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Pioglitazone Improved Limb Lipoatrophy
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Jules Levin
13th CROI, Denver, feb 5-8, 2006
Several notes of interest from reading abstract program book at CROI but of course official presentation is still to come:
Pioglitazone 30 mg once daily for 48 weeks improved limb lipoatrophy in ART-treated HIV-infected patients; this effect was not seen in patients exposed to d4t; pioglitazone did not alter lipid parameters except for HDL cholesterol that was increased; authors concluded, these results support the use of pioglitazone for the treatment of HIV-related lipoatrophy. 130 patients with HIV-associated lipoatrophy were randomized to pioglitazone 30 mg once daily or placebo for 48 weeks. The primary endpoint was change in limb fat as evaluated by DEXA.Limb fat increased by 0.38 kg in the PIO group and 0.05 kg in the placebo group at week 48, p=0.051. In patients not receiving d4t, an increase of 0.45 vs 0.04 kg was observed, p=0.013, but not in patients on d4t. Overall, there was no significant difference in subcutaneous abdominal fat or in visceral fat areas on computed tomography at L4 vetebra. Improvement in thigh circumference (+1.4 cm vs 0.2, p=0.017) and tricipital skin-fold thickness (+0.9 mm vs 0.4, p=0.047) were also observed in the PIO group. However, the patients perceived no improvement. The lipid profile was not significantly different between the 2 groups at week 48 except for HDL cholesterol which was improved in the PIO group (+0.08 mmol/L vs -0.08, p=0.005). There were 16 adverse events, 10 in the PIO group and 6 in the placebo group. LB151
DAD Study finds increased PI exposure is associated with an increased risk of myocardial infarction, partly due to dyslipidemia, no evidence of increased NNRTI exposure associated with risk of MI. abs 144
3-year followup of carotid intima-media thickness in HIV+ & uninfected adults (ACTG 5078). Neither HIV infection nor PI exposure significantly affected rate of progression of carotid IMT over 3 years of followup. Judith Currier et al concluded that these results suggest that 'classic' coronary heart disease risk factors play a more significant role than ART in the increased incidence of cardiovascular events observed in HIV-infected individuals. Individuals were excluded from study if they had or had a family history of coronary artery disease, diabetes, uncontrolled hypertension, or a body mass index >30. Three study groups: HIV+ with continuous use of PIs doe >2 yrs, HIV+ without prior PI use, and HIV+. abstract 145
Fish oil is an effective and safe agent in the treatment of ART-associated hypertriglyceridemia even though the majority of subjects did not reach triglycerides <200 mg/dl. Fish oil 3g (1500 mg elcosapentaeonoic acid + 910 mg docasahexaenoic) reduced triglycerides by a median of 46% and fenofibrate 160 mg once daily reduced triglycerides by 58% after 8 weeks. Baseline TG were 662 & 694 mg/dL, respectively. Of 47 subjects on fish oil, 4 (8.5%) and of 48 on fenofibrate, 8 (16.7%) achieved TG <200. Nonresponders (not achieving <200 TG) entered second part of study where they received fish oil + fenofibrate. The combination further decreased TG & and response rate increased to 22.7%. The median decrease in TG from baseline to week 18 was 65% for subjects participating in step two. Fish oil was well tolerated and only 1subject discontinued fish oil because of side effects and 3 subjects discontinued the combination because of side effects. Subjects on fish oil participated in an immunological study evaluating changes in antigen-specific lymphocyte proliferation assays (LPA). Fish oil had no significant effect on CD4 count, CD4%, and LPA for cytomegalovirus, Candida, or PHA. Fish oil had no effect on trough concentrations of lopinavir, the most commonly used PI. abstract 146
Metformin did not show a benefit on fat redistribution or dyslipidemia in HIV+ persons with lipodystrophy & normal glucose tolerance. There was an unexpected trend towards reduction in appendicular fat mass; metformin should be used with caution in HIV-associated lipodystrophy, and if used should be reserved for persons with impaired glucose tolerance, the study authors concluded. 48 patients were randomized to metformin 1500 mg daily or placebo for 24 weeks. After 24 weeks in this studyThere was no significant change in visceral adipose tissue, nor did metformin change TG, LDL or HDL. Metformin was associated with a trend towards decreased appendicular fat mass (-614.0 vs 95.3 kg, p=0.12). abs 148
Neither rosiglitazone alone, metformin alone, nor the combination significantly changed abdominal visceral or subcutaneous adipose tissue over 16 weeks, but significant dose reductions and discontinuations in the metformin arm may have affected these results; rosiglitazone increased lower extemity fat compared to placebo, study authors concluded. ACTG Study 5082 assessed the effects of metformin (500 mg twice daily, increasing to 1000 mg twice daily) and rosiglitazone 4 mg once daily alone and in combination vs placebo in a randomized, blinded 16-week study in HIV+ subjects with elevated waist-to-hip ratio (>0.95 for men and 0.85 for women; or waist circumference >100 cm) and hyperinsulinemia (>15uIU/mL or 2-hr glucose >140 mg/dL post-oral glucose tolerance test and fasting insulin >10 uIU/mL). 105 patients were randomized to metformin/rosiglitazone placebo, n=26, rosiglitazone/metformin placebo, n=27, metformin/rosiglitazone, n=25, or dual placebo, n=27. 91 subjects completed the study. Premature discontinuation of study drug was significantly greater in metformin/rosiglitazone placebo group, n=12, than other groups (rosi/met plac, n=3; met/rosi, n=4; dual plac, n=8; p=<0.02). Diarrhea was more common in metformin groups (65% in met/rosi plac & 52% in met/rosi; 8% in rosi/met plac & 15% in dual plac; p<0.001).
There were no significant differences among groups in changes in visceral and subcutaneous adipose tissue. Changes in trunk, upper extremity, and total extremity fat were also not significant among groups. Lower extremity fat increased significantly in the rosiglitazone group compared to placebo (+4.8 vs -8.3%, p=0.034), but not in the combined group or metformin group vs placebo. abs 147
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