Conflict of interest The author has no conflict of interest to declare, and has not received grants, speakers fees, etc., from any commerical body within the past 2 years.
Hepatitis E: Historical, contemporary and future perspectives
Article first published online: 4 JAN 2011
© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd
Journal of Gastroenterology and Hepatology
Special Issue: Silver Jubilee Supplement: Celebrating 25 years of JGH
Volume 26, Issue Supplement s1, pages 72–82, January 2011
How to Cite
Aggarwal, R. (2011), Hepatitis E: Historical, contemporary and future perspectives. Journal of Gastroenterology and Hepatology, 26: 72–82. doi: 10.1111/j.1440-1746.2010.06540.x
- Issue published online: 4 JAN 2011
- Article first published online: 4 JAN 2011
- Hepatitis E;
- clinical features;
Hepatitis E was suspected for the first time in 1980 during a waterborne epidemic of acute hepatitis in Kashmir, India. In the 30 years since then, a small virus with single-stranded RNA genome has been identified as the cause of this disease and named as hepatitis E virus (HEV). The virus has four genotypes; of these, genotypes 1 and 2 are known to infect only humans, whereas genotypes 3 and 4 primarily infect other mammals, particularly pigs, but occasionally cause human disease. In highly-endemic areas, the disease occurs in epidemic and sporadic forms, caused mainly by infection with genotype 1 or 2 virus, acquired through the fecal-oral route, usually through contaminated water supplies. The disease is characterized by particularly severe course and high mortality among pregnant women. In persons with pre-existing chronic liver disease, HEV superinfection can present as acute-on-chronic liver disease. In low-endemic regions, sporadic cases of locally-acquired HEV infection are reported; these are caused mainly by genotype 3 or 4 HEV acquired possibly through zoonotic transmission from pigs, wild boars or deer. In these areas, chronic infection with genotype 3 HEV, which may progress to liver cirrhosis, has been reported among immunosuppressed persons. Two subunit vaccines containing recombinant truncated capsid proteins of HEV have been shown to be highly effective in preventing the disease; however, these are not yet commercially available. These vaccines should be of particular use in groups that are at high risk of HEV infection and/or of poor outcome.
Hepatitis E, caused by hepatitis E virus (HEV), was unknown as a disease entity until 1980. In the initial years after its discovery, it was believed to be a common cause of sporadic and epidemic waterborne acute hepatitis in, and limited to, developing countries, primarily in Asia and Africa. However, in recent years, the host range, geographical distribution and modes of transmission of this virus, and clinical presentations of this infection have been shown to be much broader than were previously believed. In the nearly three decades since the disease was first suspected, besides the identification and characterization of the causative agent, two highly protective subunit vaccines have been developed, setting the stage for its global control. This piece reviews the historical aspects, current status of our understanding and future prospects of research into hepatitis E and HEV.
The initial discovery
Viral hepatitis was recognized as an infectious disease as early as the 8th century AD. During the middle ages, outbreaks of viral hepatitis were a frequent occurrence during wars, famines and earthquakes.1 Outbreaks of acute hepatitis were reported from several parts of the world during the 18th and 19th centuries.2 In the latter half of the 19th century, some outbreaks were recognized as being associated with immunization against smallpox. By the mid-20th century, it was clear that acute hepatitis consisted of two separate diseases, namely infectious hepatitis and serum hepatitis, acquired through enteric and parenteral routes, respectively. These two forms of disease were provisionally named as hepatitis A and hepatitis B. In the 1970s, the agents responsible for these diseases were discovered and were named as hepatitis A virus (HAV) and hepatitis B virus (HBV), respectively.3 The consequent development of sensitive serological tests for these agents soon led to the realization that a large proportion of cases with post-transfusion hepatitis were not related to either of these agents;4 such cases were provisionally labeled as being caused by a non-A, non-B post-transfusion hepatitis agent. A few cases of sporadic hepatitis were also found to lack markers of hepatitis A and B;5,6 however, this did not get much attention.
