Review and Evaluation of Treatment Procedures Using Injectable Poly-L-Lactic Acid in the Treatment of Human Immunodeficiency Virus–associated Facial Lipoatrophy

| December 13, 2010
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Douglas Mest, MD; Gail Humble, MD, Blue Pacific Aesthetic Medical Group, Hermosa Beach, California

Abstract
Injectable poly-L-lactic acid is United States Food and Drug Administration–approved for the restoration and/or correction of the signs of lipoatrophy in people with human immunodeficiency virus and for use in immune-competent people for the correction of nasolabial fold contour deficiencies. Current prescribing information recommends using either a tunneling or threading technique in a grid or cross-hatched pattern or a depot technique (in thin skin areas) to administer multiple passes of injectable poly-L-lactic acid per treatment session via a 26-gauge needle. A review of the literature and the recently published guidelines from the American Society for Dermatologic Surgery provide evidence to support the use of a cross-fanning technique with a 25-gauge needle. In conclusion, the use of a cross-fanning injection technique with a 25-gauge needle to administer injectable poly-L-lactic acid provides a clinically valid, alternate delivery option for the treatment of patients with human immunodeficiency virus-associated lipoatrophy.
(J Clin Aesthet Dermatol. 2010;3(12):43–49.)

Injectable poly-L-lactic acid (PLLA; Sculptra and Sculptra Aesthetic, Dermik Laboratories, a business of Sanofi-Aventis U.S. LLC, Bridgewater, New Jersey) is a device containing PLLA, a biodegradable, biocompatible, synthetic polymer. Injectable PLLA is approved in the United States for the restoration and/or correction of the signs of facial fat loss (lipoatrophy) in people with human immunodeficiency virus (HIV).[1,2] It is also approved for use in immune-competent people as a single regimen for the correction of shallow-to-deep nasolabial fold contour deficiencies and other facial wrinkles in which a deep dermal grid pattern injection technique is appropriate.[3] Although the exact mode of operation is unknown, preclinical studies have indicated that PLLA leads to the production of a fibrous tissue response that is hypothesized to result in the formation of collagen.[4,5] Clinical studies with injectable PLLA involving patients with HIV-associated facial lipoatrophy have demonstrated significant and prolonged increases in dermal thickness along with substantial improvement in patient quality of life.[6–10]

There are two primary injection techniques currently being used with injectable PLLA.[11] The prescribing information for Sculptra recommends either the use of a depot or bolus injection or the use of a tunneling or threading injection technique. When administering multiple passes of injectable PLLA per treatment session, the device can be injected in a grid or cross-hatched pattern. The prescribing information also recommends using a 26-gauge needle for injection.1 However, several clinical studies,[6,12,13] including the Blue Pacific study,[8] which was one of the studies included for review in the approval of injectable PLLA for the treatment of HIV-associated facial lipoatrophy in the United States, support the use of an alternative injection technique—the cross-fanning injection technique using a 25-gauge 1.5-inch needle—for the treatment of HIV-associated facial lipoatrophy. Results from the Blue Pacific extension study also support the use of the cross-fanning injection technique for the HIV patient population and provide long-term (24-month) safety and tolerability data.[14] A single case has further illustrated that the effects of injectable PLLA may persist for up to 31 months after a retreatment with injectable PLLA.[15] This article examines and evaluates evidence for using the cross-fanning technique with a 25-gauge needle as a clinically valid alternative to using the tunneling or threading technique with a 26-gauge needle for the administration of injectable PLLA in patients who have HIV-associated facial lipoatrophy.

Evidence Supporting the Use of the Cross-Fanning Technique with a 25- versus 26-gauge Needle
The cross-fanning injection technique (Figure 1) used in the two Blue Pacific studies differs from the recommended cross-hatch injection technique described in the prescribing information for injectable PLLA (Figure 2), although both require injection into the deep dermis/subcutaneous junction.[1,8,14] The technique requires 0.1 to 0.2mL threads of injectable PLLA to be placed per injection in a retrograde manner, then[14] partially withdrawing the needle in the tissue to allow redirection 15 to 20 degrees and advancement of the needle to repeat the process until a fan shape has been created. It is important that the needle is withdrawn on each pass to actually redirect it to a new location. It is also important that the needle is not removed from the skin when redirecting the fan, otherwise the benefits of the technique would be decreased. In addition, it is critical to stop injecting short of the entry point to prevent over deposition of PLLA particles at the apex of the fan. The advantages of the cross-fanning technique include fewer overall needle insertions, conferring a decreased potential for tracking injectable PLLA through the dermis, greater patient comfort, and easier administration for the physician. Moreover, fewer needle insertion sites in general tend to result in less bruising. The authors have observed in clinical practice that cross-fanning, like threading or tunneling, facilitates even product distribution (Figure 3)—the overall goal and most important factor in ensuring an effective and safe outcome with injectable PLLA.

