HIV-1 Strain and Primary Drug Resistance in Canada
Surveillance Report to June 30, 2002

[Previous] [Table of Contents] [Next]

HIV-1 Primary Drug Resistance in Canada (1997-2001)

Background

In any infected individual, the HIV population is made up of wild type and variant strains. The variants contain mutations in the viral genome that are a result of the rapid but relatively inaccurate replication of HIV. Under selective pressure (e.g. as a result of antiretroviral drug treatment), variants that are resistant to the drug are able to grow and become predominant in the viral population. For some drugs (e.g. non-nucleoside reverse transcriptase inhibitors), a single mutation is sufficient to confer drug resistance. Such a mutation is referred to as a “major” mutation. For other drugs, (e.g. protease inhibitors) a combination of mutations is often required to confer resistance. Such mutations are known as “minor” mutations. Of note is that most mutations are lethal or neutral, and the wild type strain usually dominates in the absence of selective pressure from drug therapy because it replicates more efficiently.

Drug resistance is often cited as a contributing factor to treatment failure. Drug resistance that is associated with individuals who are already receiving treatment and that is described in the context of treatment failure is commonly referred to as “secondary” drug resistance. A phenomenon that has received considerable attention recently is the transmission of drug-resistant HIV-1. This type of drug resistance, also called ‘"primary" drug resistance, has been reported in individuals who have never before received treatment for HIV and so have presumably been infected with drug-resistant HIV. Primary drug resistance is becoming more widespread in most countries where antiretroviral therapy is used. People infected with drug-resistant variants of HIV may be at increased risk of drug failure despite never having received treatment. However, the prevalence of primary drug resistance and the variation of this prevalence over time, geographic area and population risk group are not well understood.

The data presented in this report include data on major mutations associated with drug resistance from samples that were received by the National Laboratory for HIV Genetics as of June 30, 2002, and represent individuals with HIV infection newly diagnosed between 1997 and 2001.

Laboratory tests to detect drug resistance

Two types of tests are used to detect drug resistance, genotypic and phenotypic. Genotypic tests provide information about the genetic makeup of the virus by identifying the mutations that are strongly associated with resistance. Phenotypic testing measures the ability of a virus to replicate in the presence of varying drug concentrations. While the methodologies for both tests are well established, each has its limitations, described in the section Data Limitations. Genotyping was used to identify the major drug resistance mutations described in this report. A detailed description of the laboratory tests is given in the Section on Methodology.

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 whose test results were reported as HIV positive. Furthermore,the results are based only on 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 whom reverse transcriptase PCRamplification and sequencing were successful in identifying major mutations.

As of June 30, 2002, serum samples from 1,645 individuals with HIV newly diagnosed between 1997 and 2001 and corresponding non-nominal epidemiologic data received from BC, Alberta, Manitoba, Saskatchewan and Nova Scotia for drug resistance genotyping. While the goal of the CHSDRSP is to collect serum samples from all cases with newly diagnosed infection, 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 the program to the remaining provinces and territories.

At the time of writing of this report (December 2002) the National Laboratory for HIV Genetics has analyzed a total of 1,189 samples for major mutations. Viral RNA had been successfully amplified from 847 (71.2%) 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.

For this report, major mutations identified in the protease and reverse transcriptase genes of HIV were defined by a consensus of listings reported by the International AIDS Society-USA Drug Resistance Mutations Group^*. Please refer to Appendix 2 for the complete, current list of mutations associated with clinical resistance that was used for this report.

Prevalence and determinants of HIV-1 primary drug resistance in the sample population (N = 847)

Table 1 shows the prevalence of primary drug resistance in the sample of individuals with newly diagnosed HIV infection between 1997 and 2001. Major mutations were present in 7.1% of the sample population of 847 of these treatment naVve individuals. Note that since none of the individuals had previously received treatment, they may have been infected with a drug-resistant strain of HIV-1. Major mutations associated with nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors were identified in 35 (4.1%), 4 (0.5%), and 15 (1.8%) of individuals in the sample population respectively. It is notable that a major mutation (L90M) associated with resistance to the protease inhibitors nelfinavir and saquinavir was identified in a sample from Ontario that was sent through the sentinel arm of the CHSDRSP. Six individuals in the sample population (0.7%) were infected with multi-drug resistant HIV-1 harbouring major mutations to NRTI and protease inhibitors or to NRTIs and NNRTIs. Multi-drug resistant HIV was also identified in three samples from Ontario that were sent through the sentinel arm of the CHSDRSP, but since these individuals had previously been receiving antiretroviral treatment, primary drug resistance could not be identified.

