Background:  There is no clinically effective therapy for HIV lipodystrophy except switching from thymidine nucleoside analogue (NRTI) therapy. Thiazolidinediones such as rosiglitazone (RSG) promote subcutaneous fat growth, decrease visceral fat, and improve glycemic and lipid parameters in type 2 diabetics and in adults with congenital LD, and reverse protease inhibitor (PI) toxicity to adipocytes in vitro.

Methods:  HIV⁺ lipoatrophic adults on stable antiretroviral therapy were randomized to RSG 4 mg bid (n = 53) or placebo (n = 55) for 48 weeks, stratified by current PI use, lipoatrophy severity, and clinic. The study had 80% power to detect a 0.5-kg difference in limb fat (the primary endpoint, using DEXA) between groups at week 48 by intention-to-treat analysis.

Results:  Limb fat increased by 0.14 kg in the RSG group and 0.18 kg in the placebo group at week 48 (mean difference, -0.04 [95%CI, -0.29, 0.21] kg; p = 0.74 by rank-sum test), with 3 patients (1 RSG, 2 placebo) lost to follow-up. There was no benefit of RSG on:  subcutaneous thigh fat (p = 0.61), subcutaneous abdominal fat (p = 0.68), or visceral fat (p = 0.25) areas on computed tomography; total fat mass (p = 0.89), lean body mass (p = 0.46), or lipodystrophy severity (both objective [p = 0.99] and subjective [p = 0.42]); and the prevalence of overall lipodystrophy and buffalo hump.  Llimb fat failed to improve despite significant increases at week 48 in plasma adiponectin (4.1 mmol/L [101%]; p <0.0001) but not leptin (0.2 mmol/L [6%]; p = 0.33), and significant (p = 0.01 - 0.02) decreases in 3 markers of insulin resistance with RSG. No subgroup, defined by PI use, thymidine NRTI use, limb fat mass, or insulin resistance at baseline, derived benefit for limb fat with RSG. In each arm, 6 patients discontinued the study drug, 2 per arm for adverse events attributed to study drug. The key adverse effects of RSG were asymptomatic hypertriglyceridaemia (mean peak increase, 1.5 mmol/L [58 mg/dL; 40%] at week 8; +0.9 mmol/L [35 mg/dL] at week 48; p = 0.007) and hypercholesterolaemia (mean peak increase 1.9 mmol/L [170 mg/dL] at week 8; +1.5 mmol/L [132 mg/dL; 16%] at week 48; p = 0.0001). RSG had no significant effect on viral load or CD4 counts.

Conclusions:  RSG 4 mg bid for 48 weeks did not improve lipoatrophy in HIV-infected adults receiving antiretroviral therapy, despite significantly improving insulin sensitivity and plasma adiponectin levels.

Keywords: lipodystrophy; therapy; rosiglitazone