Looking in the mirror can be a humbling experience. For HIV positive people with facial wasting, or lipoatrophy, the experience can be traumatic. Facial lipoatrophy refers to subcutaneous fat loss in the cheeks and temples resulting in a bony, emaciated appearance. The condition may be mild to severe. As with other symptoms of lipodystrophy, or body fat abnormality syndrome (such as fat loss in the limbs and buttocks, and fat accumulation in the abdomen), the only thing known for certain about facial wasting is that it exists; precise causes have not been identified and successful strategies to prevent the condition remain elusive. A recently developed cosmetic treatment for facial wasting, polylactic acid (PLA) or New-Fill, appears to be well tolerated in European clinical trials and anecdotal reports. Although the treatment has been approved in Europe and Mexico, several hurdles stand in the way of PLA access in the U.S.

Visual Disconnect

Unlike the body wasting (cachexia) associated with AIDS earlier in the epidemic, facial wasting and other manifestations of lipodystrophy are not typically indicative of progressive, late-stage HIV disease. Many people with facial wasting are able to manage HIV infection with currently available anti-HIV drugs. Having an outward appearance of illness and fatigue, however, can be especially traumatizing to people who do not otherwise feel markedly unwell, and experts are concerned that the psychological impact of facial wasting may have secondary, adverse effects on an individual's health.

People with facial wasting and other symptoms of lipodystrophy have reported psychological disturbances stemming directly from the change in their appearance, including depression, anxiety, social isolation, reduced confidence and self-worth, and lack of sexual interest. These issues are not frivolous: some researchers have found that increases in psychological distress-including depression and dissatisfaction with social support networks-can weaken immune system function and accelerate disease progression in those with HIV infection. Facial wasting may further compound psychological distress already experienced by people with HIV, who tend to have higher rates of depressive disorders than the general population, according to a report in the May 2001 issue of the American Journal of Psychiatry. Additionally, changes in physical appearance may contribute to stress and anxiety by making it impossible to keep one's HIV positive status confidential among friends, family, and coworkers.

Psychological distress due to body image concerns also might have a negative impact on drug treatment. People with facial wasting may completely stop or become less adherent to their drug regimens due to depression or as a reaction to the perceived cause of the wasting problem: anti-HIV medications (see "Cause Unclear, Interventions Lacking" sidebar). Others, fearful of potential facial wasting, may delay starting anti-HIV therapy. One reason for the current interest in structured treatment interruption (STI, a closely monitored series of on-drug/off-drug cycles) and switch studies are numerous anecdotal reports of people taking "drug holidays" (unmonitored periods of time off drugs) in response to lipoatrophy and other apparent adverse drug reactions.

While some HIV positive people with facial fat loss have expressed satisfaction with their altered appearance (for example, they may prefer having more angular features), for many people facial wasting is a disturbing problem. Studies have shown that the problem is not imaginary or merely the symptom of a distorted perception of one's own body. Unusual, HIV-related facial lipoatrophy has been measured with ultrasonography (an imaging technique using sound waves) and physical examination (including the use of fat-measuring calipers), and documented with photographic evidence. For a number of people, one cosmetic solution to this very real problem, at least on a temporary basis, has been PLA.

The Natural Look

According to Biotech Industry S.A., the company in Luxembourg that markets the New-Fill brand of polylactic acid, PLA is a nontoxic synthetic compound that is immunologically inactive (having no effect on the immune system) and easily absorbed within the body. PLA has been used safely for over forty years in reconstructive surgery (e.g., of the head and neck), as an ingredient in surgical sutures, and as a vector for sustained release of medication. In November 1999 the New-Fill brand of PLA was approved in Europe for aesthetic correction of scars and wrinkles by G-MED, the authority that assesses and approves medical devices in the European Union. New-Fill also was approved in Mexico in 2000, but has not been approved by the U.S. Food and Drug Administration (FDA); see "The FDA Steps In" below. References to PLA throughout the rest of this article refer to New-Fill.

PLA is sold in kits containing two vials (150 mg each) of the substance in powder form; each vial should be used for one side of the face. Mixing 150 mg of PLA powder with 2 mL of sterile water produces a gel-like substance that, when injected properly under the skin, causes an initial filling-in of wasted areas, although the liquid is resorbed by the body within a week. The PLA particles that remain, however, stimulate collagen growth that produces a natural appearance mimicking the addition of new layers of fat in areas of wasting. Collagen is an organic protein substance found in bone, skin, and connective tissues (e.g., cartilage and tendons). Readers should note that PLA is a cosmetic treatment only, not a therapy for underlying causes of facial wasting.

