Research Papers

@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{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{A2021,
title = {Estimating an individual-level deprivation index for HIV/HCV coinfected persons in Canada},
author = {A, Palayew; AM, Schmidt; S, Saeed; CL Cooper; A, Wong; V, Martel-Laferrière; S, Walmsley; J, Cox; MB, Klein;},
url = {https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249836},
doi = {10.1371/journal.pone.0249836},
year = {2021},
date = {2021-04-19},
journal = {PLOS One},
abstract = {Background
HIV-HCV coinfected individuals are often more deprived than the general population. However, deprivation is difficult to measure, often relying on aggregate data which does not capture individual heterogeneity. We developed an individual-level deprivation index for HIV-HCV co-infected persons that encapsulated social, material, and lifestyle factors.

Methods
We estimated an individual-level deprivation index with data from the Canadian Coinfection Cohort, a national prospective cohort study. We used a predetermined process to select 9 out of 19 dichotomous variables at baseline visit to include in the deprivation model: income >$1500/month; education >high school; employment; identifying as gay or bisexual; Indigenous status; injection drug use in last 6 months; injection drug use ever; past incarceration, and past psychiatric hospitalization. We fitted an item response theory model with: severity parameters (how likely an item was reported), discriminatory parameters, (how well a variable distinguished index levels), and an individual parameter (the index). We considered two models: a simple one with no provincial variation and a hierarchical model by province. The Widely Applicable Information Criterion (WAIC) was used to compare the fitted models. To showcase a potential utility of the proposed index, we evaluated with logistic regression the association of the index with non-attendance to a second clinic visit (as a proxy for disengagement) and using WAIC compared it to a model containing all the individual parameters that compose the index as covariates.

Results
We analyzed 1547 complete cases of 1842 enrolled participants. According to the WAIC the hierarchical model provided a better fit when compared to the model that does not consider the individual’s province. Values of the index were similarly distributed across the provinces. Overall, past incarceration, education, and unemployment had the highest discriminatory parameters. However, in each province different components of the index were associated with being deprived reflecting local epidemiology. For example, Saskatchewan had the highest severity parameter for Indigenous status while Quebec the lowest. For the secondary analysis, 457 (30%) failed to attend a second visit. A one-unit increase in the index was associated with 17% increased odds (95% credible interval, 2% to 34%) of not attending a second visit. The model with just the index performed better than the model with all the components as covariates in terms of WAIC.

Conclusion
We estimated an individual-level deprivation index in the Canadian Coinfection cohort. The index identified deprivation profiles across different provinces. This index and the methodology used may be useful in studying health and treatment outcomes that are influenced by social disparities in co-infected Canadians. The methodological approach described can be used in other studies with similar characteristics.},
keywords = {Hepatitis C virus, HIV, HIV-HCV co-infection, Injection drug use, People who inject drugs},
pubstate = {published},
tppubtype = {article}
}

@article{A2019,
title = {Liver-related Events in Human Immunodeficiency Virus-infected Persons With Occult Cirrhosis},
author = {Benmassaoud A and Nitulescu R and Pembroke T and Halme AS and Ghali P and Deschenes M and Wong P and Klein MB and Sebastiani G},
url = {https://pubmed.ncbi.nlm.nih.gov/30561558/},
doi = {10.1093/cid/ciy1082},
year = {2019},
date = {2019-09-27},
journal = {Clinical Infectious Diseases},
abstract = {Background: Human immunodeficiency virus (HIV)-infected patients are at increased risk of liver-related mortality. The effect of occult cirrhosis (OcC), defined as preclinical compensated cirrhosis without any clinical findings, on liver-related events is unknown.

Methods: HIV-infected patients from 2 Canadian cohorts underwent transient elastography (TE) examination and were classified as (1) OcC (TE ≥13 kPa with no sign of cirrhosis, including absence of thrombocytopenia and signs of advanced liver disease on ultrasound or gastroscopy); (2) overt cirrhosis (OvC) (TE ≥13 kPa with signs of cirrhosis); or (3) noncirrhotic patients (TE <13 kPa). Incidence and risk factors of liver-related events were investigated through Kaplan-Meier and Cox regression analyses, respectively. We estimated monitoring rates according to screening guidelines for hepatocellular carcinoma (HCC) by OcC and OvC status.

