Changes in Insulin Resistance After Initiation of Raltegravir or Protease Inhibitors With Tenofovir-Emtricitabine: AIDS Clinical Trials Group A5260s

Abstract

Background. Antiretroviral therapy (ART) can alter glucose metabolism, but little data exist on the association of raltegravir (RAL) with insulin resistance. Methods. A5260s was a substudy of A5257, a prospective open-label randomized trial in which human immunodeficiency virus (HIV)-infected treatment-naive participants were randomized to tenofovir-emtricitabine (TDF/FTC) plus atazanavir-ritonavir (ATV/r), darunavir-ritonavir (DRV/r), or RAL over 96 weeks. Baseline and changes in insulin resistance as estimated by the homeostatic model assessment of insulin resistance (HOMA-IR) were assessed. Wilcoxon rank-sum tests were used to assess shifts in the distribution of fold increase from baseline between treatment arms, and Spearman correlation was used to assess associations between HOMA-IR and measures of inflammation and body composition. Results. Three hundred twenty-eight participants were randomized; 90% were male, baseline median age was 36, HIV ribonucleic acid copies were 4.55 log₁₀ copies/mL, and CD4 cell count was 349/mm³. Overall, HOMA-IR increased significantly after 4 weeks (1.9-fold change; 95% confidence interval, 1.73-2.05) then plateaued over the remainder of the study. Changes in HOMA-IR were not different between the arms (P ≥ .23). Changes in HOMA-IR were associated with changes in body mass index at weeks 48 and 96 (r = 0.12-0.22; P ≤ .04). There was a trend with increases in HOMA-IR and increases in visceral abdominal fat at week 96 (r = 0.12; P = .06). At 48 and 96 weeks, HOMA-IR correlated with interleukin-6, high-sensitivity C-reactive protein, and soluble CD163 (r = 0.16-0.27; P ≤ .003). Conclusions. Insulin resistance increased rapidly and then plateaued in treatment-naive participants initiating ART with TDF/FTC, and no differences were found with RAL when compared with ATV/r or DRV/r.

Keywords: inflammatory markers; insulin resistance; raltegravir.

Figure 1.

Changes in homeostatic model assessment of insulin resistance (HOMA-IR) over time by treatment arm. Median fold change in HOMA-IR from baseline by treatment arm. Error bars represent interquartile range (IQR). Abbreviations: ATV/r, atazanavir-ritonavir; DRV/r, darunavir/ritonavir; RAL, raltegravir.

Figure 2.

Association between change in homeostatic model assessment of insulin resistance (HOMA-IR) and change in fat depot. Median fold change from baseline between HOMA-IR and visceral fat. Error bars represent interquartile range (IQR). Abbreviation: VAT, visceral adipose tissue.

Figure 3.

Changes in homeostatic model assessment associated with changes in body mass index (BMI). Median fold change from baseline between homeostatic model assessment of insulin resistance (HOMA-IR) and BMI. Error bars represent interquartile range (IQR).