In the original Blue Pacific study, 99 patients with HIV-associated facial lipoatrophy received up to six treatment sessions of injectable PLLA and were followed for up to 12 months.[8] Each vial of injectable PLLA was reconstituted with 3mL of sterile water for injection (SWFI) 30 minutes prior to use; subsequently 1 to 6mL of reconstituted PLLA were injected into the deep dermal/subdermal plane by using the cross-fanning technique with a 25-gauge 1.5-inch needle. Compared with baseline, a significant increase in skin thickness of 73 percent was observed at the 12-month follow-up visit (P<0.001), and papule formation was reported in 13.1 percent of patients (13/99).[8]
The initial correction persisted for more than 36 months in approximately 12 percent of the 75 patients who completed the main Blue Pacific study (1 patient was re-treated at 30 months).[14] The remaining 65 patients continued in the single-site, open-label, 24-month extension study to evaluate the long-term safety, duration of effect of injectable PLLA, and patient satisfaction following treatment.[14] In this study, injectable PLLA was reconstituted with 5mL of SWFI, which was greater than the dilution used in the main study but consistent with the product’s prescribing information and current clinical practice at the time. After allowing two hours for hydration (compared with the 30-minute hydration time used in the original Blue Pacific study), and depending on the severity of the facial lipoatrophy and the number of retreatments necessary, up to 10mL of injectable PLLA was then administered using the cross-fanning technique with a 25-gauge 1.5-inch needle (1–2 retreatments for mild facial lipoatrophy and 3–5 retreatments for moderate-to-severe facial lipoatrophy). Based on the investigators’ and patients’ visual evaluation, approximately 50 percent of patients required up to three additional treatments to maintain satisfactory correction. The time to first retreatment, the mean number of retreatments, and the mean skin thickness change before the first retreatment all varied by the presenting James scale score (Table 1). At the end of the retreatment, the mean patient satisfaction (based on a 5-point scale; 1=dissatisfied, 5=very satisfied) was maintained at 4.9.[14] The reported rate of new, small (<5mm), nonvisible papules decreased to 7.7 percent, with onset reported within 2 to 7 months following retreatment.[14] This represents a 38.5-percent reduction in the incidence of papule formation between the main Blue Pacific study and the extension study.[8,14]

Several studies using the cross-fanning technique support the results of the Blue Pacific studies by providing comparable nodule/papule rates for injectable PLLA in patients with HIV-associated facial lipoatrophy.[2,6,8,12–14] Table 2 summarizes the nodule/papule rates from studies using the cross-fanning technique and the rates from studies using other injection procedures. Adaptations to the reconstitution method and the interval between treatments also were made in each of the studies and may have been contributing factors to the outcome of safety results (Table 2). For example, using the cross-fanning technique with a 25-gauge 1.5-inch needle and a 4 to 6mL reconstitution volume for injectable PLLA, Burgess and Quiroga[6] reported significant improvement in HIV-associated facial lipoatrophy that lasted up to two years. Six months after the last injection, 79 percent of the subjects who received fewer than four treatments rated the results of the treatment as “excellent” based on a visual, subjective, 4-point scale (1=excellent [90–100% improvement]; 4=no change [no improvement]). Only 2 of 61 patients (3.3%) developed persistent, asymptomatic, palpable, intradermal papules.

The safety results of the aforementioned studies show an improvement over the safety results noted in earlier reports in patients with HIV-related facial lipoatrophy. In the VEGA study, palpable but nonvisible subcutaneous nodules were observed in 44 percent of patients 96 weeks after the final treatment, with spontaneous resolution occurring in six patients (Table 2).[16] In the Chelsea and Westminster study, palpable, nonvisible nodules were reported in 31 percent of subjects (Table 2).[10]

The cross-fanning injection technique also has been used in studies with patients with HIV-related facial lipoatrophy and immune-competent patients treated for aging-related facial lipoatrophy. Hanke and Redbord reported the results of a study with injectable PLLA in 27 patients treated for HIV-related facial lipoatrophy and in 38 patients treated for aging-related lipoatrophy.[13] The reconstitution of injectable PLLA (3mL of sterile water and 2mL of lidocaine) and the injection technique (cross-fanning with a 25-gauge 1-inch needle) was similar for both patient groups. In the patients treated for HIV-related facial lipoatrophy, Hanke and Redbord[13] reported a seven-percent incidence of subcutaneous papules in the patients treated for HIV-related facial lipoatrophy. These investigators also reported significant improvements in facial lipoatrophy scores from pretreatment (P<0.001) and that 93 percent of patients with HIV-related facial lipoatrophy were very satisfied with treatment.[13] In the non-HIV patient group treated for aging-related facial lipoatrophy, Hanke and Redbord reported a five-percent incidence of subcutaneous papules. In addition, 90 percent of the patients were very satisfied with injectable PLLA treatment. Significant improvements from baseline in facial lipoatrophy scores also were reported for both patient groups (P<0.001 for both).[13]
Woerle et al[12] reported the results of a five-year study that also included patients with HIV-related facial lipoatrophy and immune-competent patients with aging-related facial lipoatrophy (only 9 [3%] of the 300 patients had a diagnosis of HIV-related facial lipoatrophy). In this study, which spanned from 1999 to 2004, the injectable PLLA reconstitution and injection technique (cross-fanning with a 26-gauge needle) was similar for all patients. Clinical improvement was maintained for up to two years after treatment. However, the authors provided an interesting observation. For the patients treated between 1999 through 2002, injectable PLLA was reconstituted with 3mL of sterile water. During this earlier period (1999–2002), 10 percent of all patients developed subcutaneous papules (no further differentiation was provided between patients with HIV lipoatrophy and healthy patients with facial contour deficiencies). For patients treated from 2002 through 2004, the reconstitution of injectable PLLA was increased to 5mL (3mL of sterile water plus the off-label addition of 2mL of lidocaine). During this latter period (2002–2004), the incidence of subcutaneous papules decreased to fewer than one percent.[12] The authors noted other differences in their preparation of injectable PLLA during the study. One difference included increasing the hydration time from 2 to 12 hours with the earlier group of patients (i.e., those treated during 1999–2002) to 36 to 48 hours prior to treatment with the later group of patients (i.e., those treated during 2002–2004).

