Research Papers

@article{R2019,
title = {Variation in hepatitis C virus treatment uptake between Canadian centres in the era of direct-acting antivirals},
author = {Nitulescu R and Young J and Saeed S and Cooper C and Cox J and Martel-Laferriere V and Hull M and Walmsley S and Tyndall MW and Wong A and Klein MB},
url = {https://pubmed.ncbi.nlm.nih.gov/30594080/},
doi = {10.1016/j.drugpo.2018.08.012},
year = {2019},
date = {2019-03-01},
journal = {The International Journal on Drug Policy},
abstract = {Background: Patients co-infected with HIV and hepatitis C virus (HCV) are a priority target for HCV treatment. The simplicity and efficacy of direct-acting antivirals (DAA) should help overcome patient, provider, and structural barriers to scaling up treatment.

Methods: We estimated between-centre variation in DAA treatment uptake among 1734 patients enrolled at the 18 centres of the Canadian Co-Infection Cohort-a prospective cohort of adults co-infected with HIV and HCV. We then compared this variation to that observed during the interferon era. Time to treatment uptake was modeled using a Weibull time-to-event model adjusting for centre and patient characteristics thought to have an impact on treatment initiation in the DAA era.

Results: At the time of administrative censoring (December 31, 2016), 981 cohort participants were eligible for second-generation DAA therapy (HCV RNA positive after November 21, 2013) of whom 278 initiated DAAs (16 patients per 100 person-years). Patients with low monthly income, Indigenous ethnicity, recent injection drug use, HCV genotype 3, or unknown HCV genotype were less likely to start treatment. After adjusting for patient characteristics, the estimated between-centre variance (σ2) was 0.29 (95% credible interval [CrI]: 0.09-0.89), considerably lower than during the interferon era (σ2 = 0.87, 95% CrI: 0.49-1.5). This between-centre variance was further reduced by the addition of centre-level effects for jurisdiction (σ2 = 0.15, 95% CrI: 0.02-0.60).

Conclusion: Much of the variation in treatment uptake between centres can now be attributed to regional differences. This suggests that after the introduction of DAAs, treatment barriers have shifted towards prescribing and reimbursement restrictions based on liver fibrosis, which vary by jurisdiction. The removal of these restrictions, however, will need to be paired with strategies to overcome patient-level barriers, which continue to prevent marginalized people and active substance users from accessing treatment.},
keywords = {Direct acting antivirals (DAAs), Disparities, HIV-HCV co-infection, Treatment barriers, Treatment uptake},
pubstate = {published},
tppubtype = {article}
}

@article{C2019,
title = {Direct-Acting Antiviral Treatment Failure Among Hepatitis C and HIV-Coinfected Patients in Clinical Care},
author = {Rossi C and Young J and Martel-Laferriere V and Walmsley S and Cooper C and Wong A and Gill MJ and Klein MB},
url = {https://pubmed.ncbi.nlm.nih.gov/30882016/},
doi = {10.1093/ofid/ofz055},
year = {2019},
date = {2019-02-13},
journal = {Open Forum Infectious Diseases},
abstract = {Background: There are limited data on the real-world effectiveness of direct-acting antiviral (DAA) treatment in patients coinfected with hepatitis C virus (HCV) and HIV-a population with complex challenges including ongoing substance use, cirrhosis, and other comorbidities. We assessed how patient characteristics and the appropriateness of HCV regimen selection according to guidelines affect treatment outcomes in coinfected patients.

Methods: We included all patients who initiated DAA treatment between November 2013 and July 2017 in the Canadian Co-Infection Cohort. Sustained virologic response (SVR) was defined as an undetectable HCV RNA measured between 10 and 18 weeks post-treatment. We defined treatment failure as virologic failure, relapse, or death without achieving SVR. Bayesian logistic regression was used to estimate the posterior odds ratios (ORs) associated with patient demographic, clinical, and treatment-related risk factors for treatment failure.

Results: Two hundred ninety-five patients initiated DAAs; 31% were treatment-experienced, 29% cirrhotic, and 80% HCV genotype 1. Overall, 92% achieved SVR (263 of 286, 9 unknown), with the highest rates in females (97%) and lowest in cirrhotics (88%) and high-frequency injection drug users (89%). Many patients (38%) were prescribed regimens that were outside current clinical guidelines. This did not appreciably increase the risk of treatment failure-particularly in patients with genotype 1 (prior odds ratio [OR], 1.5; 95% credible interval [CrI], 0.38-6.0; posterior OR, 1.0; 95% CrI, 0.40-2.5).

