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Dahabreh IJ, Matthews A, Steingrimsson JA, Scharfstein DO, Stuart EA. Using Trial and Observational Data to Assess Effectiveness: Trial Emulation, Transportability, Benchmarking, and Joint Analysis. Epidemiol Rev 2024; 46:1-16. [PMID: 36752592 DOI: 10.1093/epirev/mxac011] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 10/27/2022] [Accepted: 11/01/2022] [Indexed: 02/09/2023] Open
Abstract
Comparisons between randomized trial analyses and observational analyses that attempt to address similar research questions have generated many controversies in epidemiology and the social sciences. There has been little consensus on when such comparisons are reasonable, what their implications are for the validity of observational analyses, or whether trial and observational analyses can be integrated to address effectiveness questions. Here, we consider methods for using observational analyses to complement trial analyses when assessing treatment effectiveness. First, we review the framework for designing observational analyses that emulate target trials and present an evidence map of its recent applications. We then review approaches for estimating the average treatment effect in the target population underlying the emulation, using observational analyses of the emulation data alone and using transportability analyses to extend inferences from a trial to the target population. We explain how comparing treatment effect estimates from the emulation against those from the trial can provide evidence on whether observational analyses can be trusted to deliver valid estimates of effectiveness-a process we refer to as benchmarking-and, in some cases, allow the joint analysis of the trial and observational data. We illustrate different approaches using a simplified example of a pragmatic trial and its emulation in registry data. We conclude that synthesizing trial and observational data-in transportability, benchmarking, or joint analyses-can leverage their complementary strengths to enhance learning about comparative effectiveness, through a process combining quantitative methods and epidemiologic judgments.
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Farooq HZ, James M, Abbott J, Oyibo P, Divall P, Choudhry N, Foster GR. Risk factors for hepatocellular carcinoma associated with hepatitis C genotype 3 infection: A systematic review. World J Gastrointest Oncol 2024; 16:1596-1612. [PMID: 38660636 PMCID: PMC11037048 DOI: 10.4251/wjgo.v16.i4.1596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 12/21/2023] [Accepted: 01/23/2024] [Indexed: 04/10/2024] Open
Abstract
BACKGROUND Hepatitis C virus (HCV) is a blood-borne virus which globally affects around 79 million people and is associated with high morbidity and mortality. Chronic infection leads to cirrhosis in a large proportion of patients and often causes hepatocellular carcinoma (HCC) in people with cirrhosis. Of the 6 HCV genotypes (G1-G6), genotype-3 accounts for 17.9% of infections. HCV genotype-3 responds least well to directly-acting antivirals and patients with genotype-3 infection are at increased risk of HCC even if they do not have cirrhosis. AIM To systematically review and critically appraise all risk factors for HCC secondary to HCV-G3 in all settings. Consequently, we studied possible risk factors for HCC due to HCV-G3 in the literature from 1946 to 2023. METHODS This systematic review aimed to synthesise existing and published studies of risk factors for HCC secondary to HCV genotype-3 and evaluate their strengths and limitations. We searched Web of Science, Medline, EMBASE, and CENTRAL for publications reporting risk factors for HCC due to HCV genotype-3 in all settings, 1946-2023. RESULTS Four thousand one hundred and forty-four records were identified from the four databases with 260 records removed as duplicates. Three thousand eight hundred and eighty-four records were screened with 3514 excluded. Three hundred and seventy-one full-texts were assessed for eligibility with seven studies included for analysis. Of the seven studies, three studies were retrospective case-control trials, two retrospective cohort studies, one a prospective cohort study and one a cross-sectional study design. All were based in hospital settings with four in Pakistan, two in South Korea and one in the United States. The total number of participants were 9621 of which 167 developed HCC (1.7%). All seven studies found cirrhosis to be a risk factor for HCC secondary to HCV genotype-3 followed by higher age (five-studies), with two studies each showing male sex, high alpha feto-protein, directly-acting antivirals treatment and achievement of sustained virologic response as risk factors for developing HCC. CONCLUSION Although, studies have shown that HCV genotype-3 infection is an independent risk factor for end-stage liver disease, HCC, and liver-related death, there is a lack of evidence for specific risk factors for HCC secondary to HCV genotype-3. Only cirrhosis and age have demonstrated an association; however, the number of studies is very small, and more research is required to investigate risk factors for HCC secondary to HCV genotype-3.
