FOR A GREAT SUMMARY ARTICLE ON HIV RELATED LIPOATROPHY, READ THIS LINK:

http://www.aidsmeds.com/lessons/Lipoatrophy1.htm

NATAP - www.natap.org

	Lipodystrophy in HIV Disease People with HIV are living longer lives, but they often face new challenges to their health and self-esteem. Learn about the condition called lipodystrophy. Transcript >>
	Update on Lipodystrophy in HIV People taking HIV medications may experience a shift in the distribution of their body fat. Listen to experts discuss some important preliminary data showing that some features of lipodystrophy may be reversible. Transcript >>
	Dealing with Wasting in HIV Disease Body changes such as loss of lean body mass and body fat can occur in people with HIV. Some of these changes occur because of what is called HIV wasting or cachexia. This is different from body changes with conditions known as lipoatrophy or lipodystrophy. Transcript >>

HIV Metabolic Complications Myths
Some misunderstandings about treatment

by David Alain Wohl, M.D.

Introduction

One of the greatest drags on the success of potent antiretroviral (ARV) therapy has been the fear of metabolic complications associated with these medications. Disfiguring body shape changes including the loss of fat in the face, as well as unhealthy cholesterol and triglyceride levels and pre-diabetes are troublesome counter-balances to the euphoria that arose when these drugs arrived and people stopped dying. Even as ARVs have become more user-friendly—less pills, less frequent dosing, less diarrhea and nausea—the specter of metabolic problems can still overshadow these advances, leading those in need of therapy to hesitate when ARVs are recommended. For those already on treatment, metabolic disorders may prompt a change in therapy or lead to the prescription of even more medication and can raise the volume of the little voice that says it is okay to skip doses.
A major frustration for people living with HIV and their health care providers has been a lack of information regarding the cause of metabolic problems during HIV infection and ways to prevent and treat them. The field of metabolic complications of HIV and its therapies is relatively young and much has been learned during a short period of time but some conclusions have been reached with little supportive data. Below is a list of some of the most common of these metabolic complications myths. Myths that emerged in a data vacuum and that even people in the “HIV-know” often still accept. Fortunately, over the past few years a slew of studies has painted a clearer picture of these changes and together suggest that some of our closely-held beliefs about the risks for metabolic complications have been wrong. Understanding that these assumptions are no longer valid, and why, is essential if people living with this infection and their health care providers are to make informed decisions about their care.

Myth #1: Protease inhibitors are responsible for the increases in belly fat.

Like many myths, this one is based on a truth that has been stretched to extremes. People taking protease inhibitors can see an increase in their belly fat, both the deep down fat that surrounds our internal organs and the surface, pinch-an-inch fat so abundant in our land of amber waves of grain. But protease inhibitors hold no monopoly on an ability to expand trunk fat. Studies of efavirenz (Sustiva) have shown that people taking this non-nucleoside also tend to have increases in belly fat. In fact, increases in waist size have been seen in studies of every HIV regimen in which body shape has been objectively measured. For example, in a federally funded AIDS Clinical Trials Group (ACTG) clinical trial called study A5142 comparing the popular HIV medications lopinavir/ritonavir (Kaletra) and efavirenz, trunk fat was seen to increase in participants regardless of which drug they were assigned. Similarly, a Bristol-Myers Squibb sponsored head-to-head study of efavirenz and another protease inhibitor, atazanavir (Reyataz), in patients who were starting HIV therapy also found that both drugs when combined with zidovudine and lamivudine (Retrovir and Epivir, also Combivir) tended to increase abdominal fat over time. Interestingly, a recent Abbott Laboratories study that looked at using lopinavir/ritonavir by itself (i.e. monotherapy) in patients started on this protease inhibitor and zidovudine/lamivudine found that these patients experienced increases in belly fat to the same extent as a control group of patients who were maintained on zidovudine/lamivuine and efavirenz. Therefore, it looks like both protease inhibitors and, at least, the non-nucleoside efavirenz can lead to gains in belly fat.
A problem for most all of these studies is that they rely on a special type of scan called a DEXA to measure abdominal fat. This scan, commonly used to also measure bone density, cannot tell the difference between the deep and surface fat. So, one therapy could be causing accumulation of the deeper fat while another could be associated with surface fat. CT and MRI scans, however, can differentiate deep and surface fat. Unfortunately, we do not have much data regarding the relative changes in fat in deep and surface fat for most HIV regimens. Clearly, more studies need to be done on other regimens, including those that contain newer drugs, and should use CT scans when possible but one thing is clear: when it comes to increasing belly fat, protease inhibitors are not unique.

Myth #2: People who get bigger bellies on HIV meds typically also lose fat in their arms and legs.

As if a big spare tire was not bad enough, some people taking HIV medications also experience loss of fat of the arms, legs, and face. The image of an apple-shaped body with skinny limbs is a frightening one that further turns many people off to HIV therapy. However, it has become clear that most people on HIV medications do not develop this body shape. In fact, a couple of studies of people starting a variety of HIV regimens have found that for most people limb and belly fat tend to increase or decrease together. That is, if someone experiences a gain in belly fat then they are more likely to also experience a gain rather than a loss in limb fat. In one study, only a quarter of people experienced a loss of arm and leg fat while gaining abdominal fat.
Most studies suggest that overall fat gain is a major problem for HIV-positive people. As in the general population, being overweight and obese is common. In a study of HIV-infected patients receiving care in Philadelphia, rates of being overweight and obesity were more of a problem than weight loss. As people with HIV infection look to decades of living with their infection, the problem of obesity is likely to take its toll since obesity increases the risk of diabetes, heart disease and death.

Myth #3: Loss of limb fat during HIV therapy only occurs when stavudine (d4T) is included in the treatment regimen.

The profound loss of fat within the arms, legs and especially the face among people on HIV medication cocktails that was seen in the mid-1990s was quickly associated with one drug, stavudine (Zerit). The link between such disfigurement and this drug was so obvious that use of stavudine in the U.S. and Europe quickly fell and is now rarely prescribed (unfortunately, stavudine is still commonly used in developing nations as it is easy to make and, thus, cheap).
The drop in stavudine use was followed by a dramatic reduction in new cases of severe fat loss of the face and limbs. However, over time some doctors and their patients noticed a slower but undeniable depletion of fat in these same areas of the body. But, as these changes were slow to develop and DEXA, CT, and MRI scans are not routinely performed in clinics to measure and follow body fat changes, it was unclear whether these changes were real and, if so, what caused them. What was clear was that these people seemed to be losing limb and face fat but had never taken stavudine.
Some answers came from clinical trials that incorporated DEXA scans into their design. One study done several years ago by the ACTG found that people starting HIV therapy who took the protease inhibitor nelfinavir (Viracept) were more likely to lose limb fat—as measured by DEXA scans—than those taking efavirenz, even when the other medication taken was limited to zidovudine/lamivudine (Combivir). This meant that people on zidovudine/lamivudine were experiencing fat loss and that this was accelerated with nelfinavir use. Another study comparing zidovudine/lamivudine with tenofovir/emtricitabine (Truvada) when both were taken with efavirenz found that there was a progressive loss of fat among those assigned to zidovudine/lamivudine while those taking tenofovir/emtricitabine gained limb fat over time.

