Hepatitis E Virus Infection. Disclosures

Transcription

1 Hepatitis E Virus Infection Simona Rossi, MD Associate Chair, Division of Hepatology Einstein Medical Center Philadelphia Consultant for BMS Speaker for Gilead Disclosures I have no conflicts to report No off label use medications discussed 1

2 Outline of Topic Epidemiologic trends Transmission Clinical Disease course Special Populations Clinical Circumstances Management/Treatment A Note on History Outbreak in New Delhi in 1955: not HAV Enterically transmitted non A/B (ET NANBH) First partially cloned in 1990: Termed HEV Fully cloned in 1991 Burma isolate from bile of infected patient Non enveloped single stranded RNA virus Tam et al. Virology

3 Breakdown of HEV Genome ORF1: nonstructural polyprotein replication ORF2: Encodes capsid protein Vaccine target ORF3: Encodes proteins regulating cellular environment Wedemeyer et al. Gastroenterology 2012 HEV Structure Hepevirus (Orthhepevirus) 3

4 Geographic Distribution HEV HEV Accounts for greater than 25% of viral hepatitis Epidemiology Enterically transmitted Contaminated water (1,2) Perinatal transmission (3) Animal to human transmission (3) Person to person transmission (3) Genotypes less virulent (Developed Countries) Ibrahim et al. Hepatology 2015: accepted 4

5 Drobeniuc et al. Emerg Infect Dis 2013 Drobeniuc et Al. Imerg Infect Dis

6 Genotypic Distribution Wedemeyer et al. Gastroenterology 2012 Age Distribution HEV Purcell et al. J Hepatol

7 HEV Prevalence Developing Countries: 30% 80% Fecal oral/contaminated water Epidemic and sporadic cases US population: 21% (NHANES III) Zoonotic transmission (genotype 3) Immunosuppressed populations Underlying chronic liver disease Pregnancy Kuniholm et al. J infect Dis 2009 Overestimation in USA (NHANES: ) Use of high Performance Assay HEV IgM: 98% sensitivity 95.2% specificity HEV IgG: 100% sensitivity 97.5% specificity Prevalence % Prevalence % Drobeniuc et al. Clin Infect Dis 2010 Kuniholm et al. J infect Dis 2009 Ditah et al. Hepatology

8 NHANES: 2010 Ditah et al. Hepatology 2014 NHANES: 2010 Ditah et al. Hepatology

9 NHANES: 2010 Ditah et al. Hepatology 2014 Clinical Characteristics of HEV in USA CDC collected stool/blood for HEV Standardized questionnaires required International travel Demographics Risk factors identified Positive Case Criteria IgM + HEV RNA IgM with captured Conversion to IgG IgG + HEV RNA Drobeniuc et al. Emerg Infect Dis

10 Results 154 cases submitted 26 met criteria 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% International Travelers Noninternational Travelers Drobeniuc et al. Imerg Infect Dis 2013 Infects Humans Infects animals Genotype 3 Boar, deer, mongoose, rodents Seafood Contamination of vegetables and fruits MAN ANIMAL Meng XJ. Semin Liver Dis 2013 Kokkinos et al. Food Environ Virol 2012 Brassard et al. Appl Environ Mircobiol

11 Is it DILI or is it HEV? 50/318 IgG HEV 9/50 IgM HEV Davern et al. Gastroenterology 2011 Additional Observations HEV RNA positive cases All genotype 3 2/4 HIV positive The nine cases Mostly men Older age 8/9 had comorbidities Davern et al. Gastroenterology

12 Clinical Course Acute and Symptomatic Acute and Fulminant Chronic Acute and Silent Variable Course of HEV Exposure No symptoms Symptoms Chronic HEV infection Resolved IgE + Fulminant Resolved Mild chronic Cirrhosis Adapted from Wedemeyer et al. Gastroentrology

