Clinical examination results of facial lipoatrophy at baseline and after 4 sessions of polylactic acid injections in 4 patients (3 men and 1 woman) enrolled in the study: patient 1 at baseline (A and B) and month 12 (C and D), patient 2 at baseline (E and F) and month 12 (G and H), patient 3 at baseline (I and J) and month 12 (K and L), and patient 4 at baseline (M and N) and month 12 (O and P).
Mean (99% confidence interval) of total cutaneous thickness ultrasonographic values of the right (A) and left (B) cheeks at 3 different time points. The significance of the differences between the 3 time points was tested with the Wilcoxon rank sum test (P<.001 for all the differences).
Confidence interval at 95% for differences between baseline and month 12 of follow-up (higher scores mean a significant positive change) in the Medical Outcomes Study–Human Immunodeficiency Virus (MOS-HIV) quality-of-life (QoL) dimensions. CF indicates cognitive function; EF, energy/fatigue; GH, global health; HD, health distress; HT, health transition; MH, mental health; PF, physical function; PN, pain; RF, role function; SF, social function; and asterisk, P<.005.
Cattelan AM, Bauer U, Trevenzoli M, Sasset L, Campostrini S, Facchin C, Pagiaro E, Gerzeli S, Cadrobbi P, Chiarelli A. Use of Polylactic Acid Implants to Correct Facial Lipoatrophy in Human Immunodeficiency Virus 1–Positive Individuals Receiving Combination Antiretroviral Therapy. Arch Dermatol. 2006;142(3):329-334. doi:10.1001/archderm.142.3.329
Copyright 2006 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2006
To assess the efficacy, safety, and tolerability of facial injections of polylactic acid for human immunodeficiency virus (HIV) 1–associated facial lipoatrophy, which commonly affects HIV-1–infected patients receiving combination antiretroviral therapy.
A cohort of 50 consecutive HIV-1–infected outpatients with moderate to severe facial lipoatrophy who were receiving antiretroviral therapy were recruited in one institutional center and followed up for 12 months. Patients received the compound subcutaneously at baseline and on days 30, 45, and 60 of the study, for a total of 4 sets of injections; if necessary, 2 additional sets of injections were allowed on days 75 and 90. At enrollment and during follow-up, data on patients' characteristics, facial ultrasonography, and iconography were assessed. Data for 2 questionnaires, on self-perception of severity of facial lipoatrophy and on quality of life measured by the Medical Outcomes Study–HIV, were also obtained.
Polylactic acid injections led to a significant improvement in facial lipoatrophy, confirmed by the patients' facial lipoatrophy self-perception and by the ultrasonographic evaluation. The mean total cutaneous thickness of each cheek increased significantly between baseline and after completing the polylactic acid injection sessions (4.3 mm [range, 2.7-6.2 mm] [P<.001] and 4.4 mm [range, 2.7-6.1 mm] [P<.001] on the right and left cheeks, respectively) and persisted significantly until month 12 of follow-up (3.4 mm [range, 2.3-4.9 mm] [P<.001] and 3.3 mm [range, 1.6-5.0 mm] [P<.001] on the right and left cheeks, respectively). In addition, a significant (P<.01) improvement in overall quality of life was observed between baseline and the end of the study. No patients discontinued treatment because of toxic effects, and subcutaneous micronodules at the site of injection were never observed.
Polylactic acid injections can be considered an effective, safe, and simple procedure in HIV-related facial lipoatrophy. The overall improvement of quality of life was clearly associated with the correction of lipoatrophy, reflecting the positive effect of this strategy on patient well-being.
