Cohort Profile: The Canadian Observational Cohort collaboration

The human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) epidemic in Canada, as in the USA and other high-income countries, is concentrated in a number of groups. At the end of 2008, there were an estimated 65 000 HIV-positive individuals living in Canada, and 2300–4300 new infections occurring annually across the country.1 Men who have sex with men (MSM) and injection drug users (IDUs) are the key affected population in this epidemic, and represent 48 and 17% of the population infected with HIV in 2008, respectively. Heterosexuals from endemic and non-endemic areas represent 14 and 17% of cases, respectively, and are another key group. Aboriginal (First Nations, Inuit and Métis) people are disproportionately represented and, despite accounting for only 3.8% of the Canadian population, accounted for 12.5% of HIV-positive tests in 2008. The number of women living with HIV in Canada also continues to grow, with 14 300 women living with HIV at the end of 2008, which is a 17% increase from the estimated 12 200 women living with HIV at the end of 2005. Three provinces, Ontario, Quebec and British Columbia (BC), carry the greatest burden of the epidemic and the majority of the people infected in these provinces live in the cities of Toronto, Montreal and Vancouver.1 The delivery of antiretroviral therapy (ART) varies by province. Although health care is publicly funded in Canada, where medically necessary, hospital and physician services are universally provided, and medication coverage is provided through a combination of public and private mechanisms, which differ between provinces. Provincial and territorial programmes for HIV antiretroviral treatment supply and distribution range from complete coverage for all people living with HIV within a given province, to special coverage categories, or coverage through programmes with income-based deductibles. The largest programmes are in the provinces of Ontario, Québec, BC and Alberta. Combined, these programmes spent over $300 million on antiretroviral treatment in 2001–02.2 The Canadian Observational Cohort (CANOC) collaboration is Canada’s first interprovincial collaborative cohort of HIV-positive individuals on ART. This collaboration of nine cohorts from BC, Ontario and Quebec gives researchers the opportunity to conduct large and detailed analyses of HIV treatment outcomes that would not be possible within individual cohorts and to assess variations in patterns of access to treatment, patient management and treatment outcomes across Canada. CANOC is funded from 2008 to 2013 by the Canadian Institutes of Health Research (CIHR) HIV/AIDS Research Initiative, which is supported by the Federal Initiative to Address HIV/AIDS in Canada.3 There are currently nine adult clinical HIV cohorts from research centres, universities and clinics in BC, Ontario and Québec and one national prospective interval cohort (the Canadian Co-Infection Cohort Study) participating in CANOC (Table 1). The initial collaboration focused on a representative group of cohorts serving the largest population centres in Canada but the collaboration is open to cohorts from other sites and provinces in the future. These nine cohorts encompass patients from all transmission categories and various models of care (from community-based clinics to tertiary care facilities). Participating sites/cohorts in CANOC HCV = hepatitis C virus. Participating sites/cohorts in CANOC HCV = hepatitis C virus. CANOC is limited to persons who have initiated combination ART (cART), defined as the use of three or more antiretroviral drugs, on or after 1 January 2000 with no prior antiretroviral experience. We have focused on naive patients initiating cART, because this patient group was felt to be of most clinical interest for the evaluation of modern ART regimens in Canada. As of 31 March 2009, 4560 participants from these nine cohorts met the study inclusion criteria. CANOC represents ∼8% of the total HIV-positive population in Canada, one-quarter of all HIV-positive people in Canada who are currently on ART and approximately half of those who initiated cART since 2000.4 This is the largest sample of HIV-positive people on ART compiled in Canada and represents one of the most representative samples in a high-income country. The primary aims of CANOC are to develop a nationally and internationally recognized and policy relevant programme of research in HIV therapeutics and population and public health in Canada; to establish mentoring, training and research opportunities for graduate students, post-doctoral fellows and clinicians interested in HIV cohort research in Canada; and to improve research and dissemination to physicians and individuals living with HIV and to improve knowledge translation of research regarding HIV therapeutics into provincial, national and international HIV treatment guidelines. Examples of some research topics currently under investigation include: examining regional differences in viral load testing in