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Affiliation(s)
- Hamzah Z Farooq
- Blizard Institute, Queen Mary University of London, London E1 2AT, United Kingdom
| | - Michael James
- Blizard Institute, Queen Mary University of London, London E1 2AT, United Kingdom
| | - Jane Abbott
- Blizard Institute, Queen Mary University of London, London E1 2AT, United Kingdom
| | - Patrick Oyibo
- School of Health and Psychological Sciences, University of London, London EC1V 0HB, United Kingdom
| | - Pip Divall
- University Hospitals of Leicester Library, University Hospitals of Leicester NHS Trust, Leicester LE3 9QP, United Kingdom
| | - Naheed Choudhry
- Blizard Institute, Queen Mary University of London, London E1 2AT, United Kingdom
| | - Graham R Foster
- Blizard Institute, Queen Mary University of London, London E1 2AT, United Kingdom
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Hansford HJ, Cashin AG, Jones MD, Swanson SA, Islam N, Douglas SRG, Rizzo RRN, Devonshire JJ, Williams SA, Dahabreh IJ, Dickerman BA, Egger M, Garcia-Albeniz X, Golub RM, Lodi S, Moreno-Betancur M, Pearson SA, Schneeweiss S, Sterne JAC, Sharp MK, Stuart EA, Hernán MA, Lee H, McAuley JH. Reporting of Observational Studies Explicitly Aiming to Emulate Randomized Trials: A Systematic Review. JAMA Netw Open 2023; 6:e2336023. [PMID: 37755828 PMCID: PMC10534275 DOI: 10.1001/jamanetworkopen.2023.36023] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 08/22/2023] [Indexed: 09/28/2023] Open
Abstract
Importance Observational (nonexperimental) studies that aim to emulate a randomized trial (ie, the target trial) are increasingly informing medical and policy decision-making, but it is unclear how these studies are reported in the literature. Consistent reporting is essential for quality appraisal, evidence synthesis, and translation of evidence to policy and practice. Objective To assess the reporting of observational studies that explicitly aimed to emulate a target trial. Evidence Review We searched Medline, Embase, PsycINFO, and Web of Science for observational studies published between March 2012 and October 2022 that explicitly aimed to emulate a target trial of a health or medical intervention. Two reviewers double-screened and -extracted data on study characteristics, key predefined components of the target trial protocol and its emulation (eligibility criteria, treatment strategies, treatment assignment, outcome[s], follow-up, causal contrast[s], and analysis plan), and other items related to the target trial emulation. Findings A total of 200 studies that explicitly aimed to emulate a target trial were included. These studies included 26 subfields of medicine, and 168 (84%) were published from January 2020 to October 2022. The aim to emulate a target trial was explicit in 70 study titles (35%). Forty-three studies (22%) reported use of a published reporting guideline (eg, Strengthening the Reporting of Observational Studies in Epidemiology). Eighty-five studies (43%) did not describe all key items of how the target trial was emulated and 113 (57%) did not describe the protocol of the target trial and its emulation. Conclusion and Relevance In this systematic review of 200 studies that explicitly aimed to emulate a target trial, reporting of how the target trial was emulated was inconsistent. A reporting guideline for studies explicitly aiming to emulate a target trial may improve the reporting of the target trial protocols and other aspects of these emulation attempts.
