d3 retreatment sessions to maintain satisfactory correction as determined by both patient and physician.

The mean skin thickness change before first retreatment generally varied by presenting James scale score: 1 (+0.2 mm), 2 (0), and 3 (−0.3). It should be noted that the mean increase (+0.3) in skin thickness observed in patients with severe facial lipoatrophy (James scale score 4) was solely attributed to areas of overgrowth in 1 patient that skewed the results. Mean change for all other patients with James scale scores of 4, excluding this patient, was −0.2 mm.

This study design was limited by the absence of a predetermined threshold to determine the need for retreatment. This may have contributed to the large number of patients (36 of 75) who opted to have their first retreatment at the time of their 12-month, on site, follow-up from the original Blue Pacific study [21]. These patients were already at the study site, eligible for retreatment and may have elected to undergo retreatment with the goal of maintaining correction rather than wait for a decrease in correction. In addition, this study did not limit treatment to areas already treated. It was noted by the study authors that a few patients actually had an increase in skin caliper measurement in their originally treated (and measured) areas but requested treatment in other areas not previously treated. Consequently, the study authors concluded that an exact answer to the rate of loss of correction over time was not possible from their study. The study also concluded that, in general, PLLA was a safe and effective long-term treatment option for HIVassociated facial lipoatrophy. Patients with milder facial lipoatrophy required fewer injections and had more sustained correction than those with severe facial lipoatrophy. Twelve percent of patients had greater than 36 months of sustained correction. All patients receiving treatment of facial lipoatrophy with PLLA were highly satisfied with the results of the therapy.

The conclusion as to the longevity of the product is therefore somewhat variable. Whether it is 6 months or 36 months and beyond depends on a number of factors including individual response to treatment, possible ongoing fat loss, treatment technique variability, and treatment quantities utilized. Clinically, the average time to re-retreatment in the chapter authors experience is approximately 18 months. As such, it is at least reasonable to consider PLLA a semipermanent filler. Of note, there appears to be a difference in longevity when comparing the use of PLLA in HIV-Associated

facial lipoatrophy and the lipoatrophy of aging. Published reports out of Europe [39, 40, 42] have documented a cosmetic indication duration of effect of 3–4 years and beyond.

62.7 Complications

Possible adverse events common to all injectable products may include tissue response to the injection procedure itself, such as bruising and swelling. Adverse events may relate to the properties of the product used or the technique of administration [44]. In regards to PLLA, the most common adverse event that is prominently discussed is the possibility of small (<5 mm) subcutaneous papules. In key studies for PLLA, subcutaneous papules were found in 44% [16], 31% [18], 6.1% [20], and 13.1% [21] of the patients. A more complete papule/nodule rate of various studies on PLLA in HIV facial lipoatrophy is found in Table 62.2. Rates as low as 0.139% have been reported in a long-term mixed population of cosmetic and HIV+ patients [39].

These subcutaneous papules tend to be nonvisible and asymptomatic (noninflammatory). These papules are rarely biopsied as they are not usually bothersome to patients. Therefore the exact histopathology is lacking. Isolated biopsies have shown birefringent particles surrounded by giant cells (Fig. 62.6). In general, the common clinical belief is that they represent a localized, excessive, collection of PLLA particles, reactive cells, and resultant collagen bundles.

The risk of adverse events associated with PLLA is minimized if appropriate preinjection and injection procedures are employed. The area selected for treatment should be appropriate; injections to the periorbital area should be reserved for experienced injectors and injections should be avoided in areas such as the lips, neck, or glabella. Based on initial studies, a minimum of 2 weeks is recommended in the product insert, between each treatment. However, clinical experience has shown it is best to wait 4–6 weeks between treatment sessions as this allows the physician to properly assess the needs of the patient and the effects of the treatment.

It is also important that PLLA is reconstituted properly, as nonhomogeneous reconstitution of PLLA or injection less than 2 h after reconstitution have both been associated with an increased risk of side effects.

It has been found that papule/nodule formation may be associated with high concentrations of localized PLLA (i.e., dilution of the contents of one vial with 3 ml sterile water for injection [SWFI]). Published information also suggests that additional dilution time (24 h) beyond the 2 h minimum may further decrease the risk of papule/nodule formation [24, 28]. Therefore, a recommended technique is to dilute PLLA with 6 ml SWFI and to reconstitute for at least 2 h prior to use. Again, additional dilution time (>24 h) may be beneficial. Of note, in cosmetic patients the dilution amount is usually higher in an attempt to further minimize papule/nodule formation in this patient population that tends to be risk averse. Administration should be by superficial subcutaneous injection. Finally, to ensure that the product is evenly dispersed throughout the tissues the injection area should always be massaged posttreatment. Patients are also encouraged to massage the treated areas postprocedure for several days. By avoiding a localized accumulation of PLLA, the risk of papule/nodule formation will be minimized.

