The UC San Diego AntiViral Research Center sponsors weekly
presentations by infectious disease clinicians, physicians and
...
HDV: D is for deadly
Robert G. Gish MD
Epidemiology of Hepatitis Delta
Key messages
 An estimated 15-20 Million individuals are infected with HDV
worldwide!
 H...
www.hepatitis-delta.org
Prevalence of Hepatitis Delta
HDV: Modes of Transmissions
Calle Serrano, Manns & Wedemeyer, Seminars in Liver Disease 2012
HDV Infection and Transmissi...
HDV: Modes of Transmissions
Calle Serrano, Manns & Wedemeyer, Seminars in Liver Disease 2012
HBV vaccination prevents fro...
Gaeta, Rizzetto et al., Hepatology 2000
0
5
10
15
20
25
30
0-29 30-49 >50
1987
1992
1997
Age of Patients
%anti-HDV-positiv...
courtesy of Dr Carballo
Migration and viral hepatitis
Germany: Wedemeyer et al., Hepatology 2007
Heidrich et al., J Viral ...
High anti-HDV prevalence in HBsAg-positive
HIV-infected individuals
Sorriano et al., AIDS 2011
Overall prevalence: 14.5%!
1980 1990 2000 2010
ACUTE HEPATITIS DELTA
CHRONIC HEPATITIS DELTA
%ofHBsAg+patients
Hepatitis delta: evolution of clinical...
Different HDV genotypes in different regions!
Wedemeyer & Manns, Nat Rev Gastroenterol 2010
Different HDV genotypes are associated with
different clinical outcomes
Su, Wu et al., Gastroenterology 2006
Su, Wu et al., Gastroenterology 2006
HBV genotypes and outcome of Hepatitis delta
in Taiwan
Multivariate Model and Adverse...
Heidrich et al., Liver International 2012
HBV DNA is frequently suppressed even in
HBeAg+ Hepatitis Delta
Heidrich et al., Liver International 2012
The outcome of
HBeAg-positive vs. HBeAg-negative hepatitis delta
Schaper, Buti et al., J Hepatol 2010; Wedemeyer J Hepatol 2010
Fluctuating Patterns of Viral Dominance
in Hepatitis D
Decreasing HDV infection in High-Risk Groups in Taiwan
Wu et al. Hepatology 1990, J Gastroentrol Hepatol 1993, J Med Virol...
Country Prevalence Author Poster
No
India 15,2%
10,9%
Raja W.A. et al.
Asim M.
82
8
Korea 0.4% (OLT) Jung Y. J. et al. 47
...
Anti-HDV Prevalence among HBsAg-positive patients in Europe
(E.K. Manesis, EASL Special Conference 2010)
Hepatitis B/D
Legal Amazonia
PERU
COLÔMBIA
EQUADOR
VENEZUELA
BRAZIL
Anti-HBc total – >70%
HBsAg - >10%
Anti-HDV ∕ HBsAg+ -...
Reported cases of HDV infection in Brasil
Courtesy of Dr. R. Parana
Cases -2009
Amazon River
near Manaus
16 November 2007
HBV genotype F and H in South America:
A zoonosis?
Courtesy of Dr. R. Parana
North America
Dr. nn
(a well known hepatologist from North America),
September 2012:
“Your work on hepatitis delta is nice...
HDV Epidemiology in the USA
Highly variable: <1% to 30% among chronic HBV carriers!
NHANES IV (CDC: 2003-2004)
1/28 HBsAg+...
HDV Epidemiology in the USA
Kurcirka et al., JID 2010
HDV Epidemiology in the USA:
Northern California
Gish et al., EASL HDV Special Conference 2010
499 HBsAg positive patients...
Europe 43/111 (39%) 101/532 (19%) <0.000001
Smedile et al 1982
USA 24/71 (34%) 5/118 (4%) 0.000016
Govindarajan et al 1984...
138 acute hepatitis D
23 acute superinfection115 acute co-infection
104 resolution
(90%)
10 chronic
hepatitis (8%)
Outcome...
1
4
3
2
5 10 15 Years
FIBROSIS
NATURAL HISTORY
Delta hepatitis and HCC
Early studies: infrequent association due to
diminished life expectancy (Rizzetto & Verme, J Hepat...