Table 1: Prevalence of primary drug resistance among treatment naïve individuals with newly diagnosed infection (1997-2001)
Primary drug resistance	Frequency	Percentage
Wild type/minor mutations1	787	92.9
NRTI2	35	4.1
NNRTI3	4	0.5
Protease	15	1.8
MDR4	6	0.7
Total	847	100
1Wild type indicates that no major mutations associated with drug resistance were identified. Minor mutations refers to genetic variables not associated with drug resistance. 2NRTI refers to nucleoside reverse transcriptase inhibitor. 3NNRTI refers to non-nucleoside reverse transcriptase inhibitor. 4MDR 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).

Appendix 2 contains a list of the major mutations associated with drug resistance that were used in the generation of this report. The major mutations that have been added to our consensus list since the last surveillance report of samples received to June 30, 2001, include I50L, D67N, Y115F, L210W, K219E/Q, L100I, V108I, Y188C/H/L, P225H, M230L and P236L.

Table 2 shows the major mutations in the reverse transcriptase and protease genes of HIV-1 that are associated with resistance to NRTIs, NNRTIs, and protease inhibitors. Of the 35 individuals harbouring HIV-1 with mutations associated with resistance to NRTIs, the majority (21, 60%) carried virus with an M41L mutation in reverse transcriptase. The mutation M41L refers to the replacement of the amino acid methionine (M) with leucine (L) at position 41 of the reverse transcriptase enzyme. The majority (28, 80%) harboured HIV-1 resistant to AZT and d4T. Other mutations were also identified, which were associated with resistance to ddC, 3TC and adefovir. A total of four individuals harboured virus resistant to NNRTIs. Major mutations associated with resistance to all currently approved NNRTIs (delavirdine, efavirenz, and nevirapine) were identified in the sample population. Of 15 individuals harbouring major mutations associated with protease resistance, the majority (5, 33.3%) carried virus with an M46I mutation associated with resistance to indinavir; M46I refers to the replacement of methionine with isoleucine at position 46 in the protease enzyme. Major mutations associated with resistance to the protease inhibitors amprenavir, ritonavir, nelfinavir, and saquinavir were also identified in the sample population.

Table 3 shows the prevalence of primary drug resistance in the sample population by year of diagnosis with HIV infection. Larger and more representative samples are required to conduct trend analyses and determine significant associations with primary drug resistance. However, the following observations can be cautiously made: resistance to NRTIs has been observed in treatment naVve people with newly diagnosed infection as early as 1998; resistance to protease inhibitors and multi-drug resistance in this population has been observed as early as 1999; resistance to NRTIs and protease inhibitors may have reached a plateau since 1999/2000; and resistance to NNRTI and multi-drug resistance may be increasing over time in the sample population.

