Where Hepatitis B and Hepatitis E Meet: Epidemiological and Clinical Aspects

authors:

avatar Semvua B Kilonzo 1 , 2 , avatar Daniel Gunda 2 , avatar Qing Ning 1 , * , avatar Meifang Han 1 , **

Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Department of Internal Medicine, Weill School of Medicine, Catholic University of Health and Allied Sciences, Mwanza, Tanzania
Corresponding Authors:
Hepatitis Monthly: Vol.19, issue 10; e93840
published online: November 3, 2019
article type: Review Article
received: May 16, 2019
accepted: July 9, 2019
DOI: https://doi.org/10.5812/hepatmon.93840

how to cite: Kilonzo S B, Gunda D, Ning Q, Han M. Where Hepatitis B and Hepatitis E Meet: Epidemiological and Clinical Aspects. Hepat Mon. 2019;19(10):e93840. https://doi.org/10.5812/hepatmon.93840.

Abstract

Hepatitis E virus (HEV) superinfection has a significant impact on a natural course of chronic hepatitis B (CHB) patients with underlying chronic liver disease (CLD). These patients usually present with increased symptoms, rapid decompensation to liver failure, and increased mortality. An increasing rate of HEV infections worldwide with uncertainties in its prevention and treatment raises a great concern to this group of patients. Therefore, in this article, we reviewed recent studies describing the epidemiological patterns of HEV and Hepatitis B virus (HBV), both mono and dual infections. We also reviewed the literature on clinical interaction among HBV/HEV-superinfected patients with CLD and the potential preventive strategies.

1. Context

Hepatitis B virus (HBV), a member of the Hepadnaviridae family, is a small enveloped and partially double-stranded circular deoxyribonucleic acid (DNA) virus. Its genome is made up of four overlapping reading frames, which are Pol (P), Core (C), Surface (S), and X, encoding HBV proteins and promoter regions. In this regard, P encodes viral polymerase enzyme that is required for DNA synthesis, C encodes Hepatitis B envelope antigen (HBeAg), a precore/core antigen protein, which is a marker for an active infection and replication, S encodes surface proteins that are essential for viral entry and encapsulation of the core during replication, and X encodes X protein that is a key regulator of replication (1, 2). Formation of covalently closed circular DNA (cccDNA) during replication differentiates HBV from other retroviruses. This is the stable form of viral DNA that allows its persistence in the hepatocytes with significant clinical impacts, including chronicity, carcinogenesis, and anti-viral drug inefficiency. The high mutagenesis rate of HBV that is caused due to a lack of proof-reading of reverse transcriptase has resulted in the formation of ten HBV genotypes (A - J) and their several corresponding sub-genotypes with a well-characterized geographical distribution (3).

Hepatitis E virus (HEV), which is an icosahedral single-stranded RNA genome virus, has been classified as a single member of the genus Hepevirus in the family Hepeviridae. It has three overlapping open reading frames (ORFs). ORF1, ORF2, and ORF3 which respectively encode Ribonucleic acid (RNA)-dependent RNA polymerase (RdRp) protein, a capsid protein, and a small protein which induces immune suppression in HEV-infected patients (4, 5). To date, only one serotype and five genotypes (HEV-1, HEV-2, HEV-3, HEV-4, and HEV-7) are known to exist (6). Based on the new labeling approach established by the International Committee on the Taxonomy of Viruses (7), a total of 24 sub-genotypes of HEV have been identified. These include five, two, ten, and seven subtypes in HEV genotypes 1, 2, 3, and 4, respectively.

Both HBV and HEV infections affect a large number of people globally. Therefore, an interaction between the two infections in endemic areas is likely to occur, and when it does, a synergetic impact is usually observed. This review summarizes recent information in the epidemiology of both infections, HEV superinfection, pertaining to clinical interactions and prevention.

2. Evidence Acquisition

In order to achieve a comprehensive approach to find relevant articles, an extensive search was done using relevant keywords in Google Scholar, PubMed, and Scopus. The new papers were considered first and appropriate combination of the following keywords were used: Hepatitis B, Hepatitis E, coinfection, superinfection, epidemiology, liver disease, liver failure, liver cirrhosis, and hepatocellular carcinoma.

3. Results

3.1. Epidemiology

Chronic hepatitis B (CHB) infection, which embraces a large spectrum of the disease, remains a serious public health problem in the world with 257 million people affected and causes around 900000 deaths annually. The African and Western-Pacific World Health Organization’s regions harbor 68% of all infections globally (8). Most of the countries of these regions are of higher-intermediate endemicity (prevalence 5% - 7.9%) or highly endemic (prevalence ≥ 8%) for HBV. The European region is of lower-intermediate endemicity (prevalence 2% - 4.9%) and most of the countries in the American region have low endemicity (prevalence < 2%) (9). Globally, it is estimated that HEV affects a total of 20 million cases, 70000 deaths, and 3000 stillbirths (10). The HEV is endemic in many countries of Asia, Central America, and Africa. South-East Asia harbors most of the infections (60%) and deaths (65%) (11). Epidemiology of HEV infection varies greatly in each geographical location with a well-characterized viral genotype distribution.

While there is a decline in the prevalence of HBV in many regions, the prevalence of HEV is generally increasing in most countries. A recent systemic review of the studies published between 1965 and 2013 by Schweitzer et al. (8), has shown a clear decline in HBV infection rates in many countries in several WHO regions, including Western-Pacific, South-East Asia, America, Europe and Eastern-Mediterranean during the periods 1965 - 1989 and 1990 - 2013. However, this trend was not seen in the African region throughout the periods considered. Another national-wide review from China, which is one of the most affected countries by HBV infection, also showed a significant decrease of HBV seroprevalence in the general population from 7.1% in 2006 to 6.1% in 2013 (12). This pattern clearly deciphers an expanded adaptation of universal HBV immunization recommendations in newborns from the year 1992 in several countries (13), with a poor response by many African countries due to economic constraints. These data are summarized in Figure 1.

