Gray, Linsay Anne; (2003) Cinical and biological disease progression in children with vertically-acquired HIV-1 infection in Europe: Statistical determinations. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Clinical status, with HIV (human immunodeficiency virus) RNA (ribonucleic acid) viral load and immunological factors are used by clinicians in decisions regarding the management of HIV-1-infected children. Understanding of these dynamics in children infected from their mothers around birth (vertically-infected) over time thus facilitates clinical supervision. This thesis aims to elucidate patterns of clinical, virological and immunological progression over age, and how they inter-relate, using data collected since 1986 on nearly 200 vertically-infected children in the European Collaborative Study cohort study, by implementation of appropriate statistical methodology. Patterns of progression to the Centers for Disease Control categories and to death are clarified by time-to-event methods, and compared across calendar periods, reflecting changing antiretroviral treatment policies. Clinical status is also considered on a visit-by-visit basis to assess fluctuations in illness. HIV RNA viral load over age is elucidated using fractional polynomials and a specific estimation method of Hughes, to account for repeated left-censored measurements. Dynamics of immunological markers over age are investigated with multi-level splines. Methods used for the biological parameters allow stratification by factors such as gender, race and treatment. Early levels of biological markers and clinical indications are related to subsequent progression to serious disease or death by Cox proportional hazards regression. A novel fluctuating pattern in occurrence of serious HIV-related disease over the first 15 years of life was revealed. Differences in RNA levels and patterns in treatment by gender, and in immunological markers by gender and race over age were identified. Immunological measurements in the first six months of life were found to predict progression before one year of age and early clinical signs were prognostic of progression beyond the first year of life. This work provides an extension of previous knowledge and understanding of clinical and biological disease progression in children vertically-infected with HIV.

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