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HEPATITIS E and HIV
Kenneth E. Sherman, MD, PhD Gould Professor of Medicine
Director, Division of Digestive Diseases University of Cincinnati College of Medicine
Case Presentation
• A 54 yo man with HBV/HIV coinfection has abrupt onset of peripheral edema and increasing abdominal girth. He has also developed scleral icterus
• HBV and HIV well controlled for last 10 years on efavirenz/lam/zidovudine
• Symptoms began a few weeks after staying with sister on farm in central Ohio.
• HBsAg +, HBV DNA neg, anti-core IgM neg, HCV Ab and PCR neg, anti-HAV IgG+
HEPATITIS E
• Enterically transmitted zoonotic RNA virus in the genus Hepevirus • 7200 bases • 3 ORFs
• There are 4 genotypes for
HEV with different geographical distributions, morbidity, and species specificity but serologically cross-reactive
HEV Typical Clinical/Serological Course
IgG anti-HEV
Symptoms
ALT
IgM anti-HEV
Virus in stool
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Weeks after Exposure
Virus in sera
CDC
CLINICAL OUTCOMES Immunocompetent
• Hepatitis E virus (HEV) is one of the most common causes of acute symptomatic viral hepatitis (AVH) in many developing countries
• HEV never causes chronic hepatitis in immunocompetent patients and a full recovery is frequent.
• Mortality rates of 0.5 - 4 % in the general population and >20 % among pregnant women have been reported in some settings
• 20-50% of HEV-infected pregnant women develop fulminant hepatitis
(M. S. Khuroo and S. Kamili; Journal of Viral Hepatitis, 2003, 10, 61–69)
• Mortality rate is about 20% in pregnant women in India and Pakistan
• The mechanisms of high morbidity of HEV infection in pregnant women is unknown
• High mortality during pregnancy NOT observed in all settings (e.g. Egypt)
HEV Pregancy
HEV Epidemiology
• Large Scale Outbreaks • Endemic Sporadic Acute Hepatitis
– Populations with Low Rate of Early Exposure – Populations with High Rate of Early Exposure – Zoonotic Exposures – Acute on chronic
HEV Large Scale Outbreaks
• Massive waterborne epidemics of acute hepatitis in India and Bangladesh during periods of flooding during the monsoons
• In 2004, almost 4000 suspected cases of hepatitis E were reported in the Greater Darfur region of Sudan, and more than 1000 suspected cases were identified.
• In Iraq, cases of hepatitis E were identified in Sadr City and in Mahmudiya, south of Baghdad.
• Current Outbreaks: Chad and Sudan
• Cruise Ships (Said et al. Sept. 2009, EMERG INFECT DIS) – 25% on ship HEV seropositive – 4% HEV IgM seropositive – Genotype 3 (Europe strain) – Associated with shellfish consumption
HEV in SWINE & DEER
• Worldwide distribution with high rates of HEV IgG Antibody described
• In Spanish study, 15.4% of sows HEV IgM + and piglets had virus in feces after 9 weeks, with peak shedding at 15 weeks (de Deus et al., VET MICROBIOL, 2008)
• HEV in 80-100% of pigs in commercial farms in U.S. – 11% of commercial pig livers in U.S. grocery stores have infectious HEV
(Meng et al)
• HEV found in both feces and stored liquid waste in North Carolina (Kase et al., J WATER HEALTH, 2009)
• Genotype 3 and 4 isolates identified in deer • Bear infection in Japan also described
HEV SEROPREVALENCE Risk Associations in NHANES
0
0.5
1
1.5
2
2.5
3
Odds Ratio and 95% C.I. Kuniholm et. al JID 2009
OR
ACUTE HEV in HIV U.S. Military
• 4410 HIV postive persons followed for 32,468 person years
• 458 had ALT increase c/w acute hepatitis event
• 194 tested for HEV • Conclusion: HEV is in
the differential of acute hepatitis in HIV-infected patients
0
0,5
1
1,5
2
2,5
3
3,5
4
4,5