HBV seroprevalence in different countries in two-time periods (before and after the year 1990) (9). Graphs show the studies describing HBV seroprevalence (HBsAg) in countries from six WHO regions. The correlation was shown between studies that were published before the year 1990 and those published in 1990 and afterward. Apart from Africa and few countries in Europe and Americas, general declination of HBV seroprevalence is evident between two time periods.
HBV seroprevalence in different countries in two-time periods (before and after the year 1990) (9). Graphs show the studies describing HBV seroprevalence (HBsAg) in countries from six WHO regions. The correlation was shown between studies that were published before the year 1990 and those published in 1990 and afterward. Apart from Africa and few countries in Europe and Americas, general declination of HBV seroprevalence is evident between two time periods.
Figure 1.

HBV seroprevalence in different countries in two-time periods (before and after the year 1990) (9). Graphs show the studies describing HBV seroprevalence (HBsAg) in countries from six WHO regions. The correlation was shown between studies that were published before the year 1990 and those published in 1990 and afterward. Apart from Africa and few countries in Europe and Americas, general declination of HBV seroprevalence is evident between two time periods.

On the other hand, gathered evidence suggests that the rate of HEV infection is clearly escalating in many countries (14-17). In Europe for instance, the number of autochronous symptomatic cases has steadily increased from 124 cases in 2003 to 1243 cases in 2016 in England (18) and 31 cases in 2001 to 1991 cases in 2016 in Germany (19). A large multicenter study in Scotland has recently reported an increase in HEV detection among blood donors from 4.5% in 2004 - 2005 to 9.3% in 2014 - 2015 (20). Furthermore, in China, it was reported in the Third National Viral Hepatitis Prevalence Survey of 2005 - 2006 (21) that HEV seroprevalence rate was 23.5% in the country, which was higher than the previously reported seroprevalence of 17.2% in 1997 (22). These data are illustrated in Figure 2 and Appendix 1 in Supplementary File. The increasing detection rate of HEV might be a result of increased awareness and hence increased testing for the virus and/or a true increase in numbers of new infections. Moreover, the new serological tests, particularly rapid Wantai, have shown to have a significantly higher sensitivity than most of the older tests (23) and hence, it might possibly contribute to the variability.

HEV seroprevalence in different countries in two-time periods (before and after year 2005). Graphs showing the studies describing HEV seroprevalence (anti-HEV IgG) in countries from six WHO regions. The correlation was shown between studies that were published before the year 2005 and those published in 2005 and afterward. A clear inclination of HEV seroprevalence was observed between two time periods in most countries.
HEV seroprevalence in different countries in two-time periods (before and after year 2005). Graphs showing the studies describing HEV seroprevalence (anti-HEV IgG) in countries from six WHO regions. The correlation was shown between studies that were published before the year 2005 and those published in 2005 and afterward. A clear inclination of HEV seroprevalence was observed between two time periods in most countries.
Figure 2.

HEV seroprevalence in different countries in two-time periods (before and after year 2005). Graphs showing the studies describing HEV seroprevalence (anti-HEV IgG) in countries from six WHO regions. The correlation was shown between studies that were published before the year 2005 and those published in 2005 and afterward. A clear inclination of HEV seroprevalence was observed between two time periods in most countries.

Several meta-analysis studies have revealed that older subjects and males are more susceptible to HEV infection than younger people and females, respectively (14, 24-26). In most countries where HEV is prevalent, infection in children is relatively rare. However, in Egypt where the prevalence of HEV in the general population is among the highest in the world, a very high rate (56.7%) of HEV infection was seen in children among patients with acute viral hepatitis (27). These observations were at least partly attributed to possible parenteral transmission as up to 20% of these children pre-received blood transfusion (BT) that was not screened for HEV. Indeed, BT has previously correlated with the possibility of HEV transmission (28). Late presentation of HEV infection in life might be due to cumulative viral exposure in a lifetime and probably aging of the immune system. However, the reasons as to why males are more susceptible than females are yet to be clarified.

HBV affects different age groups depending on the time of infection. In countries with a high prevalence of HBV (prevalence > 2%), infection is usually acquired perinatally or during early childhood and the majority of the patients live with the infection to its chronic phase, while in countries with low prevalence (prevalence < 2%), HBV infection is usually acquired during adulthood, mostly through intravenous drug uses (IDU) or sexual intercourse (29). To date, there is no evidence of any sex predilection of HBV infection, but male sex is known to be an independent risk factor for increased progression to cirrhosis and HCC (30).

In endemic areas, HEV typically superimposes CHB in most cases since the former occurs during adulthood, while the latter occurs in early life in these areas. Thus older and male subjects comprise a higher risk group for HBV-HEV superinfection (31-33). The rates of HBV-HEV superinfection vary considerably. The prevalence of 9% - 38% has been reported in previous studies in China (34-38). In Southeast Asia, the HBV-HEV superinfection rate was reported to be 45%, 14% and 9.5% in Vietnam, India and Bangladesh, respectively (39-41). A clear territory-wise distribution of HBV-HEV superinfection has been observed in Africa where a higher prevalence of 56.7% was reported in Egypt in the northern part of the continent, while insignificant rates of 1% and 0% were reported in Kenya, the Eastern part of Africa (27, 42, 43) (Table 1).

