Therapeutic Intervention for Lipodystrophy.
Lipodystrophy can be defined as one or all of the following-elevated cholesterol and triglycerides, elevated sugar and/or insulin resistance, fat redistribution which can include wasting in face, arms and legs, and increased fat in stomach and other areas of the body. There is concern that the high elevations in cholesterol and triglycerides might lead to increased risk of premature heart disease. Sometimes use of lipid lowering drugs can reduce cholesterol and triglycerides, but they are not always effective. Diet and exercise can help control glucose and lipids for some individuals. Before starting an exercise or diet regimen you should consult with your doctor and a nutritionist.
Not much progress was reported at Retrovirus in understanding the cause and mechanism of action for this syndrome and potential treatments are not yet well characterized. But three studies were reported on switching individuals who had reported lipodystrophy and had undetectable viral load from a protease inhibitor regimen to a nevirapine regimen. Preliminary results included reduced cholesterol and triglycerides, and reported improvement in appearance (peripheral wasting). In the first study for which only 12 week preliminary data was presented, viral load was reported to have remained undetectable for the small number of patients whose data was available at this point. All patients switched to nevirapine received antihistimines to prevent nevirapine related rash and no one developed a rash. Seven of 11 patients reported normalization of their cholesterol levels. On average, cholesterol was reduced from 246 (± 46) prior to switching from the PI to nevirapine to 196 (± 54), and this was statistically significant (p<0.05). Triglyceride levels decreased but the reduction did not reach statistical significance. Liver function test (AST/ALT) levels did not significantly change. Quality of life and physician's and patient's estimation of body shape changes were reported to have improved significantly after switching to the nevirapine regimen. Although they did not reach statistical significance at week 12, anthropometric measurement, DEXA and BIA improved.
In a 2nd study reported, 23 patients had viral load <200 copies/ml and body fat redistribution on a protease inhibitor regimen (2 RTIs and at least 1 PI). Five patients had peripheral lipodystrophy (skinnier face, arms, legs) but did not have central obesity (fat stomach). Viral load had been suppressed for an average of 9 months prior to switching from a PI to nevirapine. On average it's been 7 months since patients have switched to nevirapine regimen. Six months after stopping PIs study investigators reported a significant improvement in cholesterol (-21%), triglycerides (-56%), glucose (-16%), and fasting insulin resistance index (-46%). CD4 cell counts remained the same. One person had their viral load become detectable (546 copies/ml); 21 patients (91%) reported a partial improvement in their fat redistribution, particularly in peripheral wasting. The study investigators concluded metabolic abnormalities (cholesterol, triglycerides, etc.) including lipodystrophy associated with PIs may be at least partially reversible. Viral load suppression achieved with the PI regimen may be preserved at least in the mid-term despite replacement of a PI with nevirapine.
A third study of interest was reported by Andrew Carr and his colleague from Australia. He reported on the results of switching patients who were using protease inhibitor therapy (for an average of 16 months) and who were suffering with lipodystrophy to either nelfinavir or nevirapine regimens. They evaluated individuals for 6 months after switching therapy by using testing which included-- body composition (DEXA), fasting lipids (cholesterol, triglyverides) and glucose, CD4 counts, and viral load. Total body fat measured on DEXA may not be useful in diagnosing lipodystrophy. In those who stopped protease inhibitors by switching to a nevirapine regimen, improvements were reported for all from 3 months. Improvements in the following measures were reported-total cholesterol, fasting triglycerides, C-peptide and insulin resistance (but not insulin or HDL cholesterol). Carr reported abdominal fat declined towards normal, and peripheral fat decreased for 3 months then increased. However, Carr implied that the improvements were incomplete at this time, that they did not completely restore individuals to pre-lipodystrophy. Switching to nelfinavir showed no change or a slight worsening in the measures listed above and in body fat. Of note, only 11/15 who switched to nevirapine were able to maintain viral supression <400 copies/ml.
A few lipodystrophy researchers said these study results were too preliminary upon which to base treatment switches from a PI. None of these studies used objective tools of measurement to characterize reversal in lipodystrophy. The investigators did not use objective measures to see if stomach girth actually decreased. Instead, the study investigators relied upon reported visual observations by doctors and patients. In addition, they thought patients needed to be followed for potential reversals of lipodystrophy over a longer period of time. A number of other studies are ongoing and being planned which will use objective measures to observe reversal of fat redistribution.
In a small study, Graeme Moyle looked at switching the protease inhibitor of a HAART regimen for efavirenz in patients with lipodystrophy symptoms. He presented data on 12 patients who had reached 12 weeks and 8 patients out to 24 weeks. Blood monitoring together with anthropometrics, DEXA and single-slice abdominal MRI were performed at 0, 12 & 24 weeks. Switching people to efavirenz was reported to be associated with modest improvements in weight averaging 2kg and 3.5kg after 12 and 24 weeks respectively, and were accompanied by modest reductions in abdomen girth (1cm and 0.3cm) although improvement in appearance and well-being have been reported by most patients. Of some concern was that there was significant elevation of both fasting cholesterol (5.88 mmol/l to 7.78) and triglycerides (5.1mmol/l to 8.0) at week 12, but they reversed and started to decline towards baseline. At week 24, 8/8 had <500 copies/ml.
