HIV lipoatrophy

Cosmetic Dermatologist in NYC

Comparison of Poly-L-lactic Acid and Calcium Hydroxylapatite for Treating Human Immunodeficiency Virus-Associated Facial Lipoatrophy

Eric S. Sdiweiger, MD; Christy C. Riddle, MD; Betsy J. Wernli, BA; Viseslav Tonkovic-Capin, MD

Human immunodeficiency virus (HlV)-associated lipodystrophy syndrome is a condition that may affect patients with HIV infection. It is characterized by both metabolic disturbances and changes in distribu­tion of adipose tissue, including lipoatrophy of the face. Poly-L-lactic acid and calcium hydroxy I apatite are commonly used, long-lasting, nonpermanent fillers that are approved by the US Food and Drug Administration to treat facial iipoatrophy.This article reviews the current literature on,and compares the use of, these products in HIV-associated facial lipoatrophy. Both poly-L-lactic acid and calcium hydroxyt-apatite appear to be safe and effective for treating HIV-associated facial lipoatrophy, and both are viable treatment options.

uman immunodeficiency virus (HIV)-associated lipodystrophy syndrome is a condition that may affect patients with HIV infection, especially those taking highly active antiretroviral therapy. First described in 1998, the syndrome is characterized by hyperlipidemia, insulin resistance, and lipodystrophy.1 The lipodystrophy manifests as lipoatrophy of the face, arms, legs, and buttocks and lipohypertrophy of the abdominal viscera, breasts, and dorsocervical neck (buffalo hump). Patients with the syndrome may have different combina­tions of these conditions with varying degrees of severity.2 The etiology of HIV-associated lipodystrophy has been studied extensively and has been linked to the use of protease inhibitors1-3’4 and nucleoside reverse transcrip-tase inhibitors,5 with synergy from the combination of the antiretroviral classes.4 In addition, drug-independent risk factors such as disease length and severity have also been linked to expression of the syndrome,6 A study by Miller et al7 found that approximately half of patients on highly active antiretroviral therapy met the criteria for lipodys­trophy. It also affects patients with HIV infection who are not on antiretroviral therapy, though less commonly.8

Although HIV-associated lipodystrophy syndrome has several manifestations, the most distressing to the patient is often facial lipoatrophy, which patients feel stigmatizes them. In addition, quality of life has been shown to be worse in patients with lipoatrophy,9-10 and fear of developing the syndrome may lead to medica­tion noncompliance,11

Several medical therapies have attempted to reduce or reverse lipodystrophy. Interventions include admin­istering insulin-sensitizing diabetic agents in the thiazolidinedione class,12"17 modifying or switching antiret­roviral therapies, >s~22 and using hormonal therapy.2"6 Treat­ments thus far have been ineffective or only marginally effective, prompting patients to seek reconstructive ther­apy options.

Several reconstructive options are available to treat facial lipoatrophy in patients with HIV-associated lipodys-trophy syndrome. These include surgical device implan­tation,27"3" autologous fat transfer,31-3* and injectable fillers.33-34 Injectable fillers can be classified as temporary, such as collagen, cadaveric dermal tissue, and hyaluronic acid (lasting =3-24 months); semipermanent, including poly-L-lactic acid (PLLA) and calcium hydroxylapatite (CaHA) (lasting 1-2 years); and permanent, such as liq­uid injectable silicone (lasting several years).

