At week 12, the mean change from baseline in the score for the Mental Health scale of the SF-36 Health Survey scale in PLA recipients was significantly different from the mean change in the deferred group (2.8 and −3.2, respectively; P = 0.026). At week 24, the mean change in scores for Social Functioning and Mental Health in the immediate group differed significantly from mean changes in the deferred group (P = 0.031 and P = 0.047, respectively; Fig. 5). Although the mean score for 5 SF-36 scales increased in the immediate group, the mean score for all 8 scales decreased in the deferred group. Additionally, the mean change in the Mental Health Component Summary score differed significantly in the immediate group relative to the deferred group (P = 0.048), but there was no difference in the Physical Component Summary score (P = 0.98) or in any of the scales associated with physical functioning. Body self-image assessed using the MBSRQ-AS showed that the mean change in appearance evaluation and body areas satisfaction subscale scores in the immediate group was significantly different from scores in the deferred group (0.19 and −0.03, P = 0.040 and 0.29 and −0.12, P < 0.0001, respectively) at week 12 and at week 24 (0.15 and −0.15, P = 0.010 and 0.19 and −0.11, P = 0.0004, respectively).
Forty-eight (96%) PLA recipients experienced at least 1 procedure/product-related adverse event, with pain/discomfort (76%), localized edema (64%), and erythema (53%) reported most commonly (Table 3). Most events were grade 1 or 2 and were of short duration (median = 2 [interquartile range [IQR]: 1 to 3] days). No treatment was delayed or terminated for adverse events, surgical or clinical discretion, or patient wish. At week 24, there were 4 palpable and 1 visible ongoing subcutaneous noninflammatory nodules and 1 papule at the injection site in 6 participants (12%). These events were noted at the injection site 5 to 19 weeks after the first injection. Five serious adverse events were reported in 4 participants: 3 events (epidural abscess, surgery to resect renal tumor, and hospitalization for lower lobe pneumonia) in the immediate group (2 participants) and 2 events (surgery for perianal abscess and acute renal retention) in the deferred group (2 participants). None of these events was associated with PLA. Additionally, no other grade 4 event was considered definitely, probably, or possibly related to PLA.
Four bilateral PLA treatments administered by deep subcutaneous injection every 2 weeks did not increase FSTV after 24 weeks in HIV-infected lipodystrophic adults with extensive antiretroviral exposure and moderate or severe facial lipoatrophy. Small improvements in objectively assessed facial soft tissue thickness around the planes of injection were demonstrated. Clinicians and patients perceived significant treatment benefits with reductions in facial lipoatrophy severity assessed in treated subjects relative to controls. Some quality-of-life scores also improved.
There is no validated measure of facial thickness. FSTV had not been used previously but was chosen because it is an unbiased objective measure. The lack of improvement in FSTV at week 24 may be attributable to several factors. First, the study may have not been adequately powered. Because there were no normative data, we were uncertain of the expected change, and thus based our sample size calculation on the results of an earlier randomized study,18 where a statistically significant difference in improvement in patient visual analog assessment of 47% in the treatment arm versus 7% in the placebo arm was demonstrated at week 12. We chose a more conservative estimate of 50 subjects per arm, which gave 80% power to detect a difference in the proportion with a clinically relevant improvement in cheek volume to 10% in the placebo arm versus 35% in the treatment arm. At week 24, however, only 16% of treated subjects and 10% of deferred subjects had a >10% increase in FSTV. If the observed differences were accurate, we would have required 525 subjects per arm to detect a significant between-group difference in FSTV at week 24. Second, the procedure may be more variable than envisaged. Because subjects were spread geographically, 9 CT scanning sites were required. At each imaging site, a single operator acquired the data using the same equipment and software at each visit. Although baseline scans were quality assessed, failure to reconstruct the data set at week 24 to reflect baseline image parameters could produce measurement error. Finally, it is possible that PLA is not as efficacious as previously believed. At week 24, FSTV remained unchanged in PLA recipients but had decreased in untreated subjects, suggesting that PLA benefits may lie in its ability to prevent further deterioration in treated areas.
