More than just a tongue-twister, the term "lipodystrophy" can be broken down to reveal exactly what it means. "Lipo" refers to fat and "dystrophy" refers to abnormal growth or change. Put it together in plain English and what you're left with is exactly what's being seen in many people living with HIV -- abnormal fat changes.
While researchers and healthcare providers still haven't yet officially defined lipodystrophy, it generally involves two problems that can affect physical appearance -- a buildup of fat in some parts of the body and/or a loss of fat in other parts of the body. Some people see an increase in the amount of fat around their gut, on the back of their neck and shoulders (sometimes referred to as a "Buffalo Hump"), and/or in their breasts. The medical term for this is lipohypertrophy (excessive fat growth). It's important to note that a buildup of fat around the gut and waist isn't always lipodystrophy. Lipodystrophy usually makes the abdomen look bloated or distended and often feel hard. This is because the fat increase associated with lipodystrophy (visceral fat) builds up deep within the body, around internal organs, causing the abdomen to swell. If the fat around your gut or waist feels doughy, fleshy, or soft -- a good test is to see if you can "pinch an inch" around your waist -- it's probably not lipodystrophy but, instead, typical weight gain that often comes with getting older.
Some people lose fat just below the skin (subcutaneous fat) in their legs, arms, buttocks, or face. The medical term for this is lipoatrophy (decrease in fat tissue). One of the most prominent features of facial lipoatrophy is sunken cheeks -- cheeks that have lost their fullness and appear hollow. Mild facial lipoatrophy may be barely noticeable to the person experiencing it and unnoticeable to others. If the lipoatrophy worsens, the outlines of the facial muscles can be seen and felt through the skin. Facial lipoatrophy can also result in fat loss around the nose and mouth. This can cause deep folds in the skin to form, particularly when smiling or chewing. The fat that fills out the temples, on the sides of the forehead, and the eye sockets can also be affected by lipoatrophy. When fat in these parts of the face becomes diminished, the result can be a skeletal appearance.
What Causes It?
We don't really know what causes lipodystrophy. All we know is that many HIV-positive people are experiencing one -- or both -- of the problems discussed above, along with other complications, such as elevated blood lipid levels (cholesterol and triglycerides). We also know that most patients who have lipodystrophy started noticing symptoms once they were on combination-drug therapy.
There are actually three theories being tossed around by researchers, two of which are directly related to the side effects of anti-HIV drugs:
Protease inhibitors (PIs): Some researchers believe that protease inhibitors can impair the ability of certain enzymes responsible for mopping up excess fat and keeping fat cells functional. This might explain why fat accumulates around the gut, breasts, or neck. It's still not clear which PIs are most likely to cause lipodystrophy.
Nucleoside reverse transcriptase inhibitors (NRTIs): Some NRTIs can impair mitochondria, the "power generators" of human cells. A growing number of researchers believe that this might explain many of the side effects seen in people taking NRTIs, including peripheral neuropathy, pancreatitis, decreased white blood cell counts (leukopenia), and possibly lipodystrophy. Test tube studies indicate that the "d" NRTIs -- Zerit (d4T), Videx (ddI), and Hivid (ddC) -- are the most likely to damage mitochondria, particularly if they are used for long periods of time. There have also been a number of clinical studies linking Zerit to lipoatrophy. While other NRTIs have also been linked to lipoatrophy, the risk appears to be highest in people taking Zerit .
HIV itself: It might be that HIV, and not only the drugs used to treat it, is to blame. Long before the use of anti-HIV drug combinations, people living with HIV were more likely to have higher levels of lipids in their blood and to experience body-shape changes than HIV-negative people. And because many HIV-positive people are living longer while on combination therapy, the HIV-related fat problems continue to get worse. Some researchers have suggested that lipodystrophy might also be related to an imbalance in the immune system that remains after combination therapy is started; even though combination therapy prevents HIV from attacking immune system cells, it may not halt the negative effects of HIV on other cells in the body.
Can Lipodystrophy Be Prevented?
As discussed above, it's still not clear how or why lipodystrophy occurs in HIV-positive people. However, a great deal of research has documented an association between certain anti-HIV medications and lipoatrophy. This, in turn, has altered the ways in which many doctors choose to treat their HIV-infected patients. For example, based on its connection to lipoatrophy, Zerit is now prescribed much less frequently than it used to be and is being switched for other NRTIs in patients who are currently taking it. This, in turn, may help to reduce the risk of lipoatrophy.
