A systematic review of filler agents for aesthetic treatment of HIV facial lipoatrophy (FLA)

A systematic review of filler agents for aesthetic treatment of HIV facial lipoatrophy (FLA) Jared Jagdeo, MD, MS,a,b,c Derek Ho, BS,a Alex Lo, BS,d and Alastair Carruthers, MD, FRCPC, FAADe Mather and Sacramento, California; Brooklyn, New York; and Vancouver, British Columbia, Canada HIV facial lipoatrophy (FLA) is characterized by facial volume loss. HIV FLA affects the facial contours of the cheeks, temples, and orbits, and is associated with social stigma. Although new highly active antiretroviral therapy medications are associated with less severe FLA, the prevalence of HIV FLA among treated individuals exceeds 50%. The goal of our systematic review is to examine published clinical studies involving the use of filler agents for aesthetic treatment of HIV FLA and to provide evidence-based recommendations based on published efficacy and safety data. A systematic review of the published literature was performed on July 1, 2015, on filler agents for aesthetic treatment of HIV FLA. Based on published studies, poly-L-lactic acid is the only filler agent with grade of recommendation: B. Other reviewed filler agents received grade of recommendation: C or D. Poly-L-lactic acid may be best for treatment over temples and cheeks, whereas calcium hydroxylapatite, with a Food and Drug Administration indication of subdermal implantation, may be best used deeply over bone for focal enhancement. Additional long-term randomized controlled trials are necessary to elucidate the advantages and disadvantages of fillers that have different biophysical properties, in conjunction with cost-effectiveness analysis, for treatment of HIV FLA. ( J Am Acad Dermatol 2015;73:1040-54.) Key words: facial volume loss; filler agent; highly active antiretroviral therapy; HIV facial lipoatrophy; HIV lipodystrophy; quality of life.

IV facial lipoatrophy (FLA) is a subtype of HIV lipodystrophy associated with the use of highly active antiretroviral therapy (HAART),1 and is characterized by facial volume loss that affects the contours of the cheeks, temples, and orbits. HIV FLA is socially stigmatizing and impacts patients’ adherence to HAART,2,3 psychological health, and quality of life (QoL), including feelings of distress, depression, anxiety, social isolation, and career barriers.4 HIV FLA has gained increased significance as patients have improved life expectancy with better

H

medical management on HAART. Although new HAART medications are associated with less severe FLA, the prevalence of HIV FLA among treated individuals exceeds 50%.5,6 Filler agents are frequently used for treatment of HIV FLA to provide improvement in facial volume. There are limited published data on different filler options for treatment of HIV FLA with regards to outof-pocket patient cost, required number of treatment visits, and filler longevity.7 Treatment of HIV FLA is linked to improvement in the QoL of patients in categories including health perception, mental health,

From the Dermatology Service, Sacramento Department of Veterans Affairs Medical Center, Mathera; Department of Dermatology, University of California Davis, Sacramentob; Department of Dermatology, State University of New York Downstate Medical Centerc; College of Medicine, State University of New York Downstate Medical Centerd; and Department of Dermatology and Skin Science, University of British Columbia.e Funding sources: None. Disclosure: Dr Jagdeo is currently conducting an investigatorinitiated study on HIV facial lipoatrophy (research grant) and is on the facial aesthetics advisory board (honoraria), Allergan Pharmaceuticals. Dr Carruthers has grant, research, and clinical trial support from Allergan Pharmaceuticals (onabotulinumtoxinA), Merz GmbH (incobotulinumtoxinA), and Revance Inc (RT 001 and RT 002). Dr Carruthers is a consultant and on advisory boards with Allergan Pharmaceuticals (onabotulinumtoxinA), Merz GmbH (incobotulinumtoxinA), Revance Inc (RT 001 and RT 002), and Kythera BioPharma. Jean Carruthers, MD (spouse) has grant, research,

and clinical trial support; is a consultant; and is on advisory boards with Allergan Pharmaceuticals [neuromodulators and fillers (onabotulinumtoxinA)], Merz USA and Merz GmBH [neuromodulators and fillers (hyaluronic acid)], and Kythera BioPharma [sodium deoxycholate (deoxycholate)]. Authors Ho and Lo declared no conflicts of interest. Accepted for publication August 19, 2015. Reprint requests: Jared Jagdeo, MD, MS, Sacramento Department of Veterans Affairs Medical Center, Building 801, Dermatology Service, 10535 Hospital Way, Mather, CA 95655. E-mail: [email protected]. Published online October 16, 2015. 0190-9622 Published by Elsevier on behalf of the American Academy of Dermatology, Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/). http://dx.doi.org/10.1016/j.jaad.2015.08.040

1040

J AM ACAD DERMATOL

Jagdeo et al 1041

VOLUME 73, NUMBER 6

social function, and emotional status.8,9 Most puboff-label to treat HIV FLA: HA, PAAG, PAIG, PMMA, lished studies on the efficacy and safety of filler agents silicone oil, and AFT. for treatment of HIV FLA have been observational studies. A grading criteria used for classification of HIV FDA approved for treatment of HIV FLA. FLA severity, Carruthers Lipoatrophy Severity Scale, is also often used as a standardized measure to assess Poly-L-lactic acid response of patients with HIV FLA to treatment with PLLA reconstituted in sterile water and lidocaine filler agents (Fig 1).10 improves facial volume loss The goal of our systematic by serving as a scaffold, proCAPSULE SUMMARY review is to examine published moting fibroblast proliferaclinical studies involving the tion and neocollagenesis.12 HIV facial lipoatrophy is characterized by use of filler agents for aesthetic PLLA was FDA approved in facial volume loss and is associated with treatment of HIV FLA and to 2004 as the first filler agent social stigma. provide evidence-based recfor treatment of HIV FLA. Based on published studies, poly-L-lactic ommendations based on pubAn open-label, randomacid is the only filler agent with grade of lished efficacy and safety data. ized study of either immedirecommendation: B. Other reviewed filler ate or delayed PLLA agents received grade of recommendation: METHODS treatment for HIV FLA was C or D. Search strategy and data performed in 30 patients extraction with HIV13 (LOE 2b). Filler agents are generally safe for A systematic review of the Results at 12 weeks showed aesthetic improvement of HIV facial published literature was persignificant improvement in lipoatrophy and improve patient quality formed on July 1, 2015, on visual analog scale score for of life. filler agents for aesthetic the immediate treatment treatment of HIV FLA (please group, and improvement in see Fig 2 and legend for detailed search strategy). visual analog scale score was maintained from baseline in both treatment groups at 18 months14 RESULTS (LOE 2b). The most common delayed adverse event Study selection of filler agents for aesthetic was injection-site nodules (31%). treatment of HIV FLA A different open-label, randomized study of imA total of 321 articles regarding the use of filler mediate or delayed PLLA treatment of HIV FLA agents for treatment of HIV FLA were identified. After evaluated 100 patients with HIV15 (LOE 2b). By screening of titles, abstracts, and full text, 76 original 24 weeks, patients with immediate treatment had articles were suitable in our review: poly-L-lactic acid significant improvement in FLA severity and QoL (PLLA) (29), calcium hydroxylapatite (CaHA) (6), compared with patients with delayed treatment. At hyaluronic acid (HA) (7), polyacrylamide gel (PAAG) 48 weeks, there were significant changes of (9), polyalkylimide gel (PAIG) (11), polymethylmeincreased tissue depth measured by computed tothacrylate (PMMA) (6), silicone oil (2), and autolomography imaging with subsequent 3-dimensional gous fat transfer (AFT) (6). volumetric assessments at the maxillary, base of Articles were assigned a level of evidence (LOE) nasal septum, and mandibular regions for immediate and graded according to the Oxford Center for treatment group patients16 (LOE 2b). Subcutaneous Evidence-based Medicine LOE grades of recommennodules remained in 10% of patients at week 48. dation (GOR)11 (Table I). A list of filler agents used in Another open-label, randomized study of immepublished clinical studies for aesthetic treatment of diate or delayed PLLA or PAIG treatment of HIV FLA HIV FLA can be found in Table II and detailed was performed in 134 patients with HIV17 (LOE 2b). information on published clinical studies using filler At 24 weeks, patients from the immediate treatment agents for aesthetic treatment of HIV FLA can be found group had significantly lower FLA severity compared on http://www.jaad.org in Supplemental Table I. with patients in the delayed treatment group. Twenty observational studies evaluated efficacy Filler agents for aesthetic treatment of HIV FLA and safety of PLLA treatment for HIV FLA, and all Food and Drug Administration (FDA)-approved studies reported positive outcomes for improving dermal fillers for treatment of HIV FLA are Sculptra FLA severity and achieving high patient satisfac(Galderma, Fort Worth, TX) (PLLA, 2004) and tion8,18-36 (LOE 4). Four case reports demonstrated Radiesse (Merz Aesthetics, Franksville, WI) (CaHA, PLLA treatment for HIV FLA improved FLA severity 2006). Clinicians have used the following filler agents up to 24 months37-40 (LOE 5). d

d

d

1042 Jagdeo et al

Abbreviations used: AFT: CaHA: FDA: FLA: GOR: HA: HAART: LOE: PAAG: PAIG: PLLA: PMMA: QoL: RCT:

autologous fat transfer calcium hydroxylapatite Food and Drug Administration facial lipoatrophy grade of recommendation hyaluronic acid highly active antiretroviral therapy level of evidence polyacrylamide gel polyalkylimide gel poly-L-lactic acid polymethylmethacrylate quality of life randomized controlled trial

Grade of recommendation: B for PLLA treatment of HIV FLA based on 3 randomized controlled trials (RCTs) (with 2 follow-up studies) with LOE 2b, 20 observational studies with LOE 4, and 4 case reports with LOE 5. Calcium hydroxylapatite CaHA, delivered in a soluble carrier gel, acts as a scaffold for new collagen production. The carrier gel

J AM ACAD DERMATOL

DECEMBER 2015

is degraded within months of injection and the remaining CaHA microspheres help promote fibroblast growth and new collagen deposition.12 CaHA was the second filler agent FDA approved in 2006 for treatment of HIV FLA. Six studies evaluated the efficacy and safety of CaHA for treatment of HIV FLA41-46 (LOE 4). Two different studies showed that CaHA improvement of FLA severity was maintained for 12 months.44,46 One study investigated the radiographic properties of CaHA treatment with x-ray and computed tomographic imaging,43 and computed tomography consistently visualized no evidence of CaHA migration. Grade of recommendation: C for CaHA treatment of HIV FLA based on 6 observational studies with LOE 4. Off-label filler agents for treatment of HIV FLA. Hyaluronic acid HA injectables allow immediate facial volumization with release of HA chains from the injected gel carrier.47

Fig 1. Carruthers Lipoatrophy Severity Scale. 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. (Modified and adapted with permission from James et al.10)

J AM ACAD DERMATOL VOLUME 73, NUMBER 6

Jagdeo et al 1043

Table I. Level of evidence and grades of recommendation LOE 1a. Systematic review of RCTs 1b. Individual RCT 2a. Systematic review of cohort studies 2b. Individual cohort study (including low-quality RCT) 3a. Systematic review of case-control studies 3b. Individual case-control study 4. Case series 5. Case reports, expert opinion, bench research GOR A. Studies with consistent LOE 1a and/or 1b B. Studies with consistent LOE 2a, 2b, 3a, or 3b; or extrapolations from studies with LOE 1a or 1b C. Studies with LOE 4 or extrapolations from studies with LOE 2a, 2b, 3a, or 3b D. Studies with LOE 5 or troubling inconsistent or inconclusive studies of any level Data from Oxford Center for Evidence-based Medicine LOE.11 GOR, Grades of recommendation; LOE, level of evidence; RCT, randomized controlled trial.

Fig 2. Schematic of the search strategy listing the number of articles matching inclusion or exclusion criteria modified and adapted from Moher et al.90 FLA, Facial lipoatrophy.

