15

Epidemiology of Hepatitis E in Low- and

Middle-Income Countries of Asia and Africa
Brittany Kmush, ScM1 Thomas Wierzba, PhD2 Lisa Krain, ScM3 Kenrad Nelson, MD1,3
Alain B. Labrique, PhD, MHS, MS1,3

1 Department of International Health, Johns Hopkins Bloomberg Address for correspondence Alain B. Labrique, PhD, MHS, MS, E 5543,
School of Public Health, Baltimore, Maryland 615 N. Wolfe St., Baltimore, MD 21205 (e-mail: alabriqu@jhsph.edu).
2 Translational Research Division, International Vaccine Institute,
Seoul, Korea
3 Department of Epidemiology, Johns Hopkins Bloomberg School of
Public Health, Baltimore, Maryland

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Semin Liver Dis 2013;33:1529.

Abstract Hepatitis E is an acute, viral hepatitis primarily transmitted through the fecaloral route.
The rst major epidemic of hepatitis E virus (HEV) was reported in 1955 in Delhi, India.
Since that time, numerous epidemics have been reported across the low- and middle-
income countries in Asia and Africa. Even in the absence of large-scale outbreaks,
hepatitis E is an important cause of clinical hepatitis. Serologic studies across Asia and
Keywords Africa show a high prevalence of anti-HEV antibodies. Interest in hepatitis E has
hepatitis E increased over the last two decades. However, there are many unanswered questions
HEV about the epidemiology of hepatitis E, including a low clinical illness rate in children and
Asia the high case fatality rate in pregnant women. Widespread usage of a hepatitis E vaccine
LMIC may serve to relieve the burden of HEV disease in low- and middle-income countries in
Africa Africa and Asia.

Hepatitis E virus (HEV) is the single most important cause of
acute clinical hepatitis among adults throughout Central and
Southeast Asia and the second most important cause
throughout the Middle East and North Africa, behind hepati-
tis B virus (HBV).1 Hepatitis E is usually an acute, self-limiting
illness, similar in clinical presentation to hepatitis A.2 Hepa-
titis E is distinguishable from hepatitis A due to a high attack
rate in young adults and pathognomonic increased morbidity
and mortality in pregnant women. Symptomatic, infected
pregnant women experience a case-fatality rate (CFR) as high
as 40%, whereas the CFR in the general population is between
1 to 2%.3 The largest proportion of HEV infections globally are
acquired by the fecaloral route; however, other modes of
transmission are common.3 The epidemiology of hepatitis E,
largely driven by characteristics unique to the four principal
genotypes of the virus, spans the range from sporadic or
subclinical infections to large waterborne outbreaks with tens
of thousands of cases.2 Genotypes 1 and 2 are largely associ-
ated with enteric, human infections whereas genotypes 3 and
4 are primarily zoonotic and cause sporadic human disease.2
Across South Asia, HEV outbreaks of genotype 1 tend to be
associated with the monsoon season as ooding increases
chances of contamination of drinking water.4 Between 1985
and 2004, there were at least 10 major epidemics of HEV in
developing countries due to waterborne transmission in
several countries including India, Nepal, and Sudan.4 Al-
though not supported by data from Asian outbreaks, high
rates of person-to-person transmission were inferred during
a recent outbreak in Uganda.5 Vertical transmission of HEV
from mothers to their infants has been clearly demonstrated,
and is associated with increased risk of illness and death for
the neonate.6 In contrast, genotypes 3 and 4 are usually
transmitted by the consumption of undercooked, HEV-in-
fected meat, or as a blood-borne pathogen through
transfusions.1
These differences in the basic epidemiology of HEV across
genotypes, combined with a dearth of reliable assays and
several inconsistent observations, have resulted in a fairly
complex and challenging eld of study. Our understanding of
this emerging agent has improved substantially in recent

