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 >>


For Immediate release Contact: CMS Office of Media Relations March 23, 2010 (202) 690-6145

The Centers for Medicare & Medicaid Services (CMS) today announced its decision to cover facial injections for Medicare beneficiaries who experience symptoms of depression due to the stigmatizing appearance of severely hollowed cheeks resulting from the drug treatment for Human Immunodeficiency Virus (HIV). Today’s decision is effective immediately.

Facial lipodystrophy (LDS) is a localized loss of fat from the face, causing an excessively thin appearance in the cheeks. In some cases, facial LDS may be a side effect of certain kinds of medications (antiretroviral therapies) that individuals receive as part of an HIV infection treatment regimen.
The facial LDS can leave people living with HIV looking gaunt and seriously ill, which may stigmatize them as part of their HIV-infection status. Individuals who take these medications and experience facial LDS side effects may suffer psychological effects related to a negative self-image. These effects may lead people living with HIV to discontinue their antiretroviral therapies. The new decision allows for treatment of individuals who experience symptoms of depression due to the appearance changes from facial LDS.

The injections included in today’s coverage decision are “fillers” that have been approved by the U.S. Food & Drug Administration (FDA) to be injected under the skin in the face to help fill out its appearance specifically for treatment of facial LDS. Data show that these injections can improve patient self-image, relieve symptoms of depression, and may lead to improved compliance with anti-HIV treatment.

“Today’s decision marks an important milestone in Medicare’s coverage for HIV-infection therapies,” said Barry M. Straube, M.D., CMS Chief Medical Officer and Director of the Agency’s Office of Clinical Standards & Quality. “Helping people living with HIV improve their self-image and comply with anti-HIV treatment can lead to better quality of life and, ultimately, improve the quality of care that beneficiaries receive.”

The final decision is posted on the CMS Web site at


HIV Metabolic Complications Myths
Some misunderstandings about treatment

by David Alain Wohl, M.D.


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.


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

HIV Lipodystrophy: Where Are We After Ten Years?

By Nelson Verge

Note: The following article expresses the opinions and learned lessons of the writer, not of GMHC, Treatment Issues, or their staff. It is not intended as medical advice and should not be taken as such.

Ten years have passed since the first report of lipodystrophy at an HIV conference. The excitement and hope for a longer life that accompanied the arrival of Highly Active Anti-Retroviral Therapy (HAART) has been tempered by accounts of humps, bellies, and facial wasting. A decade on, many unanswered questions and misconceptions about HIV associated lipodystrophy persist with only a limited number of treatment options available. Frustrated and tired of waiting for answers from the medical community, many people living with lipodystrophy have turned to the internet for advice, treatment and support in hopes of reversing some of the devastating effects of this stigmatizing syndrome.

Lipodystrophy is a condition of abnormal fat redistribution that can lead to either lipohypertrophy (fat accumulation in specific areas of the body such as the neck, belly, upper torso, and breasts) or lipoatrophy (fat loss in the face, buttocks, arms and legs). An online survey of 695 people (predominantly white men, over the age of 40, living with HIV for over 10 years and with exposure to HAART for at least that long) found that 20% had considered suicide because of body shape changes associated with lipodystrophy. Almost 90% of respondents believed that their HIV medications caused lipodystrophy, and 20% had stopped taking their HIV medications altogether due to this concern. Further, over 60% of respondents reported being rejected by potential sexual partners because of the syndrome. A similar number of respondents indicated that they had stopped looking into the mirror because of crippling body dissatisfaction. Nearly all of the respondents attempted to curb the effects of lipodystrophy with diet and exercise or by using costly facial reconstruction procedures, supplements and hormones -- treatments not typically covered by insurance companies or drug assistance programs.

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.

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: or to subscribe to the largest internet HIV health discussion group send a blank email to

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

More information is available at

More information is available at

Conference Report - Management of HIV-Associated
Lipoatrophy: Emerging Data in Clinical Context

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

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
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

Thymidine analogue
NRTIs (single agents)
Coformulated, fixed-dose NRTIs (containing a thymidine analogue NRTI) Non-thymidine analogue NRTIs (single agents) Coformulated, fixed-dose NRTIs (not containing a thymidine analogue NRTI)
lamivudine +
abacavir +
lamivudine +
tenofovir DF
abacavir +
tenofovir DF +
efavirenz* +
emtricitabine +
tenofovir DF

*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

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 (

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 (

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

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

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

Product/Technique Trade Name
Poly-L-lactic acid
Sculptra (Dermik)
NewFill (Ashford Aesthetics)
FDA-approved for HIV-associated
lipoatrophy (Sculptra)
Data from randomized studies
Requires multiple injections/sessions
over many weeks
Benefits observed up to 3 years
Injections in buccal area show better results relative to temporal area
Nodule formation possible
Hyaluronic acid
Restylane (Q Med)
Perlane (Q Med)
Hylaform (Inamed)
Less injection volume/more sustained
results relative to bovine collagen in
filling nasolabial folds
Benefits observed up to 6 months in
HIV lipoatrophy
Fat transfer
Patients with lipoatrophy often have
inadequate fat to harvest and transfer
Transferred fat can be rapidly lost
Fat transferred from fat accumulation
sites (eg, dorsocervical humps) may
behave abnormally at the graft site
"Lumpy" results have been observed
Radiesse (Bioform)
In a prospective trial in HIV lipoatrophy, all patients showed
improvements through 1 year, and
most through 1.5 years.
Mild adverse effects

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 delayed-treatment group received
injections at weeks 12, 14, and 16. Treatment was well tolerated, with adverse events limited to transient bruising in
1 patient and localized cellulitis in another. Assessments were made by facial ultrasound, visual analogue scales
(VAS), and the Hospital and Anxiety Depression Scale at weeks 0, 12, and 24. At week 12, patients in the
immediate-treatment group had significantly better VAS scores, lower anxiety scores, and trends toward lower
depression scores compared with the control patients in the delayed-treatment arm. Benefits persisted through week
24, with the delayed-treatment group having similar benefits measured at that time. Many patients did not achieve
complete resolution of their facial lipoatrophy.[6]

Longer term follow-up for a minimum of 18 months post treatment indicated that improvements in VAS scores for
facial appearance (P < .05) and trends to lower anxiety (P < .001) relative to baseline were sustained. One case of
injection-site induration (after 24 weeks) and 9 cases of injection-site nodules were noted.[7]

Various strategies have been suggested to decrease the risks and avoid the potential complications associated with
PLA.[8] These include:

higher volume dilution (8-12 mL/vial);
fewer vials used at each session;
injections placed in the subcutaneous plane without any going into the dermis;
adequate time between injection sessions (at least 6 weeks); and
postinjection patient massage.

Other larger but nonrandomized cohort studies have reported similar benefits to those of the Chelsea and
Westminster study sustained through week 96, with a low frequency of adverse events.[9-13]

Hyaluronic acid. Hyaluronic acid is a polysaccharide component of mammalian soft tissue. These versions of
hyaluronic acid are FDA-approved for the treatment of wrinkles. Comparative trial data in general cosmetic surgery
settings using treatment-blinded assessors have indicated that hyaluronic acid requires less injection volume and
shows more sustained results relative to bovine collagen in filling nasolabial folds; therefore, hyaluronic acid may be
better for filling deeper cutaneous defects.[14]

Hyaluronic acid has been used successfully to treat HIV facial lipoatrophy.[15] In general cosmetic practice, the
benefits are expected to last about 6-12 months. In a series of 5 individuals with HIV lipoatrophy given 5-6 mL into
the malar area, a good cosmetic result with sustained benefits through 6 months has been reported. [16]

Fat transfer. Fat transfer is an expensive and problematic approach as an intervention for HIV lipoatrophy. Many
patients do not have fat elsewhere to transfer to facial areas. To further complicate matters, if the pathologic process
that led to the fat loss is ongoing, the transferred fat can be rapidly lost. In contrast, fat transferred from fat
accumulation sites such as dorsocervical humps may behave abnormally at the graft site and lead to disfiguring
facial hypertrophy.[17] Cosmetically, lumpiness may be a problem.

