Adedeji Majekodunmi (1, 2), Nigel Klein (2), Robin Callard (1,2), Joanna Lewis (3)
(1) CoMPLEX, UCL, (2) Institute of child health, University College London, (3) Department of Infectious Disease Epidemiology, Imperial College London, St Mary’s Campus
Objectives: The overall aim of this work is to develop a differential equations model to facilitate understanding of the changes taking place within the naive CD4+ T cell compartments in HIV-infected children receiving ART. Naive T cell compartments to be considered include recent thymic emigrants and central naive CD4 T cells.
Methods: A total of 223 HIV-infected children receiving ART were included for analysis (median age- 4.7 (IQR: 2.0-9.2)). The dataset consisted of 1738 naïve CD4 counts collected prospectively from the ARROW trial [4] over a median duration of 3.2 yrs (IQR: 3.2-3.3). The total naive CD4 counts were fitted to account for age differences using the exponential functions described in Bains et al [1,2]. A single compartment model of total naive CD4+ T cells was fitted to the dataset and a total of three parameters were estimated using the framework of non-linear mixed effects modelling implemented in the NONMEM software (FOCE with random effects on all three parameters).
Results: Diagnostic plots showed that the single compartment model was a good fit for the data. We found that recent thymic emigrants (RTEs) were mostly responsible for immune reconstitution in children receiving ART whilst the central naive T cells maintained a steady state throughout the initial 3.3 years on ART. Fixed effects estimates obtained include proportion of theoretical thymic (3.55 ± 0.424 cells/day, ETA: 3.83), resultant loss rate (0.295±0.032 cells/day, ETA: 1.8) and initial CD4 count at start of ART (118 ±24.3 cells/µL, ETA: 1.32). As expected, we found that younger children had higher thymic outputs and initial CD4 counts compared to older children. Children with poor recovery of their naïve CD4 count did not demonstrate particularly low thymic outputs.
Conclusions: A mechanistic model can be used to understand naïve CD4 T cell homeostasis in HIV-infected children receiving ART. This model has been fitted without the need for transforming the raw CD4 counts prior to the fit. Recent thymic emigrants are central to CD4 T cell recovery in children receiving ART. Poor naïve CD4 recovery was not explained by low thymic outputs. Thymic output estimate will be improved further by considering addition of an extra viral load loss term into the model. Further work will extend the one-compartment model to a two-compartment model and extensive covariate analysis will be conducted.
References:
[1] Bains I, Antia R, Callard R, Yates AJ. Quantifying the development of the peripheral naive CD4+ T-cell pool in humans. Blood. 2009 May 28; 113(22): 5480-7.
[2] Iren Bains, Rodolphe Thiebaut, Andrew J. Yates and Robin Callard. Quantifying Thymic Export: Combining Models of Naive T cell Proliferation and TCR Excision Circle Dynamics Gives an Explicit Measure of Thymic Output, The Journal of Immunology, 2009; 183; 4329-4336.
[3] Kohler S, Thiel A. Life after the thymus: CD31+ and CD31- human naive CD4+ T-cell subsets. Blood. 2009 Jan 22; 113(4): 769-74.
[4] The ARROW trial team. Routine versus clinically driven laboratory monitoring and first-line antiretroviral therapy strategies in African children with HIV (ARROW): a 5-year open-label randomised factorial trial, Lancet. 2013 Apr 20; 381(9875): 1391-403.
Reference: PAGE 25 () Abstr 5920 [www.page-meeting.org/?abstract=5920]
Poster: Drug/Disease modeling - Paediatrics