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Affiliation(s)
- Harrison J. Hansford
- School of Health Sciences, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia
- Centre for Pain IMPACT, Neuroscience Research Australia, Sydney, Australia
| | - Aidan G. Cashin
- School of Health Sciences, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia
- Centre for Pain IMPACT, Neuroscience Research Australia, Sydney, Australia
| | - Matthew D. Jones
- School of Health Sciences, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia
- Centre for Pain IMPACT, Neuroscience Research Australia, Sydney, Australia
| | - Sonja A. Swanson
- Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania
- CAUSALab, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Nazrul Islam
- Oxford Population Health, Big Data Institute, University of Oxford, Oxford, United Kingdom
- Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Susan R. G. Douglas
- School of Health Sciences, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia
| | - Rodrigo R. N. Rizzo
- School of Health Sciences, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia
- Centre for Pain IMPACT, Neuroscience Research Australia, Sydney, Australia
| | - Jack J. Devonshire
- Centre for Pain IMPACT, Neuroscience Research Australia, Sydney, Australia
| | - Sam A. Williams
- Centre for Pain IMPACT, Neuroscience Research Australia, Sydney, Australia
| | - Issa J. Dahabreh
- CAUSALab, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Barbra A. Dickerman
- CAUSALab, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Matthias Egger
- Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
- Centre for Infectious Disease Epidemiology and Research, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Xabier Garcia-Albeniz
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- RTI Health Solutions, Barcelona, Spain
| | - Robert M. Golub
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Sara Lodi
- CAUSALab, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
| | - Margarita Moreno-Betancur
- Clinical Epidemiology & Biostatistics Unit, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia
- Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia
| | - Sallie-Anne Pearson
- School of Population Health, Faculty of Medicine and Health, UNSW Sydney, New South Wales, Australia
| | - Sebastian Schneeweiss
- Division of Pharmacoepidemiology, Department of Medicine, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - Jonathan A. C. Sterne
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- NIHR Bristol Biomedical Research Centre, Bristol, United Kingdom
- Health Data Research UK South-West, Bristol, United Kingdom
| | - Melissa K. Sharp
- Department of Public Health and Epidemiology, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Elizabeth A. Stuart
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Miguel A. Hernán
- CAUSALab, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Hopin Lee
- University of Exeter Medical School, Exeter, United Kingdom
| | - James H. McAuley
- School of Health Sciences, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia
- Centre for Pain IMPACT, Neuroscience Research Australia, Sydney, Australia
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Kouroumalis E, Voumvouraki A. Hepatitis C virus: A critical approach to who really needs treatment. World J Hepatol 2022; 14:1-44. [PMID: 35126838 PMCID: PMC8790391 DOI: 10.4254/wjh.v14.i1.1] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/14/2021] [Accepted: 12/31/2021] [Indexed: 02/06/2023] Open
Abstract
Introduction of effective drugs in the treatment of hepatitis C virus (HCV) infection has prompted the World Health Organization to declare a global eradication target by 2030. Propositions have been made to screen the general population and treat all HCV carriers irrespective of the disease status. A year ago the new severe acute respiratory syndrome coronavirus 2 virus appeared causing a worldwide pandemic of coronavirus disease 2019 disease. Huge financial resources were redirected, and the pandemic became the first priority in every country. In this review, we examined the feasibility of the World Health Organization elimination program and the actual natural course of HCV infection. We also identified and analyzed certain comorbidity factors that may aggravate the progress of HCV and some marginalized subpopulations with characteristics favoring HCV dissemination. Alcohol consumption, HIV coinfection and the presence of components of metabolic syndrome including obesity, hyperuricemia and overt diabetes were comorbidities mostly responsible for increased liver-related morbidity and mortality of HCV. We also examined the significance of special subpopulations like people who inject drugs and males having sex with males. Finally, we proposed a different micro-elimination screening and treatment program that can be implemented in all countries irrespective of income. We suggest that screening and treatment of HCV carriers should be limited only in these particular groups.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, University of Crete Medical School, Heraklion 71500, Crete, Greece
