Primary HIV Drug Resistance Surveillance in Canada Surveillance and Risk Assessment Division & National HIV and Retrovirology Laboratories, Public Health Agency of Canada and Participating Provinces and Territories

Canadian HIV SDR Program Partners Pubic Health Agency Of Canada (PHAC) British Columbia Manitoba Chris Archibald Michael Rekart Magdy Dawood Marianna Ofner Mel Krajden Valerie Mann Jocelyne Galloway Mark Gilbert Greg Hammond (ret) James Brooks Paul Sandstrom Saskatchewan Alberta Harriet Merks Huiming Yang Ameeta Singh Richard Pilon Fred Sidaway Jutta Preiksaitis Mark Vanderkloot Ping Yan Ontario Nova Scotia Carol Swantee Maureen Baikie Robert Remis Robert Strang I’d like to thank our provinical collaborators and fellow Public Health Agency of Canada staff

Field Surveillance Officers, PHAC Elsie Wong (British Columbia) Sabrina Plitt (Alberta) Erin Laing (Saskatchewan) Michelyn Wood (Manitoba) Claudia Rank (Ontario) Tracey MacDonald (Nova Scotia) HIV Surveillance Section, PHAC Jenni Vick Kristina Lalonde Stéphane Racette Plus our Field Surveillance Officers located within the specific participating provinces and the Agencies HIV surveillance section

Highly Active Antiretroviral Therapy for HIV Introduction of highly active antiretroviral therapy (HAART) for HIV changed the HIV landscape Morbidity and mortality have decreased The widespread use of HAART, along with continuing HIV incidence, results in the potential for transmission of drug-resistant viruses Drug resistance in untreated individuals is primary drug resistance and is due to transmission of DR strain from treated individuals -over the past 10 years, the world has witnessed one of the MOST significant chronic disease INTERVENTIONS ever seen – that of highly active antiretroviral therapy (HAART) for HIV infection. -morbidity and mortality have plummeted in Canada and other areas of the world where there is unrestricted access to these drugs…..and HIV/AIDS has transformed from almost certain death to, at least for those receiving treatment, a long-term, manageable disease, with a potentially normal life expectancy. According to recent National HIV prevalence and incidence estimates, there were an estimated 58000 people in Canada living with HIV as of the year 2005, with approximately 2500 new cases being reported to the National HIV surveillance system annually. In conjunction with the widespread use of HAART, this can lead to the transmission of drug-resistant virus from individuals under treatment.

Secondary versus Primary (Transmitted) Drug Resistance Failing Therapy Rx Secondary DR Rx HIV+ person not on treatment HIV Drug resistance comes about in 2 ways. Secondary drug resistance comes about as a result of treatment therapy Primary resistance comes about through the transmission of the HIV resistant virus to another person. The monitoring and prevention of primary drug resistance is a public health issue in which prevention and early identification become essential interventions. Primary DR WT Wild Type Virus Drug Resistant Virus

Goals of the Canadian HIV Strain and Drug Resistance Program Improve HIV diagnostics and screening strategies for circulating strains Inform vaccine development Assess genetic markers for anti-retroviral drug resistance among newly diagnosed, treatment-naïve individuals Assess HIV transmission patterns The Canadian HIV Strain and Drug Resistance Surveillance program was set up with a number of goals and research objectives in mind. We wanted to improve HIV diagnostics and screening strategies to detect all circulating strains of HIV in Canada. It is believed that when developed, an HIV vaccine will likely be strain specific. As such, having an understanding of the strains circulating in Canada will also inform vaccine development programs. Performing drug resistance testing through this program will enable us to assess the genetic markers for antiretroviral drug resistance among newly diagnosed, treatment naïve individuals. Finally, we are able to assess the transmission patterns of HIV, its pathogenesis, and the progression of HIV-related diseases.

