Research Papers

@article{Young2023,
title = {The rate of hepatitis C reinfection in Canadians coinfected with HIV and its implications for national elimination},
author = {Jim Young, Shouao Wang, Charlotte Lanièce Delaunay, Curtis L Cooper, Joseph Cox, M John Gill, Mark Hull, Sharon Walmsley, Alexander Wong , Marina B Klein; Canadian Coinfection Cohort Investigators},
doi = {10.1016/j.drugpo.2023.103981},
year = {2023},
date = {2023-04-01},
journal = {Int J Drug Policy },
volume = {114},
number = {103981},
pages = {103981},
abstract = {Background: The World Health Organisation (WHO) has set targets for the rate of new infections as a way to measure progress towards the elimination of hepatitis C virus (HCV) as a public health threat. As more people are successfully treated for HCV, a higher proportion of new infections will be reinfections. We consider whether the reinfection rate has changed since the interferon era and what we can infer about national elimination efforts from the current reinfection rate.

Methods: The Canadian Coinfection Cohort is representative of HIV HCV coinfected people in clinical care. We selected cohort participants successfully treated for a primary HCV infection either in the interferon era or in the era of direct acting antivirals (DAAs). Selected participants were followed from 12 weeks after completing a successful treatment until the end of 2019 or until their last measured HCV RNA. We estimated the reinfection rate in each treatment era, overall and in participant subgroups, using proportional hazard models appropriate for interval censored data.

Results: Among 814 successfully treated participants with additional HCV RNA measurements, there were 62 reinfections. The overall reinfection rate was 2.6 (95% confidence interval, CI, 1.2-4.1) /100 person years (PY) in the interferon era and 3.4 (95% CI 2.5-4.4) /100 PY in the DAA era. The rate in those reporting injection drug use (IDU) was much higher: 4.7 (95% CI 1.4-7.9) /100 PY and 7.6 (95% CI 5.3-10) /100 PY in the interferon and DAA eras respectively.

Conclusion: The overall reinfection rate in our cohort is now above the WHO target set for new infections in people who inject drugs. The reinfection rate in those reporting IDU has increased since the interferon era. This suggests Canada is not on track to achieve HCV elimination by 2030.},
keywords = {HCV Elimination, HCV elimination; HCV reinfection; HCV treatment; HIV-HCV coinfection; People who inject drugs, HCV reinfection, HCV treatment, HIV-HCV coinfection, People who inject drugs},
pubstate = {published},
tppubtype = {article}
}

@article{G2022,
title = {Predicting the presence of depressive symptoms in the HIV-HCV co-infected population in Canada using supervised machine learning.},
author = {G, Marathe; EEM, Moodie; MJ, Brouillette; J, Cox; C, Cooper; C, Lanièce Delaunay; B, Conway; M, Hull; V, Martel-Laferrière; ML, Vachon; S, Walmsley; A, Wong; MB, Klein; and Canadian Co-Infection Cohort investigators.},
url = {https://bmcmedresmethodol.biomedcentral.com/articles/10.1186/s12874-022-01700-y},
doi = {10.1186/s12874-022-01700-y},
year = {2022},
date = {2022-08-12},
journal = {BMC Medical Research Methodology},
abstract = {Background
Depression is common in the human immunodeficiency virus (HIV)-hepatitis C virus (HCV) co-infected population. Demographic, behavioural, and clinical data collected in research settings may be of help in identifying those at risk for clinical depression. We aimed to predict the presence of depressive symptoms indicative of a risk of depression and identify important classification predictors using supervised machine learning.

Methods
We used data from the Canadian Co-infection Cohort, a multicentre prospective cohort, and its associated sub-study on Food Security (FS). The Center for Epidemiologic Studies Depression Scale-10 (CES-D-10) was administered in the FS sub-study; participants were classified as being at risk for clinical depression if scores ≥ 10. We developed two random forest algorithms using the training data (80%) and tenfold cross validation to predict the CES-D-10 classes—1. Full algorithm with all candidate predictors (137 predictors) and 2. Reduced algorithm using a subset of predictors based on expert opinion (46 predictors). We evaluated the algorithm performances in the testing data using area under the receiver operating characteristic curves (AUC) and generated predictor importance plots.

