Research Papers

@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{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{W2018,
title = {Food insecurity may lead to incomplete HIV viral suppression and less immune reconstitution among HIV/hepatitis C virus-coinfected people},
author = {Aibibula W and Cox J and Hamelin AM and Moodie EEM and Naimi AI and McLinden T and Klein MB and Brassard P},
url = {https://pubmed.ncbi.nlm.nih.gov/29094807/},
doi = {10.1111/hiv.12561},
year = {2018},
date = {2018-02-01},
journal = {HIV Medicine},
abstract = {Objectives: The aim of this study was to determine the impact of food insecurity (FI) on HIV viral load and CD4 count among people coinfected with HIV and hepatitis C virus (HCV).

Methods: This study was conducted using data from the Food Security & HIV-HCV Sub-Study of the Canadian Co-Infection Cohort study. FI was measured using the adult scale of Health Canada's Household Food Security Survey Module and was classified into three categories: food security, moderate food insecurity and severe food insecurity. The association between FI, HIV viral load, and CD4 count was assessed using a stabilized inverse probability weighted marginal structural model.

Results: A total of 725 HIV/HCV-coinfected people with 1973 person-visits over 3 years of follow-up contributed to this study. At baseline, 23% of participants experienced moderate food insecurity and 34% experienced severe food insecurity. The proportion of people with undetectable HIV viral load was 75% and the median CD4 count was 460 [interquartile range (IQR): 300-665] cells/μL. People experiencing severe food insecurity had 1.47 times [95% confidence interval (CI): 1.14, 1.88] the risk of having detectable HIV viral load and a 0.91-fold (95% CI: 0.84, 0.98) increase in CD4 count compared with people who were food secure.

Conclusions: These findings provide evidence of the negative impact of food insecurity on HIV viral load and CD4 count among HIV/HCV-coinfected people.},
keywords = {CD4 count, Food insecurity, HIV viral load, HIV-HCV co-infection, Marginal structural models},
pubstate = {published},
tppubtype = {article}
}

@article{W2017b,
title = {Impact of Food Insecurity on Depressive Symptoms Among HIV-HCV Co-infected People},
author = {Aibibula W and Cox J and Hamelin AM and Moodie EEM and Naimi AI and McLinden T and Klein MB and Brassard P},
doi = {10.1007/s10461-017-1942-z},
year = {2017},
date = {2017-12-01},
journal = {AIDS and Behaviour},
abstract = {Food insecurity (FI) is associated with depressive symptoms among HIV mono-infected people. Our objective was to examine to what extent this association holds among HIV-hepatitis C virus (HCV) co-infected people. We used data from a prospective cohort study of HIV-HCV co-infected people in Canada. FI was measured using the ten-item adult scale of Health Canada's Household Food Security Survey Module and was classified into three categories: food secure, moderate FI, and severe FI. Depressive symptoms were measured using the Center for Epidemiologic Studies Depression Scale (CES-D-10) and was classified into absence or presence of depressive symptoms. FI, depressive symptoms, and other covariates were updated every 6 months. The association between FI and depressive symptoms was assessed using a stabilized inverse probability weighted marginal structural model. The study sample included 725 HIV-HCV co-infected people with 1973 person-visits over 3 years of follow up. At baseline, 23% of participants experienced moderate food insecurity, 34% experienced severe food insecurity and 52% had depressive symptoms. People experiencing moderate FI had 1.63 times (95% CI 1.44-1.86) the risk of having depressive symptoms and people experiencing severe FI had 2.01 times (95% CI 1.79-2.25) the risk of having depressive symptoms compared to people who were food secure. FI is a risk factor for developing depressive symptoms among HIV-HCV co-infected people. Food supplementation, psychosocial support and counseling may improve patient health outcomes.},
keywords = {Depression, Food insecurity, HIV-HCV co-infection, Marginal structural models},
pubstate = {published},
tppubtype = {article}
}

