Lipoatrophy continues to affect a significant proportion of people living with HIV. ART “switches” have been the only therapy to date proven to reverse lipoatrophy [3
]. However, the improvements in limb fat seen with these “switches” have been very slow and for the most part incomplete. Thus, more options are needed for the many individuals who remain with significant lipoatrophy.
This present study demonstrates that rosiglitazone significantly improves limb fat in subjects receiving thymidine-sparing regimens. These findings support that rosiglitazone adds to the available treatment options for ART-associated lipoatrophy. Our finding of increased limb fat from baseline in the placebo arm, in addition to in the rosiglitazone arm, is consistent with the slow improvement of lipoatrophy after discontinuation of tNRTI described in prior “switch studies.” In addition to these observed changes in both arms, significantly greater increase in limb fat was seen in the rosiglitazone arm compared with the placebo arm in our study. This finding supports an effect the study drug beyond that of the tNRTI switch. Additionally, our observation of approximately 900 grams mean increase in limb fat surpasses the mean increase of 350–450 grams of limb fat seen at 24–48 weeks in successful switch studies [3
]. The greater magnitude of these observed fat changes further supports an effect of rosiglitazone on the improvement of lipoatrophy.
Although prior studies of glitazones for the treatment of lipoatrophy have been conflicting, [13
] none of them specifically excluded the active use of tNRTI. Indeed, this is of paramount importance since Mallon et al have shown that concomitant use of tNRTIs blunt the activity of rosiglitazone on PPARγ [6
]. Also supporting the importance of tNRTI cessation in lipoatrophy, a clinical study showed that limb fat increases in the subset of subjects without d4T in the backbone were significantly (p=0.0013) greater than limb fat changes in the subjects with d4T [17
]. The amount of fat change seen in the glitazone group after 48 weeks, a mean 380 and 450 grams overall and in subjects without d4T backbone, respectively, was less overall than in our study. We were not powered to assess subset analysis of the response to rosiglitazone vs. placebo based on prior exposure d4T vs. AZT. Despite improvement in DEXA-measured limb fat, subjective changes were not seen, a similar finding to other studies that were considered successful [3
]. This is likely due to the degree of improvement of limb fat, which although significant, is not large enough during the 48-week of the study to lead to obvious clinically visible body fat change. Additionally, trunk fat increased significantly in the rosiglitazone group but not between the two groups. This may have also affected the perceptions of change in limb fat.
We acknowledge that our patients had relatively high baseline limb fat compared to prior studies. However prior studies have included patients actively on thymidine NRTIs and thus with more severe lipoatrophy. In our study, patients had already stopped tNRTIs for a median duration 3.75 years, and thus it is very likely that their lipoatrophy had already improved by the time they entered our study. Nonetheless, the finding that rosiglitazone may speed up the recovery of limb fat after discontinuation of tNRTIs is important and clinically relevant to the many patients who currently remain with lipoatrophy. Also, despite the fact that a normal limb fat is considered to be about 7–9 kg, some obese patients have a pre-lipoatrophy limb fat of up to 28 kg (McComsey, personal observation), and thus they could lose more than 50% of their limb fat and still be considered above the “normal” range..
In most of the prior studies in which rosiglitazone was shown to increase limb fat [15
], subjects had been chosen based on their insulin resistance status. Although the differing findings in these prior studies may have been related in part to tNRTIs, the role of insulin resistance in determining the response to TZD agents is not clear. In our present study, subjects were evaluated regardless of their insulin-resistance status. Over the 48 weeks of the study, insulin resistance parameters significantly improved from baseline in the rosiglitazone group and were significantly different between the groups as detailed in . Also, we did not find a correlation between baseline insulin resistance indices and subsequent changes in limb fat over 48 weeks nor that subsequent improvement in limb fat at 48 weeks differed between those with and without baseline insulin resistance.
We found that rosiglitazone had a negative, but modest impact on lipid profile. Total cholesterol did increase significantly in the rosiglitazone group as compared to placebo over 48 weeks. Although as baseline placebo values were significantly higher, this increase may represent a regression to the mean. Non-HDL cholesterol changes over 48 weeks approached statistical significance. Unlike other studies [13
], triglycerides were not significantly affected. The prevalence of metabolic syndrome was also not significantly affected.
In conclusion, in the absence of tNRTI, rosiglitazone significantly improved peripheral lipoatrophy even in subjects without insulin resistance. Rosiglitazone was safe in our study population. Although total cholesterol increased significantly in the rosiglitazone group, other lipid parameters and the prevalence of metabolic syndrome was not adversely affected. HIV immunological and virological control was not affected, and there was no negative impact on total bone mineral density. This is the first trial to our knowledge to examine the efficacy of rosiglitazone in subjects exclusively receiving thymidine-sparing regimens. The glitazones may be a promising addition for speeding the recovery of limb fat in HIV infected subjects who have already switched off tNRTIs and remain with significant lipoatrophy.