Results: A total of 1092 HIV-infected patients (51% coinfected with hepatitis C virus) were included. Prevalence of OcC and OvC at baseline was 2.7% and 10.7%, respectively. During a median follow-up of 1.8 (interquartile range, 1.5-2.8) years, the incidence of liver-related events in noncirrhosis, OcC, and OvC was 3.4 (95% confidence interval [CI], 1.2-7.3), 34.0 (95% CI, 6.0-104.0), and 37.0 (95% CI, 17.0-69.1) per 1000 person-years, respectively. Baseline OcC (adjusted hazard ratio [aHR], 7.1 [95% CI, 1.3-38.0]) and OvC (aHR, 8.5 [95% CI, 2.8-26.0]) were independently associated with liver-related events. Monitoring rates for HCC were lower in patients with OcC (24%) compared to those with OvC (40%).

Conclusions: HIV-infected patients with OcC have a high incidence of liver-related events. Greater surveillance and earlier recognition with appropriate screening strategies are necessary for improved outcomes.},
keywords = {HCC surveilance, HIV, Liver-related events, Occult cirrhosis, Transient elastography},
pubstate = {published},
tppubtype = {article}
}

@article{S2018,
title = {Real-world impact of direct acting antiviral therapy on health-related quality of life in HIV/Hepatitis C co-infected individuals},
author = {Saeed S and Moodie EEM and Strumpf E and Gill MJ and Wong A and Cooper C and Walmsley S and Hull M and Martel-Laferrière V and Klein MB},
url = {https://pubmed.ncbi.nlm.nih.gov/30141236/},
doi = {10.1111/jvh.12985},
year = {2018},
date = {2018-12-01},
journal = {Journal of Viral Hepatitis},
abstract = {Clinical trial results of direct acting antivirals (DAAs) for the treatment of hepatitis C virus (HCV) have shown improvements in health-related quality of life (HR-QoL). However, the extent to which these results are broadly generalizable to real-world settings is unknown. We investigated the real-world impact of oral DAA therapy on HR-QoL among individuals coinfected with HIV/HCV. We used data from the Canadian HIV/HCV Co-Infection Cohort Study that prospectively follows 1795 participants from 18 centres. Since 2007, clinical, lifestyle, and HR-QoL data have been collected biannually through self-administered questionnaires and chart review. HR-QoL was measured using the EQ-5D instrument. Participants initiating oral DAAs, having at least one visit before treatment initiation and at least one visit after DAA treatment response was ascertained, were included. Successful treatment response was defined as a sustained viral response (SVR). Segmented multivariate linear mixed models were used to evaluate the impact of SVR on HR-QoL, controlling for pretreatment trends. 227 participants met our eligibility criteria, 93% of whom achieved SVR. Before treatment, the EQ-5D utility index decreased 0.6 percentage-point/y (95% CI, -0.9, -0.3) and health state was constant over time. The immediate effect of SVR resulted in an increase of 2.3-units (-0.1, 4.7) in patients' health state and 2.0 percentage-point increase (-0.2, 4.0) in utility index. Health state continued to increase post-SVR by 1.4 units/y (-0.9, 3.7), while utility trends post-SVR plateaued over the observation period. Overall using real-world data, we found modest improvements in HR-QoL following SVR, compared to previously published clinical trials.},
keywords = {Direct acting antivirals (DAAs), EQ-5D, Health-related QOL, Hepatitis C virus, HIV},
pubstate = {published},
tppubtype = {article}
}

@article{T2018b,
title = {Injection drug use, food insecurity, and HIV-HCV co-infection: a longitudinal cohort analysis},
author = {McLinden T and Moodie EEM and Harper S and Hamelin AM and Anema A and Aibibula W and Klein MB and Cox J},
url = {https://pubmed.ncbi.nlm.nih.gov/29716392/},
doi = {10.1080/09540121.2018.1465171},
year = {2018},
date = {2018-10-01},
journal = {AIDS Care},
abstract = {Injection drug use (IDU) and food insecurity (FI) are highly prevalent among individuals living with HIV-hepatitis C virus (HCV) co-infection. We quantified the association between IDU and FI among co-infected individuals using biannual data from the Canadian Co-infection Cohort (N = 608, 2012-2015). IDU (in the past six months) and IDU frequency (non-weekly/weekly in the past month) were self-reported. FI (in the past six months) and FI severity (marginal FI, moderate FI, and severe FI) were measured using the Household Food Security Survey Module. Generalized estimating equations were used to estimate risk ratios (RR) quantifying the associations between IDU, IDU frequency, and FI with Poisson regression. The associations between IDU, IDU frequency, and FI severity were quantified by relative-risk ratios (RRR) estimated with multinomial regression. At the first time-point in the analytical sample, 54% of participants experienced FI in the past six months, 31% engaged in IDU in the six months preceding the FI measure, and 24% injected drugs in the past month. After adjustment for confounding, IDU in the past six months (RR = 1.15, 95% confidence interval [CI] = 1.04-1.28) as well as non-weekly (RR = 1.15, 95% CI = 1.02-1.29) and weekly IDU (RR = 1.21, 95% CI = 1.07-1.37) in the past month are associated with FI. Weekly IDU in the past month is also strongly associated with severe FI (RRR = 2.68, 95% CI = 1.47-4.91). Our findings indicate that there is an association between IDU and FI, particularly weekly IDU and severe FI. This suggests that reductions in IDU may mitigate FI, especially severe FI, in this vulnerable subset of the HIV-positive population.},
keywords = {Food insecurity, Hepatitis C virus, HIV, Injection drug use},
pubstate = {published},
tppubtype = {article}
}

