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Background
Since the first reported cases of HIV/AIDS in the mid-1980s, HIV has emerged as one of the most significant infectious agents, infecting 40 million people worldwide. Key to the pathogenicity of this virus is its genetic heterogeneity, which is the result of the error-prone reverse transcriptase, the rapid turnover of HIV-1 in vivo, recombination, and selective immune pressures by the host.
The initial classification of HIV into two main types, HIV-1 and HIV-2, was based on the geographic distribution and the animal source of the human infection - chimpanzee (Pan troglodytes) for HIV-1 and sooty mangabey (Cercocebus atys) for HIV-2. Expanding access to diverse samples of HIV-1 and the advent of new molecular tools have led to the classification of HIV-1 into three distantly related “groups”: M (for main), N (for non-M, non-O) and O (for outlier). Distinct lineages within group M have also been identified. These include subtype designations A to E (subtype E is also referred to as CRF01_AE [the circulating recombinant form, CRF A/E]), F to H, J and K.
One of the primary public health related reasons for conducting a systematic surveillance of HIV genetic variability in Canada is to inform vaccine research and development. The majority of vaccines undergoing clinical trials have been developed using strains of HIV-1 subtype B (predominant in North America and Europe). However, the ability of these vaccines to elicit cross-subtype responses is unclear. It is therefore imperative to collect data on the prevalence and incidence of HIV subtypes and other determinants of subtype diversity in Canada in order to guide vaccine strategies.
Another reason for conducting the systematic surveillance of HIV genetic diversity is to determine whether currently approved assays for HIV in Canada are capable of detecting all circulating strains. This includes our ability to control and manage HIV infection through approved viral load test assays and other tests that determine the stage and progression of the disease. This topic is addressed in more detail in the Section on National HIV Reference Services.
The data presented in this report deal with samples that were received by the National Laboratory for HIV Genetics as of June 30, 2002, and represent newly diagnosed cases of HIV-1 infection between 1984 and 2002.
Data sources
This section highlights the main findings from the CHSDRSP up to June 30, 2002. It is important to note that the results presented here represent individuals who sought testing, whose condition was properly diagnosed and reported as HIV positive. Furthermore, the results include only those individuals for whom sufficient sera, taken for the purposes of diagnostic testing, were available to send to the national HIV laboratories by June 30, 2002, and, of these samples, the subset for which RT-PCR amplification and sequencing to identify major mutations were successful.
As of June 30, 2002, serum samples from 2,242 individuals with HIV infection newly diagnosed between 1984 and 2002 and corresponding non-nominal epidemiologic data have been received from British Columbia (BC), Alberta, Manitoba, Saskatchewan, Newfoundland and Labrador and Nova Scotia for HIV-1 subtype analysis. A total of 32 serum samples have also been received from Ontario, but since these samples were received through the sentinel arm of the CHSDRSP the results are reported in the Section on National HIV Reference Services. While the goal of the CHSDRSP is to collect serum samples from all newly diagnosed cases, the data presented in this report are a result of convenience sampling methods and may not be representative. As well, discussions are under way to expand this program to the remaining provinces and territories.
At the time of writing this report (December 2002) the National Laboratory for HIV Genetics had analyzed a total of 1,634 samples for HIV-1 subtype. Viral RNA had been successfully amplified from 1,312 (80.3%) of the serum samples. This level of success in amplifying virus from serum specimens will likely improve further as sample quality is enhanced and through the identification and use of various primer combinations for reverse transcriptase PCR amplification.
Prevalence and determinants of HIV-1 subtypes in sample population (N = 1,312)
Table 13 provides information on the distribution of HIV-1 subtypes in our sample population. Between July 1998 and December 2000, the C2-V5 region (233 amino acids) of the envelope protein was used to assess HIV subtype. Since this time, sequence analysis of the pol gene (entire protease and the first 253 amino acids of reverse transcriptase) has been used for subtype analysis. While the majority (93.1%) of samples are of HIV-1 subtype B, other subtypes have been identified. In decreasing order of prevalence they include subtype C (4.1%), A (1.8%), E (0.4%), D (0.3%) and the recombinants A/B (0.1%), A/C (0.1%) and A/G (0.1%). The recombinant A/G, from two individuals, has been identified in Ontario from samples sent through the sentinel arm of the CHSDRSP. See Section 5, National HIV Reference Services, for further information.
