62.1 Introduction

Since the introduction of highly active antiretroviral therapy (HAART) in 1996, the mortality of patients with human immunodeficiency virus (HIV) has decreased greatly making HIV infection a more manageable chronic disease [1]. However, there has been an increase in metabolic and morphological changes known collectively as HIV-associated lipodystrophy. This syndrome, with a reported prevalence in 50% of patients on HAART for more than 12 months [2], is of increasing significance to patients and their physicians.

Lipodystrophy syndrome, first reported in 1998 [3] is now believed to be comprised of two main components: lipodystrophy and lipoatrophy. Lipodystrophy is manifested by serum lipid abnormalities, insulin resistance, and increased fatty deposits (especially around the viscera and in the dorsal cervical region), while lipoatrophy is manifested by loss of subcutaneous fat in the periphery, buttocks, and face. This subcutaneous fat loss is distinct from the HIV-associated wasting seen in patients before the advent of HAART, which is secondary to loss of lean body mass. Loss of facial fat is perhaps the most stigmatizing aspect of HIV-associated lipoatrophy because it cannot be disguised [4]. As a result, treatment options tend to focus on this aspect of the syndrome.

Despite years of in-depth research, both on a clinical and cellular level, the exact mechanism of HIV-associated facial lipoatrophy is unknown.

D.R. Mest ( ) and G.M. Humble

Blue Pacific Aesthetic Medical Group, Inc,

2301 Rosecrans Ave., #1135, El Segundo, CA 90245, USA e-mail: drmest@aol.com; gailhum@aol.com

Indeed, current research suggests the cause is multifactorial [5, 6]. No specific antiretroviral agent has been shown to be causative. However, a strong association exists with thymidine nucleoside reverse transcriptase inhibitors (tNRTIs), most likely through inhibition of mitochondrial DNA polymerase J, leading to depleted mitochondrial DNA in the adipose tissue and consequent cellular dysfunction. More important than specific antiretroviral agents is the influence of patient factors such as age (>40 years), gender (men more than women), and race (whites more than nonwhites) [5]. The strongest predictor of lipoatrophy development appears to be low CD4 count (<100 cells/mm3), especially in patients whose counts remained unimproved with treatment [5]. Thus prolonged delay in treatment, often requested by patients to avoid lipoatrophy, may be counterproductive to this goal.

Many methods have been used to diagnose HIVassociated lipoatrophy, including dual-energy x-ray absorptiometry (DEXA), magnetic resonance imaging, computed tomography, ultrasound, and anthropometric calipers. Although useful for research, these methods unfortunately have high costs, problematic access issues, and/or high patient-to-patient variability. A promising new technique for measuring treatment effectiveness for facial lipoatrophy is advanced photographic three-dimensional microtopography imaging. Because of these testing limitations, a clinical diagnosis is most commonly performed. James et al. [7] proposed a clinical grading scale (from 1–4) 1 = mild to 4 = severe for facial lipoatrophy (Table 62.1) based on buccal-area fat loss and visualization of underlying facial musculature. Although not validated, this scale is useful for documentation. A validated, reliable clinical scale that considers other facial areas was published by Ascher et al. [9] in 2006 but has not been widely adopted.

Table 62.1 James facial lipoatrophy severity scale

Description

Grade 1 Mild and localized facial lipoatrophy

Grade 2 Deeper and longer atrophy, with the facial muscles beginning to show through

Grade 3 Atrophic area is even deeper and wider, with the muscles clearly showing

Grade 4 Lipoatrophy covers a wide area, extending up toward the eye sockets, and the facial skin lies directly on the muscles

Reproduced with permission from Burgess and Quiroga [8]

The psychosocial effects of facial lipoatrophy are well known. Facial lipoatrophy is the most visible and perhaps the most stigmatizing manifestation of HIVassociated lipoatrophy [4, 10]. Patients often perceive facial lipoatrophy as the “Kaposi sarcoma of the twenty-first century” with resultant anxiety over the inadvertent disclosure of HIV status [11]. Gradual fat loss and resulting disfigurement of HIV-associated facial lipoatrophy have caused depression and lowered self-esteem in patients, leading to poor social functioning and increased social isolation [10, 11]. In addition, the reduced libido sometimes seen with the condition may create quality-of-life issues [12]. Perceived or genuine employment discrimination has been reported [11].

The fear of treatment-related facial lipoatrophy has been cited as a reason to postpone treatment [13]. More important, this fear has been reported to help reduce patient adherence to treatment [10]. The unsupervised cessation of treatment poses the risk for increasing the prevalence of drug-resistant strains of HIV [14]. Fortunately, physicians now recognize the psychosocial effects of facial lipoatrophy and the need for treatment [11]. Further education is needed, however, for governmental agencies and the health insurance industry.