The same principle may hold true in terms of selecting a protease inhibitor. For example, the PI Reyataz (atazanavir) appears to be the least likely of all the PIs to increase lipid levels, with early evidence also suggesting that it may be less likely than the other PIs to cause abnormal body-fat changes.
How Can It Be Treated?
Because we really don't know what lipodystrophy is or exactly what causes it, we don't know how best to treat it. Developing effective treatments for lipodystrophy depends on a more complete understanding of the nature and causes of the condition.
There are a number of treatment approaches being looked at by researchers, none of which have yet been proven to be effective. But early results from clinical trials and word-of-mouth reports by patients and doctors paint a promising picture. Here's a look at what's being tried and developed:
Because anti-HIV drugs are believed to be the most likely cause of lipodystrophy, the usual first step is to switch the possible offending drug for one that might not cause the same problems.
PIs -- with the possible exception of Reyataz -- have been said to be a likely cause of lipodystrophy. In turn, several research teams have experimented with drug switches to help control the problem. For example, some patients receiving a PI in combination with two NRTIs might be able to switch the PI for an NNRTI -- usually Sustiva (efavirenz) or Viramune (nevirapine). While a number of studies have confirmed that a switch from a PI to an NNRTI can help control elevated lipid levels in the bloodstream, it still isn't clear if such a switch can reverse the body-shape changes associated with lipodystrophy; data from clinical trials have been conflicting.
For people who have developed lipoatrophy while taking a drug regimen that contains a suspect medication -- Zerit or Retrovir (AZT), for example -- an option might be to switch to a drug that is less likely to cause lipoatrophy -- Viread (tenofovir) or Ziagen (abacavir), for example. In a handful of clinical trials, this approach has been shown to prevent further lipoatrophy and sometimes reverse the problem in patients who develop lipoatrophy while taking Zerit or Retrovir. This approach appears to work best if the medications are switched before lipoatrophy becomes severe.
We don't yet have any medications that have been proven to be safe and effective in reversing the body-shape changes associated with lipodystrophy. However, researchers are exploring possible options in clinical trials.
Thiazolidinediones -- sometimes referred to as "glitazones" -- represent one class of drugs being studied. These medications, which include Avandia (rosiglitazone) and Actos (pioglitazone), are approved for the treatment of diabetes. They have been shown to stimulate a gene (PPARgamma) that plays a vital role in regulating triglycerides, managing blood sugar levels, and promoting the healthy function of fat cells. They have been studied in a handful of clinical trials involving patients with lipodystrophy. Results, however, have been mixed. Some studies found that these therapies helped to reverse lipodystrophy -- most notably the fat loss associated with lipoatrophy -- while others failed to note any improvements. There are also lingering concerns about using this class of drugs in non-diabetic patients.
Some researchers think that anabolic drugs, such as Serostim (recombinant human growth hormone), might help control some of the body-shape changes seen in some people with lipodystrophy. In studies of Serostim for the treatment of AIDS-related wasting syndrome, it was demonstrated that the drug helped reduce fat buildup and promoted muscle growth. In HIV-positive people with lipodystrophy, a few studies have shown that Serostim might help reduce fat buildup around the waist, breasts, and back of the neck. The drug might also help increase muscle in the legs and arms, ultimately covering up the loss of fat.
Serostim does come with side effects, including increased glucose levels (which can be a big concern for people who are already experiencing this problem) and muscle aches, so researchers are currently experimenting with low-dose Serostim to see if it is still effective and causes fewer side effects. The dose currently being tested in clinical trials is 4mg every day for 12 weeks, followed by a lower dose every day or every other day (for wasting syndrome, the dose is 6mg every day continuously). The manufacturer is negotiating with the Food and Drug Administration (FDA) to determine if Serostim should be approved for the management of HIV-related body-shape changes.
Diet and Exercise
A handful of research reports have found that some patients who increased their exercise or started low-fat diets saw a reduction in their lipid levels and body-shape changes. Considering that everyone can benefit from more exercise and a healthy diet, all HIV-positive people -- whether they have lipodystrophy or not -- are encouraged to speak with a nutritionist or dietician about the steps they can take to improve their nutritional status and activity levels.
