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Systematic Review Permanent and Semi-Permanent Dermal Fillers ASERNIP-S REPORT NO. 55 February 2009 Australian Safety & Efficacy Register of New Interventional Procedures – Surgical The Royal Australasian College of Surgeons ASERNIP S Australian Safety and Efficacy Register of New Interventional Procedures - Surgical

Draft Systematic Review - RACS · The evidence-base in this review for the use of permanent and semi-permanent dermal fillers for age-related lines and wrinkles is poor, and for HIV-associated

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Systematic Review

Permanent and Semi-Permanent Dermal Fillers

ASERNIP-S REPORT NO. 55

February 2009

Australian Safety & Efficacy Register of New Interventional Procedures Surgical

The Royal Australasian College of Surgeons

ASERNIP S Australian Safety

and Efficacy

Register of New

Interventional

Procedures - Surgical

- ASERNIP-S REVIEW OF PERMANENT AND SEMI-PERMANENT DERMAL FILLERS. FEBRUARY 2009 -

Permanent and Semi-Permanent Dermal Fillers

ISBN 978-0-9806299-4-1

Published February 2009

This report should be cited in the following manner:

Sturm L, et al. Permanent and Semi-Permanent Dermal Fillers. ASERNIP-S Report No. 55. Adelaide, South Australia: ASERNIP-S, February 2009.

Copies of these reports can be obtained from:

ASERNIP-S

PO Box 553,

Stepney, SA 5069

AUSTRALIA

Ph: 61-8-8363 7513

Fax: 61-8-8362 2077

E-Mail: [email protected]

http://www.surgeons.org/asernip-s

- ASERNIP-S REVIEW OF PERMANENT AND SEMI-PERMANENT DERMAL FILLERS. FEBRUARY 2009 -

The Systematic Review of Permanent and Semi-Permanent Dermal Fillers

was ratified by:

The ASERNIP-S Advisory Committee in

December 2008

and

The Council of the Royal Australasian College of Surgeons in

February 2009

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Table of Contents

Executive Summary .............................................................................................................. vi

The ASERNIP-S Classification System ............................................................................. ix

The ASERNIP-S Review Group ........................................................................................ xi

Abbreviations and Acronyms............................................................................................. xii

1. Introduction........................................................................................................................ 1

Objective ............................................................................................................................. 1

The skin............................................................................................................................... 1

The ageing process ............................................................................................................ 1

HIV-associated lipodystrophy syndrome....................................................................... 1

Non-surgical therapies for facial augmentation ............................................................ 3

Topical therapies ........................................................................................................... 3

Injectable agents ............................................................................................................ 3

Dermal fillers ................................................................................................................. 4

Types of dermal fillers....................................................................................................... 4

Temporary fillers ........................................................................................................... 5

Semi-permanent fillers.................................................................................................. 5

Permanent fillers ........................................................................................................... 5

How dermal fillers work ................................................................................................... 9

Demand for cosmetic procedures ................................................................................. 10

Australian cosmetic industry .......................................................................................... 10

Summary ........................................................................................................................... 11

2. Methodology..................................................................................................................... 12

Literature search protocol .............................................................................................. 12

Inclusion criteria.......................................................................................................... 12

Literature search strategies ............................................................................................. 14

Databases searched and search terms used ............................................................. 14

Selection of studies .......................................................................................................... 16

Data extraction and appraisal of study methodology................................................. 16

Data analysis ..................................................................................................................... 17

3. Studies included in the review........................................................................................ 18

Literature search results .................................................................................................. 18

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Description of studies ..................................................................................................... 19

Critical appraisal ............................................................................................................... 23

Facial augmentation for ageing ................................................................................. 23

Facial augmentation for HIV-associated lipoatrophy............................................ 27

4. Results................................................................................................................................ 32

Efficacy outcomes for ageing......................................................................................... 32

Permanent vs. temporary fillers ................................................................................ 32

Permanent fillers ......................................................................................................... 33

Semi-permanent vs. temporary fillers ...................................................................... 36

Semi-permanent fillers................................................................................................ 40

Safety outcomes for ageing ............................................................................................ 40

Permanent vs. temporary fillers ................................................................................ 40

Permanent fillers ......................................................................................................... 42

Semi-permanent vs. temporary fillers ...................................................................... 45

Semi-permanent fillers................................................................................................ 46

Efficacy outcomes for HIV-associated lipoatrophy ................................................... 47

Permanent vs. semi-permanent vs. temporary fillers............................................. 47

Permanent fillers ......................................................................................................... 53

Semi-permanent fillers................................................................................................ 54

Safety outcomes for HIV-associated lipoatrophy....................................................... 64

Permanent vs. semi-permanent vs. temporary fillers............................................. 64

Permanent fillers ......................................................................................................... 67

Semi-permanent fillers................................................................................................ 68

Ongoing and unpublished trials..................................................................................... 76

5. Discussion ......................................................................................................................... 78

Limitations of the evidence ............................................................................................ 78

Efficacy outcomes ........................................................................................................... 79

Ageing ........................................................................................................................... 80

HIV-associated lipoatrophy....................................................................................... 80

Safety outcomes ............................................................................................................... 82

Ageing ........................................................................................................................... 82

HIV-associated lipoatrophy....................................................................................... 83

Other considerations....................................................................................................... 84

Future research................................................................................................................. 86

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6. Conclusions and Recommendations ............................................................................. 88

Classification and recommendations ............................................................................ 88

Safety............................................................................................................................. 88

Efficacy......................................................................................................................... 88

Clinical and research recommendations .................................................................. 89

Acknowledgments ........................................................................................................... 89

References ............................................................................................................................. 91

Appendix A Excluded studies .................................................................................. 101

Appendix B Study profile tables .............................................................................. 104

Appendix C Treatment data ..................................................................................... 128

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List of Tables

Table 1. Classification of dermal fillers by composition .................................................. 5

Table 2. Classification of injectable semi-permanent and permanent dermal fillers .... 6

Table 3. Databases searched............................................................................................... 14

Table 4. NHMRC hierarchy of evidence .......................................................................... 16

Table 5. Summary of included studies .............................................................................. 19

Table 6. Dermal fillers for ageing - number of injections or treatments ..................... 21

Table 7. Dermal fillers for HIV-associated lipoatrophy number of injections or treatments .............................................................................................................................. 22

Table 8. Semi-permanent vs. temporary fillers for ageing observer ratings of appearance............................................................................................................................. 37

Table 9. Semi-permanent vs. temporary fillers for ageing patient satisfaction ........ 38

Table 10. Semi-permanent vs. temporary fillers for ageing would recommend treatment................................................................................................................................ 39

Table 11. Semi-permanents filler for ageing - patient satisfaction ................................ 40

Table 12. Semi-permanent vs. temporary fillers - adverse event reporting: oedema (swelling), erythema (bruising) and eccymosis (bruising) ............................................... 46

Table 13. Permanent vs. semi-permanent vs. temporary fillers for HIV-associated lipoatrophy - changes in skin thickness ............................................................................ 48

Table 14. Permanent vs. semi-permanent vs. temporary fillers for HIV-associated lipoatrophy observer ratings of appearance.................................................................. 49

Table 15. Permanent vs. semi-permanent vs. temporary fillers for HIV-associated lipoatrophy - patient satisfaction........................................................................................ 50

Table 16. Permanent vs. semi-permanent vs. temporary fillers for HIV-associated lipoatrophy quality of life outcomes .............................................................................. 52

Table 17. Permanent fillers for HIV-associated lipoatrophy quality of life outcomes................................................................................................................................................. 54

Table 18. Semi-permanent fillers for HIV- associated lipoatrophy - changes in skin thickness ................................................................................................................................ 57

Table 19. Semi-permanent fillers for HIV- associated lipoatrophy - observer ratings of appearance........................................................................................................................ 58

Table 20. Semi-permanent fillers for HIV- associated lipoatrophy - patient satisfaction............................................................................................................................. 60

Table 21. Semi-permanent fillers for HIV-associated lipoatrophy - quality of life and other psychological outcomes ............................................................................................ 63

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Table 22. Permanent vs. semi-permanent vs. temporary fillers - adverse event reporting: oedema (swelling) and eccyhmosis (bruising)................................................ 66

Table 23. Semi-permanent fillers for HIV-associated lipoatrophy - adverse event reporting: oedema (swelling) and ecchymosis (bruising) and erythema (redness) ...... 72

Table 24. Semi-permanent fillers for HIV-associated lipoatrophy - adverse event reporting: other events ........................................................................................................ 75

Table 25. Ongoing and unpublished studies Ageing ................................................... 76

Table 26. Ongoing and unpublished studies HIV-associated lipoatrophy............... 77

List of Figures

Figure 1. Process for selection of studies retrieved from the literature databases...... 18

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Executive Summary

Objective The objective of this systematic review is to assess the safety and efficacy of injectable semi-permanent and permanent dermal fillers in comparison with other injectable methods of facial augmentation for age-related wrinkle reduction, and for aesthetic improvement of human immunodeficiency virus (HIV)-associated facial lipoatrophy, through a systematic review of the literature.

