Doctoral Degrees (Infectious Diseases)

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    The impact of individual donation nucleic acid testing for HIV and HBV on blood safety in South Africa
    (Stellenbosch : Stellenbosch University, 2022-05) Vermeulen, Marion; Van Zyl, Gert; Welte, Alex; Busch, Michael; Lelie, Nico; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine. Infectious Diseases.
    ENGLISH ABSTRACT: Individual donation nucleic acid testing (ID-NAT) to screen blood donations for human immunodeficiency virus (HIV) ribonucleic acid (RNA), hepatitis C virus (HCV) RNA and hepatitis B virus (HBV) deoxyribonucleic acid (DNA) using high throughput automation became available in 2005. In October 2005, in order to improve blood safety, South Africa became the first country to implement universal screening of all blood donations using this technology. The improved sensitivity of ID-NAT screening, which reduces the undetectable window period (WP), lead to the discontinuation of ethnicity as a marker of risk. The use of this highly sensitive technology for over 15 years in conjunction with a high prevalence of HIV and HBV in the general population (and to a lesser extent blood donors) allowed us to evaluate the sensitivity and efficacy of different pool sizes (number of samples tested in one test), assess the analytical sensitivity of different assays, validate and verify incidence and residual risk models, and use this information to assess trends in residual HIV and HBV transfusion transmission risk in South Africa for decision making and education at the South African National Blood Service (SANBS). This thesis includes four HBV publications and two HIV publications, in which ID-NAT screening data from SANBS were essential for research on the residual risk of HBV and HIV transmission by NAT and serology screened blood donations. After four years of screening using ID-NAT, we confirmed the first HBV WP transmission through the transfusion of a red blood cell (RBC) product giving an observed HBV transmission rate of 1:2,9 million transfusions compared to a model prediction of 1:37,000, based on assumptions about infectiousness that were broadly deemed plausible. Later, the NAT assay was modified to improve its sensitivity for HBV DNA detection and we found that the previous Ultrio assay missed a considerable number of HBV-DNA positive samples with viral loads greater than 100 copies/mL. After adjusting the values for the input parameters in the risk model we estimated a residual TT-HBV risk of 1:7300 in the last year of ID-NAT screening with the Ultrio assay and 1:15,000 in the first year of screening by the improved Ultrio Plus assay. Various reasons for the large discrepancy with empirically confirmed transmission events are posited. When comparing residual risk for HIV over a decade of ID-NAT screening, using two models in repeat donors the estimates were comparable (~1:100,000). Furthermore, we compared multiple models to estimate HIV incidence. In particular we used a HIV recency antibody (LAg avidity) test, which could also be applied to donor populations in developing countries that cannot afford to perform ID-NAT, to estimate incidence in first-time donors (the majority of blood donors in most African countries). A comparable incidence of around 3.5 per 1000-person years was obtained for each method. Our long-term ID-NAT surveillance studies for both HIV and HBV showed how the risk changed over time as donors became more representative of the racial distribution of the general population (HIV epidemiology being strongly stratifiable by ethnicity, reflecting historical inequalities) and as younger donors who had potentially been immunized against HBV entered the donor base. Ten years after introduction of ID-NAT, the proportion of Black African donors had increased from 6% to 30%, but modeled residual WP risk for HIV had stabilized at 1:75,000 in 2015, whereas only one HIV transmission case was confirmed for an observed rate of 1 in 7,7 million. For HBV we were interested to examine the impact of childhood vaccination on HBV infection rates in younger vaccinated donors (born after 1995). In this birth cohort the HBV prevalence was 0.14% as compared to 1.29% in the before 1985 birth cohort. In contrast, the rate of potential vaccine breakthrough infections in this group was 1.1 in 100,000 but was 15 per 100,000 in the post 1995 birth cohort. Overall residual HBV WP risk over nine years was estimated to be 1:27,000. We also used the nine-year cohort to estimate the residual risk of an HBV transmission from an occult HBV infection (OBI) donation. We estimated a lower residual risk from OBI donations (1:170,000) compared to WP infections, mainly due to the higher minimum infectious dose but still much higher compared to the only one confirmed OBI transmission case (observed risk of 1 in 7.4 million) during this observation period. In conclusion, the SANBS ID-NAT screening studies have helped to understand the efficacy of this technology as compared to that of serological hepatitis B surface antigen (HBsAg) and p24 antigen/anti-HIV testing. Generally theoretical residual risk was found to be 10-100 fold higher than observed transmission rates, highlighting the limitations of lookback programs in recognizing all transmission events but perhaps also explained by reduction of infectivity of HIV and HBV in stored blood components or host factors of patients, or, in South Africa by the fact that many transfusions are given to already infected or immunized patients. Although there are considerable uncertainties attached to the absolute residual risk estimates of the ID-NAT screened blood donations in our studies, the trends and relative residual risks before and after changes to the donor profile are consistent. Furthermore, the evaluation of various models may provide low income countries with cost-effective methods to assess the incidence of HIV in their settings and then use that information to influence governments and funders to implement NAT testing of blood donations.