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Abstract

Background

Psychiatric illness was a major barrier for HCV treatment during the Interferon (IFN) treatment era due to neuropsychiatric side effects. While direct acting antivirals (DAA) are better tolerated, patient-level barriers persist. We aimed to assess the effect of depressive symptoms on time to HCV treatment initiation among HIV–HCV co-infected persons during the IFN (2003–2011) and second-generation DAA (2013–2020) eras.

Methods

We used data from the Canadian Co-infection Cohort, a multicentre prospective cohort, and its associated sub-study on Food Security (FS). We predicted Center for Epidemiologic Studies Depression Scale-10 (CES-D-10) classes for depressive symptoms indicative of a depression risk using a random forest classifier and corrected for misclassification using predictive value-based record-level correction. We used marginal structural Cox proportional hazards models with inverse weighting for competing risks (death) to assess the effect of depressive symptoms on treatment initiation among HCV RNA-positive participants.

Results

We included 590 and 1127 participants in the IFN and DAA eras. The treatment initiation rate increased from 9 (95% confidence interval (CI): 7–10) to 21 (95% CI: 19–22) per 100 person-years from the IFN to DAA era. Treatment initiation was lower among those with depressive symptoms compared to those without in the IFN era (hazard ratio: 0.81 (95% CI: 0.69–0.95)) and was higher in the DAA era (1.19 (95% CI: 1.10–1.27)).

Conclusion

Depressive symptoms no longer appear to be a barrier to HCV treatment initiation in the co-infected population in the DAA era. The higher rate of treatment initiation in individuals with depressive symptoms suggests those previously unable to tolerate IFN are now accessing treatment.

Background

Treatment for Hepatitis C Virus (HCV) has evolved over time, from less effective interferon (IFN)-based regimens to direct acting antiviral (DAA) regimens with cure rates of > 95% in real-world settings, including among HIV–HCV co-infected patients [1–4]. IFN-based treatment regimens were long (lasting 1 year) with weekly injections and had low response rates (on average 30%) and many unpleasant side effects including serious neuropsychiatric outcomes such as mild to severe depression [5,6]. Up to 35% of patients treated with IFN-ribavirin based regimens developed depression [7,8]. Due to these side effects, IFN treatment was relatively contraindicated for patients with current or past major psychiatric illness. Consequently, IFN-based regimens were often not prescribed to those with depression, leading to low treatment rates in this population [9]. Treatment emergent depression was of particular concern among people living with HIV as depressive symptoms are associated with decreased adherence to HIV medication; thus, modifying the risk-benefit analysis of HCV treatment towards a more conservative approach [10–13]. The second-generation DAA regimens are shorter (8–12 weeks) and have very few adverse effects [14]. Importantly, DAAs have shown few if any psychiatric side effects thus far. Thus, treatment guidelines for HCV have been updated and the presence of current or past psychiatric illness is no longer considered a relative contraindication for treatment [15,16].

A study in the Canadian Co-infection cohort suggested an almost threefold increase (8–28 per 100 person-years) in treatment initiation in the HIV–HCV co-infected population after the second-generation DAAs were licensed in Canada in 2013 [17]. However, treatment initiation rates were lower among people who actively inject drugs, women, and Indigenous populations (5–12 per 100 person-years) compared with other co-infected people [17]. Thus, despite the advantages of the new regimens, treatment initiation is still not the same across subgroups posing a threat to HCV elimination goals [14]. Patient- and system-level barriers exist; psychiatric illness, including depression, could be one such barrier.

There is a high prevalence of depression (20–30%) among people living with HIV. Similarly, 24% of those with chronic HCV infection experience depression [18-21]. Both biological and psychosocial mechanisms are at play [18,22]. Prevalence of depression is reported to be even higher in the co-infected population, which may be due to the co-existence of risk factors and neuropsychiatric effects of both HIV and HCV [23]. The presence of significant depressive symptoms could have an impact on clinical outcomes in patients, even when not meeting diagnostic criteria for major depression.

Studies in both the IFN and DAA eras conducted in people with chronic HCV infection have found psychiatric illness among the barriers to linkage to care, treatment initiation and adherence [9], [24–27]. Whether depressive symptoms continue to prevent treatment initiation in the second-generation DAA era is unknown, especially in the co-infected population, which has higher prevalence of depression. The major improvements in HCV treatment safety increase the opportunity to treat people with psychiatric illness and hence we hypothesized improved tolerability would lead to an increase in treatment initiation in this group. Thus, in this study, we evaluated the effect of depressive symptoms on time to HCV treatment initiation comparing the IFN (2003–2011) and second-generation DAA eras (2013–2020) in the HIV–HCV co-infected population in Canada.

Methods

Study population

We used data from the Canadian Co-Infection Cohort (CCC), an open multicentre prospective cohort study, ongoing since 2003. The study has been described in detail elsewhere [28]. Briefly, the CCC recruits from 18 HIV urban and semi-urban centres across six Canadian provinces (Quebec, British Columbia, Alberta, Ontario, Nova Scotia, and Saskatchewan). Eligibility criteria include ≥16 years of age, documented HIV infection, and evidence of HCV infection (HCV RNA positive and/or HCV seropositive). The study had recruited 2018 participants as of July 2020. Participants are followed longitudinally, with follow-up visits every 6 months. Sociodemographic and behavioural data are collected from participants by a standardized self-administered questionnaire at each visit. Clinical data including HIV and HCV treatment dates, medications, co-morbidities, and psychiatric diagnoses are collected via medical chart reviews and HIV- and HCV-related blood tests performed.