The heterogeneity of studies that have investigated the use of PLA in HIV facial lipoatrophy makes efficacy comparisons difficult. Treatment numbers vary enormously, with many studies adjusting vial numbers based on subjectively assessed baseline facial lipoatrophy severity or to achieve a subjectively assessed satisfactory result or predefined outcome.17,19-25 Only 1 study administered a fixed number of treatments.18 Across studies, the number of treatments ranged from 1 to 8, with mean/medians of 4 or 5. Heterogeneity of study subjects, facial lipoatrophy severity and its assessment, or lack of these data adds additional complexity. Although most subjects were white men aged 41 to 49 years, only 1 study used a validated lipodystrophy assessment tool27 to assess facial lipoatrophy severity.18 Apart from an ultrasound-assessed facial fat thickness threshold,17 the remaining studies utilized a site-specific scale with patient and/or clinician assessment. Because these open-label studies all lacked objective lipodystrophy data, comparisons are problematic.
Significant increases in facial thickness were observed at 2 planes, the maxilla and base of the nasal septum, which were the approximate planes of injection, but the increases were less than those recorded using sonography in previous studies.17,18,23,24 In these studies, measurements were made predominantly at the nasolabial folds and showed broad interstudy variability with changes of 4.4 mm at 2 months23 and 3.5 to 6.4 mm at 24 weeks17,18,24 after 4 or 6, 4 to 5, 3, and a median of 5 (range: 2 to 8) bilateral PLA treatments, respectively. Our results are similar to those obtained using 3-D photographs with 3-D computerized reconstruction of the face to measure dermal thickness.22 In 49 patients who received a median of 5 (range: 1 to 7) PLA treatments, the median increase in dermal thickness from baseline to the end of treatment (median = 2.3 [range: 0.5 to 7] months) was 1.9 (range: 0.4 to 5.5) mm. At the last follow-up assessment, a median of 12 (range: 1 to 27) months after the first PLA injection, the maximal increase in dermal thickness was 2.4 (range: 0.7 to 6.1) mm in the right cheek and 2.2 (range: 0.9 to 5.9) mm in the left.22 Calipers were used to assess skin thickness changes in the malar region (n = 99); however, because the authors reported only mean percent change from baseline at 6 months (59.2%), comparison with other studies is difficult.19 None of these measurement methods has been validated, perhaps assisting to explain the broad interstudy variability in outcomes. Because measurement reproducibility is operator dependent, it requires consistency in measurement positioning, which is made more difficult by the absence of facial landmarks. The shortcomings of facial sonography were highlighted in an earlier study, which showed it to be a poor measure of facial lipoatrophy.11
Despite only modest improvements in objectively assessed facial thickness, patients and clinicians perceived significant improvements. This observer bias results from the open-label design of the study and was observed in an earlier lipodystrophy study, where despite significant reductions in limb fat as assessed by DEXA, lipoatrophy severity was perceived to have improved significantly.35 In the current study, these perceptions were supported by a significant association between perceived improvements and objectively assessed increases in facial thickness. The lack of change in subjectively assessed lipodystrophy and its severity was supported by no difference in other objectively assessed body composition parameters. Additionally, the lack of between-group differences in limb fat mass and limb fat percent suggests that the observed facial differences were attributable to PLA treatment and not to a change in overall lipoatrophy.
The associations observed between the objectively assessed linear measures and patient subjective assessment, and between patient and physician subjective assessments, suggest that there is a treatment benefit. The lack of correlation between change in the objective primary endpoint, FSTV, and the secondary subjective endpoints is therefore of interest. The scanning landmarks (midorbit and angle of mandible) produced a volume substantially greater than the area where PLA was injected. Because increases in tissue depth in the injection plane were modest, it is possible that the resultant volumetric increases may not have been detected, particularly if, as mentioned previously, the procedure was more variable than anticipated.