The ACTG study A5142 looking at people new to HIV medications also performed DEXA scans before HIV medications were initiated and then at regular intervals after starting the drugs. This was a large study of almost 750 people who were assigned to one of three different study treatments: a.) lopinavir/ritonavir plus two nucleosides, or b.) efavirenz plus two nucleosides, or c.) lopinavir/ritonavir plus efavirenz alone without nucleosides. Those taking nucleosides could use only lamivudine plus either stavudine, zidovudine or tenofovir (Viread). The study is very important as efavirenz and lopinavir/ritonavir are two of the most popular medications used to treat HIV infection yet, had never been compared before. The results of this trial have shaken the field of body shape changes during HIV treatment. Those taking stavudine had, as expected, the greatest loss of limb fat and those taking tenofovir had the least. But, zidovudine fell in between. This alone indicated that some people experienced limb fat loss even when not receiving stavudine and that zidovudine was capable of doing this to a greater extent than many had thought. In addition, the study found that no matter what nucleoside was used, efavirenz was more likely to cause significant fat loss compared to lopinavir/ritonavir. That is, efavirenz seemed to add to the fat loss that was associated with the nucleosides. The good news is that few of those on tenofovir lost significant amounts of limb fat at 96 weeks of study, even when on efavirenz, so fear of fat loss should not be a major concern for those who are taking or considering use of tenofovir plus efavirenz (two of the three medications in Atripla).
Taken together, these data indicate that fat loss of the arms and legs is not limited to stavudine and that other drugs can also produce these changes. Zidovudine appears to be worse than tenofovir (or abacavir [Ziagen]), albeit it is not as bad as stavudine. Additionally, efavirenz seems to be able to dial-up the fat loss effect of nucleosides to a greater extent than lopinavir/ritonavir. Unfortunately, there is not much information regarding face fat from any of these studies.

Myth #4: Sit-ups can spot reduce belly fat.

This myth falls into the same category as the belief that going out with wet hair will increase your risk for a death of a cold and that too much time spent self-pleasuring can wreak havoc on your visual acuity. A remarkable number of intelligent men and women arrive at their clinic visits complaining of increases in belly fat, and are frustrated that endless sit-ups have done nothing to reduce their mid-body girth.
Sit-ups, when done properly, can increase strength in the abdominal muscles. This leads to firmer muscles and an increase in core strength but will not melt away fat in that one area. Fat is lost when more energy is expended than taken in. While sit-ups require energy, they do not preferentially draw that energy from the deposit of fat cells found in those love handles. A better approach is to combine sit-ups with aerobic exercises that require heavy breathing and sweating for prolonged periods of time like running, cycling, stair climbing, rope jumping, etc. Small studies have shown decreases in abdominal fat when HIV-positive people followed a program of aerobic exercise and weight lifting several times a week.
Diet can also play a role here and a smart approach would be to limit simple sugars and the highly caloric fats that make up most of the so-called comfort foods of our society. For most people dietary modification need not be very complicated and can be summed up with a recommendation to greatly increase daily intake of fruits and vegetables, the latter preferably raw or lightly steamed. These are foods that are not packed with excess calories, contain cholesterol-lowering fiber and are filling—leaving less room for the fatty, super-size-me foods at the root of many of our health problems.
In addition to eating like a Buddhist monk and joining a gym there are other interventions that have been studied to reduce excess fat. Unfortunately, few have panned out. Growth hormone is an injectable agent that has been found to reduce fat in the belly and buffalo hump and some people have benefited from this therapy. However, this is an expensive drug that is not usually covered by insurance carriers for the treatment of excess fat. Also, at the doses studied for the treatment of excess fat, growth hormone has been plagued by a number of troublesome side effects including worsening glucose levels, muscle and joint aches, and feet swelling. Interestingly, exercise is known to increase the body’s own production of growth hormone.
Testosterone and other androgens (“male hormones”) have also been studied as treatments for fat accumulation in people with HIV infection. These hormones, like growth hormone, can pop fat cells but in another ACTG study were found to preferentially reduce the surface fat and not the deep fat that made for most of the enlargement of the belly. Androgens can also worsen limb and face fat loss. Therefore, although beloved by many, the data suggest that androgens may do little to reduce abdominal girth and can aggravate loss of fat beyond the trunk.
A few drugs used for the treatment of diabetes have also been studied for fat accumulation, including metformin, rosiglitazone, and pioglitazone. Most of the data informing the use of these drugs in people with HIV come from small studies. Suffice to say that their effects, if present at all, seem to be mostly limited to those with diabetes or a pre-diabetes condition. The underwhelming study results and the toxicities of these medications have diminished any enthusiasm for dedicated use of these drugs to treat fat changes in people with HIV infection.

Myth #5: People with HIV infection have higher cholesterol levels than people without HIV.

Take a survey of people living with HIV or even their docs and ask whether HIVers have higher cholesterol levels than those without HIV. Chances are most would respond that those who are HIV-positive would, on average, have higher levels than those who are uninfected. Actually, at least a couple of studies have found that people with HIV infection tend to have lower levels of LDL cholesterol, the “bad” cholesterol that has been strongly linked to heart disease, than people in general; this finding holds even when including those who are on HIV medications.
This does not mean that those with HIV infection have a better lipid profile than uninfected folks. A major problem is that levels of the “good” cholesterol, HDL cholesterol, are also lower in HIV-positive people. HDL cholesterol has been found to offer protection from heart disease and a low level is an independent risk factor for cardiovascular problems. Exercise and modest alcohol (not just red wine) intake can safely raise HDL cholesterol in some people. In addition, a little appreciated fact is that certain HIV medications also raise HDL cholesterol levels. The non-nucleosides efavirenz and nevirapine [Viramune] and the protease inhibitor atazanavir alone or in combination with ritonavir [Norvir] and most all other protease inhibitors that are boosted with ritonavir have all been found to raise HDL cholesterol levels.