A clearer picture is evolving regarding the longterm natural course of resolution of these subcutaneous papules. The 24-month VEGA study [16] reported that 6 of 22 papules resolved spontaneously. In the 36-month Blue Pacific follow-up study [33], the authors reported that all but one (12 of 13) of the small (<5 mm) papules that formed during the original study had resolved by the end of the retreatment study. In addition, in 5 (7.7%) of the 65 patients, a total of five new, small (<5 mm), nonvisible papules were reported all occurring within 2 and 7 months after retreatment. Four resolved spontaneously; one patient elected surgical excision of an infraorbital papule that was resistant to conservative treatment measures (including needle desiccation and dilution and treatment with intralesional 5-fluorouracil (5FU)/steroid injection). Another patient presented at retreatment with areas of relative overcorrection, but no discrete papules. This patient had severe lipoatrophy (James scale score of 4) in the original study; the overgrowth was believed to be secondary to an overaggressive original treatment dosage per area. The patient responded to treatment that was administered in adjacent areas of the face to minimize the contour irregularities.

The majority of the studies on PLLA and HIV facial lipoatrophy have been heavily weighted to White males. As part of the US FDA approval of PLLA, a postmarketing study looking at PLLA to treat people of color

and women with lipoatrophy was required. Enrollment started in November 2005 on a 5 year, multi-center phase four registry study. The 1-year, interim analysis abstract [22] showed that there were numerically fewer adverse events (nodules/papules) in darker skin types. There were also no reports of hypertrophic scars or keloids in darker skin types. In addition, there was no difference in clinical response between genders.

As it appears that most of these papules are self limited, the treatment of them should therefore be conservative. The ideal one is to avoid them by following the above procedures. The formation of a papule, if it is to occur, is somewhat delayed, usually in the range of 2–7 months. Initial treatment consists of physically attempting to break up the accumulation of PLLA particles. This can be accomplished by an injection of the papule and surrounding area with local anesthetic containing epinephrine and subsequent needle desiccation/subcision with a small caliber needle (25 or 26 gauge). The goal of treatment is not to completely rid the patient of the papule but to make it smaller and therefore more prone to the natural degradation process. This treatment can be done weekly as necessary. If the physician or patient requires a more aggressive treatment, low dose Triamcinolone-10 (0.2 ml) with 5FU 50 mg/ml (0.8 ml) can be used to slow the mitotic activity of the fibroblasts stimulated by the PLLA. Of note, high-dose, nondilute triamcinolone is not recommended as the majority of the papules are self limited and the subsequent skin depression possible after use of high-dose triamcinolone may become apparent after the papule resolves (Fig. 62.7).

There have been isolated reports of rare (<0.1%) inflammatory papules occurring late after PLLA usage [45]. This inflammatory reaction is very robust and routinely occurs no sooner than 12 months after PLLA treatment. It is felt to be a T cell-mediated delayed sensitivity response and therefore has been reported more in patients with an intact immune system, but the chapter authors are aware of at least two cases in patients who were HIV positive (personal communication). In both of these cases, the reactions occurred after a spike in the patients T cells. Treatment of these nodules involves short-course, high-dose, systemic steroid treatment, as well as localized steroid injection to the papules to blunt the inflammatory response in addition to several months of daily Doxycycline. Treatment of these extremely rare inflammatory papules is usually very successful (Fig. 62.7).

Subcision with 25 G needle

Inject sterile water to dilute poly-L-lactic acid at site

Massage following injection

OR

Heat treatment, ultrasound, mechanical vibration

OR

Excision of nodule (last resort)

Every 1 2 weeks:

Intralesional injection of triamcinolone or methylprednisolone + 5 fluorouracil*. Precision delivery with 27 G needle

PLUS

Systemic therapy with prednisolone or doxycycline*

* See individual summaries of product characteristics for dosing recommendations

Fig. 62.7 Papule/nodule treatment algorithm

62.8 Conclusions

HIV-associated facial lipoatrophy is a long-term issue with no simple solution. The hope of finding a single cure is doubtful because the cause appears multifactorial. Therefore, long-term, multidisciplinary solutions need to be sought. The advantages of treating this condition can be neither underestimated nor undervalued. PLLA provides a safe and effective treatment option for this condition (Table 62.5). It is important that the correct overall injection technique is employed when using PLLA, including proper reconstitution and injection, massage, and enough time between treatments to evaluate the effects. This will allow the physician to achieve the most natural-looking result with minimal adverse events.

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