Majekodunmi, Adedeji Oluwaseun; (2018) Mathematical and statistical modelling of factors affecting CD4 T cell reconstitution in HIV-infected children starting anti-retroviral therapy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Thymic output in children increases to its peak during the first 1 year of life followed by a gradual decline to a steady state by 20 years of age. Immune reconstitution in HIV-infected children is a highly dynamic process driven by factors such as thymic output, age, proliferation and loss of T cells, viral load, anti-retroviral therapy (ART) and co-infection. Understanding the mechanisms driving immune reconstitution is critical to ensuring the best clinical outcomes in HIV-infected children and in shaping the future of medical intervention. This thesis focuses on the factors affecting the degree and extent of CD4+ T cell reconstitution in HIV-infected children receiving ART. Hepatitis C virus (HCV) co-infection in HIV-infected patients has been linked to an increased incidence of hospitalisation, rapid progression to end stage liver disease and hepatocellular carcinoma. Despite effective antiretroviral drugs, liver-related complications are now a leading cause of mortality and morbidity in HIV-infected patients. The first section of this work uses a monophasic asymptotic recovery model to investigate the impact of hepatitis C co-infection on CD4+ T cell recovery in HIV-infected children. The model was fitted to age-adjusted CD4+ T cell counts using the framework of non-linear mixed-effects regression and the effects of important covariates such as age, viral load and pre-ART hepatitis C status were investigated. The results indicate that HIV/hepatitis C co-infected children recover their CD4+ T cells much more slowly compared to HIV-monoinfected individuals. The next chapter uses the same model to identify predictors of poor immune reconstitution in 2204 HIV-infected children on ART and higher age at start of therapy was highlighted as a main factor associated with poor immune recovery. Finally, a mechanistic model of naive CD4+ T cell homeostasis was developed aiming to understand the recovery of CD4+ lymphocyte subsets in HIV-infected children receiving ART. As CD31+ T cells are an important component of naive T cell pool in children, the model was further adapted to understand dynamics of CD31+ T cell homeostasis in HIV-infected children on ART. Reduced theoretical thymic output was associated with poor CD31+ T cell recovery which is strongly related to poor overall CD4+ T cell recovery.

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