Changes to Your Face (Facial Lipoatrophy)

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Changes to Your Face (Facial Lipoatrophy)

Introduction

For many HIV-positive people, facial lipoatrophy (facial wasting) has become a frustrating reality. While facial lipoatrophy is not life-threatening, it is one of the most stigmatizing and troubling complications of HIV. Numerous studies and anecdotal reports have indicated that facial lipoatrophy can have detrimental effects on an affected person's self-confidence and quality of life, and can contribute significantly to depression. And because facial lipoatrophy is believed to be a side effect of anti-HIV therapy, it can significantly affect a person's "relationship" with his or her medications, possibly resulting in poor adherence or termination of therapy altogether, even if the medications are keeping viral load undetectable and the immune system healthy.

While it is true that researchers still haven't determined the exact mechanism by which lipoatrophy occurs, progress is at hand. This lesson focuses on what we do and don't know about facial lipoatrophy and includes a comprehensive overview of some of the treatments that are being studied (and approved) to help manage it.

What is lipoatrophy?

Lipoatrophy refers to an abnormal loss of body fat, most notably the fat immediately beneath the skin (subcutaneous fat). Lipoatrophy of the face is the primary topic of this lesson, but it can also occur in the arms, legs, buttocks, and around the waist.

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 other people. If the lipoatrophy worsens, the outlines of the facial muscles can be seen and felt through the skin. Here's an example:

Facial lipoatrophy can also cause diminished fat around the nose and mouth – the nasolabial region. 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, it can result in a skeletal appearance.

What causes lipoatrophy?

It's not yet clear why or how lipoatrophy occurs in HIV-positive people. However, it is believed to be a side effect of anti-HIV therapy.

Nucleoside reverse transcriptase inhibitors (NRTIs) have been singled out as the most likely cause of lipoatrophy. While it is not entirely clear why these particular drugs cause this side effect, it is probably related to the ability of these drugs to damage cellular mitochondria.

Mitochondria are considered to be the "powerhouses" of cells in the body. All cells in the body, with the exception of red blood cells, contain mitochondria. They are primarily responsible for converting nutrients, such as sugar and fats, into energy that can be used by the cells. If something goes wrong with the mitochondria, the cell isn't able to get the energy it needs, which can prevent the cell from doing what it is supposed to do. If the cells in question are fat cells (adipocytes), responsible for storing and exporting fat for when it is needed, significant mitochondrial damage can cause these cells to loose both their function and shape. And if enough fat cells are affected, it can cause noticeable wasting of fat tissue in the face and other parts of the body.

Zerit® (d4T, stavudine) is the NRTI most frequently tied to lipoatrophy. In test tube studies, Zerit has been shown to cause mitochondrial damage and to alter the function of adipocytes. Clinical trials also suggest that HIV-positive people taking drug regimens that contain Zerit are more likely to experience lipoatrophy than those taking drug regimens that do not contain Zerit. However, drug regimens that contain Retrovir® (AZT; zidovudine) have also been shown to cause lipoatrophy, although not as frequently as drug regimens containing Zerit. In other words, Zerit is probably not the only NRTI associated with lipoatrophy. Experts reckon that the NRTIs Viread® (tenofovir), Epivir® (3TC; lamivudine), Emtriva® (emtricitabine), and Ziagen® (abacavir) are the least likely to cause lipoatrophy.

Protease inhibitors (PIs) may be cause lipoatrophy as well. While they do not interfere with cellular mitochondria, they can affect other components of fat cells that, researchers have found, can affect the way adipocytes work. Some data from clinical trials involving HIV-positive people taking protease inhibitors also suggest that these drugs may be partly to blame for lipoatrophy.

Other factors that may increase (or decrease) the risk of lipoatrophy include age, gender, genetic predisposition, the T-cell count at the time therapy is started (the lower the T-cell count, the more likely it is the lipoatrophy will occur), and the length of time on antiretroviral therapy (the longer the time on therapy, the more likely that lipoatrophy will occur).

It is still not clear if lipoatrophy results from the death of adipocytes or poor functioning of adipocytes. If it turns out that the death of adipocytes is the cause, it may be much more difficult to treat lipoatrophy, given that it is hard to bring dead cells back to life. However, if the cause is related to poor functioning of adipocytes, the possibility of reversing lipoatrophy is much more feasible. Considering that studies have documented that some reversal of lipoatrophy is seen in HIV-positive people who switch an offending anti-HIV drug for another medication that is less likely to cause lipoatrophy, it looks as if poor functioning of adipocytes is a likely cause.

How can facial lipoatrophy be prevented?

As is explained in the last section of this lesson, it is still not clear how or why facial lipoatrophy 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, Zerit® (d4T, stavudine) is being prescribed much less frequently, and is being switched for other NRTIs in patients who are currently taking it, based on its connection to lipoatrophy. This, in turn, may help to reduce the risk of lipoatrophy.

Another possible way to prevent lipoatrophy is to begin anti-HIV therapy before the T-cell count falls to very low levels. Fortunately, federal guidelines already warn against this.

How can facial lipoatrophy be treated?

