Can J Infect Dis Med Microbiol Vol 24 No 2 Summer 2013 69
RAC Siemieniuk, B Beckthold, MJ Gill. Increasing HIV
subtype diversity and its clinical implications in a sentinel North
American population. Can J Infect Dis Med Microbiol
BACkGRouND: HIV-1 is a highly diverse virus; subtypes may
exhibit differences in rates of transmission, disease progression, neuro-
toxicity, antiretroviral treatment failure profiles and accuracy of viral
load measurements. To date, the HIV epidemic in Canada and the rest
of the developed world has been largely due to subtype B; however,
shifts in subtype epidemiology could have significant implications.
oBJeCtIVe: To determine whether there has been an increase in
HIV subtype diversity in southern Alberta, Canada.
MetHoDS: All 2358 patients receiving any HIV care between
December 31, 2001 and December 31, 2010 were included in a retro-
spective analysis of subtype prevalence and incidence. In an indexed
analysis, subtype trends from 1994 to 2010 were also evaluated.
ReSultS: Between 2001 and 2010, the prevalence of non-B HIV
subtypes in patients with a known subtype increased from 7% to 24%.
In 2010, the most prevalent non-B subtypes were C (65%), A (11%),
CRF02_AG (9.7%), CRF01_AE (4.9%), D (3.9%), G (2.9%) and
CRF06_cpx (1.5%). In the indexed analysis, there was an overall pro-
portional increase in non-B subtypes of 2.3% per year. The year-over-
year increase in the prevalence of patients infected with a nonsubtype B
virus increased from 13% from 1995 to 2002 to 27% from 2003 to
2010 (P=0.01). Incident non-B subtype cases increased from 9.6% to
32.4% over these time periods.
CoNCluSIoNS: This recent and dramatic shift in HIV strain diver-
sity in Canada is unprecedented and may have important public
health, research and clinical consequences.
key Words: AIDS; Clade; Epidemiology; HIV; Strain; Subtype
la diversité croissante de sous-types du VIH et ses
répercussions cliniques dans une population
sentinelle d’Amérique du Nord
HIStoRIQue : Le VIH-1 est un virus très hétérogène, dont les sous-
types peuvent différer sur le plan du taux de transmission, de
l’évolution de la maladie, de la neurotoxicité, des profils d’échec de
traitement antirétroviral et de la précision des mesures de la charge
virale. Jusqu’à présent, l’épidémie de VIH au Canada et dans le reste
du monde industrialisé est en grande partie attribuable au sous-type B,
mais des changements dans l’épidémiologie des sous-types pourraient
avoir des conséquences considérables.
oBJeCtIF : Déterminer si la diversité des sous-types de VIH a aug-
menté dans le sud de l’Alberta, au Canada.
MÉtHoDoloGIe : Les 2 358 patients qui avaient reçu des soins du
VIH entre le 31 décembre 2001 et le 31 décembre 2010 ont participé
à une étude rétrospective de la prévalence et de l’incidence des sous-
types. Dans une analyse indexée, les tendances de sous-types ont égale-
ment été évaluées entre 1994 et 2010.
RÉSultAtS : Entre 2001 et 2010, la prévalence des sous-types de
VIH non-B chez les patients dont le sous-type est connu est passée de
7 % à 24 %. En 2010, les sous-types non-B les plus prévalents étaient
les sous-types C (65 %), A (11 %), CRF02_AG (9,7 %), CRF01_AE
(4,9 %), D (3,9 %), G (2,9 %) et CRF06_cpx (1,5 %). Dans l’analyse
indexée, on constatait une augmentation proportionnelle globale des
sous-types non-B de 2,3 % par année. L’augmentation de la prévalence
de patients infectés par un virus de sous-type non-B a augmenté d’une
année à l’autre, passant de 13 % de 1995 à 2002 à 27 % de 2003 à 2010
(P=0,01). Les nouveaux cas de sous-types non-B sont passés de 9,6 %
à 32,4 % pendant ces périodes.
CoNCluSIoNS : Ces changements récents et marqués de la diver-
sité des souches de VIH au Canada sont sans précédent et pourraient
avoir des conséquences importantes en matière de santé publique, de
recherche et de clinique.
