Lipodystrophy update
Some people taking Indinavir (Crixivan) experienced a rapid increase in their waist size. This new syndrome was called lipodystrophy, which means defective fat metabolism.
The term ”Lipodystrophy“ has never been very helpful. Some people experienced fat gain around the middle (or behind the neck), or fat loss in the arms, legs and face, or seemingly related metabolic abnormalities such as increases in cholesterol and triglycerides, and in blood glucose. People with any or all of these got classified as having lipodystrophy. The lack of an agreed-upon definition has led to estimates of lipodystrophy ranging from 10% to 80% of patients on ART.
Cardiac Risk
The increase in abdominal fat caused concern because of its known link to a higher risk of cardiac disease. Soon a major international study, the Data Collection on Adverse Events of Anti-HIV Drugs or D.A.D study, was launched that follows over 20,000 patients enrolled in cohorts in Europe, Australia and North America. The main goal of this study was to determine if there was a major problem looming. Were rates of heart attack and stroke going to increase rapidly? Would they offset the obvious benefits of antiretroviral therapy? The results from the D:A:D study require some explanation. The study found that longer exposure to ART was linked to a significantly increased risk of cardiac events, at the rate of about 16% increase in cardiac event rate per year of exposure. However, this has to be evaluated in the context of the actual rate of heart problems. The 345 heart attacks recorded in the study come out to 3.6 events per 1,000 patient-years. If the rate continues to climb at 16% per year, it would double in about 5 years, but still be extremely low at 7 events per 1,000 patient years. Clearly, the benefits of therapy far outweigh the risk of a heart attack.
Another area of research focused on thickening of the arteries or carotid intima media thickness. Initial studies showed that people taking ART had a very high rate of increase in arterial wall thickening. However, further studies have not confirmed this finding. More recently, researchers have broadened their focus on cardiac risk and fat accumulation to include insulin resistance, a condition where the movement of glucose (sugar) from the blood into the muscles becomes less efficient. This increases blood glucose levels and contributes to obesity and diabetes, as well as to cardiac risk. Decreased insulin sensitivity is a known effect of some protease inhibitors. In fact the protease inhibitors are most closely linked to increases in blood lipids, especially the older drugs. Newer introductions such as atazanavir and fosamprenavir seem to be more lipid-friendly. But non-nukes also can cause increases in blood lipids, particularly efavirenz. Nevirapine seems to have a better overall impact, and can increase good (HDL) cholesterol.
Overall, it appears that the ”traditional“ risk factors for heart disease are the most important ones for people with HIV to focus on: smoking, diet and exercise.
Fat Redistribution?
Body shape changes are often referred to as fat redistribution. This has created the erroneous impression that body fat actually migrates from areas of loss –arms, legs and face – to areas of gain, such as the abdomen. There is no research to support that this actually happens. In fact, the Fat Redistribution and Metabolism (FRAM) study, found clear evidence that fat loss and fat gain in people with HIV are two entirely separate syndromes. In a controversial finding, FRAM suggested that while fat loss is a distinctive finding in people with HIV, fat gain is actually no more common than in a normal aging population.
Some researchers consider that the body shape changes we see may actually be a kind of ”rebound“ towards – or beyond – normal as the metabolism recovers from the assault of HIV. In fact, most people starting ART experience an increase in body weight. This might explain the FRAM findings of fat gain being no more than in healthy normal people, although it is complicated to separate out the initial effects of ART and the ongoing side effects of various medications.
Fat Wasting (lipoatrophy)
People with HIV experience fat wasting in the arms, legs and face. Veins become more visible. Fat loss in the face is a highly visible symptom. For many people with HIV, facial wasting is a serious sign that they are ill. People with facial wasting often believe that other people can easily tell that they have HIV. However, as with fat gain, it’s important to note that some people who don’t have HIV also display fat wasting in the face as they age. Lipoatrophy is very different from the AIDS wasting syndrome that was fairly common early in the epidemic. AIDS wasting is characterized by a loss of lean body (mainly muscle) mass. Lipoatrophy is virtually all fat loss, with no loss of lean body mass.
