Lower Pretreatment Gut Integrity Is Independently Associated With Fat Gain on Antiretroviral Therapy

Abstract

Background: Fat accumulation and insulin resistance remain a threat to the success of antiretroviral therapy (ART). The role of gut dysfunction in metabolic complications associated with ART initiation is unclear.

Methods: Human immunodeficiency virus (HIV)-infected ART-naive participants were randomized to tenofovir disoproxil fumarate/emtricitabine plus atazanavir/ritonavir, darunavir/ritonavir, or raltegravir (RAL). Changes in the gut integrity markers zonulin, lipopolysaccharide-binding protein (LBP), and intestinal fatty acid and ileal bile acid binding proteins (I-FABP and I-BABP) were assessed over 96 weeks. Wilcoxon rank-sum tests were used to compare changes between groups and linear regression models to quantify associations between gut markers, insulin resistance, body mass index (BMI), and visceral, subcutaneous, and total adipose tissue (VAT, SAT, and TAT).

Results: : 90% were male and 48% were White non-Hispanic. The median age was 36 years, HIV-1 ribonucleic acid was 4.56 log10 copies/mL, and CD4 count was 338 cells/µL. An overall 1.7-fold increase in I-FABP was observed throughout 96 weeks, with no difference between arms. Zonulin levels increased with RAL compared to protease inhibitor-based regimens (week 96, P = .02); minimal changes in I-BABP or LBP levels were observed. Higher baseline I-FABP levels were associated with increases in VAT, TAT, and BMI (16%, 9%, and 2.5%, respectively; P < .04) over 96 weeks.

Conclusions: While ART induces changes in the markers of gut barrier dysfunction, the extent to which they improve or worsen the gut barrier function remains unclear. Nevertheless, markers of gut barrier dysfunction in ART-naive individuals predict increases in total and visceral abdominal fat with treatment initiation.

Keywords: body composition; gut integrity; microbial translocation.

Figure 1.

Changes in gut integrity markers over time by treatment arm. Median fold change in gut integrity markers from baseline by treatment arm. Abbreviations: ATV/r, atazanavir-ritonavir; DRV/r, darunavir/ritonavir; I-BABP, ileal bile-acid binding proteins; I-FABP, intestinal fatty acid binding proteins; LBP, lipopolysaccharide-binding protein; RAL, raltegravir.

Figure 2.

Associations among gut integrity markers at different study points. Heat map illustrating the associations between gut integrity markers at different time points. Blue indicates negative correlations, and red indicates positive correlations. Only correlations reaching statistical significance (P ≤ 0.05) are included in the figure. Abbreviations: I-BABP, ileal bile-acid binding proteins; I-FABP, intestinal fatty acid binding proteins; LBP, lipopolysaccharide-binding protein.

Figure 3.

Associations between gut integrity markers and markers of inflammation and immune activation. D-dimer and IL-6 were not assessed at week 24. Abbreviations: HLADR, human leukocyte antigen DR; hsCRP, high-sensitivity C-reactive protein; I-BABP, ileal bile-acid binding proteins; I-FABP, intestinal fatty acid binding proteins; IL, interleukin; LBP, lipopolysaccharide-binding protein; MNC, monocyte; sCD, soluble cluster of differentiation.