Research Papers

@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{Cox2017,
title = {Food Insecurity in HIV-Hepatitis C Virus Co-infected Individuals in Canada: The Importance of Co-morbidities},
author = {Joseph Cox and Anne-Marie Hamelin and Taylor McLinden and Erica E. M. Moodie and Aranka Anema and Kathleen C. Rollet-Kurhajec and Gilles Paradis and Sean B. Rourke and Sharon Walmsley and Marina B. Klein},
url = {https://www.ncbi.nlm.nih.gov/pubmed/26912217},
doi = {10.1007/s10461-016-1326-9},
year = {2017},
date = {2017-03-15},
journal = {AIDS and Behavior},
abstract = {While research has begun addressing food insecurity (FI) in HIV-positive populations, knowledge regarding FI among individuals living with HIV-hepatitis C virus (HCV) co-infection is limited. This exploratory study examines sociodemographic, socioeconomic, behavioral, and clinical factors associated with FI in a cohort of HIV-HCV co-infected individuals in Canada. We analyzed longitudinal data from the Food Security and HIV-HCV Co-infection Study of the Canadian Co-infection Cohort collected between November 2012-June 2014 at 15 health centres. FI was measured using the Household Food Security Survey Module and classified using Health Canada criteria. Generalized estimating equations were used to assess factors associated with FI. Among 525 participants, 59 % experienced FI at their first study visit (baseline). Protective factors associated with FI (p < 0.05) included: enrolment at a Quebec study site (aOR: 0.42, 95 % CI: 0.27, 0.67), employment (aOR: 0.55, 95 % CI: 0.35, 0.87), and average personal monthly income (aOR per $100 CAD increase: 0.98, 95 % CI: 0.97, 0.99). Risk factors for FI included: recent injection drug use (aOR: 1.98, 95 % CI: 1.33, 2.96), trading away food (aOR: 5.23, 95 % CI: 2.53, 10.81), and recent experiences of depressive symptoms (aOR: 2.11, 95 % CI: 1.48, 3.01). FI is common in this co-infected population. Engagement of co-infected individuals in substance use treatments, harm reduction programs, and mental health services may mitigate FI in this vulnerable subset of the HIV-positive population.},
keywords = {Canada, Co-infection, Food insecurity, HCV, HIV},
pubstate = {published},
tppubtype = {article}
}

@article{LI2016,
title = {Trends in Incidences and Risk Factors for Hepatocellular Carcinoma and Other Liver Events in HIV and Hepatitis C Virus–coinfected Individuals From 2001 to 2014: A Multicohort Study},
author = {Gjærde LI and Shepherd L and Jablonowska E and Lazzarin A and Rougemont M and Darling K and Battegay M and Braun D and Martel-Laferriere V and Lundgren JD and Rockstroh JK and Gill J and Rauch A and Mocroft A and Klein MB and Peters L},
url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996136/},
doi = {10.1093/cid/ciw380},
year = {2016},
date = {2016-06-15},
journal = {Clinical Infectious Diseases},
abstract = {Background. While liver-related deaths in human immunodeficiency virus (HIV) and hepatitis C virus (HCV)–coinfected individuals have declined over the last decade, hepatocellular carcinoma (HCC) may have increased. We describe the epidemiology of HCC and other liver events in a multicohort collaboration of HIV/HCV–coinfected individuals.

Methods. We studied HCV antibody-positive adults with HIV in the EuroSIDA study, the Southern Alberta Clinic Cohort, the Canadian Co-infection Cohort, and the Swiss HIV Cohort study from 2001 to 2014. We calculated the incidence of HCC and other liver events (defined as liver-related deaths or decompensations, excluding HCC) and used Poisson regression to estimate incidence rate ratios.

Results. Our study comprised 7229 HIV/HCV–coinfected individuals (68% male, 90% white). During follow-up, 72 cases of HCC and 375 other liver events occurred, yielding incidence rates of 1.6 (95% confidence interval [CI], 1.3, 2.0) and 8.6 (95% CI, 7.8, 9.5) cases per 1000 person-years of follow-up, respectively. The rate of HCC increased 11% per calendar year (95% CI, 4%, 19%) and decreased 4% for other liver events (95% CI, 2%, 7%), but only the latter remained statistically significant after adjustment for potential confounders. Older age, cirrhosis, and low current CD4 cell count were associated with a higher incidence of both HCC and other liver events.