Increasing HIV subtype diversity and its clinical
implications in a sentinel North American population
Reed AC Siemieniuk MD1,2, Brenda Beckthold MSc1, M John Gill MSc MB ChB1,3
1Southern Alberta HIV Clinic, Calgary, Alberta; 2Department of Medicine, University of Toronto, Toronto, Ontario; 3Department of
Microbiology, Immunology & Infectious Diseases, University of Calgary, Calgary, Alberta
Correspondence: Dr M John Gill, Medical Director, Southern Alberta HIV Program, Sheldon M Chumir Health Centre, #3223, 1213 – 4th
Street Southwest, Calgary, Alberta T2R 0X7. Telephone 403-955-6315, fax 403-955-6333, e-mail firstname.lastname@example.org
Health Agency of Canada reports that HIV-1 infection affects approxi-
mately 65,000 people in Canada, with 2300 to 4300 new infections each
year (2). HIV-1 is a highly diverse virus that is classified into four groups:
group M (major), group O (outlier), group N (nonmajor nonoutlier) (3)
and the new group, P (4). HIV-1 group M, the most prevalent circulat-
ing group, has nine subtypes (designated A to D, F to H, and J and K)
(5); there is 25% to 35% genetic variation among subtypes and up to
20% variation is observed within a subtype (6). By 2010, more than
50 different circulating recombinant forms (CRFs) of these subtypes
have been identified, along with an abundance of unique recombinant
forms (URFs) (6). These CRFs and URFs are believed to originate from
a recombination of viral genetic material when viruses of two different
subtypes infect the same cell. If a recombinant form has been isolated
from three independent subjects in separate transmission networks,
then, by definition, it is a CRF rather than a URF.
ore than one million people in the United States are infected with
HIV-1 and 50,000 are newly infected each year (1); the Public
Due to local founder effects, the worldwide spread of HIV resulted
in an uneven subtype distribution (6). The HIV epidemic in Canada
and in the rest of North America and Europe was likely founded in the
1960s (7) and has been remarkably homogeneous, with HIV-1,
group M, subtype B accounting for more than 19 of every 20 infections
in these regions (6).
The foundational HIV/AIDS research was mostly undertaken in
the developed world and examined largely subtype B infection.
Subtype B, however, accounts for only approximately 10% of HIV
infections worldwide. Globally, subtype C accounts for approximately
one-half of all infections (3,6). Recent research suggests that the dif-
ferences in genetic sequences among HIV groups, subtypes and CRFs
carry functional biological differences. It has been suggested that these
biological differences may have clinically important implications in
areas such as transmissibility (8-10), rate of disease progression
(11-16), neurotoxicity (17,18), increased susceptibility to antiretro-
viral resistance due to naturally occurring polymorphisms (19) and
©2013 Pulsus Group Inc. All rights reserved
Siemieniuk et al
Can J Infect Dis Med Microbiol Vol 24 No 2 Summer 201370
accuracy of commonly used viral load assays (20,21). As such, mon-
itoring the emerging diversity of HIV strains is important for public
health programs and individual care (22). Adverse clinical events
associated with subtype diversity are increasingly being reported
Large WHO/Joint United Nations Programme on HIV/AIDS epi-
demiological studies have reported that the global and regional sub-
type distributions remain stable (6). However, some cohort studies
from parts of South America (25) and Europe, including Spain (26),
Italy (27) and Switzerland (28), may have identified early signs of
increasing diversity within population subsets. Despite its importance
across many domains of HIV research, policy and clinical practice,
there has been little evidence of subtype shifts in North America
(6,29). Because there is no coordinated subtype monitoring system in
North America, geographically defined ‘sentinel’ centres offer the
most sensitive and accurate way to detect changes in subtype epidemi-
ology (30,31). We report trends in HIV diversity in a large, geograph-
ically defined Canadian population of HIV-infected patients.
