Hepatitis E Virus
Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis in the developing world. It is a waterborne virus that can cause epidemics in the face of overcrowding and poor sanitation. Although the hepatitis illness is usually self-limiting, it has a high mortality in pregnant women and can become a chronic infection in the immunosuppressed. Treatment is mostly supportive and prevention is by good water hygiene.
Before the discovery of hepatitis E virus (HEV), many epidemics of hepatitis in the developing world were found to be from a cause other then the known hepatitis A, B and C viruses. HEV was discovered in 1983 in the stool samples of a human volunteer infected with the combined stool samples of patients with non-A, non-B hepatitis (Balayan et al., 1983). HEV is a small single-stranded RNA virus spread by contaminated water.
HEV is the most common cause of clinical hepatitis in many countries in Africa, including South Sudan, and Asia. There are four known genotypes of HEV that can infect humans (Smith et al. 2013). Figure 1 illustrates the prevalence of the different HEV genotypes across the world. It should be noted that there may be some inaccuracy in the epidemiology of HEV due to the variation in the sensitivity of various anti-HEV IgG testing kits and the lack of standardization of testing (Zhou et al., 2013).
Genotypes 1 and 2 affect humans alone. They are transmitted via the faecal-oral route and survive in water. Consequently, the places of highest prevalence are areas of over crowding and poor sanitation (Hazam et al., 2010). They are endemic in the developing world, with genotype 1 being the most common cause of HEV outbreaks. Notable outbreaks include the refugee camps in Maban County, South Sudan, 2012.
Genotypes 3 and 4 affect humans and animals e.g. pigs, game. These genotypes are most commonly seen in the developed world, although low level prevalence of genotype 3 HEV has been found in locally farmed pigs in Cameroon (S de Paula et al., 2013). They are transmitted across species by consuming the raw or undercooked meat of an infected animal (Tei et al., 2003, Emerson et al., 2005). Transmission may also occur rarely between humans. This has been documented by blood transfusions (Matsubayashi, 2004).
A further two more genotypes have been discovered that do not affect humans, but can infect wild boar (Smith et al., 2013).
Figure 1. Geographic distribution of human cases of Hepatitis E (Reprinted from The Lancet; 379(9835), Kamar et al., 2477–2488, Hepatitis E, Copyright 2012, with permission from Elsevier)
Acute HEV infection
HEV infection can range from asymptomatic to fulminant hepatitis. The incubation period from infection to symptoms ranges from two to eight weeks (Purcell and Emerson, 2008). Symptoms include fever, fatigue, myalgia, arthralgia, weakness, vomiting, jaundice, pale stools and dark urine. Neurological symptoms, e.g. from peripheral neuropathy, may also occur (Kamar et al, 2011). Blood tests reveal raised liver transaminases, alkaline phosphatase, γ-glutamyltransferase and bilirubin.
Acute HEV infection can be diagnosed by the presence of anti-HEV IgM, whilst IgG suggests past infection. Due to the wide variation in the accuracy of serological testing, viral Polymerase Chain Reaction (PCR) should be used to confirm the diagnosis (Drobenuic et al., 2010).
In HEV endemic areas where HEV genotype 1 predominates, only 20% of HEV infections produce symptomatic hepatitis. HEV infection rarely causes clinical symptoms in children (Buti et al., 2008), in contrast to pregnant women who have the highest risk of symptomatic hepatitis.
Pregnant women are a particularly susceptible group to HEV transmission, symptomatic infection and mortality. Mortality is 2% if not pregnant and 20% if pregnant (Rein et al., 2012). This mortality risk is most pronounced in the 3rd trimester when the mortality approaches 31% (Guthmann et al., 2006). The risk of contracting acute HEV infection is increased by HIV infection in pregnancy (Caron et al., 2012).
Pre-existing liver disease increases the risk of fulminant hepatitis. The mortality from HEV genotype 1 infection as a cause of decompensation of chronic liver disease is almost 70%, which is considerably higher than other causes of decompensation (Kumar et al., 2004).
HEV infection only produces one symptomatic episode due to the generation of anti-HEV IgG antibodies.