Table 1.

Prevalence of HBV/HEV Coinfection

CountryReferenceCohortPrevalence (%)Sample SizeYear of Sampling
HEV Diagnostic MethodAgea
IgGIgMRNA
China(44)Pregnant women10.7026.4 ± 4.13912016
Turkey(45)Positive HBV DNA13.78.414.742.2 ± 9.11902004
China(37)General38.11.5752.1 ± 13.110222014
India(46)Cirrhotics6.346 ± 14.61922004
Vietnam(39)CHB41941 (9 - 84)7442013
Hongkong(32)Acute HEV1951 (22 - 85)1612000 - 2012
Spain(47)HIV-infected13.30046.3 (21 - 80)4482013
Nepal(48)HIV-infected14.336.2 ± 10.34592015
Italy(49)HIV-infected5.941.7 ± 6.7342013
Kenya(42)Acute hepatitis138.9 (19.83)1002012
Bangladesh(50)Pregnant with acute viral hepatitis9.432 (8 - 82)312004 - 2006
Ghana(51)Jaundiced18.7NS1552016
Central African Republic(52)Fever and jaundice4.9NS1982008 - 2010
India(40)Children with acute viral hepatitis0.7< 161491998 - 2002
Egypt(27)Children with sporadic acute viral hepatitis56.7NS1622008

Abbreviations: IQR, interquartile range; NS, not specified; SD, standard deviation.

aValues are expressed as mean ± SD or mean (IQR).

3.2. Interaction Between HBV and HEV Infections

Endemic areas for both HBV and HEV infections provide an important intersection between two diseases. Following HEV superinfection, the ordinary clinical evolution of CHB infection is usually distorted with a deterioration of most of the manifestations, with the subsequent poor patient outcomes.

3.2.1. Clinical Features

Following HEV infection, the majority of immunocompetent subjects clear an infection spontaneously with only mild and unspecific symptoms, while up to 60% of immunosuppressed individuals progress to the chronic course of the disease (53, 54) that occurs exclusively in genotype 3 (55). In rare cases, however, HEV can cause acute severe liver injury, and/or acute liver failure and acute-on-chronic liver failure (ACLF) (56). Pregnant women and individuals with chronic liver disease (CLD) are at increased risk of developing ALF.

Although the clinical progression of HBV infection is complex and usually based on the state of balance between the host’s immune response and viral replication, HBV patient may develop acute (self-limiting) infection, acute fulminant infection or chronic state that may facilitate increased risks of developing liver cirrhosis or hepatocellular carcinoma (HCC) (3). According to a new nomenclature system, the natural history of CHB has been re-categorized into 5 phases that are not necessarily sequential. These are phase 1 which was previously referred to as immune tolerant and is more frequent and prolonged in perinatally-infected people. It is characterized by minimum or no liver necroinflammation or fibrosis. Phase 2 usually occurs after several years of the first phase and is more frequently and/or rapidly reached in subjects infected during adulthood. There is a moderate or severe liver necroinflammation with a rapid progression of fibrosis. Phase 3 which was previously known as an inactive carrier and results in minimum necroinflammation activity and fibrosis. If remained in this phase, the affected patients have a low risk of progression to cirrhosis or HCC. Phase 4 is associated with a significant necroinflammation and fibrosis, and a low rate of spontaneous disease remission. Phase 5 which is also known as occult HBV infection, is associated with minimal risk of cirrhosis, decompensation, and HCC if HBsAg loss occurred before the occurrence of cirrhosis (57).

HEV superinfection has been shown to adversely modify the natural clinical progression of CHB in various aspects. Several clinical symptoms were found to be more frequently reported among HBV-HEV superinfected patients. In one study, for instance, fever was found to be significantly common among HEV + HBV group (37.7%) compared to HBV monoinfection group (1.4%). Other symptoms, including inappetence, fatigue, nausea, vomiting, and epigastric discomfort also followed the same trend (35). These findings suggest that CHB patients who develop a fever and other non-specific symptoms should be thoroughly screened for HEV. Other features such as accelerated rates of liver injury, a progression of HBV-related CLD to more severe forms and rapid decompensation to liver failure have also correlated with HEV superinfection in CHB patients. In a recent large Vietnamese survey by Hoan et al. (39), HEV seropositivity was found to be associated with the presence of liver cirrhosis and HCC among CHB patients. The poor prognosis of cirrhotic patients based on the Child-Pugh score also correlated with HEV superinfection in this study. Another study from India reported that CHB patients with liver cirrhosis that were superinfected with HEV developed decompensation to liver failure more rapidly than those without HEV. The HEV was also found to be an independent risk factor for 12-month mortality as 64.3% in HEV-infected vs 3% in HEV-uninfected (46). Similarly, a recent country-wide survey in Hong Kong that analyzed data from the year 2000 - 2016 reported that underlying CHB infection was an independent risk factor for 30-day liver-related mortality among patients with acute HEV infection (58). Similar findings have also been reported elsewhere (36, 59, 60).

3.2.2. Treatment

To date, there is no curative therapy for HBV infection; hence, the supportive treatment that is available is only recommended for patients who are likely to benefit from it (i.e. that are at higher risk for liver cirrhosis and HCC). Based on this fact, several criteria have been recommended for the initiation of therapy (61-66) that mainly consists of Nucleotide analogs and/or interferons. Regarding HEV, evidence on the effectiveness of its treatment is very limited. The currently available data from case reports and small observations are limited to chronic HEV infection among organ transplant recipients. The new European Clinical Practice Guidelines on HEV Infection (67) recommend Ribavirin, a potent antivirus, to be considered for the treatment of severe acute HEV infections, acute-on-chronic liver failure as well as chronic cases. Pegylated interferon-α should be added to ribavirin non-responder subjects. To date, there is no recommended specific treatment regime for HBV-HEV superinfected cases, especially if the patient is already on anti-HBV therapy. It is also unclear if the early initiation of anti-HEV medications will delay the development of liver dysfunction and/or liver failure in these dually infected patients. Extensive clinical studies in this area are, therefore, desirable in order to develop better management strategies for these patients as to preclude the associated complications and consequently, improve their outcomes.