@article{CC2018,
title = {Medication nonadherence, multitablet regimens, and food insecurity are key experiences in the pathway to incomplete HIV suppression},
author = {Almeida-Brasil CC and Moodie EEM and McLinden T and Hamelin AM and Walmsley SL and Rourke SB and Wong A and Klein MB and Cox J},
url = {https://pubmed.ncbi.nlm.nih.gov/29683846/},
doi = {10.1097/QAD.0000000000001822},
year = {2018},
date = {2018-06-19},
journal = {AIDS},
abstract = {Objective: To identify potential pathways by which a variety of factors act to lead to unsuppressed viral load.

Design: A prospective cohort of HIV-HCV co-infected adults receiving care from 18 HIV clinics across Canada was followed every 6 months between November 2012 and October 2015. Participants with at least two visits while receiving combined antiretroviral treatment (cART) were included.

Methods: A path analysis was conducted on the basis of ordered sequences of multivariate logistic regressions using generalized estimating equations. The first regression model used incomplete viral suppression (viral load >50 copies/ml) as the outcome of interest and all other variables (i.e. nonadherence, food insecurity, treatment attributes, and other sociodemographic, behavioural, and clinical factors) as potential predictors. Any variable determined to be a statistically significant predictor of incomplete viral suppression was then used as the next outcome of interest in the subsequent regression, until all predictors of each selected outcome were purely explanatory variables.

Results: A total of 566 participants had at least two visits. Drivers of incomplete viral suppression included injection drug use, age 45 years or less, living alone, poor health status, longer duration of HIV infection and baseline CD4 cell count less than 200 cells/μl. Nonadherence, food insecurity, and the use of multitablet regimens mediated the effects of these factors on incomplete viral suppression.

Conclusion: Our results suggest that nonadherence, multitablet regimens, and food insecurity are key points in the pathway to incomplete HIV suppression. These are potentially amenable intervention targets that would not be revealed using traditional regression analyses.},
keywords = {Food insecurity, HIV, Viral suppression},
pubstate = {published},
tppubtype = {article}
}

@article{T2018,
title = {Methadone treatment, severe food insecurity, and HIV-HCV co-infection: A propensity score matching analysis},
author = {McLinden T and Moodie EEM and Hamelin AM and Harper S and Rossi C and Walmsley SL and Rourke SB and Cooper C and Klein MB and Cox J},
url = {https://pubmed.ncbi.nlm.nih.gov/29544189/},
doi = {10.1016/j.drugalcdep.2017.12.031},
year = {2018},
date = {2018-02-20},
journal = {Drug and Alcohol Dependance},
abstract = {Background: Severe food insecurity (FI) is common among individuals living with HIV-hepatitis C virus (HCV) co-infection. We hypothesize that the injection of opioids is partly responsible for the association between injection drug use and severe FI. Therefore, this analysis examines whether methadone maintenance treatment for opioid dependence is associated with a lower risk of severe FI.

Methods: We used biannual data from the Canadian Co-infection Cohort (N = 608, 2012-2015). Methadone treatment (exposure) was self-reported and severe FI (outcome) was measured using the Household Food Security Survey Module. To quantify the association between methadone treatment and severe FI, we estimated an average treatment effect on the treated (marginal risk difference [RD]) using propensity score matching.

Results: Among participants, 25% experienced severe FI in the six months preceding the first time-point in the analytical sample and 5% concurrently reported receiving methadone treatment. Injection of opioids in the six months preceding the treatment and outcome measurements was much higher among those who received methadone treatment (39% vs. 12%). Among the treated participants, 97% had injected opioids in their lifetimes. After propensity score matching, the average risk of experiencing severe FI is 12.3 percentage-points lower among those receiving methadone treatment, compared to those who are not receiving treatment (marginal RD = -0.123, 95% CI = -0.230, -0.015).