Issue Theme Hepatitis E in 2013: Copyright 2013 by Thieme Medical DOI http://dx.doi.org/
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Krawczynski, MD, PhD Tel: +1(212) 584-4662.
16 Epidemiology of Hepatitis E in Asia and Africa Kmush et al
years, and it has become somewhat less of a moving target.
Still, signicant gaps remain in our understanding of this
pathogen, from explaining the low rate of pediatric infections
to the elevated mortality in pregnancy in certain populations.
In this review, we discuss the history, burden, and epidemi-
ology of hepatitis E, as it is currently understood, in the
disease-endemic populations across Asia and Africa, focusing
on low- to middle-income countries (LMICs).
History
Hepatitis E is often referred to as an emerging disease due to
its recent recognition as a distinct viral entity in the 1990s.
However, there is evidence of historical outbreaks that are
consistent with the epidemiologic character of hepatitis E as
early as 1794.7 These early epidemics were noted for the high
mortality observed in pregnant women in sharp contrast to
that seen in infected men and nonpregnant women.7 Until
the mid-1930s, these epidemics of jaundice were primarily
documented in Europe and the Americas.7 However, out-
breaks of infectious hepatitis in Lebanon in 1935 and Turkey
in 1936,where all of the fatalities were in pregnant women,
marked the beginning of a shift in the epidemiology of
hepatitis E.7 Over subsequent decades, epidemics exhibiting
these distinct characteristics became more frequent and were
largely reported from the Middle East and Asia.7
One of the earliest documented outbreaks, now etiologi-
cally linked to HEV, took place in New Delhi, India, spanning
late 1955 to early 1956. This massive epidemic resulted in at
least 29,000 clinical cases of jaundice, with the highest attack
rates in young adults and elevated morbidity and mortality in
pregnant women.8 Another outbreak with similar character-
istics was observed in 1978 in the Kashmir Valley.9 In the
1980s, as assays for hepatitis A and B became available, both
Fig. 1 Geographic distribution of the four hepatitis E virus (HEV) genotypes that infect humans. Each of the four genotypes of HEV that infect
humans has a distinct, and in some cases, overlapping geographic distribution. (Reprinted from Journal of Hepatology 48(3), Purcell RH, Emerson
SU, Hepatitis E: an emerging awareness of an old disease, 494503, Copyright 2008, with permission from Elsevier.)
Seminars in Liver Disease Vol. 33 No. 1/2013
viruses were ruled out as possible causative agents of these
epidemics; this novel hepatitis was thus originally called, by
exclusion, enterically transmitted, non-A, non-B (ET-NANB)
hepatitis.10 In 1983, another outbreak of hepatitis with high
mortality among pregnant women was observed in
Afghanistan.11 Samples from this outbreak were used to
visualize HEV for the rst time using immune electron
microscopy.11 In 1990 to 1991, the causative agent was
isolated, partially cloned and labeled hepatitis E virus.12,13
The virus was successfully transmitted to monkeys after it
was visualized in stool samples of a volunteer.
Another decade elapsed before the four distinct genotypes
of HEV that infect humans were elucidated.14 All belong to the
same serotype, facilitating diagnostics and possibly vaccine
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development, but each has multiple subtypes thought to
confer slightly different epidemiologic characteristics.
Burden of Disease
Since its identication as a distinct entity, HEV has become
increasingly recognized as a global cause of morbidity and
mortality. Initially, HEV was suspected to be endemic only to
resource-poor settings across South Asia and sub-Saharan
Africa, with cases identied in developed countries often
being associated with travel exposures to those areas. How-
ever, over the past decade, clear evidence has accumulated,
demonstrating frequent autochthonous infections in devel-
oped countries,15 and the ubiquitous infection of commercial
swine herds across Europe, North America, and Asia with
HEV.16,17 Today, HEV circulation has been documented in
nearly every population of the globe, with genotype 1 pre-
dominance in most of the lower-income countries affected by
hepatitis E (Fig. 1). Genotype 1 is primarily found in North
Africa and Central and South Asia, genotype 2 circulates in
 Epidemiology of Hepatitis E in Asia and Africa
Mexico and West Africa, genotype 4 is found predominantly
in China, and genotype 3 is found in North and South America,
Europe, and Japan.1,2
Over the past two decades, research on hepatitis E partic-
ularly focused on LMICs has uctuated (Fig. 2). After 1991,
when the sequence of hepatitis E was rst published, there
was a rapid rise in studies characterizing the epidemiology of
hepatitis E in resource-limited settings. However, the new
millennium revealed a landscape fraught with concerns
about the validity of the many commercial assays combined
with an unfortunately controversial, high-prole vaccine trial
in Nepal.18 One could speculate that donor interest and
funding waned until the mid-2000s when Dalton, Kamar,
Meng, and others began to uncover a previously underrecog-
nized burden of autochthonous infections in high-income
settings.15,19,20
Today, although some debate still continues regarding the
precise estimates of country-level seroprevalence, the global
epidemiology of HEV is fairly clear. Although routine surveil-
lance and reporting of hepatitis E are far from universal and
there is still a substantial lack of access to reliable, sensitive
anti-HEV assays, it is clear that the majority of disease burden
due to HEV is in LMICs across South Asia and sub-Saharan
Africa. The burden of HEV was estimated in nine global disease
burden regions in Asia and Africa, encompassing 71% of the
worlds population.21 In 2005 alone, there were an estimated
20.1 million incident infections of hepatitis E. Models derived
from epidemiologic and clinical studies project an annual
burden of
3.4 million symptomatic cases, 70,000 deaths,
and 3,000 stillbirths.21 Due to the increased risk of infection
in adolescents and young adults, the economic consequences
of hepatitis E are also likely to be high, although these effects
have been poorly studied. One study in the Kathmandu valley
of Nepal found that adults with hepatitis E were sick for
22 days on average and bedridden for 10. The illness cost
Fig. 2 Trends in hepatitis E publications over time (19912011) from low- and middle-income populations across World Health Organization regions.
Kmush et al 17
each individual an average of $37, which amounted to 19.4% of
his or her yearly income.22 In China, the average illness
duration was almost 23 days and cost each patient an average
of 10,655 RMB (
1673 USD).23 Researchers estimated that the
disease burden of a 2007 to 2009 epidemic of hepatitis E in
Kitgum, Uganda amounted to 7,066 DALYs (disability adjusted
life years).24 (This estimate takes into account the relatively
low life-expectancy in the area, but not the increased risk of
severe outcomes for pregnant women.)
Outbreaks of Hepatitis E
Asia
During the historic 1955 to 1956 Delhi outbreak, almost
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30,000 acute hepatitis cases were reported; among the
more than 250 deaths, 102 were reported in pregnant
women.8,25 Between 1978 and 1982, approximately 52,000
acute hepatitis cases were reported from the Kashmir valley
with 600 deaths; 436 among them being from pregnant
women.9,26 From 1981 to 1993, at least 28 more epidemics
have been attributed to HEV in India, the majority of these
epidemics affected thousands of people.27,28 The most recent
epidemic occurred in June 2012 in Maharashtra, with over
4,000 cases and 18 deaths.29
At least four major outbreaks have been documented in
Nepal, in 1973 to 1974, 1981 to 1982, 1995, and the most
recent in 2006.3032 There have only been two reported
outbreaks of hepatitis E in Bangladesh. Seventeen patients
from Dhaka were shown to have ET-NANB hepatitis by ruling
out other causes of hepatitis, which was later serologically
conrmed.33 In 2009, an outbreak in an urban slum resulted
in over 4,000 cases (an attack rate of 3% in a population of

