|Classification and external resources|
Hepatitis E virus
Hepatitis E is a viral hepatitis (liver inflammation) caused by infection with a virus called hepatitis E virus (HEV). HEV is a positive-sense single-stranded RNA icosahedral virus with a 7.5 kilobase genome. HEV has a fecal-oral transmission route. It is one of five known hepatitis viruses: A, B, C, D, and E. Infection with this virus was first documented in 1955 during an outbreak in New Delhi, India. A preventative vaccine (HEV 239) is approved for use in China.
Although it was originally classified in the Caliciviridae family, the virus has since been classified into the genus Hepevirus, and has been reassigned into the Hepeviridae family. The virus itself is a small non-enveloped particle.
The genome is approximately 7200 bases in length, is a polyadenylated single-strand RNA molecule that contains three discontinuous and partially overlapping open reading frames (ORFs) along with 5' and 3' cis-acting elements, which have important roles in HEV replication and transcription. ORF1 encode a methyltransferase, protease, helicase and replicase; ORF2 encode the capsid protein and ORF3 encodes a protein of undefined function. A three-dimensional, atomic-resolution structure of the capsid protein in the context of a virus-like particle has been described. An in vitro culture system is not yet available.
As of 2009 there are approximately 1,600 sequences of both human and animal isolates of HEV available in open-access sequence databases.
Species of this genus infect humans, pigs, boars, deer, rats, rabbits and birds.
There is only one serotype of the virus and classification is based on the nucleotide sequences of the genome. Genotype 1 has been classified into five subtypes. The number of genotype 2 can be classified into two subtypes. Genotypes 3 and 4 have been into ten and seven subtypes respectively.
Genotype 1 has been isolated from tropical and several subtropical countries in Asia and Africa. Genotype 2 has been isolated from Mexico, Nigeria, and Chad. Genotype 3 has been isolated almost worldwide including Asia, Europe, Oceania, North and South America. Genotype 4 appears to be limited exclusively to Asia.
Genotypes 1 and 2 are restricted to humans and often associated with large outbreaks and epidemics in developing countries with poor sanitation conditions. Genotypes 3 and 4 infect humans, pigs and other animal species and have been responsible for sporadic cases of hepatitis E in both developing and industrialized countries.
The incidence of hepatitis E is highest in juveniles and adults between the ages of 15 and 40. Though children often contract this infection as well, they less frequently become symptomatic. Mortality rates are generally low, for hepatitis E is a "self-limiting" disease, in that it usually goes away by itself and the patient recovers. However, during the duration of the infection (usually several weeks), the disease severely impairs a person’s ability to work, care for family members, and obtain food. Hepatitis E occasionally develops into an acute, severe liver disease, and is fatal in about 2% of all cases. Clinically, it is comparable to hepatitis A, but in pregnant women the disease is more often severe and is associated with a clinical syndrome called fulminant hepatic failure. Pregnant women, especially those in the third trimester, suffer an elevated mortality rate from the disease of around 20%.
Differences have been noted between the different genotypes. For genotype 1, the age at which incidence peaks is between 15 and 35 years and mortality is about 1%. Genotype 3 and 4 — the most common in Japan — are more common in people older than 60 years and the mortality is between 5 and 10%. Although prednisolone has been used in the treatment of this condition, because large scale studies have not yet been reported, the role of this drug in treatment is not yet clear.
- Chronic infections
In immunocompromised subjects - particularly in solid organ transplanted patients - Hepatitis E may cause a chronic infection. Occasionally this may cause liver fibrosis and cirrhosis. The use of low dose ribavirin (600 to 800 milligrams / day) over a three month period has been associated with viral clearance in such cases.
Hepatitis E is prevalent in most developing countries, and common in any country with a hot climate. It is widespread in Southeast Asia, northern and central Africa, India, and Central America. It is spread mainly through fecal contamination of water supplies or food; person-to-person transmission is uncommon.
The incubation period following exposure to the hepatitis E virus ranges from three to eight weeks, with a mean of 40 days. Outbreaks of epidemic hepatitis E most commonly occur after heavy rainfalls and monsoons because of their disruption of water supplies. Major outbreaks have occurred in New Delhi, India (30,000 cases in 1955-1956), Burma (20,000 cases in 1976-1977), Kashmir, India (52,000 cases in 1978), Kanpur, India (79,000 cases in 1991), and China (100,000 cases between 1986 and 1988).
Animals as a reservoir
Domestic animals have been reported as a reservoir for the hepatitis E virus, with some surveys showing infection rates exceeding 95% among domestic pigs. Replicative virus has been found in the small intestine, lymph nodes, colon and liver of experimentally infected pigs. Transmission after consumption of wild boar meat and uncooked deer meat has been reported as well. The rate of transmission to humans by this route and the public health importance of this are, however, still unclear.
A number of other small mammals have been identified as potential reservoirs: the lesser bandicoot rat (Bandicota bengalensis), the black rat (Rattus rattus brunneusculus) and the Asian house shrew (Suncus murinus). A new virus designated rat hepatitis E virus has been isolated.
A rabbit hepatitis E virus has also been described.