This article will compare 2 semipermanent fillers: CaHA and PLLA. Both are approved by the US Food and Drug Administration (FDA) for soft tissue filling and volume augmentation and are used in the treatment of HIV-associated facial lipoatrophy

POLY-L-LACTIC ACID

PLLA is a soft tissue filler approved by the FDA for treat­ing HIV-associated facial lipoatrophy.35 Its FDA approval came in August 2004, but it is not new to medicine, as it has been used safely for the past 30 years in sutures, reconstructive surgery pins, screws, soft tissue implants, and other medical devices.36 In addition, its use in cos­metic applications has been prevalent outside the United Stales since 1999, when it was approved in the European Union for restoring volume to depressed areas, including scars, creases, wrinkles, and folds.-17 In February 2004, the European indication for large-volume application of PLLA was added, allowing practitioners to address facial lipoat­rophy PLLA has been used in an estimated 150,000 people in more than 30 countries for facial volume and contour deficiencies.37

PLLA is biodegradable and biocompatible, derived from corn dextrose fermentation. One vial contains 90 mg sodium carboxymethylcellulose, 150 mg freeze-dried PLLA powder, and 127.5 mg pyrogen-free man-nitol, to which sterile water (usually 3-5 mL) is added preinjection. Different amounts of liquid may be added to dilute the solution; using larger amounts may decrease the frequency of adverse reactions. Because PLLA is composed of heavy, crystalline-shaped particles, bioresorption occurs slowly over 18 months.35 PLLA has been shown to last for up to 2 years postinjection.36 It is metabolized via the lactate pathway but does not cause a change of total body lactate. Metabolism is com­pleted by macroph age-mediated conversion of lactate to carbon dioxide, which is expelled through respira­tion.35-36 The result immediately postinjection is a soft tissue enhancement that lasts a few days before a return to baseline. This is followed by a more delayed effect visible for approximately 2 months postinjection.3t! The net filling effect of atrophic areas is thought to be from neocollagenesis that is stimulated by a foreign-body reaction, which is balanced by the slow metabolism of PLLA, leaving new type 1 collagen in facial defects.3S-37

Multiple clinical trials have been conducted to analyze the efficacy, safety, and durability of PLLA for treating HIV-associated facial lipoatrophy (Table 1). In all studies, patient and physician satisfaction were high. Several objec­tive measures have also been used to quantify the results.

The Chelsea and Westminster study analyzed 30 patients over 24 weeks who underwent 3 injection sessions of PLLA every 2 weeks.39 Half the patients received delayed treatment 12 weeks after the immedi­ate treatment group, thus serving as an initial control. As expected, patients had a significant (P<.001) increase in skin thickness only after PLLA administration, supporting the idea that the increased volume was from the PLLA injections. A Hospital Anxiety and Depression Scale was administered and showed that PLLA treatment decreased depression and anxiety39 In their long-term safety and efficacy follow-up, the authors concluded that the physi­cal and psychological benefits of PLLA treatment may be sustained for up to 18 months or longer.40

The APEX002 study involved 99 patients who under­went 1 to 6 injection sessions every 4 to 6 weeks.41 Patient and investigator satisfaction, as well as patient rating of lipoatrophy, showed positive results that were sustained 12 months posttreatnient. Adverse reactions included subcutaneous papules in 6 patients. In another single-center study, Burgess and Quiroga3S showed suc­cessful results in (i I patients with HIV infection who underwent an average of 3 injection sessions every 3 to 6 weeks. At the 6-month follow-up, all patients reported an excellent response, and the improvement was sus­tained an average of 18 months. The beneficial effects lasted up to 2 years in 5 patients, and no serious adverse reactions were recorded.

The VEGA open-label pilot study used ultrasound to measure changes in cutaneous thickness and a visual ana­log scale to assess changes in quality of life in 50 patients with an initial median facial fat thickness of 0 mm. The patients underwent a total of 4 injections ever}’ 2 weeks for 6 weeks.42 An additional injection was given at week 6 if the transcutaneous thickness was less than 8 mm. Results showed improved quality of life in all patients treated and a statistically significant (P<.001) increase in skin thickness from baseline at all monitor­ing points, including week 96. Thus, the primary end point of transcutaneous thickness greater than 10 mm at 24 weeks was met by 41% of patients; at 96 weeks, 43% of patients met this end point. Twenty-two patients devel­oped palpable subcutaneous nodules, which resolved in 6 patients by week 96.