The Southern Alberta HIV Program provides exclusive care to HIV-
infected patients living in southern Alberta, a region of approximately
1.7 million people. All patients receiving any care between December 31,
2001, and December 31, 2010 were included in the evaluation of
known HIV subtypes. Medical records from the clinic database were
used to gather data; administrative data use was reviewed and approved
by the Conjoint Health Research Ethics Board, University of Calgary,
HIV typing was derived from the pol gene sequence during routine
genotypic resistance testing. When available, whole genome sequence typ-
ing was used for further clarification. Resistance testing was introduced in
2001 exclusively for patients failing antiretroviral therapy (ART) and
formally expanded in 2006 to include all patients initiating ART.
When a subtype was only determined after years in care, this subtype
was used retrospectively for that individual.
Because subtype analysis can only be easily undertaken when the
plasma RNA viral load is >250 copies/mL, patients who moved to the
study region while on ART and with an undetectable viral load or
have consistently had <250 viral copies/mL since 2001 do not have a
subtype classification. To address these missing subtype data, country
of birth was used (currently a very strong demographic marker of HIV
subtype in this population) to predict subtype B or nonsubtype B infec-
tion. As previously established, 97% of Canadian and 5% of sub-
Saharan African-born patients were HIV subtype B (32). These
subtype proportions were applied to the remaining patients born in
sub-Saharan Africa and Canada without a known subtype. This
enabled a more accurate prediction of population-level data; however,
individual-level demographic data could not be studied for patients
with an unknown subtype. Due to uncertainty in subtype prediction
for individuals born in other geographical areas, these patients were
classified as unknown subtype. To ensure that there was no selection
bias with clinical subtype testing, the proportions of African-born and
Canadian-born patients with HIV subtype testing were compared at
the beginning and at the end of the study (2001 and 2010).
Subtype incidence is defined as the sum of patients newly diagnosed
with HIV and patients with a known HIV diagnosis but new to southern
Alberta, each calendar year. Prevalence is the point-prevalence, defined
as the total number of patients in the region on December 31; for
simplicity, only the year is mentioned hereafter.
To evaluate whether there were any changes in the year-over-year
incidence of B and non-B HIV subtypes, proportional and absolute
year-over-year changes in incidence during the first one-half of the
non-b (n=268) Total (n=2358)b (n=854) Unknown (n=1236)
Age at HIV diagnosis, years, mean ± SD
HIV-acquisition risk factor
Men who have sex with men
Injection drug users
Men who have sex with men and injection drug users
Data presented as n (%) unless otherwise indicated. *Includes First Nations, Métis and Inuit
Increasing Canadian HIV subtype diversity
Can J Infect Dis Med Microbiol Vol 24 No 2 Summer 201371
study period (1995 to 2002) were compared with the second one-half
(2003 to 2010).
Pearson’s χ2 and Student’s t tests were used as appropriate with
statistical significance set at P<0.05. All statistical analyses were per-
formed using SPSS version 20 (IBM Corporation, USA).
There were 2358 patients engaged in HIV care between December 31,
2001 and December 31, 2010 (Table 1). In patients with a known sub-
type, there was no age difference between patients with subtype B and
non-B (P=0.15). Male patients were more likely to be infected with
subtype B (P<0.001). Patients born in North America were more likely
than patients born in sub-Saharan Africa to be infected with subtype B
(P<0.001). Men who have sex with men were more likely than hetero-
sexual men and women to be infected with subtype B (P<0.001).
The number of HIV-infected patients with a known HIV subtype
increased from 284 of 683 active patients (42%) in 2001 to 831 of
1336 patients (62%) in 2010. Of the patients with a known viral sub-
type, in 2001, 95.1% of patients were infected with subtype B but 14 of
these 284 patients were infected with a non-B subtype. By contrast, in
2010, the prevalence of all non-B infections increased to 206 of
831 patients (24.7%; P<0.0001) (Figure 1).
In 2010, 66% of patients were born in Canada and 19% in sub-
Saharan Africa. There was no difference in subtype testing rates
between Canadian-born and sub-Saharan African-born patients in
either 2001 or 2010. In 2001, 45.5% (15 of 33) of sub-Saharan
African-born patients were subtyped and 43.5% (249 of 573) of
Canadian-born patients were subtyped (P=0.86); in 2010, subtyping
rates increased to 64.1% (166 of 259) and 63.6% (560 of 881), respect-
ively (P=0.94). Using a conservative index according to region of
birth for patients without a known subtype (using only data from
patients born in Canada and sub-Saharan Africa) in addition to
patients with a known subtype, it was estimated that in 2010, at least
305 of 1257 patients (24.3%) were infected with a non-B subtype,
confirming a dramatic increase from 2001, when 43 of 632 patients
(6.8%) were infected with a non-B subtype (P<0.0001).