Methods Search strategy Studies were identified by searching EMBASE, CINAHL, PubMed, The Cochrane Library and Current Contents from inception to July 2008. The Clinical Trials Database (US), NHS Centre for Research and Dissemination Databases (UK), National Research Register (UK), Meta Register of Controlled Trials, and the Australian Clinical Trials Registry were also searched in July 2008. Additional articles were identified through reference sections of the retrieved studies.

Study selection Systematic reviews, randomised controlled trials (RCTs), non-randomised comparative studies and case series of at least 40 patients reporting the use of injectable semi-permanent and permanent dermal fillers for age related lines and wrinkles, and for HIV-associated facial lipoatrophy were included for review. Efficacy outcomes included changes in skin thickness, observer ratings of appearance, success of treatment, patient/practitioner satisfaction and quality of life. Safety outcomes included mortality, allergic reactions, granuloma formation, palpable lumpiness, abscess formation and infections.

Data collection and analysis Data from the included studies were extracted by an ASERNIP-S researcher using standardised data extraction tables developed a priori and checked by a second researcher. Statistical pooling was not appropriate due to the study and result heterogeneity.

Results A total of 20 studies were included in this review: four RCTs, one pseudo-RCT, two non-randomised comparative studies, and 13 case series. The comparator used in the comparative studies was often a temporary filler, which by their nature do not last as long as permanent or semi-permanent fillers and have different mechanisms of action.

For age related lines and wrinkles, and for HIV-associated facial lipoatrophy patients, permanent and semi-permanent dermal fillers increased skin thickness or improved subjective ratings of appearance and resulted in high patient satisfaction.

Long term efficacy data were scarce, but appeared good in the few studies that

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reported it.

There was great variation in the level of adverse event reporting for both interventions. In general, many adverse events were transient and mild in nature with the majority being associated with the injection process and resolving within a matter of days. Lumps were reported many of the studies included in the review but received little follow-up. Long term safety was limited and hence could not be determined.

Classification and Recommendations On the basis of the evidence presented in this systematic review, the ASERNIP-S Review Group agreed on the following classifications and recommendations concerning the safety and efficacy of semi-permanent and permanent dermal fillers.

Classifications Evidence rating The evidence-base in this review for the use of permanent and semi-permanent dermal fillers for age-related lines and wrinkles is poor, and for HIV-associated lipoatrophy is average.

The review was limited by the lack of a valid comparator for long term outcomes. The included studies were of variable quality, and did not employ similar study protocols. This variation prevented statistical pooling and limited the conclusions which could be drawn.

Efficacy The treatment of age related lines and wrinkles, and the effects of HIV-associated lipoatrophy with permanent and semi-permanent dermal fillers is more efficacious than with temporary fillers in those studies that compared them. Case series evidence suggests that permanent and semi-permanent dermal fillers achieve their objective, which is to decrease the visible (objective or subjective) effects of age related changes for HIV-associated facial lipoatrophy, with high patient satisfaction.

Safety From the limited data included in this systematic review, the safety of permanent and semi-permanent dermal fillers appear at least as safe as temporary fillers in the short term in those studies that compared them. Long term safety could not be determined.

Clinical and Research Recommendations It is recommended that further research be done into:

Long term efficacy of permanent and semi-permanent dermal fillers

Long term safety of permanent and semi-permanent dermal fillers, including the nature and outcomes of lumps

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Facial changes around permanent and semi-permanent dermal fillers, and whether the face can adequately accommodate them long term

Potential gender differences in response to permanent and semi-permanent dermal fillers

Short and long term quality of life outcomes after permanent and semi-permanent dermal filler treatment

The development, and/or validation of assessment tools for use in cosmetic intervention studies

The development of training standards to aid physicians with injection techniques and product placement

Important note The information contained in this report is a distillation of the best available evidence located at the time the searches were completed as stated in the protocol.

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The ASERNIP-S Classification System

Evidence Rating The evidence for ASERNIP-S systematic reviews is classified as Good, Average or Poor, based on the quality and availability of this evidence. High quality evidence is defined here as having a low risk of bias and no other significant flaws. While high quality RCTs are regarded as the best kind of evidence for comparing interventions, it may not be practical or ethical to undertake them for some surgical procedures, or the relevant RCTs may not yet have been carried out. This means that it may not be possible for the evidence on some procedures to be classified as good.

Good Most of the evidence is from a high quality systematic review of all relevant randomised trials or from at least one high quality RCT of sufficient power. The component studies should show consistent results, the differences between the interventions being compared should be large enough to be important, and the results should be precise with minimal uncertainty.

Average Most of the evidence is from high quality pseudo-RCTs, or from non-randomised comparative studies without significant flaws, such as large losses to follow-up and obvious baseline differences between the comparison groups. There is a greater risk of bias, confounding and chance relationships compared to high-quality RCTs, but there is still a moderate probability that the relationships are causal.

An inconclusive systematic review based on small RCTs that lack the power to detect a difference between interventions and RCTs of moderate or uncertain quality may attract a rating of average.

Poor Most of the evidence is from case series, or studies of the above designs with significant flaws or a high risk of bias. A poor rating may also be given if there is insufficient evidence.

Safety and Efficacy Classification Safety At least as safe compared to comparator* procedure(s)

This grading is based on the systematic review showing that the new intervention is at least as safe as the comparator.

Safety cannot be determined This grading is given if the evidence is insufficient to determine the safety of the

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new intervention.

Less safe compared to comparator* procedure(s) This grading is based on the systematic review showing that the new intervention is not as safe as the comparator.

Efficacy At least as efficacious compared to comparator* procedure(s)

This grading is based on the systematic review showing that the new intervention is at least as efficacious as the comparator.

Efficacy cannot be determined This grading is given if the evidence is insufficient to determine the efficacy of the new intervention.

Less efficacious compared to comparator* procedure(s) This grading is based on the systematic review showing that the new intervention is not as efficacious as the comparator.

Research Recommendations It may be recommended that an audit or a controlled (ideally randomised) clinical trial be undertaken in order to strengthen the evidence base.

Clinical Recommendations Additional recommendations for use of the new intervention in clinical practice may be provided to ensure appropriate use of the procedure by sufficiently qualified/ experienced centres and on specific patient types (where appropriate).

* A comparator may be the current gold standard procedure, an alternative procedure, a non-surgical procedure or no treatment (natural history)

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The ASERNIP-S Review Group

ASERNIP-S Director Professor Guy Maddern ASERNIP-S Royal Australasian College of Surgeons Stepney SA 5069

Protocol Surgeon Mr. Rodney Cooter 1st Floor Waverley House 360 South Terrace Adelaide SA 5000

Advisory Surgeon Mr. Keith Mutimer 206 New Street Brighton VIC 3168

Other-specialty Surgeon Mr. John Graham St Vincents Medical Centre Suite 4, Level 2, 20 Dalley Street Lismore NSW 2480

ASERNIP-S Researcher Ms. Lana Sturm ASERNIP-S Royal Australasian College of Surgeons Stepney SA 5069

Conflict of Interest No conflicts of interest were declared.

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Abbreviations and Acronyms ABCD Adult AIDS Clinical Trails Group Assessment of Body Change

and Distress (questionnaire)

AFT Autologous fat transfer

AIDS Acquired immune deficiency syndrome

ANRS Agence Nationale de Recherche sur le SIDA

ASERNIP-S Australian Safety and Efficay Register of New Interventional Procedures - Surgical

BDI Beck Depression Inventory

CaHA Calcium hydroxylapatite

CI Confidence interval

CT Computed tomography

DEAE Dextran particles

EMA Ethylmethacrylate

ePTFE Expanded polytetrafluoroethylene

FDA Food and Drug Administration

FFAS Facial Fold Assessment Scale

FSTV Facial soft tissue volume

GAIS Global Aesthetic Improvement Score

HA Hyaluronic acid

HAART Highly active antiretroviral therapy

HEMA Hydroxyethylmethacrylate

HIV Human immunodeficiency virus

LIS Liquid injectable silicone oil (polydimethylsiloxane oil)

MBSRQ-AS Multidimensional Body-Self Relations Questionnaire Appearance Scales

MOS-HIV Medical Outcomes Study-HIV

NHMRC National Health & Medical Research Council

NLF Nasolabial folds

NR Not reported

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NRTI Nucleoside reverse transcriptase inhibitor

NS Not significant

PAAG Polyacrylamide gel

PI Protease inhibitor

PICO Patient population, intervention, comparator intervention and outcomes

PLA Polylactic acid

PMMA Polymethylmethacrylate

PTFE Polytetrafluoroethylene

PVA Polyvinyl alcohol

PVOH Polyvinylhydroxide

PVP Polyvinylpyrrolidone

RCT Randomised controlled trial

RNA Ribonucleic acid

SD Standard deviation

SF-36 Short Form 36-item health survey

TCT Total cutaneous thickness

TGA Therapeutic Goods Administration

VAS Visual analogue scale

WSRS Wrinkle Severity Rating Scale

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S E C T I O N 1 I N TR O D U C T I O N 1

1. Introduction

Objective To assess the safety and efficacy of semi-permanent and permanent dermal fillers in comparison with other methods of facial augmentation for age-related wrinkle reduction and for aesthetic improvement of human immunodeficiency virus (HIV)-associated facial lipoatrophy through a systematic review of the literature.