3.2.3. Prevention

The HEV vaccine which has been shown to be vastly effective has so far been licensed in China only. The vaccine is recommended for individuals who are above 16 years old and have a high risk of HEV infection. These include people who are engaged in animal husbandry and catering, students, women of childbearing age, and travelers to endemic areas (68). There is limited data on the efficacy of HEV vaccine in persons with CLD, the population that is likely to be affected by the superinfection. Therefore, safety and effectiveness studies of HEV vaccines among CLD patients are essential for the potential prevention of this risk group.

Provided that the majority of HEV infections (mainly genotype 3) are acquired by eating undercooked meat, avoiding of consumption of these products or thorough cooking of the same should be advised and encouraged. In a cell culture model study, it was found that heating at 70°C for 2 minutes or more effectively eliminated an infective HEV (69). However, it is unclear whether this in vitro finding can be feasibly transformed into meat preparation. Concomitantly, the majority of immunocompetent individuals are clearly known to harbor HEV infection uneventfully, thus it might be irrational to recommend that undercooked meat should be avoided by the general population to prevent HEV. It is also unclear whether this approach can be beneficial to CLD patients. Further explorative studies are, therefore, needed to confirm the preventive benefit of boiling meat and to identify the targeted population.

Despite increasing evidence of the existence of HEV contamination in donated blood from qualified blood donors (70-72), vigorous pre-transfusion screening for HEV has not received much attention in many areas probably due to the uncertainty of HEV transmission risks. While some studies did not show any HEV transmission to blood recipients (73), others showed clear evidence of transmission of the virus (74). Thus some countries including UK, Ireland, Germany, and the Netherlands have developed a universal donor screening for HEV infection, while countries such as France and Switzerland performs selective screening of blood that has been intended for use in high-risk patients only (immunocompromised and solid organ recipients) (75, 76). The CLD patients have not been embraced as a high-risk group in spite of clear evidence of their increased risk of HEV infection. In China, where most of important intersection between HEV and CHB probably occurs due to a high prevalence of both infections, screening of HEV is not routinely done in pre-transfused blood (77).

With regard to HEV genotypes 1 and 2 that are transmitted by the fecal-oral route, improvement of general hygienic measures such as hand washing and provision of clean drinking water remains a vital preventive measure. Regular and sustainable provision of health education to the risk groups such as pregnant women and those with CLD is an important preventive measure and should be encouraged and facilitated.

4. Conclusions

The HEV infection rates are alarming. In spite of unclear mechanisms of interaction between two conditions, HEV superinfection clearly alters the course of CHB disease into a detrimental pattern with patients’ poor outcomes. Prevention of HEV infection, as well as its aggressive treatment in coinfected cases, might be an important strategy for reducing related morbidity and mortality, but the paucity of comprehensive clinical evidence hinders this approach. Thus it is highly desirable to address and fill the existing important research gaps in HBV-HEV interaction in all clinical aspects.

References

  • 1.

    Berting A, Hahnen J, Kroger M, Gerlich WH. Computer-aided studies on the spatial structure of the small hepatitis B surface protein. Intervirology. 1995;38(1-2):8-15. [PubMed ID: 8666527]. https://doi.org/10.1159/000150409.

  • 2.

    Lucifora J, Arzberger S, Durantel D, Belloni L, Strubin M, Levrero M, et al. Hepatitis B virus X protein is essential to initiate and maintain virus replication after infection. J Hepatol. 2011;55(5):996-1003. [PubMed ID: 21376091]. https://doi.org/10.1016/j.jhep.2011.02.015.

  • 3.

    Locarnini S. Molecular virology and the development of resistant mutants: Implications for therapy. Semin Liver Dis. 2005;25 Suppl 1:9-19. [PubMed ID: 16103977]. https://doi.org/10.1055/s-2005-915645.

  • 4.

    Zafrullah M, Ozdener MH, Panda SK, Jameel S. The ORF3 protein of hepatitis E virus is a phosphoprotein that associates with the cytoskeleton. J Virol. 1997;71(12):9045-53. [PubMed ID: 9371561]. [PubMed Central ID: PMC230205].

  • 5.

    Koonin EV, Gorbalenya AE, Purdy MA, Rozanov MN, Reyes GR, Bradley DW. Computer-assisted assignment of functional domains in the nonstructural polyprotein of hepatitis E virus: Delineation of an additional group of positive-strand RNA plant and animal viruses. Proc Natl Acad Sci U S A. 1992;89(17):8259-63. [PubMed ID: 1518855]. [PubMed Central ID: PMC49897]. https://doi.org/10.1073/pnas.89.17.8259.

  • 6.

    Emerson SU, Clemente-Casares P, Moiduddin N, Arankalle VA, Torian U, Purcell RH. Putative neutralization epitopes and broad cross-genotype neutralization of Hepatitis E virus confirmed by a quantitative cell-culture assay. J Gen Virol. 2006;87(Pt 3):697-704. [PubMed ID: 16476993]. https://doi.org/10.1099/vir.0.81545-0.

  • 7.