Table 2: Major mutations identified in HIV-1 reverse transcriptase and protease
Anti-retroviral drug	Number of individuals (%)	Major mutation(s)1
NRTI2, Total	35 (100)
AZT, d4T	21 (60)	M41L3
AZT, d4T	1 (2.8)	M41L, L210W
AZT, d4T	2 (5.8)	K70R
AZT, d4T	1 (2.8)	K219Q
AZT, d4T ddC	1 (2.8)	M41L, T69D, T69N
AZT, d4T ddC	1 (2.8)	T69N, K70R
AZT, d4T 3TC	1 (2.8)	M184V, T215Y
ddC	1 (2.8)	T69N
ddC	2 (5.8)	T69D, T69N
Adefovir	1 (2.8)	K70E
3TC	2 (5.8)	M184V
3TC	1 (2.8)	M1841, M184V
NNRTI4, Total	4 (100)
DLV,  EFV	1 (25)	G190A, G190E, G190S
DLV,  EFV,  NVP	2 (50)	K103N
DLV,  EFV,  NVP	1 (25)	Y181C
PI5, Total	15 (100)
APV	1 (6.7)	L50V
IDV	5 (33.3)	M461
IDV, RTV	1 (6.7)	V82A
NFV	2 (13.3)	N88D
NFV, SQV	6  (40)	L90M
MDR6, Total	6  (100)
AZT, d4T, ddC, ddI, ABC, DLV, EFV, NVP	2 (33.3)	Q151M, K103N
AZT, d4T, DLV, EFV, NVP	1 (16.7)	M41L, T215Y, K103N, Y181C
3TC, DLV, EFV, NVP	2 (33.3)	M184V, K103N
3TC, NFV, SQV	1 (16.7)	M184V, L90M
1 Major mutations were identified by sequencing the entire protease enzyme and the first 253 amino acids of reverse transcriptase. 2 NRTI refers to nucleoside reverse transcriptase inhibitor. Other commonly used names for the NRTIs mentioned include AZT (zidovudine, retrovir); d4T (stavudine, zerit); ddC (zalcitabine, hivid); 3TC (lamivudine, epivir); and ABC, abacavir (1592, ziagen). 3 M41L refers to the substitution of amino acid methionine (M) by leucine (L) at position 41 of the reverse transcriptase enzyme. Other mutation nomenclature refers to substitutions as indicated; amino acid abbreviations are as follows: K, lysine; R, arginine; T, threonine; D, aspartic acid; N, asparagine; E, glutamic acid; H, histidine; Y, tyrosine; V, valine; l, isoleucine; A, alanine. 4 NNRTI refers to non-nucleoside reverse transcriptase inhibitor. Other commonly used names for the NNRTIs mentioned include DLV, delavirdine (rescriptor); EFV, efavirenz (sustiva); and NVP, nevirapine (viramune). 5 PI refers to protease inhibitor. Other commonly used names for the PIs mentioned include SQV, saquinavir (invirase, fortovase); RTV, ritonavir (norvir); APV, amprenavir (agenerase); NFV, nelfinavir (viracept); IDV, indinavir (crixivan) 6 MDR 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).

Table 3: Prevalence of drug resistance among treatment naïve individuals with newly diagnosed infection by year of diagnosis
	Primary drug resistance
	Wild type/minor mutations1	NRTI2	NNRTI3	Protease4	MDR5	Total
Year of diagnosis	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)
1997	20 (1 00)	0	0	0	0	20 (100)
1998	46 (90.2)	5 (9.8)	0	0	0	51 (100)
1999	250  (92.3)	14  (5.1)	0	6 (2.2)	1 (0.4)	271 (100)
2000	279  (95.9)	7 (2.4)	1 (0.3)	4 (1.4)	0	291 (100)
2001	155 (89.1)	9 (5.2)	3 (1.7)	4 (2.3)	3 (1.7)	174 (100)
Total	750 (92.9)	35 (4.3)	4 (0.5)	14 (1.8)	4 (0.5)	807 (100)
1 Wild type indicates that no major mutations associated with drug resistance were identified. Minor mutations refers to genetic variables not associated with drug resistance. Year of diagnosis was unknown for 37 individuals infected with wild type virus or HIV-1 with minor mutation. 2 NRTI refers to nucleoside reverse transcriptase inhibitor. Year of diagnosis was unknown for one individual infected with HIV-1 harbouring a major mutation to an NRTI. 3 NNRTI refers to non-nucleoside reverse transcriptase inhibitor. 4 Year of diagnosis was unknown for one individual harbouring major mutations associated with resistance to a protease inhibitor. 5 MDR 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). Year of diagnosis was unknown for two individuals harbouring multi-drug resistant HIV-1.

Table 4 shows the prevalence of primary drug resistance in the sample population by province. Larger samples that are more representative of all newly diagnosed cases will help determine significant associations with primary drug resistance. However, the following observations can be cautiously made: drug resistance has been identified in BC, Alberta and Manitoba; resistance to all three classes of approved antiretroviral drugs has been identified in BC; multi-drug resistance has been identified in treatment naVve individuals with newly diagnosed infection in BC and Alberta. Resistance to the protease inhibitors nelfinavir and saquinavir has been identified in one sample obtained from Ontario through the sentinel arm of the CHSDRSP.

