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HARVEY J. ALTER, MD, MACP
Distinguished NIH Scientist Chief, Infectious Diseases
Associate Director for Research Department of Transfusion
Medicine Clinical Center, NIH
TIMELINE OF HEPATITIS HISTORY
2000 YEARS
425-350 BC
1960’s
First to Describe: • Ikterus • Kirros
Campaign jaundice Vaccine jaundice Hep A vs. Hep B
Physician, first, do no harm THE OATH
JAMA 1965;191:541
Baruch S. Blumberg, Harvey J. Alter, Sam Visnich
HEPATITIS B: THE INFANT YEARS
Ø 2 billion people worldwide have been infected Ø ~ 350 million chronic carriers Ø Leading cause of cirrhosis and HCC worldwide
Ø Causes 80% of all HCC in Asian Americans
Ø 30% to 50% of HCC associated with HBV occurs in the absence of cirrhosis
Ø Second only to tobacco in causing the most cancer deaths
Ø HBV is 50-100 times more infectious than HIV
HBV: A Global Problem
HBsAg Prevalence
>8% - High 2-7% - Intermediate <2% - Low
Immigration numbers summed by continent from 1996-2002
~2 million Asians
~400,000 South Americans
~350,000 Africans
~930, 000 Europeans
Geographic Prevalence of Chronic Hepatitis B Impacted by Migration
Transfusion and transplant recipients
Individuals with multiple
sexual partners
Healthcareworkers
Newborns of long-term carriers
Intravenousdrug users
Prisoners and other institutionalised people
Transmission of Hepatitis B Infection
Health care injectionsin developing countries
0 20 40 60 Years
Immune tolerant
Immune clearance HBeAg-positive chronic hepatitis
Inactive carrier state
HBV DNA
Reactivation HBeAg-negative chronic hepatitis
ALT
HBeAg Anti-HBe
Phases of Chronic HBV Infection
Acute Infection
Chronic Infection Cirrhosis Death
30% of chronically
infected
§ > 90% of infected infants progress to chronic disease
§ < 5% of infected immunocompetent adults progress to chronic disease
23% of patients decompensate within 5 yrs of developing
cirrhosis
Liver
Cancer
Chronic hepatitis B is the 6th
leading cause of liver
transplantation in the US
Liver Transplant-
ation
Liver Failure (Decompens-
ation)
Hepatitis B Disease Progression
THE EVOLUTION OF HBV VACCINE: 1970-1975
Ø >95% of immunized subjects developed protective anti-HBs
Ø Vaccine-induced antibody persisted >24 months
Ø Hepatitis attack rate was 3.2% in vaccine recipients versus 25.6% in controls (p<0.0001)
Ø In those who received all 3 doses of vaccine, protective efficacy approached 100%
A RANDOMIZED CONTROLLED TRIAL OF HBV VACCINE IN 1083 HOMOSEXUAL MEN
Chang MH: N Engl J Med. 1997;336:1855
*Nationwide vaccination in Taiwan, implemented July 1984. Time Period Time Period
Incidence
Per 1
00,0
00 C
hild
ren
(6-1
4 Yr
s)
0.70
0.57
0.36
1.0
0.8
0.6
0.4
0.2
0 ‘84‘86 ‘86-90 ‘90-94
Mortality
Per 1
00,0
00 C
hild
ren
(6-1
4 Yr
s)
0.80
0.58
0.34
1.0
0.8
0.6
0.4
0.2
0 81- ‘84-’86
‘86 86-‘90
1990-’90-’94
Effect of HBV Vaccination on HCC Incidence and Mortality*
Yr of Follow-up
Cum
ulat
ive
Inci
denc
e of
HC
C
(%)
N = 3653 Taiwanese patients
Chen CJ, et al. JAMA. 2006;295:65-73.
0
2
4
6
8
10
12
14
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Baseline HBV DNA Level, copies/mL ≥ 1 million
100,000-999,999
10,000-99,999
300-9999
< 300
Cumulative Incidence of HCC by Serum HBV DNA Level at Study Entry
Extended Treatment With Nucleos(t)ide Analogues vs Limited Duration (1 Yr) Peginterferon Treatment
Entecavir Tenofovir Peg IFN
Und
etec
tabl
e H
BV
DN
A (%
)
90 93 87 91
1 Yr 2 Yrs 3 Yrs
100
80
60
40
20
0
63
15 16 NA
10096
Undetectable HBV DNA Over Time in HBeAg-Negative Patients
73
96
0
20
40
60
80
Histologic Improvement Fibrosis Improvement
Patie
nts
(%)
100
32
88
n = 41 55 18 50
Wk 48 Long-term
Chang TT, et al. Hepatology. 2010;52:886-893.