Since 1997, the use of combination antiretroviral therapy (CART) has widely become the standard of care in human immunodeficiency virus (HIV) infection and has led to a well-documented trend of declining morbidity and mortality among HIV-positive patients.1,2 However, because people with HIV infection tend to live longer, other complications are emerging in the clinical management of these patients. Mostly related to the antiretroviral therapy, metabolic and morphologic changes have been recently described in HIV-infected patients receiving CART, including dyslipidemia, glucose metabolism abnormalities, insulin resistance, lactic acidosis, and alteration in body fat distribution.3,4 This latter complication is generally referred to as HIV-related lipodystrophy syndrome or HIV-associated adipose redistribution syndrome, even if a precise definition of the syndrome is still not available. Prevalence estimates of lipodystrophy have shown a wide variability (10%-62% in recently published large studies5- 10) and seem to progressively increase.
Clinically, the abnormality in body shape results in progressive loss of subcutaneous fat involving the face and the arms and fat accumulation in localized areas such as the abdomen, neck, and breast.
The psychological implications of all these abnormalities may negatively reflect on the quality of life (QoL) of HIV patients, delay the initiation of antiretroviral therapy, and reduce the adherence to it. In particular, the loss of subcutaneous fat on the face is a debilitating condition that may stigmatize patients, producing anxiety, depression, erosion of self-image, and problems in social and sexual relations.11,12
The use of plastic surgery in the correction of lipodystrophy has received increasing attention in recent years, and preliminary results of the use of polylactic acid in the treatment of facial atrophy seem to be encouraging.13,14
Hydrogel of polylactic acid is a synthetic polymer of lactic acid, immunologically inert, and totally biodegradable. It has widely been used for the past 20 years in different reconstructive surgeries, and only recently has been approved by the Food and Drug Administration for the correction of facial lipoatrophy in people with HIV infection. Furthermore, it enhances neocollagenogenesis through the increase in the number of fibroblasts and in collagen production.15
We, therefore, conducted a prospective study to determine whether the injection of polylactic acid would be effective and safe in the treatment of facial lipoatrophy in HIV-infected individuals treated with CART. In addition, the self-perception of facial lipoatrophy and its effect on the patients' QoL were evaluated by 2 self-administered questionnaires.
Between January 15, 2002, and June 30, 2002, all consecutive adults with a chronic HIV infection and facial lipoatrophy attending the Outpatient Unit of the Infectious Disease Department of the University of Padova, Padova, Italy, were recruited for the study. Study eligibility criteria were as follows: documented HIV infection; 18 years or older; stable plasma HIV-RNA load of fewer than 1000 copies per milliliter in the preceding 6 months; CART therapy, including either a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor, for at least 24 months; CD4 cell count of 100/μL or more; and moderate or severe lipoatrophy, as defined by a subjective scoring system. Exclusion criteria were as follows: the presence of an AIDS-defining illness, systemic therapy for malignancy and therapy with immune modulators or systemic anabolic corticosteroids, alcohol or other drug abuse, and prior facial implants. All patients provided written informed consent after approval by the ethics committee of our institution.
A complete medical history, a lipodystrophy-specific physical examination, and laboratory tests (including those for cholesterol, triglycerides, and glucose blood levels) were performed and CD4 cell count and HIV-RNA plasma levels were obtained at enrollment and every 3 months during follow-up. The adverse effects of polylactic acid and all medical events were recorded. Safety was assessed by reporting adverse events and laboratory toxic effects, which were classified and graded according to the AIDS Clinical Trial Group/World Health Organization toxicity scales.
At enrollment and during follow-up, all patients were asked to complete 2 self-administered questionnaires. The first questionnaire aimed to assess the self-perception of the gravity of facial lipoatrophy and the degree of improvement with surgical correction. The degree of lipoatrophy was rated as absent (score of 0), mild (score of 1), moderate (score of 2), or severe (score of 3). The questionnaire was administered at study entry, after the completion of surgical treatment (month 2), and at month 12 of follow-up. The second questionnaire was the Medical Outcomes Study (MOS)–HIV, containing 35 items scored on a 6-point scale from “not at all” (0) to “extremely” (5).16 This questionnaire covered 11 dimensions of health status: global health, pain, physical function, role function, mental health, energy/fatigue, health distress, memory, social functioning, QoL, and health transition. The score of each dimension was calculated and transformed linearly to a score from 0 to 100, with 0 being the lowest possible QoL score and 100 being the highest. The MOS-HIV questionnaire was applied at baseline and at month 12 of follow-up.