Conclusions: DAAs were more effective than anticipated in a diverse, real-world coinfected cohort, despite the use of off-label, less efficacious regimens. High-frequency injection drug use and cirrhosis were associated with an increased risk of failure.},
keywords = {Direct acting antivirals (DAAs), Hepatitis C virus, HIV-HCV co-infection, Treatment failure, Treatment guidelines},
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{N2018,
title = {Previous incarceration impacts access to hepatitis C virus (HCV) treatment among HIV-HCV co-infected patients in Canada},
author = {Kronfli N and Nitulescu R and Cox J and Moodie E and Wong A and Cooper C and Gill J and Walmsley S and Martel-Leferriere V and Klein MB},
url = {https://pubmed.ncbi.nlm.nih.gov/30460791/},
doi = {10.1002/jia2.25197},
year = {2018},
date = {2018-11-01},
journal = {Journal of the International AIDS Society},
abstract = {Introduction: The prevalence of hepatitis C virus (HCV) is far higher in prison settings than in the general population; thus, micro-elimination strategies must target people in prison to eliminate HCV. We aimed to examine incarceration patterns and determine whether incarceration impacts HCV treatment uptake among Canadian HIV-HCV co-infected individuals in the direct-acting antiviral (DAA) era.

Methods: The Canadian Co-Infection Cohort prospectively follows HIV-HCV co-infected people from 18 centres. HCV RNA-positive participants with available baseline information on incarceration history were included and followed from 21 November 2013 (when second-generation DAAs were approved by Health Canada) until 30 June 2017. A Cox proportional hazards model was used to assess the effect of time-updated incarceration status on time to treatment uptake, adjusting for patient-level characteristics known to be associated with treatment uptake in the DAA era.

Results: Overall, 1433 participants (1032/72% men) were included; 67% had a history of incarceration and 39% were re-incarcerated at least once. Compared to those never incarcerated, previously incarcerated participants were more likely to be Indigenous, earn <$1500 CAD/month, report current or past injection drug use and have poorly controlled HIV. There were 339 second-generation DAA treatment initiations during follow-up (18/100 person-years). Overall, 48% of participants never incarcerated were treated (27/100 person-years) compared to only 31% of previously incarcerated participants (15/100 person-years). Sustained virologic response (SVR) rates at 12 weeks were 95% and 92% respectively. After adjusting for other factors, participants with a history of incarceration (adjusted hazard ratio (aHR): 0.7, 95% CI: 0.5 to 0.9) were less likely to initiate treatment, as were those with a monthly income <$1500 (aHR: 0.7, 95% CI: 0.5 to 0.9) or who reported current injection drug use (aHR: 0.7, 95% CI: 0.4 to 1.0). Participants with undetectable HIV RNA (aHR: 2.1, 95% CI: 1.6 to 2.9) or significant fibrosis (aHR: 1.5, 95% CI: 1.2 to 1.9) were more likely to initiate treatment.

Conclusions: The majority of HIV-HCV co-infected persons had a history of incarceration. Those previously incarcerated were 30% less likely to access treatment in the DAA era even after accounting for several patient-level characteristics. With SVR rates above 90%, HCV elimination may be possible if treatment is expanded for this vulnerable and neglected group.},
keywords = {Direct acting antivirals (DAAs), Disparities, HCV Elimination, HIV-HCV co-infection, Micro-eliminiation, People in prison},
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{W2018b,
title = {Association between depressive symptoms, CD4 count and HIV viral suppression among HIV-HCV co-infected people},
author = {Aibibula W and Cox J and Hamelin AM and Moodie EEM and Anema A and Klein MB and Brassard P},
url = {https://pubmed.ncbi.nlm.nih.gov/29374972/},
doi = {10.1080/09540121.2018.1431385},
year = {2018},
date = {2018-05-01},
journal = {AIDS Care},
abstract = {Depressive symptoms are associated with poor HIV viral control and immune recovery among people living with HIV. However, no prior studies assessed this association exclusively among people co-infected with HIV-hepatitis C virus (HCV). While people with HIV only and those with HIV-HCV co-infection share many characteristics, co-infected people may become more susceptible to the effects of depressive symptoms on health outcomes. We assessed this association exclusively among people co-infected with HIV-HCV in Canada using data from the Food Security & HIV-HCV Sub-Study (FS Sub-Study) of the Canadian Co-Infection Cohort (CCC). Stabilized inverse probability weighted marginal structural model was used to account for potential time-varying confounders. A total of 725 participants were enrolled between 2012 and 2015. At baseline, 52% of participants reported depressive symptoms, 75% had undetectable HIV viral load, and median CD4 count was 466 (IQR 300-665). People experiencing depressive symptoms had 1.32 times (95% CI: 1.07, 1.63) the risk of having detectable HIV viral load, but had comparable CD4 count to people who did not experience depressive symptoms (fold change of CD4 = 0.96, 95% CI: 0.91, 1.03). Presence of depressive symptoms is a risk factor for incomplete short-term HIV viral suppression among people co-infected with HIV-HCV. Therefore, depressive symptoms screening and related counseling may improve HIV related health outcomes and reduce HIV transmission.},
keywords = {CD4 count, Depressive symptoms, HIV viral load, HIV-HCV co-infection, Marginal structural models},
pubstate = {published},
tppubtype = {article}
}