Histologic Responses With Long-term Entecavir (Median Duration 6 yrs)
SUMMARY HEPATITIS B PREVENTION AND TREATMENT CIRCA 2016
PRIMARY PREVENTION: HBV vaccine with >95% protective efficacy at reasonable cost is currently available Future need: Universal birth vaccination on global scale; If achieved, conceivable that HBV infection can be eradicated over 3-5 generations.
TREATMENT: • At present, HBV cannot be cured because an intranuclear
driver of replication, “covalently closed circular DNA (cccDNA)” is not targetable by current drugs
• Development of cirrhosis and HCC strongly correlates with the serum level of HBV DNA
• HBV DNA can be suppressed to non-detectable with existing nucleot(s)ide inhibitors
• Long term suppression of HBV DNA results in reduction in existing fibrosis and lower incidence of cirrhosis and HCC
Ø 1978: Water-borne epidemic in Kashmir caused 20,000 icteric cases; 700 FH; 600 deaths; not HAV
Ø 1980: Epidemic hepatitis among Russian soldiers in Afghanistan; not HAV related
Ø 1983: Dr. Balayan (Russia) swallows fecal extract from 9 acute cases in the Afghan epidemic and recovers 27-30nm VLP from his acute phase stool
Ø CDC recovers identical VLP from macaques inoculated with acute phase stool; serial passage
Ø 1990: Bile from cyno macaques used in differential hybridization to clone HEV (Reyes, G: Gene Labs)
HEV: HISTORY
Family: Hepeviridae Genus: Hepevirus
Nonenveloped, 27-34 nm, ssRNA
4 Genotypes: 1-4 1 Serotype
Purcell RH et al, 2008
Feature Genotype 1 Genotype 3 (Epidemic) (Endemic)
Sex (M:F) 1:1 3:1 Age 20-45 yrs 40-80 yrs 2nd Spread Uncommon Not known Source Water Food Agent Human Swine Seasonality Yes Usually not Fatality rate Pregnancy Elderly Extrahepatic Yes (Pancreas) Yes (CNS) Chronicity No Yes (immune
deficient)
Genotype 1 vs 3 Hepatitis E
Study Year Assay Pop. Tested
No. Tests
IgG Anti-HEV
IgM Anti-HEV
CDC NHANES
1988-1994
NIH “in-house”
US Pop. Survey
18,695 21.0% NT
CDC NHANES
2009-2010
Diagnost Systems
US Pop. Survey
8,814 6.0% 0.5%
NIH 2006 Wantai Donors 916 21.8% 0.4%
NIH 2012 Wantai Donors 1,023 16.0% 0.4%
ARC 2014 MP BioMed
Donors 4,499 7.3% 0.58%
SEROPREVALENCE OF ANTI-HEV: STUDIES IN UNITED STATES
Ø Gastro Elitism Movement including wild boar pappardelli, pigs feet Milanese
Ø Figatelli (raw pork sausage) favorite in Southern France; seared pork liver favorite in Netherlands
Ø Scrapple, popular in US south, made from pig heads and liver
Ø Liver slime from pig feces is pooled and used to irrigate soil and plants
(don’t forget to eat your veggies) Ø 11% of raw pig liver in US markets tested
HEV RNA+
How Does One Acquire Gt-3 HEV Infection In Non-Endemic Countries?
CDC Lab Based Surveillance for HEV Infection in the US 2005-2012
154 Clinical Non-A,B,C Hepatitis Cases Referred to CDC
26 (17%) HEV infected
11 traveled to endemic area
15 non-travelers “autochthonus”
Mean Age 32 61 Icteric 92% 47%
Organ Transplant 0 47% Gt3 0/4 8/8
Fulm. Hep Failure 0 3
Ø Previously thought to be self-limited, now multiple cases of chronic HEV infection have been reported in liver and kidney transplant recipients, in patients with lymphoma on rituximab and in HIV/AIDS.
