transfusion-transmissible HCV and HIV in Italy Haemovigilance and the residual risk of

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1 Haemovigilance and the residual risk of transfusion-transmissible Giuliano Grazzini, MD National Blood Centre, National Institute of Health, Rome, Italy & International Federation of Blood Donor Organizations (FIODS/IFBDO) CONFLICTS OF INTEREST STATEMENT The speaker declares that he has NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this presentation.

2 BACKGROUND - 1 The risk of transmitting hepatitis C virus (HCV), human immunodeficiency virus (HIV) and hepatitis B virus (HBV) through blood transfusion has significantly decreased since the introduction of nucleic acid testing (NAT) along with the previously implemented antigen/antibody-based assays for blood screening and the adoption of restrictive criteria for donor selection. BACKGROUND - 2 Following serological and especially molecular screening of blood donors, in most countries the risk of transfusion-transmitted HCV, HIV and HBV infections has become too low (i.e. residual) for direct assessment through conventional approaches such as prospective follow-up and retrospective look-back studies of blood recipients.

3 BACKGROUND - 3 RESIDUAL RISK (RR) of transfusion-transmitted infections (TTIs) - Quantitative evaluation of the possibility that a blood component for transfusion, though negative at screening tests, is capable of transmitting an infection to the recipient. - Monitoring the residual risk of TTIs in donor populations through the systematic collection and elaboration of epidemiological data is a crucial element to assess the efficacy of the preventive measures adopted by national blood systems/authorities to ensure the safety of their blood supplies. BACKGROUND - 4 The RR of collecting an infectious donation that is undetectable by screening tests has since long been calculated by mathematical models based on the incidence rate of HCV, HIV and HBV infections among donors and on the length of the diagnostic window period (WP) of each viral infection (temporal gap spanning from the time point of donor infection to the first detectability of specific viral markers): incidence / window period model

4 WP WP WP The diagnostic window period (WP) consists of 2 phases: 1) the eclipse phase: the virus has already infected the donor but is not yet detectable in blood even by highly sensitive tests; 2) the ramp-up phase: the viral load in blood (viremia) increases exponentially - with specific doubling time - up to a peak/plateau Kleinman SH, Lelie N, Busch MP. Transfusion. 2009;49(11): Modified.

5 32 blood units tested NAT-only positive: 19 for HCVRNA (8 FT 11 RP donors), 13 for HIV-RNA (3 FT 10 RP donors). 2,641 blood donors tested positive for HCV/HIV markers: - 1,949 FT donors out of 1,934,612 FT donors x 105 or 1 in 1, RP donors out of the 10,323,975 RP donors x 105 or 0.07 in 1,000. * Busch MP, Glynn SA, Stramer SL, et al. Transfusion 2005; 45: Prevalence was calculated in the population of FT donors as the rate between the number of positive subjects and the total number of FT donors in the same period of time (x 100,000 donors)*.

6 Incidence is expressed as the number of new infected cases 100,000 person-years at risk. It was calculated in the population of RP donors as the number of positive subjects with a previous negative donation or negative testing, within the preceding 24 months, divided by the total number of donations from RP donors in the study period multiplied by the mean interdonation interval expressed in years (= person-years at risk)*. * Glynn SA, Kleinman SH, Wright DJ, Busch MP. Transfusion 2002; 42: * Busch MP, Glynn SA, Stramer SL, et al. Transfusion 2005; 45: PREVALENCE of HCV and HIV infection in first-time donors Italy, n/ HCV HIV

7 n/10 5 INCIDENCE of HCV and HIV infection in repeat donors Italy, HCV HIV copy/20 mls T-I HIV 1 copy/20 mls Figure 1. Periods T in Days (Standard Error) for HIV and HCV* T-I ID-NAT MP-NAT p24 Ag WB S/LSEIA T-II T-IIIa T-IIIb T-IV 5.6 (0.40) 3.4(0.22) 5.3 (1.02) 9.0 (0.60) 6.0 (1.08) (10.0) ID-NAT MP-NAT EIA 3.0 To calculate RR the "window period ratio method was considered the reference method since we had used it in the past, making comparisons with previous data easier. The RR was estimated, both in first-time and repeat donors, multiplying the NAT yield rate (i.e. no. of NAT-only positive cases/number donations screened) by the ratio between the infectious pre- NAT window period and that estimated as the time elapsing from NAT detectability and serological detectability. HCV T-I T-II 4.9 (0.45) 2.5 (0.22) 7.4 (0.67) T-III 50.9 (2.47) * Calculations based on the HIV and HCV Gen-Probe TMA 50% sensitivities. Busch MP, Glynn SA, Stramer SL, et al. Transfusion 2005; 45: The weighted average pre-nat infectious window period for the entire study period (different NAT screening methods had been employed during the 7-year study period) was estimated to be 4.74 days for HCV and 7.0 days for HIV. The ratios concerning the two window periods of interest resulted 4.74/53.6 days for HCV and 7.0/8.0 days for HIV, respectively.