In the absence of a validated definition, the degree of lipoatrophy was defined subjectively by the use of a severity scoring system based on the sum of patient's own perception, physician examination, and plastic surgeon assessment; each clinician (A.M.C., M.T., L.S., and U.B.) was independently assisted by patient photographic documentation comparing the images of the face before CART initiation and at screening. A score of 0 for no facial lipoatrophy and 1 for mild, 2 for moderate, and 3 for severe facial lipoatrophy was assigned. The maximum lipoatrophy score was 9. Patients with a score of 6 or more were considered eligible for the study.
Four sets of polylactic acid (New-Fill; Biotech Industry SA, Luxembourg, Europe) injections at baseline and on days 0, 30, 45, and 60 of the study were performed for each patient. Two more sets of injections on days 75 and 90 were allowed if necessary. At each surgery session, the specific facial morphologic features of the patients were carefully analyzed before the injection of study drug, and color photographs were collected before and after each injection session. Neither prophylactic antibiotics nor local anesthesia was administered preoperatively. The technical procedure consisted of the preparation of the lyophilized acid (1 vial of 125 mg) with 3 to 4 mL of sterile water; the reconstituted suspension was then injected by multiple parallel or crisscross passes into the deep dermis of the affected area. In total, on each side of the face, 3 to 4 mL of fluid was injected in 1 session. In case of thinner skin layers, a greater dilution of the fluid was necessary, using more (up to 6-8 mL) sterile water. After each surgery session, an accurate massage of the region was performed for a homogeneous distribution of the material. In addition, ice cubes were applied to the treated area together with a topical antibiotic for at least 20 minutes. Subsequently, patients were invited to massage the injected area at home twice daily for 10 minutes for at least 10 days. Overall, the surgery session lasted half an hour, with the employment of the same nurse and a plastic surgeon staff member (U.B.) for the entire study.
Ultrasonographic evaluation of the facial lipoatrophy was performed at baseline, after the 4 sets of polylactic acid injections (at month 2), and at the end of follow-up (at month 12). Measurements of total cutaneous thickness of the nasogenian area located below the malar bone, in front of the masseter of each cheek, were recorded and considered for statistical analysis. The radiologic evaluation was performed by the same trained radiologist (E.P.) using a digital, multifrequency, 7.5- to 13-MHz transducer.
Descriptive statistics were performed for all variables. For ultrasonographic data, a 99% confidence interval was computed at the 3 time points of observation (baseline, after surgery, and after 12 months); a nonparametric Wilcoxon rank sum test for paired data was also performed to test for the significance of the observed changes.
Questionnaire data were entered and stored in a database (Microsoft Access) and then exported to a commercially available software program (SPSS for Windows; SPSS Inc, Chicago, Ill) for statistical analysis. The difference between scores at baseline and the other set points was considered. Usual 95% confidence intervals were applied to judge the significance in the QoL change for each MOS dimension.
A total of 153 patients were screened, and 50 who had a face lipoatrophy score of 6 or more were enrolled in the study. Demographic and baseline characteristics for the 50 subjects are listed in Table 1. At baseline, 17 (34%) of the patients had a protease inhibitor–sparing regimen, whereas 33 (66%) were continuing a protease inhibitor combination therapy. The most common nucleoside reverse transcriptase inhibitor combination was stavudine with lamivudine (34 patients [68%]) or didanosine (12 patients [23%]). Eight patients modified their initial antiretroviral therapy (6 for inefficacy and 2 for toxic effects) after a median time from study entry of 7 months (range, 4-9 months). No AIDS-defining events were recorded during the study period, and no significant differences in viral load (<40 copies/mL in 38 [76%] vs 37 [74%] of the 50 patients; P>.50) and CD4 cell count (422/μL vs 438/μL; P>.50) were detected between baseline and month 12 of follow-up. All other biological variables remained unvaried during the study.