Conclusions. In HIV/HCV–coinfected individuals, the crude incidence of HCC increased from 2001 to 2014, while other liver events declined. Individuals with cirrhosis or low current CD4 cell count are at highest risk of developing HCC or other liver events.},
keywords = {Cohort study, HCV, Hepatocellular carcinoma, HIV, Liver disease},
pubstate = {published},
tppubtype = {article}
}

@article{Young2016,
title = {Fibroblast growth factor 23: associations with antiretroviral therapy in patients co-infected with HIV and hepatitis C},
author = {James Young and Istvan Mucsi and Kathleen C. Rollet-Kurhajec and Marina B. Klein},
url = {https://www.ncbi.nlm.nih.gov/pubmed/26307135},
doi = {10.1111/hiv.12305},
year = {2016},
date = {2016-05-15},
journal = {HIV Med},
abstract = {OBJECTIVES:
Fibroblast growth factor 23 (FGF23) has been associated with cardiovascular mortality. We estimate associations between the level of plasma FGF23 and exposure to abacavir (ABC) and to other components of antiretroviral therapy in patients co-infected with HIV and hepatitis C.
METHODS:
Both intact and c-terminal FGF23 were measured in plasma using commercial assays for a sub-cohort of 295 patients selected at random from the 1150 patients enrolled in the Canadian Co-infection Cohort. The multiplicative effects of antiretroviral drug exposures and covariates on median FGF23 were then estimated using a hierarchical Bayesian model.
RESULTS:
The median level of intact FGF23 was independent of either past or recent exposure to abacavir, with multiplicative ratios of 1.00 and 1.07, 95% credible intervals 0.90-1.12 and 0.94-1.23, respectively. Median intact FGF23 tended to increase with past use of both nonnucleoside reverse-transcriptase inhibitors and protease inhibitors, but tended to decrease with recent use of either tenofovir, efavirenz or lopinavir. There were no obvious associations between the median level of c-terminal FGF23 and individual drugs or drug classes. Age, female gender, smoking and the aspartate aminotransferase to platelet ratio index were all associated with a higher median c-terminal FGF23 but not with a higher median intact FGF23.
CONCLUSIONS:
The level of FGF23 in plasma was independent of exposure to ABC. Lower levels of intact FGF23 with recent use of tenofovir, efavirenz or lopinavir may reflect their adverse effects on bone and vitamin D metabolism relative to other drugs in their respective drug classes.
© 2015 British HIV Association.},
keywords = {Antiretroviral therapy, Fibroblast growth factor 23, HCV, HIV},
pubstate = {published},
tppubtype = {article}
}

@article{Costiniuk2016,
title = {Tobacco Smoking Is Not Associated With Accelerated Liver Disease in Human Immunodeficiency Virus-Hepatitis C Coinfection: A Longitudinal Cohort Analysis},
author = {Cecilia T. Costiniuk and Laurence Brunet and Kathleen C. Rollet-Kurhajec and Curtis Cooper and Sharon Walmsley and M. John Gill and Valérie Martel-Laferriere and Marina B. Klein},
url = {https://www.ncbi.nlm.nih.gov/pubmed/27047987},
doi = {10.1093/ofid/ofw050},
year = {2016},
date = {2016-03-04},
journal = {Open Forum Infectious Diseases},
abstract = {Background.  Tobacco smoking has been shown to be an independent risk factor for liver fibrosis in hepatitis C virus (HCV) infection in some cross-sectional studies. No longitudinal study has confirmed this relationship, and the effect of tobacco exposure on liver fibrosis in human immunodeficiency virus (HIV)-HCV coinfected individuals is unknown. Methods.  The study population consisted of participants from the Canadian Co-infection Cohort study (CTN 222), a multicenter longitudinal study of HIV-HCV coinfected individuals from 2003 to 2014. Data were analyzed for all participants who did not have significant fibrosis or end-stage liver disease (ESLD) at baseline. The association between time-updated tobacco exposure (ever vs nonsmokers and pack-years) and progression to significant liver fibrosis (defined as an aspartate-to-platelet ratio index [APRI] ≥1.5) or ESLD was assessed by pooled logistic regression. Results.  Of 1072 participants included in the study, 978 (91%) had ever smoked, 817 (76%) were current smokers, and 161 (15%) were previous smokers. Tobacco exposure was not associated with accelerated progression to significant liver fibrosis nor with ESLD when comparing ever vs never smokers (odds ratio [OR] = 1.06, 95% confidence interval [CI], 0.43-1.69 and OR = 1.20, 95% CI, 0.21-2.18, respectively) or increases in pack-years smoked (OR = 1.05, 95% CI, 0.97-1.14 and OR = 0.94, 95% CI, 0.83-1.05, respectively). Both time-updated alcohol use in the previous 6 months and presence of detectable HCV ribonucleic acid were associated with APRI score ≥1.5. Conclusions.  Tobacco exposure does not appear to be associated with accelerated progression of liver disease in this prospective study of HIV-HCV coinfected individuals.},
keywords = {Cohort study, HCV, HIV, Liver disease, Tobacco},
pubstate = {published},
tppubtype = {article}
}