Romeo et al, Gastro 2009
HCC vs. hepatic
decompensation in
HDV cirrhosis: a 28 year
follow-up study
And… if you want to be more involved in hepatitis delta:
In Germany, it is likely that more patients
are dying from hepatitis delta than from
HIV infection.
In many other countrie...
Thanks to
Heiner Wedemeyer
J.-M Pawlotsky
Collaborators:
C. Yurdaydin (Ankara, Turkey),
G. Dalekos, K. Zachou, G. Papatheo...
Hepatitis E
Robert Gish, MD,
Hepatitis E- A Major Cause of
Epidemic and Sporadic Hepatitis
Historical Aspects ~1950s
 Retrospective serologic testing of
stored sera confirmed enteric non-A-
non-E hepatitis in New...
… end of 1970s - 1980s
 Kashmir Valley, India
– Nov 1978-April 1979
– 275 clinical cases, 11-40 years old in villages
wit...
Transmission Studies
 Confirmation of new hepatitis
agent was demonstrated by
Dr. Michael Balayan in a
volunteer self-ino...
Hepatitis E Virus (HEV)-
Breakthrough of 1990s
Genelabs
 1990: Reyes isolated a nucleic acid clone
representing part of h...
Laboratory Diagnostic Events
in Acute Hepatitis Е
A Modern Outbreak of Hepatitis E,
Uganda 2007-2009
Distribution of cases of jaundice during an epidemic of hepatitis E in
...
HEV Taxonomy and
Molecular Virology
Genus- Hepevirus
Family- Hepeviridae
Genome: Single-stranded
linear RNA ~7.2 kb
Open R...
Onset of HEV Infection
 Mean incubation period: 6 w (2–9 w)
 Hepatitis-like signs and symptoms:
– jaundice, fever, loss ...
Progress of Disease
 Attack rate are highest in young adults
15-40 years
 Acute hepatitis E is frequently self-
limited
...
Hepatitis E in Organ
Transplant Recipients (OTR)*
 Solid OTR are at risk for acute and chronic
HEV infection.
 Overall p...
Natural History of Hepatitis E
in OTR*
 Acute hepatitis characterized by modest ALT
elevation- median ~150 U/L (0.5-26 UL...
Hepatitis E as a Cause of
Acute Liver Failure*
 The US ALF Study Group has enrolled
>1800 adults since 1998
 Final analy...
Hepatitis E Vaccines*
 In animal studies, several truncated recombinant
HEV capsid protein have been found to induce
spec...
Recombinant
Hepatitis E Vaccines*
 The first human vaccine contained VLPs made up of a 56-kD
truncated genotype 1 HEV ORF...
Hepatitis E Vaccine
Application*
 Whether HEV vaccines should be used for the
general population in highly endemic areas ...
Hepeviridae- Proposed
Classification and Host Range*
HEV Natural Host
Genus Hepevirus
Genotype 1 human
Genotype 2 human
Ge...
Hepatitis E in the United States
In US hepatitis E is not reportable
Previously thought to be mostly associated with trave...
Objective
 To describe the characteristics of
incident cases of hepatitis E and
seroprevalence of HEV infection in the
Un...
Case Definition
 A case of hepatitis E was defined as illness in a
person in whom IgM and IgG against HEV in serum
or HEV...
Methods
Assays:
IgM and IgG anti-HEV (DSI-EIA)
HEV RNA in serum and/or stool
Screening
Real time RT PCR
Sequencing/Genotyp...
Evaluation of IgM anti-HEV
Assays
Assay
Analytic
Sensitivity
WRU/mL
Clinical
Sensitivity
(N=51; GT1-4)
Specificity
(N=228)...
Genetic relatedness among hepatitis E virus
(HEV) strains identified in hepatitis E cases,
United States
Active Laboratory-based
Surveillance (ongoing)
 Confirmatory testing referral of all anti-HEV
screening-positive specimen...
Hepatitis E Virus Infection in
HIV-infected Persons
 To determine whether hepatitis E virus (HEV) is a
cause of hepatitis...
What is the National
Seroprevalence of anti-HEV?
● Kuniholm et al* tested a nationally
representative sample of 18,695 ser...
Comparison of NHANES III and IV
1988-94 (N= 18,695)
2009-2010 (N= 7885)
0
5
10
15
20
25
30
35
40
45
6-11
yo
12-19
yo
20-29...