129,000.). Twenty deaths were associated with this out-
break, 10 of them in women of reproductive age, 4 of whom
were pregnant at the time of infection.34
Seminars in Liver Disease Vol. 33 No. 1/2013
18 Epidemiology of Hepatitis E in Asia and Africa Kmush et al
In Pakistan, six epidemics, mostly affecting a few hundred
cases in each outbreak, were observed between 1984 and
1994.3538 The 1993 to 1994 outbreak, however, included
nearly 4,000 cases and four deaths.38 All four deaths were
among pregnant woman for an 11% case-fatality rate in
pregnant women.38 Four infants, born to mothers with acute
hepatitis during this outbreak, also died from complications
of HEV infection.38 From October 2005 to April 2006, an
outbreak of acute jaundice occurred in the aftermath of an
earthquake in Balakot and Poonch districts.39 Over 1,200
cases were reported with ve deaths.39
Two outbreaks have been reported from Indonesia, one in
Borneo in 1991 and another in Java 1998.40,41 A third
outbreak of jaundice occurred in Aceh, Indonesia after the
December 2004 tsunami.42 Only 49 cases of jaundice due to
both hepatitis A and E were reported, with no deaths.42
There is a distinct seasonality of hepatitis E outbreaks in
Southeast Asia, with the majority of outbreaks occurring
during the rainy season.28 There is also an increased risk of
epidemics after natural disasters that disrupt access to clean
drinking water and displace large numbers of people, as seen
in outbreaks in Pakistan and Indonesia.39,42,43
East and Central Asia have a history of HEV outbreaks as
well, although many fewer outbreaks have been reported
from these regions compared with Southeast Asia. Several
epidemics with characteristics similar to hepatitis E epidem-
ics were observed in the 1960s in China. However, hepatitis E
was not conrmed as the causative agent.44 Between 1982
and 1986, nine epidemics of hepatitis E have been docu-
mented in China.44 In 1986, the largest outbreak observed to
date in China of ET-NANB occurred in the southern Xinjiang
Uygur region, with the highest incidence in the young and
middle aged. A remarkable 122,000 cases were reported and
the overall case fatality rate was 0.87%.45 Poor water and
sanitation conditions were thought to be the main contribut-
ing factor to this large outbreak.45 In 1992, retrospective
sequencing of banked specimens conrmed that HEV was the
cause of the outbreak.46 A 1994 outbreak in Vietnam was also
reported, likely linked to heavy rainfall earlier in the year.47
Outbreaks of hepatitis E have occurred in several central
Asian countries. There have been reports of at least four
outbreaks in Kyrgystan since 1955 and one in Uzbekistan in
1985; however, the full versions of these outbreak reports are
not available.48 From 1984 to 1985, a large outbreak of
hepatitis E occurred in the Dashoguz province of Turkmeni-
stan.48 Over 16,000 cases were reported from the province.48
Since 1989, there have not been any reported outbreaks from
Central Asia, despite ongoing sporadic cases.48
Africa
In Africa, outbreaks of hepatitis in Tunisia from 1950 to 1953,
Algeria from 1952 to 1956, Congo in 1958, Morocco from
1958 to 1960, and Libya from 1968 to 1970 were likely caused
by hepatitis E.7 It is also speculated that a non-A non-B
hepatitis outbreak reported in Libya in 1975 was likely due
to HEV, as 922 patients, including 293 women, developed
symptoms of hepatitis.49 Thirteen percent of pregnant wom-
en died in contrast to only 1.6% of nonpregnant patients. The
Seminars in Liver Disease Vol. 33 No. 1/2013
rst well-characterized outbreak of laboratory-conrmed
hepatitis E was described in Cte dIvoire in 1986.50 In
addition to this outbreak, laboratory-conrmed outbreaks
have occurred in Chad (19831984) involving French sol-
diers,51 and among natives of Mostaganem, Algeria, during
19791980.52 Since 2000, outbreaks have occurred in Central
African Republic,53,54 Chad,55 Democratic Republic of
Congo,56 Sudan,57 and Uganda.58 Several of these outbreaks
have occurred in refugee camps in Uganda59 and Darfur,
Sudan.57 In Darfur, pregnant women were particularly affect-
ed, with the case fatality rate among pregnant women reach-
ing 31%.57 In September 2012, outbreaks occurred in several
South Sudan and Kenya refugee camps, with at least 20 deaths
reported.60,61 Besides the outbreaks mentioned above, spo-
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radic infections caused by HEV also occur. Among many
countries in Africa, some of the countries reporting sporadic
cases are Malawi,62 Nigeria,63 Kenya,64 and Egypt.65 Most
large outbreaks or epidemics of hepatitis E in Asia and Africa
where genotypic conrmation is available have been found to
be attributable to genotype 1. To date, no large outbreak of
HEV has had a genotype 3 or 4 etiology.2 Table 1 describes
the major historical and recent outbreaks of HEV across Asia
and Africa.
Population Seroprevalence and Clinical
Fraction
Asia
South Asia
Since the 1955 Delhi outbreak, the burden of HEV in South
Asia has been studied in great detail.2 Seroprevalence esti-
mates of anti-HEV IgG in India generally range from approxi-
mately 20 to 50%.6670 It is unclear whether urban or rural
settings pose a greater risk of HEV infection as studies have
had conicting results.70,71 Although children in India are less
likely to experience incident hepatitis E, the risk of asymp-
tomatic infection varies, as one study found a 64% seropreva-
lence in newborns to 18 year olds,66 while another only found
a 4.5% seroprevalence in newborns to 14 year olds.72 Granted,
these populations are heterogeneous and sources of exposure
may have varied signicantly both spatially and temporally.
Varying risks of occupational or environmental exposures
to HEV must also be considered. A survey of swine handlers
from Vellore found a 94.1% seroprevalence of IgG, nearly a
fourfold increase over rates in the general population, sug-
gesting not only increased occupational risk, but also a greater
frequency of zoonotic HEV transmission in South Asia than
previously thought.73 (Notably, however, zoonotic genotypes
3 and 4 have not been documented in large South Asian
outbreaks of HEV, and the proportionate contribution, if any,
of these genotypes to human disease is poorly understood.)
Sewage workers also show an increased risk of anti-HEV IgG
with increasing reported exposure.74
In India, HEV is a signicant causative agent of clinical
disease, with between 25% and 50% of clinical hepatitis cases
reportedly caused by HEV.69,7579 Several studies have docu-
mented that HEV is a common cause of acute viral hepatitis,
 Epidemiology of Hepatitis E in Asia and Africa Kmush et al 19