In addition, we used data from an associated sub-study within the CCC, the Food Security and HIV–HCV co-infection study (FS sub-study), to predict the presence of depressive symptoms in the CCC as a whole. Participants for the FS sub-study were recruited from the CCC (n=725) with a maximum of 5 visits integrated into the CCC visits. In the sub-study, fully described in detail elsewhere [29], depression screening was performed using the Center for Epidemiologic Studies Depression Scale-10 (CES-D-10) that assesses presence and severity of depressive symptoms in the past week. [30]. The scale has 8 items focusing on negative symptoms like feeling restless, fearful, and lonely, feeling bothered by things that usually would not bother you and not being able to concentrate. The remaining two items focus on positive symptoms like feeling hopeful about the future and being happy. Each item is measured on a 4-point scale, with reverse scoring for the positive items; score ≥10 is widely considered to represent the presence of depressive symptoms which can be used to identify patients at higher risk for having clinical depression; this cutoff of 10 has been validated in HIV populations in Canada [30–32].

Definition of treatment eras and follow-up

The IFN era was defined as the beginning of the CCC on 28 April 2003, until 1 August 2011, when the first generation DAA, boceprevir, was approved for use by Health Canada. The IFN-free DAA era began at the time that the first second-generation DAA, simeprevir, was approved for use by Health Canada on 25 November 2013, and continued until end of study period, 15 July 2020. We excluded the period between 2011 and 2013 in this analysis, because IFN regimens were used widely in combination with the first generation DAA regimens.

Participants were included in the analysis for the IFN era if eligible for treatment, that is, if they tested HCV RNA positive on or after 28 April 2003. Participants were then followed from their first documented positive HCV RNA test in this period (time zero) until treatment initiation or until censoring due to loss to follow-up (no visit for 18 months since last visit), withdrawal, death or end of the study period (1 August 2011). Participants were included in the analysis for the DAA era if eligible for second-generation DAA treatment initiation, that is, i.e. if they tested HCV RNA positive on or after 25 November 2013. Participants were excluded if they were accessing DAAs through a clinical trial or were treated with IFN. Participants were then followed from their HCV RNA positive test date in this period until second-generation DAA treatment initiation or until censoring due to loss to follow-up, withdrawal, death or end of the study period (15 July 2020). Participants from the IFN era who remained HCV RNA positive by 1 August 2011 were included in the DAA era analysis if they were still being followed in the CCC and were HCV RNA positive on 25 November 2013.

Measurement

Exposure

The exposure of interest was presence of depressive symptoms indicative of being at risk for clinical depression, hereafter called depressive symptoms for brevity. CCC participants are not screened for depression during baseline or follow-up. As described earlier, depression screening was however performed in the FS sub-study. Thus, to obtain a measure of depressive symptoms in the full CCC, we developed a random forest (RF) classifier using the CES-D-10 to classify presence/absence of depressive symptoms derived from the FS sub-study as the outcome (target of prediction) and sociodemographic, behavioural, and clinical characteristics from the parent CCC as predictors [33]. The details of the RF classifier development are in Appendix A in the Additional file 1. Using this RF classifier, the CES-D-10 score ≥10 (presence of depressive symptoms) was predicted for each CCC visit included in this analysis. We addressed exposure misclassification for the predicted depressive symptoms using the predictive value-based record-level correction method [34]. In this method, we applied the positive predictive value (PPV) and negative predictive value (NPV) estimated for the RF algorithm; PPV: 0.74 (95% CI: 0.68–0.80) and NPV: 0.76 (95% CI: 0.69–0.82). The procedure included simulation of corrected exposure at each visit by repeated Bernoulli trials with probability equal to PPV for those classified as CES-D-10 class=1 and 1-NPV for those classified as CES-D-10 class=0 ³⁴.

Outcome

The outcome of interest was time to HCV treatment initiation in each era. The date of treatment initiation in both eras was measured at each visit using exact treatment start and stop dates obtained via medical chart reviews.

Confounders

We considered both baseline and time-varying confounders in this analysis, which were selected a priori based on prior literature, as illustrated in the Directed Acyclic Graph (DAG) shown in Figure 1. The baseline confounders included age, gender, race/ethnicity, education level, sexual orientation, previous HCV treatment, immigration status (as a proxy for possible system related factors like medical insurance), marital status and province (as a proxy for sociodemographic characteristics and changes in treatment policies over time). The time-varying confounders measured at each biannual visit included living situation, employment status, monthly income, revenue source, current injection drug use, current alcohol use, current smoking status, incarceration in the past 6 months, advanced fibrosis/cirrhosis (measured by the AST to Platelet Ratio Index (APRI)≥1.5), detectable HIV viral load (>50 copies/ml), low CD4 cell count (≤250 cells/μl) and antidepressant use. We conducted multiple imputation by chained equations (MICE) to address the missing data in the baseline and time-varying confounders [35,36], as at least one confounder value was missing in >20% of the included visits in both eras. We created five imputed datasets using linear regression to impute continuous variables, logistic regression for binary variables and multinomial logistic regression for nominal categorical variables.