@article{M2018,
title = {Proteomic fingerprinting in HIV/HCV co-infection reveals serum biomarkers for the diagnosis of fibrosis staging},
author = {Golizeh M and Melendez-Pena CE and Ward BJ and Saeed S and Santamaria C and Conway B and Cooper C and Klein MB and Ndao M},
url = {https://pubmed.ncbi.nlm.nih.gov/29608613/},
doi = {10.1371/journal.pone.0195148},
year = {2018},
date = {2018-04-02},
journal = {PLOS One},
abstract = {Background: Hepatic complications of hepatitis C virus (HCV), including fibrosis and cirrhosis are accelerated in human immunodeficiency virus (HIV)-infected individuals. Although, liver biopsy remains the gold standard for staging HCV-associated liver disease, this test can result in serious complications and is subject to sampling errors. These challenges have prompted a search for non-invasive methods for liver fibrosis staging. To this end, we compared serum proteome profiles at different stages of fibrosis in HIV/HCV co- and HCV mono-infected patients using surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF MS).

Methods: Sera from 83 HIV/HCV co- and 68 HCV mono-infected subjects in 4 stages of fibrosis were tested. Sera were fractionated, randomly applied to protein chip arrays (IMAC, CM10 and H50) and spectra were generated at low and high laser intensities.

Results: Sixteen biomarkers achieved a p value < 0.01 (ROC values > 0.75 or < 0.25) predictive of fibrosis status in co-infected individuals and 14 in mono infected subjects. Five of these candidate biomarkers contributed to both mono- and co-infected subjects. Candidate diagnostic algorithms were created to distinguish between non-fibrotic and fibrotic individuals using a panel of 4 biomarker peaks.

Conclusion: These data suggest that SELDI MS profiling can identify diagnostic serum biomarkers for fibrosis that are both common and distinct in HIV/HCV co-infected and HCV mono-infected individuals.},
keywords = {Fibrosis staging, HIV-HCV co-infection, Proteomics},
pubstate = {published},
tppubtype = {article}
}

@article{C2018,
title = {Hepatitis C virus cure does not impact kidney function decline in HIV co-infected patients},
author = {Rossi C and Saeed S and Cox J and Vachon ML and Martel-Laferrière V and Walmsley SL and Cooper C and Gill MJ and Hull M and Moodie EEM and Klein MB},
url = {https://pubmed.ncbi.nlm.nih.gov/29369156/},
doi = {10.1097/QAD.0000000000001750},
year = {2018},
date = {2018-03-27},
journal = {AIDS},
abstract = {Objective: To examine the impact of sustained virologic response (SVR) and illicit (injection and noninjection) drug use on kidney function among hepatitis C virus (HCV) and HIV co-infected individuals.

Design: Longitudinal observational cohort study of HCV-HIV co-infected patients.

Methods: Data from 1631 patients enrolled in the Canadian Co-Infection Cohort between 2003 and 2016 were analyzed. Patients who achieved SVR were matched 1 : 2 with chronically infected patients using time-dependent propensity scores. Linear regression with generalized estimating equations was used to model differences in estimated glomerular filtration rates (eGFR) between chronic HCV-infected patients and those achieving SVR. The relationship between illicit drug use and eGFR was explored in patients who achieved SVR.

Results: We identified 384 co-infected patients who achieved SVR (53% treated with interferon-free antiviral regimens) and 768 propensity-score matched patients with chronic HCV infection. Most patients were men (78%) and white (87%), with a median age of 51 years (interquartile range: 45-56). During 1767 person-years of follow-up, 4041 eGFR measurements were available for analysis. Annual rates of decline in eGFR were similar between patients with SVR [-1.32 (ml/min per 1.73 m)/year, 95% confidence interval (CI) -1.75 to -0.90] and chronic infection [-1.19 (ml/min per 1.73 m) per year, 95% CI -1.55 to -0.84]. Among SVR patients, recent injection cocaine use was associated with rapid eGFR decline [-2.16 (ml/min per 1.73 m)/year, 95% CI -4.17 to -0.16].

Conclusion: SVR did not reduce the rate of kidney function decline among HCV-HIV co-infected patients. Increased risk of chronic kidney disease in co-infection may not be related to persistent HCV replication but to ongoing injection cocaine use.},
keywords = {Hepatitis C virus, Kidney function, Sustained virologic response},
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}
}