An enterically-transmitted non-A, non-B hepatitis virus was first suspected by Khuroo in 1980,7 during an outbreak of acute viral hepatitis in the Kashmir Valley, India, with 275 clinical cases among 16 620 inhabitants of the affected areas between November 1978 and April 1979. Most cases were 11–40 years old, and occurred in villages with a common water source. Of the affected persons, 12 (4.4%) had fulminant hepatic failure (FHF), and 10 died. The outbreak was characterized by a high disease attack rate and mortality among pregnant women. Of the 31 patients and their contacts tested, only one had detectable immunoglobulin M (IgM) anti-HAV antibodies and none had hepatitis B surface antigen (HBsAg); in fact, most subjects had evidence of prior immunity against HAV infection. These findings suggested existence of a water-transmissible agent distinct from HAV and HBV, and laid the foundation for discovery of a new hepatitis agent.
A few months later, Wong et al.8 reported the results of retrospective serological testing of sera stored since a large outbreak of hepatitis that had occurred in New Delhi during 1955–1956, and two smaller ones in Ahmedabad (1975–1976) and Pune (1978–1979) in the western part of India. Specimens from none of the three outbreaks showed evidence of acute hepatitis A and only a few had markers of acute hepatitis B, providing valuable support to the existence of an enteric non-A, non-B hepatitis agent.
Of these outbreaks, the one in New Delhi had been extensively investigated.9,10 This outbreak followed a short period of flooding in the river Yamuna in November 1955 leading to contamination of the city's water supplies. The epidemic reached a peak in 2 weeks and then abated rapidly, lasting for about 7 weeks. Nearly 29 000 persons, representing 2.3% of population residing in the affected areas had an icteric illness. Young adults had the highest disease rate. The illness consisted of a brief prodromal period, followed by typical acute hepatitis. The disease generally had a self-limited course, except pregnant women who more often had fulminant hepatic failure and had a high case-fatality rate.
Soon thereafter, other waterborne epidemics of enteric non-A, non-B hepatitis were reported from India, Nepal, and Africa.11–13 Two small outbreaks were also reported from Mexico.14,15 In addition, Khuroo et al. reported that most of their cases with acute sporadic hepatitis were also caused by the suspected enteric non-A, non-B agent.16
Transmission studies and identification of the virus
The confirmation of existence of a new hepatitis agent came soon. In 1983, Balayan et al.17 inoculated a human volunteer, who was immune to HAV, with pooled aqueous extract of fecal matter from nine patients with epidemic non-A, non-B hepatitis, by the oral route. The volunteer (Dr Balayan himself) developed typical acute hepatitis on day 36, which lasted for about 3 weeks. Stool specimens collected on days 28–45 showed 27- to 30-nm spherical virus-like particles (VLPs) that showed aggregation with convalescent sera from patients with enteric non-A, non-B hepatitis, but not with those from patients with hepatitis A, hepatitis B or post-transfusion non-A, non-B hepatitis. The volunteer showed seroconversion against VLPs, but no detectable HBsAg or boosting of anti-HAV antibodies. Two cynomolgus monkeys inoculated with a stool suspension from the volunteer showed excretion of similar VLPs, liver enzyme elevation and histological changes of hepatitis, fulfilling the Koch's postulates. Subsequently, other workers also showed transmission of infection to primates and excretion of VLPs in their stools.18,19
The second decade
Nearly a decade after the initial discovery of a new virus, Reyes et al.20 isolated a nucleic acid clone representing a part of its genome from bile obtained from an experimentally-infected animal. They also identified similar genomic sequences in clinical specimens obtained from several geographical regions at different time-points. This was soon followed by molecular cloning and sequencing of the entire genome of virus isolates from Asia and Mexico;21,22 the genomic sequences of these two isolates showed significant differences, indicating the presence of genomic heterogeneity. Around this time, the agent was christened as hepatitis E virus (HEV), using the next available English alphabet after the four hepatitis agents already known and the disease's propensity to cause “e”pidemics and “e”ndemic disease.
These developments paved the way for development of serological tests for detection of anti-HEV antibodies. Infection with HEV was shown to be associated with appearance of IgM anti-HEV antibodies by the time of development of disease in most patients and that of immunoglobulin G (IgG) anti-HEV shortly thereafter;23 the former were short-lived providing a marker of recent infection with HEV, whereas the latter was found to indicate past exposure. The new-found molecular and serological tests for diagnosis of HEV infection spawned several studies in different geographical areas to determine the frequency of HEV infection in patients with epidemic and sporadic hepatitis, and in different population groups.
