Antiviral Therapy 2013; 18:467–473 (doi: 10.3851/IMP2597)
Review
Distribution of viral hepatitis in indigenous
populations of North America and the circumpolar
Arctic
Carla Osiowy1,2 *, Brenna C Simons3, Julia D Rempel2
National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada
Section of Hepatology, Department of Medicine, University of Manitoba, Winnipeg, MB, Canada
3
Alaska Native Tribal Health Consortium, Clinical and Research Services, Liver Disease and Hepatitis Program, Anchorage, AK, USA
1
2
*Corresponding author e-mail: [email protected]
The burden of viral hepatitis among indigenous populations
of the United States, Canada and Greenland is greater than
in non-indigenous populations. In particular, throughout
the circumpolar Arctic regions, chronic hepatitis B infection
is highly prevalent, although incidence rates have declined
considerably in certain regions due to infant HBV vaccination. Unique HBV (sub)genotypes having distinct clinical outcomes and distribution patterns are also observed
within this region. In conjunction with hepatitis B infection, hepatitis delta infection is also apparent within North
American indigenous peoples, particularly with outbreaks in
Greenlandic Inuit communities. Incidence rates for hepatitis
C infection are higher for indigenous populations within the
United States and Canada; however, some hepatitis C antibody-positive indigenous patients are more likely to be HCV
RNA-negative compared to non-indigenous patients. Thus,
an increased understanding of the epidemiology, clinical
consequences and pathogenicity of viral hepatitis affecting
the indigenous populations will help to address and balance
the burden of infection.
Introduction
The indigenous peoples of the Americas are disproportionately affected by viral hepatitis compared to nonindigenous North- and South-American populations.
Within the contiguous United States and provinces
of Canada, viral hepatitis is known to contribute to a
higher incidence of mortality due to chronic liver disease
in indigenous peoples, as compared to non-indigenous
populations [1]. In North America (excluding Mexico),
individuals who are indigenous identify with ≥1 of the
original peoples as detailed in Table 1. Indigenous people
account for approximately 1.5% of the total population
of the United States [2] and 3.7% of the total population of Canada [3]. Although indigenous people in both
countries are becoming increasingly urban, the majority of Alaska Native people in Alaska and Aboriginal
people of the Canadian Far North (encompassing the
three northern territories of Canada, Yukon, Northwest
Territories [Inuvialuit] and Nunavut, and the northern
regions of Quebec [Nunavik] and Newfoundland and
Labrador [Nunatsiavut]) reside in rural, often remote,
communities spanning vast areas of land [3]. The Inuit
of Greenland constitute 89% of the total population,
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AVT-12-SP-2658_Osiowy.indd 467
and mainly live in settlements on the west and east
coasts of Greenland [4].
Recent studies have demonstrated a unique distribution of viral hepatitis agents throughout the indigenous
populations of the circumpolar Arctic, particularly the
identification of HBV subgenotype B6, which is unique
to Alaska Native people and Inuit throughout this
region [5]. Prior to the HBV vaccine becoming widely
available, hepatitis B infection was considered endemic
among the populations of Alaska, the Canadian Arctic
and Greenland [6–8], the majority being of indigenous
descent. Specific associations between HBV genotypes
and clinical outcomes have been observed within these
populations, which may in part be due to the infecting
genotype of the virus as well as host-specific influences.
This high prevalence of HBV infection has in turn contributed to a high prevalence of hepatitis delta virus
(HDV) infection within specific settlements of Greenland
[9]. The prevalence of HCV infection varies for indigenous peoples in North America (excluding Mexico),
but generally it is more strongly associated with urban
versus rural settings [10,11]. In addition, an association
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Table 1. Indigenous peoples of Canada, the United States and Greenland
Country and termDefinitiona
Population, %
Global
Indigenous
Peoples with historical ties to a land, prior to colonization
Canada
Aboriginal
All individuals of indigenous ancestry within Canada
Inuit
A group of 8 tribes of indigenous peoples living
throughout Northern Canada and Labrador
First Nation
Indigenous peoples with or without treaty status; also referred to as Indian
Métis
People of mixed indigenous ancestry who are not
defined as Inuit or First Nation
United States of America
American Indian or
There are approximately 566 tribes recognized by the
Native American
US government [49]; the American Indian or Native American
population is the indigenous population of the continental US
Alaska Native Alaska consists of 229 (of the 566) tribes recognized by the US government; the Alaska Native population is the indigenous
population of Alaska and consists of 3 major ethnic groups:
Eskimo, Aleut and American Indian [50]
Greenland
Inuit
The indigenous population of Greenland
a
350 million worldwide
3.7% of the population of Canada [3]b
4% of the Aboriginal population [3]
60% of the Aboriginal population [3]
36% of the Aboriginal population [3]
1.2% of the population of the US [2]
19.5% of the population of Alaska [51]
89% of the population of Greenland [4]
Definitions are for the purpose of this review and are not necessarily universally agreed upon. bOverall, 2% of Aboriginals in this census were not defined.
