Hepatitis E Virus

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Virology

Hepatitis E virus (HEV) remains taxonomically unclassified. HEV particles demonstrate icosahedral symmetry and are about 27 to 34 nm in diameter. One human serotype of HEV has been identified and homologous immunity seems likely despite the fact that 4 to 9 main genotypes and multiple subtypes have been identified. A virus closely related to human HEV has been found in swine and may replicate in extrahepatic tissues in this species, but its precise relationship to hepatitis E in humans remains uncertain. Replication of the human strain in non-human species has been reported but not confirmed (2,10,14). Other non-human HEV strains have been reported in both avian and mammalian species (3). Human HEV is a non-enveloped agent with a polyadenylated, positive‑sense, single‑stranded RNA genome with a length of about 7.2 kb. The genome comprises three discontinuous, partially overlapping open reading frames (ORF-1, ORF-2, and ORF-3) encoding nonstructural and structural proteins. A common neutralization epitope has been localized to the ORF-2 protein and recombinant proteins with HEV neutralizing activity have been identified (9). The ORF-3 protein appears to be involved in the modulation of cell signaling (6).

Epidemiology

The mean incubation period of hepatitis E is about 40 days with a range of 15 to 65 days. Contaminated drinking water is the predominant source of infection and fecal-oral transmission is the usual route of spread. HEV is shed in the stools during the second half of the incubation period, at the onset of illness, for 2 to 3 weeks thereafter in most cases, but generally for no more than 1 to 2 months (1). Viremia is generally transient but may persist in 15% of patients and has been reported as late as 4 months after the onset of jaundice.

Hepatitis E is both an epidemic and endemic disease in developing countries, particularly in those in the Indian subcontinent, Asia, and Africa. HEV also is endemic, but at relatively low levels, in some developing countries of the Western Hemisphere, e.g., Mexico, Venezuela, Brazil, and Cuba. Outbreaks have been recognized in Mexico and may occur elsewhere in the Americas. Although acute hepatitis E occasionally has been reported in developed nations throughout the world, most cases appear to be imported from endemic areas of the developing world. On rare occasions, the occurrence of sporadic infection has been reported in the U.S. in the absence of a travel history or exposure to a traveler. These instances suggest a possible role for an animal reservoir of infection but proof of this mode of transmission is not available.

The epidemiologic features of HEV infection resemble those of hepatitis A but also differ in several respects. In contrast to hepatitis A, person-to-person and household transmission of hepatitis E is unusual. Furthermore, while hepatitis A is typically transmitted early in life, hepatitis E appears to predominantly infect adolescents and young adults rather than children.

Clinical Manifestations

In children with hepatitis E, the illness is usually anicteric and may be asymptomatic. In adult patients with hepatitis E, the disease is more often icteric and symptomatic and is clinically indistinguishable from other forms of viral hepatitis, including hepatitis A. Common complaints before the onset of jaundice may include cough, pleuritic pains, and myalgias (4). A cholestatic phase with prolonged jaundice, similar to that seen in some cases of hepatitis A also has been described in hepatitis E (8).

The risk of fatal acute liver failure in hepatitis E is generally in the range of 0.5% to 3% with one notable exception: pregnant women, particularly in the third trimester, appear to have a 10% to 20% risk of fatal acute liver failure with a high risk for intrauterine fetal or neonatal death.

Laboratory Diagnosis

Serologic diagnosis requires the detection of IgM antibodies to HEV (IgM anti‑HEV) which are present in most acute specimens and may persist for several weeks. An IgG anti‑HEV may also be detected in the acute phase and remains detectable at declining levels for nearly one year. The specificity of assays for IgG anti‑HEV in low‑prevalence populations is uncertain.

Pathogenesis

The pathogenesis of liver injury in HEV infection is ill-defined. There is little support for the possibility of a direct HEV-induced cytopathic effect on hepatocytes. While a role for humoral antibodies has been suggested, cell-mediated mechanisms involving cytotoxic T-lymphocytes and the induction of cytokines may be responsible for hepatocyte degeneration and necrosis.