Because we do not yet fully understand how or why lipoatrophy occurs in HIV-positive people, the development of treatments has been challenging. Fortunately, the effective management of facial lipoatrophy has been a priority for several researchers and for companies with promising products. Here is a quick look at some of the treatment options being explored in research:

Switching therapies: For HIV-positive people who have developed lipoatrophy while taking a drug regimen that contains a suspect medication – Zerit or Retrovir, for example – one option might be to change these drugs for another drug that is less likely to cause lipoatrophy (for example, Viread or Ziagen). This, many experts point out, is the easiest of all the possible treatment approaches. 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.

Adjunctive therapies: We don't yet have any medications that have been proven to be safe and effective for the management of facial lipoatrophy. 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 rosiglitazone (Avandia®) and pioglitazone (Actos®), are approved for the treatment of diabetes. These medications have been shown to stimulate a gene (PPAR-gamma) that plays a vital role in regulating triglycerides, managing blood sugar levels, and promoting healthy adipocyte function. In turn, they have been studied in a handful of clinical trials involving patients with lipoatrophy. Results, however, have been mixed. Some studies found that these therapies helped to reverse lipoatrophy while others failed to note any improvements. There are also lingering concerns about using this class of drugs in non-diabetic patients.

Facial fillers: There has been a lot of interest in restorative therapies – such as facial filler injections and implants – for facial lipoatrophy. One facial filler, poly-L-lactic acid (Sculptra™), was approved by the U.S. Food and Drug Administration (FDA) in August 2004, and several other facial fillers are being studied all over the world for HIV-positive people with facial lipoatrophy. There are important similarities and differences between the various facial fillers being studied, which are the focus of the remainder of this lesson.

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. While there are a number of specific differences between the various fillers being studied (and used) in HIV-positive people with lipoatrophy, there are some general differences to know about:

Organic vs. synthetic: Fillers are either organic or synthetic. Organic fillers are naturally derived – that is, they are derived from humans, animals, or botanicals – and are biodegradable. Synthetic fillers are generally man-made materials that are not biodegradable.

Temporary vs. semi-permanent vs. permanent: Facial fillers are classified as 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 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 can 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 is 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 Board-certified plastic surgeon or dermatologist with experience using the product selected to treat the facial lipoatrophy. Just as it is important to make sure that a product has been documented to be safe and effective, it is also important to ensure that a qualified and experienced medical provider performs the procedure.

Where are facial fillers injected?

Skin is not just a simple flat sheet, but is composed of several layers: the epidermis, the dermis, and the hypodermis. The epidermis is the outer layer of skin. The dermis contains fibroblasts (cells that produce fibrous connective tissues including collagen), hair follicles, sebaceous (oil) glands, apocrine (scent) glands, blood vessels, and nerves. The hypodermis, or subcutaneous layer, contains the fat cells that help to give the skin shape and thickness, along with larger blood vessels. The loss of fat in the hypodermis is what causes lipoatrophy.

Facial fillers involve either the dermis or the hypodermis. Most facial fillers involve injections into the dermis, to thicken the skin. Some facial fillers involve injections into the hypodermis to fill the space once held by fat. Because these layers are only millimeters thick, expertise is required to ensure that the injections are performed safety and that the product is injected or inserted into the correct layer of skin.

What are some of the temporary fillers?

Temporary Fillers

Advantages

Disadvantages

Cost

Availability in the U.S.

Autologous fat transplant: 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 into another part of the body, such as the face.

Most natural of all the facial fillers. Good results and 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. Has been shown to last anywhere from six months to two years in some studies involving HIV-positive patients. Might be possible to increase the length of benefits through a method that involves injecting fat into the muscles of the face.

Fat can be difficult to harvest from other parts of the body, especially in HIV-positive people with advanced lipoatrophy lacking in subcutaneous fat. Post-surgical recovery can be uncomfortable and take several days. Injected fat can sometimes become abnormally enlarged (hypertrophy); this is more often seen in patients who have fat taken from existing "buffalo humps" to fill hollows in the face.

$4,000 to $6,000 per office visit, with approximately three visits over a two-year period.

Yes. Offered by many plastic surgeons who regularly perform liposuction.

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 the product 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 and limited.

Possibility of allergic reaction or severe scarring (necrosis). Can be expensive, given that a single course of injections only lasts three to five months. 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 lipoatrophy. Probably best for people with mild-to-moderate facial lipoatrophy.

Approximately $600 per visit, with an average of five visits over a two-year period ($2,500 in total for two years of therapy).

Widely available, although not specifically approved by the FDA for the treatment of facial lipoatrophy.

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 sterilizing, testing, and processing. Allergy testing is not necessary.

FDA approved and are readily available. Impressive filling of hollows in the face, at least initially.

Very temporary, with injections lasting approximately one to three months. Requires a large-gauge needle for injection. Can be very expensive, given the need for frequent touch-ups.

Can cost more than $2,000 per year.

Widely available, although not specifically approved by the FDA for the treatment of facial lipoatrophy.

