Research Papers

@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{V2017,
title = {Cocaine/crack use is not associated with fibrosis progression measured by AST-to-Platelet Ratio Index in HIV-HCV co-infected patients: a cohort study},
author = {Martel-Laferrière V and Rollet-Kurhajec KC and Cox J and Cooper C and Tyndall M and Rouleau D and Walmsley S and Wong L and Klein MB},
doi = {10.1186/s12879-017-2196-0},
year = {2017},
date = {2017-01-17},
journal = {BMC Infect Dis.},
abstract = {Background: Cocaine and crack use has been associated with HIV and HCV infections, but its consequences on HCV progression have not been well established. We analyzed the impact of cocaine/crack use on liver fibrosis progression in a cohort of HIV-HCV co-infected patients.

Methods: A Canadian multicenter prospective cohort study followed 1238 HIV-HCV co-infected persons every 6 months between 2003 and 2013. Data were analyzed from 573 patients with positive HCV RNA, not on HCV treatment, without significant liver fibrosis (AST-to-Platelet Ratio Index (APRI) <1.5) or history of end-stage liver disease at baseline, and having at least two study visits. Recent cocaine/crack use was defined as use within 6 months of cohort entry. Incidence rates of progression to significant fibrosis (APRI ≥ 1.5) were determined according to recent cocaine/crack use. Cox Proportional Hazards models were used to assess the association between time-updated cocaine/crack use and progression to APRI ≥ 1.5 adjusting for age, sex, HCV duration, baseline ln(APRI), and time-updated alcohol abuse, history of other drug use and CD4+ cell count.

Results: At baseline, 211 persons (37%) were recent cocaine/crack users and 501 (87%) ever used cocaine/crack. Recent users did not differ from non-recent users on gender, age, and CD4+ T-cell count. Over 1599 person-years of follow up (522 PY in recent users, 887 PY in previous users and 190 PY in never users),158 (28%) persons developed significant fibrosis (9.9/100 PY; 95% CI, 8.3-11.4); 56 (27%) recent users (10.7/100 PY; 7.9-13.5), 81 (28%) previous users (9.1/100 PY; 7.1-11.1), and 21 (29%) never users (11.1/100 PY; 6.3-15.8). There was no association between ever having used or time-updated cocaine/crack use and progression to APRI ≥ 1.5 (adjusted HR (95%CI): 0.96 (0.58, 1.57) and 0.88;(0.63-1.25), respectively).

Conclusions: We could not find evidence that cocaine/crack use is associated with progression to advanced liver fibrosis in our prospective study of HIV-HCV co-infected patients.},
keywords = {APRI score, Cocaine, HIV, 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{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{Thorpe2011,
title = {Antiretroviral treatment interruption leads to progression of liver fibrosis in HIV-Hepatitis C virus Co-infection},
author = {Julia Thorpe and Sahar Saeed and Erica E. M. Moodie and Marina B. Klein},
url = {https://www.ncbi.nlm.nih.gov/pubmed/21330904},
doi = {10.1097/QAD.0b013e3283455e4b},
year = {2011},
date = {2011-04-24},
journal = {AIDS},
volume = {25},
number = {7},
pages = {967-975},
abstract = {OBJECTIVE:
Despite potential negative consequences, HIV/hepatitis C virus (HCV) co-infected patients may discontinue antiretroviral treatment (ART) for several reasons. We examined the impact of ART interruption on liver fibrosis progression in co-infected adults, using the aspartate aminotransferase-to-platelet ratio index (APRI) as a surrogate marker of liver fibrosis.
METHOD:
Data were analyzed from a multisite prospective cohort of 541 HIV-HCV co-infected adults. ART interruption was included as a time-updated variable and defined as the cessation of all antiretrovirals for at least 14 days. The primary endpoint was the development of an APRI score at least 1.5. Time-dependent Cox proportional hazards regression and inverse probability-of-treatment weighting (IPTW) in a marginal structural model were used to evaluate the association of baseline and time-varying covariates with developing significant fibrosis.
RESULTS:
Patients were followed for a median of 1.02 years; 10% (n = 53) interrupted ART and 10% (n = 53) developed significant fibrosis. After accounting for potential confounders, including CD4 T-cell count, HIV viral load, baseline APRI score, age and gender, the hazard ratio for ART interruption was 2.52 (95% confidence interval 1.20-5.28). Use of IPTW resulted in a similar effect estimate, suggesting that mediation by time-varying confounders was negligible.
CONCLUSION:
ART interruption was associated with an increased risk of fibrosis progression in HIV-HCV co-infection that was only partially accounted for by HIV viral load and CD4 T-cell counts. Our findings suggest that liver disease progression observed in ART-treated co-infected patients is partly due to the consequences of treatment interruptions.},
keywords = {Antiretroviral therapy, HIV-HCV co-infection, Liver fibrosis},
pubstate = {published},
tppubtype = {article}
}

@article{Al-Mohri2005,
title = {Validation of a simple model for predicting liver fibrosis in HIV/Hepatitis C (HCV) co-infected patients},
author = {Huda Al-Mohri and Curtis Cooper and Tanya Murphy and Marina B. Klein},
url = {https://www.ncbi.nlm.nih.gov/pubmed/16268817},
doi = {10.1111/j.1468-1293.2005.00330.x},
year = {2005},
date = {2005-10-15},
journal = {HIV Med},
volume = {6},
number = {6},
pages = {375-378},
abstract = {OBJECTIVES:
Recently, several models incorporating laboratory measurements have been validated for use as surrogate markers for liver fibrosis in hepatitis C virus (HCV) mono-infection, the simplest of these being the aspartate aminotransferase (AST) to platelet ratio index (APRI). We evaluated how well the APRI predicts significant hepatic fibrosis in patients with HIV/HCV coinfection.
METHODS:
Forty-six HIV/HCV-coinfected patients who underwent liver biopsy and had concomitant laboratory measurements (+/-3 months) were included in the study. Significant fibrosis was defined as F2-F4 using Batt and Ludwig scoring (=3 Ishak). APRI=[(AST/upper limit of normal)/platelet count (10(9)/L)] x 100. We used sas proc logistic (SAS Institute, Cary, NC) to calculate the area under the receiver operating curve (ROC) (AUC). Sensitivities, specificities, positive predictive value (PPV) and negative predictive value (NPV) were compared using cut-offs previously identified in the literature.
RESULTS:
Thirty-three of 46 patients (72%) had significant fibrosis on biopsy. For significant fibrosis, the area under the ROC for the APRI was 0.847+/-0.057. APRI scores >1.5 (the higher cut-off) were 100% specific and 52% sensitive; PPV was 100% and NPV 45%. Scores <0.5 (the lower cut-off) were 82% sensitive and 46% specific in ruling out significant fibrosis (PPV 79%; NPV 50%).
CONCLUSIONS:
A simple model incorporating readily available laboratory data is highly predictive of significant fibrosis in HIV/HCV coinfection and could serve as a biopsy-sparing measure, thus making treatment more accessible for this population.},
keywords = {HIV-HCV co-infection, Liver fibrosis},
pubstate = {published},
tppubtype = {article}
}