Injection Procedure

PLA must be injected with a needle by a clinician trained specifically in treating HIV-related facial wasting. Elisabeth Laglenne, MD, general manager of Biotech Industry, was among the first to try using PLA to restore facial fat loss in people with HIV. "The indication for lipoatrophy was fortuitous," says Dr. Laglenne. "I treated a friend-my first patient-for lipoatrophy in September 1999 and, after five sessions [spaced 15 days apart], his face was again quite normal." Patrick Amard, MD, a maxillofacial surgeon based in Paris, presented the first preliminary studies of PLA for wasting (see below). While both claim to have originated the procedure for facial lipoatrophy, the two physicians (along with Thierry Saint-Marc, MD, of Lyons, France) clearly were in the vanguard with this unique use of PLA and both have trained other clinicians in the technique. Dr. Amard cautions that without special training, even clinicians familiar with other injectable implants are likely to achieve disappointing results with PLA.

The procedure involves an initial series of deep injections (about 20 on each side of the face), followed by two to six further series of less invasive injections spaced at least two weeks apart. The number of injection cycles tends to be higher in those with more severe wasting, wasting in multiple areas, male gender, older age, or thicker skin. People with darker skin have better results, says Dr. Laglenne. To date it appears that the initial round of injections triggers sufficient collagen production to last approximately 12-18 months, at which time further injections may be needed to maintain an improved appearance.

The injections themselves can be painful. Pain may be reduced by applying ice to the skin prior to the injections, by using a local anesthetic such as topical lidocaine (Anestacon, Lidoderm), or by adding lidocaine HCL (Xylocaine) or procaine HCL (Novocain) to the PLA/water mixture. Most people report little or no pain following the procedure, especially if the face is massaged by the clinician immediately after the injections. Massaging the face for up to 24 hours may reduce the likelihood of small nodes or lumps forming in treated areas.

Clinical Studies

Several studies of PLA's safety and effectiveness in people with HIV have been conducted in Europe. Results so far have been encouraging; while not all study participants have seen a return to their normal (prewasting) appearance, almost all have noted a remarkable improvement.

People with HIV developed an interest in PLA after community health media reported on 24-week data from a small study presented by Dr. Amard and colleagues at the 2nd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV in September 2000. According to Dr. Amard's team, 22 of 26 HIV positive men treated with a series of facial PLA injections reported that their lipoatrophy had been completely reversed and their faces restored to their prewasting appearance as measured by physical exam; the remaining four subjects showed "major improvements" in their physical appearance. Ultrasonography of the cheeks showed that at 24 weeks, the mean fat thickness increased by 0.014 mm (+3.11%) and the mean dermal (skin) thickness increased by about 5.3 mm (+154%) from baseline. In addition, PLA was well tolerated. Data from 54 weeks of follow-up presented at the 2nd European Workshop on Lipodystrophy in April 2001 showed similarly promising results.

Preliminary data from another recent study, known as VEGA, were reported at the VIII European Conference on Clinical Aspects and Treatment of HIV Infection in October 2001. According to Dr. Camille Aubron-Olivier and colleagues from the Hôpital Pitié-Salpêtrière in Paris, this pilot study enrolled 50 subjects (one female) with severe facial lipoatrophy defined as having less than 2 mm of adipose (fat) tissue in the Bichat fat pad (cheek) area. The median adipose tissue thickness at baseline was 0 mm. All subjects were undergoing treatment with antiretroviral therapy: 48 of 50 (96%) were taking NRTIs, 30 of 50 (60%) were taking protease inhibitors (PIs), and 22 of 50 (40%) were taking non-nucleoside reverse transcriptase inhibitors (NNRTIs). Subjects had been taking anti-HIV therapy for an average of 8.6 years. The median CD4 cell count was 396 cells/mm3, and the median HIV viral load was 2.3 log copies/mL. PLA injections were given on days 0, 15, 30, and 45, followed by a fifth round of injections on day 60 in those whose total cutaneous (skin) thickness, or TCT, remained below 8 mm (using ultrasonography). The median TCT at baseline was 2.9 mm; a TCT of at least 10 mm was one of the study endpoints.

As with Dr. Amard's study, the results were promising. By month 2, with 48 subjects remaining, the median TCT increased significantly to 8.1 mm (4.9-11.9 mm range). By month 6, the median TCT in the same group of 48 increased to 9.5 mm (6-12.6 mm range), with 19 (40%) achieving a TCT greater than 10 mm. Photographs accompanying Dr. Aubron-Olivier's slide presentation showed highly visible, natural-looking improvements in the facial appearance of several subjects (these photos were not available for publication in BETA).