@article{Brunet2016,
title = {Progression of Liver Fibrosis and Modern Combination Antiretroviral Therapy Regimens in HIV-Hepatitis C-Coinfected Persons},
author = {Laurence Brunet and Erica E. M. Moodie and Jim Young and Joseph Cox and Mark Hull and Curtis Cooper and Sharon Walmsley and Valérie Martel-Laferrière and Anita Rachlis and Marina B. Klein},
url = {https://www.ncbi.nlm.nih.gov/pubmed/26400998},
doi = {10.1093/cid/civ838},
year = {2016},
date = {2016-01-15},
journal = {Clinical Infectious Diseases},
abstract = {BACKGROUND:
Liver diseases progress faster in human immunodeficiency virus (HIV)-hepatitis C virus (HCV)-coinfected persons than HIV-monoinfected persons. The aim of this study was to compare rates of liver fibrosis progression (measured by the aspartate-to-platelet ratio index [APRI]) among HIV-HCV-coinfected users of modern protease inhibitor (PI)- and nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens with a backbone of tenofovir/emtricitabine (TDF/FTC) or abacavir/lamivudine (ABC/3TC).
METHODS:
Data from a Canadian multicenter cohort study were analyzed, including 315 HCV polymerase chain reaction-positive persons who initiated antiretroviral therapy with a PI or NNRTI and a backbone containing either TDF/FTC or ABC/3TC. Multivariate linear regression analyses with generalized estimating equations were performed after propensity score matching to balance covariates across classes of anchor agent.
RESULTS:
A backbone of TDF/FTC was received by 67% of PI users and 69% of NNRTI users. Both PI and NNRTI use was associated with increases in APRI over time when paired with a backbone of ABC/3TC: 16% per 5 years (95% confidence interval [CI], 4%, 29%) and 11% per 5 years (95% CI, 2%, 20%), respectively. With TDF/FTC use, no clear association was found among PI users (8% per 5 years, 95% CI, -3%, 19%) or NNRTI users (3% per 5 years, 95% CI, -7%, 12%).
CONCLUSIONS:
Liver fibrosis progression was more influenced by the backbone than by the class of anchor agent in HIV-HCV-coinfected persons. Only ABC/3TC-containing regimens were associated with an increase of APRI score over time, regardless of the class of anchor agent used.
© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America.

},
keywords = {APRI, Combination antiretroviral therapy, HCV, HIV, Liver fibrosis},
pubstate = {published},
tppubtype = {article}
}

@article{Brunet2016,
title = {Opioid use and risk of liver fibrosis in HIV/hepatitis C virus-coinfected patients in Canada},
author = {Laurence Brunet and Erica E. M. Moodie and Joseph Cox and John Gill and Curtis Cooper and Sharon Walmsley and Anita Rachlis and Mark Hull and Marina B. Klein},
url = {https://www.ncbi.nlm.nih.gov/pubmed/26140381},
doi = {10.1111/hiv.12279},
year = {2016},
date = {2016-01-05},
journal = {HIV Med},
abstract = {OBJECTIVES:
Opioid use and opioid-related mortality have increased dramatically since the 1990s in North America. The effect of opioids on the liver is incompletely understood. Some studies have suggested that opioids cause liver damage and others have failed to show any harm. HIV/hepatitis C virus (HCV)-coinfected persons may be particularly vulnerable to factors increasing liver fibrosis. We aimed to describe opioid use in an HIV/HCV-coinfected population in Canada and to estimate the association between opioid use and liver fibrosis.
METHODS:
We conducted a cross-sectional descriptive analysis of the Canadian Co-infection Cohort Study data to characterize opioid use. We then conducted a longitudinal analysis to assess the average change in aspartate aminotransferase-to-platelet ratio index (APRI) score associated with opioid use using a generalized estimating equation with linear regression. We assessed the progression to significant liver fibrosis (APRI ≥ 1.5) associated with opioid use with pooled logistic regression.
RESULTS:
In the 6 months preceding cohort entry, 32% of the participants had received an opioid prescription, 28% had used opioids illicitly and 18% had both received a prescription and used opioids illicitly. Neither prescribed nor illicit opioid use was associated with a change in the median APRI score [exp(β) 0.99 (95% confidence interval (CI) 0.82, 1.12) and exp(β) 0.95 (95% CI 0.81, 1.10), respectively] or with faster progression to liver fibrosis [hazard odds ratio (HOR) 1.20 (95% CI 0.73, 1.67) and HOR 1.09 (95% CI 0.63, 1.55), respectively].
CONCLUSIONS:
Although opioids were commonly used both legally and illegally in our cohort, we were unable to demonstrate a negative impact on liver fibrosis progression.
© 2015 British HIV Association.},
keywords = {HCV, HIV, Liver fibrosis, Opioids},
pubstate = {published},
tppubtype = {article}
}