In the majority of cases acute HEV infection will be cleared. An immunocompromised status may lead to the persistence of the virus and chronic HEV infection. This is particularly the case for patients with HIV (Dalton et al., 2009), organ transplants (Kamar et al., 2008) and haematological malignancy. HEV infection in this group is more difficult to confirm as the standard antibody testing for HEV infection is unreliable due to the underlying immunocompromise and so direct molecular assays should be used. To date, only genotype 3 HEV has been shown to cause chronic infection.
HEV infection is usually self-limiting and so only supportive treatment is needed. Severe infection can be treated with ribavirin, although ribavirin is contraindicated in pregnancy due to teratogenicity and fetal loss. The approach to treating chronic infection in transplant patients is first to reduce the immunosuppression to allow clearance by the host (Kamar et al., 2010), then to treat with ribavirin and/or pegylated alpha interferon for three months if infection remains (Scobie and Dalton, 2013).
Prevention and Vaccine
The main way to prevent HEV infection in developing countries is by maintaining good hygiene and to supply a safe water source. Chlorination of water has not been shown to inactivate HEV (Guthmann et al., 2006), but boiling water will kill the virus (Emerson et al., 2005).
Human and animal studies have shown the development of antibodies to HEV post infection that protect against re-infection (Bryan et al., 1994, Tsarev et al., 1994). Following subsequent work, two HEV vaccines have been developed.
The HEV 239 vaccine (Hecolin ®) was shown to induce immediate immunity to HEV following two doses within one month with 100% efficacy against symptomatic HEV, lasting five months until the third dose (Shrestha et al., 2007). This supports its use in limiting an outbreak of HEV. No adverse effects of the vaccine have been observed in pregnancy (Wu et al., 2012) and its efficacy and safety have been confirmed in a phase III trial (Zhu et al., 2010). Pregnant women or women of childbearing age could be targeted for vaccination in the face of limited resources. The HEV 239 vaccine is currently licensed for use in China, but unfortunately is not part of the WHO priority vaccines.
Comparison with hepatitis A virus
There are many similarities between HEV and hepatitis A virus (HAV). Both HEV and hepatitis A virus (HAV) are enteric viruses spread by contaminated water. HAV is only found to infect human and non-human primates, whereas HEV has a wide variety of zoonotic hosts, depending on its genotype (Purcell et al., 2008). The clinical presentation of HEV is very similar to that of HAV. There are only a few contrasting points. The incubation period of HEV is roughly ten days longer than that of HAV. The severity of disease and mortality tends to increase with age for HAV, whereas age has no bearing on HEV mortality. HEV does however, have a high mortality in pregnant women that is not seen in HAV. Finally, HAV hepatitis can relapse in contrast to HEV, which only causes a single episode of clinical illness.
HEV infection is a major cause of morbidity in areas of over crowding and poor water hygiene. Pregnant women and patients with preexisting liver disease are most likely to develop fulminant hepatitis, with an associated high mortality. They could therefore be targeted for vaccination in endemic areas. Ultimately prevention of transmission by good sanitation and boiling drinking water is the best approach to reduce morbidity and mortality from HEV and a number of other waterborne pathogens.
Balayan MS, Andjaparidze AG, Savinskaya SS, et al. Evidence for a virus in non-A, non-B hepatitis transmitted via the fecal-oral route. Intervirology 1983;20:23–31
Bryan JP, Tsarev SA, Iqbal M, Ticehurst J, Emerson S, Ahmed A, et al. Epidemic hepatitis E in Pakistan: patterns of serologic response and evidence that antibody to hepatitis E virus protects against disease. J Infect Dis. 1994;170(3):517–21.
Buti M, Plans P, Dominguez A, et al. Prevalence of hepatitis E virus infection in children in the northeast of Spain. Clin Vaccine Immu- nol 2008;15:732–734.
Caron M, Bouscaillou J, Kazanji M. Acute risk for hepatitis E virus infection among HIV-1-positive pregnant women in central Africa. Virol J. 2012 Oct 31;9:254.
Dalton HR, Bendall RP, Keane FE, Tedder RS, Ijaz S. Persistent carriage of hepatitis E virus in patients with HIV infection. N Engl J Med. 2009;361(10):1025–7.
Drobeniuc J, Meng J, Reuter G et al. Serologic assays specific to immunoglobulin M antibodies against hepatitis E virus: pangenotypic evaluation of performances. Clin Infect Dis 2010: 51(3): e24–e27
Emerson SU, Arankalle VA, Purcell RH. Thermal stability of hepatitis E virus. J Infect Dis 2005;192:930–933.
