Pathogen Reduction/Inactivation KABB Annual Meeting Elpidio Pena, MD, MA Norton Healthcare Transfusion Services

Transcription

1 Pathogen Reduction/Inactivation KABB Annual Meeting 2017 Elpidio Pena, MD, MA Norton Healthcare Transfusion Services

2 Goals Discuss the approved methods for pathogen reduction/inactivation of blood products Name the possible advantages and disadvantages of blood products pathogen reduction/inactivation Discuss the practical implications of these technologies for the transfusion services

3

4 Blood Products Are Safe USA: Collect 13 millions units of RBCs a year Transfuse 2.2 millions of platelets a year The rate of adverse events is relatively low Still morbidity and mortality associated with transfusions

5 Infectious Diseases Risks Residual risk *: HIV: 1:1,467,000 HCV: 1:1,149,000 HBV: 1:280,000 New pathogens *Zou et al, Transfusion 2010;

6 Bacterial Contamination of Platelets It is estimated that 1/1000-1/3000 platelets are contaminated with bacteria. FDA transfusion-associate fatalities report 2015: Five fatalities associated with bacterial contamination: 3 definite/2 possible

7 Pathogen Reduction 1980 s HIV, hepatitis viruses transmitted from human derived coagulation factor concentrates Heating the concentrates and other technologies Why not do the same for blood products?...

8 The Safety of the Blood Supply Time to Raise the Bar Edward L. Snyder, M.D., Susan L. Stramer, Ph.D., and Richard J. Benjamin, M.D., Ph.D. n engl j med 372;20 may 14, 2015

9 Justifications for Pathogen Reduction Technologies Existing and emerging pathogens including viruses, bacteria, protozoa, and prions continue to threaten the safety of the blood supply Reactive approach to new infectious agents Possible changes in donors selection/elegibility Bacterial contamination of platelets FDA approved technologies that are safe and effective

10 The Current Reactive Safety Approach Requires Continual Addition of Costly New Tests Average RBC Unit Charge (US) * $250 $200 $ years of testing, partial protection against just 7 agents: HIV, Hepatitis B, Hepatitis C, HTLV, leukocytes, West Nile virus, Chagas disease HIV-1 Ab HBc, HCV 1.0 ALT HTLV-I HIV-1/2, HCV 2.0 HIV-1 p24 Widespread Leukoreduction HIV-1/HCV NAT WNV NAT Chagas Test Others? Dengue? Chikungunya? Babesia? Introduction of PI could stop and even reverse the cycle of additions $ * RBC price data adapted from B Custer & JS Hoch, Transfusion Medicine Reviews, Vol 23, No 1 (January), 2009: pp 1-12

11 pathogens continue to emerge, and each incident calls transfusion safety into question. Potential threats include, but are not limited to, Ebola, dengue, chikungunya, hepatitis E, pandemic influenza, and SARS (severe acute respiratory syndrome) viruses

12 Justifications for Pathogen Reduction Conclusion: Technologies 2 We believe the FDA should mandate a proactive approach, ensuring ongoing blood safety by requiring treatment of blood components by approved pathogen-reduction technologies

13 Edward Hopper

14 What Are These Technologies?

15 Platelets Source Manufacturer and Technology Treatment Process Manner of Inhibiting Replication Regulatory Status Individual volunteer donors Cerus Intercept Blood System Psoralen (amotosalen) and UVA light exposure Formation of DNA and RNA monoadducts and crosslinkage FDA approved; CE marked Individual volunteer donors Terumo BCT Mirasol Pathogen Reduction Technology (PRT) System Riboflavin and ultraviolet light exposure Direct DNA and RNA damage and guanine modification Phase 3 study planned in the United States; CE marked Individual volunteer donors Macopharma Theraflex ultraviolet platelets UVC light exposure Direct DNA and RNA damage and thymine dimer formation CE marked