In Tables 5 to10, NNRTIs and NRTIs have been grouped together as reverse transcriptase inhibitors because of the small samples and in order to ensure the confidentiality of affected individuals.

Tables 5 and 6 show primary drug resistance in the sample population by age and gender. While the data are not representative of all newly diagnosed cases between 1997 and 2001, they demonstrate that primary drug resistance has been identified in adults of both genders between the ages of 15 and 80 years at first diagnosis of HIV infection.

Table 4: Prevalence of drug resistance among treatment naïve individuals with newly diagnosed infection by province
	Primary drug resistance
	Wild type/minor mutations1	NRTI2	NNRTI3	Protease	MDR4	Total
Province	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)
British Columbia	508 (94.6)	16 (3.1)	4 (0.7)	5 (0.9)	4 (0.7)	537(100)
Alberta	181 (92.8)	7 (3.6)	0	5 (2.6)	2 (1)	195 (100)
Saskatchewan	33  (100)	0	0	0	0	33 (100)
Manitoba	64 (79)	12 (14.8)	0	5 (6.2)	0	81 (100)
Nova Scotia5	1 (100)	0	0	0	0	1 (100)
Total	787 (92.9)	35  (4.1)	4 (0.5)	15 (1.8)	6 (0.7)	847 (100)
1 Wild type indicates that no major mutations associated with drug resistance were identified. Minor mutations refers to genetic variables not associated with drug resistance. 2 NRTI refers to nucleoside reverse transcriptase inhibitor. 3 NNRTI refers to non-nucleoside reverse transcriptase inhibitor. 4 MDR 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). 5 Amplification was successful for one out of nine samples received from individuals with newly diagnosed infection during 2001 in Nova Scotia.

Table 5: Prevalence of drug resistance among treatment naïve individuals with newly diagnosed HIV infection by age at diagnosis
	Primary drug resistance
	Wild type/minor mutations1	RTI2	Protease3	MDR4	Total
Age at diagnosis (years)	n (%)	n (%)	n (%)	n (%)	n (%)
< 15	3 (100)	0	0	0	3 (100)
15-19	9  (90)	0	1 (10)	0	10 (100)
20-29	134 (90.5)	9 (6.1)	3 (2)	2 (1.4)	148 (100)
30-39	254 (92)	16 (5.8)	6 (2.2)	0	276 (100)
40-49	194 (96)	5 (2.5)	6 (1.5)	0	202 (100)
50-59	54 (98.2)	1 (1.8)	0	0	55 (100)
>=60	26 (86.7)	3 (10)	1 (3.3)	0	30 (100)
Total	674 (93.1)	34 (4.7)	14 (1.9)	2 (0.3)	724 (100)
1 Wild type indicates that no major mutations associated with drug resistance were identified. Minor mutations refers to genetic variables not associated with drug resistance. Age at diagnosis was unknown for 113 individuals infected with wild type virus or HIV-1 harbouring minor mutation. 2 RTI refers to reverse transcriptase inhibitor and includes both nucleoside and non-nucleoside reverse transcriptase inhibitors. Age at diagnosis was unknown for five individuals harbouring HIV-1 with mutations associated with resistance to RTIs. 3 Age at diagnosis was unknown for one individual harbouring HIV-1 with mutations associated with protease inhibitors. 4 MDR 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). Age at diagnosis was unknown for four individuals harbouring multi-drug resistant HIV-1.

