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Body Shape Changes in HIV-Infected Persons
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David Alain Wohl, MD - The University of North Carolina AIDS Clinical Research and Treatment Unit
ARTICLE OUTLINE
Switching ART to Improve Body Shape
-- Changing to Tenofovir
--switching to thymidine analogue-sparing versus switch to nucleoside-sparing regimen
Therapies for Fat Redistribution: rosiglitazone
Cosmetic Procedures
Summary
This report contains the CROI abstract for the study being discussed by the author David Wohl at the end of the article, or there is a link to further NATAP coverage of the study.
Dozens of platform and poster presentations at the 12th CROI reported data from studies of metabolic complications of HIV and its therapies. For many HIV clinicians who regularly confront these troubling side effects of therapy, the focus on complications was welcome; however, some could not be blamed for leaving Boston asking what the message to take home was.
The following is an analysis of the data on body shape presented at CROI with the aim of distilling the reports to clinically useful information. Particular attention is paid to results that are supportive of previous data or that arrive at similar conclusions of other studies also reported at the conference.
Switching ART to Improve Body Shape
Treatment of body shape changes can generally fall into three categories: switching from antiretroviral agents thought to be contributing to the morphologic change, administration of medication to reverse these changes or cosmetic procedures. A series of studies assessing body shape subsequent to modification of ART were presented at CROI, including four notable trials.
Changing to Tenofovir
The most straightforward of the switch studies involved the change from nucleoside analogues (mostly d4T) to tenofovir. It would be surprising given in vitro data demonstrating tenofovirÕs relatively lack of mitochondrial toxicity, if switching to this agent did not lead to improvements in fat wasting. Further, data supporting a d4T to tenofovir switch comes from Gilead 903, a comparative trial of d4T versus tenofovir when added to 3TC and efavirenz which found there to be significantly more peripheral fat among those in the tenofovir group compared to the d4T subjects during the trial. Two studies presented at CROI tested the effects of switching to tenofovir and in both, as expected; changing to tenofovir was associated with some return of peripheral fat. These studies clearly establish that a change to tenofovir from d4T should be considered a reasonable approach to peripheral lipoatrophy. But, both of these two studies provide other important information to consider.
The larger of the pair was the RAVE Study (if RAVE stands for something, I have been unable to figure out what). In this trial 105 lipoatrophic patients achieving virologic suppression with a regimen containing either d4T or ZDV were randomized to switch to tenofovir or abacavir (Moyle et al). Over 48 weeks the median gain in peripheral fat was modest (~350 g) and was not significantly different between the tenofovir and abacavir study groups. Trunk fat also increased similarly in both groups. Virologic failure was very rare and not different between arms but as anticipated there were more treatment discontinuations in the abacavir receiving subjects due to abacavir hypersensitivity reactions. Further, tenofovir was associated with more favorable lipid parameters after the switch. There were no statistically significant differences in T-scores or the proportion of subjects with osteopenia between study arms although at entry the prevalence of osteopenia was 19% and in the tenofovir arm this increased to 27% (there was no change at all in the proportion of abacavir assigned patients who were osteopenic). Analysis of simply bone mineral density was not reported. Overall, these results suggest that tenofovir is on par with abacavir in its ability to reverse fat wasting and generally is better tolerated.
A couple of points, though, are noteworthy. First, while most of the patients entering the trial were on d4T there was an imbalance between the study arms in the use of this NRTI at baseline with 77% of those switching to tenofovir on d4T compared to 59% of those randomized to abacavir. Whether this represents a statistical difference or not is unclear and may be besides the point given the relatively small number of subjects in each arm. This imbalance could give tenofovir an edge as switching from d4T seems to be associated with greater improvements in fat wasting than changing from ZDV. A more muted effect on switching from ZDV to abacavir was noted in the MITOX Study and in this study too those on ZDV tended to have less fat gain following the switch to either drug compared to than those who were on d4T. In particular, in RAVE there was very little limb fat gain in those patients who were on ZDV and switched to tenofovir.
