Primary HIV Anti-retroviral Drug Resistance in Canada

At A Glance

The Canadian HIV Strain and Drug Resistance Program (CHSDRSP) continues to monitor and assess HIV strains and the transmission of HIV drug resistance in Canada.

Preliminary observations from the CHSDRSP of HIV drug resistance among newly diagnosed, treatment naïve individuals in Canada (i.e., primary drug resistance) are as follows:

The overall prevalence of primary drug resistance to at least one anti-retroviral drug is 7.1%.

The overall prevalence of multi-drug resistance to two or more classes of anti-retroviral drugs is 0.7%.

Primary drug resistance has been observed among both females and males, across different age groups, ethnicities, and exposure categories, in HIV-1 subtype A, B, and C infections, and among recent and older, prevalent HIV infections.

The prevalence of primary drug resistance is similar to what have been observed in other countries where highly active anti-retroviral treatment (HAART) is widely used.

HIV/AIDS Epi Updates, April 2003

April 2003

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Primary HIV Anti-retroviral Drug Resistance in Canada

Drug resistance among individuals on treatment (secondary drug resistance) is well documented. Resistance observed in newly diagnosed, treatment-naive individuals, presumably due to the transmission of a drug-resistant variant of HIV-1 (primary drug resistance) is less well understood. However, there is increasing evidence to suggest the transmission of drug resistant strains of HIV is becoming more widespread in most countries where HAART is used. Drug resistance makes treatment of HIV more complicated, has important implications for HIV related morbidity and mortality, and may result in increased health care costs.

This Epi Update provides a summary of how drug resistance arises, how drug resistance is identified, and key studies on the prevalence of primary drug resistance in countries where HAART is used.

Why conduct primary drug resistance surveillance?

Although HAART has led to a reduction in HIV-1 related morbidity and mortality in Canada and some other countries, there is a concern that its widespread use, increased number of treatment failures, and continuing risk behaviour may result in increased transmission of drug-resistant virus. The first case of primary drug resistance was reported in 1993 with the transmission of a zidovudine-resistant HIV-1 strain.¹ Since then, many reports of transmission of drug resistant HIV strains have been published and there is increasing evidence to suggest the proportion of new HIV infections involving drug resistant strains may be increasing in countries where HAART is routinely used. [For an overview of these studies see Wainberg & Friedland (1998)², and Little (2000)³ ].

What is less well understood is the prevalence of primary drug resistance and the variation of this prevalence over time, geographic area and population risk group. The Canadian HIV Strain and Drug Resistance Surveillance  Program (CHSDRSP) aims to address these questions and the resulting information will help inform the development of any guidelines for initial therapeutic regimens and more effective HIV prevention strategies, including the prevention of vertical transmission.

Evolution of drug resistance

Viral resistance develops largely due to changes in the genetic material (called mutations) coding for the HIV reverse transcriptase (RT) and protease enzymes. Both these enzymes are required for viral reproduction and current anti-retroviral drugs interact with these enzymes to impede their activity. The most commonly used anti-retroviral drugs that are approved for treatment of HIV infection fall into three classes: nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). For a review of NRTI, NNRTI, and PI resistance see Loveday (2001)⁴, Deeks (2001)⁵, and Miller (2001)⁶, respectively.

Most mutations are lethal or neutral and are not associated with conferring drug resistance. However, under conditions where treatment does not completely inhibit viral replication, virus with drug resistant mutations can develop and can replicate resulting in treatment failure. In general, it is theoretically possible for every single drug-resistant mutation to be generated daily.⁷ For some drugs (ex: NNRTIs), a single mutation is associated with a high level of drug resistance. Such a mutation is referred to as a 'major' mutation. For other drugs, (ex: most protease inhibitors) a combination of mutations is often required to confer resistance. Such mutations are known as 'minor' mutations.

Methods to identify drug resistance

Genotypic tests identify mutations in the viral genetic material through commercially available probes for particular mutations or via sequencing viral genes of interest. By comparing the generated sequences to databases containing resistance-conferring mutation algorithms, the presence or absence of drug resistance can be identified.

Phenotypic tests determine the enzymatic activity of viral genes or assess viral growth in increasing concentrations of drugs. Resistance is usually defined when, compared to the wild type strain, four or more times the amount of drug is required to inhibit viral growth by 50%. This test is similar in concept to antibiotic resistance testing in bacterial culture.

