Modelling growth in HIV-positive and HIV-exposed uninfected children

Supervisors: Dr Claire Thorne and Dr Mario Cortina-Borja

There are an estimated 3.4 million children living with HIV in the world today, mostly (-90%) in sub-Saharan Africa. The benefits of antiretroviral therapy (ART) with respect to survival and health of children with HIV are well established and WHO guidelines currently recommend that all HIV-positive children aged <2 years receive treatment'. The aim of ART is to maximize health, growth and development in HIV-positive children, whilst minimizing toxicity and adverse events in the short to long-term2. The negative impact of HIV infection in childhood on growth, including stunting, wasting and pubertal delay in the absence of effective treatment has been well documented, as has the benefits of treatment for growth. HIV has a direct impact on endocrine and metabolic function, which may be one of the mechanisms behind poor growth and pubertal delay seen in infected children, together with factors such as tuberculosis co-infection and malnutrition. Growth faltering is a common manifestation of HIV disease in childhood, and an important indicator of disease

progression, described in up to half of untreated HIV-infected children. It has been shown that by age 10 years, uninfected children were an average 7kg heavier and 7.5cm taller than infected children3. Questions remain with respect to the impact of timing of ART initiation on catch-up growth. The proposed project will lead to a better understanding of the complex interplay between HIV infection, its treatment and growth in childhood and adolescence. Today, infants diagnosed with HIV infection are started on treatment immediately, whilst in the past treatment was delayed until the child developed specific symptoms. More research is needed to explore the impact of such early treatment on growth. One of the main goals of treating HIV in children is to maximize their growth, but treatment may sometimes have a negative impact, including changes in body fat and also potentially on bone development. Once initiated, it is expected that ART will be life-long, underscoring the need to understand potential for long-term toxicities. It is therefore important to explore growth trajectories in the context of the drugs that a child is taking. Also, the effect on growth of exposure to infection and ART in utero among uninfected children born to HIV-infected women has not been completely characterised.

Analysis of longitudinal growth data collected throughout childhood is complex and requires a wide variety of statistical approaches to investigate individual growth process and to characterise them at a population level. These processes are intrinsically non-linear, and many of the biological parameters of interest, e.g. start, end, and intensity of growth spurs, age at peak growth velocity during adolescence, final height, can be difficult to estimate directly. This project is statistical in nature with emphasis on providing analysis relevant to clinical management, pharmacovigilance and policy making. It is an excellent opportunity to gain knowledge of many non-standard statistical methods, e.g. mixed-effects non-linear regression models, dynamical models and functional data analysis, as well as deep insight on models specifically designed for growth processes, e.g. Preece-Baines and SITAR4.

References:
1) World Health Organization. Antiretroviral therapy for HIV infection in infants and children: towards universal access. 2010 revision.
2) PENTA Steering Committee. PENTA 2009 guidelines for the use of antiretroviral therapy in paediatric HIV-1 infection. HIV Med. 2009; 10(10):591-613.
3) Isanaka S, Duggan C, Fawzi WW. Patterns of postnatal growth in HIV-infected and HIV-exposed children. Nutr Rev. 2009;67(6):343-59.
4) Cole T.J., Donaldson, MDC, Ben-Shlomo, Y. (2010) SITAR — a useful instrument for growth curve analysis. International Journal of Epidemiology, 39(6) 1558-1566.