Five-Drug Early HIV Treatment Does Not Correct Inflammation or Immune Deficits

Starting five-drug antiretroviral therapy (ART) in the first months of infection did not quell HIV-associated inflammation in a 22-man randomized comparison with standard ART. Intensified ART had little impact on any blood or gut immune parameter.

Despite suppressive ART, T-cell activation and elevated markers or inflammation remain hallmarks of HIV infection and may contribute to adverse outcomes. Translocation of gut microbes into the bloodstream is a major driver of these early abnormalities. University of Toronto researchers conducted a substudy of a randomized double-blind trial to see whether adding raltegravir (Isentress) and maraviroc (Selzentry, Celsentri) to a standard three-drug regimen in the first months of HIV infection would correct these harmful changes.

The parent trial randomized recently infected men to receive standard doses of tenofovir disoproxil fumarate/emtricitabine (Truvada) plus lopinavir/ritonavir (Kaletra) with placebo or with raltegravir (400 mg twice daily) and maraviroc (150 mg twice daily). Intense ART for 48 weeks did not reduce the blood HIV reservoir.

A subset of 22 men infected within the past seven months volunteered to provide paired sigmoid colon biopsies and peripheral blood samples before starting ART and at treatment week 48. The researchers also recruited six healthy HIV-uninfected controls from the same community. From colon samples, the researchers measured CD8-cell activation, CD4 cells, CD4:CD8 ratio and three T-cell subsets (Th1, Th17, Th22). From peripheral blood, they isolated CD8 T-cells and markers of inflammation/translocation (IL-6, IL-10, IL-17, tumor necrosis factor, macrophage inflammatory protein [MIP]-1b, soluble CD14 [sCD14]) and coagulation (D-dimer).

HIV-positive men had been infected for a median of four months. The men receiving intense ART were nonsignificantly older than the men receiving standard ART (median 39 versus 29 years, P = .557) and slightly younger than HIV-negative controls (median 42 years). Time to viral suppression was similar with intense ART and standard ART (medians of 1.5 and 2.0 months, P = .753). The intense-ART and standard-ART groups did not differ in baseline peripheral blood measures (CD4 count, CD4:CD8 ratio, CD8-cell activation, soluble markers of inflammation/translocation). Nor did the two groups differ substantially in changes in those values over 48 weeks of ART.

Pre-ART CD8-cell activation in blood was almost 10-fold higher in the combined ART groups than in HIV-negative controls (20.6% versus 2.9%, P < .001). Activation in the combined ART groups dropped through 48 weeks of therapy but remained significantly higher than control levels (5.95%, P = .031). Blood levels of Th17 cells (which defend against bacteria and fungi) did not differ between the combined ART groups and HIV-negative controls -- or between the two ART groups at baseline or 48 weeks.

Markers of inflammation, translocation and coagulation in blood were higher at baseline in the combined ART groups than in controls. Only D-dimer (the coagulation marker) returned to normal during 48 weeks of ART. IL-10, IL-17 and MIP-1b declined with ART but did not return to normal. IL-6, IL-17 and sCD14 (the translocation marker) did not change with ART. Levels of tumor necrosis factor (an inflammation marker) were similar at baseline in the combined-ART group and in controls but increased significantly in the HIV group during ART.

Levels of gut immune markers (CD8-cell activation, CD4:CD8 ratio and percent CD4, Th1, Th17 and Th22 cells) were similar at baseline in the intense-ART group and the standard-ART group. Intense ART for 48 weeks did not significantly improve levels of these markers. CD8-cell activation in the gut was substantially higher in the combined ART groups than in controls, and activation levels did not return to normal with ART. Baseline percent of CD4 cells and CD4:CD8 ratio were significantly lower in the combined ART groups than in controls and did not return to normal through 48 weeks of ART. Frequencies of Th22 cells were significantly lower at baseline in the combined ART groups than in controls and returned nearly to normal with ART. Capacity of Th17 cells to produce cytokines was significantly lower in the combined-ART groups than in controls both before ART and after 48 weeks.

The researchers conclude that intensification of ART in early HIV infection has no additional benefit on blood or gut immune parameters. Substantially higher blood and gut immune activation in HIV-positive participants than in HIV-negative controls sometimes improved with 48 weeks of ART but did not return to normal. The authors cite a prior study showing that ART begun even in the earliest stages of HIV infection (Fiebig I-II) did not completely restore mucosal CD4 cells after two years.