The most commonly used technique for fat transfer is known as Coleman's method. Use of this technique has been
reported in several cohorts of patients with HIV-related facial lipoatrophy. Durability for 6 months, and possibly up to
24 months, may be achieved.[18,19] In a series of 33 patients, independent assessors felt that only 12 (36%) of
individuals had improved, although self-assessment by the participants showed that 14 (43%) were very satisfied and
17 (50%) were somewhat satisfied, with 27 (81%) reporting an improved quality of life.[20]

Calcium hydroxylapatite. Preparations based on calcium hydroxylapatite (CaHA) microspheres suspended in
carboxymethylcellulose gel were first FDA-approved for vocal cord injections, for use in a range of orthopaedic
surgery approaches, and in radiology (CaHA is radiopaque). However, this product has also been widely used for
treatment of wrinkles and lip augmentation. CaHA is bioabsorbable over several years. Reported problems include
hardening and overcollagenization requiring steroid injections.

In an 18-month, prospective, open-label, multicenter clinical trial of CaHA for facial lipoatrophy, all patients (N = 100)
reported improvement in appearance at every time point through 12 months, and improvements were observed in 91%
at 18 months. Skin thickness measurements at 12 months remained significantly better than those at baseline.
Adverse events reported through 12 months were generally mild (bruising, edema, erythema, pain, and pruritus).[21]

Nonbiodegradable Agents

Silicone. Several forms of liquid injectable silicone are FDA-approved for ophthalmic, but not cosmetic, uses. The
American Society for Aesthetic Plastic Surgery has warned against the use of liquid injectable silicone for cosmetic
purposes pending further investigation. Unfortunately, silicone oil injections can cause granulomas and long-term
inflammatory changes and can migrate.

Several series and anecdotes report the use of liquid silicone for HIV-related lipoatrophy.[22-25] The use of highly
purified 1000-cSt silicone oil injected by microdroplet serial puncture technique has been evaluated for the treatment
of HIV-associated lipoatrophy. Data were reported on 77 individuals who were assessed as having achieved a
complete correction. The volume of silicone, number of treatments, and time required to reach a complete correction
were directly related to initial severity of lipoatrophy (P < .0001). Supple, even facial contours were restored, with all
patients tolerating treatments well. No adverse events were noted.[23] Although these data are encouraging, given
the potential risks of silicone relative to alternative agents, and its permanence after injection, it is not a preferred
treatment option.

Expanded polytetrafluoroethylene (ePTFE). These FDA-approved implants are more typically used for correction
of craniofacial abnormalities (such as in nasal reconstruction) and after severe trauma, but can also be used for
localized tissue augmentation. They can be inserted using a small incision while the patient is under local
anesthesia. However, there are potential problems with lumpiness and physical obviousness of the implant. In
general, adverse events, including movement, infection, swelling, induration, and uncommonly extrusion (emergence
of implant through the skin), have been reported with cosmetic use of ePTFE implants.[26]

A case series on the use of ePTFE implants with or without polyacrylamide gel has recently been published.[27] A
total of 90 consecutive persons with HIV-associated facial lipoatrophy were treated using implants alone in 11 cases,
injections alone in 68 cases, and both implants and injections in 11 cases. Mean follow-up was 17 months for
injections and 29 for implants. Adverse events included 3 cases of chronic inflammation and some lumpiness, which
usually resolved over few months.

Polymethylmethacrylate. Polymethylmethacrylate (PMMA) in smooth microspheres suspended in bovine collagen
is FDA-approved, but has no specific indication for HIV lipoatrophy. The bovine collagen in the implant is reabsorbed
over time, but the presence of the PMMA microspheres generates new collagen production in that same site. It has
been used in Europe for close to a decade and is available in other countries. A large series in Brazil described its
use in HIV associated lipoatrophy, although clear systematic collection of safety data was lacking. Side effects
reported included postinjection swelling and pain. Ultrasound data indicated an increase of dermal thickness
sustained up to 5 years.[28]

Polyacrylamide and polyalkylimide gels. These agents are not FDA-approved but have been used in clinics in
Europe (where they are approved) and Latin America. Some systematically collected data have been reported with
Bioalcamid and Eutrophill. The different products have similar characteristics. They are relatively viscous and are
injected subcutaneously. Following injection, the substances encapsulate, enabling at least partial removal (such as
with a large-bore needle) at a later time. This characteristic makes them of interest for a condition that may partially
resolve over time.

In a case series of 73 HIV-infected patients treated with Bioalcamid with up to 3 years of follow-up, "excellent"
aesthetic results were reported with no episodes of implant dislocation, migration, granuloma, or allergic reaction
recorded.[29] In a case series of 11 subjects with severe facial lipodystrophy, bilateral injections of 15 and 30 mL
of a Bioalcamid gel into the buccal, malar, and temporal areas of the face were used.[30] The authors reported that
all 11 subjects received an immediately acceptable aesthetic effect. Injections were generally well tolerated, with
only 3 adverse events (swelling and bruising) recorded. Subjects, assessed at 3 and 18 months after treatment,
continued to show improvement.

A series of 249 individuals treated with Eutrophill with up to 5-year follow-up reported good aesthetic outcomes, with
13 individuals having persistent asymptomatic papules at the injection sites and 2 patients reporting transient
inflammatory events.[31] Recently, cases of infection, phlebitis, and ulceration around the sites of Bioalcamid
injections have been reported in persons with HIV, and use of Bioalcamid in the buttock area has been associated
with implant migration.[32]

Table 3. Management of HIV-Associated Facial Lipoatrophy: Nonbiodegradable Agents

Agent Trade Name
Silicone oil   Favorable cosmetic data in
Granulomas, long-term
inflammatory changes,
migration are possible
American Society for Aesthetic
Plastic Surgery has warned
against liquid injectable silicone
for cosmetic purposes
(ePTFE) implants
Gore-Tex subcutaneous
augmentation material
(S.A.M.) (W. L. Gore &
Advanta (Atrium
More extensive experience
in Europe and elsewhere
Incomplete safety data in
Polyacrylamide and
polyalkylimide gels
Aquamid (Contura)
Bioalcamid (Polymekon)
Eutrophill (Mediform)
Not FDA-approved for HIV
lipoatrophy, but approved
in Europe and elsewhere for
general cosmetic use
Case series data in lipoatrophy:
favorable aesthetic results,
minimal adverse effects
Some reports of infection,
phlebitis, and ulceration around
the sites of polyalkylimide implants
Buccal, malar, and temporal
restoration possible; implant
migration observed following
implantation in buttocks
Partial removal possible

Comparative Data

Establishing endpoints is challenging for comparative studies of facial fillers that work by different mechanisms.
Assessment by photographs may not lead to reproducible results and is operator-dependent, and the continuation
of specific antiretroviral therapies may also influence outcomes. Fortunately, some attempts at comparison have been
made, and funding for additional comparative data is being sought.

A 24-week comparative study of autologous fat transfer, PLA, and polyacrylamide hydrogel as fillers for HIV-related
facial lipoatrophy has been reported.[33] The study was semi-randomized; individuals with enough residual
subcutaneous fat in the abdomen or in the dorsocervical region were offered fat transfer, while other individuals were
randomly assigned to 2 different surgical teams who administered either treatment with PLA or polyacrylamide
hydrogel injections every 4 weeks. The primary endpoint used was the dermal plus subcutaneous thickness
measurement of Bichat's (malar) fat pad, as well as body image evaluations, facial aesthetic satisfaction by VAS,
and aesthetic pre-and postpicture comparisons by independent reviewers.

Twenty-four individuals received fat transfer, 20 PLA, and 15 polyacrylamide hydrogel. The PLA and polyacrylamide
hydrogel groups received a mean of 5 and 6 injection sessions, respectively. The mean change in dermal and
subcutaneous thickness was 3.3 ± 4.1 mm for fat transfer, 3.5 ± 4.0 mm for PLA, and 2.1 ± 3.0 mm polyacrylamide
hydrogel (P = .687) (Table 4). Serious adverse events occurred in 4 individuals in the fat transfer group, notably fat
hypertrophy at the donor site.