Sampling methods Population-based study comprising all individuals newly diagnosed with HIV for whom left-over diagnostic serum samples are available No subjects are directly recruited Only first-time positive, treatment-naïve individuals are included

plus epidemiological data Data Collection and Transfer National HIV Laboratories Serum specimens Epidemiological data subtype data Provincial Partners PHAC primary DR mutations “detuned” assay data laboratory results plus epidemiological data Surveillance Division

http://www.phac-aspc.gc.ca/publicat/hiv1-vih1-05/index.html

Results

HIV Drug Resistance in Canada 1996-2005 (N=2703*) Wild Type 90.6% Drug Resistance 9.4% (1 case since 1996) *Results of 4 western provinces

Mutations Associated with DR This looks like a pretty overwhelming slide, but the important thing to take away is the variety and range of mutations that are responsible for drug resistance. This list is constantly being revised as new information becomes available. The mutations shown here are not mutually exclusive, so there is some overlap in the counts shown here for the 1% of cases that have a multi-drug resistance profile. Information sources on resistance include: IAS-USA and Stanford Databases. NRTI NNRTI PI

Characteristics of individuals with primary drug resistant HIV-1 Looking at some of the key variables collected, this table displays the rates of drug resistance. Among male cases, 9% of specimens had mutations associated with primary drug resistance. Similar to females at 9.8%. The mean age of those with primary DR was 37, standard deviation of 10.6 yrs. The highest proportion of cases with primary drug resistance was found among aboriginal cases (10.8%), with the lowest among African/ Caribbean cases (5.6%) None of these variables were found to be significant 9,6% of those found to be subtype B had primary DR while only 5.8% of non-B subtypes, which demonstrates a statistically significant difference. The B subtype is the primary circulating strain in Canada.

Characteristics of individuals with primary drug resistant HIV-1 Looking at exposure category and year of diagnosis, while there were some slight differences noted between groups, however these were not found to be statistically significant. For detuned results the results (recent vs. established) were not associated with year of diagnosis (p=0.21) When comparing infections identified as recent through the detuned assay, there was a significantly higher proportion of Drug Resistance than was found among established infections. Note: Year 2005 was removed from analysis of year of diagnosis due to incomplete data from BC and Alberta, we are awaiting the samples from Alberta and the BC samples we have but no results yet.

Primary HIV DR in Canada, % by drug class and year 1997 had ZERO DR in each category. All were WT strains.

Trends in primary DR over time 1999 2000 2001 2002 2003 2004 2005 0.05 0.10 0.15 0.20 0.25 0.30 For some other provinces For some provinces Proportion of resistance to any drug 1998 1999 2000 2001 2002 2003 2004 2005 0.02 0.04 0.06 0.08 0.10 0.12 NRTI* PI* NNRTI* Resistance to certain drug classes Overall trend after year 2000, there is no statistical significance to suggest a departure from a constant time-trend, but there is evidence of preliminary trends for certain drug classes While there was no clear overall increase in the proportion of drug resistance over time, recent modelling work has shown that there is evidence of difference between the drug classes, with a decrease in resistance to NRTIs over time, a peak and drop off in resistance to protease inhibitors, and an increase in resistance to NNRTIs.

Discussion 9.4% of newly diagnosed HIV cases have primary DR and no indication that this is changing recently trends are seen for certain drug classes virtually no triple-drug resistance in Canada (only 1 case recorded) Primary DR most common in: subtype B infection: may indicate differential access to treatment recently infected cases: may indicate not all mutations are persistent -some changes for individual drug classes have been seen -the trends by drug class have declined in NRTI, increased in NNRTI and there is no change in PI

Public Health Implications Data on prevalence of primary drug resistance can be used to develop population recommendations for initial treatment (especially for pregnant women and situations of post-exposure prophylaxis) Extent of transmitted drug-resistance can serve as an indicator to help evaluate the effectiveness of prevention programs

Future directions Continue to improve representativeness of program in Canada Expand analysis of data: - examine mutation distributions by HIV-1 subtype - use the detuned testing data to monitor trends and associated characteristics of the new diagnoses that are recent infections Encourage public health use of data Maintain and expand collaboration with international partners