Impact of intensified antiretroviral therapy during early HIV infection on gut immunology and inflammatory blood biomarkers.

ABSTRACT

OBJECTIVE: Standard antiretroviral therapy (ART) is slow to reverse gut mucosal immune defects that cause persistent inflammation and immune activation. We examined whether intensifying early-administered ART through the addition of maraviroc and raltegravir would accelerate their resolution. DESIGN: ART-naïve men with early HIV infection were randomized in a double-blind manner to receive ART (emtricitabine/tenofovir disoproxil fumarate + lopinavir/ritonavir), together with either combined placebo or raltegravir + maraviroc, for 48 weeks. In a predefined substudy, paired blood and sigmoid biopsies were collected at baseline and week 48. Mucosal CD4 T-cell immune subsets (Th1, Th17, and Th22 cells), CD8 T-cell immune activation, and soluble blood markers of inflammation (IL-6, IL-17, macrophage inflammatory protein-1b, soluble CD14, and IL-10) and coagulation (D-dimer) were measured. RESULTS: A total of 22 participants were enrolled, a median of 4 months after HIV acquisition. At baseline, there was substantial systemic and mucosal immune activation, and gut CD4 T-cell numbers, Th22 cell numbers, and Th17 cell function were reduced compared with controls. Early ART restored gut Th22 numbers, improved but did not restore overall CD4 numbers, and had no impact on Th17 function. Plasma levels of soluble CD14 and D-dimer normalized, whereas other inflammatory cytokines were reduced but not normalized. ART intensification had no impact on any blood or gut immune parameters. CONCLUSION: Early HIV infection causes substantial mucosal and systemic immune activation, and gut CD4 T-cell dysfunction. One year of ART improved but did not normalize most parameters, regardless of intensification with raltegravir and maraviroc, and did not restore mucosal Th17 function.