Note: Genotypic and phenotypic testing and interpretation for patient care are evolving fields that are extremely complex, requiring expert inputs.

Summary of Key Studies on the Prevalence of Primary Drug Resistance

It is difficult to make inter-study comparisons and arrive at firm conclusions because of differences in study design including study populations, types of resistance testing used, and mutations studied and reported. However, the following observations can be made in Canada:

1. Results from the CHSDRSP indicate that between 1998 and 2001, the overall prevalence of major mutations to at least one anti-retroviral drug was between 4.1% and 10.9% (Table 1, Column 8). A study conducted in Montreal, Quebec, indicates that between May 1996 and Dec 2001, the prevalence of major mutations to at least one anti-retroviral drug was between 11.4% and 23.2% (Table 1, column 8).

2. Primary drug resistance two or more classes of anti-retroviral drugs (multi-drug resistance) has been observed in Canada with an overall prevalence of up-to 9.9% (Table 1, column 7).

Table 1: Summary of key studies on HIV-1 primary drug resistance in Canada

^aBC=British Columbia, QC=Quebec, ON=Ontario, AB=Alberta, SK=Saskatchewan, MB=Manitoba, NS=Nova Scotia

^bReported proportions may not add to 100% since risk exposure categories may not be mutually exclusive IDU=Injection drug use, MSM=Men who have sex with men

^cRTI=Reverse transcriptase inhibitors, NRTI=Nucleoside reverse transcriptase inhibitor, NNRTI=Non-nucleoside reverse transcriptase inhibitor. Information on NRTI and NNRTI provided where available

^dPI=Protease inhibitors

^eMDR=Multi-drug resistance

Table 2 shows the results from studies on primary drug resistance that were conducted in the United States and in Western Europe.  Please note that this table is NOT meant for inter-study comparisons since such interpretations are difficult to make due to differences in study design including study populations, types of resistance testing used, and mutations analysed and reported. The results suggest that the prevalence of major mutations associated with at least one anti-retroviral drug is similar to that described in Canada. Of note, mother-to-child transmission of zidovudine, nevirapine, or multi-drug resistant HIV-1 has been reported in the U.S. and in France.^13,14

Table 2: Summary of key studies on HIV-1 primary drug resistance in the United States and in Western Europe

^aMSM=Men who have sex with men

^bRTI=Reverse transcriptase inhibitors, NRTI=Nucleoside reverse transcriptase inhibitor, NNRTI=Non-nucleoside reverse transcriptase inhibitor. Information on NRTI and NNRTI provided where available.

^cPI=Protease inhibitors

^dMDR=Multi-drug resistance

^fTotal may include major and minor mutations associated with primary drug resistance

Comments

The prevalence of primary HIV drug resistance is widespread in most countries where HAART is used.  Although the interpretation of results is difficult and evolving, persons infected with drug resistant variants of HIV may be at increased risk of drug failure despite being therapy-naïve.  Surveillance of primary drug resistance is needed not only to develop guidelines for initial therapy, but also to better understand and prevent the transmission of resistant variants.

References

1. Erice A, Mayers DL, Strike DG et al.  Primary infection with zidovudine-resistant human immuno-deficiency virus type 1. N Engl J Med 1993; 328:1163-5.

2. Wainberg MA & Friedland G. Public health implications of antiretroviral therapy and HIV drug resistance. JAMA 1998; 279(24): 1977-83.

3. Little S. Transmission and prevalence of HIV resistance among treatment-naïve subjects. Antiviral Ther 2000; 5:33-40.

4. Loveday C. Nucleoside reverse transcriptase inhibitor resistance. JAIDS 2001; 26:S10-S24.

5. Deeks SG. Nonnucleoside reverse transcriptase inhibitor resistance. JAIDS 2001; 26:S25-S33.

6. Miller V. Resistance to protease inhibitors. JAIDS 2001; 26:S34-S50.

7. Hirsh MS, Conway B, D'Aquila RT et al. Antiretroviral drug resistance testing in adults with HIV infection. JAMA        1998; 279(24):1984-91.

8. Alexander CS, O'Shaughnessy MV, Schechter MT et al. The prevalence of HIV drug resistance in recently infected injection drug users and individuals seeking treatment in British Columbia. Eighth Annual Canadian Conference on AIDS, Vancouver BC May 1-4 1999; #B224

9. Salomon H, Wainberg MA, Brenner B et al.   Prevalence of HIV-1 viruses resistant to antiretroviral drugs in 81 individuals newly infected by sexual contact or intravenous drug use. AIDS 2000; 14(2):F17-23.