Six observational studies evaluated the efficacy and safety of HA for treatment of HIV FLA47-52 (LOE 4). HA dermal filler for improvement of HIV FLA was sustained for 6 months49 and 12 months47,50,51 with 1 treatment and minimal touch-up. One study described nodule formation that was effectively removed using hyaluronidase injectables.47 One case report demonstrated improvement of FLA severity from baseline of between 2 and 3 to 0 as measured by FLA Severity Scale at 18 months53 (LOE 5). Grade of recommendation: C for HA treatment of HIV FLA based on 6 observational studies with LOE 4 and 1 case report with LOE 5. Polyacrylamide gel PAAG is a synthetic nonreabsorbable filler that serves as structural support to restore facial volume

loss.54 PAAG stimulates a fibrotic tissue response around the implant. A randomized study evaluated the efficacy and safety of PAAG administered in 8-mL sessions versus 2-mL sessions every eighth week until full correction in 31 patients with HIV55 (LOE 2b). At 12 months, patients who received 8 mL of PAAG over average of 2 sessions showed improvement faster than patients who received 2 mL of PAAG over average of 7.8 sessions. Eight different observational studies evaluated the efficacy and safety of PAAG for treatment of HIV FLA54,56-62 (LOE 4). Results demonstrated significant improvement in cheek thickness at 2 years60 and 5 years59 of follow-up. Grade of recommendation: C for PAAG treatment of HIV FLA based on 1 RCT with LOE 2b and 8 observational studies with LOE 4. Polyalkylimide gel PAIG is a nonreabsorbable polymer that provides structural support for facial volume loss. PAIG induces skin tissue to form a fibrous capsule around the deposit.63 An open-labeled, randomized study investigated immediate versus delayed PAIG treatment in 31 patients with HIV9 (LOE 2b). At 12 weeks, immediate PAIG treatment patients had significantly lower FLA severity and improved QoL compared with delayed treatment patients. The median change in FLA severity at 96 weeks and 4 years was
264 (LOE 2b) and
165 (LOE 2b), respectively. Delayed

Filler

Formulation

Trade names

Product cost, US$##

PLLA GOR: B Three RCTs (with 2 followup studies) with LOE 2b, 20 observational studies with LOE 4, and 4 case reports with LOE 5.

Stimulates local fibroblasts to promote neocollagenesis and produce new fibrous dermal tissue to maintain volume correction after PLLA microspheres are naturally degraded by the body.12

PLLA (of synthetic and nonanimal origin) is derived from the alphahydroxy-acid family, and is commonly used in resorbable sutures. PLLA microspheres, packaged in a freeze-dried powdered form, is reconstituted with sterile water before injection. Result is not instantaneous as injection triggers neocollagenesis of fibroblast scaffolds resulting in volumization. Usually 3 treatments over the course of 6 mo are required.12

Injectable containing microparticles of PLLA, carboxymethylcellulose, nonpyrogenic mannitol, and sterile water for injection.*

Sculptra (formerly New-Fill) (Galderma, Fort Worth, TX), 2 3 150-mg vials

$482***

CaHA GOR: C Six observational studies with LOE 4.

Acts as a space-filling bulk for soft tissue augmentation. Degradation of the gel carrier then leaves the CaHA microspheres in the dermis, which promotes new skin tissue formation via fibroblastic growth and new collagen deposition. Over time the CaHA microspheres are metabolized via macrophage phagocytosis.12

High viscosity (;350 cPa) and high elasticity (;1.5 Pa). CaHA microparticles are made of calcium and phosphate ions identical to bone, which results in outstanding biocompatibility with the human body.12

CaHA microspheres (25-45 m) suspended in a gel carrier of sodium carboxymethylcellulose, glycerin, and sterile water for injection.y An implant composed of spherical CaHA particles, 75-125 m in diameter, suspended in an aqueousbased gel carrier composed of sodium carboxymethylcellulose, sterile water for injection, and glycerin.z

Radiesse (formerly Radiance FN) (Merz Aesthetics, Franksville, WI), 1 3 1.5-mL syringe

$236***

Coaptite (Merz Aesthetics, Franksville, WI)

Varies

DECEMBER 2015

Biophysical properties

J AM ACAD DERMATOL

Mechanism of action

1044 Jagdeo et al

Table II. Filler agents for treatment of HIV facial lipoatrophy

Highly cohesive gel (;40 gmf) with great density (G9) (;300 Pa) and viscoelastic properties. These properties allow for high and long-lasting lifting capacity with small changes in volume of implant. HA fillers are considered nonirritant, nontoxic, nonsensitizing, and nonpyrogenic.12,88

Restylane (Galderma, Fort Worth, TX), 1 3 1-mL syringe

$160***

Restylane SubQ has fewer gel particles and larger droplets than other Restylane products. It is more viscous and is suitable for larger injection volumes at a deeper skin layer.47 Restylane-L has the same formulation as Restylane with 0.3% lidocaine.// A gel of HA generated by Streptococcus species of bacteria that is chemically cross-linked with BDDE, stabilized, and suspended in phosphate-buffered saline at pH 7 and concentration of 20 mg/ mL.{ A gel composed of crosslinked molecules of HA and divinyl sulfone as the cross-linking agent.# Same formula as Hylaform with a new source of HA from bacteria fermentation.**

Restylane SubQ (Galderma, Fort Worth, TX)

Varies

Restylane-L (Galderma, Fort Worth, TX)

Varies

Perlane (Galderma, Fort Worth, TX), 1 3 1-mL syringe

$186***

Hylaform (Genzyme Corporation, Cambridge, MA), withdrawn from the US market Captique (Inamed Corporation and Genzyme Corporation, Santa Barbara, CA), withdrawn from the US market

$240yyy

Varies

Continued

Jagdeo et al 1045

A gel of HA isolated from a Streptococcus species that is chemically cross-linked with BDDE, stabilized, and suspended in phosphate buffered saline at pH 7 and a concentration of 20 mg/mL.x

J AM ACAD DERMATOL

Acts as a filling substance in the skin and helps to retain water. After treatment, HA chains are released from the injected gel carrier and are biodegraded by natural mechanisms.47

VOLUME 73, NUMBER 6

HA GOR: C Six observational studies with LOE 4 and 1 case report with LOE 5.

Filler

Mechanism of action

Biophysical properties

Formulation

Same product as Hylaform with 0.3% lidocaine.yy An injectable gel that consists of cross-linked HA formulated to a concentration of 22 mg/ mL suspended in a physiological buffer.zz A gel of cross-linked HA produced by Streptococcus equi bacteria, formulated to a concentration of 20 mg/ mL and 0.3% with lidocaine in a physiologic buffer.xx High density (26 mg/mL) nonanimal HA.52 HA manufactured from streptococcal culture cross-linked with a binding agent (BDDE) and reconstituted in a physiologic buffer at pH 7 and concentration of 22.5 mg/mL.//// Plasticity of PAAG is similar to that of silicone, and PAAG is hydrophilic, allowing for high capacity water exchange with surrounding tissue.54

A gel that contains 2.5% PAAG and 97.5% water.71

2.5% Cross-linked polyacrylamide and nonpyrogenic water.

Prevelle SILK (Johnson & Johnson, Skillman, NJ) Juvederm Ultra/Ultra Plus/ 30 (Allergan Pharmaceutical, Irvine, CA), 2 3 1-mL syringe

Varies

Juvederm Voluma XC (VYC20 L) (Allergan Pharmaceutical, Irvine, CA), 2 3 1-mL syringe

$367***

STYLAGE XL (Laboratoires VIVACY, Paris, France), 2 3 1-mL syringe Belotero Balance (Belotero Basic outside of the US) and Belotero Intense (Merz Aesthetics, Franksville, WI), 5 3 1-mL syringe

$427zzz

Aquamid (CONTURA INTERNATIONAL A/S, Soeborg, Denmark), 1 3 1-mL syringe Eutrophill (Trillium Meditec Inc, Ontario, Canada)

$611//////

$328***

$209xxx

Varies

DECEMBER 2015

Acts as a nonresorbable soft tissue filler with a moderate foreign-body response, but little to no resultant fibrosis around the implant.54

Product cost, US$##

J AM ACAD DERMATOL

PAAG GOR: C One RCT with LOE 2b and 8 observational studies with LOE 4.

Trade names

1046 Jagdeo et al

Table II. Cont’d

PMMA GOR: C Six observational studies with LOE 4.

Over 1-3 mo after injection the nonbiodegradable PMMA microspheres act as a frame to support the deposit of conjunctive tissue and are encapsulated by fibroblasts and collagen.71

Silicone oil GOR: C Two observational studies with LOE 4.

Requires small injection (microdroplet serial puncture technique) to subdermal plane to avoid papule formation and granulomatous reactions.

A polymer gel composed of 96% apyrogenic water and 4% polyalkylimide.62

Bio-Alcamid (Polymekon, Brindisi, Italy)

Varies

An implant composed of PMMA particles, 30-50 m in diameter, mixed with magnesium-carboxygluconate-hydrolactic gel (ratio microspheres to gel is 3:10).72 An implant composed of nonresorbable PMMA, 3050 m in diameter, that is suspended in a waterbased carrier gel composed of 3.5% bovine collagen, 92.6% buffered, isotonic water for injection, 0.3% lidocaine hydrochloride, 2.7% phosphate buffer, and 0.9% sodium chloride.{{

Metacrill (Nutricel Laboratorios, Rio de Janeiro, Brazil)

Varies

Artefill/Artecoll (Artes Medical Inc, San Diego, CA), 1 3 0.5-mL syringe

$595//////

Medical-grade highly purified silicone oil (viscosity 1000 centistokes).79

Silikon 1000 (Alcon Laboratories, Fort Worth, TX) VitreSil 1000 (Richard James Inc, Peabody, MA)

Varies

Varies

Continued

Jagdeo et al 1047

Remains permanently in the skin without undergoing significant loss; the formation of a collagen capsule around the microdroplets may maintain the position of the droplets.71

A nonresorbable, biocompatible compound that has a reticulated structure resembling that of an adipose tissue. It has a pH of 7 and an oxidative value of approximately 0.69 Resembles that of bone cement and has been used as a bio-expander in knee and intraocular implants.74

J AM ACAD DERMATOL

Induces host tissue to form a fibrous capsule around the deposit.61

VOLUME 73, NUMBER 6

PAIG GOR: D One RCT (with 2 followup studies) with LOE 2b and 8 observational studies with LOE 4.

Filler

Autologous fat transfer GOR: C Six observational studies with LOE 4.

Mechanism of action

Fat transfer

Biophysical properties

Derived from subject’s own body, fat transfer has the same biophysical properties as that of subject’s own adipose tissue.