There are many options available for treatment of this disorder, including autologous fat transfer, surgical implants as well as a number of injectable devices. Of the injectable products, only two are FDA approved at this time in the United States. For the purpose of this chapter the remaining discussion are dedicated to the history, efficacy, mechanism of action, injection technique, duration of action, and complications associated with the use of Poly-L-Lactic Acid (PLLA) in the treatment of HIV-associated lipoatrophy.

62.2 History of Poly-L-Lactic Acid (PLLA)

PLLA was first synthesized by a French chemist in 1956. It is produced by carbohydrate fermentation of corn dextrose. Because PLLA is of a synthetic origin, no animal sensitivity testing is needed. This means no allergy testing is required. PLLA is biocompatible, biodegradable, and immunologically inert. Polylactic acid has been used since the early 1960s in the human body. When this synthetic polymer is implanted in the body, hydrolysis of the polymer backbone reduces the weight of the polymer and their degraded products are then metabolized by the body. Because of this the polymer has been used extensively in drug delivery systems and tissue engineering applications. There is at least a 45-year safety history of polylactic acid in the human body. It has been used since the early 1960s in absorbable sutures such as Vicryl™ and Dexon™. It has also been used as fixation devices in orthopedic surgery, in urethral and tracheal stents, and in dental implants. There have been over 7,000 published articles on uses of polylactic acid in humans. As previously stated the polylactides have been shown histologically to break down to the lactic acid monomer. This process takes 12–18 months, depending on the size and shape of the polylactic acid.

Injectable PLLA, which is FDA approved in the United States under the trade name Sculptra™, consists of microparticles of the L isomer of polylactic acid which are 40–60 Pm in diameter and of an irregular shape. Each particle has a molecular weight up to 140,000 Da. These microparticles come in the form of a freeze-dried powder combined with apyrogenic mannitol and sodium carboxymethylcellulose. It is thought that the irregular product shape as well as the heavy molecular weight of the microparticles contributes to the slow degradation kinetics (up to 18 months) of the product (Fig. 62.1). Each vial of Sculptra™ contains 150 mg of PLLA, Sodium Carboxymethylcellulose 90 mg, and 127.5 mg Mannitol. The lyophilizate needs to be reconstituted with sterile water prior to injection.

Metabolism involves bioabsorption and gradual degradation. Polylactic acid is gradually hydrolyzed by nonenzymatic hydrolysis into mono or oligomers (C3H6O3) of lactic acid. These fragments are then phagocytized by macrophages before being eliminated in the form of CO2 and water or glucose and lactate (Fig. 62.2).

Fig. 62.1 Degradation kinetics of PLLA

Fig. 62.2 Metabolism of

PLLA

Time from Implantation (months)

Poly-L-Lactic Acid was first marketed as a cosmetic line filler, with minimal dilution amount (1 ml) and dilution time, in Europe under the name of New Fill™. It has been used as an injectable filler since 1999 in more than 30 different countries. At that time, it was manufactured by Biotech Industries S.A. in Luxembourg. It achieved CME mark certification in Europe first as a line filler and then later as a volumizer. It is now owned and distributed by Dermik Aesthetics which is a subsidiary of Sanofi-Aventis (Bridgewater, New Jersey, USA).

The first data related to the use of PLLA in HIVassociated lipoatrophy was presented in abstract form by Amard and Saint Marc in Sept of 2000 [15]. Twenty-six HIV + lipoatrophy patients were treated with PLLA. Ultrasound measurement was used to measure dermal thickness. A 151% increase in dermal thickness was found at 3 months, 196% at 6 months, and 131% at

54weeks.

A 96 week study was presented at the 10th Confer-

ence for Retroviral and Opportunistic Infection in Boston in February of 2003 and subsequently published in the journal AIDS in 2003 [16]. Researchers from the VEGA study presented the results of 50 HIV-positive patients after receiving PLLA for correction of facial lipoatrophy using a 3 ml dilution and a 2 week treatment interval. Change in dermal thickness was evaluated using ultrasound and color Doppler preformed

by the same trained radiologists. They found a threefold increase in dermal thickness that was sustained at 72 and 96 weeks.

