No effect of integrated hepatitis C virus treatment on psychological distress in people with substance use disorders: results from a randomized controlled trial

doi:10.21203/rs.3.rs-3333591/v1

Background

People with substance use disorders (SUD) have high prevalence of chronic hepatitis C virus (HCV) infection and mental health disorders. We aimed to assess the impact of integrated HCV treatment on psychological distress measured by Hopkins-symptom-checklist-10 (SCL-10).

Methods

This multi-center randomized controlled trial evaluated psychological distress as secondary outcomes of integrated HCV treatment (INTRO-HCV trial). From 2017 to 2019, 289 participants were randomly assigned to receive either integrated or standard HCV treatment with direct-acting antiviral therapy. Integrated HCV treatment was delivered in eight decentralized outpatient opioid agonist therapy clinics and two community care centers; standard treatment was delivered in internal medicine outpatient clinics at centralized hospitals. Participants in integrated treatment arm had a sustained virologic response of 93% compared to 73% for those in standard treatment arm. Psychological distress was assessed using SCL-10 prior to initiation of HCV treatment and 12 weeks after treatment completion. A linear mixed model was applied to evaluate the impact of integrated HCV treatment on changes in the mean SCL-10 (ΔSCL-10) score.

Results

The mean SCL-10 score prior to HCV treatment was 2.2 (standard deviation [SD]: 0.7) for patients receiving integrated HCV treatment and 2.1 (SD: 0.7) for those receiving standard HCV treatment. Twelve weeks after the end of treatment, the mean SCL-10 score was 2.2 (SD: 0.8) for participants receiving integrated HCV treatment and 2.1 (SD: 0.7) for those receiving standard HCV treatment.

Conclusions

Psychological distress did not substantially change during the treatment period and was not significantly different between the treatment arms.

Substance-related disorders

mental health symptoms

opioid agonist therapy

hepatitis C virus infection

integrated treatment

People with substance use disorders (SUD) have a high prevalence of chronic hepatitis C virus (HCV) infection, and consequently liver-related complications [1, 2]. In addition, more than half of people with SUD suffer from mental health disorders with substantial symptoms of psychological distress, like fearfulness, tension, worthlessness, sleeping problems, and hopelessness [2, 3]. These symptoms have a significant impact on health-related quality of life and well-being [4–6], where the prevalence is particularly associated with the utilization of benzodiazepines, opioids, and cannabis, as well as underlying mental and somatic disorders [4, 7–9]. HCV infection by itself is also associated with certain extrahepatic events, such as neurological and psychiatric complications [1]. Therefore, it is important to explore this intricate interplay between HCV, substance use, and mental health symptoms in high-quality intervention studies. Possibly, ameliorating the burden of serious somatic conditions such as HCV infection might have an added positive effect on mental health.

The introduction of direct-acting antivirals (DAA) represented a paradigm shift, providing an effective and safe treatment for HCV infection despite co-occurring mental health disorders and SUD [10]. The realization of universal access to curative DAA treatments constitutes a fundamental human right. Along with highly effective DAA, decentralization of treatment from conventional HCV follow-up, as well as simplifying and integrating HCV care in harm-reduction sites such as opioid agonist therapy (OAT) clinics and community care centers (CCC), has been crucial to providing more widespread access to testing, linkage to care, and successful treatment for HCV in this population [11].

It is estimated that up to 80% of patients with SUD have been infected with HCV, and up to 70% have at least one mental health disorder [12, 13]. Challenges related to health and life situations, such as suicidal ideation, high fatigue levels, and unstable living conditions, may worsen psychological distress and impact HCV treatment adherence [5, 6]. Some observational studies have suggested that HCV treatment may reduce mental health symptoms, but the studies are prone to confounding and biases limiting any causal interpretations [11, 14]. Randomizing affected patients to receive HCV treatment or no treatment is not ethically acceptable, but the effects of HCV treatment can be evaluated in trials evaluating strategies to increase treatment initiation and sustained virologic response. Integrated treatment of hepatitis C in a randomized control trial (INTRO-HCV), involving multidisciplinary teams and close follow-ups in outpatients SUD clinics, improved sustained virological response (SVR) up to 93% compared to 73% in the standard arm [15]. In addition, integrated HCV treatment showed a tendency to improve fatigue in this population [16]. These findings may suggest that integrated HCV treatment can also effectively relieve symptoms related to mental health and psychological distress among patients with SUD.