    Smith DB, Simmonds P, Jameel S, Emerson SU, Harrison TJ; International Committee on Taxonomy of Viruses Hepeviridae Study Group, et al. Consensus proposals for classification of the family Hepeviridae. J Gen Virol. 2014;95(Pt 10):2223-32. [PubMed ID: 24989172]. [PubMed Central ID: PMC4165930]. https://doi.org/10.1099/vir.0.068429-0.

  • 8.

    Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence of chronic hepatitis B virus infection: A systematic review of data published between 1965 and 2013. Lancet. 2015;386(10003):1546-55. [PubMed ID: 26231459]. https://doi.org/10.1016/S0140-6736(15)61412-X.

  • 9.

    World Health Organization. Global hepatitis report 2017. 2017.

  • 10.

    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. [PubMed ID: 22121109]. https://doi.org/10.1002/hep.25505.

  • 11.

    World Health Organization. Hepatitis E fact sheet. 2015. Available from: http://www.who.int/mediacentre/factsheets/fs280/en/.

  • 12.

    Zhang W, Ji Z, Wang L, Xiao D, Yan Y. A meta-analysis of HBsAg-positive rate among general Chinese populations aged 1-59 years. Infect Dis (Lond). 2015;47(12):878-88. [PubMed ID: 26305713]. https://doi.org/10.3109/23744235.2015.1064541.

  • 13.

    Yonghao G, Jin X, Jun L, Pumei D, Ying Y, Xiuhong F, et al. An epidemiological serosurvey of hepatitis B virus shows evidence of declining prevalence due to hepatitis B vaccination in central China. Int J Infect Dis. 2015;40:75-80. [PubMed ID: 26456567]. https://doi.org/10.1016/j.ijid.2015.10.002.

  • 14.

    Kim JH, Nelson KE, Panzner U, Kasture Y, Labrique AB, Wierzba TF. A systematic review of the epidemiology of hepatitis E virus in Africa. BMC Infect Dis. 2014;14:308. [PubMed ID: 24902967]. [PubMed Central ID: PMC4055251]. https://doi.org/10.1186/1471-2334-14-308.

  • 15.

    Karbalaie Niya MH, Rezaee-Zavareh MS, Ranaei A, Alavian SM. Hepatitis E virus seroprevalence rate among Eastern Mediterranean and middle eastern countries; A systematic review and pooled analysis. Microb Pathog. 2017;110:252-6. [PubMed ID: 28688980]. https://doi.org/10.1016/j.micpath.2017.06.045.

  • 16.

    Horvatits T, Ozga AK, Westholter D, Hartl J, Manthey CF, Lutgehetmann M, et al. Hepatitis E seroprevalence in the Americas: A systematic review and meta-analysis. Liver Int. 2018;38(11):1951-64. [PubMed ID: 29660259]. https://doi.org/10.1111/liv.13859.

  • 17.

    Aggarwal R. The global prevalence of hepatitis E virus infection and susceptibility: A systematic review. Department of Immunization, Vaccines and Biologicals, World Heal Organization; 2010. 307 p.

  • 18.

    Public Health England. Hepatitis E: Symptoms, transmission, treatment and prevention. 2019. Available from: https://www.gov.uk/government/publications/hepatitis-e-symptoms transmission-prevention-treatment/hepatitis-e-symptoms-transmission-treatment-and prevention.

  • 19.

    Wehmeyer MH, Hartl J, von Wulffen M, Lohse AW, Pischke S. Time trend of reported cases and publications: hepatitis E in comparison to hepatitis A - D in Germany from 2001 to 2016. Z Gastroenterol. 2018;56(1):29-35. [PubMed ID: 29316575]. https://doi.org/10.1055/s-0043-123830.

  • 20.

    Thom K, Gilhooly P, McGowan K, Malloy K, Jarvis LM, Crossan C, et al. Hepatitis E virus (HEV) in Scotland: Evidence of recent increase in viral circulation in humans. Euro Surveill. 2018;23(12). [PubMed ID: 29589577]. [PubMed Central ID: PMC6205259]. https://doi.org/10.2807/1560-7917.ES.2018.23.12.17-00174.

  • 21.

    Jia Z, Yi Y, Liu J, Cao J, Zhang Y, Tian R, et al. Epidemiology of hepatitis E virus in China: Results from the Third National Viral Hepatitis Prevalence Survey, 2005-2006. PLoS One. 2014;9(10). e110837. [PubMed ID: 25360522]. [PubMed Central ID: PMC4215996]. https://doi.org/10.1371/journal.pone.0110837.

  • 22.

    Qea ZD. Viral hepatitis in China. Scientific and Technical Documentation Press; 1997. p. 1983-94.

  • 23.

    Cattoir L, Van Hoecke F, Van Maerken T, Nys E, Ryckaert I, De Boulle M, et al. Hepatitis E virus serology and PCR: Does the methodology matter? Arch Virol. 2017;162(9):2625-32. [PubMed ID: 28523520]. https://doi.org/10.1007/s00705-017-3395-0.

  • 24.

    Hartl J, Otto B, Madden RG, Webb G, Woolson KL, Kriston L, et al. Hepatitis E seroprevalence in europe: A meta-analysis. Viruses. 2016;8(8). [PubMed ID: 27509518]. [PubMed Central ID: PMC4997573]. https://doi.org/10.3390/v8080211.

  • 25.

    Zhang L, Jiao S, Yang Z, Xu L, Liu L, Feng Q, et al. Prevalence of hepatitis E virus infection among blood donors in mainland China: A meta-analysis. Transfusion. 2017;57(2):248-57. [PubMed ID: 28035774]. https://doi.org/10.1111/trf.13937.