Canada;5 clinical and socio-demographic characteristics associated with time to virological suppression;6 and clinical outcomes associated with CD4 cell count recovery among virologically suppressed individuals.7 Since CANOC is based on electronic submission of patients’ clinical records from each cohort, patients are not individually recruited into the study. Patients will only be lost to follow-up from CANOC when they are lost to follow-up from individual cohorts. Currently, data for approximately 500 new naïve patients initiating cART therapy are submitted to CANOC each year. The median duration of follow-up is presently 36 months but is expected to increase with time. The loss to follow-up rate was 8.3% over the study period. Electronic data extraction of a pre-defined set of demographic, laboratory and clinical variables is performed at the data centres of the nine participating cohort studies and submitted annually to the BC Centre for Excellence in HIV/AIDS in Vancouver for pooling, data cleaning and analysis. Table 2 displays the structure of the standardized data collection; future data cuts will include a wider selection of data elements. All data are stripped of names and other personal identifiers prior to being sent to the Data Coordinating Site and a unique CANOC study number is assigned to each participant. Overlap between cohorts is identified within provinces before data are sent to the Data Coordinating Site. A data dictionary has been developed by the data analysts and is shared among the investigators. All data are managed in a central relational database and an audit trail has been created for all data changes. Access to CANOC electronic data at the Data Coordinating Site is password protected and limited to essential study personnel. Standardized data collected by CANOC HIV = human immunodeficiency virus; PCR = polymerase chain reaction. Standardized data collected by CANOC HIV = human immunodeficiency virus; PCR = polymerase chain reaction. All participating cohorts received research ethics board approval to contribute anonymous patient data to CANOC adhering to established standards in data sharing/linkage and data security/residual disclosure. In the case of the Ontario HIV Treatment Network (OHTN) Cohort Study (OCS), additional approval was received from the OCS Governance Committee to release Ontario data to participate in CANOC. Data submitted to the Data Coordinating Site in Vancouver are used only to address specific research questions approved by the CANOC Scientific Steering Committee and ownership of individual cohort data remains with the contributing cohort. Data elements used in any scientific publications are aggregated and do not identify individual study participants. Baseline demographic and clinical characteristics of the CANOC participants are described in Table 3. Study enrolment in the first yeara an = 4560. All cohorts included. bOne person reported no gender and one person reported as transgender. cBaseline information. dExcluding 721 people with missing data. eExcluding 1060 people not tested for HCV antibodies. Study enrolment in the first yeara an = 4560. All cohorts included. bOne person reported no gender and one person reported as transgender. cBaseline information. dExcluding 721 people with missing data. eExcluding 1060 people not tested for HCV antibodies. There have been limited opportunities in Canada for training graduate students, post-doctoral fellows, medical trainees and interested community members in the area of HIV cohort research. The team approach to training and knowledge translation creates unique opportunities for advanced multi-site and multi-investigator training. A total of $100 000 per year will be offered for fellowships at Masters, PhD, post-doctoral and clinician scientist levels and will be awarded to the most qualified applicants at any level. Applicants must submit a proposal for a CANOC research project and must be supervised by a CANOC investigator. Training awards are for a 1-year period but are renewable. Currently, CANOC is supporting two Masters and three doctoral students. Representatives of affected communities have been invited to sit on the team’s Community Advisory Committee. The members of the Community Advisory Committee contribute to the development of research questions, advise on and help build community partnerships and assist with knowledge translation of research findings. Partnerships with non-governmental organizations will also allow the findings to be more readily available to individuals living with HIV/AIDS. There are currently five Community Advisory Committee members representing Ontario, Québec, Manitoba and BC. CANOC investigators and their institutions are involved with policy-making and programme-development initiatives in their respective provinces. For example, the BC HIV/AIDS Therapeutic Guidelines are a consensus of the BC Centre for Excellence in HIV/AIDS’s Therapeutic Guidelines Committee.8 This information represents the committee's; interpretation of research findings