1 Liver Transplantation: Past, Present and Future MICHAEL E. DEBAKEY DEPARTMENT OF SURGERY John M Vierling, MD, FACP, FAASLD Professor of Medicine and Surgery Chief of Hepatology Director of Advanced Liver Therapies Baylor College of Medicine Houston, Texas
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1
Liver Transplantation:
Past, Present and Future
MICHAEL E. DEBAKEY
DEPARTMENT OF
SURGERY
John M Vierling, MD, FACP, FAASLD Professor of Medicine and Surgery
Chief of Hepatology Director of Advanced Liver Therapies
Baylor College of Medicine Houston, Texas
2
In Memoriam
Thomas E. Starzl, M.D., Ph.D.
1926-2017
Pioneer in solid organ transplantation:
Liver
Kidney
Multi-organ
Pioneer in immunosuppression:
Cyclosporine
Tacrolimus
Micro-chimerism
Icon:
Educator and mentor
Advocate for patients
and families
Champion of hepatology
3
Past
MICHAEL E. DEBAKEY
DEPARTMENT OF
SURGERY
4
History of Transplantation
1902 1983 1963 1936 1954 2002 1998 1994 1989
First attempt at kidney transplant
First attempt at kidney transplant
with human kidney
First pediatric living donor
liver transplant
Cyclosporine FDA approved
First liver transplant
First successful kidney transplant
First US adult living donor liver transplant
Tacrolimus FDA approved
MELD implemented
5
Initial Kidney Transplant Attempts:
Year Location Surgeon Procedure
1902 Lyon Alex Carrel Dog kidney tx into dog neck
1902 Vienna Emerich Ulmann Dog kidney tx into goat
1906 Lyon Mathieu Jaboulay Pig kidney tx into
antecubital fossa
1909 Berlin Ernest Unger Monkey kidney tx into thigh
1936 Kherson Yu Voronoy First kidney tx using
cadaveric human donor
1954 Boston Joseph Murray First successful kidney tx
1956 Boston Joseph Murray First tx using
immunosuppression
6
Experimental Kidney Transplantation
7
First Successful Kidney Transplant
8
Experimental Liver Transplantation
9
First Liver Transplant
March 1, 1963: First
attempted human
liver transplant
July 23, 1967: First
successful human
liver transplant
10
First Attempts in Liver
Transplantation: 1963-1964
No. Location Age Disease Survival Death
1 Denver 3 BA 0 days hemorrhage
2 Denver 48 HCC 22 days sepsis, PE
3 Denver 68 HCC 7 days sepsis, PE
4 Denver 52 HCC 6 days liver failure
5 Boston 58 Mets. 11 days sepsis
6 Denver 29 HCC 23 days sepsis
7 Paris 75 Mets. 0 days hemorrhage
11
First Successful Multi-Organ Donor: 1968
12
Post-Moratorium Successes
Starzl TE. J Am Coll Surg 2002; 195:587.
