Ten-Year Safety with Polyacrylamide Gel Used to Correct Facial Lipoatrophy in HIV-Infected Patients

Abstract

Long-term results (>5 years) for synthetic substances used to repair facial lipoatrophy have not been published. We performed a cross-sectional study to evaluate the 10-year safety of polyacrylamide hydrogel (Aquamid) among the 751 patients from our unit who received facial infiltrations at least 10 years ago. Epidemiological and clinical data such as complications and patient satisfaction were collected. We also identified those patients who presented a facial infection at any time after infiltration. A total of 104 patients had received Aquamid at least 10 years ago. Before infiltrations, 24.0%, 41.3%, and 34.7% presented very severe, severe, and moderate facial lipoatrophy, respectively. After a mean (SD) of 10.3 (0.5) years since the infiltrations, 19.2%, 47.7%, and 31.7% of patients reported moderate, mild, and no signs of facial lipoatrophy. The values reported by physicians for the same categories were 1.9%, 10.6%, and 87.5%. Indurations were detected in 6.7% of patients and nodules in 3.8%. Five patients (4.8%) had a local infection. A further 15 patients with a shorter follow-up (less than 10 years) presented local infections (overall incidence considering the 751 patients who received infiltrations of Aquamid, 2.7%); the product had to be withdrawn in three cases. The majority of patients were highly satisfied (74.8%) or satisfied (23.4%) with the cosmetic results; among patients with severe or very severe lipoatrophy at baseline, 31.4% were satisfied and 65.7% were highly satisfied. Infiltrations with polyacrylamide hydrogel (Aquamid) are a safe strategy for the treatment of facial lipoatrophy in the long term. The rate of severe complications was low, and patient satisfaction with the cosmetic results was high. However, facial infections may appear in the long term. Therefore, HIV-infected patients who received synthetic substances should be carefully monitored over time.

Introduction

Facial lipoatrophy is the most stigmatizing sign of lipodystrophy, a syndrome involving changes in body fat distribution that easily identifies a person as being HIV infected. Latest-generation antiretroviral drugs have dramatically decreased the prevalence of these changes, with the result that new cases of lipodystrophy are extremely rare today. However, the high prevalence of lipodystrophy at the end of the 1990s and its multiple consequences (treatment interruptions, poor adherence, psychological trauma, and changes in social or sexual behavior^1

–4) led clinicians to assess different strategies for repair of facial fat loss. Infiltrations with synthetic substances or autologous fat were offered to many patients affected with facial lipoatrophy.^{5

–22} Since some of the fillers were permanent substances, their long-term safety remains a concern, although preliminary results show a low prevalence of short-term and medium-term complications.^{5

–22}

Materials and Methods

We conducted a cross-sectional study to evaluate the 10-year safety of infiltrations with polyacrylamide gel (Aquamid²³) in HIV-infected patients. Over a 1-year period, the study was proposed to all those patients from our clinical HIV unit who had received facial infiltrations with polyacrylamide gel to treat facial lipoatrophy at least 10 years before inclusion, i.e., from September 2002 to December 2003.

We collected epidemiological and clinical data (HIV-related data, severity of lipoatrophy, number of infiltrations, and nonimmediate complications related to infiltrations) and degree of satisfaction from all those who agreed to participate after having given their written informed consent.

Facial lipoatrophy was classified as mild, moderate, severe, and very severe, as reported elsewhere.⁸

The number of infiltrations recorded comprised the number of infiltrations included in the initial set of injections (one per month up to a maximum of four infiltrations in 4 months) plus any subsequent infiltrations during the 10-year follow-up (additional sets). The total cumulative volume of polyacrylamide gel injected included substance injected initially and at all additional sessions.

We defined nonimmediate complications as all adverse events related to infiltrations except those that appeared during the injection of the product (pain) or during the following 3–4 days (inflammation or hematoma in the infiltrated area). We evaluated nonimmediate complications (e.g., nodules, indurations, and local infections) and removal or migration of the infiltrated substance.

We assessed patient satisfaction using a Likert scale ranging from 0 to 10, on which 0 represented “not at all satisfied with the intervention” and 10 represented “completely satisfied with the intervention.” We then evaluated these data in qualitative terms, as follows: from 0 to 3 was considered dissatisfied, from >3 to 5 was somewhat satisfied, from >5 to 8 was satisfied, and from >8 to 10 was highly satisfied.

We determined the prevalence of local infections (considered the most severe complication of facial infiltrations) by identifying those patients treated at our unit who had presented a local infection at any time after infiltration but had not necessarily been followed for 10 years. We recorded data on their clinical condition (immunological and virological status, severity of facial lipoatrophy), the total cumulative volume of polyacrylamide gel required, the time since infiltrations, and the response to treatment.

Statistical analysis

Cosmetic effectiveness and patient satisfaction with the infiltrations, patient characteristics, complication rates, and other related variables were described. Nonnormally distributed variables were expressed as median and interquartile range (IQR), normally distributed variables as mean and standard deviation (SD), and categorical variables as frequencies and percentages. All statistical analyses were performed using SPSS version 15.0 for Windows (SPSS Inc., Chicago, IL).