Plastic Surgery and Facial Fillers
Surgery to correct changes in body fat caused by lipodystrophy has become very popular in recent years. There are two types of plastic surgery being talked about and used: 1) liposuction, a surgical procedure in which fat is sucked out of a specific area of the body, and 2) facial fillers, a general term for procedures in which fat or fat substitutes are injected into the face to help "fill out" sunken cheeks and other troubled spots (the temples and around the eyes or mouth, for example).
Although there have been no clinical trials of liposuction for the treatment of lipodystrophy, numerous HIV-positive people report that it can help reduce fat buildup in the breasts and at the back of the neck. Generally, liposuction can't be used to remove fat buildup in the abdomen, as there is a risk of internal organs being punctured or damaged during the procedure. It is also important to note that liposuction to reduce fat in the breasts or at the back of the neck may not be permanent -- some people see the fat buildup return, usually just several months after the procedure. Liposuction can also be painful and usually isn't covered by health insurance plans, although some people have had some success getting reimbursed for this expensive procedure.
There has been a lot of interest in restorative therapies -- such as facial filler injections and implants -- for facial lipoatrophy. One facial filler, Sculptra (poly-L-lactic acid), was approved by the FDA in August 2004, and several others are being studied all over the world for people with facial lipoatrophy. There are important similarities and differences between the various facial fillers being studied, which are reviewed below.
What Are Facial Fillers?
Generally speaking, facial fillers are injectable -- or surgically inserted -- products that can be used to fill hollows in the face, such as those caused by lipoatrophy. Fillers are temporary, semi-permanent, or permanent. Temporary fillers are broken down and removed from the body over time, a process that can take from weeks to months. Semi-permanent fillers are not readily broken down and removed by the body, thus establishing permanence. However, they can be easily removed from the face in the event of side effects or dissatisfaction with the results. Permanent fillers are much more difficult to remove from the face if problems or unhappiness with the results arise.
Which is best? Most experts seem to agree that temporary or semi-permanent fillers are best. There are a number of reasons for this. First, if research eventually determines the root cause of lipoatrophy and discovers ways to permanently and safely reverse its effects, permanent fillers may prevent the use of such a treatment. Second, some people who have facial fillers injected or implanted are unhappy with the results; the use of temporary or semi-permanent fillers ensures that the results need not be permanent. Third, as the face ages, skin can become thinner and sag. This might cause the outlines of the filler to become visible or more easily felt under the skin, or cause the skin to appear disfigured.
Finally, it's important to recognize that the product selected is only one factor in the success of treatment. It is very important that anyone undergoing restorative therapy for facial lipoatrophy be treated by an expert, meaning a plastic surgeon or dermatologist with experience using the product selected to treat facial lipoatrophy in HIV-positive people.
Autologous fat transplant (AFT): This procedure involves taking fat from one part of the body (such as the butt, hips, inner thighs, or abdomen), cleaning and filtering it, and injecting it into another part of the body, such as the face.
AFT can yield good results and can be very natural in appearance if performed by an experienced specialist. Harvested fat can be frozen and stored if touch-ups are needed in the future. AFT has been shown to last anywhere from six months to two years in some studies involving HIV-positive patients. It might also be possible to increase the length of the benefits through a method that involves injecting fat into the muscles of the face.
Unfortunately, fat can be difficult to harvest from other parts of the body, especially in HIV-positive people with advanced lipoatrophy who are lacking in subcutaneous fat (fat under the skin). Post-surgical recovery can be uncomfortable and take several days. Injected fat can sometimes become abnormally enlarged; this is seen more often in patients who have fat taken from existing "buffalo humps" to fill hollows in the face.
Collagen (Bovine: Zyderm and Zyblast; Human: CosmoDerm and CosmoPlast): Collagen has been used for more than 25 years for cosmetic purposes in the United States, most notably as a filler for facial wrinkles. Because it has long been approved by the FDA for this purpose, it was one of the first products evaluated and used in HIV-positive people with facial lipoatrophy. Bovine collagen is derived from calf skins; human collagen is grown in test tubes using human tissues. If bovine collagen is used, an allergy test is required before it is injected into the face.
Both bovine collagen and human collagen are widely available, and many plastic surgeons and dermatologists have experience using it (although not necessarily in HIV-positive individuals with lipoatrophy). Post-injection recovery is mild. There may be some short-term swelling and/or bruising at the injection sites.