@article{Moqueet2015,
title = {Favourable IFNL3 Genotypes Are Associated with Spontaneous Clearance and are Differentially Distributed in Aboriginals in Canadian HIV-Hepatitis C Co-Infected Individuals},
author = {Nasheed Moqueet and Claire Infante-Rivard and Robert W. Platt and Jim Young and Curtis Cooper and Mark Hull and Sharon Walmsley and Marina B. Klein},
editor = {Tatsuo Kanda},
url = {https://www.ncbi.nlm.nih.gov/pubmed/25803108},
doi = {10.3390/ijms16036496},
year = {2015},
date = {2015-03-20},
journal = {International Journal of Molecular Sciences},
abstract = {Background
In Hepatitis C virus (HCV) mono-infection, male sex is associated with faster liver fibrosis progression but the effects of sex have not been well studied in HIV-HCV co-infected patients. We examined the influence of sex on progression to significant liver fibrosis in HIV-HCV co-infected adults receiving antiretroviral therapy (ART) using the aspartate aminotransferase-to-platelet ratio index (APRI) as a surrogate biomarker of liver fibrosis.

Methods
We evaluated 308 HIV infected, HCV RNA positive participants of a Canadian multicentre prospective Cohort receiving antiretrovirals and without significant liver fibrosis or End-stage liver disease at baseline. We used multivariate discrete-time proportional hazards models to assess the effect of sex on time to significant fibrosis (APRI≥1.5) adjusting for baseline age, alcohol use, cigarette smoking, HCV duration, and APRI and time-updated CD4 count and HIV RNA.

Results
Overall, 55 (18%) participants developed an APRI ≥ 1.5 over 544 person-years of at-risk follow-up time; 18 (21%) women (incidence rate (IR)=14.0/100 PY; 7.5-20.4) and 37 (17%) men (IR=8.9/100 PY; 6.0-11.8). Women had more favourable profiles with respect to traditional risk factors for liver disease progression (younger, shorter duration of HCV infection and less alcohol use). Despite this, female sex was associated with a greater than two-fold increased risk of fibrosis progression (adjusted hazard rate (HR) =2.23; 1.22-4.08).

Conclusions
HIV-HCV co-infected women receiving antiretroviral therapy were at significantly greater risk of progressing to liver fibrosis as measured by APRI compared with men. Enhanced efforts to engage and treat co-infected women for HCV are needed.},
keywords = {Aboriginals, Genetic factors, HCV, HCV spontaneous clearance, HIV-HCV co-infection, Interferon lambda 3},
pubstate = {published},
tppubtype = {article}
}