Table 13: Prevalence of HIV-1 subtypes among treatment naïve individuals with newly diagnosed infection (N = 1,312) | ||
HIV-1 subtype | Frequency | Percentage |
A | 24 | 1.8 |
A/B | 1 | 0.1 |
A/C | 1 | 0.1 |
A/G | 1 | 0.1 |
B | 1,222 | 93.1 |
C | 54 | 4.1 |
D | 4 | 0.3 |
E1 | 5 | 0.4 |
Total | 1,312 | 100 |
1HIV-1 subtype E has also been referred to as the circulating recombinant form (CRF) A/E. |
Although existing studies on high-risk populations also suggest the predominance of HIV-1 subtype B in Canada, subtype A was reported in Canada in 1995*. As of November 2000, all samples of 31 recent seroconverters from the POLARIS cohort (comprising men who have sex with men) in Ontario are of subtype B**. The British Columbia Centre for Excellence in HIV/AIDS has identified subtypes A, C and D in at least 4% of individuals linked to cohort studies and to the BC HIV Drug Treatment Program***. All HIV-1 sequences analyzed from injecting drug users (n = 17) and men who have sex with men (n = 5) residing in Montreal were of subtype B****.
Table 14 shows the prevalence of HIV-1 subtypes by year of diagnosis with HIV infection. The results suggest a decrease in the prevalence of non-B HIV-1 subtypes, from 22.7% during 1996 to 1.7% during 2001. However, the majority of samples from 1996 were from BC, and the samples are not representative of newly diagnosed cases of HIV infection in the noted year. Therefore, significant associations between year of first diagnosis and HIV-1 subtype could not be determined.
Table 14: Prevalence of HIV-1 subtypes by year of first diagnosis with HIV-1 infection | |||||||||
HIV-1 subtype | |||||||||
A1 | B2 | C3 | D | E4 | A/B | A/C | A/G | Total | |
Year of diagnosis | n (%) | n (%) | n (%) | n (%) | n (%) | n (%) | n (%) | n (%) | n (%) |
1995 and before | 3 (4.5) | 63 (94) | 1 (1.5) | 0 | 0 | 0 | 0 | 0 | 67 (100) |
1996 | 3 (4.5) | 51 (77.3) | 11 (16.7) | 0 | 0 | 1 (1.5) | 0 | 0 | 66 (100) |
1997 | 6 (5.7) | 97 (92.3) | 1 (1) | 0 | 1 (1) | 0 | 0 | 0 | 105 (100) |
1998 | 2 (1.3) | 141 (92.7) | 8 (5.3) | 1 (0.7) | 0 | 0 | 0 | 0 | 152 (100) |
1999 | 6 (1.8) | 311 (90.9) | 20 (5.8) | 2 (0.6) | 3 (0.9) | 0 | 0 | 0 | 342 (100) |
2000 | 2 (0.7) | 292 (95.2) | 9 (2.9) | 1 (0.3) | 1 (0.3) | 0 | 1 (0.3) | 1 (0.3) | 307 (100) |
2001 | 0 | 171 (98.3) | 3 (1.7) | 0 | 0 | 0 | 0 | 0 | 174 (100) |
January 2002 | 0 | 4 (10) | 0 | 0 | 0 | 0 | 0 | 0 | 4 (100) |
Total n (%) | 22 (1.8) | 1,130 (92.9) | 53 (4.4) | 4 (0.3) | 5 (0.4) | 1 (0.08) | 1 (0.08) | 1 (0.08) | 1,217 (100) |
1Year of diagnosis was unknown for two individuals with HIV-1 subtype A infection. 2Year of diagnosis was unknown for 92 individuals with HIV-1 subtype B infection. 3Year of diagnosis was unknown for one individual with HIV-1 subtype C infection. 4HIV-1 subtype E has also been referred to as the circulating recombinant form (CRF) A/E. |
Table 15 shows the prevalence of HIV-1
subtypes by province of diagnosis. The data indicate geographic
variation in the distribution of non-B HIV-1 subtypes. Whereas all
42 samples from Newfoundland and Labrador were identified as
subtype B, 10.4%, 8.2%, 6.8% and 4.6% of the analyzed samples from
Manitoba, Saskatchewan, BC and Alberta respectively belonged to
non-B HIV-1 subtypes. BC had the greatest genetic variation in the
non-B HIV-1 subtypes. It should be noted, however, that sample
sizes are not representative of the total population with a
diagnosis of HIV in each of the indicated provinces. Furthermore,
the provinces of Quebec and Ontario, which report the highest
prevalence of HIV infections, are not represented, so the results
should be interpreted with caution. Subtypes C and A and the
recombinant subtype A/G have been identified in samples submitted
through the sentinel arm of the CHSDRSP, see Section 5, National
HIV Reference Services, for further information.