Table 6: Prevalence of drug resistance among treatment naïve individuals with newly diagnosed infection by gender
	Primary drug resistance
	Wild type/minor mutations1	RTI2	Protease3	MDR4	Total
Gender	n (%)	n (%)	n (%)	n (%)	n (%)
Male	528 (93.1)	30 (5.3)	8 (1.4)	1 (0.2)	567 (100)
Female	156 (92.3)	6 (3.6)	6 (3.6)	1 (0.5)	169 (100)
Total	684  (92.9)	36 (4.9)	14 (1.9)	2 (0.3)	736 (100)
1 Wild type indicates that no major mutations associated with drug resistance were identified. Minor mutations refers to genetic variables not associated with drug resistance. Gender was unknown for 103 individuals infected with wild type virus or HIV-1 harbouring minor mutation. 2 RTI refers to reverse transcriptase inhibitor and includes both nucleoside and non-nucleoside reverse transcriptase inhibitors. Gender was unknown for three individuals harbouring HIV-1 with mutations associated with resistance to RTIs. 3 Gender was unknown for one individual harbouring HIV-1 with mutations associated with protease inhibitors. 4 MDR 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).

Table 7 shows the prevalence of primary drug resistance by exposure category. The data are not representative of all newly diagnosed cases of HIV between 1997 and 2001, and because of the large proportion of individuals with unknown risk factors and the small samples in certain cells, significant associations between risk exposure and primary drug resistance could not be determined. However, the data indicate that primary drug resistance was found in the following risk exposures: male to male sex, injecting drug use, and heterosexual contact, specifically heterosexual contact with a person at risk of HIV infection.

Table 7: Prevalence of drug resistance among treatment naïve individuals with newly diagnosed infection by exposure category
	Primary drug resistance
	Wild type/minor mutations1	RTI2	Protease	MDR3	Total
Exposure caegory	n (%)	n (%)	n (%)	n (%)	n (%)
MSM4	187 (92.1)	14 (6.9)	1 (0.5)	1 (0.5)	203 (100)
MSM/IDU5	21 (84)	3 (12)	1 (4)	0	25 (100)
IDU	215 (95.6)	5 (2.2)	5 (2.2)	0	225 (100)
Blood/blood products
a)recipient of blood	3 (100)	0	0	0	3 (100)
b)recipient of clotting factor	0	0	0	0	0
Heterosexual contact/endemic
a)origin in pattern II country	11 (100)	0	0	0	11 (100)
b)sexual contact with person at risk	65 (92.9)	4 (5.7)	1 (1.4)	0	70 (100)
Occupational exposure	0	0	0	0	0
NIR-HET6	85 (87.6)	8 (8.3)	4 (4.1)	0	97 (100)
Other	0	0	0	0	0
NIR7	199 (93.8)	5 (2.4)	3 (1.4)	5 (2.4)	212 (100)
Perinatal	1 (100)	0	0	0	1 (100)
Total	787 (92.9)	39 (4.6)	15 (1.8)	6 (0.7)	847 (100)
1 Wild type indicates that no major mutations associated with drug resistance were identified. Minor mutations refers to genetic variables not associated with drug resistance. 2 RTI refers to reverse transcriptase inhibitor and includes both nucleoside and non-nucleoside reverse transcriptase inhibitors. 3 MDR 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). 4 MSM refers to men who have sex with men. 5 IDU refers to injecting drug use. 6 NIR-HET refers to non-identified risk related to heterosexual exposure. 7 NIR refers to non-identified risk exposures, i.e. when exposures are not identified.

Table 8 shows the prevalence of primary drug resistance by ethnicity. The data are not representative of all newly diagnosed cases of HIV between 1997 and 2001, and because of small samples in certain cells significant associations between ethnicity and primary drug resistance could not be determined. However, the data suggest that while the majority of primary drug resistance (34 cases, 75.6%) was identified in White individuals in the sample population, primary drug resistance has also been identified in affected Aboriginal and Asian people.

Table 9 shows the prevalence of primary drug resistance by HIV-1 subtype. The data are not representative of all newly diagnosed cases of HIV between 1997 and 2001, and because of small samples in certain cells significant associations between HIV-1 subtype and primary drug resistance could not be determined. However, the data suggest that while the majority (56 cases, 96.6%) of primary drug resistance has been identified in individuals with HIV-1 subtype B, primary drug resistance has also been identified in individuals infected with HIV-1 subtypes C and A. Resistance to the protease inhibitors nelfinavir and saquinavir was identified in one HIV-1 subtype C sample from Ontario that was received through the sentinel arm of the CHSDRSP.

