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Attacking Lipodystrophy
David Alain Wohl, MD - University of North Carolina AIDS Treatment and Research Center
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No magic pills, injections, ointments or bullets for the treatment of fat redistribution problems were announced at the 9th CROI, in fact, there were only a handful of presentations regarding interventions for lipodystrophy at the conference - this despite increasing concern about fat changes among those living with HIV and the threat body shape perturbations pose to antiretroviral adherence. Switch studies received the lion's share of the attention (see NATAP report: Switching Antiretroviral Therapy for Lipoatrophy) but other studies did evaluate approaches not involving the alteration of antiretroviral regimens. This is important as some persons experiencing disfiguring fat changes are reluctant or unable to modify their HIV therapy.
Rosiglitazone is a diabetes drug that holds promise as a potential therapy for fat accumulation and wasting. There is a theoretical basis for this expectation as the drug and others in its class improve insulin resistance, which is associated with fat accumulation in the setting of HIV, and laboratory data indicating these agents can act on fat cells themselves. There is also some very, very limited preliminary evidence of positive fat changes in HIV-infected persons with lipodystrophy treated with troglitazone, a related but more toxic drug and pioglitazone, a sister drug which is also approved for treatment of type-2 diabetes. The most striking data regarding these agents and improvements in fat comes from a single arm study of HIV-negative diabetics with lipoatrophy treated with troglitazone (Arioglu E, et al. Ann Intern Med 2000;133:263-274).
Here in Seattle, results of a small study from Finland (J. Sutinen, et al. Abstr LB13) were presented in which 30 subjects with HIV, no evidence of diabetes and experiencing abdominal fat accumulation were randomized to receive 8 mg of rosiglitazone daily or placebo for 6 months. MRI of the abdomen was used to assess subcutaneous and visceral fat changes. Proton spectroscopy was used to evaluate liver fat content. DEXA scans were not done. After 24 weeks, there was no significant differences in the change in visceral fat, abdominal subcutaneous fat, waist to hip ratio or serum leptin between study arms. Serum insulin did significantly decrease in the rosiglitazone group from 13 (+2) mU/L at baseline to 9 (+1) mU/L at week 24 compared to 10 (+2) mU/L to 16 (+6) mU/L in the control arm. Serum triglycerides modestly but unexpectedly increased among those taking rosiglitazone. The percentage of liver fat also decreased significantly among the treated subjects.
What these results mean is unclear. The study was very small and clearly underpowered to detect important differences in fat between the two study arms. In addition, only the abdomen was evaluated while fat changes can occur in other places above and below the belt. Rigorous evaluation of rosiglitazone is being conducted in other studies around the globe including two sponsored by the U.S. AIDS Clinical Trials Group (ACTG): protocol A5082 looking specifically at fat accumulation of the abdomen in patients also with elevated insulin levels and protocol A5154 examining the drug for treatment of fat wasting among those with lipoatrophy of the face and arms. These studies are likely to be the last word on the utility of this agent for fat redistribution problems affecting those with HIV infection. (In the spirit of full disclosure, it should be noted that this author is the chair of the ACTG A5154 study.)
Another diabetes drug, metformin, has also been considered a potential treatment for fat redistribution. Previous study of metformin has demonstrated reductions in abdomen fat when administered to HIV-positive subjects with high blood insulin levels. Martinez and colleagues (Abstr 702-T) compared metformin with gemfibrozil, a medication that lowers triglyceride and LDL cholesterol levels and increases HDL cholesterol, in 66 subjects with fat accumulation at the abdomen and triglyceride levels above 200 mg/dL. Subjects were randomized to metformin 850 mg twice a day or gemfibrozil 600 mg twice a day or placebo. Fat changes were assessed using ultrasound, which the investigators have described previously but which is not a widely used or accepted technique. The bottom line of this study is that there were no differences between the treatment arms and placebo control arm as far as subcutaneous or intra-abdominal fat, lipids, weight, fat-free mass or fat by BIA or insulin resistance. Again, this was an ambitious study involving relatively few subjects. The finding that gemfibrozil had no more effect on reducing triglycerides than metformin or placebo is surprising (if not bizarre) even with the continuation of antiretroviral therapy.
Niacin, a drug used to treat high LDL and low HDL cholesterol, was studied in a group of 16 HIV-infected subjects to examine its effects on intra-abdominal fat (J. Fessel and S. Follansbee, Abstr 703-T). The authors had previously noted that patients with increased intra-abdominal fat had low HDL cholesterol levels. Therefore, they looked at the use of open-label niacin (median dose 3000 mg/day) among patients with fat accumulation at the abdomen. Overall, intra-abdominal fat was reported to have decreased by 17% (CI, -33% to 0.8%) by about 6 months of treatment as assessed by a single slice CT scan at L2 (this is higher up the abdomen than is typically used). Decrease of intra-abdominal fat was associated with rises in HDL and decreased ratio of total cholesterol to HDL. Two subjects had mildly increased fasting blood glucose levels and two discontinued niacin due to its ability to induce skin flushing. There was no report on any changes in diet, exercise or antiretroviral therapy during the study. One would expect these patients to have considered (or at least been advised to consider) lifestyle modifications given their generally high cholesterol levels at baseline (258 mg/dL). The contribution of niacin to diabetes development has limited the application of this drug to treatment of protease inhibitor treated patients. Further study of this agent, perhaps with a better-tolerated slow-release formulation is warranted given these preliminary results.
Lastly, if you have not heard about Newfil, you probably do not have facial fat wasting. This French product, made of polylactic acid, is injected into the dermis of the skin where it fills out the hollows of the cheeks. It breaks down in the skin to purportedly benign byproducts and has to be re-injected about every two weeks. The authors present data on 16 patients treated in each cheek with the substance 4 to 5 times. Results among those treated were generally good with self-reported improvements in facial lipoatrophy. In addition, using a sophisticated camera system and software designed to calculate surface area and volume gains at the cheeks, the investigators detected increases in volume following the injections. The procedures were generally well tolerated with mild edema of the face usual for 48 to 96 hours after each injection. Many persons with this complication are following the Newfil story with interest. Obviously, few people have been treated and questions about its long-term effects and its safety need to be addressed before we can even start to think about what this stuff will cost and who will pay for it.
Overall, the interventions proposed, while sometimes novel, were studied in small numbers of patients making it difficult to have tremendous faith in many of the conclusions reported. Clearly, we need bigger and better studies to provide the answers we need right now to prevent and treat fat redistribution. Hopefully, before next year's conference we will begin to see the fruits of such investigations.
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