The skin The skin has two main layers, the epidermis and dermis. The epidermis gives rise to the outer barrier layer of dead cells, the stratum corneum, through terminal differentiation of keratinocytes, which are the predominant cell type. Below the epidermis is the dermis. This layer contains the blood vessels, lymphatics, nerves, and deeper portions of the hair follicles and glands that originate from the epidermis. The dermis is composed largely of extracellular matrix and gives skin its strength and elasticity (Hotta 2004). Below the dermis is a subcutaneous layer of fatty tissue that gives contour to the skin.

The ageing process The process of ageing leads to visible changes in facial contour as there is a loss of subcutaneous volume. Diminished dermal vasculature and blood flow, combined with a reduction of dermal extracellular matrix (including collagen, hyaluronic acid and elastin), lead to progressive thinning of the dermis. This results in a loss of elasticity and underlying atrophy of the natural fat pads. The soft tissue that encircles bony skeleton slowly collapses so that these bony landmarks are more visible (Chisholm 2005). This is exacerbated by the effects of gravity, which results in sagging of the soft tissues relative to their substructure (Mandeville & Rubin 2004). The full fibrous tissue associated with youthful appearance is replaced by less dense, less supple and less supportive tissue (Chisholm 2005).

Among the most noticeable changes in the face as it ages, is the development of wrinkles (rhytids) and furrows, and the increased visibility of blood vessels. Critical changes in the perioral area can include vertical rhytids, increased prominence of nasolabial folds (crease that runs from nose to the corner of the mouth), ptosis of the oral commissures (sagging of lines from the corners of the mouth), thinning of the lips, and flattening of the upper lip with less definition of the Cupids bow (Chisholm 2005). Transverse forehead lines become prominent and can be accompanied by a lowering of the eyebrows.

HIV-associated lipodystrophy syndrome With the long-term use of highly active antiretroviral therapy (HAART), infection

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S E C T I O N 1 I N TR O D U C T I O N 2

with human immunodeficiency virus (HIV) has been transformed (in the Western world) to a chronic disease associated with a variety of metabolic complications (Gkrania-Klotsas & Klotsas 2007). These include hyperlipidaemia, insulin resistance, diabetes mellitus, and body fat changes (Samaras 2008).

Body fat changes, commonly referred to as lipodystrophy, are known to occur in 20% to 80% of HIV-infected patients receiving antiretroviral therapy (Grinspoon & Carr 2005). The mechanisms of antiretroviral-associated lipoatrophy in patients with HIV infection remain poorly understood.

The clinical features of lipodystrophy vary, and can present in different ways:

Peripheral lipoatrophy - the loss of subcutaneous fat, resulting in hollowing of the cheeks, wasting of extremities or flattening of the buttocks (Gkrania-Klotsas & Klotsas 2007).

Central lipohypertrophy - manifesting mainly as increased abdominal girth (and less frequently as an enlarged dorso-cervical fat pad). The increase in abdominal girth is caused by increased amounts of visceral adipose tissue (Saint-Marc et al. 2000). The development of increased amounts of visceral adipose tissue is an acknowledged risk factor for cardiovascular disease, diabetes, hypertension and related conditions (Montague & O'Rahilly 2000).

A combination of the above. Although some patients develop both lipoatrophy and lipohypertrophy, this is not universal (Falutz 2007). The presence of lipoatrophy does not correlate with that of lipohypertrophy (Bacchetti et al. 2005).

Unilateral or bilateral breast enlargement due to increased glandular fatty tissue (Falutz 2007).

These body-shape changes should not be confused with the wasting syndrome of acquired immune deficiency syndrome (AIDS), as they occur more frequently among patients responding to HIV therapy and are not accompanied by substantial loss of lean tissue mass (Gkrania-Klotsas & Klotsas 2007).

Body fat changes were initially ascribed to protease inhibitors (PIs), but it is now clear that nucleoside reverse transcriptase inhibitors (NRTIs) also contribute to lipodystrophy syndrome (Baril et al. 2005). The development of body-shape changes and metabolic toxicities is partially related to the individual drugs included in the various HAART regimens (Falutz 2007), in association with other risk factors. These include non-HIV-related factors such as gender (Martinez et al. 2001) and body composition prior to infection, as well as disease-specific factors such as the nadir level of CD4+ lymphocytes and duration of HIV infection (Lichtenstein et al. 2001).

Lipoatrophy, especially of the buccal fat pads (cheeks), can affect the quality of life and body image of patients, as it potentially contributes to stigmatisation, and a perception of being recognisable as a person infected with HIV (Oette et al. 2002;

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S E C T I O N 1 I N TR O D U C T I O N 3

Power et al. 2003). As a result of this, the presence of lipoatrophy has been demonstrated to negatively affect a patients adherence to drug treatment regimes (Corless et al. 2005; Duran et al. 2001).

Non-surgical therapies for facial augmentation Facial rejuvenation and augmentation techniques include topical therapies as well as injectable agents. These products and procedures can be used alone or in combination, depending on the desired result.

For any procedure, practitioners must use caution when using products derived from animal sources. There is a risk of delayed-type hypersensitivity reactions with animal products, and the use of injectable bovine collagen requires a sensitivity test to be performed on each potential recipient in the weeks prior to use. Skin tests are positive in approximately 3% of cases, and 1.2 % of patients with non-reactive skin tests may eventually develop an immune response (Mandeville & Rubin 2004). Additionally, personal, cultural, religious and ethical issues may preclude some patients from receiving animal (as well cadaver) derived products.

Topical therapies Products and non-surgical procedures aimed at skin rejuvenation for age-related defects include:

Topical therapies, such as moisturisers (Rawlings et al. 2004), retinoids (Cho et al. 2005), bleaching agents, hydroxy acids (Tung et al. 2000) and growth factors (Ehrlich et al. 2006).

Energy-based therapies, such as laser and radiofrequency (Doshi & Alster 2005; Railan & Kilmer 2005).

Light-based therapies, both visible and infrared (Hedelund et al. 2006; Goldberg & Cutler 2000).

Other topical procedures include chemical peels (Fulton & Porumb 2004) and micro-dermabrasion (Koch & Hanasono 2001), which address superficial rhytids and variations in pigmentation by debriding the superficial layers of the epidermis. Dermabrasion and laser resurfacing address deeper rhytids by ablating into the papillary dermis and stimulating even regrowth of the epidermis (Ang & Barlow 2002; Gold 2003). However, these techniques are only appropriate for correcting age-related deficiencies in the most superficial layers of the skin, as they rely on the removal of all the layers of the epidermis (Railan & Kilmer 2005). Deeper lines and furrows are not significantly improved by these methods as they do not augment the skin.

Injectable agents Injectable agents for facial rejuvenation fall into two categories; paralytic agents for the treatment of dynamic rhytids, and dermal-filling agents for the treatment of static

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rhytids or volume defects (Mandeville & Rubin 2004). Injectable muscle relaxants, such as botulinum toxin A, work by paralysing the wrinkle-causing muscles to create an improved appearance. The results are only temporary and the treatment does not address the depressions typically caused by tissue loss. Botulinum toxin type A is most commonly used for rejuvenation of the upper third of the face (Narins & Bowman 2005) and is often used in conjunction with other facial rejuvenation techniques (Coleman & Carruthers 2006).

Dermal fillers Injectable dermal fillers and synthetic dermal implants have been developed to address volume loss and contour defects and appear to be useful in the lower third of the face (Narins & Bowman 2005). Dermal fillers are injected or inserted into the skin to give the face a fuller look, as opposed to the pulled, flat, two-dimensional look that is sometimes associated with facelift surgery (rhytidectomy) (Klein & Elson 2000; de Maio 2004). Facelifts, which eliminate loose skin folds in the neck and rhytids in the cheeks by the removing tissue and tightening or lifting of the skin, do not augment or fill the skin (Senglemann & Tull 2006).

Dermal fillers can complement surgical and topical treatments to give a greater and longer lasting aesthetic result (de Maio 2004). A combination of filler materials can be injected or inserted to give a natural contour to the face (de Maio 2004; Godin et al. 2006).