Table 8: Prevalence of drug resistance among treatment naïve individuals with newly diagnosed infection by ethnicity
	Primary drug resistance
	Wild type/minor mutations1	RTI2	Protease3	MDR4	Total
Ethnicity	n (%)	n (%)	n (%)	n (%)	n (%)
White	402 (92.2)	22 (5)	10 (2.3)	2 (0.5)	436 (100)
Black	35 (97.2)	1 (2.8)	0	0	36 (100)
Aboriginal
Native Indian	68 (94.4)	2 (2.8)	2 (2.8)	0	72 (100)
Metis	13  (100)	0	0	0	13 (100)
Inuit	3  (100)	0	0	0	3 (100)
Unspecified	37 (90.2)	3 (7.3)	1 (2.4)	0	41 (100)
Asian	12 (92.3)	1 (7.7)	0	0	13 (100)
South Asian	6 (85.7)	1 (14.3)	0	0	7 (100)
Latin-American	11 (100)	0	0	0	11 (100)
Other (mixed)	20 (100)	0	0	0	20 (100)
Total	607 (93.1)	30 (4.6)	13 (2)	2 (0.3)	652 (100)
1 Wild type indicates that no major mutations associated with drug resistance were identified. Minor mutations refers to genetic variables not associated with drug resistance. Ethnicity was unknown for 180 individuals infected with wild type virus or HIV-1 with minor mutations. 2 RTI refers to reverse transcriptase inhibitor and includes both nucleoside and non-nucleoside reverse transcriptase inhibitors. Ethnicity was unknown for nine individuals infected with HIV-1 harbouring mutations associated with RTIs. 3 Ethnicity was unknown for two individuals infected with HIV-1 harbouring mutations associated with protease inhibitors. 4 MDR 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). Ethnicity was unknown for four individuals harbouring multi-drug resistant HIV-1.

Table 9: Prevalence of drug resistance among treatment naïve individuals by HIV-1 subtype
	Primary drug resistance
	Wild type/minor mutations1	RTI2	Protease3	MDR4	Total
HIV-1 subtype	n (%)	n (%)	n (%)	n (%)	n (%)
B	729 (92.9)	37 (4.7)	13 (1.7)	6 (0.7)	785 (100)
A	6 (85.7)	0	1 (14.3)	0	7 (100)
C	29 (96.7)	1 (3.3)	0	0	30 (100)
D	3 (100)	0	0	0	3 (100)
E5	3 (100)	0	0	0	3 (100)
A/C	1 (100)	0	0	0	1 (100)
A/G	1 (100)	0	0	0	1 (100)
Total	772 (93)	38 (4.6)	14 (1.7)	6 (0.7)	830 (100)
1 Wild type indicates that no major mutations associated with drug resistance were identified. Minor mutations refers to genetic variables not associated with drug resistance. HIV-1 subtype was unknown for 15 individuals infected with wild type virus or HIV-1 with minor mutations. 2 RTI refers to reverse transcriptase inhibitor and includes both nucleoside and non-nucleoside reverse transcriptase inhibitors. Subtype was unknown for one individual infected with HIV-1 harbouring mutations associated with RTIs. 3 HIV-1 subtype was unknown for one individual infected with HIV-1 harbouring mutations associated with protease inhibitors. 4 MDR 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). 5 HIV-1 subtype E has also been referred to as the circulating recombinant form (CRF) A/E.

Table 10 shows the prevalence of primary drug resistance 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 between 1997 and 2001 or samples for which drug resistance genotyping has been completed. Therefore, significant associations between time of infection and primary drug resistance could not be determined. However, the data suggest that primary drug resistance has been identified in both prevalent and recent infections. These data also suggest that certain mutations may persist over time and contribute to drug resistance.

