Pathogen Reduction/Inactivation KABB Annual Meeting 2017

Elpidio Pena, MD, MA

Norton Healthcare

Transfusion Services

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

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

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;50 1487-94

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

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?...

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

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

The Current Reactive Safety Approach Requires

Continual Addition of Costly New Tests

HIV-1

Ab

HBc,

ALT HTLV-I

HCV 1.0 HIV-1/2,

HCV 2.0

HIV-1 p24

Widespread

Leukoreduction

HIV-1/HCV

NAT

Chagas’

Test WNV NAT

1985 1990 1995 2000 2005 2010 2015

$100

$150

$200

$250

Introduction of PI could

stop and even reverse

the cycle of additions

25 years of testing, partial protection

against just 7 agents: HIV, Hepatitis B, Hepatitis C, HTLV,

leukocytes, West Nile virus,

Chagas’ disease

Average RBC Unit Charge (US) *

Babesia?

Chikungunya?

Others? Dengue?

* RBC price data adapted from B Custer & JS Hoch, Transfusion Medicine Reviews, Vol 23, No 1 (January), 2009: pp 1-12

“…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”

Justifications for Pathogen Reduction Technologies 2

• Conclusion:

– “We believe the FDA should mandate a proactive approach, ensuring ongoing blood safety by requiring treatment of blood components by approved pathogen-reduction technologies”

Edward Hopper

What Are These Technologies?

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

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

16

Nucleic acid

intercalation

Docking Crosslinking Unable to replicate

UVA illumination

or pH reaction Amotosalen

or S-303

Terumo Mirasol System

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-n-butyl 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

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

Copyright © 2015 Massachusetts Medical Society. All rights reserved. Published by Massachusetts Medical Society. 2

.

The Safety of the Blood Supply - Time to Raise the Bar. Snyder, Edward; Stramer, Susan; Benjamin, Richard New England Journal of Medicine. 372(20):1882-1885, May 14, 2015. DOI: 10.1056/NEJMp1500154

Pathogen -Reduction Technologies Approved and in Development in the United States and Europe.

The importance of a Broad

Spectrum of Inactivation

HIV-1 HIV-2 HBV HCV HTVL-I HTLV-II

SPIROCHETES Treponema pallidum Borrelia burgdorferi

PROTOZOA Trypanosoma cruzi Plasmodium falciparum Leishmania sp. Babesia microti

LEUKOCYTES T-cells

Bluetongue virus, type 11

Simian Adenovirus-15

Feline calicivirus

Parvovirus B19

Human adenovirus 5

HIV-1

HIV-2

HBV

HCV

HTLV-I

HTLV-II

SPIROCHETES

ROUTINELY TESTED AGENTS

ENVELOPED VIRUSES

Treponema

pallidum

ENVELOPED VIRUSES

Staphylococcus epidermidis Staphylococcus aureus Streptococcus pyogenes Corynebacterium minutissimum Listeria monocytogenes Propionibacterium acnes Bacillus cereus (vegetative) Lactobacillus sp. Bifidobacterium adolescentis Clostridium perfringens

Klebsiella pneumoniae Yersinia enterocolitica Escherichia coli Pseudomonas aeruginosa Salmonella choleraesuis Enterobacter cloacae Serratia marcescens Anaplasma phogocytophilum Orientia tsutsugamushi3

GRAM-NEGATIVE BACTERIA

NON-ENVELOPED VIRUSES GRAM-POSITIVE BACTERIA

(1) Sampson-Johannes A, et al. 2003. Transfusion. 43:83A; (2) Lam S, et al. Transfusion 2007;47:131A;

(3) Rentas F. Transfusion 2004;44:104A.

DHBV BVDV CMV WNV SARS Vaccinia1 Chikungunya Dengue2 Influenza A

Pathogen Reduction Advantages

• Decrease in transfusion reactions

• Mitigation of TA-GVHD / alternative to irradiation

Disadvantages 1

• No pathogen reduction method for RBCs

• Solvent detergent plasma:

– Decreased protein S and plasminogen activation inhibitor type 1 activity

• Platelets:

– Effective

Disadvantages 2

• Cost

Almost Final Thoughts…

• Game changer:

– Donor selection

– Response to new infectious agents

• Blood Management

But being practical…

• Look at your needs

• Listen to your blood supplier

– Expertise