The impact of individual donation nucleic acid testing for HIV and HBV on blood safety in South Africa

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dc.contributor.advisorVan Zyl, Gerten_ZA
dc.contributor.advisorWelte, Alexen_ZA
dc.contributor.advisorBusch, Michaelen_ZA
dc.contributor.advisorLelie, Nicoen_ZA
dc.contributor.authorVermeulen, Marionen_ZA
dc.contributor.otherStellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine. Infectious Diseases.en_ZA
dc.date.accessioned2022-05-13T15:29:15Zen_ZA
dc.date.accessioned2023-01-23T06:50:50Zen_ZA
dc.date.available2023-01-24T03:00:14Zen_ZA
dc.date.issued2022-05en_ZA
dc.descriptionThesis (PhD)--Stellenbosch University, 2022.en_ZA
dc.description.abstractENGLISH 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.en_ZA
dc.description.abstractAFRIKAANSE OPSOMMING: Individuele skenking-nukleïensuurtoetsing (ID-NAT) as siftingstoets om bloedskenkings vir MIV-RNA, HCV-RNA en HBV-DNS deur hoë deurvloei-outomatisering, het in Oktober 2005 beskikbaar geword. Suid-Afrika was die eerste land wat universele sifting van alle bloedskenkings deur hierdie tegnologie geïmplementeer het . ID-NAT is in Suid-Afrika geïmplementeer om bloedveiligheid te verbeter. Die verbeterde sensitiwiteit van ID-NAT-sifting om die onopspoorbare vensterperiode te verminder, het toegelaat dat etnisiteit as 'n merker van risiko verwyder word. Die gebruik van hierdie hoogs sensitiewe tegnologie vir meer as 15 jaar tesame met 'n hoë voorkoms van MIV en HBV in die algemene bevolking, en tot 'n mindere mate in bloedskenkers, het ons in staat gestel om die sensitiwiteit en doeltreffendheid van verskillende poelgroottes te evalueer, die sensitiwiteit van verskillende toetse te analiseer, die insidensie- en oorblywende risikomodelle te valideer en verifieer en om hierdie inligting te gebruik om tendense in MIV- en HBV-oortappingsoordrag oorblywende-risiko in Suid-Afrika te evalueer vir besluitneming en opvoeding by die Suid-Afrikaanse Nasionale Bloeddiens. Hierdie tesis sluit vier HBV-publikasies en twee MIV-publikasies in waarin ID-NAT-siftingsdata van SANBS noodsaaklik was vir navorsing oor die oorblywende risiko van HBV- en MIV-oordrag deur NAT en serologie-gesifte bloedoortappings. Na vier jaar se sifting met ID-NAT, het ons die eerste HBV-vensterperiode (WP)-oordrag bevestig deur die oortapping van 'n rooibloedsel (RBC)-produk wat 'n HBV-oordragtempo van 1:2,9 miljoen oortappings gee in vergelyking met 'n gemodelleerde oorblywende risiko van 1:37000. Later is die NAT-toets gewysig om die sensitiwiteit daarvan vir HBV-DNS-opsporing te verbeter en ons het gevind dat die vorige Ultrio-toets 'n aansienlike aantal HBV-DNA-positiewe monsters met virale ladings groter as 100 kopieë/ml gemis het. Nadat ons die waardes vir die insetparameters in risikomodellering reggestel het, het ons 'n oorblywende TT-HBV-risiko van 1:7300 beraam in die laaste jaar van ID-NAT-sifting met die Ultrio-toets en 1:15,000 in die eerste jaar van sifting deur die verbeterde Ultrio Plus toets. By die vergelyking van oorblywende risiko vir MIV oor 'n dekade van ID-NAT-sifting, met behulp van twee modelle in herhaalde skenkers, was die skattings vergelykbaar (~1:100,000). Verder het ons verskeie modelle vergelyk om MIV-voorkoms te skat. Ons het veral 'n MIV-nuutheids-teenliggaampie (LAg-avidity)-toets gebruik, wat ook toegepas kan word op skenkerbevolkings in ontwikkelende lande wat nie kan bekostig om ID-NAT uit te voer nie, om die voorkoms van eerstekeerskenkers (die meerderheid bloedskenkers in die meeste mense) te skat. Afrika-lande). 