Impact of Testing Strategies to Reduce Transmission Risk for HBV. Ravi Reddy, M Vermeulen South African National Blood Service (SANBS) 29 July 2013

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1 Impact of Testing Strategies to Reduce Transmission Risk for HBV Ravi Reddy, M Vermeulen South African National Blood Service (SANBS) 29 July 2013

2 Overview of SANBS SANBS is a private not for profit company operating on a fee for service basis Provides a vein to vein blood transfusion service in 8 of the 9 provinces in SA. WPBTS in Western Cape 807,000 units of blood collected annually (100% voluntary) units bled daily 2 testing centres - Johannesburg and Durban Also test for Namibia BTS (ID-NAT as well) 7 blood processing centres 82 blood banks serving > 600 hospitals and clinics. SANBS is accredited with the South African National Accreditation System (SANAS) Specific laboratories are ISO accredited HQ in Johannesburg

3 Donation Testing Strategy Quality assured testing of each donation EQAS and internal QC systems in place Serology is mandatory Anti-HIV-1,2, anti-hcv, HBsAg Quality assured testing with sensitive serology assays leads to detection of most of the viral positive donations cost effectively Individual Donation Nucleic Acid Testing (ID-NAT) Implemented in October 2005 Primarily to reduce risk of HIV window period transmission but also HBV transmission as well

4 Rationale for ID-NAT in South Africa HIV prevalence in blood donors 0.21% HBV prevalence in Blood Donors is 0.1% Implemented ID-NAT testing in October 2005 ULTRIO assay on the TIGRIS platform for: HIV-1 RNA HCV RNA HBV DNA Serology testing for anti-hiv, anti-hcv and HBsAg done concurrently Evaluated and implemented Ultrio Plus assay in May 2011 because of increased sensitivity for HBV detection in window period

5 Geographic Distribution of Chronic HBV Infection HBsAg Prevalence WHO 8% - High 2-7% - Intermediate <2% - Low

6 HBV 5 Year data Code Active % New % Rejoined % Grand Total % Donations Concordant (NAT and HBsAg Pos) ID-NAT only pos HBsAg only pos Grand Total

7 Hepatitis B Summary 476 NAT+, HBsAg negative donations detected in 5 years Hundreds of cases of transmission via transfusion prevented ID NAT testing has had a significant positive impact on reducing risk of HBV transmission via blood transfusion However still a risk of non detection of very low viral load donations One confirmed HBV transmission on a donation that tested negative with routine serology and ID-NAT Donor triggered look back as subsequent donation positive Ultrio Plus Assay evaluated and in 2010/11

8 Confirmed pre-id-nat WP transmission case Donor triggered look back RBC Platelet concentrate Patient unable to be traced Donor details 47 year old white male (low risk, regular donor) 54 previous donations Negative donation 26/11/2008 Date of Transfusion 10/12/2008 Positive donation 26/01/2009

9 ID-NAT WP transmission case Donor RBC recipient 26-Jan-09 9-Apr Mar-09* S/CO HBsAg 1st screen S/CO HBsAg 2nd screen S/CO HBsAg 3rd screen S/CO Ultrio 1st screen S/CO Ultrio 2nd screen S/CO Ultrio 3rd screen S/CO dhbv 23.1 invalid 25.2 anti-hbc IgM Pos Pos anti-hbc total Pos Pos anti-hbs Neg Neg * 3.5 months after transfusion

10 Additional tests to Determine if Recipient infection caused by Transfusion Donor plasma index donation (26/11/08) SANBS 3 out of 30 replicates positive Gen Probe 7 out of 30 replicates positive with Ultrio Plus Phylogenetic analysis/sequencing Donor and recipient genotype A Intra group nucleotide divergence Donor/recipient 0.31% (99.7% Shared Identity) Transmission by Blood Tranfusion confirmed

11 Ultrio, Ultrio Plus, TaqScreen Study performed Compare Sensitivity of NAT assays with a range of samples random samples 40 HIV ID-NAT yield samples 107 HBV ID NAT positive samples on Ultrio HBsAg positive, HBV NAT negative samples Other samples (HIV Window period transmission sample and HBV window period transmission sample)

12 Proportion reactive per NAT option on 107 Ultrio HBV ID-NAT yield samples % reactive tested in 6 replicates in each test option p< p< p< P= NAT option

13 Proportion HBV NAT reactive on WP* and OBI yield samples % reactive NAT option

14 Percent ID-NAT reactive on HBsAg+/Ultrio- yield samples % reactive (12 reps) assay dona ties repli cates reac tive % Ultrio ,4% Ultrio Plus ,8% copies/ml* *determined by probit analysis in Ultrio Plus against Eurohep standard