Formulation

Not applicable

Trade names

Various techniques

Product cost, US$##

Varies

DECEMBER 2015

J AM ACAD DERMATOL

BDDE, 1,4-Butanediol diglycidyl ether; CaHA, calcium hydroxylapatite; GOR, grades of recommendation; HA, hyaluronic acid; LOE, levels of evidence; PAAG, polyacrylamide gel; PAIG, polyalkylimide gel; PLLA, poly-L-lactic acid; PMMA, polymethylmethacrylate; RCT, randomized controlled trial. *US Food and Drug Administration. PMA P030050/S2: FDA summary of safety and effectiveness data (Sculptra). Available from: URL: http://www.accessdata.fda.gov/cdrh_docs/pdf3/P030050S002b. pdf. Accessed December 1, 2014. y US Food and Drug Administration. PMA P050037: FDA summary of safety and effectiveness data (Radiesse). Available from: URL: http://www.accessdata.fda.gov/cdrh_docs/pdf5/P050037b.pdf. Accessed December 1, 2014. z US Food and Drug Administration. CoaptiteeP040047. Available from: URL: http://www.accessdata.fda.gov/cdrh_docs/pdf4/P040047b.pdf. Accessed December 1, 2014. x US Food and Drug Administration. PMA P040024/S051: FDA summary of safety and effectiveness data (Restylane). Available from: URL: http://www.accessdata.fda.gov/cdrh_docs/pdf4/ P040024S051b.pdf. Accessed December 1, 2014. // US Food and Drug Administration. PMA P040024/S056: FDA summary of safety and effectiveness data (Restylane-L). Available from: URL: http://www.accessdata.fda.gov/cdrh_docs/pdf4/ P040024S056b.pdf. Accessed December 1, 2014. { US Food and Drug Administration. PERLANE. Available from: URL: http://www.accessdata.fda.gov/cdrh_docs/pdf4/p040024s006c.pdf. Accessed December 1, 2014. # US Food and Drug Administration. PMA P030032: FDA summary of safety and effectiveness data (Hylaform). Available from: URL: http://www.accessdata.fda.gov/cdrh_docs/pdf3/P030032b.pdf. Accessed December 1, 2014. **US Food and Drug Administration. Captique. Available from: URL: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=4157 Accessed December 8, 2014. yy US Food and Drug Administration. Prevelle SILK. Available from: URL: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=25281 Accessed December 8, 2014. zz US Food and Drug Administration. PMA P050047: FDA summary of safety and effectiveness data (Juvederm). Available from: URL: http://www.accessdata.fda.gov/cdrh_docs/pdf5/P050047b.pdf. Accessed December 1, 2014. xx US Food and Drug Administration. PMA P110033: FDA summary of safety and effectiveness data (Juvederm XC). Available from: URL: http://www.accessdata.fda.gov/cdrh_docs/pdf11/P110033b. pdf. Accessed December 1, 2014. //// US Food and Drug Administration. PMA P090016: FDA summary of safety and effectiveness data (Belotero Balance). Available from: URL: http://www.accessdata.fda.gov/cdrh_docs/pdf9/ P090016b.pdf. Accessed December 1, 2014. {{ US Food and Drug Administration. PMA P020012: FDA summary of safety and effectiveness data (Artefill). Available from: URL: http://www.accessdata.fda.gov/cdrh_docs/pdf2/P020012b.pdf. Accessed December 1, 2014. ## Does not include fee for office visit or physician technical component. ***Gibson Medical Outlet. Gibson Medical Outlet: Trusted source to buy wholesale medical supplies online. Available from: URL: http://www.gibsonmedicaloutlet.com. Accessed June 17, 2015. yyy CaliMeds.com. Buy medication online & save up to 85% today at CaliMeds.com: California’s #1 medication website. Available from: URL: http://calimeds.com. Accessed June 17, 2015. zzz gMedication.com. Best prices for medications. Available from: URL: http://www.gmedication.com/. Accessed September 24, 2015. xxx Medica Depot. Buy BELOTERO BALANCE w/ Lidocaine for $179 j MedicaDepot.com Available from: URL: https://www.medicadepot.com/belotero-balance.html. Accessed September 24, 2015. ////// Dr Ashley Minas. 111 Dr Ashley Minas - Online medical consultation. Available from: URL: http://www.consultdrminas.com. Accessed June 17, 2015.

1048 Jagdeo et al

Table II. Cont’d

J AM ACAD DERMATOL VOLUME 73, NUMBER 6

Jagdeo et al 1049

Table III. Expert opinion and recommendation of filler agents for aesthetic treatment of HIV facial lipoatrophy Filler agents

PLLA (FDA approved in 2004, GOR: B)

CaHA (FDA approved in 2006, GOR: C)

HA (Off-label, GOR: C)

PAAG (Off-label, GOR: C)

PAIG (Off-label, GOR: D)

PMMA (Off-label, GOR: C)

Silicone oil, microdroplet technique (Off-label, GOR: C)

AFT (Off-label, GOR: C)

Expert opinion and recommendation based upon published studies and clinical experience

PLLA is an effective option for treatment of HIV FLA. PLLA may be best for patients who require treatment over temples and cheeks, as PLLA provides a gradual and softer fill. PLLA may be considered for global fill of large areas, as PLLA is easy to massage into adjacent tissues and able to achieve large spread effect. However, methods for prevention and management of subcutaneous nodules require further investigation. We have found in clinical practice that PLLA is relatively easy to use to treat HIV FLA. However, because of the need for several treatments to achieve sustained results, best outcomes are often achieved by combining additional filler agents. GOR: B for PLLA treatment of HIV FLA based on 3 RCTs (with 2 follow-up studies) with LOE 2b, 20 observational studies with LOE 4, and 4 case reports with LOE 5. CaHA is an effective and safe option for treatment of HIV FLA. The FDA indication for CaHA is subdermal implantation, and we believe that CaHA, which is essentially liquid bone, may be best used deeply over bone for focal enhancement as it provides a firmer fill and does not easily spread to adjacent tissues. Because of the firm consistency of CaHA, injecting larger volumes may result in an ‘‘overfilled’’ appearance. GOR: C for CaHA treatment of HIV FLA based on 6 observational studies with LOE 4. HA dermal filler is an effective and safe treatment for HIV FLA. HA dermal filler has the advantages of achieving immediate results with 1 treatment and reversibility with hyaluronidase injectables for overcorrection or adverse events. We envision future research with HA dermal fillers for treatment of HIV FLA will be important to establish HA’s long-term efficacy and safety. GOR: C for HA treatment of HIV FLA based on 6 observational studies with LOE 4 and 1 case report with LOE 5. PAAG is an effective treatment for HIV FLA. However, studies reported small papules and nodule formation, which may affect patient safety and QoL. Additional studies are needed to determine long-term safety. GOR: C for PAAG treatment of HIV FLA based on 1 RCT with LOE 2b and 8 observational studies with LOE 4. PAIG is an effective treatment for HIV FLA. However, some studies demonstrated granulomas or infectious complications that required antibiotics or incision and drainage, which is a significant patient safety concern. Additional studies are needed to determine long-term safety. GOR: D for PAIG treatment of HIV FLA safety concerns despite 1 RCT (with 2 follow-up studies) with LOE 2b and 8 observational studies LOE 4. PMMA is an effective treatment for HIV FLA. Because of PMMA’s mechanism of action of inducing a foreign-body reaction, additional studies are needed to determine long-term safety. GOR: C for PMMA treatment of HIV FLA based on 6 observational studies with LOE 4. Silicone oil is an effective treatment for HIV FLA. The microdroplet technique for silicone oil injection requires expert training and a skilled physician to minimize risks of microgranuloma formation. Additional studies are needed to determine long-term safety. GOR: C for silicone oil for treatment of HIV FLA based on 2 observational studies with LOE 4. AFT is an effective treatment for HIV FLA. However, patients with HIV FLA likely have generalized HIV lipoatrophy, and AFT may not be optimal despite proven safety. GOR: C for AFT treatment of HIV FLA based on 6 observational studies with LOE 4.

AFT, Autologous fat transfer; CaHA, calcium hydroxylapatite; FDA, Food and Drug Administration; FLA, facial lipoatrophy; GOR, grades of recommendation; HA, hyaluronic acid; LOE, levels of evidence; PAAG, polyacrylamide gel; PAIG, polyalkylimide gel; PLLA, poly-L-lactic acid; PMMA, polymethylmethacrylate; QoL, quality of life; RCT, randomized controlled trial.

1050 Jagdeo et al

complications include 5 cases of infection at median time of 2.8 years and 8 cases of ongoing nodule formation. Eight different observational studies63,66-72 (LOE 4) evaluated the safety and efficacy of PAIG for treatment of HIV FLA. Two different studies revealed long-term adverse effects of infectious complications with 19%63 and 3.3%70 of patients. Grade of recommendation: D for PAIG treatment of HIV FLA safety concerns despite 1 RCT (with 2 follow-up studies) with LOE 2b and 8 observational studies LOE 4. Polymethylmethacrylate PMMA is a synthetic nonreabsorbable polymer. PMMA microspheres induce a foreign-body reaction, become encapsulated in fibrous connective tissue, and result in long-lasting facial augmentation.73 Six observational studies evaluated the efficacy and safety of PMMA for treatment of HIV FLA74-79 (LOE 4). One study revealed significant improvement in patient QoL and median visual analog scale score at 2 years.79 A different study demonstrated 85.7% of patients were satisfied at 12 months75 and 90% of patients were satisfied at 5 years in another study.74 Grade of recommendation: C for PMMA treatment of HIV FLA based on 6 observational studies with LOE 4. Silicone oil Silicone oil is nonreabsorbable and stimulates a foreign-body fibrotic reaction around the silicone deposit.73 For silicone oil, we found 2 observational studies that used the microdroplet serial puncture technique with injection volume of 0.01 mL per depot. One observational study demonstrated that FLA severity of 1, 2, and 3 as measured by FLA Severity Scale requires at least 3, 5, and 8 treatments, respectively80 (LOE 4). A different observational study showed that 75% of patients had significant correction of FLA severity as measured by FLA Severity Scale after median of 6 treatments81 (LOE 4). No severe adverse effects were reported. Grade of recommendation: C for silicone oil for treatment of HIV FLA based on 2 observational studies with LOE 4. Autologous fat transfer AFT using Coleman82 lipostructure technique was first described in 1997 for improving facial contours and volume. Four observational studies evaluated the efficacy and safety of AFT for treatment of HIV FLA83-86 (LOE 4). Improvement of FLA severity was sustained for

J AM ACAD DERMATOL

DECEMBER 2015

at least 1 year in 2 studies83,84 and up to 4 years in 1 study.86 Two observational studies evaluated the use of either AFT or PAAG for treatment of HIV FLA87,88 (LOE 4). Results from 1 study at 1 year demonstrated significant improvement in Global Aesthetic Improvement Scale score in 78.3% of patients who received AFT treatment compared with 4.3% who received PAAG treatment.87 Grade of recommendation: C for AFT treatment of HIV FLA based on 6 observational studies with LOE 4. Expert recommendation PLLA (Sculptra) and CaHA (Radiesse) are FDA approved for treatment of HIV FLA. Comparing PLLA and CaHA, CaHA provides immediate and lasting filling properties, whereas PLLA results in an immediate fill based on sterile water volume that is temporary and gets absorbed within 1 week. In addition, PLLA requires 3 treatments in 6 months before durable aesthetic benefit. PLLA provides a ‘‘softer’’ and more gradual volumizing effect compared with CaHA because of the mechanism of action. CaHA provides immediate volumizing fill and may be thought of as ‘‘liquid bone,’’ whereas PLLA works as a scaffold stimulating fibroblast migration, proliferation, and collagen production. Although not FDA approved for treating HIV FLA, 20 mg/mL of HA (Voluma) is FDA approved to increase the volume for mid-facial atrophy. Some benefits include: immediate corrective effect without the need to retreat within a 6-month period (as with PLLA), no need to reconstitute (as with PLLA), and reversible with hyaluronidase (compared with PLLA and CaHA). Detailed recommendations of reviewed filler agents can be found in Table III. PLLA may be best for patients who require treatment over temples and cheeks, as PLLA provides a gradual and softer fill, but at a higher cost because of multiple treatments and in-office visits, along with delayed durable visible improvement. PLLA may be considered for large areas, as PLLA is easy to massage into adjacent tissues and able to achieve large spread effect. The FDA indication for CaHA is subdermal implantation, and we believe that CaHA may be best used deeply over bone for focal enhancement as it provides a firmer fill and does not easily spread. HA, as a natural component of the skin, has intermediate elasticity and viscosity, and is able to provide high volumization properties with minimal gel migration.89 Both CaHA and HA only require 1 treatment and provide immediate visible improvement, which helps minimize health care and patient cost. HA is not FDA approved for treatment of HIV FLA, and our research group (principal investigator Dr Jagdeo, ClinicalTrials.gov NCT02342223) is

J AM ACAD DERMATOL VOLUME 73, NUMBER 6

currently conducting a FDA-approved study using HA for treatment of HIV FLA. We envision future head-to-head clinical trials with PLLA, CaHA, and HA will be of significant importance to compare and contrast these agents for treatment of HIV FLA.