Figure 1:

Directed Acyclic Graph for effect of depressive symptoms on HCV treatment initiation.

Statistical analysis

Primary analysis

We estimated the overall treatment initiation rates per 100 person-years in both the IFN and DAA eras. To determine the effect of predicted depressive symptoms on time to treatment initiation, we developed models separately for each era. We fit all models with and without exposure misclassification correction.

First, we developed conventional Cox proportional hazards (Cox PH) model and obtained hazard ratios with 95% confidence intervals (CI), adjusting for baseline and time-varying confounders. The proportionality assumption was assessed by scaled Schoenfeld residuals using a test for zero slope [37, 38]. Conventional Cox PH models can yield biased estimators if time-varying covariates act as confounders and mediators simultaneously; that is, if the covariate predicts HCV treatment initiation (outcome) and subsequent presence of depressive symptoms (exposure), but past presence of depressive symptoms predicts subsequent level of the covariate; DAG in Figure 1 [39]. Thus, we developed marginal structural Cox PH models (MSCM) to address this issue of time-varying confounding [39,40]. In this method, stabilized inverse probability treatment weights (IPTW) were constructed (details in appendix B in the Additional file 1) [41]. The IPTWs were incorporated in the Cox PH model to obtain the hazard ratio estimates with 95% CIs.

Finally, we needed to consider possible competing risks, specifically deaths due to liver disease, drug overdose or other reasons. In a CCC analysis for the time-period 2013–2017, overall death rates were found to be high, with rates of 23.8 per 1000 person-years (PY) for those aged 20–49 years and 38.3 per 1000 PY among those 50–80 years of age [42]. A naïve survival analysis would censor individuals at death and assume independence of censoring and event times. This assumption is unlikely to be met in this population [43,44]. To account for death as a competing risk, we calculated inverse probability censoring weights (IPCW) (details in appendix B in the Additional file 1). We calculated the final weights as the product of IPTW and IPCW and incorporated them in the MSCM model to obtain hazard ratio estimates with 95% CIs.

Secondary analyses

We conducted two planned secondary analyses to assess the robustness of the results. First, we used a restricted subset of participants from the FS sub-study from 2012–2015, majority of which was in the second-generation DAA era, in which measured CES-D-10 scores were available, to measure the effect of exposure misclassification due to the use of predicted depressive symptoms in models. The model development was as in the primary analysis. Second, we a used a time-fixed exposure at each visit, that is, baseline predicted CES-D-10 class and developed the conventional Cox models for the IFN and DAA eras separately.

Results

Participant characteristics

The flowcharts for participants included in the final analytical samples are shown in Figure 2A—IFN era, and 2B—DAA era. We included 590 and 1127 of HCV RNA-positive participants in the IFN and DAA eras, respectively. The baseline characteristics of the participants are shown in Table 1. The baseline prevalence of predicted depressive symptoms was high in both the IFN (55%) and DAA (60%) eras. Participants in both IFN and DAA eras were both predominantly male (77%; 70%) and not employed (70%; 68%). In the DAA era, there were comparatively higher proportions of Indigenous participants (29% vs. 10%), current injection drug users (44% vs. 31%), those recently incarcerated (16% vs 8%) and those with lower levels of education (73% vs. 68% with no post-secondary education) compared with the IFN era, hence more potential barriers to HCV care. A small proportion of the participants in the IFN era (14%) and DAA era (11%) were receiving antidepressants; however, whether they were prescribed for depression or for other disorders was not known.

Figure 2:

Flowcharts of participants included in the analytical samples—A. IFN era (2003–2011) and B. DAA era (2013–2020). Abbreviations: IFN: Interferon; HCV: Hepatitis C virus; DAA: Direct acting antivirals; peg-IFN: Pegylated interferon; CCC: Canadian Co-infection Cohort.

Table 1.

Baseline characteristics for participants included from IFN and DAA eras.

Baseline characteristic	IFN era (2003–2011)	DAA era (2013–2020)
Baseline characteristic	Participants (n = 590) n (%) or median (IQR)	Participants (n = 1127) n (%) or median (IQR)
Predicted CES-D-10 class—1: Score≥10	325 (55)	678 (60)
Age (years)	45 (40–50)	45 (38–51)
Gender—male	456 (77)	786 (70)
Race/ethnicity	—	—
White	472 (80)	722 (64)
Indigenous (First Nations, Inuit, and Metis)	59 (10)	324 (29)
Asian	13 (2)	18 (2)
Black	27 (5)	36 (3)
Hispanic/Latino	9 (2)	20 (2)
Living situation —homeless	60 (10)	122 (11)
Education—high school educated and less	401 (68)	827 (73)
Employment—not employed	413 (70)	769 (68)
Monthly income—≤$1500 CAD	430 (73)	876 (78)
Revenue source—welfare	265 (45)	561 (50)
Sexual orientation—heterosexual	418 (71)	792 (70)
Immigrant to Canada	65 (11)	92 (8)
Marital status—single	376 (64)	787 (70)
Previous IFN-based HCV treatment	96 (16)	154 (14)
Injection drug use in the past 6 months	184 (31)	490 (44)
Alcohol use in the past 6 months	313 (53)	543 (48)
Smoking in the past 6 months	430 (73)	847 (75)
Incarceration in the past 6 months	49 (8)	176 (16)
Fibrosis stage (e.g. APRI)≥1.5	143 (24)	192 (17)
HIV viral load >50 copies/ml	209 (35)	358 (32)
CD4 count - ≤250 cells/uL	153 (26)	266 (24)
Antidepressant prescribed	81 (14)	120 (11)

Abbreviations: IFN, Interferon; DAA, Direct acting antivirals; IQR, Interquartile range; CES-D-10, Center for Epidemiologic Studies Depression Scale-10; CAD, Canadian dollar; HCV, Hepatitis C virus; APRI, AST to Platelet Ratio Index; HIV, Human Immunodeficiency Virus; CD4, Cluster of differentiation 4 receptor.

