Baseline Inflammatory Biomarkers Identify Subgroups of HIV-Infected African Children With Differing Responses to Antiretroviral Therapy

Abstract

Background: Identifying determinants of morbidity and mortality may help target future interventions for human immunodeficiency virus (HIV)-infected children.

Methods: CD4(+) T-cell count, HIV viral load, and levels of biomarkers (C-reactive protein, tumor necrosis factor α [TNF-α], interleukin 6 [IL-6], and soluble CD14) and interleukin 7 were measured at antiretroviral therapy (ART) initiation in the ARROW trial (case-cohort design). Cases were individuals who died, had new or recurrent World Health Organization clinical stage 4 events, or had poor immunological response to ART.

Results: There were 115 cases (54 died, 45 had World Health Organization clinical stage 4 events, and 49 had poor immunological response) and 485 controls. Before ART initiation, the median ages of cases and controls were 8.2 years (interquartile range [IQR], 4.4-11.4 years) and 5.8 years (IQR, 2.3-9.3 years), respectively, and the median percentages of lymphocytes expressing CD4 were 4% (IQR, 1%-9%) and 13% (IQR, 8%-18%), respectively. In multivariable logistic regression, cases had lower age-associated CD4(+) T-cell count ratio (calculated as the ratio of the subject's CD4(+) T-cell count to the count expected in healthy individuals of the same age; P < .0001) and higher IL-6 level (P = .002) than controls. Clustering biomarkers and age-associated CD4(+) and CD8(+) T-cell count ratios identified 4 groups of children. Group 1 had the highest frequency of cases (41% cases; 16% died) and profound immunosuppression; group 2 had similar mortality (23% cases; 15% died), but children were younger, with less profound immunosuppression and high levels of inflammatory biomarkers and malnutrition; group 3 comprised young children with moderate immunosuppression, high TNF-α levels, and high age-associated CD8(+) T-cell count ratios but lower frequencies of events (12% cases; 7% died); and group 4 comprised older children with low inflammatory biomarker levels, lower HIV viral loads, and good clinical outcomes (11% cases; 5% died).

Conclusions: While immunosuppression is the major determinant of poor outcomes during ART, baseline inflammation is an additional important factor, identifying a subgroup of young children with similar mortality. Antiinflammatory interventions may help improve outcomes.

Keywords: Africa; HIV; children; immunosuppression; inflammation.

Figure 1.

Subgroups of children at antiretroviral therapy (ART) initiation, identified from clustering of principal components. A, Compared to first 2 principal components. B, Compared to case vs control status. Abbreviation: WHO-4, World Health Organization clinical stage 4.

Figure 2.

Characteristics in subgroups of children before antiretroviral therapy initiation. P < .0001 for all comparisons except the percentage of CD4⁺HLA-DR⁺ T cells (P = .03, by the rank sum test). CD4⁺ T-cell subpopulations (CD45RA⁺, CD45RA⁺CD31⁺, HLA-DR⁺, and Ki67⁺) measured in only 37, 13, 81, and 53 children in groups 1, 2, 3, and 4, respectively. The top 8 plots are factors used to define subgroups (through clustering of principal components). Abbreviations: BMI, body mass index; CRP, C-reactive protein; IL-6, interleukin 6; IL-7, interleukin 7; sCD14, soluble CD14; TNF-α, tumor necrosis factor α.