HIV-ASSOCIATED FACIAL LIPOATROPHY

Other studies have also looked at the objective changes in skin thickness posttreatment with PLLA. Lafaurieet al 43 studied 94 patients with HIV infection who . – - _:. a median of 5 treatments every 2 weeks. They found that mean dermal thickness increased by 2.3 mm at a median of 6 months after the last treatment. As for adverse reactions, 1 patient experienced an anaphylactic reaction with generalized edema and macular rash, and 12 patients developed asymptomatic subcutaneous nod­ules at the injection site. Another study of 26 patients with HIV-associated facial lipoatrophy who were injected with PLLA found a 196% increase in dermal thickness mea­sured by ultrasound at 24 weeks after 4 treatments.44

The first US formal prospective study of patients with HIV-associated facial lipoatrophy treated with PLLA was conducted by the Blue Pacific Aesthetic Medical Group, which enrolled 99 patients between July 2002 and August 2003.+s In this single-site, open-lab el study, patients received 1 to 6 treatments of PLLA every 3 weeks, A typical session involved injection of 6 mL PLLA (2 vials, each reconstituted with 3 mL sterile water). Ninety-seven patients completed the treatment series. Mean change in skin thickness, measured by calipers, increased by 68.8% at 6 months and 73% at 12 months after the last treatment. In addition, mean physician satisfaction, with overall correction, was 4.8 out of 5 (l=dissatisfied, 5=satisfied) at the 12-month follow-up.45 Of the 76 and 54 patients who completed the 6-month and 12-month follow-ups, respectively, 100% said they would recom­mend this treatment to a friend.

In a larger study, Jansen and Graivier53 treated 609 HIV-negative patients for facial soft tissue augmen­tation, including the lips, nasolabial folds, and cheeks Patient satisfaction was then assessed by questionnaires. The majority of patients (77%) responding to the ques­tionnaire said that they were still satisfied with their results between 12 and 24 months after the initial treat­ment, and they estimated that a mean of 57% of the filler still remained present. Adverse reactions were mostly minimal and included edema, temporary pain, and bruising. Nodule formation was not reported except when the product was injected in or around the lips (12.4%, lip mucosa; 3.7%, radial lip lines).53 The majority of lip nodules responded positively to steroid injections or massage.

Patient with human immunodeficiency virus-associated facia I lipoatrophy before (A, B), immediately after (C), and B weeks after(D,E) injection of 2,9 rnL of calcium hydroxylapatite in the right cheek and 1.9 ml of calcium hydroxylapatitein the left cheek.

follow-ups at 3 and 6 months. The 6 patients who devel­oped lip nodules had prior lip augmentation procedures and were successfully treated with excision or intralesional corticosteraids. A study by Godin et also investigated the use of CaHA with Restylane® for facial augmentation. Patients treated with CaHA reported high overall satisfaction (7.6 out of 10, where l=very poor and 10=excellent), whereas patients treated with both products reported an even higher (but not statistically significant) satisfaction score. Cuevas et alsl also demonstrated a high rate of com­plete patient and physician satisfaction in their series of patients 1 year after facial augmentation with CaHA. Addi­tional uses for CaHA have included correction of minor nasal iiTegularitiesf'2 and correction of defects aiong the peri-chondrium of the ears and nose from skin cancer surgery.63 CaHA is a biologically inert, semipermanent filler that appears to be safe and effective for soft tissue augmentation, including the treatment of HIV-associated facial lipoatrophy. Its biggest strength is that it provides both immediate and long-lasting effects with few injections. In addition, no gran-ulomas or nodules have been reported when the product is injected in areas other than the lips. CaHA is now FDA approved for treating HIV-associated facial lipoatrophy and certainly appears to be a safe treatment option with high patient and physician satisfaction sustained at 1 to 2 years. The Figure depicts a patient who received CaHA
treatment for HIV-associated facial lipoatrophy