This study investigated the effect of integrated as compared to standard HCV treatment on psychological distress measured by Hopkins Symptom Checklist-10 (SCL-10) among patients with co-occurring SUD. This can be used as a proxy to understand potential impact of sustained virologic response.

This study presents a secondary outcome analysis of the INTRO-HCV trial [17]. We recruited people with SUD and chronic HCV infection who were eligible for HCV treatment with DAA in accordance with Norwegian HCV treatment guidelines (Supplementary file 1). Participants were recruited from eight outpatient clinics providing OAT in Bergen and Stavanger, and two CCC in Bergen providing primary healthcare to people with SUD. Data was collected from May 2017 to June 2019. For a more comprehensive description of the trial, a published protocol is available [17] as is the main trial paper [2].

A total of 289 participants were randomized to either receive integrated HCV treatment (n = 145) or standard HCV treatment (n = 144) (Fig. 1). For participants in the former group, all SCL-10 and HCV assessments were provided onsite at the OAT/CCC clinics. Those receiving OAT eligible for treatment were subsequently provided DAA along with their OAT medications, administrated by a nurse at the related OAT clinic. DAA medication and other HCV care were provided at the related CCC when the participant was not undergoing OAT. Participants in standard group were referred to the centralized outpatient infectious disease clinic for HCV treatment, and an appointment was usually scheduled within a few weeks after the referral. The SCL-10 questionnaires were filled out by all the participants in both groups during separate visits to either OAT clinics or CCC. For a more detailed description of the methodology, see Supplementary files 2–3.

Characteristics at baseline

The baseline sociodemographic characteristics were similar between the arms. No significant differences (p>0.05 for all comparisons) emerged between the arms for the baseline characteristics (Table 1). Achieving SVR did not significantly reduce the SCL-10 score 12 weeks after DAA treatment compared to those not achieving SVR (Supplementary files 4-5).

Table 1: Characteristics at baseline (n (%))

		*Integrated treatment (n = 145)**	Standard treatment* (n = 144)
Age (years)

	18-29	14 (10)	15 (12)
	30-39	45 (31)	46 (32)
	40-49	44 (30)	47 (33)
	≥50	42 (29)	34 (24)
	Median (IQR)	44 (36-52)	42 (34-49)
Sex
Male		106 (73)	116 (81)
Educational attainment
Not completed primary school		7 (5)	12 (9)
Completed primary school (9 years)		69 (48)	69 (49)
Completed high school (12 years)		54 (38)	46 (33)
Completed college or university		13 (9)	14 (10)
Opioid agonist therapy		124 (86)	126 (88)
Unstable housing past 30 days¹⁾		21 (15)	19 (13)
Injected drug use past 12 months		84 (58)	85 (62)
Frequent drug use past 12 months²⁾
Alcohol		35 (24)	34 (25)
Benzodiazepines		55 (38)	55 (40)
Cannabis		77 (54)	75 (55)
Opioids		18 (13)	17 (13)
Stimulants (amphetamines and cocaine)		50 (35)	41 (30)
Infectious diseases
Hepatitis C virus genotypes 1 2 3 4 6 Hepatitis B virus infection		50 (35) <10 (1) 92 (64) <5 (0) <5 (0) 0 (0)	48 (34) <10 (4) 85 (60) <5 (1) <5 (1) 0 (0)
Human immunodeficiency virus		0 (0)	<5 (1)
Liver stiffness
Transient elastography (≥ 12.5 kPa)		19 (14)	15 (11)
Aspartate transaminase to platelets ratio index (≥ 1.5)		17 (12)	20 (14)

* None basic characteristics were significantly different, comparing the integrated treatment group to the standard treatment group, with a significance level of 0.05.

Legends: IQR: Interquartile range; kPa: Kilopascal;

¹⁾ Unstable housing was defined as living in a homeless shelter, with family or friends, or on the street during the 30 days leading up to the first health assessment (baseline);

²⁾ Frequent drug use was defined as using substance at least weekly during the 12 months leading up to the first health assessment (baseline).

The table displays the sociodemographic and clinical characteristics of participants randomly assigned to integrated and standard HCV treatment groups.

Mean SCL-10 scores at baseline and 12 weeks after the end of treatment

At baseline, the SCL-10 mean score for participants in the integrated HCV treatment arm was 2.2 (standard deviation [SD]: 0.7), and 2.2 (SD: 0.8) for those on standard HCV treatment. At 12 weeks after the end of treatment (EOT12), the mean SCL-10 score for participants in both groups was 2.1 (SD: 0.7) (Supplementary files 6-8).

