Treatment of Body Shape Changes
Ten years ago, shortly after the approval of protease inhibitors, clinicians began reporting changes in the body shape of people with HIV. The first reports of what came to be known as lipodystrophy noted fat loss in the face, arms, legs, and buttocks, along with fat gain in the abdomen and sometimes in the breasts and back of the neck ("buffalo hump"). The loss of fat (lipoatrophy) was specifically fat beneath the skin, known as subcutaneous fat. In contrast, the gain of fat in the abdomen tended to be fat around the internal organs, known as visceral fat. People also frequently had high triglycerides and cholesterol levels and sometimes high blood sugar or diabetes. These problems raised concern about the long-term risk of heart disease in people with lipodystrophy.
Fast-forwarding ten years, we still do not clearly understand the underlying causes of these changes in fat distribution. But careful studies comparing people living with HIV to people without HIV have changed how we think about lipodystrophy. In these studies of both men and women, those with HIV were found to have less subcutaneous fat in their limbs than those without HIV but no more visceral fat in their abdomens. In fact, HIV-infected people in these studies who had lipoatrophy were not more likely to have increased visceral fat gain than those without lipoatrophy. These results suggest that lipoatrophy is the unique feature seen in people with HIV and is a separate process from fat accumulation. While people living with HIV did not appear to have abnormal accumulation of fat on average in these studies, there does appear to be a subset of people who do have abnormal accumulation of visceral abdominal fat with or without buffalo hump, breast enlargement, and excess fat in the neck and upper chest. The picture remains somewhat confusing, but it is fair to say that the term lipodystrophy, which does not accurately describe the type of change in fat, is falling out of favor in the medical community.
In thinking about possible treatments for these changes in fat distribution, it is best to think about lipoatrophy and fat accumulation as separate processes that might both be occurring within an individual. But first it's worth considering why we might want to treat these changes in fat. Among the obvious reasons are that people with altered fat distribution are usually quite concerned about the change in their appearance, especially those who have lost fat in the face. Their self-esteem may be affected, and they may feel that their HIV status will be obvious to others.
These concerns may cause some people to stop or skip doses of their antiretrovirals or even prevent them from starting HIV therapy when it is needed. People who have lost significant fat from the buttocks may have discomfort when sitting; women with breast enlargement may develop back pain. Others with increased neck fat may have difficulty moving their heads or with posture. In addition, the metabolic problems that often accompany the fat changes have potential to increase the risk of diabetes and heart disease. Treating the fat changes could have favorable effects on these metabolic disturbances and reduce the risk of these complications.
Treatment of Lipoatrophy
A number of studies indicate that use of either Zerit or Retrovir (AZT -- also in Combivir and Trizivir) increases the likelihood of developing lipoatrophy. Other drugs in this class (known affectionately as "nukes") -- Epivir, Ziagen, Viread -- do not appear to be linked to lipoatrophy. It is possible that using a protease inhibitor (PI) with either Zerit or Retrovir speeds up the loss of fat, but this has not been proven conclusively. Although some studies have suggested that PIs may play a role in lipoatrophy, most studies that have looked at switching from a PI to a different type of drug, such as a "non-nuke" like Sustiva or Viramune, have not shown gains of fat.
ACTG 5142, a study presented at the 2007 Conference on Retroviruses and Opportunistic Infections (CROI) reported some surprising results, and questioned the dogma that PIs contribute to lipoatrophy more than non-nukes. One aim of the study was to see if avoiding nukes would lower the chance of developing lipoatrophy. People took Sustiva plus two nukes, or the PI Kaletra plus two nukes, or Sustiva and Kaletra without any nukes. After 96 weeks, 32% of people on Sustiva plus two nukes had significant lipoatrophy, compared to only 17% of those on Kaletra plus two nukes and 9% taking Sustiva and Kaletra alone. But the lipoatrophy was mainly seen in those taking Zerit (42%) or Retrovir (27%) -- there was no significant difference in lipoatrophy between those taking Viread and those not taking any nukes.
While the choice of nuke was important, overall twice as many people taking Sustiva developed lipoatrophy compared to those taking Kaletra, regardless of which nuke they took. But those who took Sustiva and Kaletra without any nukes saw their blood lipids (cholesterol and triglycerides) rise significantly more than those taking nukes.