Primary analyses

There were 126 and 566 treatment initiations with median follow-up times of 2.3 years (range: 0.02–8.3 years) and 2.0 years (range: 0.01–6.6 years) in the IFN and DAA eras, respectively. The overall treatment initiation rate increased from 9 (95% CI: 7–10) per 100 person-years (PY) in the IFN era to 21 (95% CI: 19–22) per 100 PY in the DAA era. The primary analyses results are shown in Table 2. There was no evidence to suggest the proportionality assumption was violated. The hazard ratios were similar across the three primary models in each era. In the IFN era, the MSCM model accounting for competing risks showed lower treatment initiation among those with depressive symptoms compared to those without (hazard ratio (HR): 0.63 (95% CI: 0.43–0.93)). Exposure misclassification correction moved the HR towards the null (0.81 (95% CI: 0.69–0.95)), but still indicated a 19% lower risk of initiation among those with depressive symptoms. In the DAA era, in the MSCM model accounting for competing risks, we observed higher treatment initiation among those with depressive symptoms compared to those without (HR: 1.42 (95% CI: 1.17–1.71)). Again, exposure misclassification correction moved the HR towards the null (1.19 (95% CI: 1.10–1.27)), still indicating a 19% higher risk of initiation among those with depressive symptoms.

Table 2.

Effect of depressive symptoms on time to HCV treatment initiation in IFN and DAA eras.

Model	No misclassification correction		Misclassification correction
Model	HR	95% CI	HR	95% CI
IFN era (2003–2011)
Cox proportional hazards model^a	0.66	0.43–0.99	0.84	0.72–0.99
MSCM not accounting for competing risks^b	0.64	0.43–0.94	0.82	0.70–0.96
MSCM accounting for competing risks^c	0.63	0.43–0.93	0.81	0.69–0.95
DAA era (2013–2020)
Cox proportional hazards model^a	1.53	1.27–1.84	1.20	1.12–1.29
MSCM not accounting for competing risks^b	1.37	1.14–1.66	1.17	1.09–1.25
MSCM accounting for competing risks^c	1.42	1.17–1.71	1.19	1.10–1.27

^aConventional Cox proportional hazards model—Biased estimate due to time-varying confounders acting as mediators.

^bMarginal structural Cox proportional hazards model adjusting for confounding bias due to time-varying confounders acting as mediators.

^cMarginal structural Cox proportional hazards model with inverse probability censoring weights to adjust for death as a competing risk.

All models were adjusted for following Baseline confounders: age, gender, race/ethnicity, education level, sexual orientation, previous IFN-based HCV treatment, immigration, marital status and province; Time-varying confounders: living situation, employment, income, revenue source, injection drug use, alcohol use, smoking, incarceration, fibrosis stage (e.g. AST to Platelet Ratio Index (APRI) ≥1.5), HIV viral load, CD4 count and antidepressant use. Abbreviations: IFN. Interferon; DAA. Direct acting antivirals; HR. Hazard ratio; CI. Confidence interval. MSCM. Marginal structural Cox proportional hazards model

Secondary analyses

The secondary analyses results are shown in Table 3. In the first analysis, in the restricted subset with measured CES-D-10 classes available from the FS sub-study, 485 participants were included with 102 treatment initiations, all in the DAA era. Taking into consideration time-varying confounders and competing risks, the HR for treatment initiation was 0.82 (95% CI: 0.52–1.29). While this point estimate was comparable to the IFN era estimates, the precision was low. In the second analysis, using time-fixed exposure (baseline depressive symptoms), the results were comparable to the primary analyses, with lower treatment initiation among those with depressive symptoms than those without in the IFN era and higher in the DAA era.

Table 3.

Secondary analyses using measured CES-D-10 classes in a restricted subset and baseline predicted depressive symptoms.

Model	No misclassification correction		Misclassification correction
Model	HR	95% CI	HR	95% CI
Restricted subset with measured CES-D-10 classes (2012–2015)^a
Cox proportional hazards model	0.88	0.57–1.35	-	-
MSCM not accounting for competing risks	0.90	0.57–1.40	-	-
MSCM accounting for competing risks	0.82	0.52–1.29	-	-
Exposure: Baseline predicted depressive symptoms^b
IFN era (2003–2011)	0.78	0.50–1.23	0.92	0.77–1.08
DAA era (2013–2020)	1.17	0.97–1.42	1.12	1.05–1.20

The subset was from the FS sub-study in which data was collected from 2012–2015 during the DAA era. Models were adjusted for—Baseline confounders: age, gender, race/ethnicity, education level, sexual orientation, previous IFN-based HCV treatment, immigration, marital status and province; Time-varying confounders: living situation, employment, income, revenue source, injection drug use, alcohol use, smoking, incarceration, fibrosis stage (e.g. AST to Platelet Ratio Index (APRI) ≥1.5), HIV viral load, CD4 count and antidepressant use.

