HARVEY J. ALTER, MD, MACP Distinguished NIH Scientist ......Genotype 1 vs 3 Hepatitis E Study Year...

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


Transmitted From •  Asymptomatic patients with

chronic hepatitis • Asymptomatic implicated donors

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?

HARVEY J. ALTER, MD, MACP Distinguished NIH Scientist ......Genotype 1 vs 3 Hepatitis E Study Year...

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