Guthmann JP, Klovstad H, Boccia D, et al. A large outbreak of hepatitis E among a displaced population in Darfur, Sudan, 2004: the role of water treatment methods. Clin Infect Dis. 2006;42:1685–91.
Hazam RK, Singla R, Kishore J, Singh S, Gupta RK, Kar P. Surveillance of hepatitis E virus in sewage and drinking water in a resettlement colony of Delhi: what has been the experience? Arch Virol 2010: 155 (8): 1227–1233.
Kamar N, Abravanel F, Selves J et al. Influence of immunosuppressive therapy on the natural history of genotype 3 hepatitis-E virus infection after organ transplantation. Transplantation 2010: 89(3): 353–360
Kamar N, Bendall R, Legrand-Abravanel F et al. Hepatitis E. Lancet 2012; 379(9835): 2477–2488.
Kamar N, Bendall R, Peron JM et al, Hepatitis Virus E and Neurologic Disorders. Emerging Infectious Diseases (wwwcdc/eid); 2011, 17 (2)).
Kamar N, Selves J, Mansuy JM, Ouezzani L, Peron JM, Guitard J, et al. Hepatitis E virus and chronic hepatitis in organ-transplant recipients. N Engl J Med. 2008;358(8):811–7
Kumar A, Aggarwal R, Naik SR, Saraswat V, Ghoshal UC, Naik S. Hepatitis E virus is responsible for decompensation of chronic liver disease in an endemic region. Indian J Gastroenterol 2004: 23(2): 59–62.
Matsubayashi K, Nagaoka Y, Sakata H, et al. Transfusion-trans- mitted hepatitis E caused by apparently indigenous hepatitis E virus strain in Hokkaido, Japan. Transfusion 2004;44:934–940.
Purcell RH, Emerson SU. Hepatitis E: an emerging awareness of an old disease. J Hepatol 2008;48:494–503
Rein DB, Stevens GA, Theaker J, Wittenborn JS, Wiersma ST. The global burden of hepatitis E virus genotypes 1 and 2 in 2005. Hepatology. 2012;55(4):988–97
Scobie L and Dalton HR. Hepatitis E: Source and Route of Infection, Clinical Manifestations and New Developments. J Viral Hepat. 2013;20(1):1-11.
S de Paula V, Wiele M, Mbunkah AH, Daniel AM, Kingsley MT, Schmidt-Chanasit J. Hepatitis E virus genotype 3 strains in domestic pigs, Cameroon.Emerg Infect Dis. 2013 Apr;19(4):666-8.
Shrestha MP, Scott RM, Joshi DM, Mammen MP Jr, Thapa GB, Thapa N, et al. Safety and efficacy of a recombinant hepatitis E vaccine. N Engl J Med. 2007;356(9):895–903
Smith DB, Purdy MA, Simmonds P. Genetic variability and the classification of hepatitis E virus. J Virol. 2013 Apr;87(8):4161-9.
Tei S, Kitajima N, Takahashi K, et al. Zoonotic transmission of hepatitis E virus from deer to human beings. Lancet 2003;362: 371–373.
Tsarev SA, Tsareva TS, Emerson SU, Govindarajan S, Shapiro M, Gerin JL, et al. Successful passive and active immunization of cynomolgus monkeys against hepatitis E. Proc Natl Acad Sci U S A. 1994;91(21):10198–202.
Wedemeyer H, Pischk S, Manns M, Pathogenesis and Treatment of Hepatitis E Virus Infection. Gastroenterology 2012;142:1388–1397
Wu T, Zhu FC, Huang SJ, Zhang XF, Wang ZZ, Zhang J, et al. Safety of the hepatitis E vaccine for pregnant women: a preliminary analysis. Hepatology. 2012;55(6):2038
Zhao Q, Zhang J, Wu T, Li SW, Ng MH, Xia NS, Shih JW. Antigenic determinants of hepatitis E virus and vaccine-induced immunogenicity and efficacy. J Gastroenterol. 2013 Feb;48(2):159-68.
Zhu FC, Zhang J, Zhang XF et al. Efficacy and safety of a recombinant hepatitis E vaccine in healthy adults: a large- scale, randomised, doubleblind placebo-controlled, phase 3 trial. Lancet 2010: 376(9744): 895– 902.