Discovery of animal HEV and zoonotic transmission
The next major advance was the discovery of a closely-related virus, named as swine hepatitis E virus, which was genetically distant from the two previously recognized genetic groups of HEV, among pigs in the USA.24 Around the same time, a few indigenous human cases of hepatitis E were identified in the USA, and genomic sequences of these human HEV isolates most closely resembled those from the swine HEV.25–27 This prompted studies for HEV-like viruses among several animal species around the world, and among human cases in developed countries. These studies led to the discovery of hitherto unsuspected zoonotic transmission of the virus, leading to a major shift in our understanding of HEV.
In the last few years, there have been major advances in our understanding of the virus and its structure, biology and molecular heterogeneity. In vitro systems using complementary DNA clones that can transfect cultured cell lines, leading to replication of viral RNA, expression of viral proteins and production of viable viral particles, have been developed.28,29 Furthermore, in vitro cell culture systems for HEV, albeit relatively inefficient, have been developed.30,31 On the clinical front, occurrence of persistent HEV infection in persons receiving immunosuppressive drugs, and those with hematological diseases or HIV infection has been recognized and successful attempts at drug therapy of such infection have been made. The most important advances include development of two successful hepatitis E vaccines.
The virus: taxonomy, morphology and genomic organization
HEV is currently placed in genus Hepevirus, and is the only member of family Hepeviridae. The virions are spherical particles measuring 27–34 nm in diameter, and have prominent protrusions on their surface. These contain an approximately 7.2-Kb long, polyadenylated, single-stranded RNA genome, with short non-coding regions at each end, and three discontinuous and partially overlapping open reading frames (ORFs) (Fig. 1).21 Presence of several conserved motifs in ORF1 region suggests that it codes for viral non-structural proteins, including putative methyltransferase, protease, helicase and RNA-dependent RNA polymerase. ORF2 codes for the major viral capsid protein, and ORF3 for a small phosphoprotein which appears to have an important role in viral replication and regulation of the host response to HEV infection.32
Cryo-electron microscopy of recombinant VLPs produced in an insect cell system transfected with a recombinant baculovirus containing a truncated viral capsid gene suggests that these are T = 1 icosahedral particles. The capsid protein molecules have a shell domain that contributes to the semiclosed icosahedral shell and a protrusion domain that interacts with the neighboring molecules to form surface protrusions.33–35
Genotypic heterogeneity and genotypes
Using genomic sequence analysis, HEV isolates from human and other mammals have been divided into four genotypes, namely 1, 2, 3 and 4 (Fig. 2), and at least 24 subgenotypes (1a-1e, 2a-2b, 3a-3j and 4a-4g).36 Avian isolates of HEV are genetically distinct with a shorter (6.6 Kb) genome and only about 50% sequence homology with the mammalian isolates. The avian HEV is responsible for big liver and spleen disease in chicken,37,38 and is known to infect other bird species such as turkeys;39 initially proposed to constitute a fifth HEV genotype, these isolates are now considered as belonging to a separate genus.
