HEPATITIS E. Enterically transmitted zoonotic RNA virus in the genus Hepevirus 7200 bases 3 ORFs

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1 HEPATITIS E and HIV Kenneth E. Sherman, MD, PhD Gould Professor of Medicine Director, Division of Digestive Diseases University of Cincinnati College of Medicine

2 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+ List for OTLTx but rapidly decompensated and died HEV IgM+ one week later

3 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

4 HEV Genome Methyltransferase Protease Helicase Capsid RNA-dependent RNA polymerase

5 HEV GENOTYPES Based on 148 bp of the ORF2 gene

6 GENOTYPE DISTRIBUTION

7 CDC HEV Typical Clinical/Serological Course Virus in stool Symptoms ALT IgG anti-hev IgM anti-hev Virus in sera Weeks after Exposure

8 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 % in the general population and >20 % among pregnant women have been reported in some settings

9 HEV Pregancy 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)

10 HEV in HIV+ Pregnant Woman Gabon Caron et al., VIROLOGY JOURNAL, 2012

11 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

12 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

13 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 % 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

14 HEV ANTIBODY PREVALENCE

15 HEV U.S. Prevalence by Region in NHANES Kuniholm MH et. al., JID 2009

16 HEV SEROPREVALENCE Risk Associations in NHANES OR Odds Ratio and 95% C.I.

17 HEV SEROPREVALENCE Chronic Liver Disease OR Atiq et. al. EMERGING INFECT DIS 2009

18 ACUTE HEV in HIV 4410 HIV positive 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 U.S. Military 4,5 4 3,5 3 % 2,5 2 1,5 1 0,5 Crum-Cianflone et al, EMERG INF DIS, HEV IgM HEV IgG

19 HEV PREVALENCE IN HIV Author Sample Size (n) Location Maylin et al Paris 1.5% Prevalence Kaba et al, Marseille 4.4% IgG 1.6% IgM 0.5% RNA chronic Keane et al., SW England 9.4% IgG Kenfak-Foguena et al, Switzerland 2.6% IgG 0.1% RNA chronic Sellier et al, Paris 2.8% IgG 0.9% IgM,RNA + Renou et al, N & S France 9.0% IgG South 3.0% IgG North Fainboim et al Argentina 6.6% IgG

20 HEV IN NIH HIV SOT COHORT pre-transplant subjects 113 awaiting liver transplant Including 10 dual organ candidates 20 19,5 18,9 53 awaiting kidney transplant Adaltis and Wantai EIA % 15 IgG ORF3 PCR Amplification No positives at baseline 10 IgM Stool not available Liver Kidney Sherman et al, CROI 2012, Abstract #799

21 HEV IN SOT Sherman et al, CROI 2012, Abs #799

22 HEV Acute on Chronic Decompensation % HEV IgM

23 Dalton et al., NEJM, 2009 CHRONIC HEV in HIV

24 CHRONIC HEV INFECTION in Transplant Recipients Pischke et. al. LIVER TRANSPLANTATION 2010

25 CHRONIC HEV IN HIV Progression to Cryptogenic Cirrhosis Gurmit K. et al. Chronic Hepatitis E as a cause for cryptogenic cirrhosis in HIV. Journal of Infection 2011

26 TREATMENT OF CHRONIC HEV Pegylated Interferon Ribavirin Decreased Immunosuppression (in transplant)

27 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

28 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

29 HEV IMMUNE RESPONSE Humoral IgM and IgG Variable Levels of Neutralizing Antibody and Antibody Avidity Cellular Interferon gamma ELISPOT

30 Anti-HEV IgG neutralizing antibodies in Index subjects over time P< OD at 1:300 dilution Acute severe symptomatic HEV recovered (after 1 year) Shata et al, TRANS ROYAL SOC TROP MED HYG, 2012

31 Anti-HEV IgG neutralizing antibodies in asymptomatic and symptomatic subjects p=<0.01 OD at 1:300 dilution Contact-Index (asymptomatic) HEV infection Index (Symptomatic) Shata et al., ISVHLD, 2009

32 Evaluation of HEV-specific immune responses in HEV infected subjects HEV-specific IFN-gamma ELISPOT assay No of ISCs/one million cells Negative Positive Human subjects Shata et al, ISVHLD, 2009

33 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

34 CONCLUSION WHAT WE KNOW 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 WHAT WE DON T KNOW How is HEV being spread? Are HIV+ patients at greater risk of infection? Have we misclassified HEV as DILI in HIV+ patients? How does drug abuse/alcohol abuse affect infection risk/chronicity Does CD4 affect risk of chronicity Is there an immune reconstitution syndrome How are humoral titers, avidity and CTL response altered in HEV Can/Should those with HIV be vaccinated?

35 University of Cincinnati, USA Mohamed Tarek Shata, MD, PhD Jason Blackard, PhD Gehan Galal*, MD Soad Nady*, MD Maha Sobhy*, MD 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 EMMES Burc Barin HEV COLLABORATORS