Doctoral Degrees (Paediatrics and Child Health)

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Browsing Doctoral Degrees (Paediatrics and Child Health) by browse.metadata.advisor "Fidler, Sarah"

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    The impact of the HPTN 071 (PopART) intervention on mortality and AIDS related morbidity amongst HIV positive adults in South Africa
    (Stellenbosch : Stellenbosch University, 2018-03) Bock, Peter; Beyers, Nulda; Fidler, Sarah; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child Health.
    ENGLISH ABSTRACT: In 2015 WHO recommended antiretroviral treatment (ART) for all HIV-positive individuals regardless of CD4 count and set a target for Universal Access to ART, that >80% of HIV-positive individuals should be on ART. The HPTN 071 (PopART) trial, a community randomized trial in 21 communities in South Africa and Zambia, aims to to determine the impact of two community-level combination prevention packages on population-level HIV incidence. HPTN 071 (PopART) has implemented household-based HIV point of care testing (POCT) and provided ART regardless of CD4 count at department of health clinics (DOH) in the trial communities from January 2014. This was ahead of recent changes to WHO and South African ART guidelines, which now provide ART regardless of CD4 count. The primary outcome of HIV incidence was evaluated in a randomly selected research cohort, the Population Cohort (PC), which aims to recruit 44,500 HIV-positive and negative participants aged 18 to 45, approximately 2000 from each of the 21 communities. The aim of this PhD dissertation was to evaluate the outcomes of clinical activities key to effective provision of HIV treatment services in high burden settings. PhD objectives were to evaluate: i) the accuracy of household HIV POCT and the impact of routine initiation of ART at baseline CD4 counts > 500cells/mL on ii) attrition during early ART, iii) TB incidence during early ART, iv) the incidence of renal dysfunction during early ART and iv) adherence to ART. These objectives were addressed through the completion of five studies. Four of the five studies presented were embedded within the HPTN 071 (PopART) trial. The fifth study, evaluating ART adherence, was a systematic review and meta-analysis. The study presented in chapter 3, evaluated the accuracy of household-based HIV POCT between January 2014 and August 2016 across all 21 PopART sites in both South Africa and Zambia, through a series of cross-sectional analyses. This study showed initial low HIV POCT sensitivity in South Africa (45-54%). HIV POCT sensitivity in Zambia, which implemented more extensive quality assurance (QA) and quality control (QC) and used different HIV POCT kits, during the same time period, was significantly better (95.8%). HIV POCT sensitivity in South Africa improved over time to rates comparable to the Zambian sites when implementing rigorous HIV POCT QA/QC. The studies presented in chapters 4 to 6 analysed data on a cohort of adults (≥18years of age) initiating ART regardless CD4 count at three department of health (DOH) clinics in the Western Cape, South Africa; between January 2014 and November 2015. Cohort follow-up was completed at the end of May 2016. The cohort studies evaluated the impact of routine initiation of ART at baseline CD4 counts >500 cells/μL on i) attrition ii) TB incidence and ii) incidence of renal dysfunction during early ART. A total of 2423 adults with a median baseline CD4 count of 328 (IQR 195-468) cells/μL were included in the clinic cohort. Attrition included individuals no longer retained in ART care due to loss to follow up or death (chapter 4). A total of 636 (26.2%) adults in the cohort experienced attrition during the follow-up period. Attrition was higher amongst individuals with baseline CD4 counts >500 cells/μL compared to individuals with baseline CD4 counts 0-500 cells/μL (aHR 1.28, 95%CI 1.07 -1.55). This finding raised concerns about the potential for increased attrition from ART care when providing ART regardless of CD4 count. The overall TB incidence in the cohort was 4.4 cases/100PY (chapter 5). TB incidence was lower amongst individuals with baseline CD4 counts >500 cells/μL compared to those with baseline CD4 counts 0-500 cells/ μL (aHR=0.27; 95% CI 0.12 to 0.62). There were no incident TB cases in the first three months of ART amongst individuals with baseline CD4 counts > 500 cells/ μL. These findings were promising, highly suggestive that routine provision of ART at baseline CD4 counts >500 cells/μL will lead to a significant reduction in TB amongst individuals starting ART. The prevalence of baseline moderate or severe renal dysfunction (Estimated Glomerular Filtration Rate (EGFR) < 60ml/min) in the cohort was low (1.9%) (chapter 6), as was the rate of incident moderate or severe renal dysfunction after initiation of ART (1.9cases/100PY). The study showed no significant association between baseline CD4 count and incident moderate or severe renal dysfunction occurring after initiation of ART. Analysis restricted to individuals with normal baseline renal function, showed no cases of incident moderate or severe renal dysfunction amongst individuals with baseline CD4 counts >500cells/ μL. This is also a promising finding that needs to be confirmed by completion of further studies. The fifth study (chapter 7), was a systematic review and meta-analysis of studies published between 2004 and 2015, which evaluated the association between baseline CD4 count and ART adherence. This systematic review showed lower ART adherence amongst individuals starting ART at higher baseline CD4 counts categories (pooled OR 0.90; 95%CI 0.84-0.96). Baseline CD4 count categories used in the included studies varied. The most commonly used comparison was between individuals initiating ART at CD4 counts > 200 cells/μL and at CD4 counts 0-200 cells/μL. In the two included studies that reported on individuals with baseline CD4 counts > 500 cells/μL, there was no difference in ART adherence between individuals with baseline CD4 counts > 500 cells/μL and those with baseline CD4 counts 0-500 cells/μL. Overall the studies presented for this PhD dissertation demonstrated both benefits and challenges when conducting household-based HIV POCT and routinely initiating ART in HIV-positive individuals at baseline CD4 counts >500cells/μL. The studies presented in chapters 5 and 6 suggest potential reduction in incidence of TB and renal dysfunction with routine provision of ART at baseline CD4 counts >500cell/μL; providing a strong motivation for striving to attain universal access to ART in high burden settings. At the same time, the reported low HIV POCT sensitivity and the need for rigorous QA/QC when implementing household-based HIV POCT was concerning. As were the study findings showing higher attrition and poorer ART adherence when initiating ART at higher CD4 counts. Strategies to improve HIV POCT sensitivity, retention in ART care and ART adherence, in these contexts, should therefore be a priority for programme implementers in high-burden settings.