Each HEV genotype appears to have a specific geographic distribution (Fig. 3). Genotype 1 HEV has been isolated from human cases of epidemic and sporadic hepatitis E in parts of Asia and Africa, where the disease is highly endemic,36 and also from hepatitis E cases among travelers to these regions from low-endemic areas. These isolates have a high (>90%) nucleotide sequence homology with each other. Genotype 2 sequences, first reported from an outbreak of hepatitis E in Mexico, have subsequently been reported from cases in western Africa (Nigeria and Chad).36 These have nucleotide homology of only 75% (amino acid homology 86%) with genotype 1 isolates.22,36,40 Genotype 3 HEV, first identified in a few rare cases of locally-acquired hepatitis E in the United States (US),25–27 has subsequently been reported from human cases in several industrialized countries in Europe (United Kingdom [UK], France, Netherlands, Spain, Austria, Greece, Italy), Japan, Australia, New Zealand, Korea and Argentina.36,41 The genotype 3 isolates show only 74% to 75% nucleotide homology to genotypes 1 and 2 isolates. Genotype 4 HEV has been found in sporadic cases with acute hepatitis from China, Taiwan, Japan and Vietnam.36,42 All genotypes share at least one major serologically cross-reactive epitope and belong to a single serotype.43
Several mammalian species (pigs, cattle, sheep, goats, horses, macaques, cats, dogs, rabbits, mongoose, rats and mice) show serological evidence of HEV infection.44 HEV infection has been found in pigs in all parts of the world, irrespective of the frequency of hepatitis E in human populations. Infection in pigs occurs early in life, and is associated with transient viremia, viral excretion and seroconversion, but no disease.24 Swine HEV isolates belong to genotypes 3 and 4; of these, the predominant genotype in any geographic region is usually the same as the one predominant among human cases in that area (genotype 3 in US, Europe, Australia and Japan, and genotype 4 in Taiwan, China, Japan).36 Swine HEV isolates from USA, Taiwan, Spain and Japan have generally shown a greater genetic similarity to human HEV isolates from these respective regions than to swine and human HEV isolates from the rest of the world.45–47 In contrast, in India, where disease is highly endemic, swine HEV isolates have all been genotype 4,48,49 whereas all human cases studied have revealed genotype 1 HEV, though a case with genotype 4 HEV infection in the UK who had recently travelled to India has been reported.50 Genotype 3 HEV genomic sequences have also been isolated from other animals, such as deer and wild boar.51,52 Recently, HEV genomic sequences from rats, mongoose, rabbit and cattle have also been reported.53–55 Genotype 4 sequences have also been reported in cows.56 Genotype 1 or 2 HEV have not yet reliably been isolated from non-primate animals.
In experimental studies, genotype 3 isolates from humans and swine have been shown to cross species barriers, and to infect specific pathogen-free pigs and non-human primates (surrogate for humans), respectively.27,57 In addition, genotype 4 HEV from Indian swine has been experimentally transmitted to primates.58 However, inoculation of epidemic strains of HEV (genotype 1 and 2) into experimental animals other than primates has not led to transmission of infection, indicating that these strains have a more limited host range.59
Genotype 3 and 4 isolates of HEV appear to be somewhat less pathogenic in humans than those from genotypes 1 and 2. In one study, genotype 4 HEV appeared to be associated with more severe liver injury than genotype 3 virus.60
HEV infection is most often transmitted through contaminated drinking water. The virus can also be transmitted by other routes, including (i) food-borne transmission (ii) transfusion of infected blood products, and (iii) vertical (materno-fetal) transmission. In several cases, particularly those in low-endemic regions and sporadic cases in highly endemic regions, route of acquisition of infection cannot be identified. In epidemics, the incubation period has varied from 2 to 10 weeks.9 Two distinct epidemiological patterns have been observed, with regions where hepatitis E is highly endemic differing from those where it is not, in the relative frequency of various routes of transmission, the population groups affected and disease characteristics.
Hepatitis E in highly disease-endemic regions
Fig. 4 shows the areas where hepatitis E is highly endemic. Outbreaks of this disease have been reported frequently in the Indian subcontinent, China, Southeast and Central Asia, the Middle East, and northern and western parts of Africa. Two small outbreaks occurred in North America (Mexico) during 1986–1987, but none has been reported thereafter. Most outbreaks are related to consumption of fecally-contaminated drinking water, and may affect up to several hundred to several thousand persons.7,9,61,62 These vary from unimodal outbreaks, which last a few weeks, to prolonged, multi-peaked epidemics which may last for over a year;9,61 the prolonged outbreaks are caused by continued water contamination. The outbreaks frequently follow heavy rainfall and floods, conditions that facilitate mixing of human excreta with sources of drinking water.7,9 At times, outbreaks occur during hot and dry summer, when diminished water flow in rivers leads to an increased concentration of fecal contaminants.61,63 Some outbreaks have occurred in urban areas with leaky water pipes passing through soil that is contaminated with sewage; intermittent water supply in these areas leads to a negative pressure in pipes during periods of no flow, permitting inward suction of contaminants.64
In comparison, only a few, small food-borne outbreaks have been reported. This may be due partly to the difficulty of relating consumption of a particular food to the occurrence of a disease with a relatively long incubation period.
Overall attack rates during hepatitis E outbreaks have ranged from 1% to 15%, though these reached nearly 25% in a recent outbreak in Uganda.65 Disease rates are the highest among young adults. The lower disease rates in children are probably due to a higher proportion of asymptomatic infections in them, than to lower frequency of infection. Males often outnumber females, possibly because of their greater risk of consuming contaminated water.