DISCUSSION Although clinical studies differed with respect to filler injection volumes and follow-up periods, all filler agents discussed in our review showed improvement in HIV FLA severity by 12 weeks. Studies demonstrated sustained improvement in HIV FLA severity for at least 12 months with PLLA, CaHA, HA, and silicone oil injections, and up to 4 to 5 years with AFT, PAAG, PAIG, and PMMA injections. The degree and duration of improvement for each treatment option is closely related to initial HIV FLA severity and the biophysical and longevity profile distinct to each filler agent. Filler agents for treatment of HIV FLA were shown to be safe and well tolerated by most patients. Common transient adverse effects because of the nature of filler injections include pain and discomfort, ecchymosis, edema, and erythema that usually resolve by 1 month. Treatment with PLLA was associated with occasional subcutaneous nodules. Immunosuppression may be beneficial in reducing the incidence of immunologically related filler agent reactions such as granulomas, although HIV immunosuppression may increase infections associated with filler agent procedures. Based on long-term patient follow-up, silicone oil using the microdroplet technique does not induce palpable nodules in patients with HIV, and it is possible that their HIV disease is beneficial toward this outcome.81 Future research studies should incorporate larger sample sizes to adequately power for statistical significance, along with RCTs and longer follow-up periods to evaluate the long-term efficacy and safety for each filler agent for aesthetic treatment of HIV FLA. Limitations PLLA was the only filler agent to receive a GOR: B based on several RCTs. We found limited RCTs that evaluated the use of other filler agents for aesthetic treatment of HIV FLA. As a result, CaHA, HA, PAAG, PAIG, PMMA, silicone oil, and AFT for treatment of HIV FLA received a GOR: C or D. Other limitations with many published studies include follow-up periods of 12 or 18 months, which may be insufficient to demonstrate the long-term efficacy and safety as filler agents may last 12 months or longer. Duration on HAART and patients’ ages were not clearly stated, which may introduce bias as

Jagdeo et al 1051

HIV FLA tends to be more severe with prior generations of HAART and normal aging may also result in significant facial volume loss, respectively. Washout periods were inconsistent or not stated across all studies, which could affect filler efficacy and longevity. Interstudy comparison among studies was difficult as different objective and subjective grading scales were used. Future researchers may consider objective grading scales such as skin thickness or volume measurement by ultrasound or 3-dimensional imaging, or standardized subjective grading scales such as Global Aesthetic Improvement Scale or FACE-Q. In addition, not all researchers have adopted the Carruthers Lipoatrophy Severity Scale to grade HIV FLA. This leads to inconsistency among studies for determining baseline severity and improvement post-HIV FLA treatment. As a result of these factors, independent objective improvement from various types of fillers treated for patients with different HIV FLA severity could not be determined. Furthermore, the reviewed clinical trials evaluated different classes and brand-specific formulations of fillers, and some fillers may not be currently available on the market or may be limited to specific countries. In addition, treatment for HIV FLA may be an out-of-pocket patient expense not covered by insurance, and researchers may consider incorporating costeffectiveness analysis in future clinical trials to better comprehend improvement as related to price. Conclusion The current literature suggests that filler agents for treatment of HIV FLA are an effective and generally safe option for aesthetic improvement and help improve patient QoL. Treatment of HIV FLA is important because it affects patients’ psychological health, QoL, and adherence to HIV treatment regimen. Many filler agents exist, and when the clinician and patient decide on a treatment regimen for HIV FLA, factors such as cost, FDA approval, frequency of treatment sessions, time required until improvement, and filler longevity are important for consideration. There is currently a lack of clinical evidence on the treatment of HIV FLA that would suggest a specific filler over others as filler agents each have unique biophysical properties. Based on published studies, PLLA is the only filler agent with GOR: B. Other reviewed filler agents received GOR: C or D. We hope future researchers will implement more RCTs with direct head-to-head comparisons to evaluate the efficacy and safety of different fillers, in conjunction with cost-effectiveness analysis, for treatment of HIV FLA. In the future, we envision there will be an objective method for selecting a filler

1052 Jagdeo et al

agent regimen that incorporates HIV FLA severity, cost, and filler longevity accompanied by the development of longer-lasting, semipermanent, reversible filler agents for treatment of HIV FLA. REFERENCES 1. Carr A, Miller J, Law M, Cooper DA. A syndrome of lipoatrophy, lactic acidaemia and liver dysfunction associated with HIV nucleoside analogue therapy: contribution to protease inhibitor-related lipodystrophy syndrome. AIDS (London, England). 2000;14(3):F25-F32. 2. Duran S, Saves M, Spire B, et al. Failure to maintain long-term adherence to highly active antiretroviral therapy: the role of lipodystrophy. AIDS (London, England). 2001;15(18): 2441-2444. 3. Ammassari A, Antinori A, Cozzi-Lepri A, et al. Relationship between HAART adherence and adipose tissue alterations. J Acquir Immune Defic Syndr (1999). 2002;31(Suppl 3): S140-S144. 4. Rajagopalan R, Laitinen D, Dietz B. Impact of lipoatrophy on quality of life in HIV patients receiving anti-retroviral therapy. AIDS Care. 2008;20(10):1197-1201. 5. Haubrich RH, Riddler SA, DiRienzo AG, et al. Metabolic outcomes in a randomized trial of nucleoside, nonnucleoside and protease inhibitor-sparing regimens for initial HIV treatment. AIDS (London, England). 2009;23(9):1109-1118. 6. Leclercq P, Goujard C, Duracinsky M, et al. High prevalence and impact on the quality of life of facial lipoatrophy and other abnormalities in fat tissue distribution in HIV-infected patients treated with antiretroviral therapy. AIDS Res Hum Retroviruses. 2013;29(5):761-768. 7. Hornberger J, Rajagopalan R, Shewade A, Loutfy MR. Cost consequences of HIV-associated lipoatrophy. AIDS Care. 2009;21(5):664-671. 8. Cattelan AM, Bauer U, Trevenzoli M, et al. Use of polylactic acid implants to correct facial lipoatrophy in human immunodeficiency virus 1-positive individuals receiving combination antiretroviral therapy. Arch Dermatol. 2006;142(3): 329-334. 9. Loutfy MR, Raboud JM, Antoniou T, et al. Immediate versus delayed polyalkylimide gel injections to correct facial lipoatrophy in HIV-positive patients. AIDS (London, England). 2007; 21(9):1147-1155. 10. James J, Carruthers A, Carruthers J. HIV-associated facial lipoatrophy. Dermatol Surg. 2002;28(11):979-986. 11. Oxford Center for Evidence-based Medicine. Levels of evidence. Available from: URL:http://www.cebm.net/oxfordcentre-evidence-based-medicine-levels-evidence-march-2009/. Accessed August 5, 2014. 12. Luebberding S, Alexiades-Armenakas M. Facial volume augmentation in 2014: overview of different filler options. J Drugs Dermatol. 2013;12(12):1339-1344. 13. Moyle GJ, Lysakova L, Brown S, et al. A randomized open-label study of immediate versus delayed polylactic acid injections for the cosmetic management of facial lipoatrophy in persons with HIV infection. HIV Med. 2004;5(2): 82-87. 14. Moyle GJ, Brown S, Lysakova L, Barton SE. Long-term safety and efficacy of poly-L-lactic acid in the treatment of HIV-related facial lipoatrophy. HIV Med. 2006;7(3):181-185. 15. Carey DL, Baker D, Rogers GD, et al. A randomized, multicenter, open-label study of poly-L-lactic acid for HIV-1 facial lipoatrophy. J Acquir Immune Defic Syndr (1999). 2007; 46(5):581-589.

J AM ACAD DERMATOL

DECEMBER 2015

16. Carey D, Baker D, Petoumenos K, et al. Poly-l-lactic acid for HIV-1 facial lipoatrophy: 48-week follow-up. HIV Med. 2009; 10(3):163-172. 17. Narciso P, Bucciardini R, Tozzi V, et al. Immediate versus delayed surgical intervention for reconstructive therapy of HIV-associated facial lipoatrophy: a randomized open-label study. AIDS Res Hum Retroviruses. 2009;25(10):979-987. 18. Valantin MA, Aubron-Olivier C, Ghosn J, et al. Polylactic acid implants (New-Fill) to correct facial lipoatrophy in HIV-infected patients: results of the open-label study VEGA. AIDS (London, England). 2003;17(17):2471-2477. 19. Borelli C, Kunte C, Weisenseel P, Thoma-Greber E, Korting HC, Konz B. Deep subcutaneous application of poly-L-lactic acid as a filler for facial lipoatrophy in HIV-infected patients. Skin Pharmacol Physiol. 2005;18(6):273-278. 20. Burgess CM, Quiroga RM. Assessment of the safety and efficacy of poly-L-lactic acid for the treatment of HIV-associated facial lipoatrophy. J Am Acad Dermatol. 2005;52(2):233-239. 21. Guaraldi G, Orlando G, De Fazio D, et al. Comparison of three different interventions for the correction of HIV-associated facial lipoatrophy: a prospective study. Antivir Ther. 2005; 10(6):753-759. 22. Lafaurie M, Dolivo M, Porcher R, Rudant J, Madelaine I, Molina JM. Treatment of facial lipoatrophy with intradermal injections of polylactic acid in HIV-infected patients. J Acqui Immune Defici Syndr (1999). 2005;38(4):393-398. 23. Mest DR, Humble G. Safety and efficacy of poly-L-lactic acid injections in persons with HIV-associated lipoatrophy: the US experience. Dermatol Surg. 2006;32(11):1336-1345. 24. Negredo E, Higueras C, Adell X, et al. Reconstructive treatment for antiretroviral-associated facial lipoatrophy: a prospective study comparing autologous fat and synthetic substances. AIDS Patient Care STDs. 2006;20(12):829-837. 25. Hanke CW, Redbord KP. Safety and efficacy of poly-L-lactic acid in HIV lipoatrophy and lipoatrophy of aging. J Drugs Dermatol. 2007;6(2):123-128. 26. Ong J, Clarke A, White P, Johnson M, Withey S, Butler PE. Does severity predict distress? The relationship between subjective and objective measures of appearance and psychological adjustment, during treatment for facial lipoatrophy. Body Image. 2007;4(3):239-248. 27. Orlando G, Guaraldi G, De Fazio D, et al. Long-term psychometric outcomes of facial lipoatrophy therapy: forty-eight-week observational, nonrandomized study. AIDS Patient Care STDs. 2007;21(11):833-842. 28. Kavouni A, Catalan J, Brown S, Mandalia S, Barton SE. The face of HIV and AIDS: can we erase the stigma? AIDS Care. 2008;20(4):485-487. 29. Levy RM, Redbord KP, Hanke CW. Treatment of HIV lipoatrophy and lipoatrophy of aging with poly-L-lactic acid: a prospective 3-year follow-up study. J Am Acad Dermatol. 2008;59(6):923-933. 30. Nelson L, Stewart KJ. Experience in the treatment of HIV-associated lipodystrophy. J Plast Reconstr Aesthet Surg. 2008;61(4):366-371. 31. 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. 32. Ong J, Clarke A, White P, Johnson MA, Withey S, Butler PE. Objective evidence for the use of polylactic acid implants in HIV-associated facial lipoatrophy using three-dimensional surface laser scanning and psychological assessment. J Plast Reconstr Aesthet Surg. 2009;62(12):1627-1635.