16 INTERCEPT Mechanism of Action Small molecules (amotosalen and S-303) penetrate cellular and nuclear membranes and intercalate into helical regions of DNA or RNA present in pathogens Amotosalen forms covalent crosslinks to nucleic acid base pairs upon exposure to UVA light DNA and RNA replication are blocked, inactivating pathogens and leukocytes Amotosalen or S-303 UVA illumination or ph reaction Nucleic acid intercalation Docking Crosslinking Unable to replicate 16

17 Terumo Mirasol System

18 Plasma Source Manufacturer and Technology Treatment Process Manner of Inhibiting Replication Regulatory Status Pools of volunteer and paid donors Octapharma Octaplas Plasma pools treated with solvent, tri-nbutyl phosphate and detergent (octoxynol) Lipid membrane disruption of enveloped viruses FDA approved; CE marked Individual and minipools of volunteer donors Cerus Intercept Blood System Psoralen (amotosalen) and UVA light exposure Formation of DNA and RNA monoadducts and crosslinkage FDA approved; CE marked Individual volunteer donors Macopharma Theraflex MB Plasma System Filtration, methylene blue treatment and visible light exposure DNA and RNA damage by type I and type II redox reactions CE marked Terumo BCT Mirasol PRT System Riboflavin and ultraviolet light exposure Direct DNA and RNA damage and guanine modification CE marked

19 Red Cells Source Manufacturer and Technology Treatment Process Manner of Inhibiting Replication Regulatory Status Individual volunteer donors Cerus Intercept Blood System Frangible Anchor-Linker Effector (S303) and glutathione Formation of DNA and RNA monoadducts and crosslinkage U.S. phase 2 and European phase 3 studies complete

20 Pathogen -Reduction Technologies Approved and in Development in the United States and Europe.. The Safety of the Blood Supply - Time to Raise the Bar. Snyder, Edward; Stramer, Susan; Benjamin, Richard New England Journal of Medicine. 372(20): , May 14, DOI: /NEJMp Copyright 2015 Massachusetts Medical Society. All rights reserved. Published by Massachusetts Medical Society. 2

21 ROUTINELY TESTED AGENTS The importance of a Broad Spectrum of Inactivation ENVELOPED VIRUSES HIV-1 HIV-2 HBV HCV HTLV-I HTLV-II ENVELOPED VIRUSES HIV-1 HIV-2 HBV HCV HTVL- I HTLV- II DHBV BVDV CMV WNV SARS Vaccinia 1 Chikungunya Dengue 2 Influenza A GRAM-NEGATIVE BACTERIA Klebsiella pneumoniae Yersinia enterocolitica Escherichia coli Pseudomonas aeruginosa Salmonella choleraesuis Enterobacter cloacae Serratia marcescens Anaplasma phogocytophilum Orientia tsutsugamushi 3 SPIROCHETES Treponema pallidum Borrelia burgdorferi PROTOZOA Trypanosoma cruzi Plasmodium falciparum Leishmania sp. Babesia microti SPIROCHETES Treponema pallidum NON-ENVELOPED VIRUSES Bluetongue virus, type 11 Simian Adenovirus-15 Feline calicivirus Parvovirus B19 Human adenovirus 5 GRAM-POSITIVE BACTERIA Staphylococcus epidermidis Staphylococcus aureus Streptococcus pyogenes Listeria monocytogenes Bacillus cereus (vegetative) Bifidobacterium adolescentis Clostridium perfringens LEUKOCYTES T-cells Corynebacterium minutissimum Propionibacterium acnes Lactobacillus sp. (1) Sampson-Johannes A, et al Transfusion. 43:83A; (2) Lam S, et al. Transfusion 2007;47:131A; (3) Rentas F. Transfusion 2004;44:104A.

22 Pathogen Reduction Advantages Decrease in transfusion reactions Mitigation of TA-GVHD / alternative to irradiation

23 Disadvantages 1 No pathogen reduction method for RBCs Solvent detergent plasma: Decreased protein S and plasminogen activation inhibitor type 1 activity Platelets: Effective

24 Cost Disadvantages 2

25 Almost Final Thoughts Game changer: Donor selection Response to new infectious agents Blood Management

26 But being practical Look at your needs Listen to your blood supplier Expertise

27