Triglyceride levels, though, are a different story. Triglycerides are broken down in the body from fat and can be found floating free in the blood or in a complex with other lipids and proteins in the form of cholesterol. The more triglycerides in the cholesterol complex, the more dangerous it is in terms of cardiovascular risk with LDL cholesterol having more triglycerides than HDL cholesterol. Fasting triglyceride levels are, on average, higher in people with HIV infection and increases further with HIV therapy. While in some people the level of triglycerides can skyrocket to very concerning levels (greater than 500 mg/dL) most people with HIV infection have levels that are high but not alarming. In addition, by itself the level of triglycerides measured in the blood is not considered as nearly big a risk for cardiovascular disease as high LDL or low HDL cholesterol. Most all HIV regimens can raise triglyceride levels. The ritonavir-boosted protease inhibitors are a bit worse in this regard than efavirenz, and most studies suggest that lopinavir/ritonavir and fos-amprenavir/ritonavir (Lexiva/Norvir) may raise triglyceride levels a bit more than other commonly-used boosted protease inhibitors, but the clinical significance of these modest differences is not clear.
Overall, the data suggest that people with HIV may be at greater risk of cardiovascular problems like heart attacks due to their low HDL cholesterol levels and possibly increases in LDL cholesterol and triglyceride levels during HIV therapy. Additionally, there may be other factors such as inflammation caused by the virus that can lead to chemical changes in the body that can prompt clogging of the arteries. However, it is almost certain that smoking adds much more to the risk of cardiovascular disease than these other HIV-related factors and that of all the things a person with HIV infection could do to survive and thrive, beyond taking HIV medications when necessary, the most significant is to stop smoking.

Summary

Clinicians and their patients do not tolerate ambiguity well. Gaps in knowledge of a disease demand to be filled and when the research data come up short it is difficult not to extrapolate. In the 25 years since the AIDS pandemic ignited, much has been learned about HIV and the crowning achievement of the scientists, clinicians, and advocates dedicated to this disease has been the dramatic reversal of the lethality of this disease. However, in HIV, as in medicine in general, it has been difficult to not jump to conclusions when data are conflicting or just plain not in existence.
In the case of metabolic complications of HIV and its treatments, we have learned to learn. New investigations have revealed the accuracy and inaccuracy of previous assumptions and allow us opportunities to better choose among our options. The trick is we have to be willing to let go of our old beliefs and embrace findings that rigorously challenge these concepts. The old mantra that knowledge=power still holds, but we have to accept that better knowledge=even more power.

Dr. Wohl is an Associate Professor of Infectious Diseases and Co-Director of the AIDS Clinical Trials Unit at the University of North Carolina. Metabolic complications associated with HIV infection and the nexus between HIV and incarceration are his major areas of research interest. He can be reached via e-mail at wohl@med.unc.edu.

Lipoatrophy and HIV Medications

In 1999, the HIV drug Zerit was correlated with the development of lipoatrophy related fat loss under the skin.1 Since then, several studies have concluded that Zerit can affect the way our mitochondria (energy factories in our cells) work and multiply. Later studies also linked lipoatrophy to AZT, although at a lower rate than Zerit. Nucleoside reverse transcriptase inhibitors (NRTIs) like Zerit and AZT, keep HIV from altering the genetic material of healthy T-cells, thereby halting the reproduction of new virus cells. Additionally, NRTIs affect the mitochondria in fat cells under the skin, preventing them from multiplying and causing them to die. Also, those who have taken Zerit and Videx (another NRTI) together report more lipoatrophy than those taking Zerit alone. This combination is not recommended by guideline groups. It appears that Zerit and AZT make fat accumulation worse in the presence of protease inhibitors or non-nucleoside analogs (NNRTIs) like Sustiva, leading researchers to suspect that their negative effect may play a combined role. However, Sustiva taken with Viread (Tenofovir) and Epivir (3TC) seems to cause less lipoatrophy. Due to the high risk of developing lipoatrophy and neuropathy, the US Department of Health and Human Services guidelines committee dropped Zerit from the list of recommended drugs for first line therapy for people new to HAART.

Viread (Tenofovir) and Ziagen (Abacavir), two other NRTIs in the same drug class as Zerit and AZT, do not seem to strongly correlate with the development of lipoatrophy. Some people have even reported a slow reversal of the fat loss after switching from Zerit or AZT to either Ziagen or Viread. However, even after a number of years most patients do not experience re-accumulation of fat in their faces after going off AZT or Zerit. It is also important to note that puzzling new data from a recent study by the AIDS Clinical Trials Group2 showed that 20% of subcutaneous fat loss (loss in body fat closer to the skin's surface) occurred in a small percentage of patients starting HAART for the first time with a combination of Sustiva, Viread and Epivir. More studies are needed to determine why lipoatrophy still occurs in some patients in the absence of Zerit or AZT.

The sales of Zerit and AZT in the industrialized world have dropped considerably in the past years due to their effects on lipoatrophy. Unfortunately, these two drugs are among the primary HIV medications used in the developing world, so millions of people in poorer countries will continue to suffer with body changes.

Treatment Options for Lipoatrophy

In recent years many men have relied on an off-label injectable anabolic steroid called nandrolone decanoate (old trade name: Deca Durabolin), to "balance out" their bodies and add muscle to their thin extremities and buttocks affected by lipoatrophy. Even though Watson Laboratories ceased production of nandrolone in March of 2007, it is still available through prescription at compounding pharmacies for a low cost.3

Uridine (Nucleomaxx), a supplement made of sugar cane and available through a German supplier,4 may lessen lipoatrophy in patients taking Zerit, however it may also cause abdominal fat and high triglycerides. These side effects, along with high cost and bad taste, make Uridine an unpopular choice. However, for those who must take Zerit, Uridine may be a viable option to prevent or reverse lipoatrophy. Additionally, for those who are no longer taking Zerit, the diabetes drug Rosiglitazone (Avandia) works well for reversing lipoatrophy. There are side effects however, including weight gain and high triglycerides.

Since 2002 there have been a couple of non-permanent reconstruction procedures available to treat facial lipoatrophy. The face wasting reconstruction option, Sculptra (polylactic acid, old name: NewFill) entails an expensive series of multiple sessions, requiring additional touch ups that can be used to treat those moderately affected by lipoatrophy. Radiesse, another FDA approved option, seems to last a little bit longer but is also costly, requiring 3?5 sessions and yearly touch ups. Some patients treated with face wasting fillers experience side effects such as bruising and treatable granulomas (hardened pimple-like nodules). There are patient assistance programs available for both Sculptra and Radiesse.5

There are no FDA approved permanent solutions for facial lipoatrophy, yet many in the US seek tiny injections of silicone (Silikon 1000) from their doctors. Silikon 1000 can be used legally in an off-label manner for facial lipoatrophy. Silikon 1000 micro-injections can reconstruct patients' faces slowly over five sessions spaced one month apart. There is no patient assistance program for this option and sessions cost anywhere from $600 to $900. Here too, multiple sessions are required. Beware that very few US doctors are well trained in this procedure.