Conclusion
 Hepatitis E indigenous to the United States is more common
than previously thought, especially among middle-a...
Thank You!
Email: jdrobeniuc@cdc.gov
http://www.cdc.gov/hepatitis
Hepatitis D and E: The Forgotten Viruses
Hepatitis D and E: The Forgotten Viruses
Hepatitis D and E: The Forgotten Viruses
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Hepatitis D and E: The Forgotten Viruses

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Dr. Robert G. Gish, MD, of UC San Diego Health System Hepatology Clinic, prsesents "Hepatitis D and E: The Forgotten Viruses"

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Hepatitis D and E: The Forgotten Viruses

  1. 1. The UC San Diego AntiViral Research Center sponsors weekly presentations by infectious disease clinicians, physicians and researchers. The goal of these presentations is to provide the most current research, clinical practices and trends in HIV, HBV, HCV, TB and other infectious diseases of global significance. The slides from the AIDS Clinical Rounds presentation that you are about to view are intended for the educational purposes of our audience. They may not be used for other purposes without the presenter’s express permission. AIDS CLINICAL ROUNDS
  2. 2. HDV: D is for deadly Robert G. Gish MD
  3. 3. Epidemiology of Hepatitis Delta Key messages  An estimated 15-20 Million individuals are infected with HDV worldwide!  Hepatitis Delta is the most severe form of chronic viral hepatitis → No testing – no identification of HDV infection!  The clinical manifestation of hepatitis delta differs between regions and has changed during the last 3 decades  Hepatitis Delta is a dynamic disease: - Both HBV and HDV contribute to disease progression  Migrant populations and special risks groups show particular high HDV prevalences  The HDV genotype matters
  4. 4. www.hepatitis-delta.org Prevalence of Hepatitis Delta
  5. 5. HDV: Modes of Transmissions Calle Serrano, Manns & Wedemeyer, Seminars in Liver Disease 2012 HDV Infection and Transmission requires HBsAg!
  6. 6. HDV: Modes of Transmissions Calle Serrano, Manns & Wedemeyer, Seminars in Liver Disease 2012 HBV vaccination prevents from HDV infection! Intrafamiliar transmission vertical & sexual transmission, infection during early childhood Medical treatment blood transfusion, unsterile syringes, etc. Special risk groups IV drug user, dialysis, HIV+, hemophiliacs. HDV Transmission requires HBsAg!
  7. 7. Gaeta, Rizzetto et al., Hepatology 2000 0 5 10 15 20 25 30 0-29 30-49 >50 1987 1992 1997 Age of Patients %anti-HDV-positive/HBsAg+ Decline of anti-HDV prevalence in Eastern Europe in the 1990ies
  8. 8. courtesy of Dr Carballo Migration and viral hepatitis Germany: Wedemeyer et al., Hepatology 2007 Heidrich et al., J Viral Hepatitis 2009 France: Le Gal et al., Hepatology 2007 UK: Cross et al., J Med Virol 2008 Italy: Stroffolini et al., J Med Virol 2009 Piccolo et al., Eur J Publ Health 2010 Large proportion of immigrants among anti-HDV-positive individuals diagnosed after 2000
  9. 9. High anti-HDV prevalence in HBsAg-positive HIV-infected individuals Sorriano et al., AIDS 2011 Overall prevalence: 14.5%!