Table 10: Prevalence of drug resistance among treatment naïve individuals with recently acquired versus prevalent HIV-1 infection
	Primary drug resistance
	Wild type/minor mutations1	RTI2	Protease	MDR3	Total
HIV-1 Infection	n (%)	n (%)	n (%)	n (%)	n (%)
Recent4	144 (90.6)	9 (5.7)	4 (2.5)	2 (1.2)	159 (100)
Prevalent	378 (95.5)	15 (3.8)	3 (0.7)	0	396 (100)
Total	522 (94.1)	24 (4.3)	7 (1.3)	2 (0.3)	555 (100)
1 Wild type indicates that no major mutations associated with drug resistance were identified. Minor mutations refers to genetic variables not associated with drug resistance. Out of 524 individuals infected with wild type virus or HIV-1 harbouring minor mutations, time of HIV-1 infection was unknown for two individuals. 2 RTI refers to reverse transcriptase inhibitor and includes both nucleoside and non-nucleoside reverse transcriptase inhibitors. 3 MDR 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). 4 Because of kit availability, a combination of three assays (Organon Technika, Avidity Index, and Abbott) was used to determine recent infection. If any one test identified a sample as representing recent infection, the sample was included in this category.

Table 11 is a summary of primary drug resistance results from the CHSDRSP and other cohort and cross-sectional studies in Canada. Please note that this table is NOT meant for inter-study comparisons. It is difficult to make such comparisons and arrive at firm conclusions because of differences in study design. For example, prevalence rates depend on the population being studied (high risk versus general population), the types of laboratory tests used (genotypic and/or phenotypic testing) and differences in the mutations studied and reported. The results suggest that, in Canada, the overall prevalence of primary drug resistance to RTIs is between 4.6% and 20.0%; primary drug resistance to protease inhibitors is between 1.4% and 6.0%. Primary drug resistance to more than one class of antiretroviral drug (multi-drug resistance) has been observed in Canada, and preliminary studies suggest an overall prevalence of between 0.4% and 9.9%.

Table 12 shows the results from studies on primary drug resistance that were conducted in the United States and other countries in western Europe. Please note that this table is NOT meant for inter-study comparisons; such interpretations are difficult to make because of the differences in study design. The results suggest that the prevalence of major mutations associated with drug resistance is similar to that described in Canada.

Table 11: Summary of key studies on drug resistance among treatment naïve individuals with newly diagnosed infection in Canada
Province1	Year of diagnosis	Risk exposures2	Sample size	RTI3 %	Protease4 %	MDR5 %	Total %
BC6	1997-1998	Mixed	423	4.6 (n = 416)	4.6	–	–
QC7	1997-1999	IDU (26%) Sexual (69%)	81	20	6	9.9	–
QC8	May 1996-June 2000	Mixed	112	–	–	4.1	23.2
	July 2000-December 2001	Mixed	36	–	–	0	11.4
ON9	1997-1999	MSM	23	13	–	–	–
BC, AB, SK, MB, NS10	1997	Mixed	20	0	0	0	0
	1998	Mixed		9.8 (NRTI)	0	0	9.8
	1999	Mixed	51	5.1 (NRTI)	2.2	0.4	7.7
	2000	Mixed	271	2.4 (NRTI)	1.4	0	4.1
			291	0.3 (NNRTI)
	2001	Mixed		5.2 (NNRTI)	2.3	1.7	10.9
			174	1.7(NNRTI)
1Province abbreviations: British Columbia (BC); Quebec (QC); Ontario (ON); Alberta (AB); Saskatchewan (SK); Manitoba  (MB);  Nova Scotia (NS). 2IDU refers to injecting drug use. 3RTI refers to reverse transcriptase inhibitors. Differentiation into nucleoside and non-nucleoside reverse transcriptase inhibitors  (NRTI and NNRTI respectively) is given where this information was available. Only major mutations associated with RTI resistance  are identified. 4Only major mutations associated with protease resistance are identified. 5MDR 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 PIs). 6Alexander CS et al. 8th Annual Canadian Conference on HIV/AIDS Research, Vancouver, BC, May 1999: #B224. 7Saloman H et al. AIDS 2000; 142(2):F17-23. 8Routy JP et al. XI International Drug Resistance Workshop. Seville, Spain, July 2002: Antiviral Ther 7 (Suppl. 1): #179. 9Cassol S et al. 9th Annual Canadian Conference on HIV/AIDS Research, Montreal, QC, April 2000 #135P. 10The Canadian HIV Strain and Drug Resistance Surveillance Program (this report).

