Abstract
BackgroundEarly initiation of anti-retroviral treatment (ART) decreases mortality as compared to deferred treatment, but whether it preserves immune cells from early loss or promotes their recovery remains undefined. Determination of complex immunological endpoints in infants is often marred by missing data due to missed visits and/or inadequate sampling. Specialized methods are required to address missingness and facilitate data analysis.MethodsWe characterized the changes in cellular and humoral immune parameters over the first year of life in 66 HIV-infected infants (0–1 year of age) enrolled in the CHER study starting therapy within 12 weeks of birth (n = 42) or upon disease progression (n = 24). A convenience cohort of 23 uninfected infants aged 0–6 months born to mothers with HIV-1 infection was used as controls. Flow cytometry and ELISA were used to evaluate changes in natural killer (NK) cells, plasmacytoid dendritic cells (pDC), and CD4+ or CD8+ T-cell frequencies. Data missingness was assessed using Little's test. Complete datasets for analysis were created using Multiple Imputation (MI) or Bayesian modeling and multivariate analysis was conducted on the imputed datasets.ResultsHIV-1-infected infants had greater frequency of CD4+ T cells with naïve phenotype, as well as higher serum IL-7 levels than HIV exposed/uninfected infants. The elevated data missingness was completely at random, allowing the use of both MI and Bayesian modeling. Both methods indicate that early ART initiation results in higher CD4+ T cell frequency, lower expression of CD95 in CD8+ T cell, and preservation of naïve T cell subsets. In contrast, innate immune effectors appeared to be similar independently of the timing of ART initiation.ConclusionsEarly ART initiation in infants with perinatal HIV infection reduces immune activation and preserves an early expansion of naïve T-cells with undiminished innate cell numbers, giving greater immune reconstitution than achieved with deferred ART. Both statistical approaches concurred in this finding.
Highlights
Perinatal HIV-1 infection results in progressive immunodeficiency and death in absence of early antiretroviral therapy (ART) [1]
The CIPRA-SA Children with HIV Early antiretroviral (CHER) study was conducted under the supervision of the USA Food and Drug Administration (IND n. 71494)
Loss of naïve T cells in progressive pediatric infection has been attributed to both impairment of thymic function, as evidenced by decreased Tcell receptor excision circles (TREC) detection and, at least in part, to increased differentiation towards mature memory phenotypes [5]
Summary
Perinatal HIV-1 infection results in progressive immunodeficiency and death in absence of early antiretroviral therapy (ART) [1]. Ongoing HIV viremia and T-cell activation cause loss of peripheral naïve T cells, accompanied by homeostatic alterations, aimed at increasing thymic output. These include increased circulating IL-7 that can be sustained until late disease stages [8, 9]. The prognostic value of IL-7 in predicting immune recovery on treatment remains controversial [8,9,10,11] It remains unknown whether early ART initiation in infants (as compared to older children or adults) may cause retention of IL-7 levels in conjunction with immune reconstitution.
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