Table 1 List of major outbreaks of hepatitis E in Asia and Africa

Country Year Cases Deaths

44
Asia China 1982 10 NA
198244 35 NA
44
1983 459 NA
44
1983 61 NA
198544 9 NA
198644 24 NA
44
1986 6 NA
198644 76 NA
44,45
1986 119,280 1,062

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10,27
India 1955 29,300 75
10,27
1976 2,572 6
1978931 20,000 600
31
197980 6,000 180
31
197980 152 19
198031 865 7
27,31
1981 1,169 10
31
1981 206 NA
31
19812 15,000 450
1981231 11,000 330
27
1982 1,072 NA
27
1984 118 NA
198427 3,005 NA
27
1985 1,395 NA
27
1986 1,015 NA
198727 2,215 NA
27
1989 276 NA
27
1990 139 NA
27
1990 >3,000 NA
199027 517 NA
27
1990 132 NA
27
1991 1,442 NA
199327 2,427 NA
29
2012 >4,000 18
40
Indonesia 1991 1,688 17
199841 >600 NA
200442 49 0
31
Myanmar/Burma 19767 20,000 NA
152
1989 111 0
Nepal 1973431 10,000 NA
31
19812 4,337 304
84
1987 7,405 NA
199532 32 0
(Continued)

Seminars in Liver Disease Vol. 33 No. 1/2013

20 Epidemiology of Hepatitis E in Asia and Africa Kmush et al

Table 1 (Continued)

Country Year Cases Deaths

35
Pakistan 1984 >8 NA
198535 >11 NA
35
1985 >53 NA
37
1987 133 NA
1993438 3,827 8
Turkmenistan 198548 16,175 NA
47
Vietnam 1994 300 NA
Africa Algeria 19788052 NA NA
Botswana 1985153 273 4

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54
Central African Republic 2002 222 4
51
Chad 198384 NA NA
200455 959 30
Cote dIvoire 198650 NA NA
56
Democratic Republic of Congo 2006 NA NA
Djibouti 1993154 111 NA
155
Ethiopia 1988 423 NA
61
Kenya 2012 223 4
Namibia 1983156 201 7
157
1995 600 3
143
Somalia 198889 11,413 346
57
Sudan 2004 2,621 45
201260 NA 16
59
Uganda 2008 10,535 160
58
200708 9,500 148

Abbreviations: NA, information not available.

