Elevated markers of inflammation and coagulation declined toward normal during treatment for acute HIV infection in a 247-person study. But markers of fibrosis, monocyte activation and other disease signals remained above normal through 96 weeks of treatment.
Serious non-AIDS illnesses have emerged as leading causes of morbidity and mortality in people with antiretroviral therapy (ART)-induced HIV suppression. Markers of inflammation, coagulation and other processes predict some end-organ events and could provide valuable signals of non-AIDS illness in people responding to ART. Researchers at the U.S. National Institutes of Health and other centers hypothesized that starting ART "during the earliest stages of acute HIV infection would normalize levels of biomarkers associated with disease and death in chronic HIV infection."
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Participants were adults at high risk of HIV infection who screened positive for acute infection at a Bangkok clinic. Researchers collected samples from participants before ART began and through 96 weeks of ART. HIV-negative Thai volunteers matched by age and sex to acutely infected participants came from two ongoing studies. Chronically HIV-infected Thai participants were enrolled in a neurocognitive study or a natural history cohort.
Researchers measured biomarkers of inflammation (C-reactive protein [CRP], interleukin 6, soluble interleukin 6 receptor [sIL-6R], soluble gp130, tumor necrosis factor [TNF]), enterocyte turnover (intestinal fatty acid binding protein [I-FABP]), monocyte activation (soluble CD14 [sCD14]), coagulation cascade activation (D-dimer) and fibrosis (hyaluronic acid [HA]). The investigators compared marker levels between people with acute and chronic infection after 48 weeks of ART using linear regression adjusted for age and sex. They compared marker levels between people with acute infection and HIV-negative controls through 96 weeks.
The study included 78 people with acute HIV infection, 41 with chronic infection and 128 without HIV infection. Respective proportions of men were 92%, 59% and 77%, and median ages were 28, 29 and 27 years. Acutely infected people had been exposed to HIV for a median of 16 days (interquartile range 12 to 21).
Levels of the inflammation markers CRP, sIL-6R and TNF were elevated in acute infection compared with HIV-negative controls, as were levels of the enterocyte turnover marker I-FABP, the monocyte activation marker sCD14, the coagulation marker D-dimer and the fibrosis marker HA. I-FABP remained elevated with early ART, while levels of the inflammation markers TNF and sIL-6R and the coagulation marker D-dimer returned to normal with ART. Concentrations of some markers declined during ART but remained higher than in HIV-negative participants: the inflammation marker CRP, the monocyte activation marker sCD14 and the fibrosis marker HA.
In the acutely infected group, pretreatment levels of total HIV DNA and integrated peripheral blood mononuclear cell (PBMC) DNA decreased (to 1 and 0.1 log10 copies/million PBMCs) through 48 weeks of ART. Higher levels of plasma HIV RNA, total DNA and integrated PBMC DNA correlated with higher levels of sIL-6R, I-FABP, sCD14, D-dimer and HA. Higher integrated DNA in gut correlated with higher baseline sCD14, CRP and D-dimer. Low baseline peripheral CD4 count correlated with high CRP, while low sigmoid colon CD4 count correlated with high HIV RNA, sCD14 and HA.
During 24 weeks of treatment, increases in peripheral CD4 count were associated with falling levels of sCD14 and CRP. Declining D-dimer levels correlated with falling HIV RNA, total DNA in PBMCs and intestinal DNA. The authors propose that these changes "suggest an association of the coagulation cascade with HIV burden and of gut damage and persistent inflammation with slow CD4 T-cell recovery."
The authors summarized their comparison of acutely infected, chronically infected and HIV-negative participants in five points: (1) acute HIV infection increases markers of inflammation, intestinal damage, coagulation and fibrosis; (2) the procoagulant (clot-inducing) state of acute HIV infection returns to normal with ART; (3) enterocyte damage persists despite suppressive ART; (4) systemic inflammation, monocyte activation and fibrosis remain higher during treated acute infection than in HIV-negative people but lower than in people treated during chronic infection; and (5) a rising CD4 count correlates with decreases in sCD14 (monocyte activation) and CRP (inflammation). The researchers suggest that additional immunomodulatory therapies during acute infection may be needed to avoid the long-term consequences of infection that ART cannot reverse.