In Tables 16 to 21, HIV-1 subtypes D, E, A/B, A/C and A/G have been grouped together as ‘"other" subtypes in order to ensure the confidentiality of affected individuals.
Table 16 shows the prevalence of HIV-1 subtypes by age of diagnosis. While the samples in certain age categories are small and the data are not representative of all newly diagnosed cases of HIV infection, the results identified non-B subtypes of HIV-1 in most age groups.
Table 17 shows the prevalence of HIV-1 subtypes by gender. While the data are not representative of all newly diagnosed cases of HIV infection, the results indicate that the prevalence of non-B subtypes may be higher among females than among males (12.9% versus 5.5% respectively).
Table 16: Prevalence of HIV-1 subtypes by age of diagnosis with HIV-1 infection | |||||
HIV-1 subtype |
|||||
A1 | B2 | C3 | Other4 | Total | |
Age (years) |
n (%) | n (%) | n (%) | n (%) | n (%) |
< 15 | 2 (33.3) | 3 (50) | 1 (6.7) | 0 | 6 (100) |
15-19 | 0 | 20 (100) | 0 | 0 | 20 (100) |
20-29 | 8 (3.1) | 233(90.3) | 14 (5.4) | 3 (1.2) | 258 (100) |
30-39 | 3 (0.7) | 413 (92.8) | 24 (5.4) | 5 (1.1) | 445 (100) |
40-49 | 6 (2.1) | 265 (93) | 10 (3.5) | 4 (1.4) | 285 (100) |
50-59 | 2 (2.3) | 82 (95.4) | 2 (2.3) | 0 | 86 (100) |
>= 60 | 1 (2.6) | 35 (92.1) | 2 (5.3) | 0 | 38 (100) |
Total | 22 (1.9) | 1,015 (92.3) | 53 (4.7) | 12 (1.1) | 1,138 (100) |
1Age at diagnosis was unknown for two individuals with HIV-1 subtype A infection. 2Age at diagnosis was unknown for 171 individuals with HIV-1 subtype B infection. 3Age at diagnosis was unknown for one individual with HIV-1 subtype C infection. 4Other includes HIV-1 subtypes D, E, A/B, A/C and A/G. HIV-1 subtype E has also been referred to as the circulating recombinant form (CRF) A/E. |
Table 17: Prevalence of HIV-1 subtypes by gender | |||||
HIV-1 subtype | |||||
A1 | B2 | C | Other3 | Total | |
Sex | n (%) | n (%) | n (%) | n (%) | n (%) |
Male | 13 (1.4) | 858 (94.5) | 29 (3.2) | 8 (0.9) | 908 (100) |
Female | 9 (3.1) | 257 (87.1) | 25 (8.4) | 4 (1.4) | 295 (100) |
Total | 22 (1.8) | 1,115 (92.7) | 54 (4.5) | 12 (1) | 1,203 (100) |
1Gender was unknown for two individuals with HIV-1 subtype A infection. 2Gender was unknown for 107 individuals with HIV-1 subtype B infection. 3Other includes HIV-1 subtypes D, E, A/B, A/C, and
A/G. HIV-1 subtype E has also been referred to as the
circulating |
Table 18 shows the prevalence of HIV-1
subtypes by exposure category. While the samples in certain risk
exposure categories are small and the data are not representative
of all newly diagnosed cases of HIV infection, the results suggest
that a higher proportion of individuals infected through
heterosexual contact (particularly with other individuals at risk
of HIV infection or individuals from pattern II countries where
non-B strains of HIV-1 prevail) may be harbouring non-B HIV-1
subtypes than individuals infected through male-to-male sex or
through injecting drug use. One case of perinatally acquired HIV-1
subtype A has been identified. Receipt of blood or clotting factor
was identified as the sole exposure
category for seven individuals.