Results
We included 1,934 FS sub-study visits from 717 participants who were predominantly male (73%), white (76%), unemployed (73%), and high school educated (52%). At the first visit, median age was 49 years (IQR:43–54) and 53% reported presence of depressive symptoms with CES-D-10 scores ≥ 10. The full algorithm had an AUC of 0.82 (95% CI:0.78–0.86) and the reduced algorithm of 0.76 (95% CI:0.71–0.81). Employment, HIV clinical stage, revenue source, body mass index, and education were the five most important predictors.

Conclusion
We developed a prediction algorithm that could be instrumental in identifying individuals at risk for depression in the HIV-HCV co-infected population in research settings. Development of such machine learning algorithms using research data with rich predictor information can be useful for retrospective analyses of unanswered questions regarding impact of depressive symptoms on clinical and patient-centred outcomes among vulnerable populations.},
keywords = {HIV, HIV-HCV co-infection},
pubstate = {published},
tppubtype = {article}
}

@article{G2022b,
title = {Impact of HCV cure on depressive symptoms in the HIV-HCV co-infected population in Canada},
author = {G, Marathe; EEM, Moodie; MJ, Brouillette; C, Lanièce Delaunay; J, Cox; V, Martel-Laferrière; J, Gill; C, Cooper; N, Pick; ML, Vachon, S, Walmsley; MB, Klein; and for the Canadian Co-Infection Cohort Investigators.},
url = {https://pubmed.ncbi.nlm.nih.gov/35789253/},
doi = {10.1093/cid/ciac540},
year = {2022},
date = {2022-08-01},
journal = {Clinical Infectious Diseases},
abstract = {Background: Depression is common in people living with HIV-HCV, with biological and psychosocial mechanisms at play. Direct acting antivirals (DAA) result in high rates of sustained virologic response (SVR), with minimal side-effects. We assessed the impact of SVR on presence of depressive symptoms in the HIV-HCV co-infected population in Canada during the second-generation DAA era (2013-2020).

Methods: We used data from the Canadian Co-infection Cohort (CCC), a multicentre prospective cohort of people with a HIV and HCV co-infection, and its associated sub-study on food security. Since depression screening was performed only in the sub-study, we predicted Center for Epidemiologic Studies Depression Scale-10 classes in the CCC using a random forest classifier and corrected for misclassification. We included participants who achieved SVR and fit a segmented modified Poisson model using an interrupted time series design, adjusting for time-varying confounders.

Results: We included 470 participants; 58% had predicted depressive symptoms at baseline. The median follow-up was 2.4 years (IQR: 1.0-4.5.) pre-SVR and 1.4 years (IQR: 0.6-2.5) post-SVR. The pre-SVR trend suggested depressive symptoms changed little over time, with no immediate level change at SVR. However, post-SVR trends showed a reduction of 5% per year (risk ratio: 0.95 (95%CI: 0.94-0.96)) in the prevalence of depressive symptoms.

Conclusions: In the DAA era, predicted depressive symptoms declined over time following SVR. These improvements reflect possible changes in biological pathways and/or better general health. If such improvements in depression symptoms are durable, this provides an additional reason for treatment and early cure of HCV.},
keywords = {Depressive symptoms, Direct Acting Antivirals, HCV cure, HIV-HCV co-infection, Sustained virologic response},
pubstate = {published},
tppubtype = {article}
}

@article{D2022b,
title = {Interventions to improve uptake of direct-acting antivirals for hepatitis C virus in priority populations: A systematic review},
author = {D, Ortiz-Paredes; A, Amoako; T, Ekmekjian; K, Engler; B, Lebouché; MB, Klein;},
doi = {10.3389/fpubh.2022.877585},
year = {2022},
date = {2022-06-24},
journal = {Frontiers in Public Health},
abstract = {Background & objective: Access to Hepatitis C (HCV) care remains suboptimal. This systematic review sought to identify existing interventions designed to improve direct-acting antiviral (DAA) uptake among HCV infected women, people who inject drugs (PWID), men who have sex with men (MSM), and Indigenous peoples.