between indigenous ethnicity and reduced progression to chronicity following HCV infection has been
described in First Nations people [12]. Thus, investigation of viral hepatitis in indigenous populations of the
United States, Canada and Greenland provide unique
insight into these viral pathogens and their relationship
with the host. This review will summarize the current
understanding of hepatitis B, C and D prevalence and
genotype distribution specific to indigenous peoples in
North America (excluding Mexico) and Greenland.
HBV
The United States and Canada are considered to be
regions of low prevalence for HBV surface antigen
(HBsAg) positivity (<2%). Studies have shown genotype A to be the most prevalent genotype infecting
the general blood donor population within the United
States and Canada [13,14]. However, consistent with
the distinct global geographic distribution of HBV genotypes and the high levels of immigration to the United
States and Canada, eight genotypes of HBV, namely A
to H, are observed [14].
Information regarding the prevalence and genotype
distribution of hepatitis B in North American indigenous
people primarily derives from targeted populations or
individuals living in circumpolar regions. Unlike Alaska
and the Far North of Canada, there is no evidence to
support an historic endemic prevalence of hepatitis B
infection among indigenous peoples of the continental
468 AVT-12-SP-2658_Osiowy.indd 468
United States or Canada below the 60th parallel of latitude. Indeed, HBsAg positivity within First Nation and
Métis street-involved individuals (defined as those who
are living or working on the street) was lower than nonAboriginals having the same risk factors (2.1% versus
4.5% [15]); however, the reported rate of acute hepatitis
B infection is nearly 3× higher among indigenous persons
compared to non-indigenous persons in the United States
and Canada [16,17]. Similarly, the prevalence of previous
exposure to the virus (anti-HBc-positive) is considerably
higher among First Nations compared to the blood donor
population in Canada (2–8% versus 1.13% [18,19]).
Historically, the prevalence of HBsAg positivity, indicating chronic HBV infection, in the indigenous populations of the circumpolar Arctic has been high (>2%
[6–8]). However, these prevalence rates are based on
studies of Alaska Native people, First Nations, and
Canadian and Greenlandic Inuit prior to universal
vaccination programmes for newborns being implemented approximately 20 to 30 years ago in Canada
and Alaska, respectively [20,21]. Greenland has only
recently (September 2010) instituted universal newborn HBV vaccination [22]. Prior to these vaccination
programmes, the overall prevalence of HBsAg positivity in Alaska Native people and the indigenous population of the Canadian Far North was approximately
3%, ranging upwards of 12% to 20% depending on
the geographic region investigated [7,18,21,23]. Inuit
in Canada were generally observed to have higher rates
of HBsAg positivity than First Nations people in these
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Viral hepatitis in indigenous populations of North America
studies (3.9–6.9% versus 0.4–2.9% [18,23]). The prevalence of HBsAg positivity is estimated to be somewhat
higher (3–10%) in the Inuit of Greenland [24,25], with
rates upwards of 29% depending on the community
investigated [26]. It is important to note that incidence
rates have fallen greatly in those regions having newborn vaccination programmes coupled with adolescent
catch-up programmes, such that Alaska now has the
lowest rate of acute HBV in the world [21]. However,
it is expected that prevalence rates of chronic HBV
will remain high in these regions until the time that
the new generation of vaccinated individuals becomes
the majority.