  10. 10. 1980 1990 2000 2010 ACUTE HEPATITIS DELTA CHRONIC HEPATITIS DELTA %ofHBsAg+patients Hepatitis delta: evolution of clinical presentation young patients locally acquired special risk groups (IVDU) older patients Immigrant populations special risk groups Severe Acute + Chronic Disease Mild chronic Disease Severe chronic Disease
  11. 11. Different HDV genotypes in different regions! Wedemeyer & Manns, Nat Rev Gastroenterol 2010
  12. 12. Different HDV genotypes are associated with different clinical outcomes Su, Wu et al., Gastroenterology 2006
  13. 13. Su, Wu et al., Gastroenterology 2006 HBV genotypes and outcome of Hepatitis delta in Taiwan Multivariate Model and Adverse Outcome: HBV Genotype C RR 13.4 Age >60 years RR 12.0 HDV Genotype 1 RR 9.8
  14. 14. Heidrich et al., Liver International 2012 HBV DNA is frequently suppressed even in HBeAg+ Hepatitis Delta
  15. 15. Heidrich et al., Liver International 2012 The outcome of HBeAg-positive vs. HBeAg-negative hepatitis delta
  16. 16. Schaper, Buti et al., J Hepatol 2010; Wedemeyer J Hepatol 2010 Fluctuating Patterns of Viral Dominance in Hepatitis D
  17. 17. Decreasing HDV infection in High-Risk Groups in Taiwan Wu et al. Hepatology 1990, J Gastroentrol Hepatol 1993, J Med Virol 2004
  18. 18. Country Prevalence Author Poster No India 15,2% 10,9% Raja W.A. et al. Asim M. 82 8 Korea 0.4% (OLT) Jung Y. J. et al. 47 Pakistan 35,2% 45,3% 40,0% 45,3% Mumtaz K. et al. Zaki M. et al. Bhatti T.A. et al. Memon M. S. et al. 71 7 13 95 Iran 7,6% Azinmehr L. et al. 11 Turkey 2,5% (Izmir) 3,4% (Izmir) 8% (SE) 9% (Ddiyarbakir) Köse S. et al Akpinar Z. . et al Turhanoglu M. et al. Gulsun S. et al. 26 40 41 58 EASL Monothematic Conference Delta Hepatitis 2010 Prevalence of Hepatitis Delta in the Asia-Pacific Region Data presented at the EASL Delta Conference 2010
  19. 19. Anti-HDV Prevalence among HBsAg-positive patients in Europe (E.K. Manesis, EASL Special Conference 2010)
  20. 20. Hepatitis B/D Legal Amazonia PERU COLÔMBIA EQUADOR VENEZUELA BRAZIL Anti-HBc total – >70% HBsAg - >10% Anti-HDV ∕ HBsAg+ - 0 up to 60% Peculiar Fulminant Hepatitis Bolivia Suriname/Guianas Courtesy of Dr. R. Parana
  21. 21. Reported cases of HDV infection in Brasil Courtesy of Dr. R. Parana Cases -2009
  22. 22. Amazon River near Manaus 16 November 2007 HBV genotype F and H in South America: A zoonosis? Courtesy of Dr. R. Parana
  23. 23. North America Dr. nn (a well known hepatologist from North America), September 2012: “Your work on hepatitis delta is nice, but it is not relevant for us. We simply do not find hepatitis delta in the USA”
  24. 24. HDV Epidemiology in the USA Highly variable: <1% to 30% among chronic HBV carriers! NHANES IV (CDC: 2003-2004) 1/28 HBsAg+ individuals was anti-HDV+ (3.6%) Nath et al. Am J Epidemiol 1985: Blood Donors: 1.4% Southeast to 12% Pacific region Weisfuse et al. Hepatology 1989: Homosexual Men: 2% Rizzetto et al. JID 1982; Troisi et al. Blood 1993: Haemophiliacs: 19%; Female Prostitutes 21% Hershow et al. Ann Intern Med 1989: Hepatitis B Carriers in Illinois: 30%
  25. 25. HDV Epidemiology in the USA Kurcirka et al., JID 2010
  26. 26. HDV Epidemiology in the USA: Northern California Gish et al., EASL HDV Special Conference 2010 499 HBsAg positive patients → 42 (8%) anti-HDV positive R Gish 2013 JGH
  27. 27. Europe 43/111 (39%) 101/532 (19%) <0.000001 Smedile et al 1982 USA 24/71 (34%) 5/118 (4%) 0.000016 Govindarajan et al 1984 Fulminant Acute Hepatitis B Hepatitis B p value Proportion of patients with evidence of HDV in acute self limited vs. fulminant hepatitis B Chronicity infrequent: 5/208 patients (2.4%) Caredda et al 1987
  28. 28. 138 acute hepatitis D 23 acute superinfection115 acute co-infection 104 resolution (90%) 10 chronic hepatitis (8%) Outcome of Acute Delta Hepatitis Buti et al, J Viral Hepat 2010 (in press) 23 chronic hepatitis (100%)
  29. 29. 1 4 3 2 5 10 15 Years FIBROSIS NATURAL HISTORY
  30. 30. Delta hepatitis and HCC Early studies: infrequent association due to diminished life expectancy (Rizzetto & Verme, J Hepatol 1985) A European wide study reported a 3.2 fold increased risk compared to mono-infected pts (p<0.05); some risk for hepatic decompenstaion (2.2 fold, p= NS) (Fattovich et al, Gut 2000)
  31. 31. Romeo et al, Gastro 2009 HCC vs. hepatic decompensation in HDV cirrhosis: a 28 year follow-up study
  32. 32. And… if you want to be more involved in hepatitis delta:
  33. 33. In Germany, it is likely that more patients are dying from hepatitis delta than from HIV infection. In many other countries the scenario might be similar. What can we do?