10. Routy JP, Brenner B, Bruce S et al. Link between the declines of drug-resistance prevalence in newly infected individuals and of the proportion of patients receiving treatment in Montreal. XI International HIV Drug Resistance Workshop, Seville, Spain. July 2-5 2002; Antiviral Ther. 7(Suppl. 1): #179.

11. Cassol  S, Calzavara L, Major C et al. HIV-1 drug resistance in Ontario seroconverters Ninth Annual Canadian Conference on HIV/AIDS Research. Montreal, QC. April 27 - 30, 2000; #135P.

12. Health Canada. HIV-1 strain and primary drug resistance in Canada. Surveillance report to June 30, 2002. Division of HIV/AIDS Epidemiology and Surveillance, Centre for Infectious Disease Prevention and Control, Health Canada, 2002. URL: (http://www.phac-aspc.gc.ca/publicat/aids-sida/haic-vsac0602/index.html).

13. Johnson V, Petropoulos CJ, Woods CR, et al. Vertical transmission of multidrug-resistant human immunodeficiency virus type 1 (HIV-1) and continued evolution of drug resistance in an HIV-1-infected infant. J Infect Dis. 2001; 183:1688-93.

14. Masquelier B, Chaix ML, Burgard, M, et al. Zidovudine genotypic resistance in HIV-1-infected newborns in the French perinatal cohort. J. Acquir Immune Defic Syndr 2001; 27:99-104.

15. Little SJ, Daar ES, D'Aquila RT et al. Reduced antiretroviral drug susceptibility among patients with primary HIV infection. JAMA 1999; 282:1142-49.

16. Boden D, Hurley A, Zhang L et al. HIV-1 drug resistance in newly infected individuals. JAMA 1999; 282:1135-41

17. Wegner S, Brodine S, Mascola J et al. Prevalence of genotypic and phenotypic resistance  to antiretroviral drugs in a cohort of therapy-naïve HIV-1 infected US military personnel. AIDS 2000; 14: 1009-10.

18. Bennett D, Zaidi I, Heneine W et al. Prevalence of mutations associated with antiretroviral drug resistance among recently diagnosed persoms with HIV 1998-2000. Ninth Conference on Retroviruses and Opportunistic Infections. Seattle, WA, Feb 24-28 2002; #95.

19. Little S, Holte S, Routy JP et al. Antiretroviral drug resistance among patients recently infected with HIV. New Engl. J. Med 2002; 347(6):385-94.

20. Tamalet C, Pasquier C, Yahi  N et al. Prevalence of drug resistant mutants and virological response to combination therapy in patients with primary HIV-1 infection. J Med Virol 2000; 61:181-6.

21. Chaix ML, Descamps D, Deveau C et al. Antiretroviral resistance, molecular epidemiology and response to initial therapy among patients with HIV-1 primary infection in 1999-2000 in France. XI International HIV Drug Resistance Workshop, Seville, Spain. July 2-5 2002; Antiviral Ther. 7(Suppl. 1): #166.

22. Puig T, Perez-Olmeda M, Rubio A, et al. Prevalence of genotypic resistance to nucleoside analogues and protease inhibitors in Spain. The ERASE-2 Study Group. AIDS 2000; 14:727-32

23. De Mendoza C, del Romero J, Rodruguez C et al. Decline in the rate of genotypic resistance to antiretroviral drugs in recent HIV seroconverters in Spain. Ninth Conference on Retroviruses and Opportunistic Infections. Seattle, WA Feb  24-28 2002: 371M.

24. Yerly S, Vora S, Rizzardi P et al. Acute HIV infection: impact on the spread of HIV and transmission of drug resistance. AIDS 2001; 15:2287-92.

25. Yerly S, Jost S, Telenti A et al. Transmission of drug resistance: impact of primary and chronic HIV infection. XI International HIV Drug Resistance Workshop, Seville, Spain. July 2-5 2002; Antiviral Ther. 7(Suppl. 1): #183.

26. UK Collaborative Group on Monitoring the Transmission of HIV Drug Resistance. BMJ 2001; 322:1087-88.

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Health Canada