Anti-lymphocyte
globulin (ALG) & the
“triple cocktail”
Improved organ
preservation
Codifying definition
of “brain death”
13
Subsequent Progress
UCHSC (Denver) program, 1967-1983
1 year survival ~ 30%
ALG, Prednisone and Imuran
Introduction of cyclosporine, 1983
1-year survival increased to ~ 70%
Introduction of tacrolimus (Prograf), 1996
1-year survival ~ 85%
14
• 1968 Ad Hoc Committee of Harvard Medical School Published Criteria for Brain Death
• 1968 Uniform Anatomical Gift Act
• 1978 Uniform Brain Death Act
• 1983 NIH Consensus Development Conference:
• “…Liver Transplantation is a therapeutic modality for
National standardized anoxic adult liver donors vs CDC drug overdose rate
Anoxic Adult Liver Donors perMillion Adult Population
CDC National Drug OverdoseRate per 100,000 Population
Linear (Anoxic Adult LiverDonors per Million AdultPopulation)
Linear (CDC National DrugOverdose Rate per 100,000Population)
Goss M., et al. Liver Transplantation (2017)
48
0
0.5
1
1.5
2
2.5
3
3.5
2002 2015
Pe
r M
illio
n P
op
ula
tio
n
UNOS Designation Drug Overdose
+750%
Accounts for 30% of the SURGE Goss M., et al. Liver Transplantation (2017)
49
R² = 0.0069
-40
-20
0
20
40
60
80
100
120
140
0 50 100 150 200 250 300
2002
-20
15 A
DU
LT L
IVER
DO
NO
RS
PER
MIL
LIO
N P
ERC
ENT
CH
AN
GE
(%)
2002-2014 DRUG OVERDOSE RATE PER 100,000 PERCENT CHANGE (%)
Linear regression analysis for change in CDC drug overdose rates vs. change in liver donors pmp by
state
Goss M., et al. Liver Transplantation (2017)
50
Association
Drug Abuse amongst Brain Dead Donors
Social History
Positive Tox Screen
Positive Tox Screen and Social History
No evidence of drug abuse
Goss M., et al. Liver Transplantation (2017)
11%
16%
20%
47%
51
52
53
54
When did it start and when will it end?
55
We need to plan ahead.
2004:
22 states with primary seat belt laws2
11 states with booster seat laws3
25 states with new driver passenger
restrictions5
35 states with new driver nighttime
restrictions5
2007: 38 states with booster seat laws3
2012:
34 states with primary seat belt laws2
44 states with new driver passenger restrictions5
48 states with new driver nighttime restrictions5
Yoeli D., et al. submitted for publication
56
Key Points
• Increasing the donor supply is the best strategy to improve intent-to-treat outcomes.
• 500,000 donors have provided over 2 million years of life.
• The Supply and Demand disparity is 1:2 • There is a recent surge in donors. • The surge correlates with anoxic death donors • The surge is likely linked to the Opioid Epidemic • We need to plan ahead and secure other sources
of donors.
57
Flemming JA. AASLD 2016. Poster LB-23.
Cohort Study of 47,591 Adults in the UNOS Scientific Registry of Transplant Recipients Database 2003-2015
‡
Annual Standardized Incidence Rates (ASIR) of LT Wait-Listing per 100,000 US Population
HCC
PI Interferon DAA
2003
2005
2007
2009
2011
2013
2015
0
1
2
3
4
5
Decompensated cirrhosis
PI Interferon DAA
2003
2005
2007
2009
2011
2013
2015
0
1
2
3
4
5
6
LT
WL
rate
per
100,0
00 U
S
po
pu
lati
on
Overall
PI Interferon DAA
2003
2005
2007
2009
2011
2013
2015
0
1
2
3
4
5
6
7
8
9
10
Year of wait-list registration
HCV HBV NASH
Listing rate for decompensated HCV cirrhosis decreased by 32% in the DAA era
compared to the IFN era and is now equal to that of NASH
Reduction in Liver Transplant Wait-List in DAA Era
58
Goldberg et al. Gastroenterology 2017.
Indications for Wait Listing for OLT Non- HCC
0
500
1,000
1,500
2,000
2,500
3,000
3,500
4,000
Ab
solu
te n
um
be
r o
f liv
er
tran
spla
nts
HCV
EtOH
NASH/Cryptogenic
Other diagnoses
59
Use of HCV Positive Donors Increasing Proportion of HCV+ Recipients Receiving Younger HCV+ Donors
Stewart, D., 2017 unpublished, based on OPTN data
Bowring MG, AJT, 2017;17:519-527
Percentage of HCV+ Recipients Receiving HCV+ Donors in U.S.