| | - Argyro Voumvouraki
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
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Klein MB, Young J, Ortiz-Paredes D, Wang S, Walmsley S, Wong A, Martel-Laferrière V, Pick N, Conway B, Angel J, Baril JG, Fraser C, Lebouché B, Tan DHS, Sandre R, Trottier S, Peiris H, Jayaraman J, Singer J. Virological Outcomes After Switching to Abacavir/Lamivudine/Dolutegravir Combined with Adherence Support in People Living with HIV with Poor Adherence: A Phase IV, Multicentre Randomized Prospective Open Label Study (TriiADD-CTN 286). Patient Prefer Adherence 2022; 16:3267-3281. [PMID: 36536672 PMCID: PMC9759014 DOI: 10.2147/ppa.s379065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Accepted: 10/12/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Many people living with HIV struggle to consistently adhere to antiretroviral therapy, fail to achieve long-term virologic control and remain at risk for HIV-related disease progression, development of resistance and may transmit HIV infection to others. OBJECTIVE To determine if switching from current multi-tablet (curART) to single-tablet antiretroviral therapy (abacavir/lamivudine/dolutegravir; ABC/3TC/DTG), both combined with individualized adherence support, would improve HIV suppression in non-adherent vulnerable populations. METHODS TriiADD was an investigator-initiated randomized, multicentre, open label study. HIV+ adults with documented non-adherence on curART were randomized in a 1:1 ratio to immediately switch to ABC/3TC/DTG or to continue curART. Both arms received adherence support. The primary outcome was the proportion of participants in each arm with HIV RNA < 50 copies/mL 24 weeks after randomization. RESULTS In total, 50 people were screened and 27 randomized from 11 sites across Canada before the trial was stopped early due to slow recruitment. Participants were predominantly from ethnocultural communities, Indigenous people and/or had a history of injection drug use. The proportion achieving HIV RNA < 50 copies/mL at week 24 was 4/12 (33%) in the curART arm vs 7/13 (54%) in the ABC/3TC/DTG arm; median Bayesian risk difference, 5% (95% CrI, -17 to 28%) higher for those randomized to ABC/3TC/DTG. We encountered difficulties with recruitment of participants without prior drug resistance, retention despite intensive support, reliably measuring adherence and in overcoming entrenched adherence barriers. CONCLUSION Results of our trial are consistent with a slight improvement in viral suppression in a vulnerable population when a single tablet regimen is combined with patient-level adherence support. Beyond treatment simplicity and tolerability, tailored interventions addressing stigma and social determinants of health are still needed. The numerous challenges we encountered illustrate how randomised trials may not be the best approach for assessing adherence interventions in vulnerable populations.
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Affiliation(s)
- Marina B Klein
- Division of Infectious Diseases and Chronic Viral Illness Service, Department of Medicine, McGill University Health Centre, Montreal, Canada
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada
- Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, Montreal, Canada
- Canadian Institutes of Health Research, Canadian HIV Trials Network, Vancouver, Canada
- Correspondence: Marina B Klein, Division of Infectious Diseases and Chronic Viral Illness Service, McGill University Health Centre, 1001 Decarie Boulevard, D02.4110, Montréal, H4A 3J1, Canada, Tel +1-514-843-2090, Fax +1-514-843-2092, Email
| | - Jim Young
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada
| | - David Ortiz-Paredes
- Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, Montreal, Canada
| | - Shouao Wang
- Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, Montreal, Canada
| | - Sharon Walmsley
- Canadian Institutes of Health Research, Canadian HIV Trials Network, Vancouver, Canada
- University Health Network, University of Toronto, Toronto, Canada