Table 12. Summary of key studies on drug resistance among treatment naïve individuals with newly diagnosed infection in the United States and Western Europe
Country	Year of diagnosis	Risk exposure1	Sample size	RTI2 %	Protease3 %	MDR4 %	Total5 %
United States6	1989-1998	MSM (80%)	141	0.7 (NNRTI)	1.4	1.4	2.1
United States7	1995-1999	MSM (94%)	80	12.5  (NRTI) 7.5 (NNRTI	3.0	3.8	16.3
United States8	1997-1998	–	144	4.0  (NRTI) 15.0 (NNRTI, n = 95)	10.0	5.0	22.0
United States9	1998   1999   2000	Mixed	238   240   245	3.4 (NRTI) 0.4 (NNRTI) 8.3 (NRTI) 2.1 (NNRTI) 6.9 (NRTI) 1.2 (NNRTI)	0   1.7   2	0   1.7   1.2	3.8 10.0 9.0
United States (Montreal and Vancouver)10	1995-1998   1999-2000	MSM	377	8.5 (NRTI, n = 213) 1.7 (NNRTI, n = 176) 15.9 (NNRTI, n = 82) 7.3 (NNRTI, n = 82)	0.9  (n = 213)   9.1 (n = 88)	3.8 (n = 213)   10.2 (n = 88)	8.0 22.7
France11	1995-1998	Mixed	48	16.6	2.0	–	–
France12	1999-2000	Mixed	251	7.6 (NRTI) 4.0 (NNRTI)	5.2	4.8	–
Spain13	1996-1998	Mixed	68	16.2	6	4.4	–
Spain14	1997-1999 2000-2001	Mixed	31 21	16.1 0	9.7 4.8	0 0	25.8 4.8
Switzerland15	1996 1997 1998 1999	Mixed	193	5.6 6.9 6.8 3.1	3 7.7 2.0 1.9	– – – –	8.6 14.6 8.8 5.0
Switzerland16	1999-2001	Mixed	200	6.5 (NRTI) 0.5 (NNRTI)	1.0	1.5	10
United Kingdom17	1994-1996 1997-1999 2000	Mixed Mixed Mixed	21 22 26	0 13.6 19.2	0 0 3.8	– 0 0	0 13.6 23.0
1 MSM refers to men who have sex with men. 2 RTI refers to reverse transcriptase inhibitors. NRTI = nucleoside reverse transcriptase inhibitor, NNRTI = Non-nucleoside reverse transcriptase inhibitor. Information on NRTI and NNRTI provided when available. 3 Protease refers to protease inhibitors. 4 MDR refers to multi-drug resistance. 5 Total may include major and minor mutations associated with primary drug resistance. 6 Little SJ et al. JAMA 1999; 282:1142-49. 7 Boden D et al. JAMA 1999; 282:1135-41. 8 Wegner S et al. AIDS 2000; 14:1009-15. 9 Bennet D et al. 9th Conference on Retroviruses and Opportunistic Infections. Seattle WA. Feb 2002: #372M. 10 Little SJ et al. N Engl J Med 2002; 347(6):385-94. 11 Tamalet C et al. J Med Virol 2000;61:181-86. 12 Chaix ML et al. XI International HIV Drug Resistance Workshop. Seville, Spain. July 2002; Antiviral Ther 7(Suppl 1): #166. 13 Puig T et al. AIDS 2000; 14:727-32. 14 De Mendoza C, del Romero J, Rodruguez C, et al. 9th Conference on Retroviruses and Opportunistic Infections. Seattle WA. Feb 2002:371M. 15 Yerly S et al. AIDS 2001; 15:2287-92. 16 Yerly S et al. XI International HIV Drug Resistance Workshop. Seville, Spain. July 2002; Antiviral Ther 7 (Suppl 1): #183. 17 UK Collaborative Group on Monitoring the Transmission of HIV Drug Resistance. BMJ 2001; 322:1087-88.

*

International AIDS Society-USA Drug Resistance Mutations Group. Drug Resistance Mutations in HIV-1. Topics in HIV Medicine 2002;10(2):11-15.

[Previous] [Table of Contents] [Next]