J AM ACAD DERMATOL VOLUME 73, NUMBER 6

33. Bassichis B, Blick G, Conant M, et al. Injectable poly-L-lactic acid for human immunodeficiency virus-associated facial lipoatrophy: cumulative year 2 interim analysis of an open-label study (FACES). Dermatol Surg. 2012;38(7 Pt 2): 1193-1205. 34. Lafaurie M, Dolivo M, Girard PM, et al. Polylactic acid vs polyacrylamide hydrogel for treatment of facial lipoatrophy: a randomized controlled trial [Agence Nationale de Recherches sur le SIDA et les Hepatites Virales (ANRS) 132 SMILE]. HIV Med. 2013;14(7):410-420. 35. van Rozelaar L, Kadouch JA, Duyndam DA, Nieuwkerk PT, Lutgendorff F, Karim RB. Semipermanent filler treatment of HIV-positive patients with facial lipoatrophy: long-term follow-up evaluating MR imaging and quality of life. Aesthet Surg J. 2014;34(1):118-132. 36. Wang AS, Babalola O, Jagdeo J. The ‘‘smile-and-fill’’ injection technique: a dynamic approach to midface volumization. J Drugs Dermatol. 2014;13(3):288-290. 37. Vleggaar D, Bauer U. Facial enhancement and the European experience with Sculptra (poly-L-lactic acid). J Drugs Dermatol. 2004;3(5):542-547. 38. Wildemore JK, Jones DH. Persistent granulomatous inflammatory response induced by injectable poly-L-lactic acid for HIV lipoatrophy. Dermatolog Surg. 2006;32(11):1407-1409. 39. Kates LC, Fitzgerald R. Poly-L-lactic acid injection for HIV-associated facial lipoatrophy: treatment principles, case studies, and literature review. Aesthet Surg J. 2008;28(4): 397-403. 40. Mest DR, Humble GM. Duration of correction for human immunodeficiency virus-associated lipoatrophy after retreatment with injectable poly-L-lactic acid. Aesthet Plast Surg. 2009;33(4):654-656. 41. Comite SL, Liu JF, Balasubramanian S, Christian MA. Treatment of HIV-associated facial lipoatrophy with Radiance FN (Radiesse). Dermatol Online J. 2004;10(2):2. 42. Silvers SL, Eviatar JA, Echavez MI, Pappas AL. Prospective, open-label, 18-month trial of calcium hydroxylapatite (Radiesse) for facial soft-tissue augmentation in patients with human immunodeficiency virus-associated lipoatrophy: one-year durability. Plast Reconstr Surg. 2006;118(3 Suppl):34s-45s. 43. Carruthers A, Liebeskind M, Carruthers J, Forster BB. Radiographic and computed tomographic studies of calcium hydroxylapatite for treatment of HIV-associated facial lipoatrophy and correction of nasolabial folds. Dermatol Surg. 2008;34(Suppl 1):S78-S84. 44. Carruthers A, Carruthers J. Evaluation of injectable calcium hydroxylapatite for the treatment of facial lipoatrophy associated with human immunodeficiency virus. Dermatol Surg. 2008;34(11):1486-1499. 45. Alam M, Havey J, Pace N, Pongprutthipan M, Yoo S. Largeparticle calcium hydroxylapatite injection for correction of facial wrinkles and depressions. J Am Acad Dermatol. 2011; 65(1):92-96. 46. Rauso R, Curinga G, Rusciani A, Colella G, Amore R, Tartaro G. Safety and efficacy of one-step rehabilitation of human immunodeficiency virus-related facial lipoatrophy using an injectable calcium hydroxylapatite dermal filler. Dermatol Surg. 2013;39(12):1887-1894. 47. Skeie L, Bugge H, Negaard A, Bergersen BM. Large particle hyaluronic acid for the treatment of facial lipoatrophy in HIV-positive patients: 3-year follow-up study. HIV Med. 2010; 11(3):170-177. 48. Ritt MJ, Hillebrand-Haverkort ME, ten Veen JH. Local treatment of facial lipodystrophy in patients receiving HIV protease inhibitor therapy. Acta Chir Plast. 2001;43(2):54-56.

Jagdeo et al 1053

49. Gooderham M, Solish N. Use of hyaluronic acid for soft tissue augmentation of HIV-associated facial lipodystrophy. Dermatol Surg. 2005;31(1):104-108. 50. Denton AB, Tsaparas Y. Injectable hyaluronic acid for the correction of HIV-associated facial lipoatrophy. Otolaryngol Head Neck Surg. 2007;136(4):563-567. 51. Bechara FG, Gambichler T, Brockmeyer NH, Sand M, Altmeyer P, Hoffmann K. Hyaluronic acid new formulation: experience in HIV-associated facial lipoatrophy. Dermatology (Basel, Switzerland). 2008;217(3):244-249. 52. Pignatti M, Pedone A, Baccarani A, et al. High-density hyaluronic acid for the treatment of HIV-related facial lipoatrophy. Aesthet Plast Surg. 2012;36(1):180-185. 53. Pavicic T, Ruzicka T, Korting HC, Gauglitz G. Monophasic, cohesive-polydensified-matrix crosslinking-technology-based hyaluronic acid filler for the treatment of facial lipoatrophy in HIV-infected patients. J Drugs Dermatol. 2010;9(6):690-695. 54. de Santis G, Jacob V, Baccarani A, et al. Polyacrylamide hydrogel injection in the management of human immunodeficiency virus-related facial lipoatrophy: a 2-year clinical experience. Plast Reconstr Surg. 2008;121(2):644-653. 55. Rauso R, Gherardini G, Parlato V, Amore R, Tartaro G. Polyacrylamide gel for facial wasting rehabilitation: how many milliliters per session? Aesthet Plast Surg. 2012;36(1): 174-179. 56. Negredo E, Puig J, Aldea D, et al. Four-year safety with polyacrylamide hydrogel to correct antiretroviral-related facial lipoatrophy. AIDS Res Hum Retroviruses. 2009;25(4): 451-455. 57. Mansor S, Breiting VB, Dahlstrom K, Andersen AB, Andersen O, Christensen LH. Polyacrylamide gel treatment of antiretroviral therapy-induced facial lipoatrophy in HIV patients. Aesthet Plast Surg. 2011;35(5):709-716. 58. Rauso R, Freda N, Parlato V, Gherardini G, Amore R, Tartaro G. Polyacrylamide gel injection for treatment of human immunodeficiency virus-associated facial lipoatrophy: 18 months follow-up. Dermatol Surg. 2011;37(11):1584-1589. 59. de Santis G, Pignatti M, Baccarani A, et al. Long-term efficacy and safety of polyacrylamide hydrogel injection in the treatment of human immunodeficiency virus-related facial lipoatrophy: a 5-year follow-up. Plast Reconstr Surg. 2012; 129(1):101-109. 60. Mole B, Gillaizeau F, Carbonnel E, et al. Polyacrylamide hydrogel injection in the management of human immunodeficiency virus-related facial lipoatrophy: results of the LIPOPHILL open-label study. AIDS Res Hum Retroviruses. 2012;28(3):251-258. 61. Rauso R. 5-Year study of a polyacrylamide hydrogel-based filler for rehabilitation of HIV-related facial lipoatrophy. Aesthet Surg J. doi: http://dx.doi.org/10.1093/asj/sjv036. Published online May 7, 2015. 62. Negredo E, Puig J, Ornelas A, et al. Ten-year safety with polyacrylamide gel used to correct facial lipoatrophy in HIV-infected patients. AIDS Res Hum Retroviruses. 2015;31: 817-821. 63. Nadarajah JT, Collins M, Raboud J, et al. Infectious complications of Bio-Alcamid filler used for HIV-related facial lipoatrophy. Clin Infect Dis. 2012;55(11):1568-1574. 64. Antoniou T, Raboud JM, Kovacs C, et al. Long-term efficacy and safety of polyalkylimide gel for the treatment of HIV-associated lipoatrophy. AIDS Care. 2009;21(10): 1247-1252. 65. Loutfy MR, Brunetta J, Kovacs C, et al. Four-year follow-up of polyalkylimide gel use for the treatment of HIV-associated lipoatrophy. HIV Clin Trials. 2011;12(6):323-332.

1054 Jagdeo et al

66. Treacy PJ, Goldberg DJ. Use of a biopolymer polyalkylimide filler for facial lipodystrophy in HIV-positive patients undergoing treatment with antiretroviral drugs. Dermatol Surg. 2006;32(6):804-808. 67. Ramon Y, Fodor L, Ullmann Y. Preliminary experiences with Bio-Alcamid in HIV facial lipoatrophy. Dermatology (Basel, Switzerland). 2007;214(2):151-154. 68. Honig J. Cheek augmentation with Bio-Alcamid in facial lipoatrophy in HIV seropositive patients. J Craniofac Surg. 2008;19(4):1085-1088. 69. Karim RB, de Lint CA, van Galen SR, et al. Long-term effect of polyalkylimide gel injections on severity of facial lipoatrophy and quality of life of HIV-positive patients. Aesthet Plast Surg. 2008;32(6):873-878. 70. Schelke LW, van den Elzen HJ, Canninga M, Neumann MH. Complications after treatment with polyalkylimide. Dermatol Sur. 2009;35(Suppl 2):1625-1628. 71. Nelson L, Stewart KJ. Early and late complications of polyalkylimide gel (Bio-Alcamid)(R). J Plast Reconstr Aesthet Surg. 2011;64(3):401-404. 72. George DA, Erel E, Waters R. Patient satisfaction following Bio-Alcamid injection for facial contour defects. J Plast Reconstr Aesthet Surg. 2012;65(12):1622-1626. 73. Thioly-Bensoussan D. Non-hyaluronic acid fillers. Clin Dermatol. 2008;26(2):160-176. 74. Carvalho Costa IM, Salaro CP, Costa MC. Polymethylmethacrylate facial implant: a successful personal experience in Brazil for more than 9 years. Dermatol Surg. 2009;35(8): 1221-1227. 75. Orsi AT, Miranda AE, Souza AC, et al. Lipoatrophy in patients with AIDS: treatment with polymethylmethacrylate in Amazonas, Brazil. Int J Dermatol. 2011;50(10):1255-1258. 76. Warde M, Gragnani A, Gomes H, Hochman B, Ferreira LM. The impact of facial lipoatrophy treatment with polymethyl methacrylate in AIDS patients as measured by four quality-of-life questionnaires. Int J STD AIDS. 2011;22(10):596-599. 77. Serra MS, Oyafuso LK, Trope BM, Munhoz Leite OH, Ramos-e-Silva M. An index for staging facial lipoatrophy and evaluation of the efficacy of the treatment with polymethylmethacrylate in HIV/AIDS patients: a pilot study. J Eur Acad Dermatol Venereol. 2013;27(8):990-996. 78. Soares FM, Costa IM. Treatment of HIV-associated facial lipoatrophy: impact on infection progression assessed by viral load and CD4 count. An Bras Dermatol. 2013;88(4):570-577.

J AM ACAD DERMATOL

DECEMBER 2015

79. Quintas RC, de Franca ER, de Petribu KC, et al. Treatment of facial lipoatrophy with polymethylmethacrylate among patients with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS): impact on the quality of life. Int J Dermatol. 2014;53(4):497-502. 80. Jones DH, Carruthers A, Orentreich D, et al. Highly purified 1000-cSt silicone oil for treatment of human immunodeficiency virus-associated facial lipoatrophy: an open pilot trial. Dermatol Surg. 2004;30(10):1279-1286. 81. Chen F, Carruthers A, Humphrey S, Carruthers J. HIV-associated facial lipoatrophy treated with injectable silicone oil: a pilot study. J Am Acad Dermatol. 2013;69(3):431-437. 82. Coleman SR. Facial recontouring with lipostructure. Clin Plast Surg. 1997;24(2):347-367. 83. Strauch B, Baum T, Robbins N. Treatment of human immunodeficiency virus-associated lipodystrophy with dermafat graft transfer to the malar area. Plast Reconstr Surg. 2004; 113(1):363-372. 84. Burnouf M, Buffet M, Schwarzinger M, et al. Evaluation of Coleman lipostructure for treatment of facial lipoatrophy in patients with human immunodeficiency virus and parameters associated with the efficiency of this technique. Arch Dermatol. 2005;141(10):1220-1224. 85. Mori A, Lo Russo G, Agostini T, Pattarino J, Vichi F, Dini M. Treatment of human immunodeficiency virus-associated facial lipoatrophy with lipofilling and submalar silicone implants. J Plast Reconstr Aesthet Surg. 2006;59(11):1209-1216. 86. Dollfus C, Blanche S, Trocme N, Funck-Brentano I, Bonnet F, Levan P. Correction of facial lipoatrophy using autologous fat transplants in HIV-infected adolescents. HIV Med. 2009;10(5): 263-268. 87. Rauso R, Curinga G, Santillo V, Corvo G, Tartaro G. Comparison between lipofilling and a nonabsorbable filler for facial wasting rehabilitation in HIV-positive patients. J Craniofac Surg. 2011;22(5):1684-1688. 88. Rauso R, Tartaro G, Freda N, Rusciani A, Curinga G. A facial marker in facial wasting rehabilitation. J Drugs Dermatol. 2012;11(2):202-208. 89. Ho D, Jagdeo J. Biological properties of a new volumizing hyaluronic acid filler: a systematic review. J Drugs Dermatol. 2015;14(1):50-54. 90. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Open Med. 2009;3(3):e123-e130.