A baseline ultrasonographic evaluation showed a mean total cutaneous thickness on the right and left cheeks of 6.7 and 6.6 mm, respectively (Table 1).
All patients completed a set of 4 surgery sessions; the 16 (32%) patients with a baseline lipoatrophy score of 9 underwent another 2 sessions on days 75 and 90 of the study. The total amount of polylactic acid used for each patient is summarized in Table 2. The correction of facial atrophy and global results improved gradually from the second polylactic acid injections to the fourth to sixth polylactic acid injections. A significant visible improvement in the appearance of all patients was documented after the completion of the polylactic acid injections and persisted until the end of follow-up (Figure 1). After 4 or 6 polylactic acid sessions, a mean total cutaneous thickness on the right and left cheeks of 10.9 mm (range, 8.5-12.3 mm) and 11.0 mm (range, 9.3-12.6 mm), respectively, was recorded by the ultrasonographic study, with a marked mean increase of 4.3 mm (range, 2.7-6.2 mm) (P<.001) and 4.4 mm (range, 2.7-6.1 mm) (P<.001) on the right and left cheeks, respectively, between baseline and month 2 of follow-up. The statistically significant improvement (mean increase, 3.4 mm [range, 2.3-4.9 mm] on the right cheek and 3.3 mm [range, 1.6-5.0 mm] on the left cheek; P<.001) was maintained until month 12 of follow-up, even though a reduction in the total cutaneous thickness (mean reduction of 0.9 mm [range, 0-1.8 mm] on the right side and 1.06 mm [range, 0.2-1.9 mm] on the left side) was observed between the values at months 2 and 12 (Figure 2).
At study entry, more than 50% of patients judged the degree of their facial lipoatrophy as severe, whereas during the follow-up, more than 50% of patients rated their lipoatrophy as absent to moderate. After finishing the polylactic acid injections, no patients considered their lipoatrophy as severe, and at month 12 of follow-up, only 2 patients judged their lipoatrophy as severe. However, an overall significant improvement in facial lipoatrophy (P<.01) was observed during the study by all patients.
The MOS-HIV questionnaire revealed significant differences (P<.01) between the score at baseline and at month 12 of the study for 6 of 11 dimensions, including dimension 11 that judges the self-perception of well-being (Figure 3). No significant (P>.50) differences were found in the domains correlated with physical functioning.
Adverse events that were judged by the investigators as possibly related to the study drug occurred in 15 (30%) of the 50 patients. No serious adverse events were reported, and no patients interrupted the treatment because of adverse effects. The most frequent adverse events were grade 1 edema, reported in all 15 patients, and ecchymosis, reported in 12 of the 15 patients at the injection sites. These events were transient and subsided spontaneously after 12 to 24 hours. Of the 15 patients, 8 reported grade 1 or 2 skin erythema; it was easily treated with topical corticosteroids and resolved within 1 to 2 days. Five days after the fourth polylactic acid injection, a patient experienced an ophthalmic herpes zoster infection, successfully treated with a 10-day course of oral acyclovir. Nonvisible subcutaneous micronodules were never observed during the entire follow-up.
To our knowledge, the exact mechanisms responsible for lipodystrophy, and particularly facial lipoatrophy, have not yet been identified, but increasing evidence supports direct metabolic toxic effects from each class of antiretroviral agents.17,18 Furthermore, other risk factors that have been shown in multivariate analysis studies19- 22 to predispose to CART-induced lipoatrophy include longer duration of HIV disease, advanced HIV disease, longer antiretroviral therapy intake, greater nucleoside reverse transcriptase inhibitor experience in general, older age, lower pretherapy fat content, white race, and elevated triglyceride levels. Indeed, this “lipodystrophic phenotype” is well represented in our cohort of selected patients.
