This meta-analysis of individual-patient data from six randomized, placebo-controlled trials of TZD from five countries forms the largest assessment of the effect of TZD therapy on limb fat among HIV-positive individuals. Overall, there was a small impact of TZD on limb fat gains in the combined dataset, unlikely to be clinically meaningful. Sub-analysis demonstrated a significant effect of pioglitazone but not of rosiglitazone on increases in limb fat relative to placebo. There was no difference in limb fat response or in the effectiveness of TZDs according to whether or not patients were receiving protease inhibitors.
In this meta analysis, while the use of thymidine analogues was associated with poorer limb fat outcomes, the effectiveness of TZD therapy did not vary by thymidine analogue use. Our data contrast those recently presented in abstract form which showed rosiglitazone to be effective at increasing limb fat among HIV positive individuals with mild limb fat loss on thymidine-sparing regimens.25
However, while the mean change in limb fat to week 48 was significantly higher in the rosiglitazone group than the placebo group (911g +/− 1215 vs 253g +/− 1039, p=.018), the difference between treatment groups in median changes in limb fat was more modest although still similar in magnitude to prior switch studies off of thymidine analogue NRTIs (448 vs 153, p=.02) (personal communication, Grace McComsey, August 6, 2009). Since there was no comparison group of patients on thymidine analogues in the study, it is difficult to determine if the effectiveness of rosiglitazone was due to the absence of thymidine analogues or to differences in the patient population with regard to baseline line levels of limb fat, racial background or other factors. At this time, the data from this trial is not available for inclusion in the meta-analysis.
Our data are consistent with previous studies demonstrating that patients receiving d4T or AZT have increased risks of lipoatrophy over time.26
Since regimens containing abacavir (ABC)/lamivudine (3TC) or tenofovir (TDF)/emtricitabine (FTC) are associated with lower risks of lipoatrophy, and have been shown in vitro
to have less mitochondrial toxicity, regimens excluding d4T and AZT are now recommended among patients initiating antiretroviral therapy.13,27
Among patients with established lipoatrophy, switching drug regimens from those containing d4T or AZT to either ABC or TDF may result in peripheral fat gain.28,29,30,31,32
However, since only 15 patients in the combined meta-analysis stopped d4T or AZT during the study period, this phenomenon is unlikely to have impacted changes in limb fat in our study.
Differences in the efficacy of TZD therapy among trials may have occurred because of disparities in the study populations at enrolment with respect to age, gender, baseline BMI, use of protease inhibitors, d4T and AZT and other ARVs, duration of ARV use, the presence or degree of insulin resistance or because of differences in changes in limb fat in the placebo group. In the two trials in which rosiglitazone increased limb fat, insulin resistance was an eligibility criterion21,22
as it was in a smaller, open-label study in which rosiglitazone increased limb fat in patients with HIV-associated lipoatrophy.33
In a sub-study in the Australian cohort, PPAR-γ expression in fat biopsies was not increased in subjects on thymidine analogues randomized to rosiglitazone either at week 2 or 48 but was increased in subjects not on thymidine analogues at week 2 in those on rosiglitazone and in both rosiglitazone and placebo groups at week 48.34
This would suggest that intact mitochondrial function could be required for TZD-induced stimulation of PPAR-γ expression in human adipose tissue.
The differential efficacy between pioglitazone and rosiglitazone could be due to in part to differences in dosing, the fact that the pioglitazone study was conducted several years later than the rosiglitazone studies, unmeasured differences in the patients enrolled in the pioglitazone study or biologic differences between the agents. For example, differential impacts of rosiglitazone and pioglitazone on adiponectin could have been associated with different limb fat outcomes. However, we were not able to assess this in our meta-analysis.
Rosiglitazone was associated with increases in triglycerides18,19
and total cholesterol18,19,21,
in several of the studies in the meta-analysis. In another study, rosiglitazone increased LDL cholesterol and decreased HDL cholesterol22
while pioglitazone has been shown to improve HDL cholesterol.23
There were few documented increases in liver transaminases among participants of these studies. In a meta-analysis of randomized trials of rosiglitazone for the treatment of type 2 diabetes in non HIV populations, a significant increase in the risk of myocardial infarction and a trend towards an increase in deaths due to cardiovascular causes was demonstrated.35
While we did not observe an increased risk of cardiovascular disease in this meta-analysis, many studies excluded patients at higher cardiovascular risk, the follow up period was short and our sample size was not large enough to rule out the possibility of this adverse event.
While use of d4T and AZT is still common in resource limited settings, the incidence of HIV lipoatrophy in the developed world is decreasing due to improved knowledge of strategies to avoid the development of this syndrome among patients on HAART. To date, trials in antiretroviral-naïve patients have shown a lower incidence of lipoatrophy with the use of abacavir or tenofovir but more long term follow up is necessary to determine whether they prevent, or simply slow the development of the problem.36
While d4T and AZT might be avoided in first-line regimens, it may be necessary to use one of these drugs later in disease due to toxicity, virologic failure or drug resistance. If this is the case, the development of lipoatrophy may just be deferred to a later stage of disease.
The relative contributions of other agents in the HAART combination are also unclear. In ACTG 5005s, initiation of efavirenz was associated with relative less loss of limb fat, compared with nelfinavir.12
In ACTG 5142, a randomized trial of nucleoside, non-nucleoside and protease inhibitor sparing regimens for initial HIV treatment, the risk of lipoatrophy was greater in those randomized to efavirenz than those randomized to lopinavir/r even after controlling for NRTI use.11
In our analysis, fat gains were greater in patients on efavirenz over time. Patients in the meta-analysis were treatment experienced, on stable ARV regimens with higher CD4 counts, lower viral load and lower baseline limb fat mass than patients in ACTG 5142. Patients in the meta-analysis were attempting to reverse loss of limb fat mass whereas patients in ACTG 5142 were experiencing initial loss of limb fat mass, which may explain the difference in findings. Further, our results must be interpreted with caution, as the effect of efavirenz was not an a priori hypothesis of interest, patients were not randomized to ARV treatments and the significant association between efavirenz and limb fat mass gain may be due to an unmeasured confounder.
Strengths of our study include the large sample size which increased the statistical power to test for interactions and conduct subset analyses, the availability of individual patient data, repeated measures of limb fat over time, inclusion of trials with different doses of TZD and a broader range of patient baseline characteristics than in any single trial.
These data and concerns about cardiovascular risk from studies in non HIV-infected populations37
suggest that the use of rosiglitazone for peripheral lipoatrophy is not justified. Further research on the use of pioglitazone is justified, as it may have a stronger and more significant impact on lipoatrophy, more favorable effects on lipids and no increased risk of cardiovascular events.38
More data are needed on the safety of this compound and investigation of populations that might benefit most from this treatment strategy. Moreover, further research is needed as to the cardiovascular effects of these insulin-sensitizing strategies, independent of effects on fat atrophy.