Our understanding of HBV genotypes circulating in
indigenous populations of North America is primarily
derived from the circumpolar regions of Alaska, Canada and Greenland. The HBV genotype distribution
among indigenous people resident within the remainder of the United States and Canada is unknown,
but is likely to be similar to the distribution observed
among non-indigenous people in these regions. Overall, HBV genotypes B and D predominate in the circumpolar Arctic (Figure 1), with geographic and ethnic
demarcations among HBV genotypes observed. Five
HBV genotypes, A, B, C, D and F, are found among
Alaska Native people [27], whereas genotypes A, B
and D predominate among indigenous populations of
the Canadian Far North [28]. The prevalence of genotype D in Greenlandic Inuit differs depending upon the
geographic region of Greenland investigated, such that
genotype B predominated among four settlements in
East Greenland while genotype D was most prevalent
in two settlements of West Greenland [9,26]. Although
most genotype D strains in Greenland share approximately 97–98% sequence identity with subgenotypes
D2 and D1, respectively, some isolates have >4% nucleotide divergence with all subgenotypes of D, suggesting
a possible new subgenotype [29].
The HBV genotype B (HBV/B) observed in all North
American circumpolar regions has been shown to constitute a new subgenotype, B6 [5]. It is differentiated
from other HBV/B subgenotypes, other than B1, by the
lack of intergenotypic recombination with genotype C
within the precore/core coding region of the genome.
The most striking clinical observation associated with
HBV subgenotype B6 (HBV/B6) infection is an apparent lack of active liver disease (Table 2), as patients have
normal liver biochemistry and function [7,26]. Furthermore, hepatocellular carcinoma (HCC) has not yet been
described in the HBV/B6-infected population throughout the North American circumpolar Arctic [5,27]. The
reason behind these observations is not well understood, as it is not known if there is a host genetic basis
for improved prognosis following infection with HBV/
B6. The majority of HBV/B6-infected individuals are
Antiviral Therapy 18.3 Pt B
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hepatitis B e antigen (HBeAg)-negative, likely due to the
very high prevalence of the G1896A mutation within
the precore coding region leading to loss of expression
of HBeAg [28,30]. Therefore, this is in keeping with the
finding that, despite increased serum HBV DNA levels
in a large, prospectively followed cohort, HCC incidence was lower for those with the A1896 mutation
than with the wild-type G1896 [31]. Genotype B6 has
only been found in Inuit or Alaska Native people of the
circumpolar Arctic. This has resulted in a distinct ethnic
and geographic demarcation among HBV genotypes in
the Canadian Far North, such that HBV/B6 is confined
to the eastern Canadian Arctic (primarily Nunavut) in
patients self-identifying as Inuit, while HBV genotype
D (HBV/D) is observed within the western Canadian
Arctic (primarily Northwest Territories) in patients selfidentifying as First Nations [23,28].
Of the five HBV genotypes present among chronic
HBV carriers in Alaska, HBV/D is the most predominant followed by HBV genotype F (HBV/F) [6,27].
While genotypes D, A and B are found in other Arctic regions, HBV/F is located in Southwest Alaska and
HBV genotype C (HBV/C) is found only in Northwest
Alaska and Western Siberia [6]. There is a significant
association between HCC and HBV/F in Alaska Native
children and HBV/C in Alaska Native adults [27]. From
a cohort of Alaska Native people with chronic HBV
infection, genotype F was identified in a significantly
higher proportion (68%) of patients with HCC, versus
those without HCC (18%) [27]. For patients chronically infected with HBV/F, the median age at diagnosis of HCC was 38 years younger compared to other
HCC patients chronically infected with a different genotype (22.5 versus 60 years of age, respectively) [27].
From 1984 to 1988, the incidence of HCC in Alaska
Native persons <20 years old was 3 per 100,000, with
a corresponding incidence of acute symptomatic HBV
infection of 19 per 100,000 [21]. No significant differences in the number of basal core promoter or precore
region mutations were identified in comparing HCCdiagnosed patients chronically infected with HBV/F
or with any other HBV genotypes in Alaska [27]. In
addition, loss of HBsAg, which is associated with a
reduced risk of HCC, was not associated with any particular HBV genotype [32]. Due to universal screening
and vaccine programmes initiated in Alaska in 1983,
for individuals <20 years of age, HBsAg positivity was
reduced from 657 in 1987 to 2 in 2008, corresponding with an absence of HCC in this demographic since
1999 [21]. Screening HBsAg carriers by semiannual
a-fetoprotein testing was effective in detecting most
HCC tumours at a stage in which liver resection was
possible and screening significantly prolonged survival
rates when compared with historical controls in this
population [21].