Hepatitis E outbreaks are characteristically associated with a high disease attack rate among pregnant women. Further, the affected pregnant women are more likely to develop FHF or to have a fatal outcome. These associations were first noted during the Kashmir and the Delhi outbreaks. In the Kashmir outbreak, 17.3%; 8.8%, 19.4% and 18.6% of pregnant women in the first, second and third trimesters, respectively, had icteric disease, compared to only 2.1% of non-pregnant women and 2.8% of men. Further, pregnant cases more often (22.2%) developed FHF than the cases who were non-pregnant women (0%) or men (2.8%). Once fulminant hepatitis appears, the mortality rate may be no different among pregnant women with hepatitis E than in those with other causes of severe liver injury.66 The exact cause of this specific predilection for occurrence of disease audits worst outcome among pregnant women remains unknown; immunological or hormonal factors have been suspected.67–69 Hepatitis E during pregnancy is also associated with prematurity, low birth weight and an increased risk of perinatal mortality.
In high-endemic areas, HEV infection accounts for a large proportion of acute sporadic hepatitis in all age groups. Patients with sporadic hepatitis E resemble those of epidemic hepatitis E in age distribution, severity and duration of illness, propensity for worse prognosis among pregnant women, and absence of chronic sequelae.16 Route of transmission is unclear in such patients, but is likely to be through contamination of water or food. Identification of the HEV genomic sequences in sewage from high-endemic regions around the year suggests nearly ubiquitous circulation of HEV in these populations; this could act as a reservoir of infection responsible for sporadic cases.70
Unlike many other enterically-transmitted infections, person-to-person transmission of HEV appears to be uncommon.71,72 Thus, secondary attack rates among household contacts of patients with hepatitis E are only 0.7% to 2.2%, as compared to 50% to 75% for hepatitis A. Even when multiple cases occur in a family, the time interval between cases is usually short, indicating a shared primary water-borne infection rather than person-to-person spread.71
Hepatitis E in regions where disease is infrequent
In the US, Europe (including UK, France, the Netherlands, Austria, Spain and Greece), and developed countries of Asia-Pacific (Japan, Taiwan, Hong Kong, Australia), hepatitis E is responsible for only occasional cases with acute viral hepatitis. Initially, most such cases were found to be related to travel to high-endemic areas. However, in recent years, solitary cases or small case series related to autochthonous (locally-acquired) hepatitis E in these regions have been reported.25–27 In the UK, a seasonal variation with peaks in spring and summer has been reported.75
These rare autochthonous cases of hepatitis E in these areas are believed to be caused by zoonotic spread of infection from wild or domestic animals,75,76 since HEV isolates from them are genetically related to swine isolates.25–27 Experimental cross-species transmission of human isolates to pigs, and of swine HEV to primates supports this view.27,57 A cluster of Japanese cases among persons who had consumed inadequately-cooked deer meat a few weeks prior to the onset of illness has been reported.51 The genomic sequences of HEV isolated from these cases were identical to those from the left-over frozen meat, establishing food-borne transmission; these isolates also had a high (99.7%) genomic sequence homology with those from a wild boar and another wild deer from the forest where the implicated deer had been hunted, suggesting transmission between wild boars and deer.77
A proportion of commercial packets of pig liver sold in Japanese and US grocery stores have been shown to contain genotype 3 or 4 HEV.78,79 This finding, along with the reported association of sporadic hepatitis E cases with eating uncooked or undercooked pig livers in case-control studies, suggests that at least some autochthonous cases are related to consumption of contaminated meat. Contaminated shellfish has also been proposed as a potential vehicle.
Reservoir of infection in hyperendemic regions
The reservoir of HEV responsible for maintaining the disease in hyperendemic populations has not been clearly determined. Protracted viremia and prolonged fecal shedding of HEV have been suggested; however, we found that viral shedding in feces lasts for only a short period.80
In an experimental model, primates inoculated with a low dose of HEV were found to excrete large amounts of viable and infectious HEV, even though they had no evidence of liver injury.81 Similar fecal shedding of the virus by persons with subclinical HEV infection in high-endemic areas could maintain a continuously circulating pool of infectious individuals, who could in turn periodically contaminate drinking water supplies.