Significant diversity was identified in the patient population, with
one HIV-2 infection, eight different HIV-1 subtypes and six different
CRFs. In 2010, the predominant nonsubtype B viruses identified were
subtypes C (65%), A (11%), CRF02_AG (9.7%), CRF01_AE (4.9%),
D (3.9%), G (2.9%) and CRF06_cpx (1.5%) (Figure 2).
The increasing viral diversity in new HIV patients (incidence)
with a known subtype over this time period has driven this change. In
2001, 84% of incident cases with a known viral subtype were infected
with subtype B; however, by 2010, only 67% of 132 new patients with
known subtype were infected with subtype B (Figure 3).
The evolving diversity data were modelled in an attempt to predict
future trends (Figure 4). A linear fitted curve showed a 2.3% per-year
increase in the proportion of new patients presenting with non-B ver-
sus B viruses (R2=0.80) over the past 17 years. There was an average
proportional yearly increase in the incidence of non-B viruses from
0.1% per year from 1995 to 2002 and 3.2% from 2003 to 2010. Of new
patients with a predicted subtype, 9.6% and 32.4% were non-B over
these same periods, respectively (P<0.001). The year-over-year
increase in absolute number of patients infected with a non-B virus
was 13% from 1995 to 2002 and increased to 27% from 2003 to 2010
(P=0.01). In contrast, the average year-over-year increase in preva-
lence in patients infected with a B virus was stable (6.1%) for these
same periods, respectively (P=0.98). This represents a sevenfold
increase in non-B subtype infections over the past decade.
Our results document acceleration in HIV subtype diversity in a senti-
nel Canadian population over the past decade and suggest that the
prevalence of non-B subtypes will continue to increase disproportion-
ately to B subtypes. Travel and acquisition of infection abroad, immi-
gration policy, as well as domestic transmission of non-B subtypes may
contribute to viral diversity in developed countries (22,28,32).
Immigrants from endemic countries are more likely to be infected with
non-B subtypes and comprise approximately 17% and 35% of new
HIV diagnoses in Canada (1) and Europe (33), respectively. Although
immigration patterns may explain much of the increasing diversity, it
is an incomplete explanation because there is mounting evidence of
increasing non-B transmission within Canada as well (32).
Figure 1) Prevalence of known HIV-1 subtypes in southern Alberta,
2001 to 2010. CRF Circulating recombinant form
Figure 2) Prevalence of known HIV-1 and predicted subtypes in Southern
Alberta on December 31, 2001 and December 31, 2010. CRF Circulating
2001 2002 2003 20042005 200620072008 2009 2010
Percent of known subtypes
Siemieniuk et al
Can J Infect Dis Med Microbiol Vol 24 No 2 Summer 2013 72
Among the patients with non-B infection, the predominance of
subtype C, followed by subtype A, is similar to the prevalence seen
globally (6). Importantly, this trend may be the first signal that subtype B
will soon no longer be the dominant HIV-1 subtype in Canada and
many other developed countries. This trend has been reported in some
European HIV cohorts (26-28) but, until now, has not been apparent
in North America. Similar to other populations, there was also an
increase in the number of CRFs over the course of the study period,
reflecting an increasing complexity of HIV genetics (6). The number
and prevalence of recombinants will likely continue to increase given
the additive opportunities for genetic recombination.
While increasing diversity is of epidemiological interest, there are
far-reaching clinical implications. Adverse clinical outcomes due to
inaccurate HIV viral load quantification of non-B subtypes have been
reported by our group (23) and by others (21,24). Identifying and
addressing the challenges of HIV diversity is particularly important in
the field of molecular laboratory medicine. Several recent studies have
shown that primers designed for quantifying HIV-1 subtype B in viral
load assays may be unreliable quantifying some non-B subtypes
(20,21). Our results suggest that the local epidemiology of viral sub-
types should be a deciding factor in selecting the most appropriate
quantitative viral load assay.
