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 Genome

Methyltransferase

Protease

Helicase

RNA-dependent RNA polymerase

Capsid

HEV GENOTYPES Based on 148 bp of the ORF2 gene

GENOTYPE DISTRIBUTION

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 ANTIBODY PREVALENCE

HEV U.S. Prevalence by Region in NHANES

Kuniholm MH et. al., JID 2009

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

HEV SEROPREVALENCE Chronic Liver Disease

Atiq et. al. EMERGING INFECT DIS 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 Acute on Chronic Decompensation

Kumar et al., IND J GASTRO, 2004

% H

EV

IgM

CHRONIC HEV INFECTION in Transplant Recipients

Pischke et. al. LIVER TRANSPLANTATION 2010

CHRONIC HEV in HIV

Dalton et al., NEJM, 2009

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

TREATMENT OF CHRONIC HEV

• Pegylated Interferon • Ribavirin

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

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