Further investigation is required to
determine the accuracy of this
information.
Table 18: Prevalence of HIV-1 subtypes by exposure category | |||||
HIV-1 subtype |
|||||
A |
B |
C |
Other1 |
Total |
|
Exposure Category |
n (%) |
n (%) |
n (%) |
n (%) |
n (%) |
MSM2 MSM/IDU3 IDU |
3 (0.9) 1 (2.3) 2 (0.6) |
326 (97) 42 (95.4) 349 (97.4) |
6 (1.8) 1 (2.3) 6 (1.7) |
1 (0.3) 0 1 (0.3) |
336 (100) 44 (100) 358 (100) |
Blood/blood products a) recipient of blood b) recipient of clotting factor |
0 0 |
3 (100) 3 (100) |
0 1 (1.9) |
0 0 |
3 (100) 4 (100) |
Heterosexual contact/endemic a) origin in pattern II country b) sexual contact with person at risk |
0 5 (3.6) |
1 (8.3) 126 (91.3) |
8 (66.7) 5 (3.6) |
3 (25) 2 (1.4) |
12 (100) 138 (100) |
Occupational exposure NIR-HET4 Other NIR5 Perinatal |
0 7 (4.8) 1 (100) 4 (1.5) 1 (100) |
1 (100) 116 (79.4) 0 255 (95.2) 0 |
0 20 (13.7) 0 7 (2.6) 0 |
0 3 (2.1) 0 2 (0.7) 0 |
1 (100) 146 (100) 1 (100) 268 (100) 1 (100) |
Total |
24 (1.8) |
1,222 (93.1) |
54 (4.1) |
12 (0.9) |
1,312 (100) |
1Other includes HIV-1 subtypes D, E, A/B, A/C, and
A/G. HIV-1 subtype E has also been referred to as the circulating
recombinant 2MSM refers to men who have sex with men. 3IDU refers to injecting drug use. 4NIR-HET refers non-idenfied risk related to heterosexual exposure. 5NIR refers to non-identified risk exposures, i.e., when risk exposures were not identified. |
Table 19 shows the prevalence of HIV-1 subtypes by ethnicity. While the samples among certain ethnic groups are small and the data are not representative of all newly diagnosed cases of HIV infection, the results suggest that a higher proportion of African/Caribbean people (Black), Asians (including South Asian) and people of mixed ethnicities may be infected with non-B HIV-1 subtypes than the Caucasian (White) population. These results may be due to travel and migration from countries where non-B strains of HIV-1 prevail, but additional data and investigation are required to confirm this hypothesis.
Table 19: Prevalence of HIV-1 subtypes by ethnicity | |||||
HIV-1 subtype | |||||
A1 | B2 | C3 | Other4 | Total | |
Ethincity | n (%) | n (%) | n (%) | n (%) | n (%) |
White | 6 (0.9) | 641 (96.3) | 15 (2.3) | 3 (0.5) | 665 (100) |
Black | 5 (9.8) | 24 (47.1) | 18 (35.3) | 4 (7.8) | 51 (100) |
Aboriginal Native Indian Metis Inuit Unspecified |
1 (0.8) 0 0 3 (4.7) |
123 (94.6) 22 (100) 3 (100) 61 (95.3) |
6 (4.6) 0 0 0 |
0 0 0 0 |
130 (100) 22 (100) 3 (100) 64 (100) |
Asian | 2 (8) | 21 (84) | 1 (4) | 1 (4) | 25 (100) |
South Asian | 0 | 15 (83.3) | 1 (5.6) | 2 (11.1) | 18 (100) |
Latin-American | 0 | 19 (100) | 0 | 0 | 19 (100) |
Other (mixed) | 2 (9.1) | 12 (54.5) | 6 (27.3) | 2 (9.1) | 22 (100) |
Total | 19 (1.9) | 941 (92.3) | 47 (4.6) | 12 (1.2) | 1,019 (100) |
1Ethnicity was unknown for five individuals with HIV-1 subtype A infection. 2Ethnicity was unknown for 281 individuals with HIV-1 subtype B infection. 3Ethnicity was unknown for seven individuals with HIV-1 subtype C infection. 4Other includes HIV-1 subtypes D, E, A/B, A/C, and A/G HIV-1 subtype E has also been referred to as the circulating recombinant form (CRF) A/E. |
Table 20 shows the prevalence of HIV-1
subtypes among recently acquired (within approximately the previous
4 months) versus prevalent infections. The lack of availability of
test kits aimed at determining incident infections has affected the
extent to which these data could be generated. The sample size is
therefore not reflective of all newly diagnosed cases of HIV-1
infection or samples for which HIV-1 subtyping has been completed.