  • 26.

    Bosan A, Qureshi H, Bile KM, Ahmad I, Hafiz R. A review of hepatitis viral infections in Pakistan. J Pak Med Assoc. 2010;60(12):1045-58. [PubMed ID: 21381562].

  • 27.

    Zaki MS, Salama OS, Mansour FA, Hossein S. Hepatitis E virus coinfection with hepatotropic viruses in Egyptian children. J Microbiol Immunol Infec. 2008;41(3):254-8.

  • 28.

    Lewis HC, Wichmann O, Duizer E. Transmission routes and risk factors for autochthonous hepatitis E virus infection in Europe: A systematic review. Epidemiol Infect. 2010;138(2):145-66. [PubMed ID: 19804658]. https://doi.org/10.1017/S0950268809990847.

  • 29.

    Duffell EF, van de Laar MJ, Amato-Gauci AJ. Enhanced surveillance of hepatitis B in the EU, 2006-2012. J Viral Hepat. 2015;22(7):581-9. [PubMed ID: 25417854]. https://doi.org/10.1111/jvh.12364.

  • 30.

    Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: Special emphasis on disease progression and prognostic factors. J Hepatol. 2008;48(2):335-52. [PubMed ID: 18096267]. https://doi.org/10.1016/j.jhep.2007.11.011.

  • 31.

    Schulz M, Beha D, Plehm K, Zollner C, Hofmann J, Schott E. High prevalence of anti-hepatitis E virus antibodies in outpatients with chronic liver disease in a university medical center in Germany. Eur J Gastroenterol Hepatol. 2016;28(12):1431-6. [PubMed ID: 27552296]. https://doi.org/10.1097/MEG.0000000000000729.

  • 32.

    Chow CW, Tsang SW, Tsang OT, Leung VK, Fung KS, Luk WK, et al. Comparison of acute hepatitis E infection outcome in patients with and without chronic hepatitis B infection: A 10 year retrospective study in three regional hospitals in Hong Kong. J Clin Virol. 2014;60(1):4-10. [PubMed ID: 24646686]. https://doi.org/10.1016/j.jcv.2014.01.024.

  • 33.

    Kokki I, Smith D, Simmonds P, Ramalingam S, Wellington L, Willocks L, et al. Hepatitis E virus is the leading cause of acute viral hepatitis in Lothian, Scotland. New Microbes New Infect. 2016;10:6-12. [PubMed ID: 26904201]. [PubMed Central ID: PMC4726789]. https://doi.org/10.1016/j.nmni.2015.12.001.

  • 34.

    Cheng SH, Mai L, Zhu FQ, Pan XF, Sun HX, Cao H, et al. Influence of chronic HBV infection on superimposed acute hepatitis E. World J Gastroenterol. 2013;19(35):5904-9. [PubMed ID: 24124337]. [PubMed Central ID: PMC3793145]. https://doi.org/10.3748/wjg.v19.i35.5904.

  • 35.

    Fu J, Guo D, Gao D, Huang W, Li Z, Jia B. Clinical analysis of patients suffering from chronic hepatitis B superinfected with other hepadnaviruses. J Med Virol. 2016;88(6):1003-9. [PubMed ID: 26509653]. https://doi.org/10.1002/jmv.24417.

  • 36.

    Liu L, Xiao D, Yu JH, Shen R, Wang M, Li Q. Clinical course of sporadic acute hepatitis E in a hepatitis B virus endemic region. Int J Infect Dis. 2018;70:107-14. [PubMed ID: 29551632]. https://doi.org/10.1016/j.ijid.2018.03.008.

  • 37.

    Zhang L, Jiang Z, Lv J, Liu J, Yan B, Feng Y, et al. Comparison of hepatitis E virus seroprevalence between HBsAg-positive population and healthy controls in Shandong province, China. BMC Infect Dis. 2018;18(1):75. [PubMed ID: 29433428]. [PubMed Central ID: PMC5810058]. https://doi.org/10.1186/s12879-018-2974-3.

  • 38.

    Zhang S, Wang J, Yuan Q, Ge S, Zhang J, Xia N, et al. Clinical characteristics and risk factors of sporadic Hepatitis E in central China. Virol J. 2011;8:152. [PubMed ID: 21453549]. [PubMed Central ID: PMC3082222]. https://doi.org/10.1186/1743-422X-8-152.

  • 39.

    Hoan NX, Tong HV, Hecht N, Sy BT, Marcinek P, Meyer CG, et al. Hepatitis E virus superinfection and clinical progression in hepatitis B patients. EBioMedicine. 2015;2(12):2080-6. [PubMed ID: 26844288]. [PubMed Central ID: PMC4703726]. https://doi.org/10.1016/j.ebiom.2015.11.020.

  • 40.

    Kumar A, Yachha SK, Poddar U, Singh U, Aggarwal R. Does co-infection with multiple viruses adversely influence the course and outcome of sporadic acute viral hepatitis in children? J Gastroenterol Hepatol. 2006;21(10):1533-7. [PubMed ID: 16928213]. https://doi.org/10.1111/j.1440-1746.2006.04509.x.

  • 41.

    Sugitani M, Sheikh A, Suzuki K, Kinukawa N, Moriyama M, Arakawa Y, et al. Sero-epidemiology of sporadic acute hepatitis in Bangladesh: High prevalences of infection with type-B, type-E and multiple types of hepatitis virus. Ann Trop Med Parasitol. 2009;103(4):343-50. [PubMed ID: 19508752]. https://doi.org/10.1179/136485909X435120.

  • 42.