Table 4. Results: Comparative Study of Fillers for HIV-Related Facial Lipoatrophy

Intervention Mean Change in Dermal/Subcutaneous Thickness, mm*
Autologous fat transfer 3.3 (± 4.1)
PLA 3.5 (± 4.0)
Polyacrylamide hydrogel 2.1 (± 3.0)

*P = .687

Comparative safety data are derived largely from the general cosmetic surgery literature.[34] In an international
collaborative effort evaluating nodule formation and inflammatory events with synthetic injectable fillers, biopsies were
contributed by various plastic surgeons from Europe and Australia. (It is important to note that these data were not
derived from persons treated for HIV-associated lipoatrophy.) Data reported were based on:

5 biopsies from unreactive tissue obtained at different times after injection
of polyacrylamide hydrogel (Aquamid);

28 biopsies from 20 individuals with intermediate or late inflammatory nodules
after injection of polyacrylamide hydrogel (Artecoll);

2 cases of nodules following hyaluronic acid-polyhydroxyethylmethacrylate/ethyl
methacrylate gel (Dermalive; Derma-Tech);

6 cases of nodules after PLA use (NewFill); and

  a review of the literature on adverse reactions after injection with permanent fillers

Clinically unreactive tissues after injection with polyacrylamide hydrogel showed modest or no host reaction.
Inflammatory nodules showed an increased foreign-body reaction and a bacterial infection after injection with
polyacrylamide hydrogel, and a combination of moderate foreign-body reaction, fibrosis, and in some cases also
bacterial infection after injection with Dermalive and PLA (NewFill). Literature review suggested that inflammatory
nodules are rare beyond 1 year after injection with polyacrylamide hydrogel, but may occur up to 6 years after
injection of combination gels (Artecoll), and up to 28 years after injection of silicone gel. The authors concluded that
inflammatory nodules are likely to be caused by a low-grade infection maintained within a biofilm surrounding
silicone gel and the combination gels.


Case series and some limited controlled data indicate that treatment of HIV-associated facial lipoatrophy with facial
fillers leads to good cosmetic results, improved psychological well-being, social functioning, and quality of life.
Biodegradable fillers such as PLA are the most well-studied agents, but have the drawbacks of requiring multiple
treatment sessions and the eventual need for "top-ups" in many patients. Permanent fillers are also of interest,
particularly those agents that have the potential for partial removal. Fillers present a range of problems, most
commonly postinjection pain and discomfort, and less commonly local infection and scarring. Comparative and
systematically performed studies are needed to establish the best fillers for HIV-associated lipoatrophy.

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

Treatment for lipoatrophy: facing the real costs; should be reimbursed


AIDS:Volume 21(13)20 August 2007p 1819-1820

Margolis, David M
From the University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Patients unlucky enough to suffer chronic illnesses such as HIV infection, leprosy, tuberculosis, or mental illness bear an additional burden: stigma. Indeed, the fear of being identified as HIV infected or receiving antiretroviral therapy may lead a significant number of patients to avoid appropriate medical care. Nowhere is this a more obvious problem than in individuals suffering HIV-associated facial lipoatrophy.

The causes of facial lipoatrophy and of HIV-associated metabolic abnormalities in general, are yet to be fully defined [1]. These conditions appear to be multifactorial, owing in some part to metabolic changes induced by HIV infection, but in large part to exposure to antiretrovirals. Specific nucleoside reverse transcriptase inhibitors play a prominent role, and studies have shown modest improvements in lipoatrophy following the use of alternative antiretroviral regimens [2,3]. Given the improved recognition of these disorders, and the appreciation of antiretroviral regimens that are less likely to result in lipoatrophy, one would hope to soon see a decline in the prevalence of this troubling disorder.

Despite the efforts of many, medical approaches to treat lipoatrophy once it is apparent have met with only modest success [4]. In some studies, but not all, thiazolidinediones have been shown to result in modest recovery in fat volume [5]. The use of human growth hormone can improve visceral adiposity, but may worsen facial or peripheral lipoatrophy [6].

Given the lack of effective medical therapy, patients have turned to surgical alternatives. Facial fillers are currently the only therapy that can result in prompt improvement of lipoatrophy. A wide variety of biodegradable implants using autologous fat transfer, collagen or cadaveric dermis implants, poly-L-lactic acid, hyaluronic acid, or calcium hydroxylapatite, have been used. Permanent materials such as silicone, expanded polytetrafluoroethylene, polymethyl-methacrylate implants or polyacrylamide and polyalkylimide gels. Few well performed, fully powered studies have been done; one comparative study has recently been reported [7].

In this issue Loutfy and co-workers in Toronto compare the effects observed in a group of patients with facial lipoatrophy treated immediately with polyalkylimide gel, an injectable product, or followed for 12 weeks prior to treatment [8]. Polyalkylimide gel is licensed in Canada and Europe, and has been used there to treat HIV-associated facial lipoatrophy. Loutfy and colleagues treated 31 patients, almost all male. Most of the patients had mild to moderately severe lipoatrophy, with few graded subjectively as having the most severe disfigurement. Both patients and physicians found that the immediately treated group improved significantly, graded with a subjective scale. Obviously, all the patients and probably most clinicians who were grading the response knew which patients had received injections at week 12. The improvement persisted to 48 weeks, however, and by 48 weeks the delayed treatment group had achieved equal, sustained improvement. In this study group of modest size, they note the absence of complications, particularly site reactions and nodules noted with other products; however, unsurprisingly, others have recently reported postoperative complications after the use of polyalkylimide gel [9].

As in few other studies of facial fillers, Loufty and coworkers studied the effect of their intervention on mental health and quality-of-life scores. While the immediately treated group had improvements in these scores compared to the untreated group at week 12, when re-evaluated at week 48 after both groups had been treated the picture changed somewhat. Although mental health and quality-of-life scores had improved somewhat from baseline to week 48 for both groups, the extent of these changes was less uniform. Only improvements in depression and anxiety scores achieved statistical significance.

The authors estimate that a course of therapy for an average patient, taking into account the need for repeat injections in some, might be between US$ 1750-4375 for a 10-15 ml course (US$ 175 per ml), whereas in Europe the cost varies in the range EU 200-425 per ml depending upon nation and treatment centre. They conclude that polyalkylimide gel might be a preferred intervention due to its permanence, extractability in cases of adverse outcome, and the ability to administer high volumes of product, and sadly, the authors must conclude that treatment with polyalkylimide gel may be restricted due to its cost.

While this might be the case in the current healthcare environment, perhaps we should ask the questions that take the next logical step. While facial lipoatrophy is not fatal, it is devastating for the lives of many. Do we know what its attendant costs really are? Can facial fillers obviate some of the need for antidepressants or counseling? Are they more cost-effective? In the developed world, a treatment course of polyalkylimide gel appears to be a fraction of the annual cost of antiretroviral therapy. What is the real cost of untreated facial lipoatrophy? Should not healthcare systems provide treatment for a condition that appears to be, for the lack of a kinder word, iatrogenic ('used to describe a symptom or illness brought on unintentionally by something that a doctor does or says')?

AIDS:Volume 21(9)31 May 2007p 1147-1155
“Immediate versus delayed polyalkylimide gel injections to correct facial lipoatrophy in HIV-positive patients”

Loutfy, Mona Ra,b; Raboud, Janet Mb,c; Antoniou, Tonya,d; Kovacs, Colina,b; Shen, Sandyc; Halpenny, Robertaa; Ellenor, Darlenea; Ezekiel, Daviaa; Zhao, Alicea; Beninger, Francise
From the aMaple Leaf Medical Clinic, Canada
bDepartment of Medicine, University of Toronto
cDivision of Infectious Diseases, University Health Network, Canada
dDepartment of Family and Community Medicine, St Michael's Hospital, Canada
eDivision of Plastic Surgery, University of Toronto, Toronto, Ontario, Canada.

Objective: To evaluate the safety and efficacy of polyalkylimide gel (PAIG) in the treatment of HIV-associated facial lipoatrophy.

Design: A randomized, open-label, single-centre study.

Methods: HIV-positive individuals with facial lipoatrophy (based on physician assessment) were randomly assigned to immediate (weeks 0 and 6) or delayed (weeks 12 and 18) PAIG injections administered into the subcutaneous plane. Outcome measures included a change in facial lipoatrophy severity scores (five-point scale), adverse events, photographic assessment, and changes in quality of life (QoL), depression and anxiety using validated surveys.