These results are in contrast to a prior study that found higher rates of lipoatrophy in patients taking the PI Viracept compared to Sustiva. Taken together, these results indicate that it may be the particular combination of drugs that is most important, rather than which class they belong to. The impact of ACTG 5142 on first-line treatment recommendations, if any, remains to be seen -- it will be important to tease out exactly which combinations have the least chance of lipoatrophy without increasing blood lipids. And of course, which regimens work best: 89% of people taking Sustiva had viral loads below 50, compared to 77% of those on Kaletra -- another surprising result.
As a result of some of these observations, researchers have looked at the effects of switching from HIV drugs that are linked to lipoatrophy to other drugs. In most of these studies, people who switched from Zerit or Retrovir to Ziagen or Viread had modest gains in fat in their arms and legs compared to people who stayed on their original therapy. While researchers reported these gains using special scans, patients did not always notice changes in their appearance. Many of the studies lasted a year or less, so it is possible that with more time people who switched from the offending drug will gain enough fat back to make a noticeable difference.
Unfortunately, switching antiretrovirals is not an option for everyone. It is extremely important to consider an individual's HIV treatment history and whether he or she has resistance to certain drugs (or is likely to) before making a switch. Otherwise, there is potential for viral break-through.
Insulin is a hormone made in the pancreas that acts to lower blood sugars, especially after eating. Many people with lipoatrophy have insulin resistance, meaning that their pancreas needs to produce more insulin than normal to keep blood sugar under control.
Glitazone drugs are used to treat diabetes -- they act to control blood sugars by improving the action of insulin in the body. A large Australian study of Avandia in people with HIV did not show any beneficial effect on limb fat. A smaller study that included only people who had both lipoatrophy and insulin resistance, however, did show modest gains in limb fat. A recent study of a similar drug, Actos, also showed modest gains in limb fat compared to placebo. Of note, people who continued to take Zerit did not benefit from Actos. It is still not clear whether Avandia or Actos will have a role in treating lipoatrophy.
Laboratory studies suggest that uridine, a natural nucleoside compound, may protect fat cells from being damaged by Zerit and other nukes. NucleomaxX is a dietary supplement derived from sugar cane that is rich in uridine. The initial results of a small study of NucleomaxX in people taking Zerit or Retrovir showed modest gains of limb fat with the supplement. Based on how uridine is thought to work, this approach may work only in people taking Zerit or Retrovir. A larger study of NucleomaxX is now under way.
Lipoatrophy involving the face can often be helped by injections of substances called "fillers" by dermatologists, plastic surgeons, or other clinicians with appropriate training. These fillers come in two major varieties: temporary and permanent. As the names imply, temporary fillers may require multiple injections at regular intervals, whereas permanent fillers are intended to be a permanent fix. While permanent may sound better, there may be disadvantages to these types of fillers -- fat content in the face may change over time because of continuing fat loss or possible fat gain due to other interventions. This sometimes results in undesirable effects such as sagging of the skin.
A comprehensive review of facial fillers is beyond the scope of this article. Briefly, there are now two temporary fillers that are approved for facial lipoatrophy: Sculptra and Radiesse. There are no studies comparing these two treatments. Cheek implants (hard pieces of silicone or other substances) are another option that has shown good results in people with facial wasting.
Treatment of Fat Accumulation
There have been a few small studies of the effects of aerobic exercise and weight training on fat accumulation in people with HIV. These interventions led to modest decreases in central fat in many participants as well as improvements in metabolic problems such as elevated triglycerides and cholesterol. Persons with fat accumulation should certainly exercise for the overall health benefits if they are able to do so, although this may not necessarily take care of the problem of excess fat.
Early studies suggested that PIs might cause or contribute to fat accumulation. While this is still not clear, a number of studies have looked at switching PIs to other drugs such as Sustiva, Viramune, or Ziagen. In general, people who switched from a PI did not have major changes in central (abdominal) fat compared to those who stayed on PIs. Studies switching from Zerit or Retrovir to other drugs mentioned above, while promising for limb fat, have not had favorable effects on central fat.
Glucophage, another drug used to treat diabetes, has been studied as a potential therapy for fat accumulation, especially in people with insulin resistance. A small study of low-dose Glucophage in people with HIV-associated fat accumulation and insulin resistance showed a slight loss of central fat and a slight overall weight loss. A follow-up study of a higher dose plus a supervised exercise program also showed modest reductions in central fat. A study of Glucophage in people without insulin resistance that was presented at the 2006 CROI, however, showed no beneficial effect. In fact, in this study as well as several others, people receiving Glucophage had some worsening of lipoatrophy. Overall, people with significant lipoatrophy in addition to fat accumulation may want to avoid Glucophage.