An early study performed by Lafaurie et al. [17], involved treating 40 patients with facial lipoatrophy. In this study, the product was diluted with 3 ccs of sterile water and 1 ml Lidocaine and the patients were treated with 150 mg (1 Vial) per cheek every 15 days. Efficacy was evaluated at 2 months and after 6 months utilizing 3D photos analyzed by digital surface photogeometry software. Results showed a mean increase of dermal thickness of 2.3 mm at the end of treatment. Results were maintained at 2 and 6 months.

Moyle et al. [18] performed the first randomized clinical trial using PLLA as a treatment for HIVAssociated lipoatrophy. Thirty patients were randomized to either immediate or delayed treatments, using three fixed treatments at 2 week intervals. Efficacy was measured by ultrasound measurement of skin thickness. Mean increases in skin thickness of 4–5 mm were observed in the treated but not in the untreated group. After delayed treatment, no inter group differences were observed. Of note, ultrasound measurements in nearby, but untreated areas, did not show any increase in skin thickness.

In 2002 in the United States when PLLA was still under the name of New Fill™, PLLA was first obtained to treat individual patients with facial lipoatrophy

using the personal use importation (PUI) process regulated by the Food and Drug Administration (FDA). The PUI requires that the foreign drug or device be distributed noncommercially in volumes not considered excessive. (i.e., a 3 month period supply or less). The FDA stipulated the intended use of the drug or device be appropriately identified and affirmation had to be made in writing by the patient that the treatment was for personal use [19].

The data of two US studies, the APEX002 [20] and the Blue Pacific Study [21], were used when PLLA was submitted to the United States FDA for approval of the treatment of HIV-associated lipoatrophy, which was granted in August, 2004. Both were open-labeled single-center Investigational Device Exemption (IDE) studies meant to assess the efficacy and safety of PLLA in HIV-associated lipoatrophy.

The APEX002 trial involved 99 patients who were given one to six treatment sessions, 4–6 weeks apart, with PLLA. The average treatment sessions ranged from three to four. Patients and physicians rated the degree of lipoatrophy on a scale of 1–5 before, immediately after treatment, at 6 months and at 12 months. Patients were followed with serial photography. Seventy-seven patients considered both their cheeks and temples to be affected by lipoatrophy and 22 patients at baseline considered only their cheeks to be affected. On a scale of 1–5 (1 = mild, 5 = most severe), mean lipoatrophy at baseline was 3.58 in the cheek area, compared with 2.36 in the temples, decreasing to 1.51 and 1.32, respectively, prior to final treatment. Six months and 12 months after treatment cheek lipoatrophy was rated at 0.97 and 0.79, respectively: and at these time points the temples were rated 1.01– 0.47, respectively. On a satisfaction scale of 1–5, with 1 being unsatisfied and 5 very satisfied, at the end of treatment satisfaction was 4.71, at 6 months 4.83, and at 12 months 4.69.

In the Blue Pacific study patients received deep dermal/subdermal injections of PLLA into targeted treatment areas using 1–6 ml of PLLA, reconstituted with 3 ml of sterile water for injection per vial (50 mg of PLLA per milliliter), per session. Volume of PLLA injected at each treatment session was subjective and individualized to produce the desired filling effect for that patient based on the investigators previous experience. A typical treatment session involved injecting 6 ml of the product. No more than 6 ml of reconstituted PLLA (two vials) were used at any one treatment

session. Sessions were scheduled 3 weeks apart with an allowed variability of 10 days. In order to assess the desired correction during the study period and for 6 and 12 months following the last treatment session, buccal skin thickness was measured by skin calipers. A total of 99 patients (97 males, 2 females) consented for participation in the study.

Of the 97 patients who completed the treatment series, 75 patients physically returned to the study site for their 12-month follow-up visit. Of these 75 patients, all patients experienced an increase in skin thickness as measured by skin calipers. Compared with baseline skin thickness, patients at the end of the treatment had an average 65.1% increase, which increased to 68.8% at 6 months and was maintained at 73% at the 12-month follow-up period. The increases in skin thickness were statistically significant at all time points.

On a scale of 1–5 with 1 being Dissatisfied and 5 being Very Satisfied, 97 patients reported a mean satisfaction score of 4.6 at the end of treatment, 77 patients reported a mean of 4.6 at 6 months, and 75 patients reported a mean of 4.8 at the 12 month follow-up visit. Mean Physician Satisfaction with overall correction was 4.5 at the end of treatment, 4.7 at 6-month followup, and 4.8 at 12-month follow-up. Initial facial lipoatrophy severity, as graded by the published James Scale [7] (Table 62.1) ranged from 1 (mild) to 4 (severe). The mean was 2.8. Table 62.2 displays the median number of treatments required for full correction, as it relates to initial degree of facial lipoatrophy. Most patients required between three and six treatments. Four patients (4.1%), with the most severe lipoatrophy, clinically could have used more than six treatments but were limited by the study design. There were no

Table 62.2 Distribution of patients by James Scale Class and median number of treatments required for full correction

Reproduced with permission from Mest and Humble [21] aOne patient found to be HIV and was removed from study after one treatment

clinically significant changes seen in serum venous lactate levels throughout the study.