fulminant hepatic failure, and subsequent mortality observed
in pregnancy.7780
In Nepal, between 10 to 25% of the population has been
shown to have anti-HEV IgG in both urban and rural areas.8183
Additionally, nearly 50% of the cases of acute hepatitis seen in
hospitals are caused by HEV.84 There are few seroprevalence
studies from Pakistan, but one study of United Nations soldiers
from Pakistan found a 62% seroprevalence of total Ig.68 HEV has
also been implicated as the leading cause of acute viral
hepatitis in Pakistan. However, the exact role that HEV plays
as the etiologic agent is unclear as estimates range from 5.4 to
77%.35,85 In Bangladesh, population seroprevalence estimates
range from 22.5% in rural areas to 60.1% in the capital,
Dhaka.86,87 HEV is also recognized as the causative agent in
most cases of acute, sporadic hepatitis.33,88 A recent popula-
tion-based study of maternal mortality from Bangladesh sug-
gested that nearly 10% of maternal (pregnancy-related)
mortality is likely associated with HEV infection.89
East Asia
In China and East Asia, the epidemiology of hepatitis E seems
to differ from that of Southeast Asia in that very few large
epidemics have been reported. The differences in epidemiol-
ogy may be attributed to the predominance of genotype 4 in
China and East Asia, which is hypothesized to be less virulent
than genotype 1 in Southeast Asia.9092 In the general popu-
lation in China, anti-HEV IgG seroprevalence estimates range
from 17 to 43%.93100 Tibet, adjacent to hyperendemic India,
was shown to have a population seroprevalence of anti-HEV
IgG of 31% in 8- to 49-year-olds.94 Rural populations tend to
have higher seroprevalence when compared with urban
populations.93,95 As in South Asia, seroprevalence here tends
to increase with age.95,100 There may also be occupational
risks as frequent exposure to pigs increases the risk of being
seropositive, suggesting that zoonotic transmission plays a
signicant role in China.99,101,102
Hepatitis E plays a signicant role in clinical hepatitis in
China. Hepatitis E has been found to be the causative agent in
approximately 20% of acute hepatitis cases in several hospi-
tal-based studies,103,104 although studies in Beijing attributed
hepatitis E to 30 to 35% of the cases.105,106 Sporadic hepatitis E
tends to be more common in males than in females and the
risk of disease is most common in adults.107,108
In the Democratic Peoples Republic of Korea, the preva-
lence of HEV antibodies is somewhat lower than that in China
with estimates ranging from 11 to 17% seropositivity in the