Authors

PLLA (grade of recommendation: B) 1 Moyle et al,13 2004

2 Moyle et al,14 2006

3 Carey et al,15 2007

4 Carey et al,16 2009

5 Narciso et al,17 2009

Study type; efficacy measured

Sample size; inclusion and exclusion criteria

Findings

Significant improvement in 2b Randomized, open-label; facial 30 Subjects dermal thickness, VAS, and ultrasound, VAS, HADS Inclusion: - Moderate to severe nasolabial HADS scores was observed at wk 12 in the immediate fat pad loss - No previous HIV FLA treatment group, and in both immediate and delayed groups at wk 24 Improvements in all scores 2b Follow-up; VAS, HADS 27 Subjects persisted to the recall visit; Inclusion: - Moderate to severe nasolabial improvements in depression only reached statistical fat pad loss - No previous HIV FLA treatment significance in the delayed group At wk 24, FLA severity and 100 Subjects 2b Randomized, open-label, some QoL domains were Inclusion: multicenter; change in - Moderate to severe HIV FLA improved; tissue thickness in FSTV by CT imaging, with lipodystrophy at $1 injection planes increased, SF-36, MBSRQ-AS but PLLA injection did not sites increase FSTV At wk 48, the mean change in 2b Follow-up; change in FSTV by 100 Subjects FSTV was 14 mL in the CT imaging, SF-36, MBSRQ- Inclusion: - Moderate to severe HIV FLA immediate group and 18 mL AS with lipodystrophy at $1 in the deferred group sites Immediate treatment group 2b Randomized, controlled, open- 134 Subjects had significantly lower FLA Inclusion: label, single center; FLA severity scores compared - Severe HIV FLA Severity Scale from grade with delayed treatment - CD4 count [100 1-5, EQ-5D, ISSQoL Core group; similar efficacy was Exclusion: Evaluation Form demonstrated with PLLA and - Previous filling surgery PAIG Median TCT increased 4 Case series; facial ultrasound, 50 Subjects significantly from baseline VAS Inclusion: and persisted to wk 96 (43% - HAART for $3 y with TCT [10 mm) - HIV1 RNA level \5000 copies/mL Exclusion: - Facial implant in last 6 mo

Adverse events

2 Adverse events: bruising (n = 1) and limited superficial local cellulitis not requiring antibiotic therapy (n = 1)

1 Case of injection-site induration and 9 cases of injection-site nodules were noted at the recall visit (not described as serious or severe) 6 Subjects had nodule/papule formation at wk 24

10 Subjects had sustained nodule/papule formation at wk 48

Mild and transient

Nonvisible subcutaneous papules (44%) with spontaneous resolution in 6 subjects at wk 96

Continued

Jagdeo et al 1054.e1

6 Valantin et al,18 2003

LOE

J AM ACAD DERMATOL

No.

VOLUME 73, NUMBER 6

Supplemental Table I. Clinical studies on treatment of HIV facial lipoatrophy using filler agents

No.

7 Borelli et al,

Authors 19

2005

8 Burgess and Quiroga,20 2005

9 Guaraldi et al,21 2005

10 Lafaurie et al,22 2005

LOE

Study type; efficacy measured

4 Case series; facial ultrasound

Sample size; inclusion and exclusion criteria

14 Subjects Inclusion: - Age [18 y on HAART 61 Subjects Inclusion: - On HAART for at least 1 y

Findings

Skin thickness increased in all subjects at 6-mo follow-up

Adverse events

No serious side effects reported during treatment or followup 2 Subjects developed persistent, asymptomatic, palpable papules

Continued

DECEMBER 2015

J AM ACAD DERMATOL

All subjects had positive improvements at 6-mo follow-up; significant improvement was sustained for 6 mo in 37 subjects, for 1 y in 10 subjects, for 18 mo in 9 subjects, and for $2 y in 5 subjects All corrective options (AFT and AFT (n = 4 with disfiguring fat 4 Case series; facial ultrasound, 59 Subjects graft hypertrophy of the PLLA) appeared highly Inclusion: ABCD questionnaire, VAS, face) effective in correcting fat - On HAART for at least 6 mo pretreatment and wasting; mean subcutaneous PLLA (n = 8 developed posttreatment photograph Exclusion: nonvisible palpable papules) thickness increased by assessment by independent - CD4 count \100 3.5 mm after 24 wk and was reviewers equivalent for each intervention; aesthetic satisfaction was significantly improved; the AFT group was less satisfied with body image at the end of treatment Palpable nodules (13%) Median VAS increased 4 Case series; VAS, photographs, 94 Subjects significantly and was 3D photographs, MOS SF-36 Inclusion: sustained at 7 compared - CD4 count [200 - Stable HAART for at least with 3.4 at baseline; median dermal thickness increased 3 mo 2.3 mm Exclusion: - History of surgical or cosmetic intervention for HIV FLA 4 Case series; treatment evaluation scale grade 1-4, subjective evaluation by subject, treating physician, and a nontreating physician

1054.e2 Jagdeo et al

Supplemental Table I. Cont’d

Authors 8

LOE

Study type; efficacy measured

4 Case series; facial ultrasound, MOS-HIV

12 Mest and Humble,23 2006

4 Case series; caliper skin thickness, study questionnaire

13 Negredo et al,24 2006

4 Case series; photograph assessment by 2 independent observers, DEXA scan, MOS-HIV

14 Hanke and Redbord,25 2007

4 Case series; subjective assessment via HIV FLA grade 1-5, subject satisfaction scale grade 1-5

15 Ong et al,26 2007

4 Case series; 3D laser scans, subjective assessment from 0-3 to a casual observer, HADS, RSE

Findings

Adverse events

Transient and mild Mean TCT increased 50 Subjects significantly to 4.3 mm and Inclusion: 4.4 mm on the right and left - Moderate or severe HIV FLA - HIV RNA level \1000 copies/ cheeks, respectively; at 12-mo, improvements mL maintained at 3.4 mm and - CD4 count [100 3.3 mm Exclusion: - Prior facial implants Bruising (30.3%) and papules 75 Subjects achieved 97 Subjects (13.1%) statistically significant mean Inclusion: - $18 y with clinically signifi- increase in dermal thickness of 4.2 mm at 12 mo; subject cant HIV FLA satisfaction was very high Exclusion: - Facial injection within past throughout 3 mo All treatments (AFT, PLLA, and No adverse events reported 138 Subjects PAIG) demonstrated Inclusion: significant immediate - On HAART for $6 mo improvement in FLA and - CD4 count [100 results regressed at wk 48 in Exclusion: - Previous cosmetic facial inter- all groups; PAIG had the best and AFT had the worst longvention term result at wk 48 Transient subcutaneous 65 Subjects HIV FLA score decreased a Inclusion: mean of 2.34 after treatment; papules (n = 2) - Subjects with HIV FLA age-related FLA score decreased a mean of 1.2 after treatment Not available Significant immediate 51 Subjects improvement of clinical and Inclusion: subjective scores at 6 mo, - Subjects with HIV FLA followed by a pattern of Exclusion: gradual deterioration in - History of facial implants clinical grading scores and measures of psychological well-being at 24 mo Continued

Jagdeo et al 1054.e3

11 Cattelan et al, 2006

Sample size; inclusion and exclusion criteria

J AM ACAD DERMATOL

No.

VOLUME 73, NUMBER 6

Supplemental Table I. Cont’d

No.

Authors

16 Orlando et al,

27

LOE

Study type; efficacy measured

Sample size; inclusion and exclusion criteria

Findings

Adverse events

Nonvisible, subcutaneous All subjects (AFT- and PLLA299 Subjects micronodules (45% PLLAtreated) showed significant Inclusion: treated subjects) improvement of aesthetic - On HAART for at least 6 mo satisfaction for the face and Exclusion: had significant augmentation - Previous HIV FLA treatment of both cheeks’ thickness (right cheek, 4.3-9.5 mm; left cheek, 4.4-9.6 mm) Nodule formation (2.9%) Subject anxiety, depression, 411 Subjects and appearance satisfaction Inclusion: - $18 y with stable CD4 count scores significantly improved - Presence of HIV FLA posttreatment measured by Chelsea and Westminster scale At 3 y, statistically significant Subcutaneous papules (11%) at 65 Subjects improvement in FLA scores 3y Inclusion: - Subjects with HIV FLA

17 Kavouni et al,28 2008

4 Case series; subjective measurement by PI, HADS, Appearance Satisfaction Questionnaire

18 Levy et al,29 2008

4 Case series; subjective photograph review by blinded physicians and graded on scale of 1-5 Transient and mild Aesthetic improvement was 4 Case series; 3D facial imaging, 46 Subjects ‘‘moderate’’ and required 7 VAS Inclusion: treatment sessions - Subjects with HIV FLA Approximately 10% of subjects Small, nonvisible papules 65 Subjects 4 Case series; caliper skin (7.7%) had persistent correction at Inclusion: thickness, subjective - Clinically significant HIV FLA 36 mo photograph review by after previous treatment with physicians PLLA in the Blue Pacific study Clinical scores improved from a Bruising (7.5%) and 4 Case series; 3D laser surface 100 Subjects subcutaneous lumps (3.3%) ‘‘moderate-severe’’ grade to scanning, HADS, RSE, DAS59 Inclusion: resolved at 1-y follow-up - $18 y with HIV FLA ‘‘non-mild’’ grade posttreatment, and confirmed by 2 physicians significant improvements in Exclusion: all psychological outcomes; - History of facial implant 3D laser surface scans showed a volume increase of 2.81 mL

19 Nelson and Stewart,30 2008

20 Mest and Humble,31 2009

21 Ong et al,32 2009

Continued

DECEMBER 2015

4 Case series; facial ultrasound, VAS, ABCD questionnaire, BDI

J AM ACAD DERMATOL

2007

1054.e4 Jagdeo et al

Supplemental Table I. Cont’d

Authors 33

LOE

Study type; efficacy measured

Sample size; inclusion and exclusion criteria

Findings

Adverse events

4 Case series; MOS-HIV, Facial Appearance Questionnaire, subject and physician satisfaction assessment by 5-point Likert scale

At 2 y, injection-site nodules (8.3%) and papules (8.6%)

23 Lafaurie et al,34 2013

4

Subcutaneous nodules (41% in PLLA-treated subjects and 37% in PAAG-treated subjects); 4 PAAG-treated subjects developed severe inflammatory nodules

24 van Rozelaar et al,35 2014

4

25 Wang et al,36 2014

4

26 Vleggaar and Bauer,37 2004

5

22 Bassichis et al,

2012

Hematomas (n = 5) that spontaneous resolved; nodule formation (n = 6); inflammation (n = 3)

No adverse events reported

Not reported

Continued

Jagdeo et al 1054.e5

Mean significant improvement 290 Subjects; in FLA score was 1.4; 89.4% Inclusion: of subjects and 95.5% of - $18 y and HIV positive physicians rated treatment Exclusion: - Previous treatment with satisfaction as ‘‘very good’’ or injectable PLLA or other ‘‘excellent’’ product for HIV FLA At wk 48, mean VAS increased Case series; VAS, 3D 148 Subjects from baseline of 2.8 to 7.1 photographs, MOS SF-36 Inclusion: and 7.5 in PLLA and PAAG - CD4 count [200 - Stable HAART for at least groups, respectively; at wk 96, VAS maintained at 6.7 3 mo and 7.9, respectively Exclusion: - History of surgical or cosmetic intervention for HIV FLA Significant increase in total Case series; regional total 82 Subjects subcutaneous thickness in subcutaneous thickness by Inclusion: nearly all subjects 1-y MRI, SF-36, MOS-HIV - $18 y with CLSS grade 2-4 posttreatment; subjects Exclusion: reported improved QoL with - Earlier use of facial fillers increased score in mental health, social, and role functioning, and decreased depressive symptoms All 3 subjects benefited from Case series; subjective clinical 3 Subjects visible augmentation of assessment by physician Inclusion: cheek contours; this filling - Subjects with HIV FLA technique accentuated dynamic cheek fullness and movement associated with smiling Case report; subjective clinical 2 Subjects Aesthetic effect was visible at assessment by physician Inclusion: 12 mo and maintained at - Subjects with HIV FLA 24 mo

J AM ACAD DERMATOL

No.