An avian virus has been described that is associated with hepatitis-splenomegaly syndrome in chickens. This virus is genetically and antigenically related to mammalian HEV, and probably represents a new genus in the family.
In 2004, there were two major outbreaks, both of them in sub-Saharan Africa. There was an outbreak in Chad in which, as of September 27, there were 1,442 reported cases and 46 deaths. The second was in Sudan with, as of September 28, 6,861 cases and 87 deaths. Increasingly, hepatitis E is being seen in developed nations, with reports of cases in the UK, US and Japan. The disease is thought to be a zoonosis in that animals are thought to be the source. Both deer and swine have been implicated.
In October 2007, an epidemic of hepatitis E was suspected in Kitgum District of northern Uganda where no previous epidemics had been documented. This outbreak has progressed to become one of the largest hepatitis E outbreaks in the world. By June 2009, the epidemic had caused illness in >10,196 persons and 160 deaths.
In 2011, a minor outbreak was reported in Tangail, a neighborhood of Dhaka, Bangladesh.
In June 2012, an outbreak was reported in city of Ichalkaranji, Maharashtra, India. As of June 14, 2012, 3232 cases were reported and 18 died. and 3 died in Shirol taluka of Kolhapur Maharashtra, India in June 2012. Officials in the Indian state of Maharashtra India suspect that contaminated water from the Panchganga river was responsible for the hepatitis E outbreak in Ichalkaranji.
In July 2012, an outbreak was reported in South Sudanese refugee camps in Maban County near the Sudan border. South Sudan's Ministry of Health reported over 400 cases and 16 fatalities as of September 13, 2012. Progressing further, as of February 2, 2013, 88 have died due to the outbreak. The "Medical charity Medecins Sans Frontieres (MSF) said it had treated almost 4,000 patients." 
The most recent common ancestor of Hepatitis E evolved between 536 and 1344 years ago. It diverged into two clades - an anthropotropic and an enzootic form - which subsequently evolved into genotypes 1 and 2 and genotypes 3 and 4 respectively. The divergence dates for the various genotypes are as follows: Genotypes 1/2 367 – 656 years ago; Genotypes 3/4 417 – 679 years ago. For the most recent common acestor of the various viruses themselves: Genotype 1 between 87 and 199 years ago; Genotype 3 between 265 and 342 years ago; and Genotype 4 between 131 and 266 years ago. The anthropotropic strains (genotype 1 and 2) have evolved more recently than the others suggesting that this virus was originally a zooenosis.
The use of an avian strain confirmed the proposed topology of the genotypes 1-4 and suggested that the genus may have evolved  The use of a rat sequence also confirmed this topology and estimated date of divergence from the swine/human strains was 7.44×104 years ago (range 2.1×104 to 1.4×105 years ago) Since this date is approximately coincident with the advent of agriculture it may be that this virus originally infected rats and subsequently spread to pigs and then to humans. Additional work is required to support or refute this possibility as very few sequences have been isolated from species other than humans and suids.(range to ).
Genotypes 1,3 and 4 all increased their effective population sizes in the 20th century. The population size of genotype 1 increaded noticeably in the last 30–35 years. Genotypes 3 and 4 population sizes began to increase in the late 19th century up to 1940-1945. Genotype 3 underwent a subsequent increase in population size until the 1960s. Since 1990 both genotypes' population sizes have been reduced back to levels last seen in the 19th century.
The overall mutation rate for the genome has been estimated at ~1.4 x 10−3 substitutions/site/year.
Improving sanitation is the most important measure, which consists of proper treatment and disposal of human waste, higher standards for public water supplies, improved personal hygiene procedures and sanitary food preparation. Thus, prevention strategies of this disease are similar to those of many others that plague developing nations, and they require large-scale international financing of water supply and water treatment projects. A vaccine based on recombinant viral proteins has been developed and recently tested in a high-risk population (military personnel of a developing country). The vaccine appeared to be effective and safe, but development stopped for economical reasons, since hepatitis E is rare in developed countries.
A different vaccine (HEV 239, sold as Hecolin by its developer Xiamen Innovax Biotech) was approved for the disease in 2012 by the Chinese Ministry of Science and Technology, following a phase 3 trial on two groups of 50,000 people each from Jiangsu Province where none of the vaccinated became infected during a 12 month period, compared to 15 in the group given placebo treatment. The first vaccine batches came out of Innovax' factory in late October 2012, and will be sold to Chinese distributors.
The hepatitis E virus causes around 20 million infections a year. These result in around three million acute illnesses and 70,000 deaths annually. It is particularly dangerous for pregnant women, who can develop an acute form of the disease that is lethal in 20 per cent of cases. The virus (HEV) is a major cause of illness and of death in the developing world and disproportionate cause of deaths among pregnant women. Although HEV vaccine trials, including trials conducted in populations in southern Asia, have shown candidate vaccines to be effective and well-tolerated, these vaccines have not yet been produced or made available to susceptible populations. The exception is China. After more than a year of scrutiny and inspection by China's State Food and Drug Administration (SFDA), a hepatitis E vaccine developed by Chinese scientists will be available by the end of 2012. There is no licensed hepatitis E vaccine for use in the US.
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