HEV IgM HEV IgG
Crum-Cianflone et al, EMERG INF DIS, 2012
%
HEV PREVALENCE IN HIV Author Sample Size
(n) Location Prevalence
Maylin et al. 2012 261 Paris 1.5%
Kaba et al, 2011 184 Marseille 4.4% IgG 1.6% IgM 0.5% RNA chronic
Keane et al., 2012 138 SW England 9.4% IgG
Kenfak-Foguena et al, 2011
735 Switzerland 2.6% IgG 0.1% RNA chronic
Sellier et al, 2011 108 Paris 2.8% IgG 0.9% IgM,RNA +
Renou et al, 2010 245 N & S France 9.0% IgG South 3.0% IgG North
Fainboim et al. 1999 484 Argentina 6.6% IgG
HEV Acute on Chronic Presentation
• 48 year old man with chronic HBV – Asymptomatic chronic carrier – New onset ascites, jaundice, coagulapathy
• Recently employed part time at swine farm • Rapid decompensation complicated by sepsis • Listed for OTLTx but died from sepsis • HEV IgM, HEV ELISPOT positive
HEV IN NIH HIV SOT COHORT
• 166 pre-transplant subjects
– 113 awaiting liver transplant Including 10 dual organ candidates
– 53 awaiting kidney transplant
• Adaltis and Waitai EIA • ORF3 PCR Amplification
– No positives at baseline – Stool not available
19,5 18,9
1 0
0
5
10
15
20
25
Liver Kidney
IgGIgM
%
Sherman et al, CROI, 2012, Abstract #799
VARIABLE CLINICAL PRESENTATIONS
• High Prevalence of Antibody with Infrequent clinical illness in – U.S. – Egypt – Other developed countries
• Possible Explanations – Different viral strains with varying pathogenicity – Protective immune response due to early childhood exposure – Cross protection from exposure to other avirulent strains
HEV & DILI
• 318 Patients with Juried Drug Induced Liver Disease
• Samples tested later for HEV – 16% HEV IgG positive – 3% HEV IgM positive – 4/318 (1.25%) Viremic with Genotype 3 – 2 of IgM positive were HIV positive
• All IgM positive reclassified as NOT DILI
Davern et al., GASTROENTEROLOGY, 2011
HEV IMMUNE RESPONSE
• Humoral – IgM and IgG – Variable Levels of Neutralizing Antibody and
Antibody Avidity
• Cellular – Interferon gamma ELISPOT
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
Acute severesymptomatic
HEV recovered (after 1year)
OD at
1:30
0 dilu
tion
Anti-HEV IgG neutralizing antibodies in Index subjects over time
P<0.05
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
Contact-Index (asymptomatic) Index (Symptomatic)
HEV infection
OD
at 1
:300
dilu
tion
Anti-HEV IgG neutralizing antibodies in asymptomatic and symptomatic subjects
p=<0.01
Shata et al., ISVHLD, 2009
No stimulation Ag stimulation
EVALUATION OF HEV CELL-MEDIATED IMMUNE RESPONSE
Shata MT et al., J IMMUNOL METHODS, 2007
HEV-specific IFN-gamma ELISPOT assay
0.1
1
10
100
1000
10000
Negative Positive
Human subjects
No
of I
SCs/
one
mill
ion
cells
Evaluation of HEV-specific immune responses in HEV infected subjects
HEV VACCINE
• Recombinant HEV Vaccine
• Studied in Nepal – N= 2000 – Randomized 1:1 – 3 doses vaccine or
Placebo – Median F/U 804 days
Sresthra et. al., NEJM 2007
CONCLUSIONS
• HEV is prevalent in Western countries where it was previously unsuspected
• HEV can cause.. – Acute hepatitis (including mimic of DILI) – Hepatic Decompensation in those with other liver
diseases (acute on chronic) – Chronicity may occur in setting of
immunosuppression • Transplant • HIV
Egyptian Universities Assuit: Enas Deaf and Mohamed Nafeh Mansoura: Maysaa Zaki Mania: Sayed Abdelwahab Ministry of Health, Egypt VACSERA and EgyBlood Hoda Mansour; Nabiel Khoury University of Maryland Thomas Strickland, S. El Kamery, Mohamed Hashem National Institute of Health R. Purcell, S. Emerson
University of Cincinnati, USA Mohamed Tarek Shata, MD, PhD Jason Blackard, PhD Gehan Galal*, MD Soad Nady*, MD Maha Sobhy*, MD
HEV COLLABORATORS