Lipodystrophy or Fat redistribution

Many people are suffering with peripheral fat wasting (arms, legs, butt, face) often accompanied by elevated lipids (cholesterol & triglycerides) & glucose, and fat accumulation in the stomach. Women can experience enlarged breasts.  Metabolic changes and body changes observed also include: impaired glucose tolerance (inadequate levels of insulin in response to consumed glucose); high fasting blood sugar; insulin resistance (high levels of blood glucose & insulin at the same time). Fat accumulation in several locationsóabdomen, back of neck (buffalo hump), lipomas (bumps of fat that can occur anywhere).

This June in San Diego the First Lipodystrophy Conference was held. This conference and follow-up meetings highlight to me that we now know less about the causes of this syndrome, which includes fat redistribution, than we thought we knew last year. We continue to learn how little we know, and it appears a difficult task to get an understanding of the mechanisms and causes. One of the problems highlighted at this conference was that there is not a generally accepted definition of this syndrome. Various studies appear to be using different definitions of lipodystrophy. But, it appears difficult to put together a general definition.

Last year research from the Australian research group implicated protease imhibitors, and it was widely accepted that protease inhibitors were the sole cause of lipodystrophy or fat redistribution. This year, starting with reports at the February í99 Human Retrovirus Conference followed by reports at many conferences since, weíve seen studies reporting individuals who have never taken protease inhibitors but have taken dual NRTIs have experienced fat redistribution or lipodystrophy. Don Kotler has reported that he observed similar symptoms in individuals in the earlier years after HIV was discovered who had never taken any HIV drugs. A small study from the Australians reported seeing lipodystrophy in individuals treated during acute infection after 12 months on therapy.

Although several research groups have conducted preliminary research and claim to have some understanding of the mechanism of action causing lipodystrophy or fat redistribution, I think their findings appear preliminary and inconclusive. Limited and inconclusive success appears from therapeutic interventions so far. Switching from a PI regimen to a nevirapine regimen may improve cholesterol and  triglycerides. Patient and doctor observations reported some individuals body changes improved following switch to nevirapine. Itís been observed in preliminary studies that Human Growth Hormone can reverse fat accumulations but do not appear to nor is it expected to reverse fat redistribution: wasting in the face, arms or legs.  One study reported high prevalence of lipid abnormalities associated with PI use. I donít know of evidence that steroids reverse or prevent fat redistribution. Increasingly I think doctors are concerned that long-term steroid use may have long-term harmful effects. 

In a small study from the same Australians (A Carr, D Cooper), patients who had only taken NRTIs developed lipodystrophy but did not report lipid elevations. NRTI lipodystrophy may have different clinical and metabolic features, and result from a different cause than from PIs. Kees Brinkman has suggested that mitochondrial toxicity associated with NRTIs may be associated with the development of this syndrome. Mitochondrial toxicity may cause cells, including fat cells, to be dysfunctional. This can lead to neuropathy and myopathy. A personís genetics can play a role in developing mitocondrial toxicity. In his report on the Australian paper Dr Abhimanyu Garg said the patients in this study developing lipodystrophy after only NRTI use (n=14) were characterized by recent onset of fatigue, elevated serum lactate levels (4.6 vs. 1.2 mmol/l), nausea, weight loss, abdominal dystension, and elevated liver enzymes. As well, they did not have hypertriglyceridemia but had low serum albumin concentrations. Metabolic alterations reportedly improved after cessation of NRTIs but weight gain was limited. Thus, HIV-infected patients who developed body fat changes on NRTIs had a syndrome that is distinguishable from the lipodystrophy syndrome developing with PI-containing HAART use. Constitutional symptoms, lactic acidemia and hepatic dysfunction and recent weight loss characterize the syndrome with NRTI use. However, because significant weight loss occurred in these patients with NRTI use, it appears that this study cannot rule out wasting as a cause of the observed body fat loss.