13 Acute Symptomatic Disease HEVIgM ALT HEVIgG +HEVRNA Stool +HEVRNA Blood Incubation Symptomatic Phase > Resolution WEEKS Purcell et al. J Hepatol 2008 Wedemeyer et al. Gastroenterol 2012 Fulminant Disease in Pregnancy Patient Mediated Hormonal suppression of immune system B cell produc on Altered T cell ratio Immunologic injury Progesterone receptor gene mutations Viral Mediated Increased viral replication Altered Th1/Th2 bias HEV genotype (1a) and subtype significance Navaneethan et al. Liver International 2008 Bose et al. J Hepatol

14 HEV Why Pregnancy? Fetal demise Maternal death PR gene mutations Progesterone receptor PIBF Lack of protective immunomodulation Th1 IL 12 Pregnancy PR gene wild type Nml progesterone receptor Shift to Th2 Nml PIBF Protective immunomodulation Th2 IL 10 HEV Adapted from Bose et al. J Hepatol 2011 Recovery Blood Borne Transmission Donated blood/organs not routinely screened Pooled plasma highest risk: 10% 1 Significance depends on recipient English population /225,000 donations +HEV 43 recipients of proven positive HEV blood 42% showed evidence of infection 10 patients prolonged infection (immunosuppressed) 1 Coilly et al. Transplantation Hewitt et al. Lancet

15 Prevalence HAV vs. HEV IgG in blood donors Meng et al. J Clin Microbiol 2002 Purcell et al. J Hepatol 2008 Chronic HEV? Organ transplant recipients Up to 66% of infections became chronic Potentially correlates with tacrolimus use Think about testing Any organ transplant recipient with abnl liver tests Check HEV RNA; Antibody may be negative Impaired T cell response Kamar et al. Gastroenterology 2011 Suneetha et al. Hepatology

16 Chronic HEV Profile Genotype 3 HEVRNA Stool, Blood IgEAb ALT LEVELS ALT LEVELS weeks Adapted from Wedemeyer et al. Gastroenterol 2012 Clinical Course in Transplanted Patients HEV 40 50% Transplant Recipient 50 60% Recovery 30% Chronic infection 10% Adapted from Behrendt et al. J Hepatol 2014 cirrhosis 16

17 Extrahepatic Manifestations Renal dysfunction Cryoglobulinemia Vasculitis Guillain Barre Syndrome Extrahepatic replication has been suggested Spinal fluid Van Der Berg et al. Neurology 2014 Kamar et al. Am J transplant 2010 Prevention Treatment Clean water policies Cook meet thoroughly Person to person transmission is rare Screen blood products? Vaccination Available in China 1? Effective across all genotypes Level of titer for protection 2 Zhu et al. Lancet 2010 Abravanel et al. J Infect Dis

18 Treatment Most HEV is self limited Supportive care Treatment of at risk groups Immunosuppressed at risk for FHF Solid organ Transplant patients Patients receiving chemotherapy Elderly patients Patients with chronic liver disease Wedemeyer et al. Gastro 2012 Interferon 1 Ribavirin 2 Therapeutic options Solid organ transplant recipients 95% EOTR with 3 months 78% SVR with 3 months Longer therapy achieved SVR in 40% of relapsers Reduction of immunosuppression 3 1 Haagsma et al. Liver Transplant Kamar et al. NEJM Peron et al. Liver Int Kamar et al. Gastroenterology

19 Summary Points HEV is not limited to developing Countries Geographic Variability India, South East Asia, Sub Saharan Africa Genotype 1,2 Fecal oral Vertical transmission Industrialized Countries Genotype 3,4 Animal, fruit, vegetable contamination Chronic disease in immunosuppressed patients Summary Points Clinical course is variable Genotype Comorbidities of person infected Pregnancy genetic variability Consider HEV especially when Immunosuppressed patient SOD recipient DILI differential Serologies are not always reliable: HEV RNA 19

20 Thank you! Simona Rossi, MD 20