The last study that should be briefly mentioned for completion of the history of this product is the cosmetic trial that was completed in 2006 (Table 62.3) [29]. The study was a 13 month, multicenter trial involving 233 subjects. The study was randomized and the evaluators were blinded. A split-face subjective evaluation was

used as one side of the patients face at the nasolabial crease was injected with Cosmoplast™ (human collagen) and the other with Sculptra™. The objective of the study was to determine longevity and satisfaction with correction compared with the gold standard at the time which was Cosmoplast™. The Cosmoplast™ side demonstrated satisfactory improvement until 3 months and the Sculptra™ side up to end of the clinical trial

period which was 13 months. Evaluation of safety data showed a similar incidence of nodule production and papule rate (6.9% vs. 6.0% and 8.6% vs. 3.4%) between products.

62.3 Efficacy

Direct comparison of PLLA studies for efficacy is difficult secondary to the variability in study design. Treatment numbers vary significantly depending on whether the study used a fixed number of treatments [16, 18, 30] or adjusted number of treatment vials to obtain maximal patient correction of the underlying lipoatrophy [8, 20, 21, 28]. Variability in facial lipoatrophy severity and heterogeneity of study subjects add to the difficulty. The most common objective measure of efficacy has been ultrasound of skin thickness, ideally performed by a single radiologist [16, 18, 26, 28]. Recently, Carey has called into question the validity and reproducibility of ultrasound as a measure of facial lipoatrophy [31]. Other measures include 3D photography, Visual Analog Scale (VAS), skin calipers, and CT scans for linear measurement at fixed points. Regardless of the instrument used, the range of improvement that is documented is in the millimeters of improvement. What is more noticeable is the marked visual improvement in patients after treatment with PLLA (Figs. 62.3–62.5).

In general, the number of treatments needed for full correction of normal contours is directly related to the degree of facial lipoatrophy present. This was reinforced with the findings of the original Blue Pacific study [21]. There is a natural variability to patient response to PLLA as it is 100% dependent on the

patient’s reaction to the PLLA and reported subsequent stimulation of endogenous collagen. In the author’s experience, darker skin types respond very well to PLLA as do younger patients and patients with thicker skin. This individual patient response to treatment was documented in the VEGA study [16]. In this study, although individual variability in ultrasound thickness with treatment was noted, all patients did statistically significantly respond to treatment at all time points measured.

As a secondary measure of efficacy, patient and physician satisfaction has been measured after treatment with PLLA. Again, use of various scales and end points make direct comparisons between studies impossible. However, despite the differing measurement tools utilized, the persistent overlying finding is one of significant patient satisfaction that persists through the follow-up period (Table 62.4). This consistent degree of patient satisfaction supports the efficacy of PLLA treatment of facial lipoatrophy. In the longest study to date (36 months) Mest and Humble [33] showed a continued high degree of patient satisfaction (4.9 on a scale of 1–5) at 36 months. Of note, in a study by Orlando et al. [32], it is stated that the presence of “lumps” did not alter patient satisfaction, reflecting the importance of the return of normal contours to this patient population.

An additional secondary efficacy measure that has been studied is the effect of PLLA treatment on the Quality of Life (QoL) of patients with HIV-associated lipoatrophy. These results are at first very confusing and mixed with some studies showing a significant improvement in the QoL of patients [16, 26], others not showing any improvement, and several studies showing a mixed pattern [18, 30]. The earliest studies, such as the one by Lafaurie et al. [17] used QoL questionnaires

that were developed for HIV patients prior to the use of HAART therapy and its resultant body changes. Use of updated QoL questionnaires such as the Short Form 36v2 Health Survey [34] showed statistically significant improvement in components of the mental health portion but not the physical health summary [30]. Using newly developed scales (Multidimensional Body-Self Relations questionnaire-Appearance Scales) Carey [30]

was able to show improvement between randomized patients undergoing immediate versus delayed treatment with PLLA. Perhaps the best developed and studied tool is the AIDS Clinical Treatment Group (ACTG) Assessment of Body Change and Distress (ABCD) scale. Several studies [26, 32] have confirmed the importance of PLLA treatment for facial lipoatrophy using the ABCD scale.