| | - Alexander Wong
- Department of Medicine, University of Saskatchewan, Regina, Canada
| | - Valérie Martel-Laferrière
- Department of Microbiology and Infectious Diseases, Centre de recherche du Centre hospitalier de l’Université de Montréal, Montreal, Canada
| | - Neora Pick
- Department of Medicine, Division of Infectious Diseases, University of British Columbia, Vancouver, Canada
| | - Brian Conway
- Vancouver Infectious Diseases Centre, Vancouver, Canada
| | | | - Jean-Guy Baril
- Clinique de Médecine Urbaine du Quartier Latin, Montreal, Canada
| | - Chris Fraser
- Cool Aid Community Health Centre, Victoria, Canada
| | - Bertrand Lebouché
- Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, Montreal, Canada
- Department of Family Medicine, McGill University, Montreal, Canada
| | - Darrell H S Tan
- Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
| | - Roger Sandre
- HAVEN Program, Health Sciences North, Sudbury, Canada
| | - Sylvie Trottier
- Centre de Recherche du CHU de Québec, Department of Microbiology, Infectiology and Immunology, Université Laval, Quebec, Canada
| | - Hansi Peiris
- Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, Montreal, Canada
| | - Jayamarx Jayaraman
- Canadian Institutes of Health Research, Canadian HIV Trials Network, Vancouver, Canada
| | - Joel Singer
- Canadian Institutes of Health Research, Canadian HIV Trials Network, Vancouver, Canada
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Corrigendum. Pharmacol Res Perspect 2021; 9:e00889. [PMID: 34687269 PMCID: PMC8539414 DOI: 10.1002/prp2.889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Young J, Wong S, Janjua NZ, Klein MB. Comparing direct acting antivirals for hepatitis C using observational data - Why and how? Pharmacol Res Perspect 2021; 8:e00650. [PMID: 32894643 PMCID: PMC7507378 DOI: 10.1002/prp2.650] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 08/06/2020] [Indexed: 12/12/2022] Open
Abstract
The World Health Organisation's goal of hepatitis C virus (HCV) elimination by 2030 will require lower drug prices. Estimates of comparative efficacy promote competition between pharmaceutical companies but direct acting antivirals have been approved for the treatment of HCV without comparative trials. We emulated a randomized trial to answer the question of whether easy to treat patients with genotype 1 HCV could be treated with sofosbuvir/ledipasvir (SOF/LDV) rather than sofosbuvir/velpatasvir (SOF/VEL). Patients without comorbidities or end stage liver disease were selected from the British Colombia Hepatitis Testers Cohort. To create a conceptual trial, we matched each patient starting SOF/VEL (a ‘case’) to the patient starting SOF/LDV with the closest propensity score (a ‘control’). We estimated the probability of treatment failure under a Bayesian logistic model with a random effect for each case‐control set and used that model to give an estimate of a risk difference for the conceptual trial. Treatment failure was recorded for 27 of 825 (3%) cases and for 29 of 602 (5%) matched controls. Estimates from our model were treatment success rates of 97% (95% credible interval, CrI, 95%‐98%) for treatment with SOF/VEL, 95% (95% CrI 93%‐97%) for treatment with SOF/LDV and a risk difference between treatments of 2% (95% CrI 0%‐4%). This risk difference is evidence that SOF/LDV is not inferior to SOF/VEL for easy to treat patients with genotype 1 HCV. The approach is a template for comparing drugs when there are no data from comparative trials.
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Affiliation(s)
- Jim Young
- Division of Infectious Diseases and Chronic Viral Illness Service, Department of Medicine, Glen Site, McGill University Health Centre, Montreal, QC, Canada.,Department of Epidemiology, Biostatistics and Occupational Health, Faculty of Medicine, McGill University, Montreal, QC, Canada.,Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Stanley Wong
- British Columbia Centre for Disease Control, Vancouver, BC, Canada.,School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada
| | - Naveed Z Janjua
- British Columbia Centre for Disease Control, Vancouver, BC, Canada.,School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada
| | - Marina B Klein
- Division of Infectious Diseases and Chronic Viral Illness Service, Department of Medicine, Glen Site, McGill University Health Centre, Montreal, QC, Canada.,Department of Epidemiology, Biostatistics and Occupational Health, Faculty of Medicine, McGill University, Montreal, QC, Canada.,CIHR Canadian HIV Trials Network, Vancouver, BC, Canada
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