Therefore, significant associations between time of infection and
HIV-1 subtype could not be determined. However, in samples that
have been analyzed for time of HIV infection, the data suggest that
HIV-1 subtype C constitutes 3.1% of recent HIV infections.
Serologic assays that have been developed to detect recently
acquired infections have been based on subtype B derived antigens
and have been shown to misdiagnose incident non-B infections as
prevalent infections. Further investigation is required to
determine the sensitivity of the commercially available assays to
accurately detect recently acquired infections in other non-B
subtypes of HIV-1.
Table 20: Prevalence of HIV-1 subtypes by recently acquired versus prevalent HIV-1 infections | |||||
HIV-1 subtype | |||||
A | B1 | C | Other2 | Total | |
HIV-1 infection | n (%) | n (%) | n (%) | n (%) | n (%) |
Recent infection3 | 0 | 156 (96.9) | 5 (3.1) | 0 | 161 (100) |
Prevalent infection | 3 (0.7) | 377 (92.9) | 20 (4.9) | 6 (1.5) | 406 (100) |
Total | 3 (0.5) | 533 (94) | 25 (4.4) | 6 (1.1) | 567 (100) |
1Out of 535 HIV-1 subtype B infected individuals who were tested, time of HIV infection could not be determined for two individuals. 2Other includes HIV-1 subtypes D, E, A/C, and A/G. 3Because of kit availability, a combination of three assays (Organon Technika, Avidity Index, and Abbott) was used to determine recent infections. If any one test identified a sample as being from a recent infection, the sample was included in this category. |
Table 21 shows the prevalence of primary drug resistance among HIV-1 subtypes. Since drug resistance genotyping began in 1999, almost 1 year after subtype testing had been initiated, not all samples that have been subtyped have been tested for drug resistance. This implies that samples received before the initiation of drug resistance testing (e.g. all samples from Newfoundland and Labrador) have not yet been tested for drug resistance. Neither are the data representative of all newly diagnosed cases of HIV-1 infection. However, the results indicate that while multi-drug resistant HIV-1 has not been identified in non-B subtypes of HIV-1, primary drug resistance has been identified in subtypes C and A.