Median Donor Age by Recipients HCV Status
60
Carrillo F, Hepatology 2017, Feb 7
While MELD scores improve in majority, there remains a risk of liver-related mortality for those with higher baseline MELD
MELD Improvement Good but Survival Benefit is What is Needed
61
Treatment of Listed HCV Patients with Decompensated Cirrhosis
Saxena V et al. Clin Liver Dis 2015
HCV cure improves MELD
in majority
Important if borderline
function for LRT
Survival appears high if
low baseline MELD
~20% may avoid need for
liver transplant
Proportion (~30%+) will
end up in MELD purgatory
May limit access to HCV+
donors
62
Can Modeling Help Decide Who Should be Treated?
-1
0
1
2
3
4
5
6
7
8
9
10
10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40
Diffe
ren
ce in
Life
Ye
ars
(P
re-L
T v
s P
ost-
LT
)
MELD Score
Difference in life years if HCV is treated pre-LT versus post-LT
Chhatwal J, Hepatology 2017;65:777-788
Markov-based stimulation model compares survival in treating U.S. patients on the waiting list without HCC with MELD scores 10-40 with direct-acting antivirals (DAAs)
Threshold for treating with DAAs pre-LT was MELD ≤27
63
Variations in Results by UNOS Regions: UNOS Region 3: Shortest Waiting Time
-1
0
1
2
3
4
5
6
7
8
9
10
10 14 18 22 26 30 34 38
Diffe
ren
ce in
LY
s
(Pre
-LT
vs P
ost-
LT
)
MELD Score
Pre-LT Treatment Improves Life Expectancy if MELD ≤23
Chhatwal J, Hepatology 2017;65:777-788
64
HCV Treatment Pre- OR Post-LT? UNOS Region 9: Long Waiting Time
-1
0
1
2
3
4
5
6
7
8
9
10
10 14 18 22 26 30 34 38
Diffe
ren
ce in
LY
s
(Pre
-LT
vs P
ost-
LT
)
MELD Score
Pre-LT Treatment Improves Life Expectancy if MELD ≤27
Chhatwal J, Hepatology 2017;65:777-788
65
HCV-Treatment of Wait-Listed Patients
For liver transplant candidates, treatment needs to be careful consideration of: Risk of dying in absence of treatment Anticipated timeline for improvement in decompensation Prioritization for LT and potential harm if some but not enough
improvement
Available data suggests those with MELD <20-27 points likely derive clinical benefit Delisting and/or survival benefit MELD cut-off strongly influenced by waiting time Other factors of importance may be concurrent HCC (and need
for LRT) and availability of HCV+ donors
There is high need for high quality longitudinal studies of wait-listed patients and predictors of outcomes
66
Future
MICHAEL E. DEBAKEY
DEPARTMENT OF
SURGERY
67
“Predictions are dangerous, especially ones about the future.”. Lorenzo Pietro “Yogi” Berra
The Future
1925-2015
68
Global Impact of Chronic Liver Diseases Prevalence of Cirrhosis Per 100,000 Persons
Alcohol cause of 47.9% cirrhosis*
* Rehn H, et al J Hepatol 2013; 59:160-68
69
Unmet Need for Donor Organs Major Options
Increase Donor Supply
Change Allocation System
Change from Opt In to
Opt Out policy
Increase live donation
Perfect xenografts
Develop bioengineered
organs
Change from sickest
first to highest utility
policy
Rational rationing
Revise UNOS Regions
70
Unmet Need for Donor Organs Better Long-Term Option
Prevent Chronic Liver Diseases
and Progression to Cirrhosis
Addresses root causes
Cost effective
Greatest long-term benefits
Requires Societal and
Pharma commitment to
translational research and
development of new therapies
and diagnostics
71
Translational Medicine: Need for Greater Bidirectional Balance
and More Academic-Industry Partnerships
“Bench” “Bedside”
Oversold Promises
$1.4 billion/NDA
Under Appreciated Promise to Define
Pathogenic Mechanisms* Personalized Therapies
*Brenner, S, 2012
72
You see things and you say, “Why?” But I dream things that never were and say, “Why not?” George Bernard Shaw