The differences in response following the switch from d4T versus ZDV is a big deal as there is an effort to paint all thymidine analogues with the same mitochondrial toxicity brush. Now that few patients remain on d4T, the question of what happens when changing from ZDV becomes paramount. That lipoatrophy occurs on ZDV is the second point worth noting. The role of d4T in lipoatrophy is clear and has been well demonstrated in clinical studies. That ZDV also contributes to fat wasting has been clinically suspected but there are fewer data documenting this effect. Significant proportions of subjects in this and some of the trials described below were receiving ZDV and developed lipoatrophy. It is clear that ZDV is not in the same league as d4T when it comes to body shape changes but it is equally evident the drug can also produce such changes. Link to CROI study report: http://www.natap.org/2005/CROI/croi_9.htm
In a study conducted in Spain, patients receiving d4T at 40 mg twice a day and with plasma HIV RNA levels below 200 copies/mL were randomized to continue their pre-study therapy, reduce the dose of d4T to 30 mg twice a day or switch to tenofovir (Milinkovic A, et al). Over six months patients in the lower dose d4T and tenofovir groups experienced mean increases in peripheral fat while the full dose d4T arm lost limb fat. Lipid parameters, again, improved with tenofovir compared with worsening triglyceride and total cholesterol levels on full dose d4T (lipids on low dose d4T did not change). As in most switch studies virologic failure was uncommon. Curiously, lean fat mass decreased only in the tenofovir arm. There were no data reported on bone density. When discussing the results of this study, the presenting author opined that 40 mg twice daily of d4T likely is an over-dosing of this agent and that experience suggests lower dose d4T is virologically efficacious and safer. Her point is important given the widespread use of d4T in resource-poor settings. There is considerable concern that d4T is producing metabolic complications among those receiving the drug in Africa, Asia and the Caribbean where the low cost of the drug makes it a first line therapy. Link to CROI report:
http://www.natap.org/2005/CROI/croi_17.htm
Both these studies establish tenofovir as an attractive switch option for patients with lipoatrophy on d4T. The effectiveness of switching from ZDV to tenofovir or abacavir is less clear given the limited data available but there does seem to be less improvement when changing from this drug. However, it needs to be recognized that even if switching does not lead to major improvements in limb fat, it will likely forestall any continued worsening of lipoatrophy and this alone may justify the switch. What about the patient without evidence of or major concern regarding lipoatrophy who is receiving ZDV as part of a virologically effective regimen? It is hard to recommend a pre-emptive switch to tenofovir at this time. ZDV is not d4T.
Thymidine Analogue Sparing versus Nucleoside Sparing Switch Strategies
AIDS Clinical Trials Group (ACTG) studies 5125s and 5110 are a pair of trials developed several years ago when the contribution of various antiretroviral classes to body shape was less clear. In both studies, regimens in which a putative antiretroviral agent or class was removed replaced effective stable combination therapy. These studies provide not only evidence of possible switch options but offer insights into the pathogenesis of fat wasting and accumulation.
ACTG 5110 enrolled patients with lipoatrophy on a thymidine analogue, an HIV RNA levels less than 500 copies/mL and a CD4+ cell count greater than 100/uL (Murphy R, et al). All subjects had self-reported peripheral fat wasting during HIV therapy. While most studies use DEXA to assess body shape, this study employed CT scans of the thigh and abdomen. While this makes cross-study comparisons even more difficult than usual it does permit differentiation of subcutaneous and visceral abdominal fat - something DEXA can not do. A total of 101 patients were randomized to either switch their thymidine analogue to abacavir or change the entire regimen to lopinavir/ritonavir (LPV/r) plus nevirapine (NVP). At entry 68-78% of patients were receiving d4T, again demonstrating that ZDV can also produce clinical lipoatrophy. Link to CROI study report:
http://www.natap.org/2005/CROI/croi_19.htm
After 24 weeks, subcutaneous thigh fat increased significantly in the LPV/r+NVP group but did not change at all in the abacavir group. The lack of a change in peripheral fat in the abacavir group is surprising as other studies have demonstrated increases in limb fat following a similar switch to abacavir. The sensitivity of single slice CT scanning compared to whole body DEXA may explain this curious finding. Subcutaneous abdominal fat did increase in both study arms similarly. Visceral fat, however, declined in the abacavir group while remaining unchanged in the LPV/r+NVP assigned patients. Abacavir hypersensitivity reactions, of course, led to some treatment discontinuation and high grade hyperlipdemia in a few LPV/r+NVP treated subjects was reported.
The study supports the position that thymidine analogues contribute mostly to fat wasting. Likewise, the increase in visceral fat in the LPV/r+NVP arm supports the role of PIs (at least) in abdominal fat accumulation. As in other switch studies, the change in peripheral fat, while statistically significant, was not large at 24 weeks. These are preliminary results and longer term data will be forthcoming. As is discussed below, whether a PI+NNRTI combination represents a viable switch option remains to be seen.