15 HBV ID-NAT Yields One year Data Ultrio (2010 vs. Ultrio Plus 2011) Ultrio Ultrio Plus increase p value Donations pre-hbsag WP 47 (1:16 499) 80 (1:9 874) 170% post-hbsag WP 10 (1:77 544) 17 (1:46 468) 167% 0.19 OBI 94 (1:8249) 162 (1:46 468) 172% HBV-NAT yield 151 (1:5204) 259 (1:3 050) 172% < HBsAg positive 820 (1:946) 841 (1:939) 103% 0.89 HBsAg+/DNA- 38 (1:20 406) 16 (1: ) All HBV infections 971 (1:799) 1100 (1:718) 111% 0.016

16 Viral load distribution in all HBV NAT yields detected by Ultrio versus Ultrio Plus Ultrio 110 Ultrio Plus P<0.01 P=0.15 P<0.001 P= >1000 HBV-DNA cps/ml

17 cps/ml Estimated WP reduction with Ultrio and Ultrio Plus (14.5 vs 24.7 days; 1.7 fold) HBsAg S/CO= cps/ml Ultrio 50% LOD 63 cps/ml Ultrio Plus 50% LOD 4.1 cps/ml ID cps/ 20 ml Start WP Ultrio Plus Ultrio HBsAg screening period days 24.7 days days eclipse WP Ultrio Plus HBsAg 22.9 days 14.5 days WP Ultrio WP transmission risk Ultrio 1: Ultrio PLus 1:43 000

18 Probable OBI transmission case Donor Recipient Drawing date 25/1/12 11/4/12 11/5/12 11/6/12 4/7/12 31/1/13 Status RBC Issued Look back Follow up Follow up Ultrio Plus S/CO Neg 15.3/15.5/ /14.9 Neg Pos dhbv S/CO 22.7 neg HBsAg Neg Neg Neg Neg Pos Neg Anti-HBc IgM Neg Neg Pos Pos Anti-HBc total Pos Pos Pos Pos Anti-HBs titre <2 2.6 < IU/L Viral load 1.6 cps/ml* 43 cps/ml 100 % homology of whole HBV genotype D genome sequence of donor sample 11/4/12 and recipient sample 4/7/12 (analysis kindly performed by Dr Marco Koppelman, Sanquin, Amsterdam) * Estimated from 5/20 reps Ultrio Plus reactive by probit analysis ( 5.1% probability of transmission estimated with ID 50 of 316 virions)

19 Testing Strategy for Hepatitis B Countries with high incidence/prevalence of HBV need to carefully review algorithms for HBV testing and assay selection Maximise safety and minimise product discard High prevalence countries HBsAg and ID-NAT but not anti-hbc No discard of anti-hbc positive units (6-8% of products usable) Majority of early and occult infections detected Minimal risk of not detecting post HBV DNA window period donations and some OBI s Ultrio Plus in ID-NAT format has significantly improved sensitivity and reduced risk

20 Course of HBV markers and residual transmission risk with ID-NAT 1 st WP ~10 days (Ultrio Plus) 2 nd WP < 1day (Ultrio Plus) OBI transmission risk unknown Vermeulen et al, Transfusion 2012;52:

21 SANBS Algorithm for HBV Testing ID-NAT and HBsAg testing Concordant positive confirmed ID-NAT only (2 x U+ and dhxv) Non repeat reactive donation discarded, anti- HBc and anti-hbs marker added 0.12% of donations discarded (mostly false positive) Donor not notified When donor returns Additional tests performed Blood can be used if all routine tests and anti-hbc negative

22 Algorithm for HBV Testing (cont d) ID-NAT repeat reactive (2 out of 4), serology negative Additional tests on plasma bag Donor recalled and additional tests done If confirmed positive defer donor If deferral, medical division contacts and counsels donor If all tests on follow up donation negative (review need for additional tests or re-instate)

23 HIV infections in six years of ID-NAT screening of 4,520,230 donations HIV-RNA anti-hiv 7993 (96.5%) HIV RNA +, anti-hiv + concordant HIV RNA +, anti-hiv window period 228 (2.8%) 82/228 (38.4%) HIV-Ag HIV-Ag-, RNA+ infections avoided (1:33,237) HIV RNA, anti-hiv + elite controller 64 (0.77%) 59 in first time donors (0.71%) 4 in lapsed donors (0.05%) 1 in repeat donor (0.01%)*

24 Impact of ID NAT on Blood Safety - HIV Significant positive impact on blood safety contributing to major public health success story 136 ID- NAT positive, anti-hiv negative, p24 antigen negative donations detected in 6 years of testing. Without ID-NAT there would have been numerous HIV transmissions via blood transfusion Major public health success story Increased collections by units over 5 years and increased confidence in the blood supply Could increase Black donors from 7% to 31% of donor base over 5 years Since ID NAT implementation, no reported case of HIV transmission since October 2005 HIV prevalence in blood donors has increased (0.07% to 0.23%) Highlights impact of ID-NAT on improving blood safety

25 Summary Implementation of ID-NAT testing has resulted in a significant increase in safety of the South African blood supply compared to previous testing strategy ID-NAT continues to interdict infectious donations that are missed in mini pool format SANBS evaluation and one year data confirmed that Ultrio Plus is more sensitive than Ultrio for HBV

26 Thank You