'n Vergelykbare voorkoms van ongeveer 3,5 per 1000 persoonsjare is vir elke metode verkry. Ons langtermyn ID-NAT-toesigstudies vir beide MIV en HBV het getoon hoe die risiko met verloop van tyd verander het met meer en meer proporsionele verteenwoordiging van skenkers van verskillende etniese agtergronde en namate jonger skenkers wat moontlik geïmmuniseer is, die skenkerbasis betree het. Tien jaar na die bekendstelling van ID-NAT het die proporsie swart skenkers van 6% tot 30% toegeneem, maar gemodelleerde oorblywende WP-risiko vir MIV het in 2015 op 1:75 000 gestabiliseer, terwyl slegs een MIV-oordraggeval bevestig is vir 'n waargenome koers van 1 uit 7,7 miljoen. Vir HBV was ons geïnteresseerd om die impak van kinderjare-inenting op HBV-infeksiekoerse by jonger ingeënte skenkers (gebore na 1995) te ondersoek. In hierdie geboortekohort het die HBV-voorkoms afgeneem tot 0.14% in vergelyking met 1.29% in die voor 1985 geboortekohort. Daarteenoor was die koers van potensiële entstof-deurbraakinfeksies in hierdie groep 1,1 uit 100 000 en het toegeneem tot 15 per 100 000 in die post 1995 geboortekohort. Algehele oorblywende HBV WP-risiko oor nege jaar is op 1:27 000 geskat. Ons het ook die negejaar-kohort gebruik om die oorblywende risiko van 'n HBV-oordrag van 'n okkultiese HBV-infeksie (OBI) skenking te skat. Ons het 'n laer oorblywende risiko van OBI-skenkings (1:170 000) beraam in vergelyking met WP-infeksies, hoofsaaklik as gevolg van die hoër minimum aansteeklike dosis maar steeds hoër in vergelyking met die enigste bevestigde OBI-oordraggeval (1 uit 7,4 miljoen) gedurende hierdie waarnemingsperiode. Ten slotte, die ID-NAT-siftingstudies van SANBS het gehelp om die doeltreffendheid van hierdie tegnologie te verstaan in vergelyking met dié van serologiese HBsAg en p24-antigeen/anti-MIV-toetsing. Oor die algemeen is gevind dat teoretiese oorblywende risiko 10-100 keer hoër is as waargenome transmissietempo's, wat die beperkings van terugkykprogramme beklemtoon in die herkenning van alle oordraggebeure, maar kan ook verklaar word deur die vermindering van infektiwiteit van MIV en HBV in gestoorde bloedkomponente of in Suid-Afrika dat baie oortappings aan reeds besmette of geïmmuniseerde pasiënte gegee word. Alhoewel daar aansienlike onsekerhede verbonde is aan die absolute residuele risikoskattings van die ID-NAT-gekeurde bloedskenkings in ons studies, is die neigings en relatiewe residuele risiko's voor en na veranderinge aan die skenkerprofiel konsekwent. Verder kan die evaluering van verskeie modelle lae-inkomste lande van meer koste-effektiewe metodes voorsien om die voorkoms van MIV in hul omgewings te evalueer en dan die inligting te gebruik om regerings en befondsers te beïnvloed om NAT-toetsing van bloedskenkings te implementeer.af_ZA
dc.description.versionDoctoralen_ZA
dc.embargo.terms2022-11-17en_ZA
dc.format.extentxv, 117 pages : illustrationsen_ZA
dc.identifier.urihttp://hdl.handle.net/10019.1/126294en_ZA
dc.language.isoen_ZAen_ZA
dc.publisherStellenbosch : Stellenbosch Universityen_ZA
dc.rights.holderStellenbosch Universityen_ZA
dc.subject.lcshNucleic acids -- Testing -- South Africaen_ZA
dc.subject.lcshHIV (Viruses) -- South Africaen_ZA
dc.subject.lcshBlood safety -- South Africaen_ZA
dc.subject.lcshMedical innovations -- South Africaen_ZA
dc.titleThe impact of individual donation nucleic acid testing for HIV and HBV on blood safety in South Africaen_ZA
dc.typeThesisen_ZA
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