There are only few data on the clinical management of facial lipoatrophy, and different surgical techniques have been proposed. Levan et al23 described the correction of facial lipoatrophy by the injection of autologous fatty tissue with overall good results at 6 months of follow-up; the procedure required 2 days of hospitalization and an antibiotic prophylaxis. Talmor et al24 used the introduction of silicone implants in the submalar region with the addition of collagen and/or autologous fat in the nasolabial folds. In both studies, patients underwent surgery under local anesthesia with sedation and hospitalization.
The results of our study show that the correction of facial lipoatrophy with polylactic acid applications is safe and effective in increasing dermal thickness after a complete cycle of 4 to 6 injections, with a durability of response lasting until month 12 of follow-up. These benefits were confirmed by ultrasonographic study, with a significant increase in dermal thickness that persisted at 36 to 40 weeks after the last injection. Furthermore, in our study, the results emerging from a widely validated instrument like the MOS-HIV questionnaire give an additional assessment to the net benefits of this aesthetic treatment from the patients' perspective. Our patients did not need either hospitalization or chemoprophylaxis and were treated using an outpatient regimen, without affecting their daily activity.
When compared with previous reports, our study revealed 2 most important differences. First, the gain in fat pad as shown by ultrasonography was not so relevant as described in a previous report.13 It may reflect the interindividual variability of the technique, depending on the experience of the operator, the exact site of mapping, and the nonvoluntary tingling movements of the patients during the ultrasonographic examination. However, ultrasonography is a simple, repeatable, noninvasive method that can surely be preferred to other more sophisticated techniques like magnetic resonance imaging. Second, no micronodules and papules developed late after the injections. This could be explained, in part, by the differences in technique of injection and by the different volumes of reconstitution used, especially in thin-skinned patients.
In addition, this surgical technique presents some caveats, like long-term persistence and cost. To maintain satisfactory results, most of our patients (28/50), including all those with a score of 9 for lipoatrophy, had to repeat at least a set of 2 or more injections of polylactic acid within 18 months after the end of follow-up (data not shown); therefore, we believe that small or complete additional touches may be necessary to control the resorption of polylactic acid (ie, the reemerging of facial atrophy) in the long-term follow-up.
Finally, polylactic acid is still considered a cosmetic treatment, and is not likely to be covered by either health insurance or a national health system. However, we believe that the correction of facial lipoatrophy should be paradoxically sought as a treatment of the CART regimen rather than a therapy to apply to the patient. In this view, the concept of a simple aesthetic procedure may be markedly offset by that of an approach to a troublesome adverse effect.
Correspondence: Anna Maria Cattelan, MD, Department of Infectious Diseases, General Hospital and University of Padua, Via Giustiniani 2, 35128 Padua, Italy (firstname.lastname@example.org).
Financial Disclosure: None.
Accepted for Publication: July 28, 2005.
Author Contributions:Study concept and design: Cattelan, Trevenzoli, Sasset, and Cadrobbi. Acquisition of data: Bauer, Campostrini, Gerzeli, and Facchin. Analysis and interpretation of data: Cattelan, Pagiaro, and Chiarelli. Drafting of the manuscript: Cattelan, Bauer, Pagiaro, Facchin, and Cadrobbi. Critical revision of the manuscript for important intellectual content: Trevenzoli and Chiarelli. Statistical analysis: Campostrini and Gerzeli. Obtained funding: Bauer, Cadrobbi, and Chiarelli. Administrative, technical, and material support: Chiarelli. Study supervision: Cattelan and Trevenzoli. All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Funding/Support: This study was supported in part by a grant from Azienda Ospedaliera di Padova, Padua, Italy.
Role of the Sponsor: The funding body had no role in data extraction and analyses, in the writing of the manuscript, or in the decision to submit the manuscript for publication.
Acknowledgment: We thank all the patients who volunteered to participate in the study; Monica Fasolo, RN, and the nursing staff of the Department of Infectious Diseases, General Hospital and University of Padova; and Denise Kilmartin, PhD, for her assistance with manuscript preparation.