Another permanent product, Polymethylmethacrylate (PMMA), has been used in Brazil for eight years and in Mexico for three with relatively positive results, though more time is needed to determine the long term effects of this procedure. Usually 2?4 sessions are required and no yearly touch ups are needed. Short term, we have seen that PMMA can harden and be lumpy in certain patients, but many people seem pleased with the results. Artefill, a PMMA based product, is FDA approved for cosmetic purposes but not for HIV related lipoatrophy. Artefill is extremely expensive for the amount required to treat lipoatrophy, so some HIV positive people in the US go to Mexico or Brazil for the procedure, where costs can range from $2000 to $6000. PMMA is not removable.

BioAlcamid (poly-alkylamide gel), also permanent, is an injectable filler unavailable in the US (some patients travel to Mexico or Canada for injections). Unfortunately, BioAlcamid forms a "pocket" in the face and buttocks enabling bacteria to penetrate and posing a high risk of infection. As such, extreme caution is warranted before pursuing this option.

It is critical to remember that no long-term data on these experimental facial reconstruction treatments are available, so one must weigh the risks of injecting a foreign substance into one's body. Sadly, many people find that the emotional, psychological and social toll of living with lipoatrophy is so great as to justify these risks.

Understanding Lipohypertrophy

Unlike lipoatrophy, researchers have not been able to attribute lipohypertrophy (fat gain in the belly, back of neck and breasts) to any specific medication or drug class. Protease inhibitors were once thought to be the main culprits. However, researchers have recently discovered that fat gain in the belly may relate to inflammatory responses in the immune system when CD4 cells increase in number. This means that those who start HAART with a lower baseline CD4 count may see greater lipodystrophy. Moreover, recent data shows that patients with a CD4 count of over 250, who start a HAART regime with protease inhibitors boosted with Norvir plus Viread and Epivir, do not experience a gain in visceral fat (fat surrounding the internal organs). It is still too early to tell what happens to those on this particular regimen who start with lower CD4 counts. Some studies have shown that those who begin taking protease inhibitors in combination with Zerit, AZT or Zerit plus Videx seem to have more visceral and hump fat gain than those who start on protease inhibitors with other drugs. It may be that the same drugs that are linked to lipoatrophy may also make fat gain worse, especially in patients who start HAART with fewer CD4 cells.

A common misconception promoted by a few pharmaceutical companies and echoed by some doctors is that HIV medications that do not increase cholesterol, and that triglycerides do not cause fat gain. On the contrary, several studies have shown that people taking lipid friendly drugs like Reyataz with Viread also gain fat in the belly after starting HAART.

Dr. David Nolan, a clinician and researcher at Royal Perth Hospital in Western Australia and an expert on fat metabolism and HIV, was asked about why visceral fat does not get "burned off" by Zerit and AZT like subcutaneous fat does. Dr. Nolan hypothesized that fat cells in the organ cavity may not be as susceptible as subcutaneous fat cells to the mitochondrial toxicity caused by Zerit and AZT.

Fat gain may also be linked to insulin resistance. Insulin resistance can cause glucose intolerance, which has been associated with fat gain, increased triglycerides, and the development of diabetes. Insulin is a hormone produced by the pancreas to control blood sugar-glucose. HIV medications may block or slow down the process by which insulin converts glucose to energy. In laboratory studies, Crixivan and higher doses of Norvir and Zerit have been shown to impair the action of insulin in fat and muscle cells. In this scenario the pancreas will tend to produce more and more insulin to compensate for the decrease in function. High insulin levels may be present for years before type 2 diabetes develops. A glucose tolerance test (GTT) may reveal that problem easily but it is hardly used in clinical practices. Additionally, some people may have a genetic predisposition to insulin resistance. A sedentary lifestyle and a diet rich in sugars and animal fats may also compound this problem. In any case, insulin resistance may just be a part of the mystery of lipohypertrophy. There is no agreement among researchers whether or not monitoring insulin levels in HIV-positive people is justifiable or dependable as a tool to assess insulin resistance and fat gain.

The full body dual x-ray absorptiometry (DEXA) scan is the gold standard test in lipodystrophy. It is a highly valuable test that can provide information about body fat, muscle mass and bone density (low bone density has been associated with HIV in several studies.) Both Medicare and private insurance often cover this inexpensive test. While the scan cannot differentiate between fat accumulated in the belly on under the skin in the abdominal area, it can be useful as a baseline to assess body changes and to justify reimbursable therapies for fat, muscle, and bone mass.

Treatment Interventions for Lipohypertrophy

Some people have switched from protease inhibitors to Viramune or Sustiva to combat visceral fat gain, but this has not been shown to make a difference. It is not yet known what happens to belly fat when a patient switches from Zerit or AZT to Viread or Ziagen while taking protease inhibitors or non-nucleoside analogs like Sustiva or Viramune.
The recombinant human growth hormone Serostim is a daily injectable drug approved by the FDA for HIV associated wasting. At approximately $3000 a month, it is an expensive option for treating lipodystrophy. Serostim works well in lowering abdominal fat but has many side effects including joint pain, water retention, carpal tunnel syndrome, and irreversible diabetes. These side effects and the lack of proven long-term health benefits are why the FDA has not approved Serostim for the treatment of HIV related fat accumulation. Tesamorelin-TH9507, made by Theratecnologies, is a daily injectable growth hormone precursor that is in its last stages of FDA approval. Tesamorelin appears to have fewer side effects than Serostim, but may take a longer time to show benefits in patients. Disappointingly, fat gain returns after discontinuation of both Serostim and Tesamorelin.

Leptin, a hormone that produced by fat cells, is another new contender in the search to decrease visceral fat. Researchers have found that leptin levels in the blood are proportional to an individual's level of body fat. Leptin works in the part of the brain that controls appetite and other basic functions. High levels of leptin generally suppress the appetite and stimulate the burning of fat. Leptin does not appear to have a negative impact on glucose tolerance.

Nowadays, physicians are likely to prescribe testosterone gels, injections, and subcutaneous pellets. A testosterone gel applied to the belly can reduce the waist size in HIV-positive men. This decrease is usually as a result of a reduction in subcutaneous fat, not in visceral fat. In contrast, a small pilot study of Oxandrin (an oral anabolic steroid) has yielded encouraging results in decreasing visceral fat. Increases in the low density lipoprotein (the "bad" cholesterol) and decreases in the high density lipoprotein (the "good" cholesterol) correspond to a small decrease in subcutaneous fat. There are no data yet on a connection with the popular anabolic steroid, nandrolone decanoate, and visceral fat reductions.

Some individuals who have been looking elsewhere for fat burners have fallen prey to advertisements pushing growth hormone supplements or fat burners. These products do little but increase blood pressure and anxiety and are generally considered scams.

Metformin (trade name, Glucophage), is a generic diabetes drug that has been shown to improve glucose tolerance and lower visceral fat. Its effects may be enhanced by exercise. Metformin improves insulin sensitivity, triglycerides and fatty liver but can also cause diarrhea and weight loss. There have also been reports of low blood sugar and dizzy spells associated with this drug.