Seminars in Liver Disease Vol. 33 No. 1/2013

 Epidemiology of Hepatitis E in Asia and Africa
general population.109,110 The prevalence of HEV antibodies
seems to be slightly higher in rural populations and those
over 40 years old.109 There have been several reports of
sporadic hepatitis E from Korea, although the exact burden
of hepatitis E in this setting is unclear.111,112
The seroprevalence of HEV antibodies is lower in Taiwan
than in both China and Democratic Peoples Republic of Korea.
Several studies of the general population have found between 4
and 8% seropositivity.113115 Seroprevalence estimates tend to
be lower in children and increase with age, with the highest
estimates in those 46 to 55 years old.113,114,116 In one study in
Taiwan, HEV was the cause of only 3.9% of cases with acute
hepatitis and caused less than 1% of cases of fulminant hepati-
tis.117 However, another study found that 50% of acute hepatitis
cases studied were due to HEV.118 The majority of these cases
may have been due to recent travel to endemic areas.83 The
reason for this lower seroprevalence is unclear, but may reect
different population-level exposures to safe water or cultural
practices in the consumption of undercooked pork and game.
Central Asia
Despite being considered highly endemic for hepatitis E, the
population seroprevalence estimates of hepatitis E are rela-
tively low in Central Asian populations compared with East
and Southeast Asia. In the Ifstan province of Iran, the
population-based seroprevalence was found to be only
3.8% in those over 6 years old.119 In Kyrghizstan, an area
considered endemic for hepatitis E, the population seroprev-
alence was only 4.6%.120 However, from 1980 to 1989, HEV
was indicated as the causative agent in a signicant portion
of cases of acute hepatitis tested (ranging from 1786% by
location and year).120 These results may be unreliable as
cases were detected using an early version of an Abbott
enzyme immunoassay (EIA) diagnostic test.
Data from Mongolia are conicting: In one 2002 study,121 a
population survey found around 11% of adults had antibodies
to HEV. A subsequent study, 4 years later, revealed a sero-
prevalence among children and young adults of less than
1%.122 These data are perplexing and may reveal shifts in
population exposures, with improved sanitation and access to
clean water.121123 A clinical study of 110 adult patients with
acute hepatitis found no cases of hepatitis E.124
Africa
Data on anti-HEV IgG seroprevalence suggest that symptom-
atic and asymptomatic HEV infections may be more wide-
spread in Africa than suggested from acute icteric cases alone.
Estimates of anti-HEV in rural African populations vary
widely, from 4.4% in Ghana in the late 1990s,125 14.0% in
Burundi in 1992 to 1993,126 15.3% in South Africa in the early
1990s,127 and 67.7% in Egypt.128 A seroprevalence study in
Tunisia also showed that 4.3% of the total population was
positive for anti-HEV antibodies without any history of out-
breaks.129 There appears to be substantial ongoing HEV
transmission in many African countries.
The epidemiologic patterns of HEV infection in Egypt
appear to be inconsistent with other African countries,
despite the demonstrated common circulation of genotype
Kmush et al 21
1.130 Serologic data from Egypt suggest that anti-HEV sero-
prevalence can reach close to 100% in certain subpopula-
tions.131 Despite the high seroprevalence of anti-HEV
antibodies in Egypt, large epidemics have not been reported
and only sporadic cases seem to occur.3,132 A possible expla-
nation for this may be that the genotype 1, subtype 3 strain
circulating in Egypt is reported to be less virulent, but highly
contagious.128 Researchers have also found very high sero-
prevalence with few symptomatic infections in highly en-
demic rural Egyptian communities.132 The age-specic
prevalence of HEV antibodies in Egyptian populations differs
from that in Asia, exhibiting a very high seroprevalence in
young children. These younger initial infections in Egypt are
most likely asymptomatic infections, similar to the epidemi-
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ology of hepatitis A in populations with poor
sanitation. Tables 2 and 3 summarize the seroprevalence
of hepatitis in both healthy and clinical populations across
Africa and Asia.
Epidemiology of HEV in Endemic Countries
Age and Gender Distribution
Across most populations in LMIC, where genotype 1 is
prevalent, symptomatic HEV infections are most common
in individuals aged 15 to 40 years, while asymptomatic or
very mild cases (anicteric) are more common in children.2 A
model developed by Rein and colleagues, based on multiple
population-based epidemiologic studies, projects annual in-
cidence rates as roughly 0.5% and 1% for ages 0 to 15 years,
peaking to between 1% and 1.4% for ages 15 to 20 years, and
falling to 0.2% and below at ages above 30 years.21 This pattern
is conrmed by epidemiologic data from Africa and Asia.37,133
Across most populations, the seroprevalence of antibodies to
HEV begins to rise in late adolescence and peaks between the
second and third decade of life.133 A population-based cohort
study from Bangladesh showed a peak in seroprevalence in
the 36 to 40 age group (Fig. 3).86 This pattern of seropreva-
lence is consistently observed across genotype 1 endemic
regions with the largest increases in prevalence occurring
between ages 5 and 20.21
It is surprising that a fecaloral pathogen like HEV does not
appear to routinely infect young children. This age pattern is
very different from the enterically transmitted hepatitis A
virus, where illness occurs at a very young age and most
children have antibodies by age 10.134,135 As described earli-
er, this pattern holds true with the exception of pediatric
populations in Egypt, and recently in Sudan.136 One study
found a 57% seroprevalence of anti-HEV in 21 Egyptian
children between ages 4 and 9.137 HEV has been shown to
be the cause of acute viral hepatitis in up to 22% of hospital-
ized Egyptian children,136,138,139 while 59% of hospitalized
pediatric acute viral hepatitis (AVH) cases were anti-HEV IgM
seropositive in Sudan.140 The reasons for the difference in the
epidemiology of hepatitis E in children in Egypt and Sudan is
unclear. It is possible that other hepatotropic coinfections
may increase susceptibility to HEV infection.141 However, it is
also likely that local factors including viral subtype, infectious
dose, or host genetic factors inuence the epidemiologic
Seminars in Liver Disease Vol. 33 No. 1/2013
22 Epidemiology of Hepatitis E in Asia and Africa Kmush et al

Table 2 Prevalence of hepatitis E antibodies in healthy populations in Asia and Africa, as reported in selected representative studies
across these populations

Country N Age range (Years) Calendar period Prevalence % Method

Asia
Bangladesh68 105 Adults 1995 27 Total Ig
87
Bangladesh 273 1570 19951996 7.3 IgM
86
Bangladesh 1,134 188 20032004 22.5 Total Ig
China94 426 849 2001 31 IgG
97
China 44,861 <20>41 20022008 32.6 IgG
0.94 IgM
0.07 RNA

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China93 7,284 087 20032004 43 IgG
90
China 4,654 1070 20032006 27.7 IgG
39.9 IgM
China98 546 2975 2005 22.7 IgG
2 IgM
95 a
China 12,052 0>60 2007 17.2 IgG
China96 3,701 Adults 2007a 29.2 IgG
1.35 IgM
0.16 RNA
99
China
Frequent swine contact 985 NA 2009a 31.6 IgG
0.6 IgM
a
Infrequent swine contact 514 NA 2009 28.6 IgG
0.0 IgM
a
Rare swine contact 3,994 NA 2009 21.1 IgG
1.6 IgM
China100 173 17>37 2011a 39.9 IgG
6.4 IgM
66
India 474 145 1982 18 IgG
664 145 1992 26 IgG
India68 107 Adults 1995 37 Total Ig
India69 500 Adults 19961997 35.6 IgG
67
India 75 018 1997 64 IgG
20 >18 1997 50 IgG
70
India
Urban 1135 140 19992000 19.9 IgG
rural 1144 140 19992000 9.1 IgG
71
India
Urban, high SES 884 6 1998 6.9 IgG
Urban, low to middle SES 1497 6 1998 10.6 IgG
Rural, low to middle SES 1710 6 1998 14 IgG
74 a
India 201 2657 2003 18.9 IgG
a
Sewage workers, low contact with sewage 55 2657 2003 47.3 IgG
Sewage workers, high contact with sewage 92 2657 2003a 61.95 IgG