VOLUME 73, NUMBER 6

Supplemental Table I. Cont’d

No.

Authors

LOE 38

27 Wildemore and Jones,

2006

28 Kates and Fitzgerald,39 2008

29 Mest and Humble,40 2009

CaHA (grade of recommendation: C) 1 Comite et al,41 2004

2 Silvers et al,42 2006

3 Carruthers et al,43 2008

Sample size; inclusion and exclusion criteria

5 Case report; subjective clinical 1 subject; assessment by physician Inclusion: - Subject with HIV FLA

5 Case report; subjective clinical 2 Subjects assessment by physician Inclusion: - Subjects with HIV FLA 5 Case report; subjective clinical 1 Subject assessment by physician Inclusion: - Subject with HIV FLA

Findings

3 y Posttreatment, skin biopsy Persistent red bumps specimen of persistent red bumps revealed marked foreign-body giant-cell reaction with numerous fragments of polarizable foreign material and surrounding dermal fibrosis At 12 mo, there was no papule Mild and transient formation FLA correction maintained at No adverse events reported 2 y and 7 mo posttreatment

3 Subjects Inclusion: - Subjects with HIV FLA

None reported

Mild and transient

Not reported

Mild and transient

DECEMBER 2015

Significant improvement after initial treatment (75%-90%) with some loss of improvement at 9 mo (55%-90%) 100% of subjects who followed 4 Case series; GAIS 100 Subjects up were ‘‘improved or Inclusion: better’’ at 12 mo and 91% at - CD4 count [250 - HIV RNA level \5000 copies/ 18 mo; improvement in skin thickness measurements was mL sustained at 12 mo - On HAART for at least 3 y 4 Case series; x-ray, CT scans to 58 Subjects CT showed consistent blinded radiologists Inclusion: visualization of CaHA - Subjects with HIV FLA immediately after treatment whereas x-ray did not Cheek thickness measurements 4 Case series; GAIS by a blinded 30 Subjects increased substantially over Inclusion: observer, change in cheek baseline; subjects were rated - CD4 count [250 thickness - HIV RNA level \5000 copies/ as ‘‘improved or better’’ on the GAIS, and subject mL satisfaction was ‘‘very high’’ - On HAART for at least 3 y - CLSS grade 2, 3, or 4 Exclusion: - Any collagen or silicone injections in the cheek area in previous 6 mo

4 Case series; subjective clinical assessment by physician

Adverse events

J AM ACAD DERMATOL

4 Carruthers and Carruthers,44 2008

Study type; efficacy measured

1054.e6 Jagdeo et al

Supplemental Table I. Cont’d

Continued

5 Alam et al,

Authors 45

2011

6 Rauso et al,46 2013

HA (grade of recommendation: C) 1 Ritt et al,48 2001

LOE

Study type; efficacy measured

4 Case series; subjective clinical assessment by physician 4 Case series; subjective clinical assessment by physician

4 Case series; subjective clinical assessment by physician

4 Case series; subjective clinical assessment by physician

3 Denton and Tsaparas,50 2007

4 Case series; facial assessment using a 7-point Likert scale

4 Bechara et al,51 2008

4 Case series; GAIS, DLQI

Findings

3 Subjects All subjects self-reported 50% Inclusion: improvement at 15 mo - Subjects with HIV FLA High subject satisfaction was 26 Subjects achieved with all subjects Inclusion: - CD4 count [250 - HIV RNA level \5000 copies/mL Exclusion: - Previous facial injection of any other products

Adverse events

Mild and transient

Mild and transient

Subjects had positive reactions Mild and transient from their social environment and were satisfied with their treatment; authors recommended injections should be subcutaneous rather than intradermal for better treatment outcome Mild and transient ‘‘Good’’ cosmetic result and 5 Subjects improvement was Inclusion: - Subjects with HIV FLA CLSS maintained at 6 mo grade 2 or 3 Significant early improvement 1 Subject who previously 18 Subjects underwent external beam that maintained at 12 mo Inclusion: with high subject satisfaction radiation for Kaposi sarcoma - Clinically evident HIV FLA had prolonged palpability, - On HAART for at least 3 mo erythema, and telangiectasia Exclusion: up to 4 mo - Previous malar augmentation in previous 2 y Mild and transient 21 Subjects At 3 mo, 19 subjects were Inclusion: ‘‘much improved’’ and 2 - CD4 count [250 subjects were ‘‘improved’’ and received a touch-up; at 12 mo, 16 subjects were ‘‘much improved’’ and 4 ‘‘improved’’; subject satisfaction was high and subject QoL improved 7 Subjects Inclusion: - Subjects with HIV FLA

Continued

Jagdeo et al 1054.e7

2 Gooderham and Solish,49 2005

Sample size; inclusion and exclusion criteria

J AM ACAD DERMATOL

No.

VOLUME 73, NUMBER 6

Supplemental Table I. Cont’d

No.

Authors 47

5 Skeie et al,

2010

6 Pignatti et al,52 2012

7 Pavicic et al,53 2010

LOE

Study type; efficacy measured

Sample size; inclusion and exclusion criteria

Findings

Adverse events

Mean TCT increased from 6 mm Local swelling and tenderness 17 Subjects were common at baseline to 12 mm at Inclusion: posttreatment; persistent - Severe nasogenian atrophy 36 mo with response rate papules in several subjects that is noticeable to a casual (TCT [10 mm) of 70%; were removed effectively subject report of facial observer with hyaluronidase injections appearance, VAS, and selfExclusion: - Previous HIV FLA treatment esteem scores were increased with injectable fillers Mean soft tissue thickness of Mild and transient 4 Case series; facial ultrasound, 54 Subjects the cheek increased GAIS, VAS Inclusion: - HIV FLA ‘‘moderate to severe’’ significantly from 9.4513.12 mm; subject - On HAART for at least 6 mo satisfaction was ‘‘very high’’ Exclusion: - Previous injectable fillers within previous 6 mo Both subjects had FLA score of Mild and transient 5 Case report; subjective clinical 2 Subjects 0 at 6- and 12-mo follow-up assessment by physician Inclusion: - Subjects with HIV FLA

4 Case series; facial ultrasound, GAIS, VAS

PAAG (grade of recommendation: C) 1 Rauso et al,55 2012 2b Randomized, single center; facial ultrasound

3 Negredo et al,56 2009

4 Case series; subjective clinical assessment by physician

Continued

DECEMBER 2015

4 Case series; facial ultrasound, VAS, ABCD, BDI

31 Subjects Inclusion: - Subjects with HIV FLA Exclusion: - Previous facial injection

J AM ACAD DERMATOL

2 de Santis et al,54 2008

Small, nonvisible papules At 12 mo, subjects who (n = 6) received 8 mL of PAAG in 1 treatment noted faster improvements than subjects who received several 2-mL PAAG treatments; ultrasound demonstrated no difference in terms of tissue response in both groups Mild and transient Mean cheek thickness 50 Subjects improved from mean of 4.5 Inclusion: 6 2.5 mm pretreatment to - On HAART for at least 6 mo mean of 8.4 6 2.7 mm at 6- CD4 count [100 mo follow-up Exclusion: - Previous permanent filler or resorbable filler within previous 6 mo 145 Subjects 88.9% of Subjects were Small, nonvisible, palpable Inclusion: ‘‘satisfied’’ or ‘‘very satisfied’’ nodules (19.3%) and - Subjects with HIV FLA at 4 y indurations (6.2%)

1054.e8 Jagdeo et al

Supplemental Table I. Cont’d

Authors

4 Mansor et al,

57

2011

LOE

Study type; efficacy measured

4 Case series; subjective clinical assessment by blinded physician, subject satisfaction on a 4-point Likert scale, QoL rate on a 5point scale 4 Case series; facial ultrasound, VAS

6 Rauso,61 2015

4 Follow-up; facial ultrasound, VAS

7 de Santis et al,59 2012

4 Case series; facial ultrasound, GAIS, VAS, BDI, ABCD questionnaire

8 Mole et al,60 2012

4 Case series; facial ultrasound, Overall Treatment Satisfaction score, ABCD questionnaire

Findings

Adverse events

Improvement of FLA score was None reported observed in all cases: 1-grade reduction in 11 cases, 2grade reduction in 20 cases, and 3-grade reduction in 3 cases with high subject satisfaction Subject satisfaction was ‘‘high’’ Small, palpable, nonvisible 32 Subjects nodules (n = 13) during follow-up period; Inclusion: ultrasound revealed a thin - Subjects with HIV FLA capsule around the product Exclusion: - Previous facial injection with with no interaction with surrounding tissues any other products Small, palpable, nonvisible At 5-y follow-up, VAS 32 Subjects nodules (n = 13), which were demonstrated slight decline Inclusion: present since the 18-mo from first year (8.3-7.6); no - Subjects with HIV FLA complications were observed follow-up Exclusion: - Previous facial injection with any other products Localized permanent Significant improvement of 38 Subjects indurations (n = 4) cheek thickness, aesthetic Inclusion: Caudal migration of injected result, satisfaction, and - On HAART for at least 6 mo PLLA (n = 3) - HIV FLA ‘‘moderate to severe’’ psychological improvement over 5-y follow-up Exclusion: - Previous permanent filler or resorbable filler within previous 6 mo at the site Mild and transient Mean cheek thickness 111 Subjects improved by average of Inclusion: 4.4 mm at 12 mo and - On HAART for at least 3 mo additional 0.87 mm at 24 mo; - CD4 count [100 subject QoL and treatment Exclusion: - Previous treatment with facial satisfaction improved over time implants 42 Subjects Inclusion: - CD4 count [100 - On HAART for at least 1 y

Continued

Jagdeo et al 1054.e9

5 Rauso et al,58 2011

Sample size; inclusion and exclusion criteria

J AM ACAD DERMATOL

No.

VOLUME 73, NUMBER 6

Supplemental Table I. Cont’d

No.