8 Residual risk of transfusing an infected blood unit collected during the Window Period of the HCV infection in Italy, Window period ratio model* *Busch MP, Glynn SA, Stramer SL, et al. Transfusion 2005; 45: RP positive donations/donations tested 11/19,873,740 RP RR x 10 6 (95% CI) ( ) or 1 in 20,430,235 FT positive donations/donations tested 8/1,934,612 FT RR x 10 6 (95% CI) ( ) or 1 in 2,734,578 Total RR x 10 6 (95% CI) ( ) or 1 in 12,979,949 Residual risk of transfusing an infected blood unit collected during the Window Period of the HIV infection in Italy, Window period ratio model* RP positive donations/donations tested 10/19,873,740 RP RR x 10 6 (95% CI) ( ) or 1 in 2,271,285 *Busch MP, Glynn SA, Stramer SL, et al. Transfusion 2005; 45: FT positive donations/donations tested 3/1,934,612 FT RR x 10 6 (95% CI) ( ) or 1 in 736,995 Total RR x 10 6 (95% CI) ( ) or 1 in 1,917,250

9 Residual risk (n/10 6 ± 95% C.I. ) for HCV, HIV and HBV in Italy Velati C et Al. Impact of nucleic acid testing for hepatitis B virus, hepatitis C virus, and human immunodeficiency virus on the safety of blood supply in Italy: a 6-year survey. Transfusion 2008 Oct;48(10): Updated in 2009 Haemovigilance and the residual risk of transfusion-transmissible HCV and HIV in Italy Residual risk (n/10 6 ± 95% C.I. ) for HCV, HIV and HBV in Italy HCV HIV 0,3 (0,1-0,6) 1,9 (0,6-3,9) 0,2 (0,1-0,4) 1,8 (0,8-2,8) HBV - - 0,2 (0,1-0,3) 1,4 (0,7-2,1) 1,6 (0,3-1,8) 0,2 (0,1-0,3) 1,3 (0,7-1,9) 0,1 (0,1-0,2) 0,8 (0,6-1,6) Società Italiana di Medicina Trasfusionale e Immunoematologia Settore Ricerca & Sviluppo Gruppo Italiano per lo Studio delle Malattie Trasmissibili con la Trasfusione 1,9 (0,9-2,7) 1,6 (0,6-2,1) 0,1 (0,1-0,2) 0,7 (0,5-1,6) 1.6 (0,6-2,1)

10 Evolution of the Residual risk in Italy vs RR RR HCV 1 in 10,000,000 1 in 13,000,000 HIV 1 in 1,200,000 1 in 1,900,000 - The overall frequency of HCV and HIV markers is 15-fold higher in FT than in RP donors - The frequency of NAT-only positive blood units is 7.4-fold (HCV) and 3-fold (HIV) higher in FT donors - RR for HCV and HIV results remarkably higher in FT vs. RP donors FT Donors RP Donors RR HCV 1 in 2,734,578 1 in 20,430,235 RR HIV 1 in 736,995 1 in 2,271,285

11 HCV+ (n=1,658) HIV+ (n=291) HCV (n=238) HIV+ (n=454) Haemovigilance and the residual risk of transfusion-transmissible Risk factors of FT and RP donors positive for HCV and HIV markers in Italy, FT donors RP donors Gender: Male Female Risk factor: N (%) 1,106 (66.7) 552 (33.3) N (%) 232 (79.7) 59 (20.3) N (%) 150 (63) 88 (37) N (%) 406 (89.4) 48 (10.6) Sexual of whom: Heterosexual MSM 171 (9.2) 132 (77.2) 39 (22.8) 163 (49.2) 104 (63.8) 59 (36.2) 41 (14.3) 38 (92.7) 3 (7.3) 311 (60.6) 193 (62.1) 118 (37.9) Parenteral 425 (22.7) 36 (10.9) 89 (31.1) 50 (9.7) Household contact 19 (1.0) 1 (0.3) 4 (1.4) 4 (0.8) Not identified? 1,254 (67.1) 131 (39.6) 152 (53.2) 148 (28.9) The RR for HCV and HIV was also calculated according to EMA (2016) and WHO (2017) Guidelines, obtaining data significantly different - MUCH LOWER RISK - from those obtained with the Busch et Al. s method, which have been assumed as the worst scenario and therefore as national reference data.

12 Thanks for your attention! Giuliano Grazzini, MD National Blood Centre, National Institute of Health, Rome, Italy & International Federation of Blood Donor Organizations (FIODS/IFBDO)