Results: Thirty-one patients (median age 48 years, 97% male) were enrolled and completed 48 weeks of follow-up. Overall, the median volume of product injected bilaterally was 16.0 ml. Adverse events, including swelling, redness, bruising and pain, were mild, and resolved after a median of 3 days. There were no cases of necrosis, nodules or infection. Compared with patients randomly assigned to delayed treatment, patients in the immediate therapy group had significantly lower physician-rated facial lipoatrophy scores (0 versus 2; P < 0.0001), improved QoL (P = 0.01), and lower anxiety (P = 0.02) at week 12. At week 48, median physician and patient facial lipoatrophy scores were 0 and 1, respectively, for the entire cohort, and were not significantly different between the groups. Significant improvements in patient anxiety (P = 0.001) and depression (P = 0.01) were observed from baseline to week 48.

Conclusion: Treatment with PAIG was effective and safe and led to improvements in facial lipoatrophy grading, QoL, anxiety and depression scores in HIV-infected patients with facial lipoatrophy.

Facial lipoatrophy has emerged as perhaps the most distressing and devastating manifestation of the antiretroviral therapy (ART)-associated lipodystrophy syndrome for patients infected with HIV. The profound depletion in both superficial and buccal facial fat is highly stigmatizing for patients, resulting in feelings of low self-esteem, social withdrawal and forced disclosure of HIV status [1-3]. In addition, the appearance of facial lipoatrophy may adversely affect adherence to ART, and act as a deterrent to initiating therapy in patients for whom ART would otherwise be indicated [1,4]. Although some progress has been made in elucidating the aetiology of and risk factors for facial lipoatrophy [5], currently available medical treatments appear insufficient for managing this adverse effect. In particular, intervening with either recombinant human growth hormone or thiazolidinediones has yielded negligible, if any, effect on facial lipoatrophy [6-8]. Furthermore, although switching from a thymidine analogue to either an abacavir, tenofovir or nucleoside-sparing-based regimen has improved peripheral fat loss in randomized controlled trials evaluating this approach, this option is not always virologically feasible, and the clinical significance of the observed fat recovery is questionable [9,10]. Given the lack of improvement associated with pharmacological approaches, interest has increased in the surgical correction of lipoatrophy with facial fillers.

Poly-L-lactic acid (PLA; New-Fill, Biotech Industry SA, Luxembourg) is an aliphatic polyester that is the first filler to be approved by the United States Food and Drug Administration for the treatment of ART-associated facial lipoatrophy. Approval of PLA was based on data from four open-label studies documenting the safety and efficacy of this product in 278 patients with facial lipoatrophy [11-14]. Long-term follow-up of one cohort suggested that the benefits of PLA persist for up to 96 weeks [11]. Although it is the most extensively studied facial filler, PLA has several potential drawbacks. As a biodegradable product, the effect of PLA is temporary, and therefore re-treatment is eventually necessary. Multiple treatment sessions are required to administer PLA, necessitating repeat visits and injections for the patient. Furthermore, subcutaneous nodules have been reported after the injection of PLA [11-14]. Assessment of alternative options for patients with facial lipoatrophy is therefore important.

Polyalkylimide gel (PAIG; Bio-Alcamid, Polymekon, Biotech Industrie, Milan, Italy), a non-biodegradable, non-allergenic, non-toxic polymer composed of 96% non-pyrogenic water and 4% polyalkylimide, possesses several properties that make further study of this compound in HIV-positive patients worthwhile [15]. In particular, once implanted, PAIG is unique among injectable fillers in that a fine (0.02 mm) collagen capsule develops around the gel, isolating it from host tissue [16]. As a result of the encapsulation process, the implant can be readily identified and, should the need arise, easily removed by expressing the capsule and squeezing the material out. Also, the cosmetic effects of PAIG are permanent, obviating the need for further treatments [15]. The benefits and safety of PAIG have been reported in a multicentre study of 2000 otherwise healthy patients, who attained excellent cosmetic results, with no evidence of implant migration, dislocation, granuloma or allergic responses noted. Although 12 patients developed postoperative staphylococcal infections, these could be attributed to the implanted material in only three cases [15]. These findings have been replicated by several published case series of HIV-positive patients with facial lipoatrophy, in whom restorative treatment with PAIG was assessed as being safe and effective [16,17]. Randomized trials of PAIG incorporating measures of patient quality of life (QoL) have yet to be performed.

The objectives of this study were to evaluate the efficacy, safety and impact on QoL of PAIG given in a single session, with an additional follow-up session as needed if the level of correction was deemed less than optimal by the treating surgeon (i.e. a 'touch up' session).

Materials and methods
The study was an open-label, randomized, 24-week study of immediate versus delayed treatment with PAIG injections in HIV-infected patients with facial lipoatrophy. The study design was modelled after a previous trial of immediate versus delayed injections of PLA, with the intention of assessing the temporal association between treatment and improvements in both facial lipoatrophy score and patient QoL [12].

Study participants
HIV-positive individuals, 18 years of age or older who self-identified as having facial lipoatrophy with confirmation by their primary care physician were eligible for the study. The severity of facial lipoatrophy was determined using the validated Carruther's scale of facial lipoatrophy which goes from grade 1 (mild lipoatrophy) to grade 4 (most severe lipoatrophy) (Fig. 1) [18]. Exclusion criteria included pregnancy or intent for pregnancy, injectable therapy for facial lipoatrophy within the past 9 months, the presence of an inflammatory condition of the face and the use of anticoagulation or non-steroidal inflammatory agents in the 7 days before injection. The study protocol was approved by our Research Ethics Board and all patients provided written informed consent. Consent for the publication of photographs was also obtained.

Study injection technique
Patients received PAIG injections at their first treatment visit by a single trained plastic surgeon into the subcutaneous plane, avoiding the muscle or dermal planes (Fig. 2). At this initial visit, patients received deposits of PAIG in several injections because this product works on the principle of applying a minimum of 0.3 ml, or preferably, 0.5 ml per aliquot, which encourages the encapsulation process. Smaller aliquots do not encapsulate and are absorbed by the body. A 16 gauge, 11/2 inch needle was used for the baseline large aliquot injection. A 20 gauge, 11/2 inch needle was used when PAIG was transferred from a 5 ml syringe to a 1 ml syringe. Care was taken to ensure not to go medial to the midpupilar line as this might broaden the aspect of the nose and not to go above the midline of the zygomatic bone because this may deepen the orbital rim. When filling the cheeks, a minimum amount of PAIG was always applied over the zygomatic bone to blend in with the existing structures. To minimize pain, 1-2% lidocaine with or without epinephrine was injected locally before the procedure. Patients were given a 5-day course of antibiotic prophylaxis with oral cephalexin 500 mg four times per day, to be started one day before the treatment. Levofloxacin 500 mg a day was used in cases of penicillin allergy. The quantity of PAIG injected varied with the severity of skin depression. At the end of the initial injection, the cheeks were thoroughly and aggressively massaged to smoothen out all the aliquots of PAIG, including intra-oral massage techniques. A second session was organized 6 weeks after the initial injection if the surgeon judged the level of correction to be less than optimal and not fully corrected. In that case, the surgeon would provide a 'touch up', defined as the necessary volume of PAIG needed to optimize the aesthetic result. A 20 gauge, 11/2 inch needle was used for the small aliquot touch ups. Additional touch-up injections could be arranged as required to optimize treatment outcome at the discretion of the plastic surgeon. Treatment was discontinued if any severe or moderate reaction developed after injection.

Study design and follow-up
Study participants were randomly assigned to immediate treatment with injections of PAIG to the buccal area, and in some cases, the temple region, on day 0 with a touch up at week 6, or to delayed treatment with the injections being done at week 12 with a touch up session at week 18. Randomization was performed by the sequential opening of sealed opaque envelopes containing treatment assignments as determined with a random number generator. At the baseline visit, patients were evaluated by clinical examination, fasting blood work (complete blood count, biochemistry, liver function, lipids, glucose, lactate, viral load and CD4 cell count), standardized facial photography and QoL, anxiety and depression questionnaires. Clinical examination, facial photography and the administration of all questionnaires were repeated at weeks 2, 6, 12 and 24 of follow-up. Additional visits are planned for weeks 48, 72 and 96. The clinical examination and scoring were performed by two HIV specialists and the injecting plastic surgeon at each facial lipoatrophy grading visit using the Facial Lipoatrophy Severity Scale (FLSS) (Fig. 1). Each patient was scored by the three reviewers, the average of which was used to derive the score for the analysis. Adverse events and safety reporting were performed at each of the visits.