Research into lipoatrophy found a strong association with damage to the mitochondria, elements of the cells that produce energy. It was also quickly associated with use of the drug d4T (stavudine, Zerit).
What Causes Body Shape Changes?
There was an early trend to blame HIV related body shape changes on medication side effects. It now seems clear that these changes are due to a variety of factors, including age, sex, race, family history (especially of metabolic disorders), weight and weight change, diet, and exercise. The lowest (nadir) CD4 count has also been linked to body shape changes. As noted above, at least some of the symptoms we see may also be due to a normalization of metabolism following initiation of ART.
Although there has not been much research that focused on differences between men and women, an early finding was that women are more likely to complain of fat gain (and to experience it in the breast/chest area) while men are more likely to complain of fat loss. This may, at least in part, be due to normal differences in body composition and fat content between men and women.
What Can We Do About Body Shape Changes?
The most direct approach to dealing with fat accumulation is liposuction. It works fairly well for buffalo humps although the humps may recur in up to 50% of cases. Some women have had breast reduction procedures. However, in the US it can be very difficult to convince an insurance company that these procedures are not simply cosmetic. Some impairment of normal body function must be argued. Some people have successfully argued that buffalo humps have interfered with sleep or breathing, normal range of motion, or cause serious headaches.
Liposuction is not appropriate for visceral (abdominal) fat accumulation. This fat is typically not located just below the skin. Rather, it surrounds the internal organs. Any procedure to try to remove it would be quite dangerous.
Fat wasting is the only aspect of body shape changes with an FDA-approved treatment: Sculptra® in the US and New Fill® in Europe. This is injected into the face (or buttocks) to replace lost fat. There are several other facial fillers not specifically approved for HIVassociated wasting, including Bio-Alcamid, collagen injections, Fascian, Alloderm, silicone injections, polymethyl methacrylate (PMMA), and polyacrylamide gel. These products vary in their safety and durability.
The only approach to dealing with peripheral fat wasting has been to switch medications. There have been several studies, mostly switching away from thymidine analogs (d4T in particular). Results have been modest. Although there have been statistically significant increases in limb fat following these switches, the results have often not been noticeable to doctor or patient. Also, they seem to occur very slowly following a switch in therapy.
Metabolic Syndrome
In America, there are twin epidemics of obesity and diabetes. These underscore the importance of early intervention to avoid problems rather than waiting to deal with disease later on. Metabolic syndrome is a warning sign of impending diabetes. Metabolic syndrome is characterized by abdominal fat, weight gain and difficulty losing weight, high blood pressure (which can be an effect of HIV medications), high ”bad“ (LDL) cholesterol and low ”good“ (HDL) cholesterol, high triglycerides, and insulin resistance.
Diet and exercise changes have shown their value in the general population in heading off the metabolic syndrome. Recommended changes include reduced intake of sugars and refined carbohydrates, increases in high-fiber carbohydrates that have a low glycemic index (are slow to convert to sugar), and switching ”bad“ fats for ”good“ fats like olive oil. Unfortunately, these recommended changes, plus increased physical activity, have shown only limited results in people with HIV. In some cases they may find it difficult to be motivated to make major lifestyle changes while also dealing with HIV, its medications and their side effects. In addition,drug side effects may work against these changes.
Various interventions have been tried for specific metabolic abnormalities. For example, statin drugshave been used to reduce LDL cholesterol, althoughinteractions with protease inhibitors must be carefully reviewed. It should be noted that although statins have resulted in reductions in cholesterol levels, they have not normally reached the target levels of the US National Cholesterol Education Program (NCEP). Niacin, especially in an extended release formulation, can help normalize cholesterol and triglyceride levels. However, it can cause liver damage and increase blood glucose levels. Fish oil supplements can help lower high triglycerides. Changes in diet and physical activity can help deal with glucose intolerance. However, the overall best advice at present seems to be to avoid the problems of lipodystrophy if at all possible. This entails avoidance of stavudine among the nukes, careful assessment of overall cardiac risks for all patients, and response to those risks as for any other patient.
Bob Munk
EATN - European AIDS Treatment News, Volume 15, I – Spring 2006
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