@article{Cooper2015,
title = {HIV virological rebounds but not blips predict liver fibrosis progression in antiretroviral-treated HIV/hepatitis C virus-coinfected patients},
author = {Curtis Cooper and Kathleen C. Rollet-Kurhajec and Jim Young and Colins Vasquez and Mark Tyndall and John Gill and Neora Pick and Sharon Walmsley and Marina B. Klein},
url = {https://www.ncbi.nlm.nih.gov/pubmed/24837567},
doi = {10.1111/hiv.12168},
year = {2015},
date = {2015-01-15},
journal = {HIV Med},
volume = {16},
number = {1},
pages = {24-31},
abstract = {OBJECTIVES:
Antiretroviral interruption is associated with liver fibrosis progression in HIV/hepatitis C virus (HCV) coinfection. It is not known what level of HIV viraemia affects fibrosis progression.
METHODS:
We evaluated 288 HIV/HCV-coinfected cohort participants with undetectable HIV RNA (<50 HIV-1 RNA copies/mL) on two consecutive visits while on combination antiretroviral therapy (cART) without fibrosis [aspartate aminotransferase to platelet ratio index (APRI) <1.5], end-stage liver disease or HCV therapy. An HIV blip was defined as a viral load of ≥ 50 and <1000 copies/mL, preceded and followed by undetectable values. HIV rebound was defined as: (i) HIV RNA ≥ 50 copies/mL on two consecutive visits, or (ii) a single HIV RNA measurement ≥ 1000 copies/mL. Multivariate discrete-time proportional hazards models were used to assess the effect of different viraemia levels on liver fibrosis progression (APRI ≥ 1.5).
RESULTS:
The mean age of the patients was 45 years, 74% were male, 81% reported a history of injecting drug use, 51% currently used alcohol and the median baseline CD4 count was 440 [interquartile range (IQR) 298, 609] cells/μL. Fifty-seven (20%) participants [12.4/100 person-years (PY); 95% confidence interval (CI) 9.2-15.7/100 PY] progressed to an APRI ≥ 1.5 over a mean 1.1 (IQR 0.6, 2.0) years of follow-up time at risk. Virological rebound [hazard ratio (HR) 2.3; 95% CI 1.1, 4.7] but not blips (HR 0.5; 95% CI 0.2, 1.1) predicted progression to APRI ≥ 1.5. Each additional 1 log10 copies/mL HIV RNA exposure (cumulative) was associated with a 20% increase in the risk of fibrosis progression (HR 1.2; 95% CI 1.0-1.3).
CONCLUSIONS:
Liver fibrosis progression was associated with HIV rebound, but not blips, and with increasing cumulative exposure to HIV RNA, highlighting the importance of achieving and maintaining HIV suppression in the setting of HIV/HCV coinfection.
© 2014 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.},
keywords = {Fibrosis, HCV, HIV, Virological blips, Virological rebound},
pubstate = {published},
tppubtype = {article}
}

@article{Kared2014,
title = {CD127 Expression, Exhaustion Status and Antigen Specific Proliferation Predict Sustained Virologic Response to IFN in HCV/HIV Co-Infected Individuals},
author = {Hassen Kared and Sahar Saeed and Marina B. Klein and Naglaa H. Shoukry},
url = {https://www.ncbi.nlm.nih.gov/pubmed/25007250},
doi = {10.1371/journal.pone.0101441},
year = {2014},
date = {2014-07-09},
journal = {PLoS One},
volume = {9},
number = {7},
abstract = {Hepatitis C virus (HCV) infection is a major cause of morbidity and mortality in the HIV co-infected population. Interferon-alpha (IFN-α) remains a major component of anti-HCV therapy despite its deleterious effects on the immune system. Furthermore, IFN-α was recently shown to diminish the size of the latent HIV reservoir. The objectives of this study were to monitor the impact of IFN-α on T cell phenotype and proliferation of HIV and HCV-specific T cells during IFN therapy, and to identify immune markers that can predict the response to IFN in HICV/HIV co-infected patients. We performed longitudinal analyses of T cell numbers, phenotype and function in co-infected patients undergoing IFN-α therapy with different outcomes including IFN-α non-responders (NR) (n = 9) and patients who achieved sustained virologic response (SVR) (n = 19). We examined the expression of activation (CD38, HLA-DR), functional (CD127) and exhaustion markers (PD1, Tim-3, CD160 and CD244) on total CD4 and CD8 T cells before, during and after therapy. In addition, we examined the HIV- and HCV-specific proliferative responses against HIV-p24 and HCV-NS3 proteins. Frequencies of CD127+ CD4 T cells were higher in SVR than in NR patients at baseline. An increase in CD127 expression on CD8 T cells was observed after IFN-α therapy in all patients. In addition, CD8 T cells from NR patients expressed a higher exhaustion status at baseline. Finally, SVR patients exhibited higher proliferative response against both HIV and HCV antigens at baseline. Altogether, SVR correlated with higher expression of CD127, lower T cell exhaustion status and better HIV and HCV proliferative responses at baseline. Such factors might be used as non-invasive methods to predict the success of IFN-based therapies in co-infected individuals.},
keywords = {HCV, HIV-HCV co-infection, Interferon alpha, Mortality, Sustained virologic response},
pubstate = {published},
tppubtype = {article}
}