  34. 34. Thanks to Heiner Wedemeyer J.-M Pawlotsky Collaborators: C. Yurdaydin (Ankara, Turkey), G. Dalekos, K. Zachou, G. Papatheodoridis (Larissa, Greece), T. Bock (RKI, Berlin, Germany), E. Herrmann (Frankfurt, Germany), E. Gordien, J.M. Pawtlosky (Paris, France), H.P. Dienes (Cologne, Germany) A. Erhardt (Düsseldorf, Germany) The Hep-Net International Delta Hepatitis Study Group!
  35. 35. Hepatitis E Robert Gish, MD,
  36. 36. Hepatitis E- A Major Cause of Epidemic and Sporadic Hepatitis
  37. 37. Historical Aspects ~1950s  Retrospective serologic testing of stored sera confirmed enteric non-A- non-E hepatitis in New Delhi (1955- 1956) – November 1955: Flooding of Yamuna river and contamination of city water – 29,000 icteric cases  Highest attack rate in adults – Wang DC et al., Lancet 1980; 2
  38. 38. … end of 1970s - 1980s  Kashmir Valley, India – Nov 1978-April 1979 – 275 clinical cases, 11-40 years old in villages with common water source, among 16,620 inhabitants – Rate of fulminant hepatitis was 4.4%  Khuroo MS. Am J Med 1980; 68  Former soviet republics of Central Asia- Turkmenistan, Kyrgyzstan, Uzbekistan, 1980 and 1986 Ketiladze / Favorov / Shahgildyan  Smaller outbreaks: India (1982), Nepal (1984), Algeria (1985), Mexico (1986)
  39. 39. Transmission Studies  Confirmation of new hepatitis agent was demonstrated by Dr. Michael Balayan in a volunteer self-inoculation with pooled fecal material  12 August 1981  Day 36: Acute hepatitis  Duration: 3 weeks  Days 28-45: in IEM aggregates of 27-30 nm VLP from stool with sero- conversion sera, but not hep A, B or PT NANB Two Cy macaques inoculated with stool suspension from the experiment showed excretion of same VLP, LFT elevation and histological changes in liver
  40. 40. Hepatitis E Virus (HEV)- Breakthrough of 1990s Genelabs  1990: Reyes isolated a nucleic acid clone representing part of hepatitis E viral genome from bile of an experimentally-infected animal.  1991-1992: Tam and Huang sequenced entire HEV genome showing heterogeneity of Asian and Mexican isolates- genotypes 1 and 2, respectively.  1992: Dawson developed first anti-HEV EIA showing that IgM is a short-lived marker of recent infection  1992-2000: Improvement of serologic assays and development of molecular tests
  41. 41. Laboratory Diagnostic Events in Acute Hepatitis Е
  42. 42. A Modern Outbreak of Hepatitis E, Uganda 2007-2009 Distribution of cases of jaundice during an epidemic of hepatitis E in Kitgum District, Uganda (N = 7,919), by week of report, October 2007 through January 2009 Teshale, et al., Emerg Infect Dis. 2010;16:126-9
  43. 43. HEV Taxonomy and Molecular Virology Genus- Hepevirus Family- Hepeviridae Genome: Single-stranded linear RNA ~7.2 kb Open Reading Frames: 3 Capsid gene (ORF2); 660 aa Genotypes: 4 Single serotype Spherical, non- enveloped, icosaedral particle ~32-34 nm Ø
  44. 44. Onset of HEV Infection  Mean incubation period: 6 w (2–9 w)  Hepatitis-like signs and symptoms: – jaundice, fever, loss of appetite, abdominal pain, lethargy – High ALT  Viremia is usual, lasting for 2 weeks  Viruses are excreted into the bile and shed in the feces for 4 weeks
  45. 45. Progress of Disease  Attack rate are highest in young adults 15-40 years  Acute hepatitis E is frequently self- limited  Chronic hepatitis E is recognized in organ transplant recipients  Mortality: overall 0.5% - 4.0% – in pregnant women: ~20%
  46. 46. Hepatitis E in Organ Transplant Recipients (OTR)*  Solid OTR are at risk for acute and chronic HEV infection.  Overall prevalence: 1.8% - 11.3%  Prevalence of chronic HEV infection defined by persistent viremia: 0-6.5% (median 0.8%)  Only genotype 3 reported  Most common risk factors: consumption of game and domestic meat *Data from NIH HEV Scientific Workshop, Bethesda, 26 March 2012