Types of dermal fillers Dermal fillers can be temporary, semi-permanent or permanent and can be classed on the basis of biodegradability or their mechanism of action (Table 1). Permanence of fillers refers to a lack of degradation of the in vivo material over time rather than to a permanent cosmetic result. Permanent aesthetic results are seldom possible because of continued tissue volume loss and other factors associated with the ageing face (including continued HAART therapy in the case of HIV-infected patients).

The longevity of the effects of dermal filler products vary and are generally based on their composition and level of biodegradability within the tissues. Permanent and semi-permanent dermal fillers were developed as an alternative to biodegradable dermal fillers to increase the durability of the aesthetic effect, with a lower risk, less expense and a faster recovery time (Senglemann & Tull 2006).

Fillers that are placed superficially can be injected without anaesthesia, whereas deeper implants, such as those used for lip augmentation, usually require nerve blockade (Narins & Bowman 2005). Autologous fat transfer (AFT) requires local or general anaesthesia or deep sedation depending on the volume of fat harvested and the harvesting location. Harvesting is done using cannulae and syringes under negative pressure. Other materials, such as expanded polytetrafluoroethylene (ePTFE), are inserted in the tissues through small incisions under local anaesthesia.

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Table 1. Classification of dermal fillers by composition Temporary biodegradable (< 1 year)

Semi-permanent biodegradable (1 - 2 years)

Permanent non-biodegradable (> 2 years)

Autologous fat transfer (AFT) Calcium hydroxylapatite (CaHA) Collagen implant porcine Acellular dermis - cadaver Dextran particles (DEAE) Silicone oil (polydimethylsiloxane oil) (LIS) Collagen human, bovine, porcine Hydroxyethylmethacrylate (HEMA) Polyacrylamide gel (PAAG) Cultured fibroblasts - human Polylactic acid (PLA) Polymethylmethacrylate (PMMA) Fascia autograft - human Polyvinyl alcohol (PVA) Expanded polytetrafluoroethylene (ePTFE) Hyaluronic acid (HA) avian, bacterial

Polytetrafluoroethylene (PTFE)

Adapted from Moretti & Greenwood (2006) and Broder & Cohen (2006).

Temporary fillers Most biological materials such as collagen, hyaluronic acid (HA) gels and human-derived products last temporarily, persisting generally for less than 12 months before being resorbed into the tissues (Rohrich et al. 2003; Carruthers 2006). To maintain the visible filling effect produced by these materials, patients must receive regular reapplications. Temporary fillers can be appealing to patients who want to experiment with soft tissue augmentation, but do not necessarily want to commit to their new look.

Semi-permanent fillers To achieve a longer visible filling effect, slowly resorbable substances such as polylactic acid (PLA), calcium hydroxylapatite (CaHA), hydroxyethylmethacrylate (HEMA) and dextran (DEAE) have been used (Morhenn et al. 2002). These substances slowly biodegrade and typically persist for one to two years in the tissues. In some cases, multiple injections may initially be required to get the desired effect. Over time, this may need to be repeated because the visible effect deteriorates as the filler breaks down.

Permanent fillers To address the issue of materials being resorbed over time, non-biodegradable materials have emerged as dermal filler materials. Liquid injectable silicone (LIS), certain polyacrylamide gels (PAAG), polymethylmethacrylate (PMMA) and polytetrafluoroethylene (PTFE) are non-resorbable and remain in the tissues permanently (Carruthers 2006; Morhenn et al. 2002). Used correctly, permanent fillers offer certain advantages over non-permanent ones, particularly as they do not require touch-up sessions once the expected result has been achieved (Haneke 2004). However, permanent dermal fillers are much more technique sensitive than temporary fillers.

Table 2 provides a summary and taxonomy of the semi-permanent and permanent dermal fillers available in Australia and the US.

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Table 2. Classification of injectable semi-permanent and permanent dermal fillers Type of Filler Product Name Mode of Action Longevity Aust TGA

Approval* US FDA Approval

SUSPENSION OF INSOLUBLE POLYMER FRAGMENTS OR MICROSPHERES AND A RESORBABLE LIQUID SILICONE PARTICLES 100 600 m irregular shaped, solid silicone particles suspended in a polyvinylpyrrolidone (PVP) carrier

Bioplastique Bioplasty Inc, St Paul, MN, USA

Injected into subcutaneous tissue (below dermis). Collagen encapsulates and localises the particles. Particles remain in tissue and produce a local foreign body host response, ending in fibrosis, which contributes to the filling effect. Not for fine wrinkles. No allergy test needed.

Permanent

No No

POLYMETHYLMETHACRYLATE (PMMA) MICROSPHERES 30-42 m smooth particles of PMMA suspended in bovine collagen

Arte-Fill Artes Medical, Inc, San Diego, CA, USA. Superceeded products: Artecoll & Arteplast

Injected into sub-dermis (at junction of dermis and subcutaneous fat). Collagen encapsulates and localises the particles. Collagen degraded in 1-3 months and replaced by bodys own connective tissue. Particles remain in tissue and produce a local foreign body host response. Final result takes up to 1 2 years. Not for fine wrinkles. Allergy test recommended.

Permanent No

Yes P020012 Approved 27/10/2006

POLYVINYLHYDROXIDE (PVOH) PARTICLES IN POLYACRYLAMIDE GEL (PAAG) 5 80 m porous PVOH microspheres suspended in PAAG

Evolution ProCytech Labs, Bordeaux, France

Gel is phagocytosed. Microparticles surrounded by fibrous capsule. After 9 months implant is totally infiltrated by macrophages, fibroblasts and giant cells. No allergy test needed.

Permanent No No

HYDROXYETHYLMETHACRYLATE (HEMA) AND ETHYLMETH-ACRYLATE (EMA) PARTICLES IN HYALURONIC ACID (HA) GEL Smooth, non-spherical acrylic hydrogel (HA) particles (copolymer of hydroxyethylmethacrylate (HEMA) and ethylmethacrylate (EMA)) and cross-linked hyaluronic acid

DermaLive 45 65 m DermaDeep 80 110 m Dermatech, Paris, France

DermaLive injected into deeper layers of dermis (junction of dermis and hypodermis). DermaDeep injected into subperiosteal layer or hypodermis. Hyaluronic acid is completely broken down over months. Particles produce a local foreign body host response. No skin test required.

Semi-Permanent No No

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Table 2. Classification of injectable semi-permanent and injectable permanent dermal fillers (continued) Type of Filler Product Name Mode of Action Longevity Aust TGA

Approval* US FDA Approval

SUSPENSION OF SLOWY DEGRADABLE POLYMER MICROSPHERES AND A RESORBABLE LIQUID POLYLACTIC ACID (PLA) MICROSPHERES 1 50 m PLA microspheres in mannitol/ carbomethoxycellulose gel

Sculptra Dermik Laboratories, Berwyn, PA (Also known as New-Fill)

Injected into deep dermis or subcutaneous space. Local foreign body host response. Polylactic acid is completely broken down within months. New collagen growth can last for up to 2 years or longer. No skin test necessary.

Semi-Permanent

Sculptra ARTG No: 151888 Product Id: 241585 Sponsor Name: Sanofi-Aventis Australia Pty Ltd

Yes P030050 (HIV lopoatrophy) Approved 3/8/2004

CALCIUM HYDROXYLAPATITE (CaHA) PARTICLES 25 - 45 m calcium hydroxylapatite (CaHA) microspheres suspended in cellulose gel.

Radiesse BioForm Medical, Inc. Franksville, Wisconsin (formerly Radiance FN)

Injected subcutaneously (sub-dermis). Product incorporated by tissues and then replaced by collagen. CaHA broken down into calcium and phosphate. Good for deeper folds. No skin test necessary.

Semi-Permanent No Yes P050037 (HIV lipoatrophy) P050052 (ageing) Approved 22/12/2006

DEXTRAN PARTICLES IN HA 40 60 m dextran micro beads suspended HA gel

Reviderm Intra Rofil Medical International, Breda, The Netherlands

After injection, there is in an initial macrophage response followed by fibroblast proliferation and new collagen formation.

Semi-Permanent

No

No

80-120 m micro particles with a positively charged surface suspended in cross linked hyaluronic acid

Matridex BioPolymer GmbH & Co. KG

Stimulates new collagen production. Semi-Permanent No No

Biodegradable cross-linked HA gel with positively charged dextranomer beads

ReDexis (formerly HylaDex) Prollenium Medical Technologies Inc, ON, Canada

Positively charged dextranomer beads attract bodys own collagen and elastin to injection site. Results in filling through cross-linked HA and collagen regeneration. HA broken down, but microspheres remain permanently.