Models were adjusted for baseline confounders: age, gender, race/ethnicity, education level, sexual orientation, previous IFN-based HCV treatment, immigration, marital status and province. Abbreviations: IFN, Interferon; DAA, Direct acting antivirals; HR, Hazard ratio; CI, Confidence interval; CES-D-10, Center for Epidemiologic Studies Depression Scale-10; MSCM, Marginal structural Cox proportional hazards model.

Discussion

In this multicentre prospective cohort study, we observed lower HCV treatment initiation among those with depressive symptoms compared to those without in the IFN era, whereas higher initiation among those with depressive symptoms in the DAA era. There was a high prevalence of depressive symptoms (over 50% in both eras); thus, the ability of DAAs to overcome a significant barrier to HCV treatment historically faced by this substantial population should help the goal of eliminating HCV.

Our results are in line with expectations that, during the IFN era, providers would be less likely to prescribe IFN-based regimens to those with depressive symptoms and that neuropsychiatric side-effects of IFN would deter such patients from initiating therapy. A multicentre cohort study of veterans in the US similarly found that those with pre-existing psychiatric conditions (18%) had a much higher odds of not being treated (OR: 9.62; 95% CI: 6.85–13.50) [45]. In the DAA era, there have been studies examining depression prevalence before and after DAA treatment [15, 46-49]. A few studies have addressed depression and other psychiatric illness as possible risk factors for reduced linkage to care and treatment in the HCV mono-infection cascade of care [24-26]. Higher Patient Health questionnaire-8 (PHQ-8) scores indicating more severe depression have been found among those not treated for HCV [24]. In a retrospective study of barriers to HCV linkage to care and treatment initiation in Florida, uncontrolled psychiatric illness was found to be a smaller barrier to treatment initiation in the DAA era compared to the IFN era [26]. Though these studies assessed depression as a possible barrier for treatment initiation, they did not explore the effect of depressive symptoms independently. In our study, we present the first quantitative estimates of the effect of depressive symptoms on time to HCV treatment initiation, contrasting uptake in the IFN and second-generation DAA eras among HIV–HCV co-infected people, who may differ from those with HCV mono-infection due to distinct patient- and system-level barriers to care. Unlike other studies, we accounted for potential time-dependent confounding and competing risk of death which could bias estimates of treatment uptake.

An overall increase in HCV treatment initiation rates was observed from the IFN to the DAA era. The percentage of eligible participants that initiated treatment increased from 21% to 50% in this analysis; this is important progress towards reaching the HCV elimination goals in Canada [50]. Additionally, it was encouraging that this increase occurred in the DAA era in spite of higher prevalence of many possible barriers to treatment such as lower education, higher rates of injection drug use and incarceration and being Indigenous—barriers that may themselves be linked with depression. Interestingly, we not only observed that treatment initiation increased among those with depressive symptoms, which was anticipated, but also that in the DAA era, initiation was found to be higher among those with depressive symptoms compared those without, which was surprising. One of the possible explanations for this could be that a backlog of patients for whom IFN-based treatments were contraindicated, or were not tolerated, are now accessing treatment, that is, a warehousing effect. This effect could either persist or plateau over time, which would be expected with a warehousing effect. In our study, we observed that almost 65% of the people with baseline depressive symptoms initiated DAAs between 2015– and 2017 and comparatively lower number of people (31%) initiated between 2018 and 2020, which provides some evidence for possible plateauing; however, additional data would be needed to confirm this change over time. With the percentage of the eligible participants initiating HCV treatment still being much lower than the WHO elimination goal of 80% and possible plateauing, it is possible that depressive symptoms may have additional impacts on the care cascade beyond medication safety that need to be addressed to further enhance treatment uptake. This might be achieved, for example, by integration of mental health education, screening and treatment as a part of routine care for HIV–HCV co-infected people.

This study has several strengths. The CCC recruits participants from primary and tertiary care clinics in urban and semi-urban areas across Canada. Thus, our estimates are generalizable to HIV–HCV co-infected patients engaged in care in Canada. We leveraged longitudinally collected data over 15 years, applied robust methods to account for time-dependent confounding, competing risk and conducted multiple secondary analyses. However, the study does have limitations. The clinically relevant depressive symptoms were predicted via a random forest algorithm, and not measured directly in the cohort. Thus, misclassification was expected and therefore we corrected for potential misclassification in our analysis, resulting in attenuation of our estimates. We predicted the depressive symptoms based on a screening questionnaire, CES-D-10, and not a clinical depression diagnosis. Thus, this study does not provide an effect estimate for depression but rather for presence of these clinically relevant depressive symptoms.

We demonstrated a high baseline prevalence of depressive symptoms in HIV–HCV co-infected people and showed a substantial increase in treatment initiation rates with the availability of DAAs. Our study suggests that depressive symptoms are no longer a barrier to HCV treatment initiation in the second-generation DAA era in the HIV–HCV co-infected population in Canada.