Authors

9 Negredo et al,

62

2015

PAIG (grade of recommendation: D) 1 Loutfy et al,9 2007

2 Antoniou et al,64 2009

Study type; efficacy measured

Sample size; inclusion and exclusion criteria

4 Case series; subjective clinical 104 Subjects Inclusion: grading by physicians, - Subjects with HIV FLA subject satisfaction score using Likert scale from 0-10

Findings

Adverse events

After PAAG treatment at least Indurations resulted in 6.7% of subjects, nodule formation in $10 y, moderate, mild, and 3.8% of subjects, and local no signs of HIV FLA were infection in 4.8% of subjects reported in 19.2%, 47.7%, and 31.7%, respectively; physicians reported 1.9%, 10.6%, and 87.5%, respectively; subjects were highly satisfied (74.8%) and satisfied (23.4%), and subjects with severe and very severe HIV FLA were satisfied (31.4%) and highly satisfied (65.7%)

Continued

DECEMBER 2015

Mild and transient Subjects in the immediate 2b Randomized, open-label, single 31 Subjects treatment group had Inclusion: center; improvement with significantly lower physicianCLSS, MOS-HIV, HADS, sDQLS - Subjects with HIV FLA rated FLA scores, improved Exclusion: - Previous HIV FLA treatment QoL and lower anxiety score at 12 wk; at 48 wk, FLA scores within past 9 mo remained low in both the immediate and delayed treatment groups and differences between the groups were minimal No differences between No long-term adverse events 2b Follow-up; improvement with 31 Subjects immediate and delayed CLSS, MOS-HIV, HADS, sDQLS Inclusion: treatment groups at 96 wk - Subjects with HIV FLA Exclusion: - Previous HIV FLA treatment Infection (n = 5), nodules Physician and subject CLSS 2b Follow-up; improvement with 31 Subjects (n = 8), and bleeding (n = 1) scores changed a median of CLSS, MOS-HIV, HADS, sDQLS Inclusion:
2 and
1 from baseline to - Subjects with HIV FLA year 4, respectively; Exclusion: - Previous HIV FLA treatment improvements with depression and anxiety within past 9 mo maintained at 4 y

J AM ACAD DERMATOL

3 Loutfy et al,65 2011

LOE

1054.e10 Jagdeo et al

Supplemental Table I. Cont’d

Authors

4 Treacy and Goldberg,

LOE 66

2006

5 Ramon et al,67 2007

6 Honig,68 2008

Study type; efficacy measured

Sample size; inclusion and exclusion criteria

4 Case series; subjective clinical 11 Subjects assessment by physician, BDI Inclusion: - ‘‘Severe’’ HIV FLA Exclusion: - Previous HIV FLA treatment 4 Case series; subjective clinical 13 Subjects assessment by physician Inclusion: - Subjects with HIV FLA 4 Case series; subjective clinical 9 Subjects assessment by physician Inclusion: - Subjects with HIV FLA

4 Case series; subjective clinical 17 Subjects assessment by physician, SF- Inclusion: 36, MOS-HIV, CES-D - Subjects with HIV FLA Exclusion: - Grade-1 HIV FLA

8 Schelke et al,70 2009

4 Case series; survey, biopsies

3196 Subjects Inclusion: - Subjects with HIV FLA

9 Nelson and Stewart,71 2011

4 Case series; subjective clinical assessment by physician

7 Subjects Inclusion: - Subjects with HIV FLA

Adverse events

Improvement of FLA severity Mild and transient was maintained at 18 mo; QoL improved ‘‘dramatically’’ for all subjects at 3 mo Most subjects had ‘‘good or excellent’’ results as reported by subjects and physicians Improvement of FLA with 63% of cases as ‘‘excellent,’’ 32% of cases as ‘‘good’’; correction was maintained at median of 2-y follow-up Severity of FLA significantly decreased at 48 wk and improvements with QoL in mental health, social function, and depression score Subject complication rate was 4.8% and treatment complication rate 3.3%; the Dutch Society of Cosmetic Medicine considered this overall rate and severity of the complications too high a risk for a cosmetic treatment, thus they advise against use of PAIG Complications in 7 subjects after PAIG injection treatment from 2 mo to 3 y, and 6 subjects developed [1 type of complication

Small hematoma (n = 1)

Mild and transient

Capsule formation or gel migration (n = 3); injectionsite infection (n = 1)

Inflammation, hardening, migration, and accumulation of filler

Infection (n = 4), inferior migration of product (n = 3), excessive capsule formation (n = 2) Continued

Jagdeo et al 1054.e11

7 Karim et al,69 2008

Findings

J AM ACAD DERMATOL

No.

VOLUME 73, NUMBER 6

Supplemental Table I. Cont’d

No.

Authors

10 George et al,

72

2012

11 Nadarajah et al,63 2012

PMMA (grade of recommendation: C) 1 Carvalho Costa et al,74 2009

LOE

Study type; efficacy measured

Sample size; inclusion and exclusion criteria

4 Case series; subjective clinical assessment by physician, subject satisfaction survey

69 Subjects Inclusion: - Subjects with HIV FLA

4 Case series; subjective clinical assessment by physician

267 Subjects Inclusion: - Subjects with HIV FLA

Findings

Adverse events

Despite relatively high subject Required removal of PAIG from the cheek more frequently satisfaction, the authors no than the temple because of longer recommend this infection (n = 1) or superficial treatment for cosmetic lump (n = 8); 50% of survey indications because of responders identified at least significant long-term 1 complication complication rates Surgical drainage and High incidence of infectious antibiotics were required for complications (19%); median time from initial treatment to the majority of subjects with infectious complications infection was 32 mo

4 Case series; subjective clinical assessment by physician

Mild and transient

2 Orsi et al,75 2011

4

Nodular lesion (n = 1)

3 Warde et al,76 2011

4

4 Serra et al,77 2013

4

5 Soares and Costa,78 2013

4

Not reported

Mild and transient

DECEMBER 2015

J AM ACAD DERMATOL

Treatment maintained 266 Subjects significant aesthetic Inclusion: correction at 5 y - Subjects with HIV FLA posttreatment; 90% of Exclusion: - Previous treatment with any subjects were ‘‘satisfied’’ with the results and achieved filler agent ‘‘significant’’ improvement in self-esteem Case series; subjective clinical 49 Subjects At 12 mo, 85.7% of subjects assessment by physician Inclusion: reported satisfaction - Subjects with HIV FLA Case series; SF-36, RSE/ 40 Subjects Statistically significant UNIFESP-EPM, BSQ, BDI Inclusion: improvement observed in - Subjects with HIV FLA immediate treatment group for most aspects of SF-36 questionnaire, and no observed improvement in delayed treatment group All subjects had either ‘‘good’’ 20 Subjects Case series; improvement in or ‘‘excellent’’ response to classification of lipoatrophy Inclusion: treatment according to a 5-point scale - Subjects with HIV FLA Exclusion: - CD4 count \200 Statistically significant increase Case series; plasma viral load 44 Subjects in CD4 count posttreatment and CD4 count Inclusion: with no significant - On HAART for at least 6 mo improvement with viral load

1054.e12 Jagdeo et al

Supplemental Table I. Cont’d

Not reported

Continued

Authors

6 Quintas et al,

79

2014

LOE

Study type; efficacy measured

4 Case series; SF-36, HAT-QoL, VAS, BDI

Sample size; inclusion and exclusion criteria

Findings

Adverse events

Significant improvement of Mild and transient 51 Subjects median VAS and subject QoL Inclusion: - CD4 count [250 - On HAART for at least 3 mo Exclusion: - Previous HIV FLA treatment Mild and transient

Severe postinjection pain (n = 1), and severe edema (n = 2)

Not reported

Mild and transient

None reported

Continued

Jagdeo et al 1054.e13

Silicone oil (grade of recommendation: C) The volume of silicone, number 1 Jones et al,80 2004 4 Case series; improvement with 77 Subjects of treatments, and time CLSS Inclusion: required to reach a complete - Subjects with HIV FLA correction were directly Exclusion: - History of treatment with per- related to the initial FLA severity; majority of subjects manent fillers were ‘‘very satisfied’’ with their treatment At 18 mo, FLA severity scores 2 Chen et al,81 2013 4 Case series; improvement with 20 Subjects significantly improved (mean CLSS, Functional Assessment Inclusion: 2.625) compared with - HIV FLA CLSS 2 or 3 of HIV Infection QoL - Display $1 metabolic fea- baseline (mean 0.225), and measurement scale tures since initiation of subject QoL improved from 2.15-4.3 HAART AFT (grade of recommendation: C) 1 Strauch et al,83 2004 Aesthetic results were 4 Case series; subjective clinical 5 Subjects ‘‘dramatic and stable,’’ and assessment by physician Inclusion: maintained at 1- to 2-y - Subjects with HIV FLA follow-up 2 Burnouf et al,84 2005 FLA severity improved in 12 4 Case series; subjective clinical 33 Subjects Inclusion: subjects by 3 evaluators, 17 assessment by 3 blinded - Subjects with HIV FLA subjects by at least 2 physicians, subject evaluators, and in 25 subjects satisfaction questionnaire by at least 1 evaluator; subject satisfaction rate of 93% at 1 y 3 Mori et al,85 2006 4 Case series; subjective clinical 12 Subjects Both techniques (lipofilling assessment by physician Inclusion: using Coleman technique - Subjects with HIV FLA and bilateral malar implants) resulted in ‘‘good’’ to ‘‘very good’’ long-lasting results

J AM ACAD DERMATOL

No.

VOLUME 73, NUMBER 6

Supplemental Table I. Cont’d

No.

Authors

4 Dollfus et al,

86

2009

LOE

Study type; efficacy measured

Sample size; inclusion and exclusion criteria

4 Case series; subjective clinical assessment by physician

6 Subjects Inclusion: - Subjects with HIV FLA

5 Rauso et al,87 2011

4 Case series; GAIS

23 Subjects Inclusion: - Subjects with HIV FLA

6 Rauso et al,88 2012

4 Case series; subjective clinical assessment by 2 blinded physicians, VAS

28 Subjects Inclusion: - Subjects with HIV FLA

Findings

Adverse events

None reported Subjects were ‘‘satisfied’’ or ‘‘very satisfied’’ with the cosmetic results and reported a positive impact on daily life Subjects who underwent AFT Mild and transient had statistically significant improvement compared with PAAG-treated subjects according to physiciangraded GAIS None reported Mean satisfaction score with VAS for both AFT-treated and PAAG-treated subjects was 8.7 (subjects) and 7.6 (blinded evaluators); authors present a triangular area of depression that provided good aesthetic outcome to restore facial wasting for HIV FLA

1054.e14 Jagdeo et al

Supplemental Table I. Cont’d

ABCD, Adult AIDS Clinical Trials Group Assessment of Body Change and Distress; AFT, autologous fat transfer; BDI, Beck Depression Inventory questionnaire; BSQ, Body Shape Questionnaire; CaHA, calcium hydroxylapatite; CES-D, Center for Epidemiological Studies Depression scale; CLSS, Carruthers Lipoatrophy Severity Scale; CT, computed tomography; DAS59, Derriford Appearance Scale; DEXA, Dual-energy X-ray absorptiometry; DLQI, Dermatology Life Quality Index; EQ-5D, EuroQoL 5 domains; FLA, facial lipoatrophy; FSTV, facial soft tissue volume; GAIS, Global Aesthetic Improvement Scale; HA, hyaluronic acid; HAART, highly active retroviral therapy; HADS, Hospital Anxiety Depression Scale; ISSQoL, Istituto Superiore di Sanita’ Quality of Life; LOE, levels of evidence; MBSRQ-AS, Multidimensional Body-Self Relations Questionnaire-Appearance Scales; MOS-HIV, Medical Outcomes Study-HIV questionnaire; MOS SF-36, Medical Outcome Study Short Form 36-item health survey; MRI, magnetic resonance imaging; PAAG, polyacrylamide gel; PAIG, polyalkylimide gel; PLLA, poly-L-lactic acid; PMMA, polymethylmethacrylate; PI, principal investigator; QoL, quality of life; RSE, Rosenberg Self-Esteem Scale; RSE/UNIFESP-EPM, Brazilian version of the Rosenberg Self-Esteem scale; sDQLS, slightly modified Dermatology Quality of Life Survey; SF-36, Short Form 36v2 Health Survey; TCT, total cutaneous thickness; VAS, visual analog scale score; 3D, 3-dimensional.

DECEMBER 2015

J AM ACAD DERMATOL