Ø Common denominator is immunosuppression Ø Almost all cases represent HEV Gt3 infection in
non-endemic regions Ø Persistent viremia with titers 10e5-10e7 cop/ml Ø Evolution to cirrhosis occurs in up to 50% of
chronic infections and can occur in 2-5 years Ø Rare cause of acute liver failure in US (<1%); most
cases of severe HEV represent “acute on chronic,” i.e., HEV superimposed on prior liver disease
PARADIGM SHIFT IN PERCEPTION OF HEV INFECTION
Clinical Course of Transfusion-Transmitted HEV: First case in Japan
Matsubayashi K. Transfusion 2004;44:934
0 2 4 6 8 10 12 14 16 18 20
0 200 400 600 800
1000 1200 1400 1600 1800 2000
-10 8 18 50 60 72 82 92 110
Tot
al b
iliru
bin
mg/
dL
AST
IU/L
Days after transfusion -1 20 0 10 40 6 70 130 9
Donor ALT HEV RNA IgM a-HEV
IgG a-HEV
Prior Donation 11 Neg Neg Neg Index Donation 10 Pos* Neg Neg F/U @ 5 months 8 Neg Pos Pos * Complete sequence identity with recipient (Gt 4)
6/18 donors unrelated to this case who had ALT >500 were HEV RNA+; 5/6 IgM+
DETECTION OF HEV RNA IN HEALTHY BLOOD DONORS
COUNTRY HEV RNA POSITIVE
FREQUENCY
Scotland 0.007% 1:14,520
Sweden 0.013% 1:7,986
Germany 0.022% 1:4,525
Ireland 0.030% 1:8409
England 0.035% 1:2,848
Japan 0.012% 1:8,185
US (ARC) 0.011% 1:9,414
Asymptomatic Viremia
Significant Clinical Disease
Proven Transfusion- Transmission
Test or
Not?
THE TRIANGLE OF TRANSFUSION TESTABILITY
At an average of 0.01% HEV RNA+
donors and 14 million donations, 1400 HEV viremic donations might be transfused in
US/year
LONG-TERM EFFICACY OF HEV VACCINE
A randomized controlled trial in China comparing 56,302 HEV vaccine recipients with 56,302 HBV
vaccine recipients. F/U=4.5 years.
Vaccine # HEV Cases
Cases/10,000 person-years
HEV Gt 4
HEV (3-dose) 7 (0.01%) 0.3 3 (43%)
HBV (3-dose) 53 (0.09%) 2.1 23 (43%)
Vaccine efficacy: 87% (mod. ITT) Anti-HEV maintained at least 4.5 yrs.
Jun Zhang: NEJM 2015
SWINE ARE NOT BENIGN COOK WELL BEFORE YOU DINE
Post-Transfusion Hepatitis at NIH-1
Post-Transfusion Hepatitis at NIH-2
Post-Transfusion Hepatitis at NIH-3
Transmitted From • Asymptomatic patients with
chronic hepatitis • Asymptomatic implicated donors
Post-Transfusion Hepatitis at NIH-4
A POEM OF FRUSTRATION
While the clinical severity of NANBH became increasingly evident over the next
decade, no serologic, enzymatic, radioimmunologic or early molecular
method led to a specific NANB assay or further elucidated the nature of the agent.
“I Can’t See The Forest
For The HB Ags”
Post-Transfusion Hepatitis at NIH-5 Estimated that in US, transfusion
may have transmitted: • 4.8 million HCV infections from
1970-1990 • HCV testing prevented 2.4 million
transmissions from 1990-2010
60-70%!
20-30%!Cirrhosis in 15-40
years!
Cirrhosis in 5-10 years!
< 5%!
Assuming no change in standard of care, cases of decompensated cirrhosis, HCC and need for tspl. will inc.>4-fold in next 10-20 yrs.
SVR
(%)
IFN PegIFN/ RBV
IFN IFN/RBV PegIFN
2001
1998
2011
Standard interferon
Ribavirin
Peginterferon
1991
Direct-acting antivirals
PegIFN/RBV/PI
IFN/RBV
6 16
34 42 39
55
70+
0
20
40
60
80
100
Months Rx 6 6 12 12 12 12 6-12
90+
NS5a +NS5b
3
HCV ECONOMICS 101
• 90-98% of HCV-infected patients can be cured with a 12 week course of oral, non-toxic DAAs
• The cost of treatment in US is $50,000-$85,000/case • Cost analyses show treatment to be cost effective
when balanced against cost of end-stage liver disease and liver transplantation
• Cost to Cure: 3.2 million carriers X $50,000 per Tx = 160 billion to cure US alone; 10% of US health-care budget jeopardizing Medicare and other treatments • Is this high cost justified by pharmaceutical research
investment and capitalism or is it usury? • This cost debate is heated for many “blockbuster”
drugs; The difference here is that we are talking CURE after only 8-12 weeks
REMARKABLE ACHIEVEMENTDS OVER 5 DECADES OF HEPATITIS VIRUS RESEARCH
Ø Identification of HBV, HAV, HDV, HEV, NANB/HCV Ø Established strong link between HBV, HDV, HCV and hepatocellular carcinoma Ø Development of vaccines for HBV, HAV and HEV Ø The virtual eradication of post-transfusion hepatitis Ø Successful transplantation for HCC/end-stage LD Ø Highly effective long-termsuppression of HBV replication with oral nucleos(t)ide inhibitors Ø Greater than 90% cure rates in chronic hepatitis C using oral direct acting anti-virals
Is it possible, or even likely, that viral hepatitis can be eradicated over the next 3-5 decades?