Supplemental Material

sj-pdf-1-avt-10.1177_13596535211067610 – Supplemental Material for Depressive symptoms are no longer a barrier to HCV treatment initiation in the HIV–HCV co-infected population in Canada

Supplemental Material, sj-pdf-1-avt-10.1177_13596535211067610 for Efficacy of Second-line Dolutegravir Plus 2 NRTIs by Baseline NRTI Resistance and NRTI Use in the DAWNING Study by Dannae Brown, Richard Kaplan, Marcelo Losso, Carlos Brites, Ruolan Wang, Mark Underwood, Judy Hopking, Michael Aboud, and Jörg Sievers in Antiviral Therapy

Footnotes

Acknowledgements

We would like to acknowledge the participants of the Canadian Co-Infection Cohort (CTN222), the study coordinators and nurses for their assistance with study coordination, participant recruitment and care and the Canadian Co-Infection Cohort (CTN222) co-investigators—Drs Lisa Barrett, Jeff Cohen, Brian Conway, Curtis Cooper, Pierre Côté, Joseph Cox, M. John Gill, Shariq Haider, David Haase, Mark Hull, Valérie Martel-Laferrière, Julio Montaner, Erica E. M. Moodie, Neora Pick, Danielle Rouleau, Aida Sadr, Steve Sanche, Roger Sandre, Mark Tyndall, Marie-Louise Vachon, Sharon Walmsley and Alexander Wong.

Declaration of conflicting interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: MBK reports grants for investigator-initiated studies from ViiV Healthcare, AbbVie, Merck and Gilead; and consulting fees from ViiV Healthcare, Merck, AbbVie and Gilead. JC received grants and consulting fees from ViiV Healthcare, Merck and Gilead and personal fees from Bristol-Myers Squibb. CC has received personal fees for being a member of the national advisory boards of Gilead, Merck, Janssen and Bristol-Myers Squibb. MH has served as a consultant for Merck, Vertex Pharmaceuticals, Pfizer, Viiv Healthcare and Ortho-Jansen. MH has also received grants from the National Institute on Drug Abuse, as well as payment for lectures from Merck and Ortho-Janssen. JG has served as ad hoc member on National HIV advisory boards to ViiV healthcare, Gilead and Merck. SW received grants, consulting fees, lecture fees, nonfinancial support and fees for the development of educational presentations from Merck, ViiV Healthcare, GlaxoSmithKline, Pfizer, Gilead, AbbVie, Bristol-Myers Squibb and Janssen. NP reports honoraria from Gilead and ViiV Healthcare. GM, EEM, MJB and CLD have no conflict of interest to disclose.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This work was supported by Fonds de recherche du Québec-Santé; Réseau sida/maladies infectieuses, the Canadian Institute for Health Research (CIHR; FDN-143270); and the CIHR Canadian HIV Trials Network (CTN222 & CTN264). GM and CLD are supported by a PhD trainee fellowship from the Canadian Network on Hepatitis C. CLD received a doctoral training award from the Fonds de recherche du Québec - Santé. EEMM is supported by a chercheur boursier de mérite award from the Fonds de recherche du Québec-Santé and a Canada Research Chair Tier 1. MBK is supported by a Tier I Canada Research Chair. For the remaining authors, none were declared. The funders had no role in the production of this manuscript.

Ethics approval and consent to participate

This study was approved by the Research Ethics Board of the McGill University Health Centre (2021–6985). The CCC and the FS Sub-Study were approved by the Research Ethics Board of the McGill University Health Centre (2006–1875, BMB-06–006t, 2013–994) and the research ethics boards of participating institutions. The study was conducted according to the Declaration of Helsinki. Informed consent was obtained from all individual participants included in the study.

Data Availability

The datasets generated and/or analysed during the current study are not publicly available. According to stipulations of the patient consent form signed by all study participants, ethical restrictions imposed by our Institutional Ethics review boards, and legal restrictions imposed by Canadian law, anonymized data are available upon request by contacting Dr Marina B. Klein.

ORCID iDs

Gayatri Marathe

Charlotte L Delaunay

Marina B Klein

Supplemental Material

Supplemental material for this article is available online.

References

Burstow

Mohamed

Gomaa

, et al.

Hepatitis C treatment: where are we now?

Int Journal General Medicine 2017; 10: 39–52. doi: 10.2147/ijgm.s127689.

Webster

Klenerman

Dusheiko

. Hepatitis C. Lancet (London, England) 2015; 385: 1124–1135. doi: 10.1016/s0140-6736(14)62401-6.

Hull

Shafran

Wong

, et al. CIHR Canadian HIV Trials Network Coinfection and Concurrent Diseases Core Research Group: 2016 Updated Canadian HIV/Hepatitis C Adult Guidelines for Management and Treatment. Can J Infect Dis Med Microbiol 2016; 2016: 4385643. doi: 10.1155/2016/4385643.

Wyles

Sulkowski

Dieterich

. Management of Hepatitis C/HIV Coinfection in the Era of Highly Effective Hepatitis C Virus Direct-Acting Antiviral Therapy. Clin Infect Dis 2016; 63 Suppl 1: S3-s11. doi: 10.1093/cid/ciw219.

Fried

. Side effects of therapy of hepatitis C and their management. Hepatology 2002; 36: S237–S244. doi: 10.1053/jhep.2002.36810.