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Figure 1. HBV genotype distribution in the North American circumpolar Arctic
B
4%
A
12%
F
20%
C
7%
n=1,175
D
57%
Alaska (USA)
Canada
D4
3%
A
1%
D3
21%
n=277
B
75%
Greenland
(Denmark)
D
8%
Mixed
2%
A
17%
n=52
n=17
D
83%
B
90%
Map of North American circumpolar Arctic adapted with permission from UNEP/GRID-Arendal (cartographer Hugo Ahlenius) [52]. The percentage prevalence and
distribution of HBV genotypes are shown for Alaska [27], Canada [28] and Greenland [9,26]. Subgenotype data for HBV genotype D was only available for Canada. The
HBV genotype B shown has been described as subgenotype B6 [5].
HDV
The prevalence of HDV infection in North America is
relatively low among blood donors (0% to 3.8%) but
increases considerably among chronically HBV-infected
injection drug users (IDU) and others at high risk for
infection [33,34]. Throughout the North American circumpolar Arctic, the rates of HDV seroprevalence are
470 AVT-12-SP-2658_Osiowy.indd 470
surprisingly varied, despite the high prevalence of HBsAg
positivity. Across Alaska and the Far North of Canada,
HDV seroprevalence ranges from 0% to 1.6% [6,8].
Conversely, Greenland has much higher rates, ranging
from 1.1% to 10%, with outbreaks of infection reported
[9,25,35]. HDV genotype characterization has either not
been reported for circumpolar region strains, or seroprevalent patients were found to be aviraemic [25].
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Table 2. Results of age- and sex-matched case-control study of clinical differences between HBV subgenotypes Bj, Ba and B6a
HBV/Bj (n=50)
HBV/Ba (n=50)
P-value
Characteristic
HBV/B6 (n=50)
Male sex
Mean age, years (sd)
Hepatitis B e antigen
HBV DNA>5 log copies/ml
Mean alanine transaminase, U/l (sd) Clinical state
Asymptomatic
Chronic hepatitis
Liver cirrhosis/HCC
33 (66)
34 (68)
36 (72)
Matched
48.1 (19.6)
48.1 (16.9)
47.9 (13.1)
Matched
6 (12)
8 (16)
20 (40)b
<0.02
9 (18)
18 (36)
36 (72)c
<0.001
40.3 (36.3)
43.1 (33.4)
94.0 (94.1)d
<0.001
35 (61)e
22 (44)
15 (30)
<0.02
15 (30)
24 (50)
21 (42)
NS
0
4 (8)
14 (28)f
<0.03
Reproduced from [5] by permission of Oxford University Press, Infectious Diseases Society of America. Data are n (%), unless otherwise indicated. aHBV subgenotype
Bj (HBV/Bj; B1) and HBV subgenotype Ba (HBV/Ba; recombinant HBV/B subgenotypes). bFor B6 versus Ba, P=0.0026; for Bj versus Ba, P=0.0143. cFor B6 versus Ba,
P<0.0001; for Bj versus Ba, P=0.0006. dFor B6 versus Ba, P=0.0006; for Bj versus Ba, P=0.0005. eFor B6 versus Ba, P=0.0001; for B6 versus Bj, P=0.0154. fFor B6 versus
Ba, P<0.0001; for Bj versus Ba, P=0.0214. HBV/B6, HBV subgenotype B6; HCC, hepatocellular carcinoma; NS, no significant difference.