Semi-Permanent No No

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Table 2. Classification of injectable semi-permanent and injectable permanent dermal fillers (continued) Type of Filler Product Name Mode of Action Longevity Aust TGA

Approval* US FDA Approval

HOMOGENOUSLY BUILT POLYMER GEL (SILICONE GEL , POLYACRYLAMIDE HYDROGEL NO PARTICLES/SPHERES) LIQUID SILICONE Injectable liquid silicone -poly dimethylsiloxane

Silikon 1000, Alcon Laboratories Inc, Fort Worth, TX, USA PMS 350, Vikomed, Meinerzhagen, Germany VitreSil 1000 & SilSkin 1000, RJ Development Corp. Peabody, MA, USA Adatosil 5000, Bausch & Lomb Inc

Injected into sub-dermis. Each micro-droplet induces its own fibroblastic response resulting in augmentation by forming a fibrous capsule around each silicone particle. No skin test needed.

Permanent No No

POLYACRYLAMIDE GEL (PAAG) Polyacrylamide gel: 95% sterile water and 5% hydrophilic, cross-linked polyacrylamide polymer

Aquamid Contura, Soeberg, Denmark (aka Formacryl (Russia), Interfall (Ukraine), Royamid (Sweden), BioFormacryl, Argiform, Kosmogel) Phigel Outline, Original (2 years), Ultra (5 years) & Fine Line (1 year), ProCytech Labs, Bordeaux, France Beautical 2 (2 years) & Beautical 5 (5 years), Rofil Medical International, Breda, The Netherlands Eutrophill, Mediform

Aquamid injected subcutaneously. Permanent filler where the volume of the implant is given by water not from a solid product. Body accepts the gel readily and forms a thin membrane around the implant which helps to keep it in place; as the gel is very elastic it moves with all facial expressions. Aquamid marketed under different names in different countries. Similar products available with different polyacrylamide/water ratio.

Permanent No No

Polyalkylimide gel (based on polyacrylamide gel): 96% sterile water and 4% hydrophilic, cross-linked polymer (poly-Alkyl-Imide)

Bio-Alcamid Polymekon, Biotech Industrie, Milan, Italy

Injected into subcutaneous tissue. Product becomes covered by thin collagen capsule which completely surrounds the gel, isolating it from the host tissues. Does not become integrated into surrounding tissues and can be removed. Volume of the implant given by water not from a solid product.

Permanent No No

Based on polyacrylamide gel: 92% sterile water and 8% polyvinyl alcohol

Bioinblue Polymekon, Biotech Industrie, Milan, Italy

As for polyacrylamide gel Semi-Permanent No No

*As found on Australian Therapeutic Goods Administration website: www.tga.gov.au As found on US Food and Drug Administration website: www.fda.gov

http://www.tga.gov.au/http://www.fda.gov/

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How dermal fillers work Dermal fillers can be classed by their mechanism of action as either volumisers (fillers) or stimulators (sculptors) (Thioly-Bensoussan 2006; Carruthers 2006). When injected into the skin, volumisers increase facial volume and fill out the skin directly. Volumisers are normally of minimal viscosity and are injected into the upper layers of the dermis to fill superficial lines (Carruthers 2006). They do not initiate a chronic immune response and hence cause little foreign body reaction in the tissues. Volumisers include silicone, collagen, certain PAAGs and HA.

Stimulators can also directly create volume, but primarily, they stimulate the tissues to create a foreign body reaction over a limited time. This stimulates long-term or permanent collagen deposition. Stimulators include PLA, DEAE, CaHA, HEMA and PMMA. Fillers such as PLA and DEAE cause a foreign body reaction for a limited time before they are absorbed, whereas PMMA is non-biodegradable and stimulates collagen deposition indefinitely (Carruthers 2006). Stimulators are intended for deeper lines and furrows, and are generally injected into the deep dermis or upper subcutaneous tissue (Thioly-Bensoussan 2006). Some fillers contain both volumising and stimulating components and fall into both categories.

The majority of stimulators consist of microparticles suspended in a carrier gel. The carrier gel provides some distance between the particles and holds them in place so they do not move during the initial phases of wound healing. According to their chemical composition, size, shape, surface structure and surface charge, different microparticles demonstrate different biocompatibility (Marler et al. 2000). According to the chemical composition and surface charge of the microparticle, the tissue reacts either with protein attachment and consequent encapsulation with fibrous tissue, or with an attempt to phagocytose the particle (Morhenn et al. 2002). Microparticle size determines whether it is phagocytosable, and hence biodegradable. Small particles (< 60 m) are phagocytosed, whereas larger particles remain in the tissue (Ersek & Beisang, 1991). Macrophages containing phagocytosed particles may migrate toward distant organs such as the spleen, the lymph nodes or liver (Morhenn et al. 2002; Tomazic-Jezic et al. 2001).

Smooth-walled microparticles become enveloped by a fibrous capsule that holds them in place. A monolayer of macrophages then surrounds the surface of the microparticle. Fibroplasia is initiated and results in fibroblast adhesion and collagen synthesis, resulting in augmentation (Laeschke 2004). There is no chronic inflammation, and the microparticle becomes embedded in the new collagen.

Microparticles with rough surfaces and irregular shape encourage tissue ingrowth and create a foreign body reaction (Lemperle et al. 2004). Activated macrophages and tissue monocytes release cytokines, such as angiogenic growth factors, to induce the invasion of capillaries into the granulation tissue. Collagen is then synthesised, which forms a scaffold for cellular reconstruction and remodelling in this tissue.

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Demand for cosmetic procedures The number of people undergoing cosmetic procedures continues to grow. In the US, nearly 11.7 million surgical and non-surgical cosmetic procedures were performed in 2007 (American Society of Aesthetic Plastic Surgery 2007). In 2007, a study by the American Society of Aesthetic Plastic Surgery found that the overall number of cosmetic procedures performed in the US increased 457% since 1997. This study also found that the most frequently performed procedure in the US was botulinum toxin injections and the most popular surgical procedure was liposuction (American Society of Aesthetic Plastic Surgery 2007). Almost 54% of cosmetic procedures in the US in 2007 were performed in office-based facilities; 28% in freestanding surgicentres; and 17% in hospitals (American Society of Aesthetic Plastic Surgery 2007). Americans spent just over $13 billion on cosmetic procedures; $8.3 billion of this being on surgical procedures, and $4.7 billion on non-surgical procedures (American Society of Aesthetic Plastic Surgery 2007). No figures are available for facial augmentation procedures alone. There are no accurate figures on how many procedures are performed each year.

Although it has been estimated that lipoatrophy occurs in 20 to 80% of people receiving antiretroviral therapy (Grinspoon & Carr 2005), exact statistics regarding the numbers of people living with facial lipoatrophy are not known. It is therefore difficult to comment on the demand for dermal filler treatment for HIV-associated lipodystrophy. As the development of HAART as an effective therapy for HIV an AIDS continues to substantially reduce the death rate and increase life expectancy in those areas where these drugs are widely available (Lohse et al. 2007), the number of people living with this condition could be expected to increase, and therefore increase the number of people seeking treatment . In Australia, it has been estimated that approximately 17,000 are currently living with HIV and AIDS (up to 30 June 2007) (NCHECR, 2007) suggesting that 20 80% of these people could seek treatment.

Australian cosmetic industry In Australia, the cosmetic industry is largely self-regulated and there is little research on clinical standards and skills required to perform cosmetic procedures (Health Care Complaints Commission 1999). Additionally, there are no figures on the number of cosmetic procedures conducted in Australia or their complication rates. Cosmetic and plastic surgery are considered elective procedures and are not, with very few exceptions, covered by Medicare or private health insurance plans.

Anyone with a medical degree can perform cosmetic surgery in Australia (Australian Society of Plastic Surgeons 2006). The outcome of dermal filler products can be influenced by the experience of the practitioner, indication and injection technique (Haneke 2004; Narins & Bowman 2005). The relationship between a potential consumer and service provider can be a direct one, without mediation or quality control by a referring doctor. Consumers considering cosmetic procedures could potentially be at risk in this unregulated field of medicine.

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Summary Many people wish to improve the appearance of their face. Facial rejuvenation therapies, which are minimally invasive and provide a long-lasting visible improvement, are very appealing to people who want to improve their appearance. Topical therapies rejuvenate the superficial layers of the skin, but do not address the lines and furrows associated with the loss of subcutaneous volume that occur with either the ageing process or the effects of HIV-associated lipoatrophy.

Dermal fillers address volume loss to give the face a fuller, more youthful appearance. They have become a popular means of addressing volume loss and contour defects resulting from ageing, photo-damage, disease, trauma and/or scarification (Senglemann et al. 2006). Fillers that are biodegradable are resorbed over time by the tissues and require repeat applications. Semi-permanent and permanent dermal fillers have emerged as alternatives, to give patients a longer lasting or permanent effect. However, the potential side effects and complications associated with these fillers have not been well documented, may be difficult to manage, and can last as long as the filler. Thus, the aim of this review is to assess the safety and efficacy of semi-permanent and permanent dermal fillers, compared with other facial augmentation techniques, for the management of lines and rhytids on the ageing face and for volume loss resulting from HAART therapy for HIV infection.