Results

Of the 1,044 patients who received infiltrations with synthetic fillers at our center, 169 had been infiltrated at least 10 years previously. Of these 169, we assessed 111 patients, of whom 104 had received polyacrylamide gel (Aquamid) and 7 polylactic acid (New-Fill or Sculptra); the remaining patients were lost to follow-up and thus were not interviewed. We described the cosmetic benefit and safety only among the 104 patients who had received infiltration with polyacrylamide gel; very few patients had received polylactic acid, and most of those who did also received other substances during follow-up because of the biodegradable nature of the product. Table 1 summarizes the epidemiological and clinical characteristics of the 104 patients.

Table 1.

Current Epidemiological, Clinical, and HIV-Related Characteristics of Patients

N=104 patients
Age (years)^a	54.4 (6.5)
Gender (male), %	80.0
Time with HIV infection (years)^a	23.1 (4.1)
Risk behavior, %
Men who have sex with men	51.9
Heterosexual relations	14.4
Intravenous drug use	19.2
Other	14.5
Viral suppression, %	89.4
CD4 T cell count, cells/mm^3a	682 (296)
Nadir CD4 T cell count, cells/mm^3a	202 (144)
Hepatitis C virus, %	30.8
Lipid profile, mmol/liter^a
Total cholesterol	4.89 (1.04)
LDL cholesterol	2.85 (0.9)
HDL cholesterol	1.21 (0.39)
Triglycerides	1.86 (1.10)

Mean (SD).

LDL, low-density lipoprotein; HDL, high-density lipoprotein.

A large percentage were men (80%), and the mean (standard deviation, SD) age was 54.4 (6.5) years. The mean time since diagnosis of HIV infection was 23.1 (4.1) years. At baseline, 44.2% had received a protease inhibitor-based regimen, 10.58% stavudine, and 48.08% didanosine; currently, 62.5% are receiving a protease inhibitor, and no patients are on stavudine or didanosine.

Before infiltration, 24.0%, 41.3%, and 34.7% presented very severe, severe, and moderate facial lipoatrophy, respectively. The median (minimum; maximum) total cumulative volume of polyacrylamide gel injected was 6 ml (4; 8 ml). Each patient had a median of two (1; 4) sessions in the initial set, which was followed by a median of one (1; 2) additional set of infiltrations some months later. At least one additional set was administered in 86% of cases. After a mean of 10.3 (0.5) years postinfiltration, 19.2%, 47.7%, and 31.7% of patients reported moderate, mild, or no signs of facial lipoatrophy, respectively. According to the physician, 1.9%, 10.6%, and 87.5% had moderate, mild, and no signs of facial lipoatrophy. Sixty percent of patients reported that they needed more infiltrations (Table 2).

Table 2.

Lipoatrophy-Related Data in the 104 Patients

N=104 patients
Time after facial infiltration^a	10.3 (0.46)
Severity of facial lipoatrophy, %
Baseline
Moderate	34.7
Severe	41.3
Very severe	24.0
Ten years after infiltration (patient's opinion)
No signs of lipoatrophy	31.7
Mild	47.7
Moderate	19.2
Ten years after infiltration (physician's opinion)
No signs of lipoatrophy	87.5
Mild	10.6
Moderate	1.9
Total injected volume of Aquamid, ml^b	6 (4; 8)
Number of sessions per patient in the initial set of infiltrations^b	2 (1; 4)
Number of sets of infiltrations after the initial one^b	1 (1; 2)
Nonimmediate complication, %
Subcutaneous nodules	3.8
Migration of product	0
Induration of injected area	6.7
Local infection	4.8

Mean (standard deviation);

Median (minimum; maximum).

Indurations of the infiltrated area were detected in 6.7% of patients and small palpable nonvisible nodules in 3.8%. No patients presented with migration of the product. Considering patients with a 10-year follow-up, five patients (4.8%) had a local infection, which was resolved using oral antibiotics in all cases. The product had to be withdrawn in one case.

In addition to the five cases of local infection, when we considered the 751 patients who received infiltrations of Aquamid (including those with a follow-up of less than 10 years), a further 15 patients presented local infections in the infiltrated area. These data correspond to an overall incidence of facial infection of 2.7% (20/751 cases). The clinical characteristics of the 20 patients with local infection are shown in Table 3. Six patients were infected within the first 3 years after infiltration (from 14 to 32 months of follow-up), seven patients during the third and fourth years (from 27 to 53 months), six patients during the fifth and sixth years (from 50 to 67 months), and the last one after 126 months of follow-up. All the patients responded well to antibiotics, although the product had to be removed in a total of four cases. One patient, in whom local infection occurred in the context of a severe systemic infection, died of multiorganic failure (panarteritis nodosa). Another patient presented facial infection in the context of pneumonia.

Table 3.

Clinical Characteristics of the 20 Patients Who Presented Local Infection

N=20 patients
Age, years^a	45.6 (6.4)
Male gender, %	85
Time with HIV infection, years^a	10.4 (2.4)
Viral suppression, %	95
CD4 T cell count, cells/μl^a	480 (208)
Time of facial infection from infiltrations, years^a	2.3 (1.3)
Severe or very severe lipoatrophy at baseline), %	100
Total injected volume of Aquamid, ml^a	7.9 (2.7)
Use of antibiotics, %	100
Removal of the product, %	20.0

Mean (standard deviation).