SUSCEPTIBILITY IN VITRO AND IN VIVO

No model has been established for susceptibility testing for Hepatitis E virus.

ANTIVIRAL THERAPY

As in the case of hepatitis A, no antiviral agent has been shown to be useful in the treatment of acute hepatitis due to hepatitis E. Treatment therefore remains supportive and symptomatic. An effective drug that could be safely given to pregnant women with acute hepatitis E who are at risk of acute liver failure is not likely to become available in the near future.

ADJUNCTIVE THERAPY

In the pregnant woman with acute liver failure due to hepatitis E in the third trimester, early delivery may be beneficial to both mother and infant. Where feasible, referral for liver transplantation is appropriate. Unfortunately, in developing countries transplantation is unlikely to be available.

IMMUNE GLOBULIN AND VACCINES

Immune Globulin

IG preparations manufactured in the U.S. or elsewhere in the developed world are unlikely to contain adequate levels, if any, of neutralizing concentrations of anti‑HEV and are not likely to protect travelers to endemic regions. In general, IG prepared in countries in which the disease is endemic also have failed to provide sterilizing immunity. However, the incidence of infection was reported to be lower in immunized pregnant women in one study which has yet to be confirmed (1).

Passive immunization of cynomolgus monkeys with anti‑HEV in the form of convalescent serum from experimentally infected animals failed to protect against challenge with live HEV. Interestingly, this preparation of anti-HEV did appear to reduce fecal shedding of the virus and to ameliorate the disease (12). The efficacy of passive immunization with HEV-specific monoclonal antibodies to the ORF-2 capsid protein or with high-titered, hyperimmune globulin remains to be established (11).

VACCINES

Because propagation of HEV in cell culture has yielded relatively low quantities of virus, an inactivated or live, attenuated whole particle HEV vaccine seems unlikely at this time. Oral immunization of mice with recombinant HEV virus-like particles elicited both mucosal HEV-specific IgA antibody as well as HEV-specific serum IgG, IgM and IgA antibodies (7). Clinical studies with this material are not yet available.

Development of a subunit HEV vaccine has been focused on the use of the highly conserved ORF-2 capsid protein of HEV as the immunogen since this region is thought to contain the immunodominant epitope. While it is not yet certain that a vaccine prepared from one HEV isolate would provide protection against all isolates, the ORF-2 immunogen may be cross-reactive among the different HEV genotypes. In an early study, inoculation of cynomolgus monkeys with a 55‑kDa recombinant HEV fusion protein from ORF-2 provided protection against challenge with live HEV (12). Similarly, in a study reported in preliminary form, inoculation with a plasmid construct expressing the ORF-2 protein protected monkeys from challenge with a heterologous strain of hepatitis E (5). However, in another report, a recombinant ORF-2 protein vaccine did not provide sterilizing immunity after intravenous challenge with HEV in rhesus monkeys but did reduce the duration and extent of viremia and fecal shedding (13). It is not yet certain whether the optimal dose and dosing schedule has been determined or whether this vaccine could induce sterilizing immunity against an oral challenge with live HEV. Following immunogenicity and safety studies in healthy volunteers in the U.S., a two-dose recombinant HEV ORF-2 capsid protein-containing vaccine is now being studied in field trials in an endemic region.

Indications

Were an effective and safe HEV vaccine available, initial candidates for immunoprophylaxis would include susceptible pregnant women in endemic regions, in whom the risk of fatal acute liver failure due to HEV is high. Routine use for residents in endemic regions or those regions in which outbreaks have occurred would be appropriate but if the vaccine was costly, its initial use would most probably be limited to travelers to endemic areas from non-endemic ones.

The relatively low frequency of hepatitis E in the developed world is such that the development and routine use of a HEV vaccine is not a current high priority public health issue. On the other hand, the need to protect the military, peace-keeping forces, and travelers to endemic regions within the developing world may serve to spur HEV vaccine development.

