Invited update on blood safety issues delivered to the Plasma Users Group Dublin 11 January 2018

1. Update on product
safety issues 2018
Albert Farrugia PhD
a/Professor, Department of Surgery, University of Western
Australia
Senior Director, Almar Therapeutics Pty Ltd, Victoria,
Australia
Platform of Plasma Protein Users (PLUS)
CONSENSUS CONFERENCE 2018
Dublin, Ireland (Radisson Blu Royal Hotel)
11-12 January 2018

2. Disclosure
I provide compensated services to the manufacturers of
biological therapies, one of whom has paid for my
attendance at this meeting.

3. Issues covered
• Aftermath of MSM relaxation
Selection
Screening
• Emerging viruses
• Transmissible Spongiform Encephalopathies

4. HIV Trends in the United States: Diagnoses and Estimated
Incidence
Diagnoses of HIV infection and estimated HIV infections among
MSM, United States, 2008-2013.
Name of the
model
Stratified
extrapolatio
n approach
Bayesian
hierarchical
model
CD4 model
Method Biomarker-
based sample
survey
Bayesian-based
back-calculation
CD4 based back-
calculation
Data
requirement
All new
diagnoses
All new
diagnoses
All new
diagnoses
Testing and
treatment
history
Strengths Annual
estimates
Annual
estimates
Annual
estimates
More accurate
for recent years
Data for entire
epidemic period
not required
Weaknesses False recent rate
of incidence
assay used
HIV data in
earlier years
incomplete as
jurisdictions
implemented
HIV reporting
over time; hence
relies on
accuracy of data
adjustment for
incomplete
reporting
Relies on
accuracy of CD4
depletion model
Relies on
accuracy of
testing and
treatment
information
The CD4 and Bayesian hierarchical models, but
not the stratified extrapolation approach,
indicated decreases in incidence among MSM

5. Opinions toward and rates of blood donation among men who believe their blood
is safe to donate
The beliefs and willingness of men who have sex with men to
comply with a one-year blood donation deferral policy
Transfusion. 2017 Sep;57(9):2234-2239

6. HIV pre-exposure prophylaxis
(PrEP)
Seed et al Vox Sanguinis (2017) 112, 473–476
• The use of one or more antiretroviral medications (in combination) to prevent HIV infection.
• Early initiation of antiretroviral treatment (ART) can compromise the diagnostic capabilities
of HIV tests EIA and NAT).
• Commonest drug is 44 to 75 % effective in preventing infection vs placebo (incomplete
dosage compliance). Full compliance should give efficiency of 91 to 99%.
• Conceivable that a donation might be collected from a donor with acute HIV infection (i.e.
PrEP HIV breakthrough infection) which is not detected by either HIV NAT or serological
testing and consequently issued for transfusion.
• Suspicion for possible PrEP ‘interference’ should be highest in the context of concomitant
low level positive (S:CO >/~ 1) or ‘high negative’ reactivity (S:CO </~ 1).

7. Shortcomings of Current HIV Diagnostics in the Early Treatment Era
Clin Infect Dis. 2016;63(4):562-564
Early treatment with antiretroviral
therapy aborts the development
of antibodies if treatment is
initiated very early and
subsequent seroreversion may
occur if treatment is initiated
shortly following seroconversion,
making it difficult to detect or
confirm HIV infection by standard
diagnostic tests.

8. Seroreversion in participants initiating antiretroviral therapy (ART) during acute human
immunodeficiency virus infection
Clin Infect Dis. 2016;63(4):555-561.
Using second-
and third-
generation
antibody IAs
Using fourth-
generation IA
Western blot seroreversion profile

9. Cognitive evaluation of the AABB
Uniform Donor History Questionnaire
(UDHQ)
• Respondents recognised that the purpose of the UDHQ was to assess the safety of
their blood.
• Each question was understood as asking the same thing :“Is my blood safe to
donate?”
• Did not vary among MSM versus non-MSM or by region.
• Rationale for answers was framed as much or more by the questionnaire's general
purpose as by the specific topic of individual questions.
Key factor responsible for both false-positive and false-negative response errors and
did not vary by demographic, including in MSM. TRANSFUSION 2016;56;1662–1667

10. Observed and predicted number of HIV‐positive male
donors before and after the implementation of a
temporary MSM deferral
Transfusion Volume 56, Issue 6pt2, pages 1603-1607, 7 MAR 2016

11. Consequences of HEV infection
Reviews in Medical Virology
Volume 27, Issue 5, RMV-2017-013.R1, 6 SEP 2017 DOI: 10.1002/rmv.1937
http://onlinelibrary.wiley.com/doi/10.1002/rmv.1937/full#rmv1937-fig-0001

12. Modes of HEV transmission in developing and developed
countries
Reviews in Medical Virology Volume 27, Issue 5, RMV-2017-013.R1, 6 SEP 2017

13. HEV epidemiology and genotype distribution
Reviews in Medical Virology Volume 27, Issue 5, RMV-2017-013.R1, 6 SEP 2017

14. Low hepatitis E virus RNA prevalence in a large‐scale survey of United States source
plasma donors
Transfusion
21 AUG 2017 DOI: 10.1111/trf.14285

15. Hepatitis E virus and the safety of plasma products: investigations into the reduction capacity of
manufacturing processes
Low‐pH treatment of Gammagard liquid/KIOVIG
Transfusion Volume 56, Issue 2, pages 383-391, 24 SEP 2015

16. Hepatitis E virus and the safety of plasma products: investigations into the reduction
capacity of manufacturing processes
Heat treatment of human serum albumin.
Transfusion Volume 56, Issue 2, pages 383-391, 24 SEP 2015