  47. 47. Natural History of Hepatitis E in OTR*  Acute hepatitis characterized by modest ALT elevation- median ~150 U/L (0.5-26 ULN)  Spontaneous clearance occurs in ~40% cases – More frequently among those infected later after the transplantation  Viral clearance not always associated with development of anti-HEV IgG  Reactivation in persons previously exposed (IgG anti- HEV) does not occur- no need for special monitoring  For those with chronic HEV infection cirrhosis can occur within 2-3 years in some cases *Data from NIH HEV Scientific Workshop, Bethesda, 26 March 2012
  48. 48. Hepatitis E as a Cause of Acute Liver Failure*  The US ALF Study Group has enrolled >1800 adults since 1998  Final analysis was conducted on 699 – 3/699 (0.4%) tested igM anti-HEV + – 2 had high titer of IgG anti-HEV – No HEV RNA detected  Conclusion: Acute HEV infection is rare cause of ALF in the United States *Data from NIH HEV Scientific Workshop, Bethesda, 26 March 2012
  49. 49. Hepatitis E Vaccines*  In animal studies, several truncated recombinant HEV capsid protein have been found to induce specific a antibodies, and to protect against liver injury following subsequent challenge with homologous and heterologous strains of the virus.  An HEV DNA vaccine has also been shown to induce serum anti-HEV antibodies in cynomolgus macaques, and protect against a heterologous challenge. *Aggarval R., JGH 2011; 26; Suppl. 1
  50. 50. Recombinant Hepatitis E Vaccines*  The first human vaccine contained VLPs made up of a 56-kD truncated genotype 1 HEV ORF2 protein (aa 112–607) produced in Spodoptera frugiperda cells infected with a recombinant baculovirus. – Ph II-III: 20ug administered to 2000 Nepalese solders at 0, 1, 6 m. – Efficacy rate was dose dependent: 3-doses – 95%; 2-doses – 86%  The second vaccine- HEV 239 vaccine, contains a more truncated HEV capsid protein (aa 368–606) expressed in Escherichia coli – Ph II-III: 30ug administered to 113,000 volunteers in China at 0, 1, 6 m. – Efficacy rate was not dose dependent: 3 and 2-doses – 100% – The Chinese vaccine has been shown to provide protection against genotype 4 HEV infections, even though it is based on genotype 1 virus *Aggarval R., JGH 2011; 26; Suppl. 1
  51. 51. Hepatitis E Vaccine Application*  Whether HEV vaccines should be used for the general population in highly endemic areas will depend on: – cost considerations, – the duration of protection afforded by the vaccines and – need for booster doses and the ability of the vaccines to interrupt transmission of infection.  Neither vaccine has currently reached the market. *Aggarval R., JGH 2011; 26; Suppl. 1
  52. 52. Hepeviridae- Proposed Classification and Host Range* HEV Natural Host Genus Hepevirus Genotype 1 human Genotype 2 human Genotype 3 human, pig, deer, mongoose, rabbit Genotype 4 human, pig Putative Gt 5 rats Putative Gt 6 Wild boar Putative Genus Avihepeviridae Genotype 1 chicken (Australia) Genotype 2 chicken (USA) Genotype 3 chicken(Europe and China) Putative Genus Piscihepevirus Cutthroat throut virus fish *XJ Meng, Hepatitis E in US/An NIH Research Workshop, March 26, 2012
  53. 53. Hepatitis E in the United States In US hepatitis E is not reportable Previously thought to be mostly associated with travel to hyperendemic regions 1995 and 2004 – Several case reports of isolated autochthonous acute hepatitis E cases in MN, CA, AZ and TX* were published *Amon et al., JMV 2006
  54. 54. Objective  To describe the characteristics of incident cases of hepatitis E and seroprevalence of HEV infection in the United States – Passive laboratory-based surveillance (2005-2012) – Active laboratory-based surveillance (2009-ongoing) – National sero-survey
  55. 55. Case Definition  A case of hepatitis E was defined as illness in a person in whom IgM and IgG against HEV in serum or HEV RNA in serum or stool samples were detected.  A person in whom IgM but not IgG against HEV was detected in serum was excluded unless HEV RNA was found or IgG againstHEV was detected in follow- up serum samples.  A person in whom IgG but not IgM against HEV was detected in serum samples was included if HEV RNA was found in serum or stool samples.
