Glucose metabolism, lipid, and body fat changes in antiretroviral-naive subjects randomized to nelfinavir or efavirenz plus dual nucleosides
ABSTRACT To determine if particular components of antiretroviral drug regimens are associated with greater insulin resistance, dyslipidemia, and peripheral lipoatrophy.
Metabolic and body composition variables were measured prospectively over 64 weeks in 334 antiretroviral-naive, HIV-infected subjects who were randomized to receive nelfinavir, efavirenz, or both, combined with zidovudine/lamivudine or didanosine/stavudine in a factorial design, multicenter trial. Subjects assigned to efavirenz (n = 110) were compared with those assigned to nelfinavir (n = 99); subjects assigned to zidovudine/lamivudine (n = 154) were compared with those assigned to didanosine/stavudine (n = 180). A subset of 157 subjects had serial dual-energy X-ray absorptiometry (DEXA) scans.
Lipid measures increased in all groups. Greater increases in high density lipoprotein (HDL) cholesterol occurred with efavirenz than with nelfinavir. Greater increases in total cholesterol, non-HDL cholesterol and HDL cholesterol occurred with stavudine and didanosine than with zidovudine/lamivudine. There were no differences in insulin resistance in the comparisons. After initial increases in the first 16 weeks, median limb fat decreased. Greater changes in percentage changes in limb fat occurred with didanosine/stavudine (-16.8%) than with zidovudine/lamivudine (+4.0%; P < 0.001 for overall change from baseline) and with nelfinavir (-13.1%) compared with efavirenz (+1.8%; P = 0.003).
Over 64 weeks, all regimens were associated with increases in lipids but insulin resistance did not differ between groups. Regimens containing didanosine/stavudine and regimens containing nelfinavir were associated with greater loss of limb fat.
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ABSTRACT: Highly active antiretroviral therapy (HAART)-associated metabolic complications include lipoatrophy (loss of subcutaneous adipose tissue (SAT)) and insulin resistance. Thiazolidinediones are insulin-sensitizing antidiabetic agents which-as an untoward side effect in obese diabetic patients-increase SAT. Furthermore, troglitazone has improved lipoatrophy and glycemic control in non-HIV patients with various forms of lipodystrophy. These data have led to 14 clinical trials to examine whether thiazolidinediones could be useful in the treatment of HAART-associated metabolic complications. The results of these studies indicate very modest, if any, effect on lipoatrophic SAT, probably due to ongoing HAART negating the beneficial effect. The benefit might be more prominent in patients not taking thymidine analoges. Despite the poor effect on lipoatrophy, thiazolidin-ediones improved insulin sensitivity. However, especially rosiglitazone induced harmful effects on blood lipids. Current data do not provide evidence for the use of thiazolidinediones in the treatment of HAART-associated lipoatrophy, but treatment of lipoatrophy-associated diabetes may be warranted. The role of thiazolidinediones for novel indications, such as hepatosteatosis, should be studied in these patients.PPAR Research 02/2009; 2009(1687-4757):373524. DOI:10.1155/2009/373524 · 1.64 Impact Factor
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ABSTRACT: HIV-associated lipodystrophy, arising as a result of long-term therapy with antiretroviral medications, is a complex syndrome characterized by changes in regional fat mass, dyslipidemia, and insulin sensitivity that, once established, is difficult to reverse. The syndrome arises largely as a result of effects of nucleoside reverse transcriptase inhibitors and protease inhibitors on lipid metabolism. Many of these effects have their basis at a molecular level with nucleoside reverse transcriptase inhibitors linked to inhibition of mitochondrial RNA transcription, depletion of mitochondrial DNA and mitochondrial dysfunction and protease inhibitors linked with adipocyte toxicity through interference with the function of essential cellular transcription factors such as sterol regulatory element binding protein 1c. These molecular toxicities can affect non-adipose tissues, and together with secondary effects on lipid and glucose metabolism of changes in body fat mass, help to contribute to the dyslipidemia and insulin resistance characteristic of this syndrome. This review will summarize what is known of the molecular mechanisms underlying HIV-associated lipodystrophy. A greater understanding of these mechanisms is essential if effective therapeutic options are to be found.AIDS reviews 9(1):3-15. · 4.02 Impact Factor