According to Dr. Aubron-Olivier's team, all subjects reported satisfaction with the treatment. No serious adverse events were observed. Nearly all subjects experienced slight edema (swelling) at the injection site that resolved within 48 hours. Small (3-5 mm), invisible but palpable subcutaneous nodes were detected in 10% of subjects between months 3 and 6; the nodes appeared to "decrease further on," according to the researchers. Fifteen people with pre-existing dilated facial capillary vessels experienced minimal ecchymosis (bruising or purple spots due to ruptured vessels); all rapidly resolved.
Studies completed so far demonstrate short-term promise for using PLA to treat HIV-related facial wasting. Nevertheless, as Dr. Aubron-Olivier points out, long-term efficacy and tolerability of PLA in people with HIV remain to be assessed. As people with HIV live longer due to antiretroviral treatment, gathering long-term data becomes increasingly necessary.

Anecdotal Reports

In 2001 word of impressive results in PLA trials, no matter how preliminary, and anecdotal tales from satisfied patients spread quickly among people with HIV and contributed to a high level of excitement in the community press. The enthusiasm for PLA is understandable: for many people with access to PLA, this injectable compound has had a profound, Lazarus-like effect on their quality of life. John Stevens, from the UK Coalition of People Living with HIV and AIDS in London, told BETA that he had a successful outcome with the procedure and no problems to report after six months. He also mentioned that he is "still a little overwhelmed" by PLA's positive impact on his well-being. "I can't believe how different my quality of life is." Some people with severe wasting, however, have reported disappointing outcomes even after six or seven cycles of injections.

The FDA Steps In

Despite the mainly good clinical and anecdotal news about PLA, few people in the U.S. currently have access to the treatment. Since October 2001 the FDA has considered PLA to be an unapproved medical "device" and therefore subject to further review and testing before it can be distributed and used legally in the U.S. Those who started their PLA injections before October have been unable to continue purchasing the substance for their own personal use (see below); however, it appears that enough PLA already had been distributed to allow these people to complete their treatment.

Prior to being classified as a device, PLA was available either directly from the manufacturer in Luxembourg or through the Direct Access Alternative Information Resources (DAAIR) nonprofit buyer's club in New York City, which started distributing PLA in July 2001. Those buying PLA through DAAIR, at $250 per two-vial kit, were required to pay buyer's club membership dues and furnish DAAIR with a physician's prescription as well as a personal use importation form. According to DAAIR, the importation document was required by the FDA, which had sanctioned access to PLA as an unapproved drug (not a device) under the "personal use guidelines" established by the FDA in 1988. These guidelines-formally issued following drug importation demonstrations by AIDS activists in the late 1980s, but discreetly observed by the FDA for many years prior-allow people in the U.S. to import for their personal use small quantities (a three-month supply or less) of medicine approved abroad.

Direct consumer access to PLA came to an end when a shipment of approximately $25,000 worth of New-Fill, ordered by DAAIR, was stopped from entering the country by the U.S. Customs Service in October 2001. An FDA spokesperson explained that this shipment-and a phone call from DAAIR about its holdup in customs-first alerted the FDA that significant amounts of PLA were entering the country "for commercial distribution, not personal use."

After looking at the contents of the shipment, the FDA, including members of the agency's Center for Devices and Radiological Health (CDRH), concluded moreover that the personal use guidelines do not apply to PLA because it is in fact a device. The FDA responded to this author's queries about the agency's assessment of PLA with the following statement:

New-Fill is classified as a device because of the way it is intended to be used, and the way it works. Devices include products, including implants, that are intended to affect the structure or function of the body, and do not achieve their intended purposes through chemical action within or on the body, and which are not dependent upon being metabolized to achieve their primary intended purposes. New-Fill has not, to our knowledge, been studied for this indication in Europe, and the clinical trial data for the current indication of filling small lines, wrinkles, and skin depressions have not been submitted to the FDA.

The FDA further commented that "since this product needs to be injected by a trained physician, it does not fall within the personal use guidelines." Indeed, most drugs imported under the personal use guidelines have been pills that can be taken by an individual without a clinician's intervention. Collagen and other materials used in cosmetic surgery are assessed and approved by the CDRH, not the FDA's Center for Drug Evaluation and Research (CDER).

The FDA also stated that "DAAIR's promotional material was misleading, containing unsubstantiated statements about the product's safety and effectiveness." In addition, the FDA claimed that DAAIR's distribution of PLA "offered no patient protections, such as informed consent outlining the regulatory status of the product, possible risks, etc. Patients were asked, instead, to sign a release of liability."