Schaefer

Engelbrecht

Gut

, et al. Interferon alpha (IFNalpha) and psychiatric syndromes: a review. Prog Neuro-Psychopharmacology Biological Psychiatry 2002; 26: 731–746.

McHutchison

Lawitz

Shiffman

, et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009; 361: 580–593. doi: 10.1056/NEJMoa0808010.

Loftis

Hauser

. The phenomenology and treatment of interferon-induced depression. J Affective Disord 2004; 82: 175–190. doi: 10.1016/j.jad.2004.04.002.

Fleming

Tumilty

Murray

, et al. Challenges in the Treatment of Patients Coinfected with HIV and Hepatitis C Virus: Need for Team Care. Clin Infect Dis 2005; 40: S349–S354. doi: 10.1086/427452.

10.

Levintow

Pence

Powers

, et al. Depression, antiretroviral therapy initiation, and HIV viral suppression among people who inject drugs in Vietnam. J Affective Disord 2021; 281: 208–215. doi: 10.1016/j.jad.2020.12.024.

11.

Horberg

Silverberg

Hurley

, et al. Effects of Depression and Selective Serotonin Reuptake Inhibitor Use on Adherence to Highly Active Antiretroviral Therapy and on Clinical Outcomes in HIV-Infected Patients. JAIDS J Acquired Immune Deficiency Syndromes 2008; 47: 384–390. doi: 10.1097/QAI.0b013e318160d53e.

12.

Gonzalez

Batchelder

Psaros

, et al. Depression and HIV/AIDS treatment nonadherence: a review and meta-analysis. J Acquired Immune Deficiency Syndromes (1999) 2011; 58: 181–187. doi: 10.1097/QAI.0b013e31822d490a.

13.

Bengtson

Pence

Mimiaga

, et al. Depressive Symptoms and Engagement in Human Immunodeficiency Virus Care Following Antiretroviral Therapy Initiation. Clin Infect Dis 2018; 68: 475–481. doi: 10.1093/cid/ciy496.

14.

Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection. Report no. License: CC BY-NC-SA 3.0 IGO, 2018. Geneva: World Health Organization.

15.

Gallach

Vergara

da Costa

, et al. Impact of treatment with direct-acting antivirals on anxiety and depression in chronic hepatitis C. PloS One 2018; 13: e0208112. doi: 10.1371/journal.pone.0208112.

16.

Sundberg

Lannergård

Ramklint

, et al. Direct-acting antiviral treatment in real world patients with hepatitis C not associated with psychiatric side effects: a prospective observational study. BMC Psychiatry 2018; 18: 157. doi: 10.1186/s12888-018-1735-6.

17.

Saeed

Strumpf

Moodie

, et al. Disparities in direct acting antivirals uptake in HIV-hepatitis C co-infected populations in Canada. J Int AIDS Soc 2017; 20. doi: 10.1002/jia2.25013.

18.

Nanni

Caruso

Mitchell

, et al. Depression in HIV infected patients: a review. Curr Psychiatry Reports 2015; 17: 530. doi: 10.1007/s11920-014-0530-4.

19.

Younossi

Park

Henry

, et al. Extrahepatic Manifestations of Hepatitis C: A Meta-analysis of Prevalence, Quality of Life, and Economic Burden. Gastroenterology 2016; 150: 1599–1608. doi: 10.1053/j.gastro.2016.02.039.

20.

Bing

Burnam

Longshore

, et al. Psychiatric disorders and drug use among human immunodeficiency virus-infected adults in the United States. Arch Gen Psychiatry 2001; 58: 721–728. doi: 10.1001/archpsyc.58.8.721.

21.

Ciesla

Roberts

. Meta-analysis of the relationship between HIV infection and risk for depressive disorders. Am J Psychiatry 2001; 158: 725–730. doi: 10.1176/appi.ajp.158.5.725.

22.

Yeoh

Holmes

ACN

Saling

, et al. Depression, fatigue and neurocognitive deficits in chronic hepatitis C. Hepatol International 2018. doi: 10.1007/s12072-018-9879-5.

23.

Fialho

Pereira

Rusted

, et al. Depression in HIV and HCV co-infected patients: a systematic review and meta-analysis. Psychol Health Medicine 2017; 22: 1089–1104. doi: 10.1080/13548506.2017.1280177.

24.

Spradling

Zhong

Moorman

, et al. Psychosocial Obstacles to Hepatitis C Treatment Initiation Among Patients in Care: A Hitch in the Cascade of Cure. Hepatol Commun 2021; 5: 400–411. doi: 10.1002/hep4.1632.

25.

Nguyen

Vutien

Hoang

, et al. Barriers to care for chronic hepatitis C in the direct-acting antiviral era: a single-centre experience. BMJ Open Gastroenterol 2017; 4: e000181. doi: 10.1136/bmjgast-2017-000181.

26.

Malespin

Harris

Kanar

, et al. Barriers to treatment of chronic hepatitis C with direct acting antivirals in an urban clinic. 2019; 18: 304–309. doi: 10.1016/j.aohep.2018.06.001.

27.

Chen

Y-C

Thio

Cox

, et al. Trends in hepatitis C treatment initiation among HIV/hepatitis C virus-coinfected men engaged in primary care in a multisite community health centre in Maryland: a retrospective cohort study. BMJ Open 2019; 9: e027411. doi: 10.1136/bmjopen-2018-027411.