In addition to the aforementioned treatments many patients explore liposuction. Ultrasound-assisted liposuction can be used to successfully remove fat accumulated in buffalo humps and around the neck.

Some patients complain about the enlargement of salivary glands on each side of the face commonly referred to as the "chipmunk look." While only a few radiologists know how to use it for this purpose, low dose electron radiation has worked very effectively in treating the enlargement of salivary parotid glands. It is unknown whether the "chipmunk look" is related to lipodystrophy or caused by immune reconstitution.

Another under explored intervention is diet and exercise. A study at Tufts University revealed a trend towards less lipodystrophy in those who had higher consumption of soluble fiber (fruits and vegetables) and who exercised. However more research is needed with the use of diets lower in simple carbohydrates. These diets have been shown to improve insulin resistance and visceral fat in non-HIV studies. One observational cohort showed that people with HIV eat more saturated fats. A small pilot on a combination of cardiovascular and resistance exercise showed decreased triglycerides and visceral fat. However, adherence to exercise remains a challenge to many people, and exercise research in HIV generally remains in its infancy.

Increased Lipids: Low Density Lipoprotein (LDL) and Triglycerides

The most common lipid abnormalities in HIV are high triglycerides and LDL, "bad" cholesterol, and low High Density Lipoprotein (HDL), "good" cholesterol. Before HIV-positive people start HIV medication for the first time, both their high and low density lipoprotein may be lower than normal. However, after HIV drugs are started, low and high density lipoproteins and triglycerides increase in some people. Some studies have shown that LDL increases to "pre-HIV" levels while HDL never returns to normal levels. Increased triglycerides is the most strongly associated lipid change caused by HIV medications such as protease inhibitors, Zerit, AZT, or Sustiva. Among protease inhibitors, Reyataz seems to correlate with the lowest lipid increases.
Many people want to start supplements before they start lipid lowering medications. The only supplements with solid emerging data on lipids are omega-3 fatty acids (fish oils), and niacin (also available as Niaspan). Fish oils can decrease triglycerides but some patients' stomachs cannot tolerate them. Niacin is better than any lipid lowering drug in increasing the "good" cholesterol (HDL). It can cause flushing of the face and a hot sensation for a half an hour at a time, but most people get used to it. Non-flush versions are available but their effectiveness is unknown.

It is not clear if Raltegravir (Isentress, the first integrase inhibitor) or Maraviroc (Celsentry -- a CCR5 entry inhibitor) have any effect on body composition. So far, they appear to be lipid friendly when taken with Viread and Epivir. Fuzeon (an injectable entry inhibitor) also seems to be lipid friendly, but it is usually used with boosted protease inhibitors that can cause increases in lipids. It seems that there may be genetic factors that make some patients more prone to increased low density lipoprotein (bad) cholesterol and triglycerides.

Lipid lowering agents like statins (Lipitor, etc) or fibrates (Tricor, etc.) can work wonders in many, but even with their use, some patients never reach "normal" lipid levels. A combination of niacin, lower sugar and animal fat intake, exercise, fish oil supplements or an increase in fatty cold water fish consumption (salmon) and soluble fiber (fruits, vegetables, oats) are sometimes used to treat lipids. Some individuals have tried combining statins and fibrates, but this combo can lead to an increase in muscle related disorders in some patients.

Conclusion
We have learned a lot during the past 10 years about body changes associated with HIV, but many more questions remain. It is the hope that those new to HAART therapy will not have to suffer the devastating drug side effects that their predecessors have had to contend with in the past 20 years. As patients, it is our responsibility to stay educated and learn from others about emerging options that may make it possible one day to live fully without HIV related body changes and other side effects.

For more information visit: www.facialwasting.org or to subscribe to the largest internet HIV health discussion group send a blank email to pozhealth-subscribe@yahoogroups.com

Nelson Vergel is director of Program for Wellness Restoration.

A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy. Saint-Marc T, Partisani M, Poizot-Martin I, Bruno F, Rouviere O, Lang JM, Gastaut JA, Touraine JL. AIDS. 1999 Sep 10;13(13):1659-67.

Metabolic Outcomes of ACTG 5142: A Prospective, Randomized, Phase III Trial of NRTI-, PI-, and NNRTI-sparing Regimens for Initial Treatment of HIV-1 Infection. Richard H. Haubrich, S Riddler, G DiRienzo et al.

More information is available at www.medibolics.com.

More information is available at www.nucleomaxx.com.

More information is available at www.facialwasting.org.

Conference Report - Management of HIV-Associated
Lipoatrophy: Emerging Data in Clinical Context
Andrew Carr, MBBS, MD, FRACP, FRCPA
Of all the toxicities linked to antiretroviral therapy (ART), HIV lipodystrophy has
been perhaps the most important from the perspective of patients. Lipodystrophy is
a combination of peripheral, subcutaneous lipoatrophy with a lesser degree of
relative fat accumulation in the abdomen, breasts, and upper trunk. This condition
is cosmetically distressing and stigmatizing for many persons, and it is also
associated with reduced adherence to ART.[1] Furthermore, it is associated with lipid
and glycemic abnormalities, such as higher levels of total cholesterol and triglycerides,
lower levels of high-density lipoprotein cholesterol, and insulin resistance and
type 2 diabetes mellitus. These abnormalities are strongly linked to an increased risk
for myocardial infarction and other atherosclerotic disease.[2]

This report focuses on clinical management issues associated with lipoatrophy.
Although published data are cited throughout, particular attention is given to emerging
data from the 8th International Workshop on Adverse Drug Reactions and Lipodystrophy
in HIV, which was held September 24-26, 2006, in San Francisco, California. This
relatively small conference has become one of the most important annual meetings
devoted to original research on morphologic and metabolic disorders associated with
HIV and its treatment.

Treatment Issues
Since its identification, there has been substantial progress in describing the phenotype,
risk factors, and natural history of lipodystrophy. There are now 3 major treatment-related
issues specific to HIV lipoatrophy:
• how to prevent lipoatrophy;
•how to predict lipoatrophy in those at risk; and
•what to do about established lipoatrophy.

How to Prevent Lipoatrophy
Prospective, randomized trials have found that antiretroviral treatment initiation with
regimens containing abacavir + lamivudine (ABC/3TC) or tenofovir + emtricitabine (TDF/FTC)
results in less lipoatrophy than regimens that contain stavudine (d4T) or zidovudine (AZT),
particularly regimens containing d4T + didanosine (ddI).[3,4] Whether use of ABC/3TC or
TDF/FTC causes any lipoatrophy at all is unknown and requires formal comparison with
nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimens; the body-composition
data from ACTG 5142 will be reported in early 2007 and should shed some light on this
question. The contribution of protease inhibitors (PIs) to lipoatrophy is unclear. Nelfinavir was
associated with more lipoatrophy than efavirenz, each in combination with dual NRTIs, in the
ACTG 384 body-composition substudy.[5] In contrast, the fat-friendly effects of ABC-3TC do
not seem to be diminished by coadministration of a PI, and 3 PI switch studies found no
improvement in lipoatrophy (although reductions in visceral adiposity were observed in one
study).[6-8] Again, ACTG 5142 should further help our understanding of the relative contribution
of certain antiretrovirals or antiretroviral drug classes to this adverse effect.