    Muchiri I, Okoth FA, Ngaira J, Tuei S. Seroprevalence of Hav, HBV, HCV, and HEV among acute hepatitis patients at Kenyatta National Hospital in Nairobi, Kenya. East Afr Med J. 2012;89(6):199-205. [PubMed ID: 26856042].

  • 43.

    Ochwoto M, Kimotho JH, Oyugi J, Okoth F, Kioko H, Mining S, et al. Hepatitis B infection is highly prevalent among patients presenting with jaundice in Kenya. BMC Infect Dis. 2016;16:101. [PubMed ID: 26932656]. [PubMed Central ID: PMC4774020]. https://doi.org/10.1186/s12879-016-1409-2.

  • 44.

    Huang H, Xu C, Zhou X, Liu L, Dai Y, Xu B, et al. Incidence and seroprevalence of hepatitis E virus infection in pregnant women infected with hepatitis B virus and antibody placental transfer in infants. J Clin Virol. 2016;82:84-8. [PubMed ID: 27467017]. https://doi.org/10.1016/j.jcv.2016.07.010.

  • 45.

    Bayram A, Eksi F, Mehli M, Sozen E. Prevalence of hepatitis E virus antibodies in patients with chronic hepatitis B and chronic hepatitis C. Intervirology. 2007;50(4):281-6. [PubMed ID: 17570930]. https://doi.org/10.1159/000103916.

  • 46.

    Kumar Acharya S, Kumar Sharma P, Singh R, Kumar Mohanty S, Madan K, Kumar Jha J, et al. Hepatitis E virus (HEV) infection in patients with cirrhosis is associated with rapid decompensation and death. J Hepatol. 2007;46(3):387-94. [PubMed ID: 17125878]. https://doi.org/10.1016/j.jhep.2006.09.016.

  • 47.

    Mateos-Lindemann ML, Diez-Aguilar M, Galdamez AL, Galan JC, Moreno A, Perez-Gracia MT. Patients infected with HIV are at high-risk for hepatitis E virus infection in Spain. J Med Virol. 2014;86(1):71-4. [PubMed ID: 24136591]. https://doi.org/10.1002/jmv.23804.

  • 48.

    Shrestha A, Adhikari A, Bhattarai M, Rauniyar R, Debes JD, Boonstra A, et al. Prevalence and risk of hepatitis E virus infection in the HIV population of Nepal. Virol J. 2017;14(1):228. [PubMed ID: 29162143]. [PubMed Central ID: PMC5696774]. https://doi.org/10.1186/s12985-017-0899-x.

  • 49.

    Scotto G, Grisorio B, Filippini P, Ferrara S, Massa S, Bulla F, et al. Hepatitis E virus co-infection in HIV-infected patients in Foggia and Naples in southern Italy. Infect Dis (Lond). 2015;47(10):707-13. [PubMed ID: 25994453]. https://doi.org/10.3109/23744235.2015.1049658.

  • 50.

    Mamun-Al-Mahtab, Rahman S, Khan M, Karim F. HEV infection as an aetiologic factor for acute hepatitis: Experience from a tertiary hospital in Bangladesh. J Health Popul Nutr. 2009;27(1):14-9. [PubMed ID: 19248644]. [PubMed Central ID: PMC2761807]. https://doi.org/10.3329/jhpn.v27i1.3314.

  • 51.

    Owusu M, Bonney JK, Annan AA, Mawuli G, Okyere K, Mutocheluh M, et al. Aetiology of viral hepatitis among jaundiced patients presenting to a tertiary hospital in Ghana. PLoS One. 2018;13(9). e0203699. [PubMed ID: 30208084]. [PubMed Central ID: PMC6135398]. https://doi.org/10.1371/journal.pone.0203699.

  • 52.

    Gadia CLB, Manirakiza A, Tekpa G, Konamna X, Vickos U, Nakoune E. Identification of pathogens for differential diagnosis of fever with jaundice in the Central African Republic: A retrospective assessment, 2008-2010. BMC Infect Dis. 2017;17(1):735. [PubMed ID: 29187150]. [PubMed Central ID: PMC5707826]. https://doi.org/10.1186/s12879-017-2840-8.

  • 53.

    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. [PubMed ID: 18287603]. https://doi.org/10.1056/NEJMoa0706992.

  • 54.

    Centres for Disease Control and Prevention. Viral hepatitis-hepatitis E information. 2019. Available from: www.cdc.gov/hepatitis/hev/hevfaq.htm.

  • 55.

    Murali AR, Kotwal V, Chawla S. Chronic hepatitis E: A brief review. World J Hepatol. 2015;7(19):2194-201. [PubMed ID: 26380044]. [PubMed Central ID: PMC4561773]. https://doi.org/10.4254/wjh.v7.i19.2194.

  • 56.

    Kumar A, Saraswat VA. Hepatitis E and acute-on-chronic liver failure. J Clin Exp Hepatol. 2013;3(3):225-30. [PubMed ID: 25755504]. [PubMed Central ID: PMC3940130]. https://doi.org/10.1016/j.jceh.2013.08.013.

  • 57.

    European Association for the Study of the Liver. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67(2):370-98. [PubMed ID: 28427875]. https://doi.org/10.1016/j.jhep.2017.03.021.

  • 58.

    Lai JC, Wong GL, Yip TC, Tse YK, Lam KL, Lui GC, et al. Chronic hepatitis B increases liver-related mortality of patients with acute hepatitis E: A territorywide cohort study from 2000 to 2016. Clin Infect Dis. 2018;67(8):1278-84. [PubMed ID: 30265321]. https://doi.org/10.1093/cid/ciy234.

  • 59.

