continues to increase at a similar rate it would take an additional 6 years to return to the normal amount of limb fat seen in adult, white men. Carr said lipoatrophy may take as long to resolve as it does to develop (if improvement continues at the same rate). This study did not evaluate whether patients had experienced improvements in fat in the face. In speaking with researchers at this meeting they said that in theory return of fat to face may take longer. Fat loss in the face has not yet been objectively evaluated by DEXA or CT scan in studies. However, there was a poster at this conference which shows for the first time that CT scan imaging can be used to evaluate the face. The concern is do you want to repeatedly expose your head to x-rays. Perhaps taking pictures can be utilized to effectively assess changes in facial fat, but this method has yet to be properly evaluated.
Details of the study.
Australian researcher Andrew Carr reported brand new data from a follow-up of patients in the MITOX Study. The MITOX study previously demonstrated modest (mean 0.39 kg) recovery of limb fat over 6 months in adults with lipoatrophy who replaced d4T or AZT with abacavir. The improvement was not clinically evident, however, over this period. 85% of patients were taking d4T and 15% were taking AZT. Patients had been on NRTIs 6 years before switching to abacavir in this study.
The new follow-up data reported at the Workshop reports on whether improvement in limb fat continues over a longer period of time and if the improvement is clinically relevant. Patient self-report assessment was taken. At the beginning of the MITOX Study the patients had on average lost 50% of their fat. HIV-RNA was <400 copies/ml for greater than 6 months.
Patients enrolled in MITOX were followed beyond the 24 week randomization phase up to 128 weeks. Patients randomized to remain on d4T ot AZT were allowed to switch to abacavir at week 24. Serial DEXA and CT scans were used to assess changes in subcutaneous and central (belly) fat.
Of the original 111 patients randomized, 104 had long-term follow-up data. Carr said limb fat is normally 7-8 kg in adult, white, HIV-negative men. 99% of study participants were men. At the beginning of the study patients in the abacavir arm had 3.54 kg of limb fat and patients in the d4T/AZT arm had 3.75 kg of limb fat. So the patients had lost 50% of their limb fat over the course of 6 years on their NRTI regimen when they started this study.
At week 24, patients in the abacavir group had a mean increase in limb fat of 0.39 kg, which was an 11% increase in limb fat after switching to abacavir. Patients who stayed on d4T for 24 weeks had the same amount of limb fat at week 24 as when they started the study. Limb fat continued to increase steadily for the patients who switched to abacavir as far as they were followed which so far is week 108, when limb fat had increased 1.26 kg. Since limb fat was 3.54 kg, this was a 36% total increase in limb fat after switching to abacavir in 108 weeks (2 years).
Patients who were originally randomized to remain on d4T/AZT had limb fat of 0.49 kg. However, when separating these patients into those who stayed on d4T/AZT vs those who switched at week 24 to abacavir: limb fat in patients who switched at week 24 (about 1 year) saw limb fat increase 0.55 kg at week 72, a 15% increase in limb fat. While patients who remained on d4T/AZT had an increase of 0.16 kg (4%) from the time of entering the study. Remember these patients had already lost 50% of their limb fat during 6 years on d4T/AZT based regimens before entering this study. At week 72, 15 patients of the original 50 randomized to abacavir at the beginning of the study had discontinued during the follow-up period. There was also a comparable number of discontinuations from the patient group who remained on d4T/AZTÑabout 20 discontinued. And these 20 discontinuations were equally distributed between those who stayed on d4T/AZT or switched after 24 weeks from d4T/3TC to abacavir.
Lipid and glycaemic parameters did not change significantly. Patients who switched to abacavir reported slightly greater improvement in self-assessed lipodystrophy over 72 weeks. Regional DEXA showed right leg fat continually increased over course of 108 weeks for patients who initially switched to abacavir. Right thigh fat increased by regional CT scan by 24% for patients who switched to abacavir and the difference compared to those who nstayed on d4T/AZT was significant (-12%). Total subcutaneous fat increased (32%) significantly more in the patients who initially switched to abacavir.
Uridine Improves Mitochondrial Toxicity In Vitro (in the laboratory)
The purpose of the uridine study was to evaluate whether it may be suitable to prevent and treat nucleoside reverse transcriptase inhibitor related mitochondrial toxicity. This was tested in vitro, in the laboratory. Human HepG2-hepatocytes were exposed to NRTIs with or without uridine for 25 days. DDC was used and produced a severe mtDNA depletion in this experiment. After inserting uridine into the cell culture mitochondrial toxicity was significantly improved and damage was reversed. These effects were dose-dependent and maximal at 200 uM of uridine. Uridine also rapidly and fully restored cell function despite continued ddC exposure, when added to cells displaying severe mitochondrial dysfunction. Similar results were found in HepG2 cells exposed to 36 uM of d4T, but not to 11.8 uM of ddI. Uridine also fully improved the increase in lactate and all the cell toxicity of AZT (7 uM) plus 3TC (8 uM) to HepG2 cells.
Walker went on to explain that uridine appears to be safe. Uridine 150 mg/day is recommended for lifetime in patients with hereditary orotic aciduria. Oral dosing was limited by diarrhea at excessive doses when given through peripheral veinÑphlebitis. Walker reported that Mitocnol (also called NucleomaxX, an extract from sugar cane, is offered as a nutritional supplement and can be taken orally. Walker reported on one patient he treated with this product. The patient is a 50 yr-old man taking HAART that included d4T and had hepatitis, steatosis (fatty liver), CK elevation, and elevated lactate. The patient took NucleomaxX 3 sachets/day for 4 days, and Walker reported resolution of his symptoms. Walker also reported that NucleomaxX achieves high uridine serum levels.
HOWEVER, this product has yet to be tested in humans with HIV for safety and effectiveness, or for potential drug interactions. Walker is planning additional study to begin next week and if efficacy is shown itÕs expected the product will be tested in patients with lipoatrophy.
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