  56. 56. Methods Assays: IgM and IgG anti-HEV (DSI-EIA) HEV RNA in serum and/or stool Screening Real time RT PCR Sequencing/Genotyping Conventional RT PCR Questionnaire addressed demographics, Clinical signs and biochemical indicators, Major risk factors The information was not available for all patients
  57. 57. Evaluation of IgM anti-HEV Assays Assay Analytic Sensitivity WRU/mL Clinical Sensitivity (N=51; GT1-4) Specificity (N=228) I - 56kD (NIH) NT 98% 78.5% II - p166 (CDC) NT 98% 93.4% III - IID 120 82% 92.1% IV - MP 250 72% 93% V – DSI 10 98% 95.2% VI - Mikrogen 50 90% 95.6% Drobeniuc J et al., Clin Infect Dis 2010; 51:e24-7
  58. 58. Genetic relatedness among hepatitis E virus (HEV) strains identified in hepatitis E cases, United States
  59. 59. Active Laboratory-based Surveillance (ongoing)  Confirmatory testing referral of all anti-HEV screening-positive specimens from >40 diagnostic laboratories  Sep 2009 – Aug 2012 – De-duplicated and analyzed n=829 – Hepatitis E (IgG & IgM anti-HEV+) n=227 (27.4%)  HEV PCR and genotyping - Underway – Males 53% – Median age 50 yr (3-94)  >51 yr 44%  Risk factors assessment is ongoing
  60. 60. Hepatitis E Virus Infection in HIV-infected Persons  To determine whether hepatitis E virus (HEV) is a cause of hepatitis among HIV-infected persons, we evaluated 1985–2009 data for US military beneficiaries.  Evidence of acute HEV infection was detected for 7 (4%) of 194 people with HIV infection. – Prior HEV infection was detected in 5 (3%).  HEV might be a cause of acute hepatitis among HIV-infected persons. Crum-Cianflone N et. al. Emerging Infectious Diseases 2012;18: 502-506
  61. 61. What is the National Seroprevalence of anti-HEV? ● Kuniholm et al* tested a nationally representative sample of 18,695 serum samples from the US population for anti-HEV IgG antibodies using a research (non- commercial) enzyme immunoassay ● Serum from NHANES, 1988-1994, showed, overall, 21% anti-HEV IgG * Kuniholm et al, J Infect Dis 2009; 200:48-56
  62. 62. Comparison of NHANES III and IV 1988-94 (N= 18,695) 2009-2010 (N= 7885) 0 5 10 15 20 25 30 35 40 45 6-11 yo 12-19 yo 20-29 yo 30-39 yo 40-49 yo 50-59 yo 60-69 yo 70+ yo 1988-1994 2009-2010
  63. 63. Conclusion  Hepatitis E indigenous to the United States is more common than previously thought, especially among middle-aged males  Hepatitis E virus infects organ transplant recipients and immuno-compromised individuals leading to chronic infection  Hepatitis E should be considered in the differential diagnosis of suspected viral hepatitis regardless of the patient's travel history  Decrease in sero-prevalence of HEV infection over last 20 years requires further investigation  The health-burden it imposes, and the role of autochthonous transmission of genotype 3 HEV strains merits further investigation
  64. 64. Thank You! Email: jdrobeniuc@cdc.gov http://www.cdc.gov/hepatitis

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