There is some evidence to suggest that HIV subtype may affect
disease transmission, progression and response to therapy. For example,
subtype C may be more easily transmitted from mother to child (8)
and may exhibit higher viral shedding in the vagina than subtypes A
or D (9). There may also be differences in rates of heterosexual trans-
mission (10). These results remain intriguing, but the role of con-
founders needs to be addressed. Subtype D may progress more rapidly
(13-16), while subtype A may have a slower disease progression
(12,13). Further in vivo and in vitro evidence also suggests differences
in progression rates between subtypes (11); however, the full clinical
implications for each subtype are not yet understood (3).
One group suggested that subtypes may vary in neuropathogenicity
based on studies with animal models (17). Early observational studies
have supported this suggestion by reporting a difference in rates of
dementia between subtypes (18). The role of subtypes in other areas of
disease severity is as yet poorly understood.
Low-frequency natural polymorphisms associated with drug resist-
ance to nucleotide and non-nucleotide reverse-transcriptase inhibitors
(NRTI and NNRTI) have been widely described in subtype C, but not
subtype B (34). This raises the concern that some NRTI/NNRTI com-
binations are more likely to fail than other regimens in subtype C
infection due to selection of these mutations conferring resistance
(35). The implications for NRTI-based pre- and postexposure prophyl-
axis of low frequency polymorphisms, such as the K65R in subtype C,
which are associated with drug resistance and are more common in
certain subtypes, warrant further study. Polymorphisms leading to
decreased susceptibility to protease inhibitors (36) and integrase
inhibitors (37) have also been identified in certain non-B subtypes.
Subtype differences in HIV coreceptor tropism have been reported,
with potential implications for disease progression and therapy with
entry inhibitors (38).
All of these observations raise the concern that certain subtypes
may be more likely to fail therapy in the common scenario of good but
suboptimal drug adherence, ultimately leading to poor outcomes (19).
Clinical cohort studies have not yet been adequately powered to
address failure rates of individual subtype-regimen combinations.
While subtle differences have been suggested in population-based
studies investigating rates of viral load suppression, they have not had
sufficently long follow-up or enough statistical power for definitive
results (3,39). A recent study (40) implied superior response to therapy
among subtypes A and CRF02_AG compared with subtype B. The
role of subtype-tailored combination therapy in minimizing the risk of
future failure remains uncertain at present.
There are some limitations to the present study. Being retrospect-
ive in nature, the study did not have complete subtype classification
on all patients in care over the study period. To address any bias of
using a clinical database retrospectively, we indexed unknown sub-
types based on region of birth, which was such a specific marker that
indexing to birth region on a population level likely had higher accur-
acy than predicting subtypes for individual patients. Furthermore, we
have also assumed that if any, the number of super infections ‘changing’
a viral subtype over time was insignificant. Subtypes were based on the
pol region in most patients and, thus, it is possible that the true preva-
lence of CRFs may be underestimated. The study was limited to south-
ern Alberta and may not completely reflect the size or diversity of
subtypes elsewhere due to differing immigration and migratory travel
patterns. Many factors, such as federal government immigration poli-
cies and other social and geopolitical factors, may impact future HIV
subtype trends beyond the scope of the present analysis. However,
there is no reason to believe that these trends are unique to this geo-
graphical region of Canada and, if anything, the trend may be more
dramatic in large urban centres with higher immigration rates and
Over the past 10 years, there has been a dramatic increase in viral
diversity in a large, geographically defined cohort of HIV-infected
patients in Canada – the prevalence of non-B subtype infections rose
from 6.8% to 24% over the past decade. Furthermore, this trend is
accelerating, with a dramatic 27% yearly increase in prevalence of
non-B viruses over the past eight years. To our knowledge, we are the
first to report such a major change in HIV viral diversity within North
Figure 3) Incident HIV-1 cases to the Southern Alberta HIV Program,
2001 to 2010, according to subtype. CRF Circulating recombinant forms
Figure 4) Proportion of new patients with non-B subtypes indexed accord-
ing to year, 1994 to 2010
Percent of known subtypes
Increasing Canadian HIV subtype diversity Download full-text
Can J Infect Dis Med Microbiol Vol 24 No 2 Summer 201373
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