Research Papers

@article{G2022b,

title = {Impact of HCV cure on depressive symptoms in the HIV-HCV co-infected population in Canada},

author = {G, Marathe; EEM, Moodie; MJ, Brouillette; C, Lanièce Delaunay; J, Cox; V, Martel-Laferrière; J, Gill; C, Cooper; N, Pick; ML, Vachon, S, Walmsley; MB, Klein; and for the Canadian Co-Infection Cohort Investigators.},

url = {https://pubmed.ncbi.nlm.nih.gov/35789253/},

doi = {10.1093/cid/ciac540},

year  = {2022},

date = {2022-08-01},

journal = {Clinical Infectious Diseases},

abstract = {Background: Depression is common in people living with HIV-HCV, with biological and psychosocial mechanisms at play. Direct acting antivirals (DAA) result in high rates of sustained virologic response (SVR), with minimal side-effects. We assessed the impact of SVR on presence of depressive symptoms in the HIV-HCV co-infected population in Canada during the second-generation DAA era (2013-2020).



Methods: We used data from the Canadian Co-infection Cohort (CCC), a multicentre prospective cohort of people with a HIV and HCV co-infection, and its associated sub-study on food security. Since depression screening was performed only in the sub-study, we predicted Center for Epidemiologic Studies Depression Scale-10 classes in the CCC using a random forest classifier and corrected for misclassification. We included participants who achieved SVR and fit a segmented modified Poisson model using an interrupted time series design, adjusting for time-varying confounders.



Results: We included 470 participants; 58% had predicted depressive symptoms at baseline. The median follow-up was 2.4 years (IQR: 1.0-4.5.) pre-SVR and 1.4 years (IQR: 0.6-2.5) post-SVR. The pre-SVR trend suggested depressive symptoms changed little over time, with no immediate level change at SVR. However, post-SVR trends showed a reduction of 5% per year (risk ratio: 0.95 (95%CI: 0.94-0.96)) in the prevalence of depressive symptoms.



Conclusions: In the DAA era, predicted depressive symptoms declined over time following SVR. These improvements reflect possible changes in biological pathways and/or better general health. If such improvements in depression symptoms are durable, this provides an additional reason for treatment and early cure of HCV.},

keywords = {Depressive symptoms, Direct Acting Antivirals, HCV cure, HIV-HCV co-infection, Sustained virologic response},

pubstate = {published},

tppubtype = {article}

}

@article{N2021,

title = {Liver Fibrosis in Human Immunodeficiency Virus (HIV)-Hepatitis C Virus (HCV) Coinfection Before and After Sustained Virologic Response: What Is the Best Noninvasive Marker for Monitoring Regression?},

author = {N, Kronfli; J, Young; S, Wang; J, Cox; S, Walmsley; M, Hull; C, Cooper; V, Martel-Laferriere; A, Wong; N, Pick; MB, Klein; Canadian Coinfection Cohort Study Investigators.},

url = {https://academic.oup.com/cid/article/73/3/468/5854053?login=false},

doi = {10.1093/cid/ciaa702},

year  = {2021},

date = {2021-08-02},

journal = {Clinical Infectious Diseases},

abstract = {Background: Noninvasive markers of liver fibrosis such as aspartate aminotransferase-to-platelet ratio (APRI) and transient elastography (TE) have largely replaced liver biopsy for staging hepatitis C virus (HCV). As there is little longitudinal data, we compared changes in these markers before and after sustained virologic response (SVR) in human immunodeficiency virus (HIV)-HCV coinfected patients.



Methods: Participants from the Canadian Coinfection Cohort study who achieved SVR after a first treatment with either interferon/ribavirin or direct acting antivirals (DAAs), with at least 1 pre- and posttreatment fibrosis measure were selected. Changes in APRI or TE (DAA era only) were modeled using a generalized additive mixed model, assuming a gamma distribution and adjusting for sex, age at HCV acquisition, duration of HCV infection, and time-dependent body mass index, binge drinking, and detectable HIV RNA.



Results: Of 1981 patients, 151 achieved SVR with interferon and 553 with DAAs; 94 and 382 met inclusion criteria, respectively. In the DAA era, APRI increased (0.03 units/year; 95% credible interval (CrI): -.05, .12) before, declined dramatically during, and then changed minimally (-0.03 units/year; 95% CrI: -.06, .01) after treatment. TE values, however, increased (0.74 kPa/year; 95% CrI: .36, 1.14) before treatment, changed little by the end of treatment, and then declined (-0.55 kPa/year; 95% CrI: -.80, -.31) after SVR.



