Microbial Translocation Does Not Drive Immune Activation in Ugandan Children Infected With HIV

Abstract

ObjectiveImmune activation is associated with morbidity and mortality during human immunodeficiency virus (HIV) infection, despite receipt of antiretroviral therapy (ART). We investigated whether microbial translocation drives immune activation in HIV-infected Ugandan children.MethodsNineteen markers of immune activation and inflammation were measured over 96 weeks in HIV-infected Ugandan children in the CHAPAS-3 Trial and HIV-uninfected age-matched controls. Microbial translocation was assessed using molecular techniques, including next-generation sequencing.ResultsOf 249 children included, 142 were infected with HIV; of these, 120 were ART naive, with a median age of 2.8 years (interquartile range [IQR], 1.7–4.0 years) and a median baseline CD4+ T-cell percentage of 20% (IQR, 14%–24%), and 22 were ART experienced, with a median age of 6.5 years (IQR, 5.9–9.2 years) and a median baseline CD4+ T-cell percentage of 35% (IQR, 31%–39%). The control group comprised 107 children without HIV infection. The median increase in the CD4+ T-cell percentage was 17 percentage points (IQR, 12–22 percentage points) at week 96 among ART-naive children, and the viral load was <100 copies/mL in 76% of ART-naive children and 91% of ART-experienced children. Immune activation decreased with ART use. Children could be divided on the basis of immune activation markers into the following 3 clusters: in cluster 1, the majority of children were HIV uninfected; cluster 2 comprised a mix of HIV-uninfected children and HIV-infected ART-naive or ART-experienced children; and in cluster 3, the majority were ART naive. Immune activation was low in cluster 1, decreased in cluster 3, and persisted in cluster 2. Blood microbial DNA levels were negative or very low across groups, with no difference between clusters except for Enterobacteriaceae organisms (the level was higher in cluster 1; P < .0001).ConclusionImmune activation decreased with ART use, with marker clustering indicating different activation patterns according to HIV and ART status. Levels of bacterial DNA in blood were low regardless of HIV status, ART status, and immune activation status. Microbial translocation did not drive immune activation in this setting.Clinical Trials RegistrationISRCTN69078957.

Effect of Stopping Cotrimoxazole Preventive Therapy on Microbial Translocation and Inflammatory Markers Among Human Immunodeficiency Virus–Infected Ugandan Adults on Antiretroviral Therapy: The COSTOP Trial Immunology Substudy

“…We did not assess systemic drug concentrations of both ART and CPT in this study. While microbial translocation was shown to increase immune activation in cross-sectional studies in HIV-infected patients from the United States [ 11 ], studies in African populations did not show such association [ 21 , 22 ].…”

Biological Aging and Immune Senescence in Children with Perinatally Acquired HIV

“…However, another study on a cohort of perinatally HIV-infected children [137] showed that ART initiation normalized sCD163 (marker of monocyte activation) levels and improved long-term pediatric outcomes. A recent study [138] agreed that immune activation decreases over time in children after starting ART, which does not have adverse effects itself on microbial translocation.…”

Daily variations of gut microbial translocation markers in ART-treated HIV-infected people

“…Measurement of microbial translocation plasma markers have been frequently performed in studies evaluating therapeutic interventions and assessing the risk of developing non-AIDS co-morbidities [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]. Circulating levels of lipopolysaccharide (LPS) are commonly measured to assess the level of bacterial translocation.…”