17. Biologicals 44 (2016) 403e411
Inactivation kinetics of HEV during 60 °C liquid heating of plasma derivatives
Arrows: no virus was detected
Albumin 25% Albumin 5% Haptoglobin
Antithrombin IVIG

18. Inactivation and removal of Zika virus during manufacture of
plasma‐derived medicinal products
Transfusion Volume 57, Issue 3pt2, pages 790-796, 12 OCT 2016
Heat treatment of albumin
S/D treatment of albumin

19. Inactivation of Zika virus by solvent/detergent treatment of human
plasma and other plasma‐derived products and pasteurization of
human serum albumin
Transfusion Volume
57, Issue 3pt2, pages
802-810, 26 DEC 2016
S/D treatment OctaplasLG S/D treatment Octagam
S/D treatment Octanate
Pasteurization of 25% HSA

20. Inactivation of emerging viruses and other viruses of potential concern by
pasteurization
TRANSFUSION 2018;58;41–51

21. Global examples of emerging and reemerging infectious
diseases
1984
2017
Ann Intern Med. 2017;167:805-811

22. Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 23, No. 6, June 2017

23. BSE and vCJD: What will happen?
Around 250 cases in total and disease will virtually disappear by year 2020!!
1985 1990 1995 2000 2005 2010 2015
0
10000
20000
30000
40000
0
10
20
30
Years
NumberofBSEcases
NumberofvCJDcases
1985 1990 1995 2000 2005 2010 2015
0
10000
20000
30000
40000
BSE
vCJD
Years
Numberofcases
8 years
Incubation period

24. 1 in 2000 people (i.e. ~30,000 persons) carry potentially
infectious prions in UK
BSE and vCJD: What will happen?

25. BSE and vCJD: What will happen?
Disease has not begun yet!!!
The few cases so far are just part of the noise of people infected before the BSE
epidemic or that have a higher predisposition
1990 2000 2010 2020 2030
0
10000
20000
30000
40000
BSE
vCJD
Years
Numberofcases
30 years
Incubation period

26. Early transmission studies to detect infectivity in the blood of humans with CJD
Transfusion Volume 8, Issue 2 March 2002 Pages 63–75

28. Clinical diagnosis Total patients PrPSc
detected in blood
vCJD 14 14/14
sCJD 16 0/16
Other neurodegenerative
diseasesa
62 0/62
Other neurological diseasesb
23 0/26
Healthy controls 49 0/49
a
Includes samples from patients with Alzheimer's disease, Parkinson's disease, Lewy Body
dementia, and fronto-temporal dementia
b
Include samples from patients with vascular dementia, seizures, epilepsy, psychiatric diseases,
traumatic brain injury, mild cognitive impairment, demyelinating disease and encephalitis.
Sensitivity of 100 % (95% CI: 76.8 - 100%)
Specificity of 100 % (95% CI: 97.6 - 100%)
PrPSc
detection in vCJD blood
Concha-Marambio et al (2016) Science Transl. Med. 8: 370

29. PrPSc
detection in vCJD blood

30. Detection of PrPTSE
in plasma samples from U.K
Daisy Bougard et al., Sci Transl Med 2016;8:370ra182
NB
sCJD

31. TSE Agent strain Species
Blood
component
Titer range (ID mL−1
)
Scrapie 263K Hamster Whole blood ca. 40–60*
Scrapie 263K Hamster
Whole blood 9–24
Buffy coat 26–35
Whole blood 13
BSE 301v Mouse Plasma 4–5
GSS Fukuoka-1 Mouse
Buffy coat ca. 60*
Buffy coat 44–106
Plasma 10–21–34
vCJD Human isolate Mouse
Buffy coat 18
Plasma 21
Blood infectivity titers during symptomatic phase of disease in TSE-infected
rodents

32. Mouse
model Donor Specimen
Inoculated
mice
Positive
mice
Incubation
period, d ID/mL (95%CI)‡
tgBov vCJD Leukocyte 24 3 476, 567, 576 2.23 (0–4.87)
Plasma 24 1 453 2.12 (0–6.52)
Erythrocyte 24 1 433 2.12 (0–6.52)
tgHu sCJD case 1 Plasma 14§ 1 338 3.70 (0–11.65)
Brain 6 6 216 ± 2 NA
sCJD case 2 Plasma 24 0 >700 0 (0- 6.24)
brain 6 6 217 ± 5 NA
sCJD case 3 Plasma 24 1 233 2.12 (0–6.52)
Brain 6 6 205 ± 5 NA
sCJD case 4 Plasma 24 0 >700 0 (0–6.24)
Brain 6 6 207 ± 3 NA
Blood Infectivity in Variant and Sporadic Creutzfeldt-Jakob Disease
Emerg Infect Dis. 2014 Jan; 20(1): 114–117.
Intracerebral inoculation of blood components collected from 1 vCJD and 4 sCJD cases
(MM1) in transgenic mice expressing the bovine or human prion protein gene

33. Transfusion Volume 51, Issue 7 July 2011 ,p1556–1566

34. Infectivity in spiked process starting materials and final materials of chromatography and Cohn
process
Vox Sanguinis (2006) 91 , 292–300

35. Different products…..different clearance….different
outcomes

36. Safety Update TTDs – final
reflections
• MSM deferral relaxation has possibly increased HIV risk to transfusion fresh
component recipients, heightened by HIV pre-exposure prophylaxis (PrEP).
• Nevertheless, modelled predictions are not reflected in real world data.
• Emerging and re-emerging infectious agents continue to threaten the blood
supply but have little relevance to the plasma product landscape.
• Accruing findings indicate that pathogenic prion strains other than vCJD are
also transmissible by blood but current clearance levels are high enough to
give comfort if not complacency.
Plasma protein therapies manufactured under GMP and under adequate
regulatory oversight and safe and effective medicines.