The impact of integrated HCV treatment on psychological distress

Integrated HCV treatment did not significantly reduce the mean SCL-10 score from baseline to EOT12 compared with standard HCV treatment (ΔSCL-10 mean score: –0.1, 95% confidence interval [CI]: –0.3; 0.0) (Table 2, Figure 2). Substantial individual variations in mean SCL-10 score were observed over time across the treatment groups (Figure 3). Per protocol analysis and sensitivity analyses showed similar results (Supplementary file 9-13).

Table 2: Linear mixed model of changes in mean SCL-10 scores from baseline to EOT12 for integrated HCV treatment (intention-to-treat) (N = 289)

	Effect estimates
	Coefficient (95 % CI)	p-value
Time trend	–0.0 (–0.1;0.0)	0.314
Δ Mean SCL-10 score from baseline to EOT12
Standard HCV treatment	0.0 (ref.)	-
Integrated HCV treatment	–0.1 (-0.3;0.0)	0.091

Legends: EOT12: 12 weeks after the end of HCV treatment; SCL-10: The Hopkins Symptoms checklist-10; SVR: Sustained virological response.

The table displays a linear mixed model analysis (Restricted Maximum Likelihood) regression of the impact of integrated HCV treatment on changes in mean SCL-10 scores (Δ mean SCL-10 score) from baseline to EOT12 (intention-to-treat analysis). The mean SCL-10 score ranged from 1 “not bothered at all” to 4 “extremely bothered”.

This randomized controlled trial has showed that psychological distress did not substantially change during the treatment of HCV and was not significantly different between integrated and standard treatment arms. Overall, and regardless of treatment approach, the symptom burden was substantial both at baseline and 12 weeks after DAA treatment. A small non-significant trend of –0.1 (ΔSCL-10 mean score, p = 0.091) reduction in psychological distress was observed with integrated HCV treatment.

The symptom burden reported at EOT12 was substantial for participants in both the integrated and standard HCV treatment groups with mean SCL-10 scores of 2.2, which is far above the considered threshold for significant symptoms of psychological distress and symptoms of mental health disorder (mean SCL-10 score of 1.85). This is considerably higher compared to the general Norwegian population with mean SCL-10 score of 1.4 [18]. This finding on the level of psychological distress in this population is consistent with our previous research on a large cohort of SUD patients. Furthermore, in a retrospective study from Australia 30% of the HCV infected patients reported a pre-existing mental health disorder of which 25% had depression, 2.6% bipolar disorder, 3.5% schizophrenia and 0.4% schizoaffective disorder [19]. Compared to interferon-based therapies, treatment with DAA has been associated with lower incidence of depressive symptoms [20]. In contrast to our findings, one other study of patients with HCV and co-occurring mental health disorders and SUD, showed significantly reduced symptoms of depression at EOT12 with DAA treatment, although diversities in study design and methodology should make such interpretations careful [21].

Substantial intra-individual variations in mean SCL-10 score were observed from baseline to EOT 12 in both the integrated and standard treatment groups. In addition, these variations seem to go in both positive and negative directions and correspond with the findings in another study on SCL-10 among participants with SUD [3]. This is likely attributable to a range of external factors such as unstable living conditions, worrying debt situation, educational attainment, and severity of substance use, which also seems to be independent predictors of life-time symptoms of mental health disorders [22]. This indicates that, despite a strong trial design, a large intra-individual variation may reduce the analytic power. Finally, achieving SVR did not impact the mean SCL-10 score when adjusting for sociodemographic factors, intravenous injecting use, and any legal and illegal substance use in sensitivity analyses. This finding may be interpreted in the way that a considerable effect of HCV treatment on psychological distress is unlikely to expect within the assessed time perspective.

A major strength of this study is its design of individual randomization with balanced groups, which minimizes potential confounding. A limitation of this study might be the selection of outpatient clinics, where most participants received OAT, affecting the generalizability of our results to non-OAT populations. The sample size may also be too low to could observe a potential significant difference between the arms. Another limitation is the almost 31% loss-to-follow-up of the SCL-10 assessments at EOT12, which may make the findings more uncertain. Furthermore, due to system and individual delays and changes in national guidelines for HCV treatment during the study period, the SCL-10 assessments were not conducted in exact concurrence with HCV treatment initiation and EOT12. This may have affected the results.

