Switching to a Protease Inhibitor-containing, Nucleoside-sparing Regimen (lopinavir/ritonavir Plus Efavirenz) Increases Limb Fat But Raises Serum Lipid Levels: Results of a Prospective Randomized Trial (aids Clinical Trial Group 5125s)

The impressive success of antiretroviral therapy (ART) in reducing the morbidity and mortality associated with HIV disease has been tempered by frequent toxicities associated with chronic ART use. Lipid abnormalities, insulin resistance, increased cardiovascular risk, and lipodystrophy have been reported.1 Lipodystrophy refers to body fat distribution changes that occur after the initiation of ART. Two distinct components have been described: limb fat atrophy (lipo-atrophy) and trunk and visceral fat accumulation. Limb lipoatrophy has become a common distinguishing characteristic associated with HIV and its treatment.2,3 This complication can profoundly affect the well-being of the patient, can be stigmatizing, and can be coincident with a cluster of metabolic complications. Longitudinal studies evaluating the effect of ART initiation have demonstrated that within weeks of initiating ART, lean body mass and limb and trunk fat mass increase.4,5 With continued treatment for more than a year, limb fat mass slowly and progressively declines, whereas the gain in trunk fat mass is maintained.4,6,7 Patient-related factors that are associated with progressive limb fat mass loss include age,8,9 white race, female gender,7 low nadir CD4+ cell count, hepatitis C virus (HCV) coinfection,9–12 and specific polymorphisms in the tumor necrosis factor-α (TNFα) and ApoC3 genes.13 Treatment-related factors that may also contribute include exposure to stavudine (d4T)14 and, potentially, zidovudine (ZDV). Protease inhibitors (PIs) were initially thought to play a significant role in the development of lipoatrophy,15 but subsequent data have also implicated the nucleoside reverse transcriptase inhibitors (NRTIs).16,17 Some authors have suggested that PIs may contribute to the development of osteopenia or osteoporosis associated with HIV or its treatment,18 fat accumulation and lipid abnormalities,19 and glucose intolerance or diabetes.20 Effective interventions for managing HIV lipoatrophy have not been identified. Several studies report that substituting the PI component of ART does not improve or reverse limb lipoatrophy.21 Treatment with the peroxisome proliferator-activated receptor-γ (PPARγ) agonist rosiglitazone seemed to increase limb fat mass in patients with HIV-associated lipoatrophy,22 but these findings were not confirmed in a large prospective randomized trial.23 Pioglitazone was only modestly active in improving subcutaneous fat in the extremities.24 Switching d4T or ZDV to abacavir (ABC) or tenofovir (TDF) has been reported to increase limb fat mass,25–28 however, with a decrease of limb lean mass in a study by Boyd et al.28 Switching to regimens without NRTIs increased mitochondrial DNA content in fat and peripheral blood mononuclear cells,28 a potential mechanism implicated in the development of lipoatrophy.29 If osteopenia or osteoporosis, fat accumulation, lipid abnormalities, and insulin resistance are linked to PI use, the expectation would be that clinical improvements should occur after switching to alternative regimens that do not include these drugs. In the AIDS Clinical Trials Group (ACTG) A5125s, we examined the effects of PI-containing NRTI-sparing and NRTI-containing PI-sparing regimens on fat distribution, changes in bone mineral density (BMD), and metabolic parameters in patients who switched their currently successful antiretroviral regimen to a PI-sparing or NRTI-sparing regimen. The primary objective was to quantify the changes in limb fat mass (using regional dual-energy x-ray absorptiometry [DEXA]) within and between each of the 2 treatment arms. The secondary objectives were to quantify changes in fasting lipids (high-density lipoproteins [HDLs], low-density lipoproteins [LDLs], total cholesterol, and triglycerides), fasting glucose, insulin, the homeostasis model assessment of insulin resistance (HOMA-IR), hip and spine BMD, and serum markers of bone metabolism after switching ART; to examine relations between changes in regional fat, lipids, and insulin resistance; and to examine relations between baseline demographic variables, CD4+ lymphocyte cell counts, body mass index (BMI), limb fat mass, and changes in indices of glucose metabolism, lipids, and bone metabolism after switching ART.