Methods: Studies published in high- and middle-income countries were retrieved from eight electronic databases and gray literature (e.g., articles, research reports, theses, abstracts) were screened by two independent reviewers. Identified interventions were summarized using textual narrative synthesis.

Results: After screening 3,139 records, 39 studies were included (11 controlled comparative studies; 36 from high-income countries). Three groups of interventions were identified: interventions involving patients; providers; or the healthcare system. Interventions directed to patients included care co-ordination, accelerated DAA initiation, and patient education. Interventions involving providers included provider education, telemedicine, multidisciplinary teams, and general practitioner-led care. System-based interventions comprised DAA universal access policies and offering HCV services in four settings (primary care, secondary care, tertiary care, and community settings). Most studies (30/39) described complex interventions, i.e., those with two or more strategies combined. Most interventions (37/39) were tailored to, or studied among, PWID. Only one study described an intervention that was aimed at women.

Conclusions: Combining multiple interventions is a common approach for supporting DAA initiation. Three main research gaps were identified, specifically, a lack of: (1) controlled trials estimating the individual or combined effects of interventions on DAA uptake; (2) studies in middle-income countries; and (3) interventions tailored to women, MSM, and Indigenous people.},
keywords = {antiviral agents, hepatitis C, Indigenous peoples, People who inject drugs, sexual and gender minorities},
pubstate = {published},
tppubtype = {article}
}

@article{C2022,
title = {Gaps in hepatitis C virus prevention and care for HIV-hepatitis C virus co-infected people who inject drugs in Canada},
author = {C, Laniece Delaunay; M, Maheu-Giroux; G, Marathe; S, Saeed S; V, Martel-Laferriere; C, Cooper; S, Walmsley; J, Cox; A, Wong A; MB, Klein; },
url = {https://www.sciencedirect.com/science/article/pii/S0955395922000470?via%3Dihub},
doi = {10.1016/j.drugpo.2022.103627},
year = {2022},
date = {2022-02-01},
journal = {International Journal of Drug Policy},
abstract = {Background: People who inject drugs (PWID) living with HIV are a priority population for eliminating hepatitis C virus (HCV) as a public health threat. Maximizing access to HCV prevention and treatment strategies are key steps towards elimination. We aimed to evaluate engagement in harm reduction programs and HCV treatment, and to describe injection practices among HIV-HCV co-infected PWID in Canada from 2003 to 2019.

Methods: We included Canadian Coinfection Cohort study participants who reported injecting drugs between 2003 and 2019 in Quebec, Ontario, Saskatchewan, and British Columbia, Canada. We investigated temporal trends in HCV treatment uptake, efficacy, and effectiveness; injection practices; and engagement in harm reduction programs in three time periods based on HCV treatment availability: 1) interferon/ribavirin (2003-2010); 2) first-generation direct acting antivirals (DAAs) (2011-2013); 3) second-generation DAAs (2014-2019). Harm reduction services assessed included needle and syringe programs (NSP), opioid agonist therapy (OAT), and supervised injection sites (SIS).

Results: Median age of participants (N = 1,077) at cohort entry was 44 years; 69% were males. Province-specific HCV treatment rates increased among HCV RNA-positive PWID, reaching 16 to 31 per 100 person-years in 2014-2019. Treatment efficacy improved from a 50 to 70% range in 2003-2010 to >90% across provinces in 2014-2019. Drug injecting patterns among active PWID varied by province, with an overall decrease in cocaine injection frequency and increasing opioid injections. In the most recent time period (2014-2019), needle/syringe sharing was reported at 8-22% of visits. Gaps remained in engagement in harm reduction programs: NSP use decreased (58-70% of visits), OAT engagement among opioid users was low (8-26% of visits), and participants rarely used SIS (1-15% of visits).