ACTG 5125s was a substudy of a larger clinical trial in which treatment na•ve patients were treated with 2 NRTIs plus indinavir alone or indinavir plus efavirenz or indinavir plus nelfinavir (Tebas et al). Subjects with viral loads less than 200 copies/mL in the substudy were randomize to either switch all but their NRTIs to efavirenz (EFV) or swap the entire regimen to LPV/r+EFV. In this study, 62 patients were enrolled. Use of d4T was low at entry with 19% of the LPV/r+EFV arm and 25% in the 2NRTI+EFV arm on this agent. DEXA scanning was performed for body shape assessment. Over a median of 104 weeks, limb fat increased significantly (over 700 g) in the LPV/r+EFV group but declined by almost as much in those who continued their NRTIs. The improvement in peripheral fat on LPV/r+EFV came at a cost. Serum lipids increased with this therapy, although glucose related parameters were unchanged.
Like A5110, this study reinforces clinical observations regarding the associations between antiretroviral agents and body shape changes. Elimination of the PIs and maintenance of the NRTIs in A5125s did not prevent continued fat loss while a complete change to a NRTI-free regimen actually led to fat gain. In both studies, PI+NNRTI combinations were effective. But, as expected lipid increases accompanied such regimens. With the advent of atazanavir, the worldÕs lipid friendliest PI, the obvious question is whether this PI (boosted with ritonavir) along with an NNRTI can produce similar fat gains without the lipid problems. Drug interactions between atazanavir and NNRTIs would need to be worked out but this is a combination worthy of future investigation.
Therapies for Fat Redistribution
The idea of using rosiglitazone for fat changes wonÕt die. In a study of 78 patients with self-described lipodystrophy were randomized to 4 mg of rosiglitazone daily or placebo for 24 weeks (Cavalcanti R
et al). As seen in other similarly designed studies, there was no effect on fat compartments as assessed by DEXA. To investigate why rosiglitazone does not improve fat wasting, investigators from the ROSEY Study, a large clinical trial of rosiglitazone 4mg twice daily for lipoatrophy, conducted a substudy in which changes in RNA expression of subcutaneous mitochondrial fat by biopsies were compared across treatment groups and those receiving or not receiving a thymidine analogue (Mallon P et al-see abstract below). Subjects on thymidine analogues had no increase in PPAR-gamma expression regardless of rosiglitazone treatment suggesting that this therapy can not overcome the effect of continuous thymidine analogue exposure.
These add to the accumulated data that rosiglitazone does not improve fat wasting.
Cosmetic Procedures
There was very little new information on cosmetic procedures for fat wasting at CROI. The requisite polylactic acid poster was present complete with before and after pictures (Mijch A, et al, see abstract below). As in other presentations, the adverse effect rate was low and transient (redness, soreness, pain) and the positive cosmetic effects durable without repeat injections at 12 months. Besides demonstrating the impressive cosmetic effect of these injections, this poster also described the use of spiral CT scanning of the face to assess facial fat volume. There is no standardized method for assessing facial fat gains or loss. The technique did not require specialized CT scanners but does utilize 3D imaging software.
Polylactic acid injection, now marketed as Sculptura, provides a relatively immediate benefit in appearance and seems safe. The need for repeated injections (touch-ups) and the expense are the major concerns regarding this treatment. A patient assistance program helps make the procedure accessible for many.
Summary
Body shape complications of HIV therapy received deserved attention at CROI this February; however, the results presented delivered a mixed blessing. On the one hand, the switch studies solidified our appreciation of the relationship between particular antiretrovirals and different body shape changes but they provided less than ideal remedies for correcting fat redistribution. In areas where combination ART is widely available, most patients with fat changes on d4T have already been switched to alternative agents and the improvements in fat following such substitutions have been somewhat lackluster - at least at this point. As has been said, it generally takes years for fat redistribution to manifest and it will likely take just as long for clinically significant reversal of fat wasting to be noticeable.
A take home message that should be lost on no one is that the extensive use of d4T abroad may increase the relevance of switch studies if this agent produces lipoatrophy at anywhere near the rate it did in the US, Europe and Australia. Avoidance of this cheap and easy to manufacture antiretroviral is essential but is complicated by lack of ready access to an alternative. However, without alternatives, it is all too probable that during future CROIs our colleagues working in resource poor regions will be at the podium, showing us the gaunt, lipoatrophic faces of Thais, Chinese and Africans. Maybe we can wake-up now instead of having to go through that nightmare.