@article{S2017,
title = {Disparities in direct acting antivirals uptake in HIV-hepatitis C co-infected populations in Canada},
author = {Saeed S and Strumpf EC and Moodie EEM and Young J and Nitulescu R and Cox J and Wong A and Walmsely S and Cooper C and Vachon ML and Martel-Laferriere V and Hull M and Conway B and Klein MB},
url = {https://pubmed.ncbi.nlm.nih.gov/29116684/},
doi = {10.1002/jia2.25013},
year = {2017},
date = {2017-11-01},
journal = {Journal of the International AIDS Society},
abstract = {Background: Direct acting antivirals (DAAs) have revolutionized hepatitis C (HCV) treatment with >90% cure rates even in real-world studies, giving hope that HCV can be eliminated. However, for DAAs to have a population-level impact on the burden of HCV disease, treatment uptake needs to be expanded. We investigated temporal trends in HCV treatment uptake and evaluated factors associated with second-generation DAA initiation and efficacy among key HIV-HCV co-infected populations in Canada.

Methods: The Canadian HIV-HCV Co-Infection Cohort Study prospectively follows 1699 participants from 18 centres. Among HCV RNA+ participants, we determined the incidence of HCV treatment initiation per year overall and by key populations between 2007 and 2015. Key populations were based on World Health Organization (WHO) guidelines including: people who actively inject drugs (PWID) (reporting injection drug use, last 6 months); Indigenous people; women and men who have sex with men (MSM). Multivariate Cox models were used to estimate adjusted hazard ratios (aHR) and 2-year probability of initiating second-generation DAAs for each of the key populations.

Results: Overall, HCV treatment initiation rates increased from 8 (95% CI, 6-11) /100 person-years in 2013 to 28 (95% CI, 23-33) /100 person-years in 2015. Among 911 HCV RNA + participants, there were 202 second-generation DAA initiations (93% with interferon-free regimens). After adjustment (aHR, 95% CI), active PWID (0.60, 0.38-0.94 compared to people not injecting drugs) and more generally, people with lower income (<$18 000 CAD/year) (0.50, 0.35, 0.71) were less likely to initiate treatment. Conversely, MSM were more likely to initiate 1.95 (1.33, 2.86) compared to heterosexual men. In our cohort, the population profile with the lowest 2-year probability of initiating DAAs was Indigenous, women who inject drugs (5%, 95% CI 3-8%). Not having any of these risk factors resulted in a 35% (95% CI 32-38%) probability of initiating DAA treatment. Sustained virologic response (SVR) rates were >82% in all key populations.

Conclusion: While treatment uptake has increased with the availability of second-generation DAAs, marginalized populations, already engaged in care, are still failing to access treatment. Targeted strategies to address barriers are needed to avoid further health inequities and to maximize the public health impact of DAAs.},
keywords = {Direct acting antivirals (DAAs), Disparities, HIV-HCV co-infection, Indigenous peoples, Men who have sex with men (MSM), People who inject drug (PWID), Women},
pubstate = {published},
tppubtype = {article}
}

@article{T2017,
title = {Hepatic steatosis progresses faster in HIV mono-infected than HIV/HCV co-infected patients and is associated with liver fibrosis},
author = {Pembroke T and Deschenes M and Lebouché B and Benmassaoud A and Sewitch M and Ghali P and Wong P and Halme A and Vuille-Lessard E and Pexos C and Klein MB and Sebastiani G},
url = {https://pubmed.ncbi.nlm.nih.gov/28527666/},
doi = {10.1016/j.jhep.2017.05.011},
year = {2017},
date = {2017-10-01},
journal = {Journal of Hepatology},
abstract = {Background & aims: Hepatic steatosis (HS) seems common in patients infected with human immunodeficiency virus (HIV). However, the relative effect of HIV, as well as hepatitis C virus (HCV) in those co-infected, and the influence of HS on liver fibrosis progression are unclear.