NRTIs and Lipodystrophy. Results presented at Retrovirus from 3 studies reported on individuals who developed lipodystrophy who have taken NRTIs but have never taken protease inhibitors. Thierry Saint-Marc reported on a small study of individuals who had HIV for about 6-7 years, had received mostly double NRTI therapy for about 2.5 years, and had viral loads of about 1,000 copies/ml or lower. They never took protease inhibitors. Twenty of 43 developed peripheral fat wasting. A number of objective measures were used as well as self-reporting. These individuals were compared to a control group who had HIV but were therapy-naïve. None in the control group developed peripheral fat wasting. Mean subcutaneous fat was lower in the treatment group than the control group, and mean visceral fat (deep stomach fat) was higher in the treatment group than the control group. Although the authors reported those currently receiving a d4T regimen had a higher incidence of peripheral fat wasting than those currently receiving an AZT regimen, I found that questionable because 63% of those receiving the d4T regimen had prior AZT experience with combination or mono-therapy. S Madge and colleagues from London updated their Retrovirus report at the 5th Annual Meeting of the British HIV Association in England March 26-28. In reviewing patient charts at 2 out-patient HIV clinics, researchers found 9 (3 men, 6 women) patients with evidence for "clinical and biochemical" lipodystrophy. They had 23 months prior NRTI experience and the median time since their diagnosis for HIV was 6 years. Median CD4 before treatment was 170 and currently 183. Median viral load before treatment was 365,000 copies/ml and currently 1,100 copies/ml. All had raised fasting triglycerides but normal fasting glucose; 5/6 women experienced breast enlargement. Most patients had facial and limb wasting, and truncal obesity. One of the 5 patients reported on at Retrovirus was taking a NNRTI regimen with 2 NRTIs. The study concludes by suggesting that low viral load may be associated with the syndrome, as Don Kotler has suggested. A third study reported by C. Gervasconi and others from Italy reported that 12/32 women receiving only double NRTI therapy developed lipodystrophy. They characterized the syndrome by breast and abdominal girth, and wasting of the thigh, calves and glutei. They suggested that lipodystrophy was associated with 3TC because all who developed lipodystrophy were taking 3TC. These studies suggest, as has Kotler, that understanding lipodystrophy may be more complicated. Kotler has suggested that lipodystrophy may be associated with individuals who have long-term infection, well suppressed viral load and increased CD4s from therapy, but not necessarily due to PIs.
Human Growth Hormone. Results from a small study (n=8) were reported at Retrovirus using Human Growth Hormone (HGH). It reduced fat deposits but does not appear to be able to improve fat redistribution or peripheral wasting and lipid elevations. Four patients completed 3 months of taking HGH and were reported to have 25-75% reduction in buffalo hump and stomach size, but no change in peripheral lipodystrophy (thinning of the face, arms or legs). Body weights remained the same and there were no consistent changes in total body fat and lipids (cholesterol & triglycerides). There was, however, a 5-10% gain in fat-free mass. There have been reports of difficult side effects or toxicities related to taking HGH, such as glucose.
Metformin: anti-diabetic drug. A study was reported on using Metformin (Glucophage) for treating lipodystrophy. Metformin is generally used as an anti-diabetic medication. After the 8 week treatment period during which individuals received 850 mg Meformin orally 3 times daily, study investigators reported a slight weight decrease (2.1 kg), a slight decrease in waist to hip ratio (0.81 to 0.72), and a decrease in ratio of visceral fat (deep fat in stomach) to total abdominal fat as assessed by abdominal CT. Significant reductions were reported in triglycerides (30%), FFA (free fatty acid), apo A1 (apolipoprotein) and testosterone levels. The investigators were impressed with the reduction in basal plasma insulin in those receiving Metformin while there was an increase in individuals not receiving Metformin in this study. You may want to consult with your doctor about this. Although, no improvement was reported in peripheral wasting or fat redistribution, which can be the hallmark of lipodystrophy, the authors concluded metformin appears to be effective for improvement in central fat deposition (stomach). Lipodystrophy researchers I consulted were preliminarily impressed enough with study to want to conduct a larger study with Metformin for lipodystrophy.
Extended reproduction requires the permission of NATAP.
All subscription lists are kept confidential.
NATAP has a unique mission. We are committed to providing the most comprehensive, accurate and real-time up-to-date treatment information available. Therefore we do not have a set publication schedule. When there are advances in AIDS treatment we will publish them either in this newsletter, on our web site or if they are urgent in a priority fax or e-mail notice.
NATAP is a 501(c)-3 non-profit corporation, so donations are tax-deductible.
580 Broadway, Ste 403 NY, NY 10012