CROI ABSTRACT
"The Effect of Rosiglitazone on PPARg Expression in Human Adipose Tissue Is Limited by Continued Exposure to Thymidine NRTI"
Authors and Affiliations: Patrick Mallon*1,2, R Sedwell1, G Rogers3, D Nolan4, P Unemori1, H Wand1, K Samaras5, A Kelleher1,2, S Emery1, D Cooper1,2, A Carr2, and The Rosey Investigators
1Natl Ctr in HIV Epidemiology and Clin Res, Univ of New South Wales, Sydney, Australia; 2St Vincent's Hosp, Sydney, Australia; 3Univ of Adelaide, Australia; 4Royal Perth Hosp, Australia; and 5Garvan Inst of Med Res, Sydney, Australia
Background: Decreases in peroxisome proliferators-activated receptor gamma ( PPAR-g) expression in subcutaneous adipose tissue may be important in the pathogenesis of lipoatrophy. Despite this, rosiglitazone (RSG), a PPAR-g agonist, has not been shown to increase limb fat in lipoatrophic HIV-infected patients.
Methods: We completed a sub-study of a randomized, placebo-controlled, 48-week trial examining the effect of RSG 4 mg twice daily on limb fat in 100 HIV-infected adults with lipoatrophy. We examined changes in mRNA expression in subcutaneous fat biopsies, performed at weeks 0, 2, and 48. RNA was extracted and real-time RT-PCR performed for mitochondrial and lipid metabolism genes, with results presented relative to b-actin expression, which did not change. Non-parametric analyses were applied.
Results: We recruited 44 men (RSG n = 21, placebo n = 23) to this sub-study of which 21 were receiving the thymidine analogues (tNRTI) zidovudine (AZT) (n = 3) or stavudine (d4T) (n = 18) at baseline. Although groups were matched for baseline PPAR-g expression (p = 0.8), limb fat was lower in the RSG group (1.9 kg vs 2.3kg). Mitochondrial-encoded cytochrome-b expression was significantly lower in those treated with tNRTI (median 2.53 [IQR 4.45] vs 6.04 [4.54] for the no-tNRTI group, p = 0.001). At week 2, only those randomized to RSG in the no-tNRTI group experienced a significant rise in PPAR-g expression (p = 0.046). Similar significant increases in PPAR-g co-activator 1 (PGC-1) expression were also observed in the RSG no-tNRTI group. At week 48, PPAR-g expression was significantly higher only in the no-tNRTI group, regardless of randomized treatment allocation (p = 0.04), with RSG having no effect in the tNRTI group (see the table). No significant correlations were observed between changes in PPAR-g or PGC-1 expression and change in limb fat.
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CROI abstract
"Subcutaneous Polylactic Acid in HIV-1-associated Facial Lipoatrophy: Clinical and Spiral CTScan Outcome as Predictors of Response"
Anne Mijch*, C Bowtell-Harris, B Archer, and J Hoy
Alfred Hosp, Melbourne, Australia
Background: Loss of facial subcutaneous fat is a distressing durable component of the lipodystrophy syndrome for some HIV-infected individuals treated with combination ART, and treatment options are few. Methods: We report the 6-month outcome of an open-label study of subcutaneous injection of polylactic acid (PLA) in 27 individuals, with moderate to severe facial thinning. Primary efficacy measure is facial atrophy assessed by independent plastic surgical review of standardized clinical photography (baseline and 6 months post-treatment). Secondary efficacy measures include patient-scored changes in facial thinning, and changes in facial soft-tissue volume on Spiral CT scan (baseline and 4 months post treatment), quality of life and HIV treatment outcome (adherence). Adverse events were assessed by patient questionnaires at end of treatment and at 6 months.
Results: Of 27 individuals, 20 patientsÕ self-assessment indicated improvement in facial appearance at 6 months (concordance with photography grading -48.1%). Age, baseline CD4 cell count, and type of ART did not predict the degree of facial improvement. Facial volume (cm3 ± SD) prior to 140.9 (16.3) and after 149.3 (16.3) correlated with photographic grade at baseline and follow-up, patient distress at baseline but not at follow-up. Psychological/emotional distress was reported as substantially reduced in those with photographically as well as patient self-assessed improved appearance. Local pain was recorded by 63% of individuals, mean severity 3.4/10; redness by 74%, mean severity 3.7/10; and swelling by 89%, mean duration 2.4 days, severity 4.04/10. No patient withdrew because of adverse events.
Conclusions: Subcutaneous injection of PLA produced durable improvement over 6 months in facial appearance in 74% of these individuals with moderate to severe facial atrophy. Spiral CT-scan volume provided a quantifiable measure of severity. Few adverse events were recorded and patientsÕ distress was markedly improved.
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