Methods: The LIVEr disease in HIV (LIVEHIV) is a Canadian prospective cohort study using transient elastography and associated controlled attenuation parameter (CAP) to screen for HS and liver fibrosis, in unselected HIV-infected adults. HS progression was defined as development of any grade HS (CAP ⩾248dB/m), or transition to severe HS (CAP >292dB/m), for those with any grade HS at baseline. Fibrosis progression was defined as development of significant liver fibrosis (liver stiffness measurement [LSM] >7.1kPa), or transition to cirrhosis (LSM >12.5kPa) for those with significant liver fibrosis at baseline. Cox regression analysis was used to assess predictors of HS and fibrosis progression.

Results: A prospective cohort study was conducted, which included 726 HIV-infected patients (22.7% HCV co-infected). Prevalence of any grade HS did not differ between HIV mono-infected and HIV/HCV co-infected patients (36.1% vs. 38.6%, respectively). 313 patients were followed for a median of 15.4 (interquartile range 8.5-23.0) months. The rate of HS progression was 37.8 (95% confidence interval [CI] 29.2-49.0) and 21.9 (95% CI 15.6-30.7) per 100 person-years in HIV mono-infection and HIV/HCV co-infection, respectively. HCV co-infection was an independent negative predictor of HS progression (adjusted hazard ratio [aHR] 0.50, 95% CI 0.28-0.89). HS predicted liver fibrosis progression in HIV mono-infection (aHR 4.18, 95% CI 1.21-14.5), but not in HIV/HCV co-infection.

Conclusion: HS progresses faster and is associated with liver fibrosis progression in HIV mono-infection but not in HIV/HCV co-infection. Lay summary: Fatty liver is the most frequent liver disease in Western countries. People living with HIV seem at high risk of fatty liver due to frequent metabolic disorders and the long-term effects of antiretroviral therapy. However, due to the invasiveness of liver biopsy, the traditional method of diagnosing fatty liver, there are few data regarding its frequency in people living with HIV. In this study, we used a non-invasive diagnostic tool to analyze the epidemiology of fatty liver in 726 HIV+ patients. We found that fatty liver affects over one-third of people living with HIV. When followed over time, we found that HIV+ patients without HCV co-infection develop fatty liver more frequently than those co-infected with HCV.},
keywords = {Controlled attenuation parameter, Hepatic steatosis, HIV mono-infection, HIV-HCV co-infection, Incidence, Liver fibrosis, Liver stiffness, Prevalence, Transient elastography},
pubstate = {published},
tppubtype = {article}
}

@article{N2017,
title = {A prognostic model for development of significant liver fibrosis in HIV-hepatitis C co-infection},
author = {Moqueet N and Kanagaratham C and Gill J and Hull M and Walmsley S and Radzioch D and Saeed S and Platt RW and Klein MB},
url = {https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0176282},
year = {2017},
date = {2017-05-03},
journal = {PLOS One},
abstract = {Background
Liver fibrosis progresses rapidly in HIV-Hepatitis C virus (HCV) co-infected individuals partially due to heightened inflammation. Immune markers targeting stages of fibrogenesis could aid in prognosis of fibrosis.

Methods
A case-cohort study was nested in the prospective Canadian Co-infection Cohort (n = 1119). HCV RNA positive individuals without fibrosis, end-stage liver disease or chronic Hepatitis B at baseline (n = 679) were eligible. A random subcohort (n = 236) was selected from those eligible. Pro-fibrogenic markers and Interferon Lambda (IFNL) rs8099917 genotype were measured from first available sample in all fibrosis cases (APRI ≥ 1.5 during follow-up) and the subcohort. We used Cox proportional hazards and compared Model 1 (selected clinical predictors only) to Model 2 (Model 1 plus selected markers) for predicting 3-year risk of liver fibrosis using weighted Harrell’s C and Net Reclassification Improvement indices.

Results
113 individuals developed significant liver fibrosis over 1300 person-years (8.63 per 100 person-years 95% CI: 7.08, 10.60). Model 1 (age, sex, current alcohol use, HIV RNA, baseline APRI, HCV genotype) was nested in model 2, which also included IFNL genotype and IL-8, sICAM-1, RANTES, hsCRP, and sCD14. The C indexes (95% CI) for model 1 vs. model 2 were 0.720 (0.649, 0.791) and 0.756 (0.688, 0.825), respectively. Model 2 classified risk more appropriately (overall net reclassification improvement, p<0.05).