Conclusions: TE should be the preferred noninvasive tool for monitoring fibrosis regression following cure. Future studies should assess the risk of liver-related outcomes such as hepatocellular carcinoma according to trajectories of fibrosis regression measured using TE to determine if and when it will become safe to discontinue screening.},

keywords = {APRI, Fibrosis regression, HIV-HCV coinfection, Sustained virologic response, Transient elastography},

pubstate = {published},

tppubtype = {article}

}

@article{Kronfli2020,

title = {Liver fibrosis in HIV-Hepatitis C virus (HCV) co-infection before and after sustained virologic response: what is the best non-invasive marker for monitoring regression?},

author = {Nadine Kronfli and Jim Young and Shouao Wang and Joseph Cox and Sharon Walmsley and Mark Hull and Curtis Cooper and Valerie Martel-Laferriere and Alexander Wong and Neora Pick and Marina B Klein and Canadian Co-infection Cohort Study Investigators},

url = {https://pubmed.ncbi.nlm.nih.gov/32504083/},

doi = {10.1093/cid/ciaa702},

year  = {2020},

date = {2020-06-05},

journal = {Clinical Infectious Diseases},

abstract = {Background: Noninvasive markers of liver fibrosis such as aspartate aminotransferase-to-platelet ratio (APRI) and transient elastography (TE) have largely replaced liver biopsy for staging hepatitis C virus (HCV). As there is little longitudinal data, we compared changes in these markers before and after sustained virologic response (SVR) in HIV-HCV coinfected patients.



Methods: Participants from the Canadian Coinfection Cohort study who achieved SVR after a first treatment with either interferon/ribavirin or direct acting antivirals (DAAs), with at least one pre- and post-treatment fibrosis measure were selected. Changes in APRI or TE (DAA era only) were modelled using a generalised additive mixed model, assuming a gamma distribution and adjusting for sex, age at HCV acquisition, duration of HCV infection, and time-dependent BMI, binge drinking and detectable HIV RNA.



Results: Of 1981 patients, 151 achieved SVR with interferon and 553 with DAAs; 94 and 382 met inclusion criteria, respectively. In the DAA era, APRI increased (0.03 units/year; 95% credible interval (CrI): -0.05, 0.12) before, declined dramatically during, and then changed minimally (-0.03 units/year; 95% CrI: -0.06, 0.01) after treatment. TE values, however, increased (0.74 kPa/year; 95% CrI: 0.36, 1.14) before treatment, changed little by the end of treatment, and then declined (-0.55 kPa/year; 95% CrI: -0.80, -0.31) after SVR.



Conclusions: TE should be the preferred non-invasive tool for monitoring fibrosis regression following cure. Future studies should assess the risk of liver-related outcomes such as hepatocellular carcinoma according to trajectories of fibrosis regression measured using TE to determine if and when it will become safe to discontinue screening.},

keywords = {APRI, Fibrosis regression, HIV-HCV co-infection, Sustained virologic response, Transient elastography},

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{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}

}

@article{Yeung2015,

title = {Changes in quality of life, health care use and substance use in HIV- Hepatitis C coinfected patients after Hepatitis C therapy: a prospective Cohort study},

author = {Man Wah Yeung and Jim Young and Erica E. M. Moodie and Kathleen C. Rollet-Kurhajec and Kevin Schwartzman and Christina Greenaway and Curtis Cooper and Joseph Cox and John Gill and Mark Hull and Sharon Walmsley and Marina B. Klein},

url = {https://www.ncbi.nlm.nih.gov/pubmed/25972048},

doi = {10.1179/501100000024},

year  = {2015},

date = {2015-05-14},

journal = {HIV Clinical Trials},

abstract = {OBJECTIVE:

Clinical benefits of achieving a sustained virologic response (SVR) with hepatitis c virus (HCV) therapy beyond reducing liver-related outcomes have not been documented in HIV-coinfected patients, who have multiple competing health problems. To gauge the potential benefits of curing HCV in coinfected people, we examined changes in health-related quality of life (HRQOL), healthcare and substance use, and overall mortality after treatment for HCV Coinfection.

DESIGN:

Prospective multicentre cohort study.

METHODS:

Among patients treated for HCV in the Canadian Coinfection Cohort study, self-reported HRQOL (using the EQ-5D), inpatient and outpatient medical visits, and substance use were assessed before, 6 months and 1 year after completing HCV therapy, comparing SVR-achievers and non-responders. Analysis of covariance and zero-inflated negative binomial regression were used to model the effects of SVR on HRQOL and healthcare use, respectively.

RESULTS:

Of 1145 patients chronically infected with HCV, 223 (19%) received treatment while under follow-up in the cohort and had HRQOL data collected - 86 (36%) achieved SVR, 68 (29%) did not, 30 (13%) had ongoing treatment, and 39 (17%) had unknown responses. Compared to non-responders, those achieving a SVR had higher HRQOL scores over time (11-unit increase 1 year posttreatment, 95% CI: 2, 21 measured 1 year posttreatment) and a lower rate of health service utilization (adjusted incidence rate ratio: 0.5, 95% CI: 0.3, 0.9). Short-term mortality was low but appeared lower in SVR-achievers (incidence rates: 0.10 vs 0.12 deaths per 100 person-years). However, after successful treatment, a substantial number of patients increased alcohol consumption and continued to inject drugs.

CONCLUSIONS:

Successful HCV treatment results in a range of health benefits for HIV/HCV-coinfected patients. Ongoing substance use, however, may mitigate the short- and long-term benefits associated with curing HCV.},

keywords = {HCV virus treatment, Health services, HIV, Mortality, Quality of life, Sustained virologic response},

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}

}