Clinical experience with a new injectable hyaluronic acid designed to improve skin quality in a private clinic in Brazil: A retrospective cohort study

Abstract Background Juvéderm Volite is a skin‐conditioning hyaluronic acid (HA) gel for intradermal injection that provides longer‐lasting effects with a lower concentration of hyaluronic acid. Few studies evaluating its use for aesthetic purposes are available. Aim To examine the use and safety of Juvéderm Volite in daily clinical practice. Methods A retrospective cohort study of subjects treated with Juvéderm Volite for aesthetic purposes from May 2018 to October 2019 in Rio de Janeiro. Data were extracted from the attending physician's records obtained at each medical appointment. Subjects were assessed according to their age group and treatment characteristics, which include the use of cannulas vs needles and the effectiveness and safety of associated treatments in a single session. Need for subsequent treatment was stratified by touch‐up treatment (<3‐month period) and repeat treatment (≥3‐month period). Safety assessment was based on the report of nodule formation and late hypersensitivity in patients. Appropriate statistical tests were used for data analysis. Results One hundred and eight subjects were included in the study analysis. The total number of treatment sessions consisted of 159, with a mean follow‐up time of 300.3 days. Of the total 108 subjects, 8.4% required touch‐up treatment for optimum correction and repeat treatment occurred in 9.0%. No cases of adverse events were reported during the follow‐up period. Conclusions This study has shown, based on clinical observation, that Juvéderm Volite is a useful tool to improve skin quality, requiring fewer and less frequent maintenance treatments. No serious adverse events were reported during the follow‐up period.


| INTRODUCTION
Minimally invasive procedures using hyaluronic acid-based dermal fillers have seen a significant rise over the years worldwide. According to the International Society of Aesthetic Plastic Surgery (ISAPS), hyaluronic acid injection is the second most frequently performed non-surgical cosmetic procedure in the world, with over 3 million treatments carried out in the United States alone in 2017, approximately 15% higher than the number reported in 2015. 1,2 In this context, Brazil ranks second in terms of number of cosmetic procedures performed worldwide with more than 2 million treatments in 2017. If we consider only non-surgical cosmetic procedures, hyaluronic acid injection was the second most common treatment in the country, with an estimated 254 375 procedures performed that same year. 1 Despite existing evidence attesting to the efficacy and safety of hyaluronic acid-based dermal fillers for aesthetic purposes and multiple HA products available for use in clinical practice, not much has been described regarding the clinical use of Juvéderm Volite in previous studies.
The prevention of complications associated with treatment depends on technical expertise and domain knowledge of the different products. [3][4][5] Complications are generally rare and may be classified as early (<14 days), late (14 days to 1 year), and delayed (>1 year). Ecchymosis, edema, erythema, infection, allergic reaction, nodule formation, angioedema, skin necrosis, and embolism are examples of early-onset complications; late complications include hyperpigmentation, infection, and granulomas; and biofilm-associated infected nodules are a type of delayed-onset complication. 6 A study conducted in Brazil on the use of Juvéderm Volift for rhinomodulation showed that some patients experienced swelling and pain-evoked touch (resolved 14 days after treatment) and mild adverse events such as hematoma and erythema. 7 Currently available products differ in terms of hyaluronic acid concentration and technology. Juvéderm Volite is an injectable crosslinked HA gel with lidocaine intended for intradermal injection and designed to improve skin quality attributes such as surface smoothness, hydration, and elasticity. The product uses Vycross technology (Allergan Inc.), which incorporates short-chain HA together with longchain HA to provide more efficient crosslinking than fillers based on other technologies, with a lower concentration of hyaluronic acid and longer-lasting results. The less hydrophilic gel makes it a safer product with more predictable and natural-looking results. 7 However, it is interesting to note that there are relatively few studies describing the efficacy and safety of Juvéderm Volite for aesthetic purposes, despite its widespread use in clinical practice. [8][9][10] Ogilvie et al (2020) published an expert consensus on the use of Volite to treat fine lines recommending micro-depot injections of Volite into the deep dermis with a 32G ½ needle inserted at <45 to the skin, spaced 0.5 to 1.0 cm apart, with 0.01 to 0.05 mL volume per injection (full-face total volume: 2 mL). Primary target areas of treatment were the malar, perioral, neck, and décolletage regions. The panel did not identify the forehead and dorsum of the hands as primary targets for Volite treatment. Small adjustments to the volume and spacing of injection may be recommended based on specific skin regions and patient characteristics. 11 Studies published to date have all described the placement of Volite in the intradermal plane using a sharp needle. 8

| Eligibility criteria
Convenience sampling was used as practical criteria for subject inclusion in the study. All patients who underwent treatment with Juvéderm Volite for aesthetic purposes from May 13, 2018 to October 11, 2019 at the Les Peaux Dermatological Clinic, located in the city of Rio de Janeiro, were included in the study sample. Individuals without clinical indication, with a known allergy to hyaluronic acid, pregnant or breastfeeding or having skin inflammatory conditions such as acne or erysipelas are not eligible for treatment with Juvéderm Volite and therefore were not considered for the study. The following variables were collected from each treatment session: number of syringes, treatment area, needle or cannula use, size of cannula, combined treatments (ie, other hyaluronic acid dermal fillers, botulinum toxin, poly-L-lactic acid, calcium hydroxyapatite, superficial peeling, or laser), and reports of mild adverse events (visible or palpable mass) or moderate adverse events (nodule formation and late hypersensitivity). Figure 1A shows treatment areas of injection with Juvéderm Volite recommended by the author. Injection technique with needle ( Figure 1B); injection technique with cannula ( Figure 1C).