Table 21: Prevalence of HIV-1 subtypes by primary drug resistance | |||||
HIV-1 subtype | |||||
A1 | B2 | C3 | Other4 | Total | |
Drug resistance mutations | n (%) | n (%) | n (%) | n (%) | n (%) |
Wild type/minor mutations5 | 6 (85.7) | 727 (92.7) | 29 (96.7) | 8 (100) | 770 (92.9) |
NRTI6 | 0 | 34 (4.3) | 1 (3.3) | 0 | 35 (4.2) |
NNRTI7 | 0 | 4 (0.5) | 0 | 0 | 4 (0.5) |
Protease | 1 (14.3) | 13 (1.7) | 0 | 0 | 14 (1.7) |
MDR8 | 0 | 6 (0.8) | 6 (0.7) | ||
Total | 7 (100) | 784 (100) | 30 (100) | 8 (100) | 829 (100) |
1Out of 11 HIV-1 subtype A infected individuals who were eligible for drug resistance testing, amplification was unsuccessful for one individual. 2Out of 841 HIV-1 subtype B infected individuals who were eligible for drug resistance testing, amplification was unsuccessful for 56 individuals. 3Out of 35 HIV-1 subtype C infected individuals who were eligible for drug resistance testing, amplification was unsuccessful for five individuals. 4Other includes HIV-1 subtypes D, E, A/C, and A/G. Eight individuals infected with these HIV-1 subtypes were eligible for drug resistance testing. 5Wild type indicates that no major mutations associated with drug resistance were identified. Minor mutations refers to genetic variables not associated with drug resistance. 6NRTI refers to nucleoside reverse transcriptase inhibitor. 7NNRTI refers to non-nucleoside reverse transcriptase inhibitor. 8MDR refers to multi-drug resistance and includes mutations in HIV-1 that are associated with resistance to any two of the three classes of antiretroviral drugs (NRTIs, NNRTIs, and protease inhibitors). |
Tables 22 shows the results of univariate
analyses to determine factors that are significantly associated
with HIV-1 non-B subtype infection. Because of small samples in
certain categories and associated low statistical power, any
differentiation between no true association and an association that
was detected by this analysis could not be made. However, the
following observations can be cautiously made. Significantly higher
proportions of non-B infections were newly diagnosed during 1996 as
compared with 1997 (22.7% versus 7.6% respectively, odds ratio [OR]
= 3.6). However, when compared with 1997 the proportion of newly
diagnosed non-B infections was significantly lower during 2001
(1.7% versus 7.6% respectively, OR = 0.21). Significantly higher
proportions of non-B infections were also observed among females
than males (14.7% versus 5.8% respectively, OR = 2.5); among
individuals who reported heterosexual contact as their primary
exposure factor as compared with male to male sex (17.9% versus
3.0%, respectively, OR = 7.1); and among individuals of Black,
Asian or mixed ethnicities as compared with Whites (52.9%, 16.3%,
45.5% versus 3.6% respectively, OR = 30, 5.2, 22.5
respectively).
Table 22.1: Epidemiologic characteristics of individuals infected with non-B subtypes of HIV-1 | ||||
Sample size | HIV-1 non-B | Univariate analysis | ||
n (%) | p value | Crude OR (95% CI)1 | ||
Year of first diagnosis2 | ||||
<= 1995 | 67 | 4 (6) | 0.77 | - |
1996 | 66 | 15 (22.7) | 0.01 | 3.6 (1.4-9.0) |
1997 | 105 | 8 (7.6) | Ref | Ref |
1998 | 152 | 11 (7.2) | 1 | - |
1999 | 342 | 31 (9.1) | 0.84 | - |
2000 | 307 | 15 (4.9) | 0.33 | - |
2001 | 174 | 3 (1.7) | 0.02 | 0.21 (0.06-0.82) |
2002 | 4 | 0 | not done | not done |
Age (years)3 | ||||
< 15 | 6 | 3 (50) | not done | not done |
15-19 | 20 | 0 | not done | not done |
20-29 | 259 | 26 (10) | 0.15 | - |
30-39 | 444 | 31 (7) | Ref | Ref |
40-49 | 285 | 20 (7) | 1 | - |
50-59 | 86 | 4 (4.7) | 0.63 | - |
>=60 | 38 | 3 (7.9) | 0.74 | - |
Gender | ||||
Male | 858 | 50 (5.8) | Ref | - |
Female | 257 | 38 (14.7) | < 0.001 | 2.53 (1.6-4.0) |
1 Odds ratios were based on a comparison of the variable of interest with the reference (Ref) variable in the group. Only significant ORs are indicated. 2 The data from 1996 are largely from B.C., and additional data are needed to interpret the findings from this year. 3 Age reflects age at first diagnosis and is calculated by subtracting year of birth from year at first diagnosis of HIV. |
Montpetit M. HIV-1 Subtype A in Canada. AIDS Res Hum Retroviruses. 1995;11(11):1421-22.
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Alexander C, Dong W, Chan K, et al. HIV-1 non-B Subtypes in a
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7th Conference on Retroviruses and Opportunistic Infections. San
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