Study endpoints
The primary endpoint of the study was the change from baseline to week 12 in the facial lipoatrophy severity score as assessed by the three physicians using the FLSS. The FLSS is a validated four-point grading of facial lipoatrophy from 1 (mild facial lipoatrophy) to 4 (severe facial lipoatrophy) developed by Dr Carruther (Fig. 1). Grade 0 was used to represent the condition of no facial lipoatrophy. The secondary endpoints include the change in facial lipoatrophy grading score as determined by the patient using the FLSS, the nature and incidence of adverse events, and the change in QoL and depression scores from baseline to weeks 12 and 48. QoL and depression were assessed using the Medical Outcomes Study HIV Health Survey (MOS-HIV), the Hospital Anxiety and Depression Scale (HADS) and the slightly modified Dermatology Quality of Life Survey (sDQLS). The MOS-HIV is the standard validated survey used to assess QoL in HIV-positive patients, and includes functional, mental health and QoL subscales [19]. The subscales are scored out of 600, 700 and 100, respectively, with a higher number indicating better health. The HADS is a validated survey assessing both depression and anxiety that has been used in the setting of facial lipoatrophy treatment [20]. Each subscale is measured out of 21, with higher numbers representing greater degrees of depression and anxiety. The sDQLS is a survey that has been validated using the word 'skin' and measures the impact of skin diseases on QoL [21]. For this study, the survey was slightly modified by changing the word 'skin' to 'facial lipoatrophy'. The sDQLS is scored out of 30, and the literature has identified that the higher the score, the more a given individual's impaired QoL is caused by appearance.

Statistical analysis
The primary analysis was a comparison of the difference in the change from baseline to week 12 in the FLSS score, as graded by the three physicians between the immediate and delayed groups using a Wilcoxon rank sum test. Wilcoxon rank sum tests were also used to compare the change in secondary outcomes from baseline to week 12 and primary and secondary outcomes between the treatment groups at week 48. The proportion of patients experiencing each adverse event was tabulated by treatment group. Pain was assessed by duration, peak severity on a scale of 0-10, and current severity out of 10. Medians and interquartile ranges (IQR) were used to summarize peak and current severity. Wilcoxon signed rank tests were used to compare the patient FLSS score and survey score between baseline and week 48 for the entire study group.

The interrater agreement was assessed using the AC1 statistic (K. Gwet, 2002, unpublished observation) instead of the more widely used kappa. Kappa is low when the outcome of many subjects falls into one category. In this study, many subjects had an FLSS score of zero at the last visit. As kappa measures the agreement over and above the 'agreement by chance', it indicates a low level of agreement when the agreement-by-chance is high. The AC1 statistic is similar in nature to kappa, but accounts for the large proportion of outcomes in one group; therefore it is a more robust chance-corrected statistic.

Thirty-one patients were enrolled between April and July 2005. The baseline characteristics of the cohort are summarized in Table 1 by treatment group. Twenty-three patients (74%) had moderate to severe facial lipoatrophy at baseline with a median physician FLSS of 2 (IQR 1, 3). In addition to facial lipoatrophy, 27 patients (90%) complained of evidence of fat loss elsewhere in the body. All 31 patients received PAIG injections, with 16 randomly assigned to the immediate group and 15 to the delayed group. Week 12 data are available for 30 patients, as one participant in the immediate group missed the week 12 visit. Similarly, week 48 data are available for 30 patients as one patient was lost to follow-up subsequent to the week 12 visit. The two groups were similar with respect to baseline patient and physician-graded FLSS score as well as QoL indices. The median volume of PAIG injected in the immediate and delayed group was 16.6 ml (IQR 14.8, 22.3) and 13.5 ml (IQR 10.5, 18.0), respectively (P = 0.18). Overall, the median total volume of PAIG injected by week 48 was 16.0 ml (IQR 12, 20), with the median volume for each grade and arm presented in Table 2. The majority of patients (58%) required either one injection of PAIG (n = 5; two in the immediate group, three in the delayed group) or one injection with one touch-up session 6 weeks later (n = 13; five in the immediate group, eight in the delayed group). Eight patients (six in the immediate group, two in the delayed group) required three injections (baseline with two touch-up injections), four patients (two in the immediate group, two in the delayed group) received four injections, whereas the remaining patient (immediate group) received five injections. The number of patients requiring touch-up injections of PAIG was not significantly different between the two groups (P = 0.15).

The median change in the physician FLSS score from baseline to week 12 was -2 (IQR -3, -2) for the immediate group and 0 (IQR 0, 0) for the delayed group (P < 0.0001; Table 3). The interreviewer agreement for the three physicians was 0.79 [95% confidence interval (CI) 0.64-0.94] at baseline and 0.75 (95% CI 0.61-0.89) at 12 weeks' follow-up. The median change in the patient FLSS score from baseline to week 12 was -2 (IQR -2, -1) for the immediate group and 0 (IQR 0, 0) for the delayed group (P = 0.002; Table 3). The interperson agreement between patient's self grade and the median physician score was 0.44 (95% CI 0.20-0.68) at baseline and 0.47 (95% CI 0.24-0.70) at 12 weeks' of follow-up. High resolution digital photographs were taken at baseline and at each follow-up visit, and a representative selection are presented in Fig. 3. The median change in MOS-HIV, HADS and sDQLS scores by week 12 is presented in Table 3 by treatment group. All three subscales of the MOS-HIV were improved for the immediate group compared with the delayed group, although the QoL (P = 0.01) and psychological subscales (P = 0.02) were more significantly affected than the physical subscale. Statistically significant improvements in the anxiety portion of the HADS and the sDQLS were seen in the immediate groups compared with the delayed group at week 12 (P = 0.02 and P = 0.001, respectively).

Fig. 3. Pictures before and after injection of polyalkylimide gel. (a) before and (b) after grade 1 FLA; (c) before and (d) after grade 2 FLA; (e) before and (f) after grade 3 FLA; (g) before and (h) after grade 4 FLA. FLA, facial lipoatrophy.

Adverse events were mostly mild and transient, resolving after a median of 3 days (IQR 2, 5). Swelling, pain, bruising and erythema were the most common adverse effects, occurring in 24 (77%), 21 (68%), 18 (58%) and 13 (42%) patients, respectively. The median duration of swelling, pain, bruising and erythema was 4 days (IQR 3, 7), one day (IQR 1, 3), 3 days (IQR 3, 5) and 3 days (IQR 2, 3), respectively. The median peak degree of pain was 2 (IQR 1, 4) on a scale of 0-10. There were no serious adverse events and no cases of cellulitis or necrosis. No nodules or micronodules were found up to week 48.

Although the groups were different with regard to the endpoints at week 12, no significant difference between groups was evident in any endpoint by week 48 (Table 4). Subsequently, the week 48 analysis was carried out for the entire group as a single cohort. Relative to baseline, physician and patient FLSS scores both changed by a median of -2 (IQR -3, -1; P < 0.0001) and -2(IQR -2, -1; P < 0.0001), respectively, such that the median physician and patient FLSS scores at week 48 were 0 (IQR 0, 1) and 1 (IQR 0, 1), respectively. Whereas improvements in all domains of the MOS-HIV were observed from baseline to week 48, statistical significance was attained only for the mental health summary score (P = 0.01). In terms of the sDQLS from baseline to week 48, there was a statistically significant change observed with a median change of -3 (IQR -7, -1; P < 0.0001). Furthermore, statistically significant improvements were noted in both the depression (-3, IQR -5, 1; P = 0.01) and anxiety (-3, IQR -4, -1; P = 0.001) portions of the HADS scale from baseline to week 48.