relating to current treatment of HIV/AIDS. Through such mechanisms, the cohort team has direct avenues for disseminating findings to interested health-care practitioners in their respective provinces. Relevant treatment-related results are also relayed to the appropriate therapeutic guideline committees across Canada, so that further decisions about whether these findings have any implications for current guidelines can be made. CANOC encompasses a broad spectrum of expertise with individuals skilled in biomedical statistics, epidemiology, health services research, infectious diseases, population health, primary care, psychology, respiratory medicine and virology. Team members have demonstrated track records in publishing research findings in high-impact peer-reviewed scientific journals and presenting at academic conferences,9–26 and will continue to pursue these avenues as a means of promoting knowledge translation. Although the team recognizes that publishing in academic journals alone is not sufficient to ensure knowledge translation, our experience is that adherence to the highest standard of peer review is still required to ensure widespread acceptance of research findings, in particular the more controversial studies that are common to our programme. Finally, our website (http://www.canoc.ca) is an important tool for communicating our findings to other research groups in Canada and worldwide. Plain language summaries of research findings will be posted on the website. As noted above, a number of studies are being conducted and the results of these works have been presented at conferences in Canada and internationally.5–7 Unique to this cohort collaboration is our ability to create individual community profiles for each participant based upon Canadian Census data. Participants that have a defined geographic location based on either their postal codes or census dissemination areas were linked to the 2006 Census at the dissemination area level. The variables of interest from the 2006 Census included median income, prevalence of low income, education, unemployment and aboriginal identity. Table 4 shows a comparison of CANOC participants and the general population, broken down by CANOC census catchment areas. Preliminary analyses demonstrate that people enrolled in CANOC generally have lower income and higher unemployment rates and are more likely to have finished high school than the general population. Eleven additional protocols/projects are currently underway. A comparison of CANOC participants and the general Canadian population (n=3842) aLow income is determined by the Statistics Canada low income cut-off which is ∼$29 013 in 200830. Source: Statistics Canada Census, 2006. A comparison of CANOC participants and the general Canadian population (n=3842) aLow income is determined by the Statistics Canada low income cut-off which is ∼$29 013 in 200830. Source: Statistics Canada Census, 2006. With nine cohorts, 4560 participants and 31 investigators with a broad spectrum of expertise, we have good representation of the HIV-positive individuals in Canada who initiated ART after January 2000 and strong commitment from the HIV research community in Canada. Although the initial combined data set was quite streamlined, the data set will be enhanced annually at each subsequent data cut by inclusion of more cohort members and a wider selection of data elements. Linkages with vital statistics and census tract databases will further enrich our dataset. As with any cohort study, there are a number of inherent limitations with our study. Most notably, patients were not randomly assigned to ART or sampled, so may not be representative of the Canadian population infected with HIV/AIDS and on treatment. Patients who initiated therapy prior to January 2000 are not included in the cohort, so our findings will only be generalizable to individuals who have initiated therapy more recently. The cohorts involved in the collaboration are currently limited to three provinces (BC, Ontario, Quebec) of Canada. Although these provinces are representative of the largest HIV-positive populations in Canada, the collective cohort may not be fully representative of the HIV-infected population in Canada. Differences in clinical outcomes among cohorts may result due to by variations in the timing of follow-up visits and differential losses to follow-up between cohorts. Although there is a likely considerable heterogeneity between the cohorts, these differences are more of a strength than a weakness, since this heterogeneity will allow us to better understand how various factors work together to influence the health of HIV-infected individuals. We welcome Canadian cohorts that are not members of CANOC to join our collaboration. Our ‘principles of collaboration’ are based on those principles approved and active in the ART Cohort collaboration,27 the North American AIDS Cohort Collaboration on Research and Design28 and the Ontario HIV Treatment Network cohort.29 The cohorts in the current collaboration were set up for various