Disadvantages include possible allergic reaction or severe scarring. Repeated maintenance injections can increase the annual cost of therapy. Large volumes of collagen may be needed to restore facial features in HIV-positive people with severe lipoatrophy, so this option is probably best for people with mild-to-moderate facial lipoatrophy.
Calcium hydroxylapatite (Radiance, Radiesse): These products contain synthetic calcium hydroxylapatite, a natural substance found in bones and teeth. It is primarily used in the reconstruction of bony structures. When it's injected into the dermis layer of skin -- the deep inner layer of skin that contains cells that produce fibrous connective tissues including collagen (fibroblasts), hair follicles, oil and scent glands, blood vessels, and nerves -- natural collagen forms around the calcium hydroxylapatite, providing long-term, natural-looking fullness.
Calcium hydroxylapatite is approved by the FDA for various uses in the United States, including orthopedic and reconstructive surgery and in dentistry, and has a good safety record. Even though it is considered to be a temporary filler, it appears to have a longer-lasting effect than most other temporary fillers.
These products can be very expensive. They can also cause nodules -- hard lumps -- at the injection site (they can be felt but not usually seen) in some patients.
Human cadaveric dermis (Cymetra, Dermalogen) and fascia (Fascian): These products are derived from cadavers at the time of death. The dermis or muscle fascia (the gray/white covering over the muscles) is harvested and brought to a lab for sterilization, testing, and processing. Allergy testing isn't necessary.
These products are FDA approved -- but not for HIV-associated lipoatrophy -- and are readily available. Experts report impressive filling of hollows in the face, at least initially.
Injections of human cadaveric dermis are very temporary, with injections lasting approximately one to three months. This approach can also be very expensive, given the need for frequent touch-ups.
Hyaluronic Acid (Restylane, Perlane, Hylaform): Hyaluronic acid is naturally found in human connective tissues. These three brands are synthetic versions of hyaluronic acid and have been designed to prevent rapid breakdown by the body.
Injections of hyaluronic acid have been shown to last six to 12 months in HIV-positive individuals with lipoatrophy. It is cheaper than many other products, given that fewer touch-ups are needed. The product can easily be removed in the event of side effects or dissatisfaction with the results.
Post-injection recovery can be slightly uncomfortable. Large amounts of hyaluronic acid are needed for patients with moderate-to-severe facial lipoatrophy.
Poly-L-lactic acid (Sculptra, New-Fill): Poly-L-lactic acid is a synthetic product that has a long history of use in reconstructive surgery. Even though it is synthetic, it is eventually broken down and removed by the body, meaning that its effects are temporary. It is the only facial filler to be approved by the FDA for the reconstructive management of HIV-associated facial lipoatrophy. It usually requires between two and six treatment sessions, four to six weeks apart.
The safety and effectiveness of this product for HIV-associated lipoatrophy has been evaluated by the FDA. Even though it is considered to be a temporary filler, it appears to have a longer-lasting effect than most other temporary fillers. Repeat injections, within a year or two after an initial treatment, are likely necessary.
The cost of poly-L-lactic acid can be high, although the manufacturer of Sculptra (Dermik Laboratories) has implemented a sliding-scale fee for the product based on an individual's income. Multiple sessions can be cumbersome and increase the cost of treatment. Like calcium hydroxylapatite, poly-L-lactic acid can also cause nodules -- hard lumps -- at the injection site in some patients.
Semi-Permanent and Permanent Fillers
Silicone Oil (Silikon 1000, VitreSil 1000): Silicone comes in both solid and liquid formulations. Solid silicone is rarely used for facial lipoatrophy. Silicone oil is more commonly used, but its safety and effectiveness for cosmetic purposes are still controversial. At present, silicone oil is approved to treat retinal detachment; it is still being investigated for facial augmentation.
Silicone oil is safe and highly effective when injected in very small amounts (microdroplets). It's also very long lasting, limiting the cost and the need for follow-up procedures.
The most notable disadvantage of silicone oil is that it can't be removed. It can be toxic and damaging to the face if too much is injected. In some cases, silicone can migrate -- usually down toward the jaw line -- causing new cheeks to become jowls.