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2. Methodology

Literature search protocol

Inclusion criteria Articles were selected for inclusion in this systematic review on the basis of the following criteria.

Participants Humans recieving either injectable semi-permanent or permanent dermal fillers in the face to reduce the visibility of lines, wrinkles and fat loss associated with ageing or with HIV-associated facial lipoatrophy were included.

Studies reporting on patients with facial reconstruction, injury, scarring, disease (except HIV-associated facial lipoatrophy), or a history of previous facial filling within three months of the study were excluded.

Index intervention Semi-permanent and permanent injectable dermal fillers.

Comparative intervention Non-surgical, injectable methods of skin augmentation.

Outcomes Studies that report at least one of the following outcomes were included:

Efficacy

Rhytid assessment factors which included, but were not limited to:

Dermal thickness measurements

Visual aesthetic changes

Photographic comparisons

Patient satisfaction factors which included, but were not limited to:

Patient satisfaction

Pain

Palpable lumpiness

Safety

Periprocedural and postprocedural mortality.

Periprocedural and postprocedural morbidity, which included, but was not limited to:

Granuloma formation

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Allergic reactions

Toxic/adverse effects

Histopathology

Migration, dislocation or resorption of filler

Types of studies Systematic reviews, randomised controlled trials, pseudo-randomised controlled trials, non-randomised comparative studies, and case series (with pre- and post- test outcomes) with a total sample size of at least 40 patients were included for review.

Study design Systematic reviews were defined as those studies that met all the following criteria as defined by Cook et al. (1997):

1. Focused clinical question

2. Explicit search strategy

3. Use of explicit, reproducible and uniformly applied criteria for article selection

4. Critical appraisal of the included studies

5. Qualitative or quantitative data synthesis.

RCTs published after the search dates of the most recent systematic review were also included.

RCTs and pseudo-randomised controlled trials were considered eligible for inclusion and critical appraisal. A study was deemed to be an RCT if the author(s) explicitly stated (usually by some variant of the term random to describe the allocation procedure used) that the groups compared in the trial were established by random allocation (Higgins & Green 2008). Studies in which the method of allocation was known but was not considered strictly random (for example, alternation, date of birth and medical record number) were classified as pseudo-randomised controlled trials (Higgins & Green 2008).

When overlapping patient groups were reported in studies, only the paper quoting the most complete data set was used.

Background information Where appropriate; additional relevant published material in the form of letters, conference material, commentary, editorials and abstracts were included as background information.

Language restriction Searches were restricted to studies reported in the English language.

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Literature search strategies

Databases searched and search terms used Searches are shown in Table 3. Initial searches were conducted in August 2007. The searches were updated in July 2008.

Table 3. Databases searched Edition and date searched Database Platform

Initial search Updated search Cochrane Library Issue 2, 2006 2007 to 2008 Current Contents Ovid Searched 21 August 2007 2007 to 2008 EMBASE Ovid Week 1 1980 to 21 August 2007 2007 to 2008 MEDLINE Ovid 1966 to 21 August 2007 - CINAHL Webspirs 1982 to 21 August 2007 August 2007 to 7 July 2008 PubMed Entrez 1953 to 21 August 2007 August 2007 to 7 July 2008 Clinical Trials Database (US) Searched 29 August 2007 10 July 2008 NHS CRD (UK) NHS HTA (UK) Searched 29 August 2007 10 July 2008 National Research Register (UK) Issue 2, 2006 10 July 2008 Current Controlled Trials (mRCT) Searched 29 August 2007 10 July 2008

Search terms In The Cochrane Library the search terms used were:

dermal filler

soft tissue augmentation

For MEDLINE, EMBASE, CINAHL, Entrez-PubMed and Current Contents Connect the following search terms were used:

1. (Artecoll OR Artefill OR Arteplast)

2. Bioplastique

3. (DermaLive OR DermaDeep)

4. (New Fill OR Newfill OR Sculptra)

5. (Radiesse OR Radiance FN)

6. Reviderm

7. Matridex

8. (Hylan dex OR Hylandex OR Hyla dex OR Hyladex OR ReDexis)

9. (Silikon OR Silskin OR VitreSil OR PMS 350 OR Adatosil)

10. (Aquamid OR Formacryl OR Interfall OR Royamid OR Bioformacryl OR Argiform OR Kosmogel OR Beautical OR Phigel)

11. Eutrophill

12. (Bio Alcamid OR Bio Alkamid OR Bioalcamid)

13. Bioinblue

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14. Isalogen

15. Amazingel

16. (Permacol OR Fibroquel)

17. (Metacrill OR Bioplasty OR Aphrodite Gold)

18. (Outline OR Evolution)

19. 1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 15 OR 16 0R 17 OR 18.

20. Polyalkylimide

21. (calcium hydroxylapatite OR CaHA)

22. (sephadex OR Dextran OR DEAE)

23. (hydroxyethylmethacrylate OR HEMA)

24. (poly-L-lactic acid OR polylactic acid OR PLA)

25. (polyvinyl alcohol OR PVA)

26. (porcine dermal collagen)

27. (liquid silicon* OR injectable silicon* OR silicon* OR polydimethylsiloxane OR LIS)

28. (polyacrylamide OR PAAG)

29. (polymethylmethacrylate OR PMMA)

30. 20 OR 21 OR 22 OR 23 OR 24 OR 25 OR 26 OR 27 OR 28 OR 29.

31. 30 AND (facial fill* OR facial volume OR cosmetic OR aesthetic OR facial contouring OR facial implant* OR permanent fill* OR dermal fill* OR soft tissue augmentation OR skin fill* OR soft tissue fill* OR dermal implant*)

32. 19 OR 31.

33. explode bone/all SUBHEADINGS

34. explode teeth/all SUBHEADINGS

35. explode incontinence/all SUBHEADINGS

36. 32 NOT (33 or 34 or 35)

The NHS CRD databases were searched using the above terms. The National Research Register, Clinicaltrials.gov, Meta-Register and the Australian Clinical Trials Registry were also searched using the above search terms for RCTs in progress.

Note: * is a truncation character that retrieves all possible suffix variations of the root word e.g. surg* retrieves surgery, surgical, surgeon, etc. In Cochrane the truncation character is *; in Current Contents, EMBASE, CINAHL and MEDLINE (Ovid) it is $.

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# is a wildcard symbol that substitutes for one required character in Current Contents, EMBASE, CINAHL and MEDLINE (Ovid).

Selection of studies One reviewer applied the inclusion criteria to identify those studies potentially eligible for selection and appraisal based on their abstracts; these studies were retrieved as full text. The selection criteria were then applied fully to the retrieved studies to identify those to be appraised and included in the review. Full publications subsequently found not to meet the inclusion criteria were excluded and reasons for exclusion are documented.

The bibliographies of all publications retrieved were manually searched for relevant references that may have been missed in the database search (pearling).

Data extraction and appraisal of study methodology Data from all included studies was extracted by one reviewer and checked by a second reviewer using standardised data extraction tables that were developed a priori. The studies included in the review were classified according to the National Health & Medical Research Council (NHMRC) hierarchy of evidence (NHMRC 2000) (Table 4). Any differences were resolved through discussion.

Table 4. NHMRC hierarchy of evidence Level of Evidence Study Design I Evidence obtained from a systematic review of all relevant randomised controlled trials. II Evidence obtained from at least one properly designed randomised controlled trial.

III-1 Evidence obtained from well-designed pseudo-randomised controlled trials (alternate allocation or some other method).

III-2 Evidence obtained from comparative studies (including systematic reviews of such studies) with concurrent controls and allocation not randomised, cohort studies, case-control studies, or interrupted time-series with a control group.

III-3 Evidence obtained from comparative studies with historical control, two or more single arm studies, or interrupted time series without a parallel control group. IV Evidence obtained from case-series, either post-test or pre-test/post-test.

(NHMRC 2000)

If systematic reviews were eligible for inclusion in the review, the methodology of these secondary studies were evaluated with respect to the following factors:

Did the review ask a focused research question that incorporates the elements of the patient population, intervention, comparator intervention and outcomes (PICO)?

Were the inclusion and exclusion criteria of included studies clearly stated?

Did the review use a clear and comprehensive search strategy?

Did the review assess the validity of included studies, and if so which validity criteria were used?

Was the analysis or synthesis of the results appropriate?

Did the review include a summary of its main results, including a discussion of its strengths and limitations?

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Where primary studies were eligible for inclusion in the review, the following criteria were used to appraise their methodology, where applicable:

Were the objectives of the study clearly defined?

Were the inclusion and exclusion criteria clearly described?

Was there a clear description of the interventions used?

Were the characteristics of patients included in the study clearly described?