Conclusions
Including IFNL genotype and inflammatory markers IL-8, sICAM-1, RANTES, hs-CRP, and sCD14 enabled better prediction of the 3-year risk of significant liver fibrosis over clinical predictors alone. Whether this modest improvement in prediction justifies their additional cost requires further cost-benefit analyses.},
keywords = {HCV, HIV-HCV co-infection, Liver fibrosis},
pubstate = {published},
tppubtype = {article}
}

@article{Moqueet2016,
title = {Responder Interferon Lambda genotypes are associated with higher risk of liver fibrosis in HIV-Hepatitis C Virus Co-infection},
author = {Nasheed Moqueet and Curtis Cooper and John Gill and Mark Hull and Robert W. Platt and Marina B. Klein},
url = {https://www.ncbi.nlm.nih.gov/pubmed/26984148},
doi = {10.1093/infdis/jiw088},
year = {2016},
date = {2016-07-15},
journal = {The Journal of Infectious Diseases},
abstract = {BACKGROUND:
Liver fibrosis progresses faster in individuals coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Interferon λ3 (IFN-λ3) has both antiviral and proinflammatory properties. Genotypes at IFNL single-nucleotide proteins (SNPs; rs12979860CC and rs8099917TT) are linked to higher HCV clearance, potentially via rs8103142. We examined the relationship between IFN-λ genotypes and significant liver fibrosis in HIV-HCV coinfection.
METHODS:
From the prospective Canadian Co-infection Cohort (n = 1423), HCV RNA-positive participants in whom IFN-λ genotypes were detected and who were free of fibrosis, end-stage liver disease, and chronic hepatitis B at baseline (n = 485) were included. Time to significant fibrosis (defined as an aspartate transaminase level to platelet count ratio index [APRI] of ≥1.5) by IFN-λ genotypes was analyzed using Cox proportional hazards, with adjustment for age, sex, ethnicity, alcohol use, CD4(+) T-cell count, HCV genotype, γ-glutamyl transferase level, and baseline APRI. Haplotype analysis was performed, with adjustment for ethnicity.
RESULTS:
A total of 125 participants developed fibrosis over 1595 person-years (7.84 cases/100 person-years; 95% confidence interval [CI], 6.58-9.34 cases/100 person-years). Each genotype was associated with an increased fibrosis risk, with adjusted hazard ratios of 1.37 (95% CI, .94-2.02) for rs12979860CC, 1.34 (95% CI, .91-1.97) for rs8103142TT, and 1.79 (95% CI, 1.24-2.57) for rs8099917TT. Haplotype TCT was also linked with a higher risk (hazard ratio, 1.14 [95% CI, .73-1.77]).
CONCLUSIONS:
IFN-λ SNPs rs12979860, rs8099917, and rs81013142 were individually linked to higher rates of fibrosis in individuals with HIV-HCV coinfection. IFN-λ genotypes may be useful to target HCV treatments to people who are at higher risk of liver disease.
© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.},
keywords = {HIV-HCV co-infection, IFNL, Liver fibrosis},
pubstate = {published},
tppubtype = {article}
}

@article{MA2016,
title = {Influence of Hepatitis C Virus (HCV) sustained virological response on immunosuppressive Tryptophan catabolism in ART-treated HIV/HCV co-infected patients.},
author = {Jenabian MA and Mehraj V and Costiniuk CT and Vyboh K and Kema I and Rollet K and Ramirez RP and Saeed S and Klein MB and Routy JP},
url = {https://pubmed.ncbi.nlm.nih.gov/26436613/},
doi = {10.1097/QAI.0000000000000859},
year = {2016},
date = {2016-03-01},
journal = {JAIDS},
keywords = {HIV-HCV co-infection, Tryptophan, Virologic response},
pubstate = {published},
tppubtype = {article}
}