Hepatitis E: What’s New?

HEPATITIS E: WHAT’S NEW?
Naglaa Zayed, MD
Cairo University

■ Epidemiology
■ HEV Genome
■ Clinical Picture
■ Diagnosis
■ Treatment
■ Prevention
Agenda
HEV What’s New

Known Facts: HEV
■ 20 million HEV infections worldwide annually
- 3.3 million symptomatic cases
-70,000 HEV-related deaths
■ Self-limiting, acute liver failure may develop.
■ Transmitted via the faecal-oral route, via contaminated water.
■ Highest prevalence in East and South Asia.
■ Prevention: HEV vaccine, ??protective Igs against future reinfection.
.Rein DB,et al. Hepatology 2012; 55(4):988-97.
Lozano R, et al. Lancet 2012;380:2095-2128
WHO. Viral Hepatitis July 2015

■ Higher in developing (10-70%) than developed countries (1-21%).
■ Adults 15-40 years of age.
Epidemiology of HEV
■ Risk groups elderly men, pregnant women, young children,
immunocompromised patients, CLD, contact with HEV-infected animals.
Epidemic and Sporadic Hepatitis
in Endemic Areas
Outbreaks
Faecal contamination of
drinking water supplies
Sporadic Cases
contamination of water or food
Gust ID, Purcell RH. J Infect Dis 1987; 156:630.
Villarejos VM, et al.Am J Epidemiol 1982; 115:577.
Teshale EH, et al.Clin Infect Dis 2010; 50:1006.

Geographical Distribution of HEV
Egypt: anti-HEV IgG
45.2% (43/95) blood donors
39.6% (38/96) haemodialysis patients
https://www.cdc.gov/hepatitis/hev/hevfaq.htm
Abdel Hady S et al. J Egypt Public Health Assoc. 1998;73(3-4):165-79.

■ Member of the Hepeviridae family.
HEV Genome
■ Small virus (27-34 nm in diameter)+ve-sense, non-enveloped singlestranded
RNA genome, about 7.2 kilobases long.
NS proteins; viral processing and replication
Structural proteins
Reyes GR, et al.Science 24713351339 Reyes GR, et al.Arch Virol 71525 Tam AW,et al. Virology 185120131
Kumar S, et al. International Journal of Infectious Diseases 2913; 17(4): e228–33

HEV Genotypes
Four genotypes/24 subtypes with different geographic distributions
Kar P, et al.Am J Gastroenterol 10324952501
Mizuo H, etal. J Med Virol 76341349

G5/6 Pigs G7 Camels
HEV Genotypes

Modes of HEV Transmission
Fecal-oral, Food-borne
Contaminated water
undercooked meat/
Shellfish /vegetables
Vertical or Perinatal
transmission
Limited data
Perinatal morbidity and mortality
TRANSMISSION
Blood-borne
In UK, 225,000 blood donations,
79 HEV G-3 RNA +ve
Breast milk??
HEV isolated in breast milk
during acute HEV(case report)
Hewitt PE, et al. Lancet 2014; 384:1766.Khuroo MS,et al. Lancet 1995; 345:1025. Kumar RM, et al. Eur J Obstet Gynecol Reprod Biol 2001; 100:9.
Romanò L, et al. J Hepatol 2011; 54:34. Ijaz S, et al. J Infect Dis 2005; 192:1166.
Arankalle VA, et al. J Hepatol 2002; 36:417. Rutjes SA, et al. Emerg Infect Dis 2009; 15:381.

Blood donors In China(n=9069)
Anti-HEV IgM Anti-HEV IgG HEV antigen
Elevated ALT >40 IU/L
n=5023
Normal ALT
n=4046
Anti-HEV IgG 33.3%
Anti-HEV IgG 29.4%
Anti-HEV IgM 1.41%
Anti-HEV IgM 1.46%
HEV antigen +ve 1.23%
HEV antigen -ve 0.17%
HEV-RNA +ve in 6 donors with acute HEV
Wang M et al. Transfusion. 2017 Feb;57(2):273-9.

Clinical Picture of HEV

Acute Hepatitis E
Clinical Picture of HEV
■ Self-limited acute infection, resolves within 2–6 weeks.
■ Incubation period 15-60 days.
■ Acute hepatic failure can develop in a small proportion of patients.
■ Asymptomatic or minimally symptomatic.
■ Clinical symptoms occur in 2-5%.
Acute viral hepatitis
Extrahepatic findings (wide range of neurological disorders)
Perrin HB, et al. Emerging Infectious Diseases. 2015;21(11):1928-1934.

Complications of Acute HEV
Acute Liver
Failure
Cholestatic
Hepatitis
Chronic
Hepatitis E
Mortality
Low 0.5%-4%
Increase in young infants

HEV and Pregnancy
In endemic regions
■ Up to 70% of pregnant women progress to AHF in 2 nd & 3 rd trimester. 1
■ Worse fetal and maternal outcomes.
■ High mortality rate 15-25% in 3 rd trimester. 2
■ HEV G-1 and 2, virulence of these human-specific viruses, hormonal and
immunological changes.
■ AHF and poor pregnancy outcomes not observed with G-3. 3,4
1.Patra S, et al. Ann Intern Med 2007; 147:28. 2.Khuroo MS, et al. Am J Med 1981; 70:252.
3.Anty R, et al. J Clin Virol 2012; 54:76. 4.Tabatabai J, et al. J Clin Virol 2014; 61:170.