How to Predict Lipoatrophy
Risk factors for lipoatrophy have mostly been identified from cross-sectional studies.[1]
Factors identified consistently include:
• NRTI use (both type and duration);
•PI use and duration;
•prior AIDS diagnosis; and
•low CD4+ cell count.
(It is important to note that both prior AIDS diagnosis and low CD4+ cell count are perhaps
surrogate markers for wasting and less baseline limb fat.) In prospective studies, use of d4T,
AZT, or indinavir (IDV) was most commonly associated with lipoatrophy risk. Unfortunately,
most studies have not defined lipoatrophy objectively with body composition techniques such
as dual-energy x-ray absorptiometry (DEXA), and no study has looked at whether any biomarker
might predict objectively defined lipoatrophy.

At this year's Lipodystrophy Workshop, Calmy and colleagues[9] evaluated lipoatrophy objectively
in 54 patients (53 men) who initiated various first-line ART regimens including 2 NRTIs (mostly d4T
and ddI) and who had serial body-composition studies over 2 years. The investigators evaluated
whether metabolic markers could predict long-term lipoatrophy development; they looked for
associations between plasma markers and subsequent development of lipoatrophy (change in limb
fat mass between weeks 24 and 96 by DEXA) and lipohypertrophy (increase in visceral adipose
tissue [VAT] by abdominal CT through week 48). Using stored samples from 2 prospective studies
that were collected at baseline and at weeks 12, 24, and 48, this group performed serial measurements
of plasma adipokines, cytokines, lipids, and glycemic and acid-base parameters related to fat mass
and lipodystrophy.

There were 2 findings of note from this study:

• Higher baseline body mass index and limb fat predicted greater loss of limb fat at week 96. This finding
contrasts with cross-sectional studies that found lower limb fat to be a risk factor for lipoatrophy (and
therefore, by inference, that starting earlier with higher limb fat somehow protects against lipoatrophy).
The implication of these data is that lipoatrophy occurs in all patients, but that fat loss is greater in those
with more fat at baseline.

• Increases in leptin* levels at week 24 correlated with greater fat loss at week 96, which suggests that
measuring leptin levels early in treatment might identify those patients at greatest risk for lipoatrophy.

[*Editor's note: Leptin is a peptide hormone transmitter produced only by fat cells and acts in muscle
to promote insulin sensitivity and in the central nervous system to control appetite and, in turn, body
fat mass.]

What to Do About Established Lipoatrophy

Antiretroviral drug switches. The main approach to improving or reducing the progression of
lipoatrophy is to switch NRTIs, generally from d4T or AZT, to either ABC or TDF.[10,11] Switching
antiretroviral drugs is most commonly done for one drug in a regimen for patients with complete viral
suppression. ABC and TDF appear to allow for similar improvements in lipoatrophy, although the
improvements observed at 1-2 years after these switches still are inadequate, with the mean gain in
limb fat of approximately 400 g per year. [Editor's note: See Dr. Graeme Moyle's report in this program
for a graphic representation of these study data.] To put this in perspective, this improvement is fairly
modest if one considers that men with severe lipoatrophy have limb fat masses of about 3 kg and that
normal limb fat mass for men is about 8 kg. (Unfortunately, there are minimal data for HIV-infected
women or children.) These data suggest, therefore, that resolution of lipoatrophy might take 5 or even
10 years with this strategy alone.

ART cessation. The cessation of all ART has not been well studied, although this is no longer a
strategy for most patients because of negative results that have been recently observed in a large
trial evaluating CD4-guided strategic treatment interruptions. Kim and coworkers[12] evaluated adipose
gene expression in subcutaneous abdominal fat following a 6-month interruption of all ART in 40 adults
with suppressed HIV replication, including 29 of whom had available paired data:

• NRTIs+ PI (n = 10); NRTIs without PI (n = 19)

• d4T (n = 5) or AZT (n = 12); other NRTIs (n = 12)

The investigators evaluated adipose morphology, mitochondrial DNA, and adipose tissue gene expression.
At 6 months, no subjective, clinical change in lipoatrophy was observed, although objective body-composition
parameters were not measured. At 6 months, adipose fibrosis did not change, but there was less adipose
inflammation such as fewer lipogranulomas and macrophages, fewer TNF-alpha or IL-6-staining cells, and
less CD68 gene expression (CD68 is a macrophage-specific gene). There were also improvements in the
expression of some mitochondrial genes (COX4 mRNA, and increased mtDNA and COX2/COX4 ratio).

Unfortunately, this study was not randomized, and patients were receiving very heterogenous ART regimens,
so the effects of specific antiretroviral drugs and drug classes were not clear. The major weakness, however,
was the lack of body-composition data. Without these data, it is not clear whether any of the tissue changes
might be associated with improvements in lipoatrophy, and it is even less clear whether there is an association
with body-composition changes that are large enough to be objectively measured and clinically useful.

Poly-L-lactic acid (PLA). Injections of PLA are now licensed in the United States and Europe for cosmetic
management of facial lipoatrophy. The drug appears to be safe,[13,14] but its efficacy is less clear, as no
randomized trial of PLA with objective endpoints has been performed to determine how much PLA is required
and for how long PLA maintains its benefit. The results of a randomized trial with objective endpoint data should
be available in early 2007. PLA probably won't help the problem if the underlying cause is not removed, as
lipoatrophy will continue to worsen in those taking drugs such as AZT and d4T, so PLA injections probably
cannot take the place of d4T or AZT cessation. [Editor's note: See Dr. Graeme Moyle's report on
surgical/cosmetic interventions for HIV lipoatrophy within this program.]