Conclusion: HCV treatment uptake and outcomes have improved among HIV-HCV coinfected PWID. Yet, this population remains exposed to drug-related harms, highlighting the need to tie HCV elimination strategies with enhanced harm reduction programs to improve overall health for this population.},
keywords = {drug injecting patterns, harm reduction, HCV Elimination, HCV treatment, HIV-HCV coinfection, People who inject drugs},
pubstate = {published},
tppubtype = {article}
}

@article{EEM2022,
title = {Depressive symptoms are no longer a barrier to HCV treatment initiation in the direct acting antiviral era},
author = {G Marathe; EEM, Moodie; MJ, Brouillette; J, Cox; C, Laniece Delaunay; C, Cooper M, Hull; J, Gill; S, Walmsley; N, Pick; MB, Klein; and Canadian Coinfection Cohort investigators.},
url = {https://journals.sagepub.com/doi/10.1177/13596535211067610},
doi = {10.1177/13596535211067610},
year = {2022},
date = {2022-01-27},
journal = {Antiviral Therapy},
abstract = {Background
Psychiatric illness was a major barrier for HCV treatment during the Interferon (IFN) treatment era due to neuropsychiatric side effects. While direct acting antivirals (DAA) are better tolerated, patient-level barriers persist. We aimed to assess the effect of depressive symptoms on time to HCV treatment initiation among HIV–HCV co-infected persons during the IFN (2003–2011) and second-generation DAA (2013–2020) eras.
Methods
We used data from the Canadian Co-infection Cohort, a multicentre prospective cohort, and its associated sub-study on Food Security (FS). We predicted Center for Epidemiologic Studies Depression Scale-10 (CES-D-10) classes for depressive symptoms indicative of a depression risk using a random forest classifier and corrected for misclassification using predictive value-based record-level correction. We used marginal structural Cox proportional hazards models with inverse weighting for competing risks (death) to assess the effect of depressive symptoms on treatment initiation among HCV RNA-positive participants.
Results
We included 590 and 1127 participants in the IFN and DAA eras. The treatment initiation rate increased from 9 (95% confidence interval (CI): 7–10) to 21 (95% CI: 19–22) per 100 person-years from the IFN to DAA era. Treatment initiation was lower among those with depressive symptoms compared to those without in the IFN era (hazard ratio: 0.81 (95% CI: 0.69–0.95)) and was higher in the DAA era (1.19 (95% CI: 1.10–1.27)).
Conclusion
Depressive symptoms no longer appear to be a barrier to HCV treatment initiation in the co-infected population in the DAA era. The higher rate of treatment initiation in individuals with depressive symptoms suggests those previously unable to tolerate IFN are now accessing treatment.},
keywords = {HIV, HIV-HCV co-infection},
pubstate = {published},
tppubtype = {article}
}