Fred Bingham, executive director of DAAIR, questions the FDA's concerns about PLA's safety, and speculates that there may be commercial reasons (i.e., relating to other products being considered for approval) behind the FDA's decision. As for the issue of DAAIR's large shipment prompting closer scrutiny from the FDA, Bingham maintains that "there wasn't a lot of PLA coming into the country."

Dr. Laglenne offered another explanation for why the U.S. government agency took an unexpected interest in her company's product. "The problem with the FDA," she says, is that "a doctor in the U.S....advertised New-Fill, which is forbidden."

Not surprisingly, the FDA's decision to halt personal use importation of PLA came as a blow to many people with HIV. Yet some treatment advocates feel that FDA monitoring of PLA ultimately will prove advantageous to more people. As Daniel Berger, MD, of NorthStar Medical Center in Chicago (who is trained to inject PLA for facial wasting) commented, "The only way to get a good product to everyone who needs it is to get [PLA] approved." According to Dr. Berger, classifying PLA as a device may involve a shorter approval process than if it were investigated as a new drug, especially if earlier safety studies of polylactic acid used for surgical procedures are considered adequate by the FDA and do not need to be duplicated. Others believe the FDA acted out of a genuine concern about HIV-related safety issues, since PLA for cosmetic uses had been studied in cohorts of HIV negative people.

U.S. Trials and Beyond

Furthermore, despite lingering confusion about the events of this past autumn, the FDA has not banned PLA entirely from the U.S. Clinicians may import PLA and treat a limited number of people who did not use it prior to October 2001, provided the clinician applies for and receives an Investigational Device Exemption (IDE) from the FDA. An IDE protocol, unlike the personal use guidelines for drugs, requires clinicians to collect data and make their findings available to FDA monitoring bodies. Such data collection is necessary for determining long-term performance and safety of a medical device; an IDE protocol therefore is considered a clinical trial, according to a CDRH spokesperson. Yet while Dr. Laglenne says that "many [U.S.] doctors want to begin clinical trials," to date very few U.S. clinicians have applied for an IDE; one, Peter Engelhard, D.O., of Miami Beach, Florida, received an IDE to treat 200 people in late December 2001. Since it is not known if or when other types of PLA trials will begin enrolling, people unable to obtain treatment from a clinician with an IDE have one other option: travel abroad (repeatedly) for their PLA injections.

Nelson Vergel of the Program for Wellness Restoration (PoWeR) in Houston, Texas, and other treatment advocates are concerned that clinicians with an IDE may overcharge their patients to profit from what is essentially an investigational (i.e., unapproved) procedure done under the aegis of the FDA. "It's not fair to be making money on an IDE," says Vergel. Such advocates hope that clinicians with an IDE will establish fees that are equal to their costs. Interestingly, Drs. Laglenne and Amard both claim to have treated many people with HIV in Europe free of charge.

Even if PLA eventually is approved by the FDA, several obstacles are likely to prevent large numbers of HIV positive people in the U.S. from using the substance. Cost is one factor. The price of PLA itself must be multiplied not only by the number of injection cycles, but also by the fees charged by a clinician ($500 or more per visit in 2001, before the FDA halted personal use importation). Some clinicians and advocates argue that Biotech Industry should lower the cost of PLA for treating HIV-related wasting, which requires far more product to be used than the amount needed to treat wrinkles. Pricing issues are likely to play a major role in access (as in Europe) primarily because PLA is considered a cosmetic treatment, and is not likely to be covered by health insurance. Physicians who can justify facial injections as a treatment for a drug-related side effect, however, may have more success in obtaining reimbursement. Another obstacle would be access to a trained clinician; at present, the number of clinicians able to perform the procedure is quite small and mostly limited to a handful of large U.S. cities.

While Dr. Laglenne states that Biotech Industry is able to manufacture enough PLA to keep up with demand, especially in Europe, approval in the U.S. might place a burden on the small company's production capacity. If problems with increasing output arise, Biotech Industry conceivably could sell PLA manufacturing rights to a larger U.S. pharmaceutical company such as Johnson & Johnson, which already produces a PLA material used in resorbable surgical sutures.

Other Treatments

Other cosmetic treatments for facial lipoatrophy are available in the U.S. According to Michael Echavez, MD, a plastic surgeon based in San Francisco who has treated people with HIV-related facial lipoatrophy, a few (see below) have led to good results in some people, though to date none compare to PLA. (Dr. Echavez started using PLA in July 2001, and claims that all of his patients improved in appearance after the treatment.)

