Project Inform - September, 1998

Some researchers report observations of lipodystrophy in the pre-protease era, when people were treated with two-drug nucleoside analogue combinations. Further, there is controversy over the incidence of this phenomenon. Some researchers contend that they have rarely, if ever, seen lipodystrophy among their patients while others report they see it frequently. Notably, an Australian group reports an incidence rate of almost 65%, although their figures are based on self-reporting by the patients. The cause of lipodystrophy is still unknown. Information on treating lipodystrophy is sorely lacking and as yet, there isn't a standardized definition for the condition.

The most commonly accepted descriptions of lipodystrophy may include:

• wasting in face and limbs (a decrease in the fat amount in the face, arms and/or legs),
• buffalo hump, a protruding pad of fat accumulated at base of the neck or top of the back, or
• protease paunch, a pad of fat that develops behind the stomach muscles (sometimes referred to as central or truncal obesity)

From the limited information currently available it appears that people experiencing lipodystrophy are not commonly experiencing decreases or increases in their overall body weight. Individual and anecdotal reports from some patients and physicians, however, claim overall weight loss. For the most part, the distribution of weight is changing—perhaps moving away from arms and legs and into the gut area. In effect, it appears to be a change in the way and places the body stores fat. The difference between this phenomenon and normal changes in body fat distribution is that lipodystrophy results in the fat being found under the abdominal muscles and not directly under the skin where fat usually builds up. Additionally, this fatty buildup is solid and can't be pinched like a beer belly. Furthermore, both women and men have reported increased breast size in addition to the other changes in body composition.

Other side effects, which may be associated with lipodystrophy or independently associated with protease inhibitor therapy, are metabolic changes. These include elevated triglyceride and cholesterol levels (increases in LDL [bad cholesterol] and decreases in HDL [good cholesterol]), onset of diabetes or insulin resistance, and elevated blood pressure. One recent study indicated that the risk of elevated triglyceride levels was nearly 20 times greater in patients using ritonavir, compared to some other protease inhibitors. High triglcyeride levels might be predictive of an increased risk of pancreatitis, while excessive cholesterol levels might be associated with greater risk of heart disease. Other less common, non-metabolic side effects include increased bleeding in people with hemophilia, loss of body hair and ingrown toe nails. These changes usually occur despite effective control of HIV replication, a more robust immune system and otherwise generally improved health.

There are several theories on the cause of lipodystrophy and the metabolic changes. The Australian group has proposed that the protease inhibitors may bind to a human protein, a "lipid binding" protein, which is structurally similar to the HIV protease enzyme. The role of this protein is to gather up and destroy lipids (fatty substances). They speculate that because the protease inhibitors may be partially blocking the function of this protein, they may change the lipid concentrations in blood as well as the death of certain fatty cells resulting in an accumulation of fat under the abdominal muscle. Furthermore, this protein transports essential materials to the same liver enzyme (known as cytochrome P450 3A4) that is used by the protease inhibitors to be broken down. Since the protease inhibitors block this liver enzyme, it may further worsen the situation. This theory may partially explain why some people developed lipodystrophy before the advent of protease inhibitors as there are other drugs which potently block this liver enzyme, including the antifungal drug ketoconazole (Nizoral^®).

One potential effect of these metabolic changes is heart disease. One recent report showed three cases of narrowing of the coronary arteries, which prevents an adequate supply of blood to the heart and can result in damage to the heart muscle. All three cases involved men 40 years of age or younger and who were being treated with a protease inhibitor containing regimen. Two men subsequently had heart attacks.

Several studies presented at the International AIDS conference in Geneva showed that there were differences in metabolic changes and lipodystrophy between people receiving protease inhibitors, those non-nucleoside reverse transcriptase inhibitors (NNRTIs) or no anti-HIV therapies. However, people in these studies were not matched for viral loads (HIV RNA levels) and the groups receiving protease inhibitors had much lower HIV levels. Since one of the major theory attributes lipodystrophy to high levels of HIV suppression, it may be unfair to compare the outcomes of these studies.

Another study showed that people receiving the dual protease combination ritonavir (Norvir^®) and saquinavir (Invirase^® or Fortovase^®) were significantly more likely to have high cholesterol levels that warrants starting cholesterol-lowering therapy compared to people receiving a single protease inhibitor.

An important finding from a small study shows that men and women equally were likely to develop truncal obesity and that this type of change in body composition is not only observed among people receiving protease inhibitors and/or anti-HIV therapy.

A study looking specifically at body shape changes in women taking protease inhibitors showed that of the women (16%) who noticed body shape changes, most reported increases in breast size, increase in abdominal size and peripheral (arm and leg) wasting. For more information on these and other relevant studies on side effects and body composition changes, please call the Project Inform National HIV/AIDS Treatment Hotline and ask for the Drug Side Effects Chart.

There is still no strategy proven effective to combat metabolic changes and lipodystrophy. There have been mixed reports of using anti-lipidemic medications such as clofibrate (Atromid^®) and gemfibrozil (Lopid^®) to lower triglyceride levels. Similarly there have been mixed results with using the `statin' inhibitors such as cerivastatin (Baycol<sup>®</sup>), fluvastatin (Lescol<sup>®</sup>), atorvastatin (Lipitor<sup>®</sup>), lovastatin (Mevacor<sup>®</sup>), pravastatin (Pravachol<sup>®</sup>) and simvastatin (Zocor<sup>®</sup>). People who are considering starting a `statin' inhibitor who are using a protease inhibitor should discuss potential interactions between these two classes of drugs with their healthcare provider and pharmacist. These drugs are both processed through the same liver enzyme and there is a strong potential for interaction. There have been some anecdotal reports of success using human growth hormone to reduce the buffalo hump and the fatty deposit around the abdomen. However, these have involved a very small number of people and larger studies are needed to determine whether this is a useful therapeutic approach. In some severe cases of buffalo hump, people have had liposuction to remove the excess fatty buildup. This is usually only considered when the fatty buildup causes pain or hinders mobility. It is not yet clear whether liposuction results in a permanent solution or whether the hump will simple reoccur over time. In any case, patients should be advised that lipsosuction can sometimes have serious complications, and few if any practitioners have much experience using it for this purpose.

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The original of this article can be found at http://www.projinf.org/pub/25/sideeffects.html