Polymethylmethacrylate (PMMA; Artecoll, Artefill): PMMA is best known for its use in manufacturing hard contact lenses and Plexiglas. The facial filler products contain small particles of PMMA that are surrounded by bovine collagen. Approximately three months after it is injected, the bovine collagen is broken down and removed from the body, but is replaced by natural collagen. The PMMA molecules and the surrounding collagen persist indefinitely. The FDA has indicated that it is safe and effective for the correction of facial wrinkles, lines, and furrows, but has not yet officially approved the product.
PMMA can be removed in the event of side effects or dissatisfaction with the end result. It is also relatively inexpensive. PMMA can cause side effects if large amounts are used. It can sometimes be felt, but rarely seen, under the skin in some people.
Expanded Polytetrafluoroethylene (ePTFE) Implants (Gore-Tex, Gore S.A.M., SoftForm): These solid implants require minor surgery, via a small incision, under local anesthesia. They have been used for many years to help restore deep facial defects and may be useful for HIV-associated lipoatrophy in terms of filling large, sunken areas. Some experts believe that ePTFE should be used in combination with other fillers, particularly those that spark collagen production in the dermis.
The implants are said to be one of the better options for people with severe lipoatrophy. They can be removed in the event of side effects or dissatisfaction with the end result.
Because minor surgery is involved to insert the implants, there is the possibility of post-operative complications, including infection and swelling. It can cause scarring around the implant and can be visible and felt if not inserted correctly.
Polyalkylimide (Bio-Alcamid): Polyalkylimide is a synthetic product that can be injected using a high volume, making it a possible option for HIV-positive individuals with severe lipoatrophy. There is very little experience testing or using Bio-Alcamid in the United States. However, it has been used in Europe for cosmetic and reconstructive purposes, with good results, and is the product of choice at a clinic in Tijuana that has yielded a lot of encouraging before-and-after photographs. An American division of the Italian company that makes Bio-Alcamid is planning clinical trials in the United States.
This is a long-lasting filler that can easily be removed in the event of over-filling, side effects, or dissatisfaction with the end results. Thus far, side effects have been minimal.
It is not available in the United States and, as of yet, there is very little sound, scientific data supporting its safety or effectiveness. It can be expensive, especially when international travel to and from clinics offering polyalkylimide injections is necessary.
Covering the Cost of Facial Fillers
Unfortunately for many people with HIV, these products -- and the expertise needed to inject them safely and effectively -- are a costly out-of-pocket expense well beyond their reach. Depending on the product, the cost can range anywhere between $800 and $15,000, not including provider fees. Few private health insurance companies cover the cost of these procedures, even for Sculptra, which has been approved by the FDA to treat facial lipoatrophy. And neither Medicaid nor ADAP covers the costs.
Some people with lipoatrophy have had luck getting their insurance companies to pay for facial fillers. Working with their doctors, some have been able to convince their insurance companies that they require the facial filler to restore their features lost to anti-HIV treatment, not simply for cosmetic purposes. This is similar to the successful argument made by many women with breast cancer who require a mastectomy and request that breast reconstruction be a covered expense.
Hopefully the medical establishment, particularly the HIV medical establishment, will universally accept these facial fillers as necessary restorative therapies for HIV-positive people with lipoatrophy. Fortunately, this is already happening and it may eventually result in routine coverage of these products and procedures by private and public insurers.
Where Do We Go From Here?
Researchers, obviously, have their work cut out for them. While they have come up with a handful of possible theories regarding what might be causing lipodystrophy -- and, more importantly, how it might be treated -- there are still no definitive answers.
The uncertainties of lipodystrophy research is frustrating, especially for people who are experiencing one or more of its symptoms. The truth is that there are no easy answers to come by. The good news is that this problem has become a major focus of research efforts -- there are a lot of scientists working on finding the answers we need.
If you are experiencing any symptoms of lipodystrophy, such as changes in your body shape, be sure to discuss them with your healthcare provider. And don't be afraid to discuss new information that you find in ACRIA Update or any other reputable treatment information resources. The AIDS epidemic has taught many of us to be resourceful with treatment strategies that are already available to us. Dealing with lipodystrophy will require the same optimistic approach, at least until effective therapies become available.
Tim Horn is Executive Editor of The PRN Notebook, published by the Physicians' Research Network, and Senior Editor of AIDSmeds.com. This article is an adaptation of two articles focusing on lipodystrophy and lipoatrophy available at www.AIDSmeds.com.