This randomized controlled trial of integrated HCV treatment is unlikely to have substantially co-benefits related to psychological distress beyond the known reductions in somatic health consequences. Nevertheless, the benefits of facilitated HCV treatment initiation with implications for potential future somatic complications and improved quality of life, emphasizes the importance of integrated treatment approaches in people with substance use disorders.

CCC

Community care centers

CI

Confidence interval

DAA

Direct-acting antiviral agent

EOT12

12 weeks after the end of treatment

SCL-10

Hopkins symptom checklist-10

HCV

Hepatitis C virus

OAT

Opioid agonist therapy

SD

Standard deviation

SUD

Substance use disorder

SVR

Sustained virological response

Ethics approval and consent to participate

The present study was reviewed and approved by the Regional Ethical Committee for Health Research (REC) West, Norway (reference number: 2017/51/REK Vest, dated 29.03.2017/20.04.2017). All recruited participants were fully informed about the study, and their written informed consent was provided before their inclusion and randomization. All methods were carried out in accordance with relevant guidelines and regulations.

Consent of publication

Not applicable

Availability of data and material

The datasets analyzed during the current study are not publicly available due data protection requirements but are available from the corresponding author on reasonable request.

Competing interests

Not applicable

Funding

This work was supported by The Norwegian Research Council (BEHANDLING, contract no 269855); and the Western Norway Regional Health Authority («Åpen prosjektstøtte») with Department of Addiction Medicine, Haukeland University Hospital, Bergen, Norway as responsible institution. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors were funded by their respective affiliations.

Authors’ contributions

JHV and CFA have led the study design, analysis, and writing the article preparation. FC, EML, AGL, PV, KAJ, and LTF have contributed to the study design, analysis, and article preparation. All authors have read and approved the final article.

Acknowledgements

We thank Nina Elisabeth Eltvik, Christer Kleppe, Rafael Alexander Leiva, and Christian Ohldieck for valuable help and input during the planning and preparation phases. We also thank the INTRO-HCV Study Group for important contribution relating to data collection. AGL and PV acknowledge support from the National Institute for Health and Care Research (NIHR) Health Protection Research Unit (HPRU) in Behavioural Science and Evaluation at the University of Bristol (NIHR200877). AGL and PV acknowledge support from the Well- come Trust (WT 220866/Z/20/Z) and UK NIHR (NIHR133208).

INTRO-HCV Study Group participating investigators:

Bergen: Christer Frode Aas, Vibeke Bråthen Buljovcic, Fatemeh Chalabianloo, Jan Tore Daltveit, Silvia Eiken Alpers, Lars T. Fadnes (principal investigator), Trude Fondenes Eriksen, Per Gundersen, Velinda Hille, Kristin Holmelid Håberg, Kjell Arne Johansson, Rafael Alexander Leiva, Siv-Elin Leirvåg Carlsen, Martine Lepsøy Bonnier, Lennart Lorås, Else-Marie Løberg, Mette Hegland Nordbotn, Cathrine Nygård, Maria Olsvold, Christian Ohldieck, Lillian Sivertsen, Hugo Torjussen, Jørn Henrik Vold, Jan-Magnus Økland

Stavanger: Tone Lise Eielsen, Nancy Laura Ortega Maldonado, Ewa Joanna Wilk

proLAR: Ronny Bjørnestad, Ole Jørgen Lygren, Marianne Cook Pierron

Oslo: Olav Dalgard, Håvard Midgard, Svetlana Skurtveit

Bristol: Aaron G. Lim, Peter Vickerman

Authors’ information

Christer F. Aas, MD, PhD, and Jørn Henrik Vold, MD, PhD, both affiliated at the Department of Addiction Medicine and Division of Psychiatry, Haukeland University Hospital, and Department of Public Health and Primary Care, University of Bergen. Mailing address: Department of Addiction Medicine, Haukeland University Hospital, Jonas Lies vei 65, N-5021 Bergen, Norway. E-mail: christer.frode.aas @helse-bergen.no.

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Supplementary files 1 to 13 are not available with this version

No competing interests reported.

Supplementaryfileslegends.docx

No effect of integrated hepatitis C virus treatment on psychological distress in people with substance use disorders: results from a randomized controlled trial

Status:

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Abstract

Background

Methods

Results

Conclusions

Figures

1. Introduction

2. Methods

3. Results

Discussion

Conclusion

Abbreviations

Declarations

References

Supplementary files

Additional Declarations

Supplementary Files

Status:

Version 1