Clinical Picture: Complications
Acute Hepatic Failure(AHF) 0.5-4%.
■ Pregnant, malnourished patients or those with preexisting liver disease
(e.g HBV) may experience exacerbation; AHF and increased mortality.
■ Characterized by hepatic encephalopathy, elevated aminotransferases and
impaired synthetic function.
■ High mortality (0.5-3%) if intensive care support and LT are not available.
Aggarwal R. Semin Liver Dis 2013; 33:30.
CDC.MMWR Morb Mortal Wkly Rep 1987; 36:241.

Clinical Picture: Complications
Cholestatic Hepatitis
■ Prolonged cholestasis, protracted period of jaundice (>3 months), in up
to 60% of patients with acute HEV.
■ Asymptomatic or have symptoms of pruritus.
■ Spontaneous resolution within weeks to months with no sequelae.
■ Recovery is marked by viral clearance, an increase in IgG titers, and a
decrease in IgM levels.
Mechnik L, et al. J Clin Gastroenterol 2001; 33:421.
Hoofnagle JH, et al. N Engl J Med 2012; 367:1237.

Chronic Hepatitis E
Persistently elevated
aminotransferase levels
Detectable serum
HEV RNA
Histologic findings
compatible with
chronic viral hepatitis
serum or stool HEV
RNA> 6m
Exclusively in context of solid organ transplantation,
hematological disorders, immunosuppression(IS) or HIV

Chronic Hepatitis E
Solid organ transplants (kidney, liver, and kidney-pancreas) 1-3
■ Exclusively in G3-infected individuals.
■ A cohort of 700 solid organ Tx recipients, 34 (5%) acquired HEV infection,
of whom 47% developed chronic infection. 3
■ Impaired T-cell responses, lower counts of lymphocytes, CD4 T cells; use
of FK; low platelet count; younger age; LTx.
■ Natural history not understood, rapid progression to cirrhosis. 1
■ Risk for HEV reactivation.
1.Gérolami R, et al. N Engl J Med 2008; 358:859.
2.Khuroo MS and Khuroo MS. Curr Opin Infect Dis 2008; 21:539.
3.Legrand-Abravanel F, et al. Emerg Infect Dis 2011; 17:30.

Chronic Hepatitis E
Other Immunosuppressed hosts
■ Case reports in patients with non-Hodgkin lymphoma receiving rituximab
and in patients with HIV infection. 1,2
■ Low risk of acute HEV compared with the general population.
■ Failure to clear HEV and consequently develop chronic infection. 3
1.Ollier L, et al. Ann Intern Med 2009; 150:430.
2.Dalton HR, et al. N Engl J Med 2009; 361:1025
3.Goel A, Aggarwal R. Expert Rev Gastroenterol Hepatol 2016; 10:1065.

HEV Diagnosis
General approach
■ Clinical suspicion in acute or chronic hepatitis that cannot be explained by
other causes, particularly in the setting of known risk factors.
■ Suspected among patients with rapidly progressive liver disease in pregnant
women, patients with underlying CLD, solid organ transplant recipients, and
hematologic malignancies.
■
Patients presenting with an elevation in aminotransferases & neurological
manifestations.
Wedemeyer H, et al.Gastroenterology 2012; 142:1388.
Pawlotsky JM. Lancet 2014; 384:1729.

Diagnostic tests for HEV
IgM anti-HEV
Early phase of clinical illness
Sensitivity 80-90% Specificity 92%
IgG anti-HEV
Appears shortly after IgM
Persist as long as 14 yrs after acute illness
HEV-RNA
Appear early in stool
Short-lived in acute infection
Two real-time PCR assays

Centers for Disease Control and Prevention. www.cdc.gov/hepatitis/index.htm

HEV Diagnosis
Acute HEV
Chronic HEV
Immuno
competent
Immuno
compromised
HEV-RNA in serum
IgM anti-HEV
HEV-RNA
Baylis SA, et al. J Clin Microbiol 2011; 49:1234.
Khudyakov Y, Kamili S. Virus Res 2011; 161:84.
HEV-RNA in
serum
IgG anti-HEV Ab
marker of exposure
titers decline with time

Treatment of HEV
Immune Status
Stage of disease
Acute HEV
• Supportive treatment.
• Fulminant hepatic failure require LTx.
• RBV monotherapy in CLD patients & those on IS therapy or chemotherapy.
• ??Improvement: spontaneous or due to RBV.
Dalton HR, et al. Nat Rev Neurol 2016; 12:77.
Del Bello A, et al. Transpl Infect Dis 2015; 17:279.
Blasco-Perrin H, et al. Aliment Pharmacol Ther 2015; 42:574.