Were patients randomly assigned to intervention groups, and if so was the method of randomisation described?

Was the randomised assignment of patients to intervention groups concealed from both patients and staff administering the study until recruitment was complete?

Was an attempt made to blind both patients and staff responsible for measuring outcomes of the intervention to the interventions patients received?

Was the number of patients who withdrew or dropped out of the study reported, and were the characteristics of these patients described?

Were the main outcomes of interest adequately reported?

Were point estimates and measures of variability presented for the primary outcome measures?

Non-randomised studies were assessed for other features of study design or execution that may have introduced bias, such as comparability of patient groups at baseline, method of patient selection and comparability of outcome assessment. Case series were assessed in relation to patient selection and whether patients were selected consecutively or retrospectively.

Data analysis If the data were suitable for statistical pooling, meta-analyses of the main outcomes were performed. If possible, the data were stratified into clinically relevant groups. Otherwise, data for the main outcomes were reported narratively.

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3. Studies included in the review

Literature search results Details of the searching and retrieval process are shown in Figure 1.

Figure 1. Process for selection of studies retrieved from the literature databases

Potentially relevant citations identified as a result of initial electronic searches (August 2007) n = 214

Citations excluded after application of inclusion criteria

n = 171

Citations excluded after detailed evaluation

n = 30

Studies retrieved for more detailed evaluation n = 43

Potentially relevant additional citations identified as a result of updated electronic searches (July 2008) n = 82

Citations excluded after application of inclusion criteria

n = 56

Citations excluded after application of inclusion criteria

n = 19

Additional studies included in systematic review n = 7

Randomised controlled trials n = 3 Non-randomised comparative studies n = 1 Case series n = 3

Studies retrieved for more detailed evaluation n = 26

Studies initially included in systematic review n = 13

Randomised controlled trials n = 1 Pseudo-randomised controlled trilas n = 1 Non-randomised comparative studies n =1 Case series n = 10

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Description of studies Excluded studies are given in Appendix A. A total of 20 studies were included in this review (Table 5): four RCTs, one pseudo-RCT, two non-randomised comparative studies, and 13 case series. There were a total of 3853 participants in the included studies. The profiles for these studies are given in Appendix B. Table 6 and Table 7 detail the number of injections or treatments given to patients for ageing and HIV-associated facial lipoatrophy, respectively, in those studies that reported these data. Appendix C details the injection technique used for each study, the facial areas addressed, and the volume of product injected into each area.

Table 5. Summary of included studies Study Study type Level

of E Interventions N Follow-up

(years) Ageing P E R M A N E N T F I L L E R S V S . T E M P O R A R Y F I L L E R S Cohen et al. 2006 (USA) RCT II PMMA (Artecoll*) 128 4 5 Collagen (Zyderm II/Zyplast) 123 0.5 P E R M A N E N T F I L L E R S Cohen et al. 2007 (USA) Case series IV PMMA (Artecoll*) 145 5 Mladick 1992 (USA) Case series IV Silicone particles (Bioplastique) 40 1 Fulton et al. 2005 (USA) Case series IV Liquid silicone (Silikon) 608 3 Reda-Lari 2008 (Kuwait) Case series IV PAAG (name not specified) 1306 0.3 6 S E M I - P E R M A N E N T F I L L E R S V S . T E M P O R A R Y F I L L E R S

RCT II CaHA (Radiesse) 70 1.3 HA 1 (Juvederm 24) 33 1.3 HA 2 (Juvederm 24HV) 33 1.3

Moers-Carpi et al. 2007 (Germany)

HA 3 (Perlane) 69 1.3 Smith et al. 2007 (USA) RCT II CaHA (Radiesse) (one side of face) 117 0.5 Collagen (Cosmoplast) (other side) 117 0.5 S E M I - P E R M A N E N T F I L L E R S Jacovello et al. 2006 (Argentina) Case series IV CaHA (Radiesse) 40 1.5 Sklar & White 2004 (USA) Case series IV CaHA (Radiance FN) 64 0.5 HIV-associated lipoatrophy P E R M A N E N T F I L L E R S , S E M I - P E R M A N E N T F I L L E R S V S . T E M P O R A R Y F I L L E R S Guaraldi et al. 2005 (Italy) Pseudo-RCT III-1 PAAG (Aquamid) 15 0.5 PLA (New-Fill) 20 0.5 AFT 24 0.5 Negredo et al. 2006 (Spain) III-2 PAAG (Aquamid) 115** 1 PLA (New-Fill) 26 1

Non-randomised comparative

AFT 8 1 Orlando et al. 2007 (Italy) III-2 PAAG (Aquamid) 130 1

Non-randomised comparative PLA (Sculptra) 91 1

AFT + PLA (Sculptra) 24 1 AFT 54 1 P E R M A N E N T F I L L E R S De Santis et al. 2008 (Italy) Case series IV PAAG (Aquamid) 50 2 Jones et al. 2004 (USA) Case series IV Liquid silicone (Silikon 1000 or

VitreSil 1000) 77 6.8

Continued over page

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Table 5. Summary of included studies continued

Study Study type Level of E

Interventions N Follow-up (years)

S E M I - P E R M A N E N T F I L L E R S Carey et al. 2007 (Australia) RCT II PLA (Sculptra) Immediate 50 0.5 PLA (Sculptra) Deferred 50 0.5 Cattelan et al. 2006 (Italy) Case series IV PLA (New-Fill) 50 1 Lafaurie et al. 2005 (France) Case series IV PLA (New-Fill) 94 1 Mest & Humble 2006 (USA) Case series IV PLA (name not specified) 99 1 Valantin et al. 2003 (France) Case series IV PLA (New-Fill) 50 1.9 Silvers et al. 2006 (USA) Case series IV CaHA (Radiesse) 100 1.5 AFT, autologous fat transfer; CaHA, calcium hydroxylapitite; Level of E, Level of evidence; NA, not applicable; RCT, randomised controlled trial; PAAG, polyacrylamide gel; PLA, polylactic acid; PMMA, polymethylmethacrylate.

* In Cohen & Holmes (2004), the original publication, Artecoll was used for all patients. Cohen et al. (2006) is the follow-up publication. In this article, the product is referred to as Arte-Fill because this is now the manufacture name of the product. As Artecoll was used for all patients in the original study, and because Arte-Fill has a slightly different composition, the name Artecoll was used for this review.

Same study patients as Cohen et al. (2006). Original PMMA patients followed up. Patients initially in the Collagen group who crossed over to PMMA at 6 months also followed up. Original PMMA study patients n = 100; Cross over patients n = 45. Authors grouped patients together, resulting in duplication of some results.

142 patients included for efficacy, and 145 for safety. 5 lost to follow-up at 4 months after initial treatment. Any losses at 8 and 12 months not described. 2 lost to follow-up at 4 months after initial treatment. Any losses at 8 and 12 months not described. 4 lost to follow-up at 4 months after initial treatment. Any losses at 8 and 12 months not described. ** 10 patients dropped out of follow-up (after the first intervention). Data for these patients not included in the analyses.

1 patient dropped out of follow-up (after the first intervention). Data for this patient not included in the analyses. Patients were followed up a mean of 58.9 weeks since their first treatment and 27.1 weeks since their last treatment. Bilateral PLA at weeks 0, 2, 4 and 6. Deferred group had the same, but delayed by 24 weeks. Therefore, the Deferred group had no

treatment during the study period. Study reported to follow patients for 96 weeks, but only reported 24 week outcomes.

1 patient had a single treatment and was discontinued (was not HIV positive). The data for this patient were not included in the analyses. 1 patient dropped out after a third treatment before complete correction.