28.

Klein

Saeed

Yang

, et al. Cohort profile: the Canadian HIV-hepatitis C co-infection cohort study. Int Journal Epidemiology 2010; 39: 1162–1169. doi: 10.1093/ije/dyp297.

29.

Cox

Hamelin

McLinden

, et al. Food Insecurity in HIV-Hepatitis C Virus Co-infected Individuals in Canada: The Importance of Co-morbidities. AIDS Behavior 2017; 21: 792–802. doi: 10.1007/s10461-016-1326-9.

30.

Radloff

. The CES-D Scale:A Self-Report Depression Scale for Research in the General Population. Appl Psychol Meas 1977; 1: 385–401. doi: 10.1177/014662167700100306.

31.

Andresen

Malmgren

Carter

, et al. Screening for depression in well older adults: evaluation of a short form of the CES-D (Center for Epidemiologic Studies Depression Scale). Am Journal Preventive Medicine 1994; 10: 77–84.

32.

Zhang

O'Brien

Forrest

, et al. Validating a shortened depression scale (10 item CES-D) among HIV-positive people in British Columbia, Canada. PloS One 2012; 7: e40793. doi: 10.1371/journal.pone.0040793.

33.

Breiman

Random Forests. Machine Learn 2001; 45: 5–32. doi: 10.1023/A:1010933404324.

34.

Banack

Stokes

Fox

, et al. Stratified Probabilistic Bias Analysis for Body Mass Index-related Exposure Misclassification in Postmenopausal Women. Epidemiology (Cambridge, Mass) 2018; 29: 604–613. doi: 10.1097/EDE.0000000000000863.

35.

Raghunathan

Lepkowski

Van Hoewyk

, et al. A Multivariate Technique for Multiply Imputing Missing Values Using a Sequence of Regression Models. SURVEY METHODOLOGY 2001; 27: 85–96.

36.

van Buuren

. Multiple imputation of discrete and continuous data by fully conditional specification. Stat Methods Med Res 2007; 16: 219–242. doi: 10.1177/0962280206074463.

37.

Abrahamowicz

MacKenzie

Esdaile

. Time-Dependent Hazard Ratio: Modeling and Hypothesis Testing With Application in Lupus Nephritis. J Am Stat Assoc 1996; 91: 1432–1439. doi: 10.2307/2291569.

38.

Grambsch

Therneau

. Proportional hazards tests and diagnostics based on weighted residuals. Biometrika 1994; 81: 515–526. doi: 10.1093/biomet/81.3.515.

39.

Robins

Hernan

Brumback

. Marginal structural models and causal inference in epidemiology. Epidemiology (Cambridge, Mass) 2000; 11: 550–560.

40.

Hernan

Brumback

Robins

. Marginal structural models to estimate the causal effect of zidovudine on the survival of HIV-positive men. Epidemiology (Cambridge, Mass) 2000; 11: 561–570.

41.

Moodie

Stephens

. Marginal Structural Models: unbiased estimation for longitudinal studies. Int Journal Public Health 2011; 56: 117–119. doi: 10.1007/s00038-010-0198-4.

42.

Kronfli

Bhatnagar

Hull

, et al. Trends in Cause-specific mortality in HIV-Hepatitis C Co-infection following hepatitis C treatment scale-up. AIDS (London, England) 2019. doi: 10.1097/qad.0000000000002156.

43.

Lau

Cole

Gange

. Competing risk regression models for epidemiologic data. Am Journal Epidemiology 2009; 170: 244–256. doi: 10.1093/aje/kwp107.

44.

Andersen

Geskus

de Witte

, et al. Competing risks in epidemiology: possibilities and pitfalls. Int Journal Epidemiology 2012; 41: 861–870. doi: 10.1093/ije/dyr213.

45.

Bini

Bru

Currie

, et al. Prospective multicenter study of eligibility for antiviral therapy among 4,084 U.S. veterans with chronic hepatitis C virus infection. Am Journal Gastroenterology 2005; 100: 1772–1779.

46.

Nardelli

Riggio

Rosati

, et al. Hepatitis C virus eradication with directly acting antivirals improves health-related quality of life and psychological symptoms. World J Gastroenterol 2019; 25: 6928–6938. doi: 10.3748/wjg.v25.i48.6928.

47.

Miarons

Sánchez-Ulayar

Sempere

, et al. New direct-acting antivirals for hepatitis C treatment and neuropsychiatric symptoms in psychiatric risk groups. Eur J Hosp Pharm 2019; 26: 135–139. doi: 10.1136/ejhpharm-2017-001352.

48.

Khalil

Shousha

El-Nahaas

, et al. Depression in patients with chronic hepatitis-C treated with direct-acting antivirals: A real-world prospective observational study. J Affective Disord 2021; 282: 126–132. doi: 10.1016/j.jad.2020.12.128.

49.

Abdel Moez

El Hawary

Al Balakosy

. Can successful treatment by direct-acting antivirals improve depression in chronic HCV patients? Eur J Gastroenterol Hepatol 2020. doi: 10.1097/meg.0000000000001790.

50.

The Canadian Network on Hepatitis C Blueprint Writing Committee and Working Groups . Blueprint to inform hepatitis C elimination efforts in Canada . Montreal, QC.

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