purposes and all existed prior to the development of CANOC. The majority are clinic-based populations, except in BC, where the study population is based on all people accessing therapy. In addition, we welcome collaborations with other international HIV observational cohorts interested in pursuing joint or comparative analyses. Cohort collaborations provide the strongest level of evidence for research in areas such as disease progression, rare adverse events and rare exposures. Our present efforts of collaboration provide us with the largest amount of current Canadian patient information ever collected. Implementing successful research will require knowledge of patient-important clinical issues, population-level issues and issues likely to be of relevance to policy makers. The CANOC collaboration aims to put Canadian HIV/AIDS research on par with other international collaborations in the field. This will be achieved through the development of a nationally and internationally recognized and policy-relevant programme of research in HIV therapeutics and population and public health, and through the establishment of training and research opportunities for graduate students, post-doctoral fellows and clinicians across the country interested in HIV/AIDS cohort research. Our efforts to improve research dissemination to physicians and persons living with HIV as well as to improve knowledge translation of research on HIV/AIDS therapeutics into provincial, national and international HIV/AIDS treatment guidelines will contribute to global recognition of the CANOC collaboration. Canadian Institutes for Health Research (grant number 169621); Canadian Trials Network (project number 242). The authors would like to thank all the participants for allowing their information to be a part of the CANOC collaboration. They also like to thank colleagues who have provided additional assistance with the dataset and the manuscript: David Milan, Anya Shen, DeSheng Su and Eric F Druyts. Conflict of interest: None declared. Community Advisory Committee: Sean Hosein (Chair), Bruno Lemay, Shari Margolese, Evelyne Ssengendo, Zoran Stjepanovic. Investigators: Gloria Aykroyd (Ontario HIV Treatment Network), Louise Balfour (Ontario HIV Treatment Network, University of Ottawa), Ahmed Bayoumi (Ontario HIV Treatment Network, University of Toronto), John Cairney (Ontario HIV Treatment Network, University of Toronto), Liviana Calzavara (Ontario HIV Treatment Network, University of Toronto), Curtis Cooper (Ontario HIV Treatment Network, University of Ottawa), Kevin Gough (Ontario HIV Treatment Network, University of Toronto), Silvia Guillemi (British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia), Richard Harrigan (British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia), Marianne Harris (British Columbia Centre for Excellence in HIV/AIDS), George Hatzakis (McGill University), Robert Hogg (British Columbia Centre for Excellence in HIV/AIDS, Simon Fraser University), Don Kilby (Ontario HIV Treatment Network), Marina Klein (Montreal Chest Institute Immunodeficiency Service Cohort, McGill University), Richard Lalonde (The Montreal Chest Institute Immunodeficiency Service Cohort and McGill University), Viviane Lima (British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia), Mona Loutfy (University of Toronto, Maple Leaf Medical Clinic), Nima Machouf (Clinique Medicale l’Actuel, Université de Montréal), Ed Mills (British Columbia Centre for Excellence in HIV/AIDS, University of Ottawa), Peggy Millson (Ontario HIV Treatment Network, University of Toronto), Julio Montaner (British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia), David Moore (British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia), Janet Raboud (University of Toronto, University Health Network), Anita Rachlis (Ontario HIV Treatment Network, University of Toronto), Stanley Read (Ontario HIV Treatment Network, University of Toronto), Sean Rourke (Ontario HIV Treatment Network, University of Toronto), Marek Smieja (Ontario HIV Treatment Network, McMaster University), Irving Salit (Ontario HIV Treatment Network, University of Toronto), Darien Taylor (Ontario HIV Treatment Network, Canadian AIDS Treatment Information Exchange), Benoit Trottier (Clinique Medicale l’Actuel, Université de Montréal), Chris Tsoukas (McGill University), Sharon Walmsley (University Health Network, University of Toronto), and Wendy Wobeser (Ontario HIV Treatment Network, Queens University). Svetlana Draskovic (British Columbia Centre for Excellence in HIV/AIDS), Mark Fisher (Ontario HIV Treatment Network), Sandra Gardner (Ontario HIV Treatment Network, University of Toronto), Nada Gataric (British Columbia Centre for Excellence in HIV/AIDS), David Milan (British Columbia Centre for Excellence in HIV/AIDS), Sergio Rueda (Ontario HIV Treatment Network, University of Toronto), Anya Shen (British Columbia Centre for Excellence in HIV/AIDS), and Benita Yip (British Columbia Centre for Excellence in HIV/AIDS).

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