The importance of an animal reservoir in high-endemic regions remains unresolved. Its existence is suggested by a high prevalence of anti-HEV antibodies in several animal species, and isolation of HEV genomic sequences from pigs in these regions. However, data on genomic sequence homology between human and animal HEV isolates from regions with high endemicity are conflicting. Whereas HEV isolates from animals and sporadic human cases have belonged to the same genotype (genotype 4) in China and Vietnam, such concordance has not been found in India.48,49 Genotype 1 HEV, which is responsible for the large majority of cases in hyperendemic countries, has never been isolated from pigs, and has failed to infect pigs in experimental studies.59 Thus, based on current evidence, zoonotic transmission appears unlikely to be responsible for the widely prevalent genotype 1 HEV infections in these areas.
Anti-HEV seroprevalence data
Anti-HEV IgG antibodies are believed to represent evidence of prior exposure to HEV. The available anti-HEV IgG assays have variable sensitivity and specificity rates,82 and better assays are needed. Furthermore, the duration of persistence of circulating IgG anti-HEV antibodies remains unclear. In one study, nearly half of those who had been affected during a hepatitis E outbreak had no detectable anti-HEV 14 years later.83 In another study of patients with acute hepatitis E, IgG anti-HEV was still detectable 14 months later, though its titers had declined.84
Anti-HEV antibodies have been found in a subset of healthy persons residing in all parts of the world. In general, prevalence rates are higher in developing countries where hepatitis E is common than in countries where clinical cases due to hepatitis E are uncommon. However, some discordant findings stand out. In India and other high-endemicity countries, where clinical cases and outbreaks of hepatitis E are common, age-specific seroprevalence rates of anti-HEV are much lower than those for HAV and other enteric infections, such as Helicobacter pylori.85 In contrast, anti-HEV detection rates among adults in Egypt are above 70%, despite notable absence of disease outbreaks.86 These differences cannot be fully explained on differences in performance characteristics of various anti-HEV assays.
In developed countries, anti-HEV antibody prevalence rates ranging from 1% to above 20% have been reported.23,75,87 These appear to be markedly higher than those expected from the low rate of hepatitis E disease in these areas. The reason for this high anti-HEV seroprevalence is unclear, and may reflect exposure to animals, prior subclinical HEV infection, serologic cross-reactivity with other agents and/or false-positive serologic tests. In these areas, veterinarians and swine farm workers who come in close contact with pigs have higher anti-HEV seroprevalence rates than general populations.
Clinical presentations in hyperendemic areas
Hepatitis E most commonly manifests as self-limiting, acute icteric hepatitis, indistinguishable from that caused by other hepatotropic viruses. The illness usually lasts for a few weeks and improves spontaneously. A few patients have a prolonged illness with cholestatic manifestations including troublesome itching, though the outcome is usually good. Some patients have a particularly severe illness, presenting as FHF (acute liver failure); as indicated above, this is particularly common in pregnant women.
Frequent detection of anti-HEV antibodies among residents of high-endemic regions who do not recall prior acute hepatitis indicates that asymptomatic or inapparent HEV infection is common. During hepatitis E outbreaks, some persons show evidence of anicteric hepatitis (elevated liver enzymes with normal serum bilirubin) and HEV infection (HEV viremia and seroconversion).
Factors that determine disease severity are poorly understood. In animal studies, the viral inoculum dose determines severity of liver injury, and lower doses are associated with subclinical infection;81 the role of this factor in humans has not been studied.
In areas where hepatitis E is common, HEV superinfection can occur in patients with pre-existing chronic liver disease of viral or non-viral etiology, leading to superimposed acute liver injury and clinical presentation with acute on chronic liver disease. We found evidence of recent HEV infection in nearly one-half of Indian patients with chronic liver disease and recent decompensation.88 Such patients may be at a higher risk of a poor outcome. In some patients, chronic liver disease had been clinically silent till the time of HEV superinfection.