The results of our study indicate that injections of PAIG are associated with improvements in FLSS scores, as assessed by both physicians and patients. Benefits persisted through to week 48 of the study, with the delayed treatment group attaining similar benefits at the end of the study. In addition, treatment was associated with improved QoL and physical scores using the MOS-HIV, attributable predominantly to the mental health portion of the instrument. Similarly, anxiety scores on the HADS questionnaire and the sDQOL score were significantly reduced among patients receiving immediate therapy with PAIG compared with patients receiving deferred therapy, whereas the HADS depression score was less affected. Improvements in the mental health portion of the MOS-HIV, the sDQOL and the depression and anxiety portions of the HADS were maintained to 48 weeks when the cohort was analysed as a whole. Furthermore, treatment with PAIG was safe, with local side effects of a mild and transient nature being reported most often. Importantly, no infections were noted, and palpable nodules or micronodules were absent through the first 48 weeks of follow-up. As facial lipoatrophy is not directly harmful to health, the improvements noted in patient levels of anxiety and depression and QoL are probably the most relevant clinical indices of efficacy associated with the use of PAIG in our study.

Our study has several limitations, including the lack of assessment of dermal thickness by objective methods and short-term follow-up. Patients will continue to be followed in the study from an efficacy and toxicity perspective for a total of 96 weeks, thereby providing longer-term follow-up. Furthermore, the lack of blinding at the time the FLSS score was derived may have introduced bias into the study, particularly in the week 48 evaluation of the persistence of treatment effect. Blinding of the observers at the time of FLSS scoring to patient treatment status or time on-study, or the use of a control group would have remedied this limitation of our study. Finally, our cohort was composed almost exclusively of men, the majority of whom had either grade 1 or 2 lipoatrophy. We are therefore unable to draw conclusions about the safety, efficacy and impact on QoL of this product in women with facial lipoatrophy and patients with more severe facial lipoatrophy.

A practical limitation of therapy with all facial fillers for patients with facial lipoatrophy is the cost associated with these products. At the time of writing, the cost of PAIG in Canada was US$175.00 per millilitre, such that patients requiring 10-25 ml of the product would have to pay US$1750.00-4375.00 for a course of treatment. European prices vary by nation and treatment centre, ranging from 200 to 425 Euros per millilitre. Controlled trials with extended follow-up are required to determine whether improvements in patient anxiety and depression associated with corrective treatment of facial lipoatrophy offers a financial advantage compared with the costs associated with the psychological morbidity of this condition.

In summary, PAIG is a safe and effective corrective option for the correction of HIV-associated facial lipoatrophy, resulting in clinically important improvements in patient appearance, QoL, anxiety and depression. Extended follow-up of patients is necessary to confirm that the benefits of this product persist beyond the 48-week period of our study.

Treatments for lipoatrophy. Are there improvements? Are they noticeable?

Written by Donald P. Kotler, MD
St. Luke’s-Roosevelt Hospital Center


Of all of the changes that are included in the umbrella-term,
‘lipodystrophy’, fat loss or lipoatrophy has been the most difficult to manage.  Treatment
options are limited; no therapy has received FDA approval.  Several studies
have suggested that factors which influence the development of lipoatrophy, and
those that promote fat accumulation, are different.  The treatments proposed
for lipoatrophy and fat accumulation differ as well.  Treatments for fat
accumulation that have been reported in the literature include diet and exercise,
growth hormone (Serostim), and metformin (Glucophage).  Treatments for
lipoatrophy that have been reported include antiretroviral switches and treatment with
thiazolidinediones (glitazones).  The published results on these two therapies
will be reviewed.

What is normal?

In order to put the effects of therapy in context, it helps to know what is
normal fat content and distribution, quantitatively.  Table 1 lists average DXA
results from two groups of healthy adults.  The data from control group C1
were published from our laboratory (1) and include both men and women.  The data
from control group C2 were taken from the initial publication about
lipodystrophy by Carr and colleagues (2).  Total fat content is similar in men and
women but is higher as a percentage of weight in women (30%) than in men (21%). 
In contrast, fat-free mass is substantially higher in men, as demonstrated
previously by others.  There is a difference in the percentage of fat that is
central (trunk) and peripheral (limb), with women having more fat peripherally
than do men, a difference also shown by others.   The results in the men studied
by DXA in New York City and Sydney, Australia are very similar.  The average
man studied in New York has 36.7 pounds of fat, of which 19.4 pounds are in the
trunk and 15.6 pounds are in the limbs (6.2 pounds per leg and 1.6 pounds per

Table 1: Fat-free mass, total body fat content and its distribution in
healthy adults
Data in all Tables expressed as Kg (1 kg=2.2 lbs)

          Fat-free mass Total fat   Trunk fat Limb fat
female        39.4             17.7       8.3           9.1

male           59.4            16.7       8.8           7.1

male           59.6            17.9       9.4           7.2

Data as kg; C1=healthy male adults studied at St. Luke’s-Roosevelt Hospital 
Center (1), C1=healthy female adults studied at St. Luke’s-Roosevelt Hospital
Center (1), C2=healthy male adults studied in Sydney, Australia (2)

How different is body composition in subjects with lipodystrophy?
    Table 2 lists average DXA results, at baseline, taken from subjects in
three published studies in which abacavir was switched for zerit (3-5).  Most or
all of the subjects studied were male.  Average fat-free mass, when reported,
was not substantially different from the controls.  Total and limb fat
averaged 2.5-5 kg lower in the lipodystrophy groups than in the controls, while
trunk fat was slightly higher in subjects with lipodystrophy than in the controls.
The ratio of trunk-to-limb fat was about 2.5 times higher in subjects with
lipodystrophy than in controls.  The absolute amount of fat in the arms and
legs were about one half that of the controls.

Table 2: Baseline body composition in HIV-infected subjects with lipoatrophy

          Fat-free mass     Total fat   Trunk fat   Limb fat
Carr (3)         58.6              12.6        9.1             3.5
John (4)         -----               ------        ----            5.5
Moyle (5)      67.3             14.3         10.8              3.5

What is the effect of switching antiretrovirals?

    Table 3 lists the absolute and percentage changes in fat-free mass, total
fat, trunk fat, and limb fat, again estimated from the published papers,
using the patients who switched from zerit to abacavir.  The switch did not affect
fat free mass in any study.  In the study by Carr et al (MITOX), total fat
mass rose by around 9%, while limb fat rose by 11% and trunk fat rose by 15%
after 6 months (3).  The change in limb fat was statistically significant. 
However, the subjects were unable to detect the change in fat content.  The data
were updated to a 2 year follow up, during the Fifth Workshop on Lipodystrophy
(6). There was continued increase in limb fat totaling a 36% increase from
baseline values.  However, the changes continue to be clinically inapparent in
many patients.  In addition, the 36% rise represents about one third of the
difference between the subjects at baseline, and controls.  In this study, measures
of visceral fat did not change, nor did the presence and size of buffalo

    John and colleagues from Perth, Australia also studied subjects who
switched from zerit to abacavir to prevent or reverse lipoatrophy, and noted an
increase in absolute limb fat of about 500 gm over 48 weeks (4).  The change,
while statistically significant compared to those who continued therapy, is the
equivalent of about 4 ounces of fat per limb.  No clinical correlations were

    Moyle and colleagues from London performed a complicated switch study,
and the results in 10 subjects who switched from zerit to abacavir are lilsted
in the table (5).  Total fat rose by 3.5 kg, or almost 25% after one year.  The
increase was split relatively equally between trunk and limbs.  Because of
the loss of limb fat, the increase in limb fat after one year, 1.7 kg,
represented almost one half of the difference between baseline and control values. 
Visceral fat content was unaffected by the switch.  Surprisingly, self-assessment
and quality of life scores did not change over 48 weeks.  One might question
the robustness of the measurement tool, though the group size, at 10, is very
low for a subjective scale to show significant changes.

Table 3: Changes in fat-free mass, total body fat, trunk and limb fat after
switching antiretrovirals

           D fat-free mass     D total fat      D trunk fat   D limb fat
Carr (3)     -0.4 (0.07%)      1.1 (8.7%)      1.4 (15.4%)    0.4 (11.4%)
John (4)        --------------       ------------      ---------------    0.5
Moyle (5)    -0.7 (1.0%)     3.5 (24.5%)      1.8 (16.6%)     1.7 (48.5%)

(3) switch from zerit to abacavir, 24 weeks, 109/111 male, (4) switch to
combivir/abacavir, 48 weeks, all male, (5) switch zerit to abacavir, 48 weeks
(genders not specified)

    To summarize, switching from zerit to abacavir leads to a statistically
significant increase in limb fat with progressive rises over periods up to 2
years.  However, the degree of increase does not return limb fat to normal.  In
addition, there is a relative wide variation in individual results.