A case study reported the use of the cross-fanning injection technique in a patient treated for aging-related facial lipoatrophy. Burgess presented a case study of a 69-year-old African-American patient who did not have HIV.[2] Injectable PLLA was reconstituted with 5mL of SWFI and injected via the cross-fanning technique with a 25-gauge 1.5-inch needle. The patient experienced significant and sustained enhancement in facial contours for 18 months after receiving two treatment sessions of injectable PLLA, with no adverse events noted.[2]

A second case study in which the cross-fanning injection technique was used has been published.[15] A 45-year-old Caucasian man with HIV who had participated in the Blue Pacific study underwent five treatment sessions at three-week intervals. At each session, two vials of injectable PLLA were reconstituted with 3mL of sterile water for injection; the midface was treated using the cross-fanning method with a 25-gauge 1.5-inch needle in all sessions, and the temples were additionally treated in the fifth session. Twelve months after the last treatment session, a James scale assessment showed no lipoatrophy, but the patient requested and received a single retreatment. At this time, each vial was reconstituted with 5mL of sterile water for injection and allowed to rehydrate for about 24 hours; 1mL of lidocaine 2% was added immediately before injection into the midface and temple areas. The patient experienced a sustained facial correction for two years seven months after the retreatment. Localized bruising that resolved within one week occurred following the injection sessions, but no other adverse events were reported.[15]

The guidelines published by the American Society for Dermatologic Surgery (ASDS) also support using a cross-fanning pattern with a 25- or 26-gauge 1.5-inch needle to inject reconstituted PLLA into the deep dermis or subcutaneous tissues in a series of treatments separated by at least four weeks.[11] Moreover, the guidelines state that reconstitution involves the use of 4 to 6mL of normal saline and 1mL of 1% lidocaine, with the possibility of using more dilute solutions. However, the guidelines clearly acknowledge that these higher reconstitution volumes along with the addition of the lidocaine, are all off label; the prescribing information provided by the manufacturer of injectable PLLA recommends reconstitution with 5mL of SWFI.[1,11] Consistent with the ASDS guidelines, it is the authors’ current practice to reconstitute injectable PLLA more than 12 hours prior to injection, using up to 8mL of diluent, for aesthetic use, which differs from the United States Food and Drug Administration–approved prescribing information.

Summary
A review of the literature suggests that the cross-fanning injection technique, along with the use of a 25-gauge 1.5-inch needle, is a clinically valid alternative to the cross-hatching method using a 26-gauge 0.5-inch needle described in the prescribing information for injectable PLLA. These findings are supported by recently published guidelines for the use of available injectable fillers, including injectable PLLA.[11] The data highlighted in this review further suggest that increasing reconstitution volume for injectable PLLA, as well as increased hydration time combined with longer intervals between treatments, may lead to a reduction in the incidence of nodule and papule formation. The deep-dermal/subdermal cross-fanning technique with a 25-gauge 1.5-inch needle may be equally safe and efficacious, offer improved tolerability, and may provide an additional option for the physician injector.

Acknowledgment
Editorial support for this article was provided by the editorial staff at Embryon. Editorial support was funded by Dermik Laboratories, a business of Sanofi-Aventis U.S. LLC. The authors gratefully acknowledge Shilpa Lalchandani, PhD, who assisted in the preparation of this article based on author-provided comments. The authors are fully responsible for the content, editorial decisions, and opinions expressed in the current article. The authors received no honoraria or other form of financial support related to the development of this manuscript.

References
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14.    Mest DR, Humble GM. Retreatment with injectable poly-L-lactic acid for HIV-associated facial lipoatrophy: 24-month extension of the Blue Pacific study. Dermatol Surg. 2009;35(Suppl 1):350–359.
15.    Mest DR, Humble GM. Duration of correction for human immunodeficiency virus-associated lipoatrophy after retreatment with injectable poly-L-lactic acid. Aesthetic Plast Surg. 2009;33(4):654–656.
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Category: 12-2010 (December 2010), Human Immunodeficiency Virus–associated Facial Lipoatrophy, Poly-L-Lactic Acid, Special Communication

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