Case-fatality rates of hepatitis E have been reported as 0.5% to 4%. However, these data are derived from hospitalized cases with more severe disease. In population surveys during disease outbreaks, much lower mortality rates of 0.07% to 0.6% have been observed.61,62
Clinical manifestations in areas with lower disease prevalence
In low-endemicity areas, the disease is most often recognized when serological tests are undertaken in patients with unexplained liver injury. Clinical illness in these patients is generally similar to that in high-endemicity regions, except that most patients have been middle aged or elderly men, who often had another coexistent disease.89,90 Common clinical presentations have included icteric hepatitis, anicteric illness with non-specific symptoms, and asymptomatic transaminase elevation;75 some cases were initially suspected to have drug-induced liver injury.91 Prognosis of HEV infection appears to be worse in patients in these areas than those in high-endemicity areas, mainly because of their older age and higher frequency of coexistent illnesses.
Chronic hepatitis E
Persistent HEV infection was reported for the first time in 2008, by a French group. They described a case series of 14 solid-organ transplant recipients who were receiving immunosuppressive drugs and had a recent onset of transaminase elevation (7 asymptomatic, 7 with non-specific symptoms) and were found to have evidence of HEV infection.92 All patients had genotype 3 HEV. Of these 14 patients, 8 had persistent HEV viremia and liver enzyme elevation. Liver biopsies in some of the patients with chronic HEV infection showed portal hepatitis with dense lymphocytic infiltrate, and variable degrees of piecemeal necrosis and fibrosis. The patients with persistent infection had a significantly shorter time from organ transplantation to the development of HEV infection, and thus had lower total, and CD2, CD3, and CD4 lymphocyte counts than those with resolving HEV infection. Chronic HEV viremia has also been reported in patients receiving anti-cancer chemotherapy, hematological conditions and persons with human immunodeficiency virus infection. In a few cases with persistent HEV infection and prolonged transaminase elevation, serial liver biopsies have shown active chronic hepatitis and progression to liver fibrosis,93 suggesting the possibility that chronic HEV infection may lead to cirrhosis.
All reports of chronic hepatitis E have been among immunosuppressed persons and have involved genotype 3 virus. No cases of persistent infection with genotype 1 HEV, the predominant disease-causing strain worldwide, or among otherwise healthy persons have yet been reported.
Drug treatment for chronic hepatitis E
Acute hepatitis E is usually self-limiting and does not need treatment. Recent recognition of chronic HEV infection and the associated risk of progressive liver injury has led to attempts at anti-viral treatment using pegylated interferon, ribavirin or both,94,95 with fairly good results. However, the published reports are mostly in the form of case reports or small case series. Whether these drugs will be useful in patients with FHF due to hepatitis E, or those with chronic liver disease and HEV superinfection remains unclear. Teratogenicity of ribavirin may pose a problem for use during pregnancy. In view of the rapid downhill course of such patients, the temporal window of opportunity for the drug to act and alter the outcome in such patients may also be limited.
In animal studies, several truncated recombinant HEV capsid protein have been found to induce specific antibodies, and to protect against liver injury following subsequent challenge with homologous and heterologous strains of the virus. An HEV DNA vaccine has also been shown to induce serum anti-HEV antibodies in cynomolgus macaques, and protect against a heterologous challenge.96 These findings have led to the development of two separate subunit vaccines, which have been tested in clinical trials.
The first human vaccine contained VLPs made up of a 56-kD truncated HEV ORF2 protein (aminoacids 112–607) produced in Spodoptera frugiperda cells infected with a recombinant baculovirus. In a phase I trial, three doses of 1, 5, 20 or 40 µg of this recombinant protein, administered in an alum-adjuvanted formulation, induced production of anti-HEV antibodies among healthy volunteers.97 The antibody response was found to be dose-dependent.97 In a phase II–III efficacy trial, nearly 2000 volunteer Nepalese soldiers who lacked detectable anti-HEV antibodies were randomized to receive either 20 µg of this vaccine or a matched placebo, each given as three doses at 0, 1 and 6 months, and were followed up for a median of 804 days.98 The study subjects were overwhelmingly (>99%) male and mostly young (mean age = 25 years). Clinically overt acute hepatitis E occurred less frequently among vaccine recipients who completed the 3-dose schedule than among placebo recipients, with a vaccine efficacy rate of 95%. Administration of two doses was associated with a somewhat lower efficacy rate of 86%. Adverse events were similar except for more frequent injection-site pain with the vaccine.