What is the effect of therapy with thiazolidinediones?

    Four studies have reported the effects of therapy with
thiazolidinediones, three using rosiglitazone (Avandia) and one using pioglitazone (Actos). 
Jarvinen  and colleagues from Helsinki performed a placebo-controlled trial using
8 mg of rosiglitazone for 6 months, and was unable to show a statistically
significant difference in either visceral (VAT) or subcutaneous (SAT) adipose
tissue by whole body MRI (7).  Gelato and colleagues from Stony Brook performed
an open-label study in 8 subjects, and demonstrated a 23% increase in mean SAT
and a 21% fall in mean VAT by single slice CT scanning (8).  No clinical
correlations were reported.  Calmy and colleagues from Geneva reported on an
open-label trial of pioglitazone for 6 months and documented significant increases
in total fat, trunk fat, and leg fat (9).  They reported that some subjects
noted improvement ranging from modest to substantial, while others noted no
change, and some even reported progression of the changes.   Hadigan presented the
results of a randomized, placebo-controlled trial of rosiglitazone at the
recent 5th Workshop on Lipodystrophy.  Therapy was placebo-controlled for 3
months, then followed by 3 months of open-label; therapy (10).  A 5% increase in
leg fat by DXA, which was not statistically significant, was noted at 3 months. 
However, an increase in abdominal subcutaneous fat of 8%at 3 months and 12%
at 6 months were found, and were statistically significant.  Trunk fat and VAT
did not change.  No clinical correlates were reported.

Table 4: Effect of thiazolidinediones on body fat content and distribution

                     TAT     %D TAT     SAT  %D SAT     VAT %D VAT
Jarvinen (7)      3050       2.9        1140        5.3    1920      1.6
Gelato (8)          264     -1.5         26      23      -30        -21
Calmy (9)            ----      20.1      ----        28      ----      17.3
Hadigan (10)       ----      ----        ----        12      ----        -0-

(7)  RCT, 24 weeks, whole body MRI , (8)  Open-label, 6-12 weeks, single
slice CT, (9)  Open-label, 6 months, DXA (SAT for limb fat, VAT for trunk fat),
(10)  RCT, 24 weeks, single slice CT


Three points are worthy of discussion.  The first is that both antiretroviral
switching and thiazolidinedione therapy may lead to some reversal of
lipoatrophy.  The fact that these two completely different approaches may have benefit
supports the contention that the development of lipoatrophy is
multifactorial, or at least that treatment approaches may be multi-pronged.  Furthermore,
the results indicate that the process of lipoatrophy is not irreversible.

A wide intra-individual variation in treatment effects was seen in several of
the studies, which suggests that medications and other factors variably
affect body fat content and distribution in different subjects.  In other words,
one or another antiretroviral may be the major cause of lipoatrophy in some
subjects while other factors, e.g., a rigorous exercise training program plus
anabolic steroids may be more important in others.  It is important to note that
no study reported complete reversal of lipoatrophy, though it might have
occurred in some subjects.  This author’s experience is similar, in that many
patients show little change after switching or even discontinuing antivirals, or
with thiazolidinedione therapy, while a few patients have an excellent response.

An unanswered question is how much of a change is noticeable.  Several of the
studies did not report clinical correlations and others remarked that the
increases in limb fat or SAT were unappreciated or labeled as mild by the
subject.  Subject perception was not a primary endpoint in any study and most of the
studies were grossly underpowered for this question.  Prospective studies
using validated instruments in larger study groups will be needed to determine if
the changes in limb fat/SAT after switching antiretrovirals or treating with
thiazolidinediones are clinically relevant in addition to being statistically


1. Engelson EE, Kotler DP, Tan YX, Wang J, Pierson RN, Heymsfield SB. Fat
distribution in HIV-infected patients reporting truncal enlargement quantified by
whole-body magnetic resonance imaging. Am J Clin Nutr. 1999;69:1162-9.

2. Carr A, Samaras K, Burton S, et al. A syndrome of peripheral
lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease
inhibitors. AIDS. 1998;12:F51-8.

3. Carr A, Workman C, Smith DE, Hoy J, Hudson J, Doong N, Martin A, Amin J,
Freund J, Law M, Cooper DA; Mitochondrial Toxicity (MITOX) Study Group.
Abacavir substitution for nucleoside analogs in patients with HIV lipoatrophy: a
randomized trial. JAMA. 2002;288:207-15.

4. John M, McKinnon EJ, James IR, Nolan DA, Herrmann SE, Moore CB, White AJ,
Mallal SA. Randomized, controlled, 48-week study of switching stavudine and/or
protease inhibitors to combivir/abacavir to prevent or reverse lipoatrophy in
HIV-infected patients. J Acquir Immune Defic Syndr. 2003;33:29-33.

5. Moyle GJ, Baldwin C, Langroudi B, Mandalia S, Gazzard BG. A 48-week,
randomized, open-label comparison of three abacavir-based substitution approaches
in the management of dyslipidemia and peripheral lipoatrophy. J Acquir Immune
Defic Syndr. 2003;33:22-8.

6. Martin A, Carr A, Ringland C, Amin J, Workman C, Freund J, Hoy J, Doong N,
Smith D, Cooper DA for the MITOX study. Long term changes in lipodystrophy
after switching from nucleoside analogues to abacavir. Program and abstracts,
Fifth International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV.
Paris, France, July 8-11, 2003, Abstract 16.

7. Yki-Jarvinen H, Sutinen J, Silveira A, Korsheninnikova E, Fisher RM,
Kannisto K, Ehrenborg E, Eriksson P, Hamsten A. Regulation of Plasma PAI-1
Concentrations in HAART-Associated Lipodystrophy During Rosiglitazone Therapy.
Arterioscler Thromb Vasc Biol. 2003;23:688-94.

8. Gelato MC, Mynarcik DC, Quick JL, Steigbigel RT, Fuhrer J, Brathwaite CE,
Brebbia JS, Wax MR, McNurlan MA. Improved insulin sensitivity and body fat
distribution in HIV-infected patients treated with rosiglitazone: a pilot study.
J Acquir Immune Defic Syndr. 2002;31:163-70.

9. Calmy A, Hirschel B, Hans D, Karsegard VL, Meier CA. Glitazones in
lipodystrophy syndrome induced by highly active antiretroviral therapy. AIDS.

10. Hadigan C, Yawetz S, Thomas A, Havers F, Sax P, Grinspoon S. A
randomized, double-blind, placebo-controlled study of rosiglitazone for patients with
HIV lipodystrophy. Program and abstracts, Fifth International Workshop on
Adverse Drug Reactions and Lipodystrophy in HIV. Paris, France, July 8-11, 2003,
Abstract 12.





By Nelson Vergel- March 2006

I have been seeing many HIV positive men with enlarged parotid glands in my 14 years of travels giving lectures around the country. I am also one of those men with moderate inflammation of the parotid glands. No one really knows what causes this disfiguring inflammation. It could be due to the HIV virus itself, inflammatory cytokines and too many CD8 cells produced by immune reconstitution, hormones, fat build up in the glands, etc. Some people have this problem along with facial wasting, which makes their faces look very abnormal. So even if you treat your facial wasting with facial fillers, this problem needs to be treated so that you can attain a more normal look that resembles what you normally would look like without the effects of HIV and its medications.

The parotid gland is the largest of the salivary glands that produce saliva that is important in the digestion of food. The gland lies under the angle of the jaw just beneath the ear.

I have been searching for a long time for an answer. Not a single HIV conference has had a presentation on this problem that may affect around 20 percent of men with HIV. It does not seem to affect as many women with HIV for unknown reasons. I had heard about radiation treatments in the past but they created severe side effects like burning of the salivary glands, salivary production problems, and eventual tooth decay. A few months ago my dear friend Dr. Tony Mills from Los Angeles called me to tell me about the great results he had seen in his patients referred to Dr Patricia Gordon. I decided to call Dr. Gordon myself to talk to her about her experiences. Dr. Gordon did her undergrad at Harvard and her residency at UCLA. She is a radiation oncologist and practices at Century City Hospital in Los Angeles.