Seminars in Liver Disease Vol. 33 No. 1/2013

 Epidemiology of Hepatitis E in Asia and Africa Kmush et al 23

Table 2 (Continued)

Country N Age range (Years) Calendar period Prevalence % Method

72
India 578 014 20072008 4.5 IgG
India73
swine handlers 34 Adults 2011a 94.1 IgG
70 a
rural (included in ) 100 Adults 2011 59 IgG
urban (included in70) 100 Adults 2011a 73 IgG
119
Iran 816 >6 2005 3.8 Total Ig
120
Kirghizstan 173 160 19801989 4.6 IgG
Korea109 361 1060 20032004 11.9 IgG
Mongolia123 520 712 2004 0.6 IgG

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122
Mongolia 717 020 20052006 0.7 IgG
81
Nepal 757 1248 19921993 25 IgG
Nepal82 94 773 1993 12 ?
Nepal32 692 Adults 1995 30 IgG
68
Nepal 114 Adults 1995 37 Total Ig
Pakistan68 109 Adults 1995 62 Total Ig
120
Russia 165 160 19801989 0.6 IgG
47
Vietnam 100 Adults 1994 38 IgG
Africa
Burundi126 129 Adults 19921993 14 IgG
128
Egypt
Pregnant women 2428 1648 19972003 84.3 Total Ig
Ghana125 803 618 1993 4.4 Total Ig
127
South Africa
urban 407 18 1998a 6.6 Total Ig
rural 360 18 1998a 15.3
Tunisia129 1505 Mean 20.71 2008a 4.3 Total Ig

Abbreviations: SES, Socioeconomic status; NA, information not available; Ig, immunoglobulin.
a
Publication date; cohort date not available.

patterns observed.139 Although detailed, population-based
data for genotype 3 and 4 areas are scant, infections, as
reected by the majority of documented clinical cases,
seem to be more common in the middle-aged and elderly.93
Adult men are more likely to become clinically ill from HEV
than nonpregnant women, as shown by increased attack rates
during epidemics in both Africa and Asia.38,58,142 In
Bangladesh, men were also more likely to have antibodies
to HEV than women; a pattern that was consistent across all
age categories.86 Explanations for this discrepancy include
behavioral risk factors, such as travel or working outside of
the home, or differences in health-seeking behaviors between
men and women.142,143 When exposure is equal, there have
not been any signicant differences in attack rates.53,54,57
HEV and Pregnancy
In genotype 1 endemic populations, hepatitis E is character-
istically associated with a high disease attack rate among
pregnant women. Hepatitis E infection during pregnancy has
a more severe pathogenesis, with substantially elevated case
fatality rates. Hepatitis E may lead to fulminant hepatic
failure, hepatic encephalopathy, disseminated intravascular
coagulation, fetal distress, premature deliveries, and death of
both the mother and fetus.2 The risks of these adverse
events increase with trimester of pregnancy.144 Pregnant
women are at a higher risk of developing acute liver failure
from hepatitis E resulting in a mortality rate varying between
30 to 100%.144 This association was rst reported during
outbreaks in India,8,9 but has also been found in sporadic
cases in endemic areas.145 Similar patterns of elevated mor-
tality in pregnancy have been observed in epidemics in
Africa.57,146 It is postulated that the severe pathogenesis in
pregnant women may be immune-mediated.144
However, this more severe pathogenesis is not seen in all
populations. Infected pregnant women in Egypt and South
India have experienced low case fatality rates (03.4%) in

Seminars in Liver Disease Vol. 33 No. 1/2013

24 Epidemiology of Hepatitis E in Asia and Africa Kmush et al

Table 3 Prevalence of hepatitis E antibodies in clinical populations in Asia and Africa, as reported in selected representative studies
across these populations

Condition Country N Age range (Years) Calendar period Prevalence % Method

Hepatitis Bangladesh33 19 Adults 1987 90 NA
Bangladesh88 74 1567 19951996 39.1 IgM
China103 77 NA 19861992 24.7 IgG
106
China 203 <10>60 19952000 33 IgM
China104 102 NA 2000a 22.1 RNA
108
China 4,920 10>70 20002004 18.6 IgG
3.6 IgM
131
Egypt 50 1.515 2007 2 RNA
India75 57 Adults 19921994 25 IgM, IgGb

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India76 25 NA 1983 40 IgM
Pregnant women 36 NA 19831984 53 IgM
India76 15 NA 1989 36 IgM
77
India
Pregnant women 83 1835 19921999 48.19 IgM
women 129 1835 19921999 50 IgM
India78
Pregnant women 76 1545 19931996 86 IgG and IgMc
women 337 1545 19931996 41.5 IgG and IgMc
69
India 75 NA 19961997 53.3 IgM
India79
Pregnant women 60 24  3.7 19971998 37 IgM
India80
Pregnant women 71 24.4  4.9 20012004 38 IgM and RNA
Kirghizstan and Uzbekistan120 86 NA 19801989 58.1 IgG
124
Mongolia 110 1648 20042005 0.0 IgM
Nepal158
sera 67 1372 1993 93 RNA
stool 70 RNA
79 IgM
87 IgG
85
Pakistan 93 35  15 2007 4.3 IgG
5.4 IgM
Taiwan117 334 1681 19951997 1.5 IgM
87
Fulminant Bangladesh 22 1860 19951996 63.6 IgM
hepatitis
India159 95 575 19921996 41 IgM
Pregnant women 31 NA 19921996 94 IgM
India77
Pregnant women 44 1835 19921999 75 IgM
women 17 1835 19921999 12 IgM
Taiwan160 32 Adults 19821992 25 IgG
3.1 IgM