Treatment of HEV
Acute HEV
Significant improvement of liver functions
Retrospective study in France
Acute HEV G-3/ 4 (n=21)received RBV monotherapy for median 26 days
IS therapy /chemotherapy was suspended in 6 patients
All patients cleared HEV within 6 weeks
median time to viral clearance of 29 days
2 patients died from liver failure(underlying CLD)
Péron JM, et al. Liver Int 2016; 36:328.

Treatment of HEV
Chronic HEV
Reduction of
Immunosuppressive
Therapy
Antiviral
Therapy(RBV)
G3 & G4
Eradicate HEV-RNA & achieving SVR
SVR: absence of HEV-RNA 12 weeks
after cessation of treatment
SVR predictor: HEV-RNA 1 st week after therapy/Total lymphocyte count

Treatment of Chronic HEV
Reduction of Immunosuppressive Therapy
HEV-RNA in blood and stool after 12 weeks
Viral clearance in 30% in a series of 85 recipients
of solid organ transplants who had chronic HEV
Kamar N, ]et al. Gastroenterology 2011; 140:1481.

Treatment of Chronic HEV
■ 12-week course of RBV monotherapy (600 mg daily): 1,2
-IS therapy cannot be reduced.
-Persistent HEV-RNA despite a reduction in IS for 3 months. 1,2
■ ??No RCT, only case series
■ 59 solid-organ transplant recipients with chronic HEV-G3 received 3
months of RBV monotherapy.
Outcome
HEV clearance 95% (n=56)
SVR 78% (n=46)
AEs
Anemia: reduction in RBV dose (29%)
EPO(54%), blood transfusion(12%) 3
1.Wedemeyer H et al. Gastroenterology 2012; 142:1388.
2.Kamar N. et al Clin Microbiol Rev 2014; 27:116.
3.Kamar N, et al. N Engl J Med 2014; 370:1111.

Response to Antiviral Therapy
Stool & serum HEV RNA at
12 weeks
Subsequent Management
Undetectable
HEV RNA
Detectable HEV
RNA serum±stool
Relapse
Treatment
failure
Stop RBV
SVR 12
Extend RBV 3m 1
Initiate
6m RBV 2 Follow Up 3
3m PEG-IFN??
1.Abravanel F, et al. Clin Infect Dis 2015; 60:96. 2.Kamar N, et al. N Engl J Med 2014; 370:1111. 3.Kamar N, et al. Clin Infect Dis 2010; 50:e30

Response to Antiviral Therapy
RBV Therapy
■ Up to 38% of treated patients do not how an SVR or even relapse.
■ RBV dose reductions/Mutation in the viral polymerase (G1634R).
Peg-IFN alfa
■ Alternative treatment option if there is no contraindication.
■ Peg-IFN for 3-12 months led to sustained clearance of HEV-RNA in
chronic HEV who underwent LT.
■ Cause significant adverse effects & organ rejection in transplant recipients.

Treatment of HEV: Future Therapy
■ SOF inhibits HEV-G3 replication both in sub-genomic replicon systems
as well as a full-length infectious clone.
■ SOF+RBV results in an additive antiviral effect.
■ More studies to explore antiviral potential of SOF+RBV, especially if
RBV monotherapy fails.
■ SOF as an add-on therapy to RBV for the treatment of chronic HEV in
immunocompromised patients.
Dao Thi VL, et al. Gastroenterology. 2016 Jan. 150(1):82-85.e4.
Debing Y, et al. J Hepatol. 2016 Jul. 65(1):200-12

Monitoring for Toxicity
■ Basic laboratory monitoring during and after HEV treatment.
■ CBC at weeks 8 and 12 to evaluate for RBV-induced anaemia.
■ Women of childbearing-age taking RBV, assessment of contraception
use and pregnancy testing should be performed during and for 6
months after treatment.
■ Men taking RBV-containing regimen should be counseled on
contraceptive use during and for 6 months after treatment.

Randomized trial in China, 112,604 healthy adults assigned to receive
3 doses of HEV recombinant vaccine against G 1 and 4 (Hecolin)
Protective efficacy over a 12-month period 96% 4
Efficacy 4.5 yrs after the 1 st vaccination 87% 5 1.Zhang M, et al. Vaccine 2002; 20:3285.
2.Tsarev SA, et al. Proc Natl Acad Sci U S A 1994; 91:10198.
3.Khuroo MS, Dar MY. Indian J Gastroenterol 1992; 11:113.
4.Shrestha MP, et al. N Engl J Med 2007; 356:895
5.Zhang J, et al. N Engl J Med 2015; 372:914.
Prevention of HEV Transmission
Advice to
travelers to HEV
endemic regions
Recombinant
vaccines 1
2,3
Pre- or postexposure
Ig prophylaxis??

Conclusion
■ HEV is increasingly recognized as a pathogen in the developed world.
■ Transfusion transmission of HEV is an emerging health risk, yet blood
donors are rarely screened.
■ HEV should be tested:
-When you suspect drug induced liver injury.
-Elevated liver enzymes with neurological manifestations or in immunocompromised patients
■ Chronic persistent HEV infection may develop.
■ Additional studies are needed to determine treatment regimens for HEV.