A very pleasant and seemingly dedicated doctor, she immediately told me how happy she was with the excellent remission rates she had been seen in her patients. Most noticed complete resolution of the problem after a few sessions of low dose electron-based radiation. She stressed the fact that this protocol differs greatly from the ones used in the past that created greater side effects because of the nature of the radiation, Unlike the old method that used photons that penetrate the skin more deeply, she uses electrons that penetrate a very thin layer of tissue instead, so they do not cause the burning and salivary gland dysfunction seen in the past.

She has had over 200 male patients referred to her practice (not one female has been referred). At baseline, all patients get a CT scan of their parotid gland area for assessment. They get a customized molded lead mask that only exposes the area to be treated. They then receive 16 sessions (once a day for five days a week, for five minutes each) on both sides of the face. She said that most patients see improvements after four sessions. However, she did not have before and after pictures to share with me. All procedures have been reimbursable by Medicare and insurance.

I decided to get my parotid glands treated and I am happy to say that they got back to normal after 7 sessions. It has been 4 years now (March 2006) and they are still normal! I had no significant side effects besides redness for a few days, no beard for a month (which I liked), and a temporary loss of normal saliva production. All returned to normal after a month or so. I am not sure, but I think I had a slight decrease in CD4 cells (around 20) but this is hard to tell unless someone performs a controlled study. My CD4 cells also returned baseline after two months.


Dr. Gordon will publish a paper on her experiences soon. Her phone number is 310-201-6739. Her email is .She is happy to talk to doctors or patients about this procedure.

PoWeR Releases Groundbreaking Lipodystrophy Resources for HIV-Positive People

Apr 8, 2008

HOUSTON, April 8 (AScribe Newswire) -- Program for Wellness Restoration, PoWeR, released the results of the largest online patient surveys performed to date on lipodystrophy options and resources along with a free Spanish translation of PoWeR's book, Built to Survive. The 776-person survey summarizes the main therapeutic options used in the HIV community along with a list and ratings of providers who specialize in reconstructive procedures for HIV-related body changes.

Ten years have passed since the first report of lipodystrophy at an HIV conference. The excitement and hope for a longer life that accompanied the arrival of Highly Active Anti-Retroviral Therapy (HAART) has been tempered by accounts of humps, bellies, and facial wasting. A decade on, many unanswered questions and misconceptions about HIV associated lipodystrophy persist with only a limited number of treatment options available. Frustrated and tired of waiting for answers from the medical community, many people living with lipodystrophy have turned to the internet for advice, treatment and support in hopes of reversing some of the devastating effects of this stigmatizing syndrome.

Lipodystrophy is a condition of abnormal fat redistribution that can lead to either lipohypertrophy (fat accumulation in specific areas of the body such as the neck, belly, upper torso, and breasts) or lipoatrophy (fat loss in the face, buttocks, arms and legs). I am very happy that we have been able to provide this key information to the HIV community, said Nelson Vergel, founding director of PoWeR. People have been wanting this important health resource for 10 years after the first report of lipodystrophy was reported at an HIV conference,, added Vergel.

The results of the survey can be found at: _Survey Results_ (

A list of providers with comments from patients can be found at : _Survey Results_ (

A free PDF copy of the Spanish translation of the book Built to Survive can be downloaded from : _

Another distressing and unaddressed issue related to HIV lipodystrophy is buttock wasting. Currently, there is no research being performed in the US or abroad on this debilitating problem that can cause pain and discomfort in patients who have to sit down for extended periods of time at work or school. PoWeR gathered all available anecdotal and research information on the subject and made it available in their new web page:

PoWeR is a national non-profit all-volunteer organization that provides patient-friendly educational information to HIV-positive people and their clinicians about ways to improve HIV treatment response, side effects, and quality of life. More information can be found at .

For an update on were we are after ten years of lipodystrophy, please visit

- - - -

CONTACT: Nelson Vergel, PoWeR Director,, 713-539-1978


Thanks to the person who took the time to do this research! Great email for all to save

Hi Nelson,

To our friends in other countries - ignore this message! It's about US tax.

As is usual with tax, there's no simple yes/no answer to your question. My answer boils down to - it SHOULD be deductible, and it's worthwhile trying, but if you are audited, there's a good chance that it will be reversed and you will be billed for tax and interest, and possibly penalty.

Deductibility of medical expenses comes down to "medical necessity." Internal Revenue Code section 213(a) says this:

"There shall be allowed as a deduction the expenses paid during the taxable year, not compensated for by insurance or otherwise, for medical care of the taxpayer, his spouse, or a dependent ..., to the extent that such expenses exceed 7.5 percent of adjusted gross income."

In other words, you add up all your allowable medical expenses, and if they are more than 7.5% of your adjusted gross income (also called AGI - the last line of page 1 of your Form 1040), then the excess is allowed as an itemized deduction. If your AGI is $100,000, and your total medical expenses are $10,000, your itemized deduction will be $2,500. Your total itemized deductions have to exceed your "standard deduction" to get any benefit. The standard deduction for a single person in 2007 is $5,350.

By the way, as for medication, section 213(b) says "An amount paid during the taxable year for medicine or a drug shall be taken into account ... only if such medicine or drug is a prescribed drug or is insulin."

So, no deduction for aspiring or cough syrup.

Now, in the tax code, you always have to look for the definition of everything. Section 213(d)(1) says "The term 'medical care' means amounts paid for the diagnosis, cure, mitigation, treatment, or prevention of disease, or for the purposes of affecting any structure or function of the body ..." And then it goes on to also allow deductions for certain medical-related travel expenses, for long-term care, and for medical insurance premiums.

It sounds from the above like facial and buttock reconstruction would be covered - it mitigates disease (effect of the treatment of a disease, which amounts to the same thing), and does affect bodily structures.

However, section 163(d)(9) says "(A) The term 'medical care' does not include cosmetic surgery or other similar procedures, unless the surgery or procedure is necessary to ameliorate a deformity arising from, or directly related to, a congenital abnormality, a personal injury resulting from an accident or trauma, or disfiguring disease. (B) ... The term 'cosmetic surgery' means any procedure which is directed at improving the patient's appearance and does not meaningfully promote the proper function of the body or prevent or treat illness or disease."

We have two problems, then. First, anything that can ALSO be cosmetic, is very hard to prove as being medically necessary - it's the same reason we have trouble getting our insurance providers to cover the treatment. The IRS is extremely skeptical of such deductions. In addition, the IRS is very skeptical of any treatment that addresses a mental/emotional problem, as opposed to a physical problem. So if you have your butt fixed because it's painful to sit, that's a physical issue. If you have your face fixed because you can't even recognize yourself in the mirror and it throws you into a deep depression - the IRS may not be sympathetic.

This is a heavily-contested subject - not lipoatrophy treatment, but deduction of cosmetic treatment.

There is no requirement that treatment be provided in the US, and if you can show that it cost less because you had it done elsewhere, that may help, although it also may look to suspicious to examiner, particularly if it was done in a place that is also a vacation spot (hmmm, Baja Mexico, Brazil) ... and the regulations related to medical travel expenses mention that a "vacation for to improve general health" is not deductible so you'll need to be ready to defend against that.

The IRS has a publication on Medical Expenses called Publication 502. Here's what it says about cosmetic surgery:

"Generally, you cannot include in medical expenses the amount you pay for unnecessary cosmetic surgery. This includes any procedure that is directed at improving the patient's appearance and does not meaningfully promote the proper function of the body or prevent or treat illness or disease. You generally cannot include in medical expenses the amount you pay for procedures such as face lifts, hair transplants, hair removal (electrolysis), and liposuction.

"You can include in medical expenses the amount you pay for cosmetic surgery if it is necessary to improve a deformity arising from, or directly related to, a congenital abnormality, a personal injury resulting from an accident or trauma, or a disfiguring disease."

Here's the link to the on-line version of Publication 502:

If you want to download it:

So, you need to be able to prove that you meet this definition. A letter from a doctor will be a necessity here. Discuss all this with your own tax provider. Large medical expenses are a red flag for audit, so if you have other stuff in your tax return you don't want them asking questions about, then you'll want to think twice about taking this deduction.

I hope this helps!


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