PREVENTION AND INFECTION CONTROL

Increasing the availability of clean drinking water supplies in endemic areas is currently the key to control of HEV infection. In developing countries where hepatitis E is either endemic or epidemic, this will require the improvement of hygienic and sanitary standards.

REFERENCES

1. Arankalle VA, Chadha MS, Dama BM, Tsarev SA, Purcell RH, Banerjee K. Role of immune serum globulins in pregnant women during an epidemic of hepatitis E. J Viral Hepatitis 1998;5:199-204. [PubMed]

2. Arankalle VA, Joshi MV, Kulkarni AM, Gandhe SS, Chobe LP, Rautmare SS, Mishra AC, Padbidri VS. Prevalence of anti-hepatitis E virus antibodies in different Indian animal species. J Viral Hepatitis 2001;8:223-227. [PubMed]

3. Haqshenas G, Shivaprasad HL, Woolcock PR, Read DH, Meng XJ. Genetic identification and characterization of a novel virus related to human hepatitis E virus from chickens with hepatitis-splenomegaly syndrome in the United States. J Gen Virol 2001; 82:2449-2462.[PubMed]

4. Isaacson M, Frean J, He J, Seriwatana J, Innis BL. An outbreak of hepatitis E in northern Namibia, 1983. Am J Trop Med Hyg 2000;62:619-625. [PubMed]

5. Kamili S, Spelbring J, Krawczynski K. DNA vaccination protects non-human primates against hepatitis E virus. Hepatology 32:380a, 2000 [PubMed]

6. Korkaya H, Jameel S, Gupta D, Tyagi S, Kumar R, Zafrullah M, Mazumdar M, Lal SK, Xiaofang L, Sehgal D, Das SR, Sahal D. The ORF3 protein of hepatitis E virus binds to the Src homology 3 domains and activates MAPK. J Biol Chem 2001;276:42389-42400.[PubMed]

7. Li TC, Takeda N, Miyamura T. Oral administration of hepatitis E virus-like particles induces a systemic and mucosal immune response in mice. Vaccine 2001;19:3476-3484 [PubMed]

8. Mechnik L, Bergman N, Attali M, Beergabel M, Mosenkis B, Sokolowski N, Malnick S. Acute hepatitis E virus infection presenting as a prolonged cholestatic jaundice. J Clin Gastroenterol 2001;33:421-422. [PubMed]

9. Meng J, Dai X, Chang JC. Lopavera E, Pillot J, Fields HA, Khudyakov YE. Identification and characterization of the neutralization epitope(s) of the hepatitis E virus. Virology 2001;288:203-211. [PubMed]

10. Meng XJ, Halbur PG, Shapiro MS, Govindarajan S, Bruna JD, Mushahwar IK, Purcell RH, Emerson SU. Genetic and experimental evidence for cross-species infection by swine hepatitis E virus. J Virol 1998; 72:9714-9721. [PubMed]

11. Schofield DJ, Glamann J, Emerson SU, Purcell RH. Identification by phage display and characterization of two neutralizing chimpanzee monoclonal antibodies to the hepatitis E virus capsid protein. J Virology 2000;74:5548-5555. [PubMed]

12. Tsarev SA, Tsareva TS, Emerson SU, Govindarajan S, Shapiro M, Gerin JL, Purcell RH. Successful passive and active immunization of cynomolgus monkeys against hepatitis E. Proc Natl Acad Sci USA 1994; 91:10198- 10202. [PubMed]

13. Tsarev SA, Tsareva TS, Emerson SU, Govindarajan S, Shapiro M, Gerin JL, Purcell RH. Recombinant vaccine against hepatitis E: dose response and protection against heterologous challenge. Vaccine 1997;15:1834-1838. [PubMed]

14. Williams TP, Kasorndorkbua C, Halbur PG, Haqshenas G, Guenette DK, Toth TE, Meng XJ. Evidence of extrahepatic sites of replication of the hepatitis E virus in a swine model. J Clin Microbiol 2001;39:3040-3046. [PubMed]

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