| Juvéderm Volite injection technique
Considering that Juvéderm Volite is intended for intradermal injections, the use of a needle is preferable. When using a cannula, Injection technique with a cannula can be seen in Figure 1C. Juvéderm Volite is deposited in a linear droplet fashion following the direction of the arrows, as close as possible to the dermis. The amount of product required when using a cannula is usually greater than when injecting with a needle. But, by contrast, the risk of bruising, especially in the perioral region (area 6), is greatly reduced, as well as other common complications like visible lumps and bumps that occur with filler placement in areas with scarce subcutaneous fat, such as the infraorbital region (area 4) and lateral forehead (area 1).
When treatment is specifically aimed at improving lip hydration or promoting a lip gloss-effect (area 7), both needles and cannulas can be used. However, due to a lower risk of intravascular injection and bruising, cannulas are more commonly used.

| Study endpoints
Besides descriptive analysis concerning the use of Juvéderm Volite for aesthetic purposes, two primary endpoints were defined: need for touch-up treatment within 3 months of the initial treatment and repeat treatment 3 months after initial treatment. Need for subsequent treatment was defined by the attending physician based on subjective criteria, and therefore, it was solely up to the injector to decide whether the patient needed further treatment.
Safety was based on the reporting of treatment-related adverse events (AEs), such as nodule formation and late hypersensitivity.

| Statistical analysis
Frequency measures were used for categorical variables, and measures of central tendency and dispersion for numerical variables.
For demographic data, the analysis was performed considering the total number of patients in the sample and for treatment characteristics, the number of sessions was used as the unit of analysis.
These were stratified by the sample size, age group (≤40 or >40 years old), and treatment with needle or cannula. Touch-up treatment and repeat treatment variables were measured according to the number of sessions, gender, and age of patients.
F I G U R E 1 Treatment areas A; technique with a needle B; technique with a cannula C A Mann-Whitney U test (non-normal distribution) and a t test (normal distribution) were used to assess the association between patient and treatment characteristics. The Shapiro-Wilk test was used to check data normality. Correlation was used to verify the linear relationship between age and number of Volite syringes per area. In addition, a χ 2 was used to determine whether there is a pattern of dependence between patient and treatment characteristics (ie, treatment area, associated treatments, and injection technique-needle vs cannula). A 5% confidence level was considered. Software R version 3.6.1 and Microsoft Office 365 were used.  Table 1 shows characteristics of the study subjects according to gender and age groups, stratified by needle use and cannula use.

| RESULTS
Patients were primarily female (91.7%), with a mean age of 53.3 years (SD = 11.8). Table 2 Table 3 shows the mean number of syringes used per area. Of the treatment areas shown in Figure 1A, the lateral face was the area that required the most amount of product (mean: 1.3; SD: 0.5) and the glabella, the lowest (mean: 0.4; SD: 0.1).
The need for subsequent treatment is presented in Tables 4 and   5, stratified by patient characteristics and areas of treatment, respectively, according to the injector's clinical observation.
Of the 108 subjects, 8.5% received touch-up treatment: Of those older than 40 years of age, the rate was 9.3%; of the women who par- Repeat treatment was performed in 9.0% of the subjects in the sample. Of those older than 40 years of age, the rate was 9.3% and 6.7% in those younger than 40. Of the women who participated in the study, 9.6% received repeat treatment. With regard to areas that There was a significant increase in the number of Volite syringes used to treat female patients (P = .019), aged over 40 years (P = .012), in the perioral region (P < .001) and lateral face (P < .001;  Previous studies evaluating the efficacy of Juvéderm Volite for improving skin quality attributes have described touch-up treatment 30 days after initial treatment, 8 at day 45, 10 and repeat treatment 9 months after last treatment (initial or touch-up). 8 The retrospective design of the present study did not permit the objective assessment of the efficacy of Juvéderm Volite to improve overall skin quality attributes, such as roughness, fine lines, hydration, and elasticity. The efficacy of Juvéderm Volite, however, has been previously reported in the literature in at least two studies. 8 The significantly lower number of touch-up and repeat treat-  A second limitation is associated with the retrospective design of the study. As participants were not randomly selected, the sample frame may not be representative of the population of interest. Collecting data from medical records retrospectively will depend largely on the timeliness and accuracy of the attending physician, which in turn may be considered less reliable.
In summary, this study has shown that Juvéderm Volite is a useful tool to improve skin quality and, according to clinical observation, requires fewer and less frequent maintenance treatments. The product can be injected using both cannula and needle. Besides the ability to improve skin quality, the major contribution of the present analysis was to attest the safety profile of the new cross-linked HA gel, in which no adverse events were observed during the entire period of the study.

ACKNOWLEDGEMENTS
Writing and editorial assistance was provided to the authors by Ana

CONFLICT OF INTEREST
Daniel Dal'Asta Coimbra is a speaker from Allergan (now AbbVie); however, no funding was provided for the conduction of this study.

Conceptualization: Daniel Dal'Asta Coimbra
Writing-original draft preparation: Daniel Dal'Asta Coimbra Writing-review and editing: Daniel Dal'Asta Coimbra

TRANSPARENCY STATEMENT
Daniel Dal'Asta Coimbra affirms that this manuscript is an honest, accurate, and transparent account of the study being reported, that no important aspects of the study have been omitted, and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

DATA AVAILABILITY STATEMENT
The authors confirm that the data supporting the findings of this study are available within the article or its supplementary materials.