@article{D2022,
title = {Semiparametric Bayesian inference for optimal dynamic treatment regimes via dynamic marginal structural models},
author = {D, Rodriguez Duque; D, Stephens; EEM, Moodie; MB, Klein;},
url = {https://academic.oup.com/biostatistics/advance-article-abstract/doi/10.1093/biostatistics/kxac007/6564195?redirectedFrom=fulltext&login=false},
doi = {10.1093/biostatistics/kxac007},
year = {2022},
date = {2022-01-01},
journal = {Biostatistics},
abstract = {Considerable statistical work done on dynamic treatment regimes (DTRs) is in the frequentist paradigm, but Bayesian methods may have much to offer in this setting as they allow for the appropriate representation and propagation of uncertainty, including at the individual level. In this work, we extend the use of recently developed Bayesian methods for Marginal Structural Models to arrive at inference of DTRs. We do this (i) by linking the observational world with a world in which all patients are randomized to a DTR, thereby allowing for causal inference and then (ii) by maximizing a posterior predictive utility, where the posterior distribution has been obtained from nonparametric prior assumptions on the observational world data-generating process. Our approach relies on Bayesian semiparametric inference, where inference about a finite-dimensional parameter is made all while working within an infinite-dimensional space of distributions. We further study Bayesian inference of DTRs in the double robust setting by using posterior predictive inference and the nonparametric Bayesian bootstrap. The proposed methods allow for uncertainty quantification at the individual level, thereby enabling personalized decision-making. We examine the performance of these methods via simulation and demonstrate their utility by exploring whether to adapt HIV therapy to a measure of patients' liver health, in order to minimize liver scarring.},
keywords = {Bayesian inference, Dynamic treatment regimes, Marginal structural models},
pubstate = {published},
tppubtype = {article}
}

@article{D2021b,
title = {Barriers and facilitators related to HCV treatment uptake among HIV coinfected populations in Canada: Patients and treatment provider perceptions},
author = {D, Ortiz-Paredes; A, Amoako; D, Lessard; K, Engler; B, Lebouché; M, Klein; },
url = {https://canlivj.utpjournals.press/doi/full/10.3138/canlivj-2021-0020},
doi = {10.3138/canlivj-2021-0020},
year = {2021},
date = {2021-12-01},
journal = {Canadian Liver Journal},
abstract = {BACKGROUND: Direct-acting antiviral (DAA) uptake is challenging across HIV-hepatitis C (HCV) coinfected populations. This study sought to identify barriers and facilitators related to DAA uptake in priority populations in Canada. METHODS: This qualitative descriptive study included 11 people living with HIV with a history of HCV and 15 HCV care providers. Participants were part of either nominal groups (n = 4) or individual interviews (n = 6) in which they identified and ranked barriers and facilitators to DAA uptake. Consolidated lists of barriers and facilitators were identified thematically. RESULTS: Patient participants highly ranked the following barriers: competing priorities and needs (ie, social instability and mental health), delays in care, lack of adherence, and polypharmacy. Provider participant top barriers were the following: competing priorities and needs (ie, social chaos), delays in care (eg, systemic barriers, difficulties engaging patients, lack of trained HCV providers), and HCV-related stigma. Patient participants identified having a strong network of health care providers, family, and friends, possessing intrinsic motivation, and DAAs being a simple and tolerable oral treatment as important facilitators. Provider participant top-ranked facilitators were having resources to identify hard-to-reach populations (eg, patient navigation, outreach), holistic care and addiction management, provider HCV education, and a strong network of interprofessional collaboration. CONCLUSION: The barriers to DAA initiation addressed by patients and providers overlapped, with some nuances. Multidisciplinary care fostering a strong supportive network and intrinsically motivated patients along with HCV education emerged as key facilitators. This study provides insights for developing potential strategies to improve DAA uptake among HIV-HCV coinfected people in Canada.},
keywords = {direct-acting antivirals uptake, hepatitis C, men who have sex with men, MSM, People who inject drugs},
pubstate = {published},
tppubtype = {article}
}