Thiazolidinediones. The first drugs explored for the treatment of HIV lipoatrophy were the thiazolidinediones,
which are drugs that can make fat cells grow and that act by improving tissue insulin sensitivity. The best studied
thiazolidinedione in patients with HIV is rosiglitazone.[15-17] Four randomized, placebo-controlled trials of
rosiglitazone found improvements in insulin resistance but relatively unexpected deteriorations in total cholesterol
and triglycerides.[1] Three of the studies found no significant improvement in limb fat mass, although one found a
benefit at 6 months in those not receiving d4T or AZT that was lost by 12 months.  Pioglitazone was subsequently
reported as an effective treatment for HIV lipoatrophy in a randomized, placebo-controlled study conducted by the
ANRS in France and first presented at the 13th Conference on Retroviruses and Opportunistic Infections (CROI) in
2006.[18] The mean improvement in limb fat mass over 48 weeks was about 0.3 kg, with the benefit largely
confined to those persons not receiving d4T. At this year's Lipodystrophy Workshop, Maachi and associates[19]
presented additional metabolic data from this study. No significant changes in plasma levels of leptin, resistin*,
and soluble TNF receptor I (sTNFRI)* were observed at week 48 in the pioglitazone group as compared with the
placebo group. In contrast, plasma adiponectin* levels increased by about 150% with pioglitazone relative to placebo.
Of interest, this effect was observed both in patients not receiving and receiving d4T. The change of limb fat mass
between baseline and week 48 correlated with both plasma pioglitazone concentration (r = 0.476, P < .001, n = 51).
Given the availability of a higher dose of pioglitazone (45 mg tablet given once daily) than was used in this study (30
mg once daily), perhaps a higher dose warrants study and might be more effective. Overall, the results of this study
support the use of pioglitazone in the treatment of peripheral lipoatrophy in HIV-infected adults, but the relatively
modest effect observed in fat gain means that pioglitazone is no substitute for cessation of d4T or AZT.

[*Editor's note:
• Resistin causes cells to be less sensitive to insulin.
• TNF-alpha also downregulates insulin sensitivity (it antagonizes leptin and adiponectin), and the level of its
soluble receptor in plasma is linked to insulin sensitivity.
• Adiponectin is another adipocyte cytokine that, with leptin, promotes insulin sensitivity in muscle and liver.
Low levels of adiponectin are associated with accelerated cardiovascular disease.]

Uridine. In-vitro studies pioneered by Ulrich Walker[20] have found that the mitochondrial toxicity of AZT and d4T
could be prevented and reversed in fat cell culture by uridine, even in the presence of ongoing AZT or d4T exposure.
Uridine is a substance required for the synthesis of pyrimidines, which are building blocks of DNA and RNA. A small,
randomized, placebo-controlled study in 20 adults receiving AZT or d4T showed that limb fat increased significantly
by a mean 700 g over only 12 weeks.[21] Provided that these data can be replicated in larger and longer studies
currently in progress, the main question relating to uridine will be whether it can still exert benefit in those who are no
longer receiving d4T or AZT. This is very important given that d4T is barely used in developed countries and AZT use
is declining, particularly in light of the Gilead 934 study showing superiority of TDF over 48 weeks on an
intention-to-treat basis.[22] Unfortunately, uridine is not licensed in North America, but can be imported at
considerable expense (about US$300 per month). This considerable expense precludes use of the drug in
the developing world.

Pravastatin. One unexpected positive therapeutic outcome for lipoatrophy has come in the form of pravastatin, a
drug widely used for the treatment of high cholesterol levels for the primary and secondary prevention of
ardiovascular disease. In a randomized, placebo-controlled, 12-week trial, pravastatin did not have much effect on
cholesterol levels in men receiving ART (mostly including a ritonavir-boosted PI without d4T or AZT).[23] As with
uridine, however, limb fat mass increased significantly (by about 500 g), again a far greater increase than seen with
NRTI switch strategies over 48 weeks. Although the mechanism of action is unknown, we know that the drug is safe
and, in particular, has few HIV drug interactions (with the exception of darunavir). What we really need to know is
whether this statin or other statins will show benefits over longer periods.

Other interventions under study. No new treatment intervention for lipoatrophy was reported at this year's
Workshop. However, Boccara and colleagues[24] reported on the effects of irbesartan in an in-vitro model of
ART-induced lipoatrophy (3T3-F442A murine adipocytes). Irbesartan is an antihypertensive angiotensin II type 1
receptor blocker that recently was shown to activate peroxisome proliferator-activated receptor gamma
(PPAR-gamma) in adipocytes and to reduce the incidence of diabetes mellitus in hypertensive patients. PPAR-
gamma is a key adipocyte differentiating and maturation factor, and its expression is reduced in HIV lipoatrophy.
The investigators found that irbesartan suppressed the adverse effects of IDV and of ritonavir boosted-atazanavir
(ATV/r) on lipogenesis and lipid accumulation, but not of ritonavir boosted-lopinavir (LPV/r). Irbesartan also prevented
IDV and ATV/r-induced insulin resistance (normalizing insulin-induced tyrosine phosphorylation [ie, activation] of the
insulin receptor and insulin-mediated glucose transport), as well as the expression of 2 major proteins, CCAAT-
enhancer-binding protein (C/EBP)-alpha and PPAR-gamma, which are involved in adipogenesis and the insulin
response.

These data suggest that irbesartan may prevent or even treat the lipoatrophy and insulin resistance induced by
some HIV PIs. The relevance of the dose used, however, was not clear; a pilot study in humans seems justified.
The effects of NRTIs were not evaluated, which is unfortunate as NRTIs clearly have more of a lipoatrophic effect
than PIs and because NRTIs also inhibit PPAR-gamma expression. The effects of other angiotensin II type 1
receptor blockers also deserve investigation.

Another drug that has been of some interest in the management of HIV lipoatrophy is leptin, an adipocytokine
(a key adipocyte-produced hormone). Leptin levels may be low in HIV lipodystrophy, but because it is a fat cell
product rather than a fat cell stimulant whose plasma levels are low in HIV lipodystrophy, it seems unlikely that
leptin would improve lipoatrophy. However, it might well improve the downstream insulin resistance and dyslipidemia
associated with the leptin deficiency that is seen in congenital and other acquired lipodystrophies.

Khatami and colleagues[25] performed an open-label study to determine whether leptin could produce similar
metabolic benefits in HIV-infected patients with lipoatrophy. Eight men with HIV lipoatrophy, low plasma leptin levels
(< 3 ng/mL), dyslipidemia, and insulin resistance received leptin for 6 months (0.01 mg/kg twice daily for 3 months,
followed by 0.03 mg/kg twice daily for 3 months). Hepatic insulin sensitivity improved (reduce fasting insulin of about
20%) as did endogenous glucose production, glycogenolysis, and gluconeogenesis. However, there was no
significant change in peripheral glucose uptake in fat or muscle, nor in limb fat mass, although lipolysis (breakdown)
of fat declined somewhat, which suggests an effect of leptin on adipose tissue. Visceral fat decreased by about 30%
(183 to 129 cm2; P = .001); this improvement without a decline in limb fat suggests that leptin may have a depot-
specific effect in adipose tissue.

Supported by an independent educational grant from Gilead.
Click here for artical, with references in PDF format.