Abbreviations: NA, information not available; Ig, immunoglobulin.

a
Publication year; cohort year not available.
b
Patients were considered positive for hepatitis E if at least one of the tests listed was positive.
c
Patients were considered positive for hepatitis E if both tests listed were positive.

Seminars in Liver Disease Vol. 33 No. 1/2013

 Epidemiology of Hepatitis E in Asia and Africa Kmush et al 25

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Fig. 3 Age-specic seroprevalence, by sex, of antihepatitis E virus (anti-HEV) in a representative rural population of Bangladesh: 1,136 randomly
selected individuals were enrolled in a cross-sectional survey of anti-HEV total IgG from 2003 to 2004 in Matlab, Bangladesh. Participants ages
ranged from 1 to 88 years: 520 (45.9%) were male and 614 (54.1%) were female. In total, 255 of the participants were anti-HEV Ig reactive. (From
Labrique AB, Zaman K, Hossain Z, et al. Population seroprevalence of hepatitis E virus antibodies in rural Bangladesh. Am J Trop Med Hyg 2009;81
(5):875881. Reprinted with permission.)

some studies.128,147 The reasons for this discrepancy are not
understood, but may be due to different subtypes causing
infection, differential exposures in early childhood, or preva-
lence of micronutrient deciencies.144 Recent work from
Bangladesh suggests that women who were infected with
HEV in late pregnancy, showed signs of immune dysregula-
tion as well as vitamin D and zinc deciency during their rst
trimester, compared with uninfected controls.148 Although
these data raise the possibility of a predisposing phenotype
for increased risk of HEV infection, this needs further
investigation.
Another explanation for increased pathogenicity could be
due to viral mutations. Recent work found that HEV isolated
from two chronically infected patients and later cultured in a
hepatic cell line contained a human genome sequence encod-
ing for a ribosomal protein. This insertion seemed to promote
viral growth and enable the virus to better adapt to the cell
culture.149 Additionally, a study in India compared the ge-
nome of genotype 1 strains from fulminant hepatitis cases
with acute viral hepatitis cases.150 They found that the viruses
that caused fulminant hepatitis had many more nucleotide
substitutions compared with the strains that caused acute
hepatitis. Specically, six substitutions were signicantly
associated with FHF, including one nonsynonymous muta-
tion, suggesting that mutations may play a role in determin-
ing outcome of HEV infection.150 However, the host and viral
characteristics that lead to elevated risk of aggravated pro-
gression toward severe morbidity and death are still poorly
understood.
Conclusion
Since its recognition as a distinct entity, the epidemiology of
hepatitis E in low- and middle-income countries has been
widely studied. There have been numerous epidemics docu-
mented throughout Asia and Africa and the contribution of
HEV as the predominant etiologic agent responsible for acute
viral hepatitis is increasingly appreciated. Improved surveil-
lance, recognition, and assessment methods have led to
improved estimates of country- and region-specic preva-
lence. However, there are many areas of the globe where
more research is needed into the burden and consequences of
HEV infection. Hepatitis E has not been studied in numerous
countries in Asia and Africa where it is likely that hepatitis E is
present. Although recognition of hepatitis E has increased in
recent years, it has yet to become a top research priority.
There are several puzzling factors about hepatitis E that
have yet to be understood. It is unclear why children in low- to
middle-income countries experience a low burden of disease,
particularly in settings that have nearly ubiquitous exposure

Seminars in Liver Disease Vol. 33 No. 1/2013

26 Epidemiology of Hepatitis E in Asia and Africa Kmush et al
to hepatitis A by age 10. Furthermore, the exceptional epide-
miologic characteristics of HEV infections in Egypt add to a
perplexing twist to this paradigm. The hallmark characteristic
of hepatitis E, elevated mortality in pregnant women remains
poorly explained, resulting in suboptimal understanding of
the severe pathogenesis and possible avenues for treatment.
Efforts to minimize the burden of disease through vaccination
were initially controversial. However, a new vaccine has just
completed a large, phase III trial with promising results,151
and is now licensed for use in China. However, several
questions still remain about vaccine effectiveness in genotype
1-predominant populations and the safety and efcacy in
pregnant women. More research with this and potentially
other vaccines is needed to determine the most effective
vaccination strategy for the prevention of morbidity and
mortality in pregnant women. Although there have been
many advances in hepatitis E research in the past two
decades, there is still a general lack of awareness of the
disease in both the general population and the clinical/
scientic community. The research and treatment gaps,
combined with the clear burden of illness and death associ-
ated with HEV, especially in low- and middle-income coun-
tries, should serve as a strong incentive for increased
attention to this emergent pathogen.
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