There has been much discussion about what may be causing fat redistribution? Associations have been observed with:

The cause for lipodystrophy may be multi-factorial for a person. As well, the causes for lipodystrophy may be different for one person than another. HIV causes immune dysregulation and immune deficiency. Either or both may play a role in fat redistribution. It could be due to the partial immune reconstitution that occurs from successful therapy, or there may be an abnormal immune response to therapy. For example, when CD4s start to return to normal after effective HIV therapy, the immune system is not normalized. Some people still experience an OI. Another suggestion by Kathleen Mulligan is perhaps an immune system that continues to be 'turned on', to respond to HIV that is no longer present, and instead attacks and kills subcutaneous fat cells. Many potential explanations are being offered, but research has yet to make clear headway in understanding this phenomenon.

Kotler and others have said they see the syndrome more often in people whoíve had HIV for a while, and have had the best responses to HAART with undetectable viral loads and significantly increased CD4s. It may be that several years of double NRTIs may start the process of lipodystrophy but after adding a PI this could lead to more pronounced lipodystrophy.

Several studies including the Australianís more recent paper implicating NRTIs, have reported associations, not causation, between d4T and lipodystrophy. But these studies appeared not designed adequately to sort out various factors such as duration and type of prior therapy, exposure to AZT prior to d4T, and reasons for discontinuing AZT. In fact, many of the studies at the Lipodystrophy Conference appeared flawed by the same types of problems. Sometimes study results appeared inconsistent, possibly because various potentially contributing factors were not characterized. Ongoing research is trying to sort out contribution of individual NRTIs to lipodystrophy.

Julian Falutz of Montreal reported in study presented at Lipodystrophy Conference that men (n=21) on long-term saquinavir HAART with a mean viral load of 1400 copies/ml were less likely to develop "HIV/HAART associated lipodystrophy" than a comparable group of men (n=23) on indinavir HAART. A separate study shows only minor changes in lipids and glucose to individuals taking Fortovase regimen at 24 weeks.. The SALSA study found women were more likely than men to have truncal obesity (98% vs 76%), and less likely to have peripheral wasting (e.g. limb lypodystrophy 68% vs 54%; butt LP 59% vs 44%). Men were more likely to have elevated triglycerides (84% vs 32%) and cholesterol (53% vs 29%). 98% of individuals in this study were receiving combination therapy with a PI, and 51/210 had <500 copies/ml viral load. M Galli study reported higher incidence of "altered fat tissue distribution" in women than men (26% vs 6.5%).

Interventions. Individuals with elevated cholesterol and triglycerides may be at risk for premature heart disease. Lipids and glucose should be monitored. Lipids can be lowered with lipid lowering drugs. Glucose can also be managed. Insulin resistance can be treated in individuals without HIV with troglitazone (associated with liver side effects) and rosiglitazone. But these drugs have not yet been tested in HIV lipodystrophy. The ACTG is planning such studies. Doctors express concern about placing individuals on poly pharmacies (various drugs for various syndromes) without clear evidence of success. Diet and exercise can control lipids, glucose and slim down a protruding stomach for some individuals. Exercise can also enhance oneís self of well-being, improve overall health, prevent premature heart disease, and tighten oneís muscles. In preliminary studies, Human Growth Hormone (HGH) reduced fat deposits but did not and are not expected to reverse fat redistribution. As well, in Kotlerís preliminary study of HGH fasting glucose increased. Follow-up studies are planned. In some studies described in this newsletter, switching individuals to PI-sparing regimens have shown partial improvements. Switching may entail what appears to be a low risk of losing control of viral suppression. This may depend on a personís treatment history. Some doctors have anecdotally reported seeing improvement following switch to amprenavir in some individuals but not in others. Some researchers say they need more objective data, not observations by doctors and patients, confirming that switching from a PI to a PI-sparing regimen can improve body shape alterations.

Metformin is an anti-diabetic drug that improves insulin sensitivity. Abnormal lipids and glucose improved in a small study but no improvement was seen in fat redistribution. Studies are ongoing. Some people opt for cosmetic surgery. Kees Brinkman has suggested that riboflavin, L-carnitine, and co-enzyme Q may improve cell dysfunction due to mitochondrial toxicity and thus fat redistribution, but there is little evidence yet supporting this.

Progress in understanding and treating fat redistribution appears stalled to me. Although many research efforts are addressing many questions, I think more attention needs to be paid to mechanisms of action that may be causing the syndrome. At a recent conference, a researcher discussed how diabetes and insulin resistance is still not well understood after years of research, but treatments are available.