Expert Column -Cosmetic Interventions for HIV-Associated Lipoatrophy
Graeme J. Moyle, MD, MBBS
Introduction
The development of facial changes associated with generalized lipoatrophy during antiretroviral therapy is perceived
by patients as a highly stigmatizing manifestation of their HIV infection. These facial changes may lead to the
unmasking of HIV status to colleagues, affect social and personal relationships, and suggest that an individual who
is otherwise healthy is unwell.[1] It has been reported not only to affect mood and quality of life, but also to reduce
adherence to antiretroviral medication. Lipoatrophy in other body areas may also lead to changes in personal
confidence and habits.

Lipoatrophy: Prevention Is the Best Policy
Lipoatrophy appears to be a preventable toxicity that is largely restricted to individuals who have received prolonged
therapy with thymidine analogue nucleoside reverse transcriptase inhibitors (NRTIs). Use of thymidine analogs in
combination with (certain) protease inhibitors (PIs) may accelerate the rate of fat loss. Prospective data from studies
in which persons have begun regimens with thymidine-sparing NRTI backbones (Table 1) --such as abacavir-
lamivudine, tenofovir-lamivudine, tenofovir-emtricitabine, and didanosine-emtricitabine --have reported few instances of
lipoatrophy, even over prolonged follow-up. These data offer hope that in the future, the incidence of lipoatrophy
observed in clinical practice will decline relative to the prevalence currently observed among HIV-infected persons who
have a treatment history that includes a regimen containing a thymidine analogue NRTI plus a PI.

Table 1. Nucleoside Reverse Transcriptase Inhibitors (NRTIs) for the Treatment of HIV Infection

*This coformulated tablet also contains efavirenz, an NNRTI, in addition
to 2 NRTIs.

Pharmacologic strategies to manage lipoatrophy. The only approach to management of lipoatrophy that has
demonstrated benefit in 2 or more controlled clinical trials is switching therapy away from a thymidine analogue NRTI.
Alternatives to thymidine analogue NRTIs include abacavir, tenofovir, or NRTI-sparing antiretroviral regimens. While
recovery of peripheral fat mass can be detected by dual-energy x-ray absorptiometry (DEXA) scanning, these studies
did not report impressive clinical recovery or subjective improvements in fat gain The rate of limb fat recovery appears
similar with each of these approaches, with comparative data from the RAVE switch study[2] observing similar
recovery with switch from a thymidine analog to abacavir or tenofovir DF (Figures 1 and 2). Of note, some individuals
experience little of no limb fat recovery over 48 weeks, suggesting that for some individuals lipoatrophy may not be
reversible (Figure 3). Laser facial imaging, reported from a subset of patients in the RAVE study, indicated that cheek
volumes also increased over 48 weeks (Figure 4).[3] Changes in cheek volume were noted to correlate with limb fat
recovery.



Figure 1. Design of the RAVE switch study.[2]


Figure 2. Mean change in limb fat at week 24 and week 48 in the RAVE

study.[2] (DEXA arm fat and total leg fat in grams: intent-to-treat, missing = failure analysis).
Published with permission from Lippincott Williams & Wilkins (http://lww.com)

Figure 3. Mean changes in limb fat after switch (± interquartile range) at week 48 according to
baseline antiretroviral drugs and limb fat in the RAVE study.[2] Published with permission from
Lippincott Williams & Wilkins (http://lww.com)



Figure 4. Median change in volume after 48 weeks in the RAVE facial
substudy measured by laser facial imaging.[3]

For those with established facial lipoatrophy who have modified therapy and are waiting for clinically evident fat
recovery to occur, the process is at best slow and has an uncertain outcome. Prolonged treatment interruption
(longer than 6 months) does not yield clinically evident improvements in lipoatrophy[4] and may risk disease
progression events.

More recently a large, randomized, placebo-controlled study of pioglitazone 30 mg once daily has indicated a similar
rate of limb fat recovery over 48 weeks to that observed in switch studies. However, the benefit was restricted to
persons not receiving stavudine.[5] Other agents under investigation as lipoatrophy treatments include uridine and
pravastatin.

Facial Fillers for Lipoatrophy
The slowness, and in some cases apparent absence, of clinical recovery from lipoatrophy underscores the need for
cosmetic surgical interventions for people with facial lipoatrophy. The agents used in these surgical approaches are
known as implants or "facial fillers" (Tables 2 and 3). Evaluation of the potential of using fillers to enhance the
buttocks or manage discomfort in feet has been very limited and largely unsuccessful.

Facial fillers may be natural (such as transferred fat) or synthetic, and they may be biodegradable (temporary) or
nonbiodegradable (permanent). Of note, some "permanent" fillers may be wholly or partially removable. Fillers are
necessary because of the loss of tissue mass from the lipoatrophy process. "Face lifts" cannot make up for lost
tissue but merely tighten some of the skin that has become looser following the loss of tissue mass.

[Editor's note: Because many clinicians who manage patients with HIV may be unfamiliar with many of these fillers,
trade names and manufacturers are noted in Tables 2 and 3. In some cases in the text, trade names are used. This
is because some fillers that are the same or similar in type/composition share a generic name, yet are sold under
different trade names. Some of the studies that the author discusses were conducted with a particular branded
product.]

Biodegradable Agents
Biodegradable agents (Table 2) are attractive in a situation in which there is the potential for recovery or partial
recovery of the underlying condition, as has been suggested by the RAVE facial scan substudy.[3] The duration of
benefit varies among agents, and there may be a need for "refilling" at a later time. Many of these agents are
generally best suited to filling mild-to-moderate areas of tissue loss.

Table 2. Management of HIV-Associated Facial Lipoatrophy: Biodegradable Agents

Poly-L-lactic acid (PLA). PLA is an injectable bioabsorbable material for use in HIV-associated lipoatrophy. While
all agents or procedures discussed in this brief review have been used off-label for management of lipoatrophy, PLA is
the only agent that has a specific FDA indication for this condition.

The substance stimulates dermal fibroblasts to produce collagen, leading to thicker but natural-feeling skin. It is
given as multiple subcutaneous or dermal injections. The injected area requires frequent massage in the days
following injection to avoid nodule formation. Results in the temporal area are generally less satisfactory than those
in the buccal area. It is immunologically inert, with inflammatory responses being very infrequent. PLA gradually
reabsorbs over a 2-to 3-year period, with benefits in HIV lipoatrophy reported over this period. Treatment is generally
given in 3-5 sessions separated by 2-6 weeks, leading to a gradual change in facial appearance.

PLA has been evaluated in HIV lipoatrophy using a range of endpoints, both objective and subjective. At the Chelsea
& Westminster Hospital in London, we randomized 30 persons with facial lipoatrophy to immediate and delayed
treatment with PLA. The immediate-treatment group received 3 bilateral injections of 4-5 mL administered 2 weeks
apart (weeks 0, 2, and 4) in the deep dermis overlying the buccal fat pad; the delaye