@article{D2021,
title = {Potential interventions to support HCV treatment uptake among HIV co-infected people in Canada: Perceptions of patients and health care providers},
author = {D, Ortiz-Paredes; A, Amoako; D, Lessard; K, Engler; B, Lebouché; M, Klein; },
url = {https://canlivj.utpjournals.press/doi/full/10.3138/canlivj-2021-0021},
doi = {10.3138/canlivj-2021-0021},
year = {2021},
date = {2021-11-05},
journal = {Canadian Liver Journal},
abstract = {BACKGROUND: Increasing direct-acting antiviral (DAA) treatment uptake is key to eliminating HCV infection as a public health threat in Canada. People living with human immunodeficiency virus (HIV) and hepatitis C (HCV) co-infection face barriers to HCV treatment initiation. We sought to identify interventions that could support HCV treatment initiation based on patient and HCV care provider perspectives. METHODS: Eleven people living with HIV with a history of HCV infection and 12 HCV care providers were recruited for this qualitative descriptive study. Participants created ranked-ordered lists of potential interventions during nominal groups (n = 4) and individual interviews (n = 6). Following the nominal group technique, transcripts and intervention lists underwent thematic analysis and ranking scores were merged to create consolidated and prioritized lists from patient and provider perspectives. RESULTS: Patient participants identified a total of eight interventions. The highest-ranked interventions were multidisciplinary clinics, HCV awareness campaigns and patient education, nurse- or pharmacist-led care, peer involvement, and more and better-prepared health professionals. Provider participants identified 11 interventions. The highest-ranked were mobile outreach, DAA initiation at pharmacies, a simplified process of DAA prescription, integration of primary and specialist care, and patient-centred approaches. CONCLUSION: Participants proposed alternatives to hospital-based specialist HCV care, which require increasing capacity for nurses, pharmacists, primary care providers, and peers to have more direct roles in HCV treatment provision. They also identified the need for structural changes and educational initiatives. In addition to optimizing HCV care, these interventions might result in broader benefits for the health of HIV–HCV co-infected people.},
keywords = {Direct-acting antivirals, hepatitis C, HIV infection, Indigenous peoples, men who have sex with men, People who inject drugs, Treatment uptake, Women},
pubstate = {published},
tppubtype = {article}
}

@article{A2021b,
title = {Patient and Provider Perceived Barriers and Facilitators to Direct Acting Antiviral Hepatitis C Treatment Among Priority Populations in High Income Countries: A Knowledge Synthesis.},
author = {A, Amoako; D, Ortiz-Paredes; K, Engler; B, Lebouché; MB, Klein; },
url = {https://www.sciencedirect.com/science/article/pii/S0955395921001523?via%3Dihub},
doi = {10.1016/j.drugpo.2021.103247},
year = {2021},
date = {2021-10-02},
journal = {International Journal of Drug Policy},
abstract = {Background: Direct acting antivirals (DAAs) have increased cure rates for hepatitis C virus (HCV) infection; however, there are several obstacles to the uptake of DAAs in populations where substance use contributes to HCV risk. This synthesis aimed to identify the patient and provider perceived barriers and facilitators to DAA treatment initiation in key patient subgroups-people who inject drugs (PWID), men who have sex with men (MSM), and Indigenous people.

Methods: We systematically searched seven databases and conducted a gray literature search for studies that qualitatively explored patient and provider perceived barriers and facilitators to DAA treatment in our populations of interest. Selected studies were published after 2013 when second generation DAAs became available. The titles, abstracts, and subsequently full texts were screened by two independent reviewers and critically appraised. Barriers and facilitators to DAA treatment uptake were then extracted and thematically synthesized.

Results: 2144 titles and abstracts were identified and screened; 29 full texts were subsequently reviewed. Twelve qualitative studies were finally included. Among providers, perceived barriers to DAA treatment uptake included lack of resources and lack of provider knowledge on HCV while facilitators to treatment provision included simplicity of DAA regimens and professional identity as a doctor to advocate for patients. Among patients, perceived barriers to treatment uptake included current drug use, concerns about side effects of DAAs, stigma, gaps in community care, competing social responsibilities and mental health issues while facilitators included having a trustworthy provider and access to multidisciplinary HCV care.

Conclusion: Despite simplicity of DAAs, many structural barriers to optimal HCV care continue to be experienced by patients and providers. In highlighting nuanced patient and provider perceived barriers and facilitators, this review underscores the need to involve participatory methods in the design and evaluation of interventions to best improve access to care.},
keywords = {Direct-acting antivirals; Hepatitis C; Indigenous; People who inject drugs; Qualitative; Systematic review.},
pubstate = {published},
tppubtype = {article}
}