    Chen C, Zhang SY, Zhang DD, Li XY, Zhang YL, Li WX, et al. Clinical features of acute hepatitis E super-infections on chronic hepatitis B. World J Gastroenterol. 2016;22(47):10388-97. [PubMed ID: 28058019]. [PubMed Central ID: PMC5175251]. https://doi.org/10.3748/wjg.v22.i47.10388.

  • 60.

    Zhang X, Ke W, Xie J, Zhao Z, Xie D, Gao Z. Comparison of effects of hepatitis E or A viral superinfection in patients with chronic hepatitis B. Hepatol Int. 2010;4(3):615-20. [PubMed ID: 21063485]. [PubMed Central ID: PMC2940009]. https://doi.org/10.1007/s12072-010-9204-4.

  • 61.

    Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 2016;63(1):261-83. [PubMed ID: 26566064]. [PubMed Central ID: PMC5987259]. https://doi.org/10.1002/hep.28156.

  • 62.

    Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: A 2015 update. Hepatol Int. 2016;10(1):1-98. [PubMed ID: 26563120]. [PubMed Central ID: PMC4722087]. https://doi.org/10.1007/s12072-015-9675-4.

  • 63.

    Spearman CW, Sonderup MW, Botha JF, van der Merwe SW, Song E, Kassianides C, et al. South African guideline for the management of chronic hepatitis B: 2013. S Afr Med J. 2013;103(5 Pt 2):337-49. [PubMed ID: 23967497].

  • 64.

    European Association for the Study of the Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol. 2012;57(1):167-85. [PubMed ID: 22436845]. https://doi.org/10.1016/j.jhep.2012.02.010.

  • 65.

    Gastroenterology Society of Kenya. Guidelines for the treatment of chronic hepatitis B and C viral infections in Kenya, 2012. 2012.

  • 66.

    World Health Organization. Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. 2015.

  • 67.

    European Association for the Study of the Liver. EASL clinical practice guidelines on hepatitis E virus infection. J Hepatol. 2018;68(6):1256-71. [PubMed ID: 29609832]. https://doi.org/10.1016/j.jhep.2018.03.005.

  • 68.

    Xiamen Innovax Biotech. Recombinant hepatitis E vaccine. 2019. Available from: http://www.innovax.cn/en/pro1.aspx?ProductsCateID=52&CateID=52&CurrCateID=52.

  • 69.

    Johne R, Trojnar E, Filter M, Hofmann J. Thermal stability of hepatitis E virus as estimated by a cell culture method. Appl Environ Microbiol. 2016;82(14):4225-31. [PubMed ID: 27208095]. [PubMed Central ID: PMC4959202]. https://doi.org/10.1128/AEM.00951-16.

  • 70.

    Takeda H, Matsubayashi K, Sakata H, Sato S, Kato T, Hino S, et al. A nationwide survey for prevalence of hepatitis E virus antibody in qualified blood donors in Japan. Vox Sang. 2010;99(4):307-13. [PubMed ID: 20576022]. https://doi.org/10.1111/j.1423-0410.2010.01362.x.

  • 71.

    Lucarelli C, Spada E, Taliani G, Chionne P, Madonna E, Marcantonio C, et al. High prevalence of anti-hepatitis E virus antibodies among blood donors in central Italy, February to March 2014. Euro Surveill. 2016;21(30). [PubMed ID: 27494608]. https://doi.org/10.2807/1560-7917.ES.2016.21.30.30299.

  • 72.

    Stramer SL, Moritz ED, Foster GA, Ong E, Linnen JM, Hogema BM, et al. Hepatitis E virus: seroprevalence and frequency of viral RNA detection among US blood donors. Transfusion. 2016;56(2):481-8. [PubMed ID: 26434952]. https://doi.org/10.1111/trf.13355.

  • 73.

    Xu C, Wang RY, Schechterly CA, Ge S, Shih JW, Xia NS, et al. An assessment of hepatitis E virus (HEV) in US blood donors and recipients: No detectable HEV RNA in 1939 donors tested and no evidence for HEV transmission to 362 prospectively followed recipients. Transfusion. 2013;53(10 Pt 2):2505-11. [PubMed ID: 23829163]. [PubMed Central ID: PMC4542147]. https://doi.org/10.1111/trf.12326.

  • 74.

    Hewitt PE, Ijaz S, Brailsford SR, Brett R, Dicks S, Haywood B, et al. Hepatitis E virus in blood components: A prevalence and transmission study in southeast England. Lancet. 2014;384(9956):1766-73. [PubMed ID: 25078306]. https://doi.org/10.1016/S0140-6736(14)61034-5.

  • 75.

    Domanovic D, Tedder R, Blumel J, Zaaijer H, Gallian P, Niederhauser C, et al. Hepatitis E and blood donation safety in selected European countries: A shift to screening? Euro Surveill. 2017;22(16). [PubMed ID: 28449730]. [PubMed Central ID: PMC5404480]. https://doi.org/10.2807/1560-7917.ES.2017.22.16.30514.

  • 76.

    Dreier J, Knabbe C, Vollmer T. Transfusion-transmitted hepatitis E: NAT screening of blood donations and infectious dose. Front Med (Lausanne). 2018;5:5. [PubMed ID: 29450199]. [PubMed Central ID: PMC5799287]. https://doi.org/10.3389/fmed.2018.00005.

  • 77.

    Shi L, Wang J, Liu Z, Stevens L, Sadler A, Ness P, et al. Blood donor management in China. Transfus Med Hemother. 2014;41(4):273-82. [PubMed ID: 25254023]. [PubMed Central ID: PMC4164075]. https://doi.org/10.1159/000365425.