PLA injections were safe and well tolerated. Although most patients experienced at least 1 procedure/product-related adverse event, most were of low grade and transient consistent with those observed in previous clinical studies.17,18,22 The incidence of injection-site nodules (12%) is comparable to that reported in other HIV studies.19,22,25 Although considerably lower than the incidences of 31% to 52% reported previously,17,24,37 it is higher than that found by other investigators (0% to 6%).19,21,23 Onset times for nodules of 2 to 9 months22 and a median of 7 months26 after the first injection have been reported; therefore, it is possible that with longer follow-up, the incidence reported here may increase.
There are limitations to this study. Most participants were white men, reflecting the HIV epidemic in Australia. There are no data describing normal FSTV in men; thus, we could not determine to what extent facial lipoatrophy normalized. Nevertheless, FSTV did not change, suggesting that additional PLA treatments might provide some benefit.
In summary, we showed in a multicenter, open-label, randomized controlled trial with objective endpoints that PLA treatment in HIV-infected adults with moderate or severe facial lipoatrophy achieved only modest increases in facial thickness but not in facial volume. In contrast, patient-perceived benefits were significant in terms of aesthetic improvement and increased well-being, social functioning, and quality of life. PLA does not address fat loss in other body regions. Restoration of lost fat mass is gradual. In the interim, further well-designed comparative studies with objectively assessed endpoints are needed to ascertain the optimal treatment for HIV facial lipoatrophy.
The authors thank all participants for their time and commitment.
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Protocol Steering Committee: Andrew Carr (St. Vincent's Hospital, Sydney; Principal Investigator); Dianne Carey, David A. Cooper, Sean Emery, and Kathy Petoumenos (National Centre in HIV Epidemiology and Clinical Research, The University of New South Wales, Sydney); John Chuah (Gold Coast Sexual Health Centre, Miami), Nicole Easey (St. Vincent's Hospital, Sydney); David Menadue and Kirsty Machon (National Association of People Living with HIV/AIDS), and Gary Rogers (Secretariat of the Pacific Community, Noumea)
Other Investigators (Listed in Order of Number of Patients Recruited): William Genn, Robert McFarlane, Marilyn McMurchie, and Robyn Vale (407 Doctors, Sydney); William Donohue, Sarah Makinson, Brenton Wait, and Michael Curry (Department of General Practice, University of Adelaide); Sarah Pett, Sam Milliken, Karen Macrae, and Richard Norris (St. Vincent's Hospital, Sydney); David Nolan and Claire Forsdyke (Royal Perth Hospital); Mark Kelly, John Patten, Paul Negus, and Jo Murray (AIDS Medical Unit, Brisbane); David Sowden, Kenneth Clare, and Alan Walker (Nambour Hospital); Cassy Workman and Vanessa Rees (AIDS Research Initiative, Sydney); Don Smith, Virginia Furner, Derek Chan, Julian Gold, Jeffrey Post, Jega Sarangapany, and Jason Gao (Albion Street Centre, Sydney); John Quin, Louise Evans, Gary Keogh, and Helen Best (Bigge Park Centre, Sydney); Nicholas Doong and Jeff Hudson (Burwood Road Practice, Sydney); Mark Bloch, David Austin, Ercel Ozser, and Shikha Agrawal (Holdsworth House Medical Practice, Sydney); Robert Finlayson, Cathy Pell, Ross Price, Neil Bodsworth, and Sophie Dinning (Taylor Square Private Clinic, Sydney); George Kotsiou, Joanne Holahan, and Peter Jenkins (Royal North Shore Hospital, Sydney); David Orth and David Youds (Gladstone Road Medical Centre, Brisbane); Stuart Aitken, Denise Lester, and Fiona Clark (Gold Coast Sexual Health Clinic, Miami); Roger Garcia and Marry Moussa (Royal Prince Alfred Hospital, Sydney); Dominic Dwyer and Margaret Piper (Westmead Hospital, Sydney); and Pam Konecny and Robyn Dever (St. George Hospital, Sydney)
Data Management: Wendy Lee, Rose Chevkenova, and Robyn Munro (National Centre in HIV Epidemiology and Clinical Research)
Surgeons: Andrew Booker, Mary Dingley, Steven Liew, and Fiona Wood