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Table 6. Dermal fillers for ageing - number of injections or treatments

P E R M A N E N T F I L L E R S V S . T E M P O R A R Y F I L L E R S N Intervention Number of treatments (mean)* Glabella NLF Upper lip Mouth Corners 128 PMMA (Artecoll) 2.0 2.3 1.7 2.1 123 Collagen (Zyderm II/

Zyplast) 2.0 2.0 1.8 2.2

Cohen et al. 2006 Level II

P-value 0.97 0.32 0.71 0.61 P E R M A N E N T F I L L E R S

N Intervention Number of treatments 100 PMMA (Artecoll) As for Cohen et al. 2006

Cohen et al. 2007 Level IV 45 PMMA (Artecoll)

Cross over patients NR

N Intervention Percentage of patients treated in number of lip augmentation sessions 2 3 > 3

Fulton et al. 2005 Level IV 608 Liquid silicone

(Silikon) 73% 51% 31%

S E M I - P E R M A N E N T F I L L E R S N Intervention Percentage of patients treated in 2 sessions for each facial area NLF

(n = 52) Tear trough (n = 15)

Lips (n = 15)

Mouth (n = 11)

Above upper lip (n = 9)

Cheek (n = 5)

Chin (n = 2)

Sklar & White 2004 Level IV

64 CaHA (Radiance FN) 37% 40% 27% 17% 0% 60% 50% S E M I - P E R M A N E N T V S . T E M P O R A R Y F I L L E R S

N Intervention Number of treatments 70 CaHA (Radiesse) 2 33 HA 1 (Juvederm 24) 2 33 HA 2 (Juvederm

24HV) 2

Moers-Carpi et al. 2007 Level II

69 HA 3 (Perlane) 2 N Intervention Number of injection sessions** Baseline injection

only N (%) Two injection sessions N (%)

Three injection sessions N (%)

117 CaHA (Radiesse) one side of face

61 (52.1%) 51 (43.6%) 5 (4.3%)

117 Collagen (Cosmoplast) other side of face

38 (32.5%) 70 (59.8%) 9 (7.7%)

Smith et al. 2007 Level II

P-value 0.017 NR NR CaHA, calcium hydroxylapitite; NA, not applicable; NR, not applicable; PMMA, polymethylmethacrylate; HA, Hyaluronic acid; NLF, nasolabial folds

* During the 4 weeks after initial treatment, up to 2 additional treatments were permitted. In Cohen & Holmes (2004), the original publication, Artecoll was used for all patients. Cohen et al. (2006) is the follow-up publication. In this

article, the product is referred to as Arte-Fill because this is the name that it is now manufactured under. As Artecoll was used for all patients in the original study, and because Arte-Fill has a slightly different composition, the name Artecoll was used for this review.

It was unclear how these percentages were calculated as they do not add up to 100%. One month after initial treatment, there was a follow-up visit where reinjection could occur. Desired augmentation was gradually achieved with a series of treatments at monthly intervals.

The number of patients receiving less or more than 2 treatments was not reported. || Includes zygoma and buccal regions. Patients received an initial treatment and a touch-up treatment 4 months later. Only nasolabial folds treated. ** After initial treatment patients were allowed up to 2 touch up treatments at 2 week intervals.

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Table 7. Dermal fillers for HIV-associated lipoatrophy number of injections or treatments

P E R M A N E N T F I L L E R V S . S E M I - P E R M A N E N T F I L L E R V S . T E M P O R A R Y F I L L E R N Intervention N sets of injections*, n (range) 20 PAAG (Aquamid) 6 (2 11) 24 PLA (New-Fill) 5 (2 8) 15 AFT 1

Guaraldi et al. 2005 Level III-1

P-value NR N Intervention N sets of injections* (mean SD) 130 PAAG 7 3 91 PLA 5 3 24 PLA after AFT 75% patients 5 3 PLA infiltrations after 1 AFT procedure

17% patients 4 1 PLA infiltrations after 2 AFT procedures 8% patients 6 2 PLA infiltrations after 3 AFT procedures

54 AFT 80% patients 1 procedure 20% patients 2 procedures

Orlando et al. 2007 Level III-2

P-value NR N Intervention Number of sessions, n (maximum allowed) 115 PAAG (Aquamid) 2 26 PLA (New-Fill) 3 8 AFT NR

Negredo et al. 2006 Level III-2

P-value NR P E R M A N E N T F I L L E R S

N Intervention Average number of procedures for each patient De Santis et al. 2008 Level IV

50 PAAG (Aquamid) 6

N Intervention Number of treatments per patient by pre-treatment lipoatrophy score (mean SD)

1 (mild) (n = 37)

2 (moderate) (n = 30)

3 (severe) (n = 10)

P-value

Jones et al. 2004 Level IV 77 Liquid silicone (Silikon

1000 or VitreSil 1000) 3.2 1.2 5.6 1.9 8.6 2.3 < 0.0001**

S E M I - P E R M A N E N T F I L L E R S N Intervention N treatments 50 PLA (Sculptra)

Immediate 4

Carey et al. 2007 Level II 50 PLA (Sculptra)

Deferred 0

N Intervention Number of injection sessions per patient by pre-treatment lipoatrophy score, n (injection sessions)

6 7 8 9

Cattelan et al. 2006 Level IV

50 PLA (New-Fill) 7 (4) 13 (4) 14 (4) 16 (6) N Intervention Number of injections per cheek per patient, median (range) Lafaurie et

al. 2005 Level IV

94 PLA (New-Fill) 5 (1 - 7)

N Intervention Median number of treatments by pre-treatment James Scale class 1 (mild) 2 3 4 (severe) 99 PLA (name not

specified) 3 4 5 6

N Intervention Number of treatments for completed patients, n (%) 1 2 3 4 5 6

Mest & Humble 2006 Level IV

99 PLA (name not specified)

1(1)*** 2 (2) 16 (16) 17 (17) 20 (20) 43 (44)

Continued over page

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Table 7. Dermal fillers for HIV-associated lipoatrophy number of injections or treatments continued N Intervention Number of sets of injections per patient, n (%) 3 4 5

Valantin et al. 2003 Level IV 50 PLA (New-Fill) 4 (8) 26 (52) 20 (40)

N Intervention Number of injections per patient n (%) 1 2 3

Silvers et al. 2003 Level IV 100 CaHA (Radiesse) 4 (4) 18 (18) 78 (78)

AFT, autologous fat transfer; NR, not reported; PAAG, polyacrylamide gel; PLA, polylactic acid; PMMA, polymethylmethacrylate. * PLA and PAAG administered as a set of injections every 4 weeks. The number of injections was not fixed. Number of injections was

dependent on physicians opinion and patients desire of aesthetic result. Two patients required an additional surgical procedure due to asymmetric absorption of the fat graft. Two weeks after initial treatment, all patients received another treatment session. After another 2 weeks, only patients in the PLA group

received another treatment session. This constituted the first round of injections. Patients were evaluated after 1 year to determine whether a second round of injections was necessary. At the 1 year follow-up 17/20 (85%) of the PLA group; 5/65 (8%) of the PAAG group, and 7/8 (88%) of the AFT group required a second round of injections.

10 patients dropped out of follow-up (after the first intervention) and were not included in the analyses. 1 patient dropped out of follow-up (after the first intervention) and was not included in the analyses. Developed by James et al. 2002. Measured on a scale of 1, mild; to 4, severe. ** The number of treatments and volume of silicone injected significantly increased with severity of lipoatrophy score.

Bilateral injections at weeks 0, 2, 4 and 6. Injections were given to patients at baseline, day 30, day 45 and day 60. If necessary, additional treatments were allowed at day 75 and day

90 (16 (32%) patients with a baseline lipoatrophy score of 9 underwent these additional treatments). To maintain satisfactory results 28/50 (56%) patients required at least a set of 2 or more injections of PLA within 18 months after the end of follow-up.

Injections given every 2 weeks. The number of sets of injections was left to the patients and surgeons discretion. New injections were allowed during follow-up but could not be performed in the first 3 months following the last injection.

|| || Treatment sessions were conducted 3 weeks apart (with an allowed variability of 10 days). 1 patient had a single treatment and was discontinued (was not HIV positive). This patients data not included in the analyses. 1 patient

dropped out after third treatment before complete correction. *** This patient had a single treatment and was discontinued (was not HIV positive).

Injections given at baseline, week 2, week 4 and week 6. If ultrasound evaluation at week 6 indicated a total cutaneous thickness < 8 mm, a fifth set of injections could be given.

Injections given at baseline followed with touch up injections at 1 month, 6 months, and 18 months from initial injection, as deemed appropriate by investigators.

Critical appraisal

Facial augmentation for ageing

Permanent fillers vs. temporary fillers

Randomised controlled trials A single RCT compared the safety and efficacy of a permanent PMMA filler (Artecoll), with a temporary collagen filler (Zyderm II/Zyplast) (Cohen et al. 2006).

The method of randomisation was not described in this study, but was found in Thaler and Ubogy (2005), which reported the results of one of the eight study centres. Randomisation was reported as being done by an off-site computer. No details regarding allocation concealment were reported. Patients and evaluators were blinded to treatments groups, while injecting physicians were not. Each of the three evaluators rated photographs independently. It was stated that inter-rater reliability for observer Facial Fold Assessment Scale ratings was evaluated using intraclass correlation, but no values were reported.

Intention-to-treat analysis, power calculations and the study period were not reported. Losses to follow-up were reported, but reasons for these losses were not given. Efficacy was measured by three masked observers using a validated assessment scale. Neither the scale used by investigators to measure success of treatment nor the scale used to measure patient

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satisfaction were validated.

It was not reported if there were any significant differences in baseline characteristics between groups, with only age and gender being reported. Inclusion criteria and exclusion criteria were reported in detail.

This study was a US Food and Drug Administration trial, and was sponsored by Artes Medical, the manufacturer of Artecoll. In Thaler & Ubogy (2005) it was reported that both authors had a financial interest in Artes Medical.

Permanent fillers

Case series Four case series were included for review. These studies investigated the use of PMMA in the nasolabial folds (Cohen et a