Conclusions: After adjustment for socioeconomic, sociodemographic, behavioural, and clinical confounders, methadone treatment is associated with a lower risk of severe FI. This finding suggests that methadone treatment may mitigate severe FI in this vulnerable subset of the HIV-positive population.},
keywords = {Hepatitis C virus, HIV, Methadone treatment, Propensity score matching, Severe food insecurity},
pubstate = {published},
tppubtype = {article}
}

@article{T2017b,
title = {Injection Drug Use, Unemployment, and Severe Food Insecurity Among HIV-HCV Co-Infected Individuals: A Mediation Analysis},
author = {McLinden T and Moodie EEM and Hamelin AM and Harper S and Walmsley SL and Paradis G and Aibibula W and Klein MB and Cox J},
url = {https://pubmed.ncbi.nlm.nih.gov/28726043/},
doi = {10.1007/s10461-017-1850-2},
year = {2017},
date = {2017-12-01},
journal = {AIDS and Behaviour},
abstract = {Severe food insecurity (FI), which indicates reduced food intake, is common among HIV-hepatitis C virus (HCV) co-infected individuals. Given the importance of unemployment as a proximal risk factor for FI, this mediation analysis examines a potential mechanism through which injection drug use (IDU) is associated with severe FI. We used biannual data from the Canadian Co-infection Cohort (N = 429 with 3 study visits, 2012-2015). IDU in the past 6 months (exposure) and current unemployment (mediator) were self-reported. Severe FI in the following 6 months (outcome) was measured using the Household Food Security Survey Module. An overall association and a controlled direct effect were estimated using marginal structural models. Among participants, 32% engaged in IDU, 78% were unemployed, and 29% experienced severe FI. After adjustment for confounding and addressing censoring through weighting, the overall association (through all potential pathways) between IDU and severe FI was: risk ratio (RR) = 1.69 (95% confidence interval [CI] = 1.15-2.48). The controlled direct effect (the association through all potential pathways except that of unemployment) was: RR = 1.65 (95% CI = 1.08-2.53). We found evidence of an overall association between IDU and severe FI and estimated a controlled direct effect that is suggestive of pathways from IDU to severe FI that are not mediated by unemployment. Specifically, an overall association and a controlled direct effect that are similar in magnitude suggests that the potential impact of IDU on unemployment is not the primary mechanism through which IDU is associated with severe FI. Therefore, while further research is required to understand the mechanisms linking IDU and severe FI, the strong overall association suggests that reductions in IDU may mitigate severe FI in this vulnerable subset of the HIV-positive population.},
keywords = {Hepatitis C virus, HIV, Injection drug use, Severe food insecurity, Unemployment},
pubstate = {published},
tppubtype = {article}
}

@article{J2017,
title = {Risk Factors for Hepatitis C Virus Reinfection After Sustained Virologic Response in Patients Coinfected With HIV},
author = {Young J and Rossi C and Gill J and Walmsley S and Cooper C and Cox J and Martel-Laferriere V and Conway B and Pick N and Vachon ML and Klein MB},
url = {https://pubmed.ncbi.nlm.nih.gov/28199495/},
doi = {10.1093/cid/cix126},
year = {2017},
date = {2017-05-01},
journal = {Clinical Infectious Diseases},
abstract = {Background: Highly effective hepatitis C virus (HCV) therapies have spurred a scale-up of treatment to populations at greater risk of reinfection after sustained virologic response (SVR). Reinfection may be higher in HIV-HCV coinfection, but prior studies have considered small selected populations. We assessed risk factors for reinfection after SVR in a representative cohort of Canadian coinfected patients in clinical care.

Methods: All patients achieving SVR after HCV treatment were followed with HCV RNA measurements every 6 months in a prospective cohort study. We used Bayesian Cox regression to estimate reinfection rates according to patient reported injection drug use (IDU) and sexual activity among men who have sex with men (MSM).

Results: Of 497 patients treated for HCV, 257 achieved SVR and had at least 1 subsequent RNA measurement. During 589 person-years of follow-up (PYFU) after SVR, 18 (7%) became HCV RNA positive. The adjusted reinfection rate (per 1000 PYFU) in the first year after SVR was highest in those who reported high-frequency IDU (58; 95% credible interval [CrI], 18-134) followed by MSM reporting high-risk sexual activity (26; 95% CrI, 6-66) and low-frequency IDU (22; 95% CrI, 4-68). The rate in low-risk MSM (16; 95% CrI, 4-38) was similar to that in reference patients (10; 95% CrI, 4-20). Reinfection rates did not diminish with time.

Conclusions: HCV reinfection rates varied according to risk. Measures are needed to reduce risk behaviors and increase monitoring in high-risk IDU and MSM if HCV elimination targets are to be realized.},
keywords = {Hepatitis C treatment, Hepatitis C virus, HIV, Reinfection, Sustained virologic response},
pubstate = {published},
tppubtype = {article}
}