Glucophage may be reasonable to try in people with fat accumulation who have diabetes or what is called impaired glucose tolerance. Impaired glucose tolerance refers to having a higher than normal blood sugar at the end of a 2-hour oral glucose tolerance test. While researchers were originally concerned that both Glucophage and nukes can cause lactic acidosis, a severe build-up of acid in the body, this has not been a problem in the small studies in people with HIV to date.
The recombinant human growth hormone Serostim is approved for the treatment of AIDS-related wasting. Researchers have noted that, in addition to gaining weight primarily in the form of lean tissue (including muscle), people taking growth hormone often lose fat. These observations, as well as reports of people who had reductions of buffalo humps while receiving growth hormone, led to several small studies of Serostim in people with HIV-associated fat accumulation.
These studies, including one done at ACRIA in conjunction with Dr. Donald Kotler's research group at St. Luke's-Roosevelt, suggested that Serostim injections can cause selective reductions in visceral fat, sometimes accompanied by mild loss of subcutaneous fat. Follow-up studies comparing growth hormone to placebo have confirmed these findings, and the FDA is currently reviewing their results to determine if Serostim should be approved for the treatment of HIV-associated fat accumulation.
Most studies of growth hormone have used doses that are about ten times more than the body normally produces. At these doses, side effects are quite common but often manageable by reducing the dose. The most common side effects include fluid retention, swelling, and joint and muscle aches. Growth hormone can also cause high blood sugar and diabetes. As a result, the major studies of growth hormone have excluded people who have high fasting blood sugars or impaired glucose tolerance. Also, once Serostim is stopped, some of the fat that was lost tends to come back over the course of months. It is not known whether something can be done to prevent this rebound in fat or if the drug can safely be taken only when fat accumulates.
Since growth hormone can raise blood sugars and also may result in mild loss of subcutaneous fat, there has been interest in seeing if it can safely be combined with a glitazone drug, which might prevent the problem with blood sugars and possibly prevent the loss of subcutaneous fat. ACRIA plans to participate in a study funded by the National Institutes of Health to test this strategy in people with HIV-associated fat accumulation who have evidence of insulin resistance but not frank diabetes.
TH9507 is a synthetic growth hormone releasing factor that, like growth hormone, is given by injection beneath the skin. It causes the pituitary gland in the brain to produce growth hormone. Because it more closely mimics the body's normal production of growth hormone, which may be reduced in people with HIV-associated fat accumulation, it may be an attractive option.
To date, TH9507 has led to an average 15% reduction in visceral fat. It has been generally well tolerated and notably did not lead to blood sugar elevations even in people with impaired glucose tolerance at study entry. ACRIA participated in a recent study of TH9507 and will also be a site for the confirmatory clinical trial required by the FDA.
Leptin is a hormone-like substance produced in fat that acts in the brain to affect appetite and metabolism. A synthetic form of leptin, recombinant human leptin, has been studied in very small numbers of people with HIV-associated lipoatrophy who were found to have low amounts of leptin in their bloodstreams. In one very small study of eight people, twice-daily injections of leptin led to significant reductions in visceral fat and improvements in cholesterol and insulin resistance. The studies to date are very preliminary and hopefully will be followed up with larger studies.
Because the abdominal fat accumulation is visceral fat that is deep inside, around the organs, liposuction is not a safe treatment option. Plastic surgery, including liposuction, can sometimes be done to remove neck fat, such as buffalo humps. While generally safe, buffalo humps often recur over many months. Insurance companies will sometimes pay for removal of neck fat, especially if its presence causes functional problems, such as difficulties with neck movement or sleep apnea (breathing problems during sleep).
It's important to think about lipoatrophy and fat accumulation as separate processes that may exist simultaneously in the same individual. There are several promising approaches that are being studied for each of these conditions, but our best hope is that use of newer HIV therapies will prevent the development of lipoatrophy in particular. The only way for us to better understand and treat these conditions is through further clinical research.
Marshall Glesby is an Associate Professor of Medicine and Public Health at Weill Cornell Medical College, Co-Director of the Cornell HIV Clinical Trials Unit, and Clinical Director of the New York-New Jersey AIDS Education and Training Center.
This article was provided by AIDS Community Research Initiative of America. It is a part of the publication ACRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.