COMMENT

Both PLLA and CaHA are biodegradable, bio compatible, long-lasting, nonpermanent fillers that have been shown to be effective for treating HIV-associated facial lipoat­rophy. Neither product requires allergy testing. When used in patients with HIV-associated facial lipoatrophy, PLLA and CaHA both require multiple treatments, with an average of 3 to 5 injection sessions for PLLA and 3  sessions for CaHA. Both PLLA and CaHA have an immediate filling effect related to the amount injected plus additional edema and hemorrhage. After the edema and hemorrhage resolve in approximately 1 week, patients who receive CaHA will retain volume from the effects of the product in combination with the carrier gel. However, patients who receive PLLA will usually return to base­ line or close to it 1 week postinjection, and the increase in volume will occur slowly secondary to the body's reaction to PLLA. The volume enhancement from

neocollagenesis usually becomes apparent 2 months post-treatment. Although CaHA appears to maintain filling effects 12 or more months posttreatment series, PLLA may last slightly longer. Longer-term data collection on CaHA treatment for HIV-associated facial lipoatrophy are under way. Table 3 compares PLLA with CaHA.

Comparing the effectiveness of the 2 products is chal­lenging without a head-to-head study. Most studies that have examined changes in cheek thickness posttreatment with PLLA used varying methods of measuring thick­ness, including ultrasound, 3-dimensional photography, and skin calipers.38'41'41'44 The Blue Pacific Aesthetic Medical Group study45 of PLLA and the study by Silvers et alis of CaHA used identical methods of assessing cheek thickness, thus making it logical to compare the 2 stud­ies. Both measured cheek thickness at each visit using calipers at the same fixed point: the intersection of the vertical axis through the lateral canthus and the horizon­tal axis of the nares. In the Blue Pacific Aesthetic Medical Group study, 80% of the patients had 4 to 6 treatments with PLLA, and at 6 months posttreatment, they had a 69% mean increase of skin thickness.45 In the study by Silvers et al,s' 78% of the patients received 3 injections with CaHA and at 6 months had a 45% mean increase of skin thickness. Patients and physicians have been pleased with the effects of both products.

The most common adverse reactions with PLLA and CaHA are local and include injection-site bruising, dis­comfort, and edema. However, subcutaneous nodule for­mation has been reported in 3% to 44% of PLLA-treated patients with HIV-associated facial lipoatrophy.38'39'41'42'44 Generally, these nodules are palpable and not visible. The formation of these nodules is not predictable, and they may develop within weeks or 6 or more months postinjection. Many appear unresponsive to treatment. Although using larger amounts (=5 mL sterile water) to reconstitute PLLA may decrease the rate of nodule for­mation substantially, this adverse reaction still remains a concern to physicians and patients.40 When CaHA is injected in or around the lips, the incidence of nodule formation has been reported to be approximately 12%.40 However, subcutaneous papules have not been reported from CaHA injections into the cheeks of patients with HIV-associated facial lipoatrophy.55'56

When comparing the costs of the 2 products, it appears that CaHA is the least expensive. The average amount of CaHA used by Silvers et al55 for all 3 injections was 8.4 mL, This would require 7 prefilled, 1.3-mL syringes ($295 each), bringing the product cost to $2065. The cost of PLLA for the entire treatment is harder to estimate because most of the studies on treating HIV-associated facial lipoatrophy with PLLA do not mention the precise amount of product used. Estimating 2 vials ($480 each) per treatment with 4 total treatments, the cost of PLLA would be approximately $3840.

In conclusion, 2 viable, long-lasting, nonpennanent filler options are available for treating HIV-associated facial lipoatrophy, CaHA appears to be slightly less expen­sive, with no reported subcutaneous nodule formation associated with lipoatrophy treatment. It also has the benefit of an immediate and long-lasting effect. PLLA has been used much more extensively and may have a longer-lasting filling effect than CaHA, but longer-term data are needed. The choice of filler should be individu­alized, based on physician experience and preference, as well as patient preference.

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