Project R-4167

Advanced modelling of CD4 count decline in ARV naive, HIV positive individuals in South Africa (Research)

A deeper understanding of HIV progression and factors which affect this progression can facilitate the development of novel treatment approaches. CD4+ T lymphocytes (CD4) are the main target of the human immunodeficiency virus. In patients who do not receive antiretroviral therapy, a decreasing CD4 count is strongly associated with an increasing risk of AIDS and an increasing risk of death. Another key marker of HIV/AIDS progression is the viral load, which quantifies the amount of virus in the blood. The primary objective of this thesis is to apply multistate models and linear mixed models to examine the rate of HIV progression. The dataset . The methodology developed will be applied to the Sinikithemba cohort study. The stidy commenced in 2003 and to date has enrolled 451 chronically HIV-1 subtype C-infected adults. Socio-demographic characteristics, plasma viral load measurements, and CD4 cell counts were obtained at baseline. Follow-up CD4 cell counts and plasma viral load measurements were performed at 3 and 6 month intervals, respectively. The study was approved by the Biomedical Research Ethics Committee of the University of Kwazulu-Natal and each participant gave written informed consent for participation in the study. High-resolution HLA class I typing was performed using molecular methods and interleukin-10 (IL-10) APOBEC and PSIP1 polymorphisms were examined. Previous research has found possession of a protective HLA allele correlated significantly with the rate of CD4 cell count decrease and examination of PSIP polymorphisms revealed that rs12339417 (SNP3)C was associated with slower decline of CD4 cells. Although various genetic markers have proven to be significant predictors of rapid HIV progression, no previous research has been conducted to determine the interaction between the various genetic markers and their joint effect on CD4 count decline. The CD4 count is a marker that is prone to fluctuation and measurement error, hence smoothing techniques and methods for quantifying fluctuation and random variation will be examined. An additional objective of this thesis is to jointly model CD4 count and viral load and develop a composite marker for HIV Special Research Fund - Call for tender Doctoral grants in the framework of the Bilateral Programme progression. This research can offer a deeper understanding of the natural progression of HIV/AIDS and possibly guide clinicians on appropriate criteria to determine the timing of ARV initiation.

01 February 2013 - 31 December 2016