HCV
The global estimation of HCV infection is 170–200 million people. In the continental United States, approximately 1.6% of the population has been acutely infected,
with an estimated 60–85% of acute infections progressing to chronicity [36]. In Canada, it is estimated that
0.8% are HCV-infected [37]. HCV prevalence in certain indigenous populations may be higher, as noted in
a Nebraskan general admissions clinical survey, where
HCV antibody prevalence ranged between 8.1% and
18.3% [10]. However, incidence rates in the United
States for newly acquired or diagnosed HCV appear to
be declining. In 2001, incidence rates were sixfold higher
for Native Americans relative to the United States general population. By 2009, rates for American Indian and
Alaska Native populations were observed to be 0.41
per 100,000 people, comparable to other ethnic groups
[38]. In Canada, surveys of two central First Nation
communities found HCV seropositivity rates of 2.2%
(n=7/315) [39]. Incidence studies within Canada over
six health regions indicated that Aboriginals accounted
for 15.2% of newly acquired infections between 1999–
2004, corresponding to an HCV infection incidence of
18.9 per 100,000 (95% CI 15.5, 23.1) relative to 2.8
per 100,000 (95% CI 2.6, 3.1) for non-Aboriginal individuals [40]. For higher risk populations, such as IDU
or prison populations, there appears to be a comparable
seroprevalence between First Nation or self-identified
Aboriginals and non-Aboriginal populations [15].
Collectively, genotypes 1, 2 and 3 account for the
majority (>75%) of HCV infections throughout North
America, with genotype 1 predominating in blood
donors [14,41], and high risk groups [42]. The distribution of HCV genotypes in the indigenous population of
the United States and Canada is not well understood.
Generally, there appears to be a comparable genotype
distribution among indigenous and non-indigenous
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patients. One study found genotypes 1, 2 and 3 present
in indigenous patients at 70%, 9% and 20%, respectively, with corresponding non-indigenous patient genotypes at 66%, 11% and 3%, respectively [43].
For the circumpolar region, reports indicate a low
prevalence of HCV infection. In Greenland, the antiHCV-positivity rate was 0–1.5% without any corresponding HCV RNA positivity [9,25]. Similarly, Alaska
Native people have an HCV seroprevalence of 0.8%,
ranging up to 2.6% in those aged 40–59 years [44].
By contrast, HCV seroprevalence in northern Canada
ranged from 1% to 15% depending on the region
investigated [7]. The distribution of HCV genotypes
in the circumpolar region follows the distribution
observed in the rest of North America, and thus is similar between indigenous and non-indigenous groups.
HCV genotypes in Alaska Native people comprise 1a
(42%), 1b (20.3%), 2b (14.7%), 3a (14.3%) and 2a
(7.8%) [44], whereas genotypes in First Nations people of the Canadian Far North consist of 1a (81%), 2a
(7%) and 3a (12%; A Andonov, Public Health Agency
of Canada, personal communication). Considering the
lack of HCV viraemia observed with Greenlandic Inuit,
no genotype distribution is available for this region.
Rates of HCV chronicity or HCV RNA positivity
within indigenous peoples vary between regions of
North America. In parts of the United States, rates of
chronicity in indigenous people appear similar to nonindigenous peoples of the Americas [10,44]. However,
in Greenland and regions of central Canada, HCV
RNA positivity was not detected in antibody-positive
individuals [9,25,39]. In IDU cohorts on the west
coast of Canada, HCV spontaneous clearance was
observed with 37% (n=86/231) of Aboriginal participants compared with 17% (n=82/471) of Caucasian
participants, giving an odds ratio of developing protective immunity against HCV of 2.9 (95% CI 2.0,
4.3; P<0.001) for individuals of Aboriginal ethnicity
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[12]; an association also noted at a central provincial
testing centre [45]. Recent genetic and cell-based investigations suggest that unique immune characteristics
might contribute to enhanced spontaneous clearance
of HCV in certain Aboriginal populations [46,47]. In
the province of Manitoba, peripheral blood mononuclear cells (PBMC) from Aboriginal cohorts demonstrated a lower genetic tendency to produce the antiinflammatory cytokine interleukin (IL)-10; in parallel,
PBMC displayed a reduced susceptibility to HCV protein induction of IL-10, a mechanism of HCV immune
inhibition, compared to Caucasian counterparts [46].
This suggests that for certain Aboriginal populations,
increased pro-inflammatory immune activation may
circumvent the immune inhibitory activities that promote chronic HCV infection.
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Accepted 26 August 2012; published online 21 June 2013
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