Collagen can be injected in areas of facial atrophy to give the face a fuller appearance, but it is resorbed by the body within a few months. Injections of Cymetra, a form of human dermal tissue (also marketed in sheets of tissue as AlloDerm), last longer than collagen treatments (typically 6-12 months) and are more expensive. Synthetic implants, such as the SoftForm implant, can achieve good results, although they work well only in the cheek area, says Dr. Echavez. Excision of deep skin folds in the face, as well as dermal or fat grafts from the individual's own tissue, may achieve a more natural appearance, though transplanted fat tends to be absorbed quickly by the body.

The FDA also is currently considering approval of the Artecoll formulation of polymethylmethacrylate (PMMA) suspended in bovine (cow-derived) collagen to treat wrinkles. A Brazilian study of PMMA, presented in October 2001 at the international lipodystrophy workshop, reportedly showed some success in reversing HIV-related facial wasting. Several other cosmetic products, such as polyacrylamide gel, are being investigated (or simply used off-label) outside the U.S. for HIV-related facial wasting, particularly in Europe and Latin America. Many of these products (such as silicone gel) have not been approved or studied by the FDA due to safety concerns and the risk of poor outcomes. Results from the use of several unapproved products will be reported in late April 2002 at the 3rd European Workshop on Lipodystrophy and Metabolic Disorders in Marbella, Spain.

People considering any form of aesthetic treatment, including PLA, should consult a physician and gather as much scientifically accurate information as possible before being treated. Infection and other complications may arise, even when using approved products.

Advocacy and Coping Strategies

Many people with HIV consider facial lipoatrophy to be distressing and stigmatizing. While a few treatments are available, most are temporary, experimental, costly, and limited in availability. People in the U.S. with an interest in using PLA may want to contact the manufacturer and the FDA to advocate for greater access to the product, as well as for additional studies to be conducted (see "Resources" sidebar for contact information). Likewise, U.S. clinicians trained to use PLA in HIV positive people should be encouraged to apply for an IDE.

In addition to exploring cosmetic remedies, and until specific causes of lipodystrophy are known and treatable, people who experience psychological distress related to their appearance should consider different coping strategies. Depression can be treated successfully-even in people with late-stage AIDS-with drug therapy, psychotherapy (individually or in a group), or by using a combination of both approaches. Similarly, improving and sustaining social networks can greatly enhance a sense of well-being.

Nicholas Cheonis is associate editor of BETA.

Selected Sources

Amard, P. and others. The effects of polylactic acid (PLA) as therapy for lipoatrophy of the face. 2nd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV. Toronto, Ontario. September 13-15, 2000. Abstract P94.

Aubron-Olivier, C. and others. VEGA: an open pilot study of polylactic acid filler (Newfill) in HIV infected patients with severe facial lipoatrophy. VIII European Conference on Clinical Aspects and Treatment of HIV Infection. Athens, Greece. October 27-30, 2001.

Carr, A. and others. "Switching stavudine or zidovudine to abacavir for HIV lipoatrophy: a randomised, controlled, open-label, multicentre, 24-week study", 9th CROI. Seattle, Washington. February 24-28, 2002. Abstract 32.

Carr, A. and others. "A syndrome of lipoatrophy, lactic acidaemia and liver dysfunction associated with HIV nucleoside analogue therapy: contribution to protease inhibitor-related lipodystrophy syndrome", AIDS 2000 Feb 18;14(3):F25-32.

Ciesla, J.A. and Roberts, J.E. "Meta-analysis of the relationship between HIV infection and risk for depressive disorders", Am J Psychiatry 2001 May;158(5):725-30.

Clark, A. Improvement in facial atrophy after substitution of stavudine. 2nd International Workshop on Adverse Drug Reactions and Lipodystrophy. Abstract P85.

Cole, S.W. and Kemeny, M.E. Psychobiology of HIV infection. Critical Reviews in Neurobiology 11: 298-321. 1997.

DAAIR. New-Fill/PLA Information Sheet (www.daair.org). Accessed January 8, 2002.

Frieze, G. and others. Psychological assessment of patients referred to a multidisciplinary lipodystrophy/metabolic clinic. 7th Annual Conference of the British HIV Association. Brighton, UK. April 27-29, 2001. Abstract P15.

Leserman, J. and others. Impact of stressful life events, depression, social support, coping, and cortisol on progression to AIDS. Am J Psychiatry 2000 Aug;157(8):1221-8.

Paterson, D. and others. "How much adherence is enough? A prospective study of adherence to protease inhibitor therapy using MEMSCaps", 6th Conference on Retroviruses and Opportunistic Infections. Chicago. January 31-February 4, 1999. Abstract 92.

Vergel, N. Facial wasting-potential cosmetic procedures. Metabolics (www.medibolics.com/FacialWasting&Cosmetics.htm). June 2001. Accessed February 28, 2002.

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