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. Cheaper than many other products, given that fewer touch-ups are needed. Can easily be removed in the event of side effects or dissatisfaction with the end results.

Post-injection recovery can be slightly uncomfortable. Large volumes are needed for patients with moderate-to-severe facial lipoatrophy.

Approximately $1,500 per visit, depending on the brand and volume of hyaluronic acid needed and the treatment fee charged by the specialist.

Only Restylane is approved for use in the United States. Perlane and Hylaform are available in Europe and South America.

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 is injected into the dermis layer of skin, 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.

Can be very expensive. Can also cause nodules – hard lumps – at the injection site (they can be felt but not usually seen) in some patients.

As much as $3,000 per office visit.

Currently being explored in clinical studies for HIV-associated facial lipoatrophy – at cost to the patient.

Poly-l-lactic acid (Sculptraâ„¢, New-Fillâ„¢): 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. Usually requires between two and six treatment sessions every four to six weeks.

Safety and effectiveness have 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. Can also cause nodules – hard lumps – at the injection site (they can be felt but not usually seen) in some patients.

Approximately $1,500 per visit, depending on the amount of poly-L-lactic acid needed and the treatment fee charged by the specialist.

FDA approved for HIV-associated facial lipoatrophy with many specialists throughout the country now providing access to treatment. Dermik Laboratories has developed a searchable database to help HIV-positive individuals locate a nearby specialist offering this service: click here.

What about semi-permanent and permanent fillers?

All of the semi-permanent and permanent fillers reviewed here are synthetic products and are not readily broken down and removed by the body. In other words, they are supposed to have lasting effects upon being injected or inserted into the face. Semi-permanent fillers can be removed, usually through a minor procedure, in the event of side effects of dissatisfaction with the results. Permanent fillers cannot be easily removed.

Semi-Permanent and Permanent Fillers

Advantages

Disadvantages

Cost

Availability in the U.S.

Silicone Oil (Silikon® 1000, VitreSil® 1000): Silicone comes in solid formulations 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 for eye repair only; it is still being investigated for facial augmentation.

Safe and highly effective when injected in very small volumes (microdroplets). Very long lasting, limiting the cost and the need for follow-up procedures.

Cannot be removed. 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.

Highly variable, depending on amount of silicone used and costs associated with the procedure.

Although it is not approved for cosmetic purposes, silicone is widely available. Be sure that silicone injections are performed by a reputable, knowledgeable, and experienced healthcare provider.

Polymethylmethacrylate (PMMA; Artecoll®, Artefill®): PMMA is best known for its use in manufacturing hard contact lenses and Plexiglas. These products contain small particles (microspheres) 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 is safe and effective for the correction of facial wrinkles, lines, and furrows, but has not yet officially approved the product.

Semi-permanent; can be removed in the event of side effects or dissatisfaction with the end result. Relatively inexpensive.

Can cause side effects if large amounts of PMMA are used. Can sometimes be felt, but rarely seen, under the skin in some people.

$800 to $2,500 for product and insertion.

Not readily available, given that FDA approval is pending. Available in Mexico and Brazil.

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.

An option for HIV-positive people with severe lipoatrophy. Semi-permanent; can be removed in the event of side effects or dissatisfaction with the end result.

Post-operative complications, including infection and swelling. Can cause fibrosis/scarring around the implant. Can be visible and felt if not inserted correctly.

Expensive; approximately $2,000 per cheek.

Widely available, although none of the ePTFE implants are specifically approved by the FDA for the treatment of facial lipoatrophy.

Polyalkylimide (Bio-Alcamidâ„¢): 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.

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.

Not yet available in the United States. Very little sound, scientific data supporting its safety or effectiveness. Expensive, especially when international travel to and from clinics offering polyalkylimide injections are necessary.

Total costs of approximately $4,500 – including travel, the necessary amount of product, and injections – have been cited.

Not yet available in the United States. Many HIV-positive people in the United States have visited the Clinic'estetica in Tijuana, Mexico for the procedure.

Does insurance cover the cost of these facial fillers?

The truth of the matter is that few private health insurance companies are routinely covering the cost of these procedures, even for poly-L-lactic acid, which has been approved for use in HIV-positive people with facial lipoatrophy. And at this point in time, neither Medicaid nor ADAP are covering the costs of these procedures.

This is not to say that some people haven't had luck getting their insurance companies to pay for facial fillers. Working with their doctors, HIV-positive people with lipoatrophy have been able to convince their insurance companies that they require the facial filler to restore their facial features lost to anti-HIV treatment, not simply for cosmetic purposes. This is very similar to the successful argument made by many women with breast cancer, who required a mastectomy, and request that breast reconstruction be a covered expense.

It is with hope that 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. This may eventually result in routine coverage of these products and procedures by private and public health insurers.

Unfortunately, for many HIV-positive people with facial lipoatrophy, these products – and the expertise needed to inject these products safely and effectively – is and out-of-pocket and costly expense.

Last Revised: 4/12/05

This content is written by the Founder & Writers of AIDSmeds.com, and reviewed by Dr. Grossman, our Medical Editor.Please find profiles of this writing team on our "About Us" page.

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