Ten years after the infiltrations, most patients were satisfied (23.4%) or highly satisfied (74.8%) with the cosmetic results; on a scale from 0 to 10, the mean satisfaction was 8.7 (1.8). In the case of patients with severe or very severe lipoatrophy at baseline, the percentages of satisfied and highly satisfied patients were 31.4% and 65.7%, respectively.

Discussion

Many publications have demonstrated the benefit of synthetic substances in the treatment of facial lipoatrophy in HIV-infected patients in the form of favorable cosmetic results, patient satisfaction, and a low rate of adverse events. Safety was mainly assessed 2 years after the infiltrations,^{5

–19} although some publications have reported a longer follow-up—up to 4–5 years—in the case of polyacrylamide gel.^20

–23 Data from this report are particularly relevant, considering that polyacrylamide gel is a permanent filler for which no data are available beyond 5 years. Our data support the benefits of polyacrylamide gel in terms of cosmetic results and patient satisfaction 10 years after infiltration in patients with mostly severe or very severe facial lipoatrophy.

The most prevalent nonimmediate adverse event associated with infiltration of synthetic substances is the presence of injection-site nodules. The rate ranges from 5%^14,18 to 41% of patients.¹⁷ A review including 19 studies with 724 patients (549 in the hyaluronic acid or polylactic acid cohort) reported subcutaneous nodules in 22% of patients.¹⁵ Most studies included patients who received polylactic acid. We published a similar prevalence of nodules in our cohort at 4 years after infiltration (19.3%).²⁰ After 10 years, however, the percentage of hidden but palpable subcutaneous nodules was much lower (3.5%), suggesting that subcutaneous nodules can disappear over time. We did not record the time from infiltration to the appearance of nodules, thus preventing us from knowing whether this is a short- to medium-term complication that subsequently resolves. In any case, the prevalence of nodules has not been increasing over time.

Five patients (4.8%) presented a local infection in the injected area throughout the 10-year follow-up. The prevalence in our cohort (751 patients) was 2.7%. Although this percentage is reasonably low, local infections sometimes require the product to be removed, thus increasing the risk of recurring infections in the event of future invasive treatments.²⁴ The time of appearance of facial infections could not be predicted, since our cases appeared progressively, even 10 years after infiltration, suggesting that infection in connection with a foreign body is not only a short-term adverse event.

Recent published data indicate that delayed-onset complications of infiltration (e.g., abscess formation) varied according to the filler used and that in almost a third, patients reported a previous dental procedure or manipulation of the area after infiltration (such as previous infections or other invasive treatments in the same area).²⁴ It was also reported that abscess formation was significantly more frequent in HIV-infected patients.²⁴ Nonetheless, we observed that infections following the injection of polyacrylamide gel were not necessarily associated with (1) previous manipulation of the area, (2) other clinical conditions (only two patients were affected, one with a severe systemic infection and the other with pneumonia), (3) poor virological control (all patients but one were virologically suppressed), or (4) immunological status (patients had CD4 T cell counts ranging from 52 to 848 cells/μl). However, the quantity of product injected was slightly higher than in the overall population (8 ml versus 6 ml; from 5 to 14 ml in one case).²⁰

Prophylaxis with oral antibiotics was not used among our patients and probably should not be widely recommended despite the possibility of silent bacterial infections of the infiltrated area, due to the low incidence of local infections. Therefore, it seems reasonable to recommend long-term follow-up of these patients and provide appropriate information about the possibility of long-term complications, especially facial infection. Rapid intervention could obviate removal of the product.

A considerable proportion of patients with lipodystrophy report changes in their lifestyle associated with the syndrome, mainly in social and sexual behavior, thus highlighting the wide psychological impact of body fat redistribution.^1

–4 In our study, the high levels of patient satisfaction reflect the favorable cosmetic and safety outcomes of synthetic infiltrations, even though patients presented severe facial lipoatrophy at baseline and therefore had more demanding cosmetic requirements. The degree of satisfaction was always higher when it was reported by the physician than by the patient, and many patients asked for more infiltrations, even if they were satisfied with the results.

In conclusion, data from patients who received infiltrations with polyacrylamide gel (Aquamid) 10 years ago for the treatment of facial lipoatrophy indicate that this filler is safe and provides a high degree of patient satisfaction in the long term, even in cases of severe lipoatrophy. The complication rate was as low as those described in the short or medium term. However, local infection may appear in the long term. Therefore, HIV-infected patients who receive synthetic substances should be carefully monitored over time.

Footnotes

Author Disclosure Statement

EN and BC have received personal fees from VIIV, Merck, Jansen Cilag, Abbott, Roche, and Boehringer Ingelheim; PE has received personal fees from VIIV, Jansen Cilag, and Abbott; AB has received fees from VIIV, Jansen Cilag, Abbott, and Roche. The remaining authors report no competing interests.

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