The second vaccine, named as the HEV 239 vaccine, contains a more truncated HEV capsid protein (corresponding to aminoacids 368–606) expressed in Escherichia coli, which has been purified and adsorbed on aluminum hydroxide suspended in buffered saline.99 In a phase II human trial, all volunteers who lacked anti-HEV antibody showed seroconversion one month after three doses of 20 µg each, administered at 0, 1 and 6 months, respectively.100 A large, community-based, randomized, double-blind, placebo-controlled, phase III trial of this vaccine has recently been completed in China.101 This study enrolled nearly 113 000 participants, aged 16–65 years and of either gender, irrespective of their anti-HEV antibody status. Among the approximately 97 000 participants who received three dose of the vaccine (30 µg each, at 0, 1 and 6 months), the protective efficacy rate was 100% during the next one year. Even after two doses of the vaccine, 100% protection was noted, though these data were more limited.
No comparative data on the safety and immunogenicity of the two vaccines are available. Further data are needed on the safety of these vaccines among pregnant women and children, and in special groups such as persons with chronic liver disease. Studies with both the vaccines have focused on clinical disease and have not studied the HEV infection rates; it thus remains unclear whether these vaccines can reduce transmission of infection in a community. The duration of protection with both the vaccines also remains unclear. In addition, more data are needed on protective efficacy of these vaccines when these are administered post-exposure. The Chinese vaccine has been shown to provide protection against genotype 4 HEV infections, even though it is based on genotype 1 virus. Whether these vaccines provide protection against genotype 3 virus strains prevalent in developed countries needs further study.
The exact role for HEV vaccines currently remains unclear. Both the vaccines appear very useful for travelers from developed countries to areas with high prevalence of hepatitis E. In the latter areas, such vaccines may be useful for persons who are at a high risk of severe disease following HEV infection, such as pregnant women, persons with pre-existing chronic liver disease and immunosuppressed persons at risk of chronic HEV infection. In addition, these may help interrupt outbreaks of hepatitis E in high-endemicity areas and among underprivileged groups such as flood-affected and displaced populations.
Whether HEV vaccines should be used for the general population in highly endemic areas will depend on cost considerations, the duration of protection afforded by the vaccines and consequent need for booster doses and the ability of the vaccines to interrupt transmission of infection. Neither vaccine has currently reached the market.
As indicated above, the landscape of hepatitis E has changed quite drastically in the last few years. The realization that HEV infection may be geographically more widespread than was previously believed has led to a resurgence of interest in the field, as indicated by a near doubling of number of papers published annually in peer reviewed journals included in PubMed over the last five years (Fig. 5). This increased research activity may be expected to lead in the next few years to a better understanding of virus biology, host-pathogen interaction, disease epidemiology, immune responses during HEV infection and factors determining disease outcomes and viral persistence. Recent successes in cell culture of the virus should be particularly fruitful in this regard.30,31
In addition, one may expect developments in prevention of HEV infection and strategies for the use of HEV vaccines. Years of extensive research have provided us two safe and highly effective vaccines. Their effective application requires more detailed population-based studies to assess and estimate burden of disease caused by HEV infection. As indicated above, these vaccines may be of particular use in some high risk groups or certain situations, for example populations displaced due to floods, war and conflict. It is likely that studies to prove the benefits and safety of using HEV vaccines in these settings will be undertaken, along with those on duration of protection, and on the need, role and frequency of boosters. These studies may also spawn work to improve the available vaccines, including attempts to use the oral route, the natural route of HEV infection.
Overall, hepatitis E research is passing through an interesting phase. We currently appear poised for a quantum jump in the ability to understand this enigmatic agent, and to intervene and reduce the morbidity and mortality caused by it.
The authors has recently found another paper102 describing an epidemic of acute viral hepatitis in northern India in 1949, much before the 1955-56 outbreak in New Delhi. This outbreak and epidemiological and clinical features closely resembling those of subsequent outbreaks, either proven or believed to be related to HEV infection.
The author thanks Dr M S Khuroo, Srinagar, India; Dr Krzysztof Krawczynski and Dr C G Teo, Division of Viral Hepatitis, Centers for Disease Control, Altanta, USA; and Dr Robert H Purcell, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA for sharing some historical material for this manuscript.
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