The efficacy of integrated hepatitis C virus treatment in relieving fatigue in people who inject drugs: a randomized controlled trial

The original study, the INTRO-HCV trial, was designed as a multi-center, randomized controlled trial [20]. This study evaluated fatigue as a secondary outcome of the INTRO-HCV trial. We recruited PWIDs with chronic HCV infection who were eligible for HCV treatment with DAAs in accordance with Norwegian HCV treatment guidelines (Additional file 1). Participants were recruited from eight outpatient clinics providing opioid agonist therapy (OAT) in Bergen and Stavanger, Norway, as well as two community care centers (CCCs) in Bergen providing primary healthcare to PWIDs. Enrollment was conducted from May 2017 to June 2019. For a more comprehensive description, a published protocol is available [20].

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.

Inclusion criteria were defined as follows: 1) receiving OAT opioids in the OAT outpatient clinics or people injecting drugs receiving healthcare from the two CCCs; 2) having chronic HCV infection defined as detecting HCV with HCV polymerase chain reaction in two separate blood samples drawn with an interval of at least six months; 3) eligibility for treatment according to the Norwegian HCV treatment guidelines; and 4) willingness to sign a written informed consent to participate in the trial. We excluded people who 1) currently received treatment for HCV; 2) were co-infected with human immunodeficiency virus (HIV) or hepatitis B virus (positive surface antigen) at the time of inclusion; 3) had severe extrahepatic manifestations (e.g., cryoglobulinemia or membranoproliferative glomerulonephritis); 4) had chronic renal disease stages 4–5 (glomerular filtration rate < 30 ml/min/1.73 m²); and 5) had decompensated liver disease (Child–Pugh class B or C). Additionally, people who did not complete the FSS-9 questionnaire during the study period were excluded. For details on demographic and clinical variables, see Table 1.

A total of 148 participants were randomized into the integrated HCV treatment group and 150 into the standard HCV treatment group (Fig. 1). Ultimately, seven participants in the integrated treatment group and 15 in the standard treatment group were excluded due to death or lack of FSS-9 assessments. In total, 276 participants were included in the study – 141 in the integrated treatment group and 135 in the standard treatment group.

Participants in the standard HCV treatment group were referred to the centralized outpatient infectious disease clinic at the collaborating referral hospital for HCV treatment. An appointment was given and usually scheduled within a few weeks after the referral; the participants were informed of this by mail. Their clinical assessment could involve additional blood samples and imaging before initiating HCV treatment. In the first year of the study, HCV consultation with a consultant in infectious diseases was mandatory, but with increasing clinical experience and growing evidence, the primary assessment became voluntary. Participants were offered follow-up assessments, including blood samples, during treatment in the infectious disease outpatient clinic every four weeks as well as a posttreatment assessment 12 weeks after completion. This typically involved a total of 4 to 5 consultation visits at the outpatient clinic. They were responsible for retrieving and adhering to their prescriptions, and attending assessment appointments. At 12 weeks after the end of treatment (EOT12), blood samples, including HCV polymerase chain reaction, were drawn at infectious disease outpatient clinics, OAT clinics, and CCCs. In addition, participants met at OAT clinics or CCCs to assess their FSS-9 levels.

In the standard HCV treatment, participants needed to travel to the hospital clinic and pay for the transport themselves, a distance that ranged from 1 to 25 km. They received standard follow-up in the OAT clinic for drug use disorders, and all other types of care – apart from HCV care – were integrated into the OAT follow-up. The OAT site staff encouraged participants to visit the infectious disease hospital clinics, but no further extensive follow-up was performed. There was a risk that scheduled appointments may overlap with other activities such as receiving OAT medication and other drug use treatment, since arrangements were not coordinated.

All assessments and medications for participants in the integrated treatment groups were provided onsite at the OAT clinics or CCCs, including DAAs, blood samples, and FSS-9 assessments. Compared with participants in the standard treatment group, participants in the integrated treatment group had no follow-ups in the referral hospital, and they received all assessments and medications at the local OAT clinics or CCC. In addition, they drew only two blood samples; prior to HCV treatment and at EOT12, and blood samples drawn every four weeks during the HCV treatment were not necessary. Integrated treatment was delivered at OAT clinics and CCC by multidisciplinary teams in both of the settings. The OAT clinics differed from the CCCs by offering OAT medications in addition to psychosocial approaches. The multidisciplinary teams at the OAT clinics were equipped with consultants in addiction medicine who were responsible for the OAT and other medical follow-ups and also psychologists providing mental health treatment. In both OAT and CCC settings, nurses and social workers, in cooperation with peer counselors, provided most of the participants’ daily follow-ups. All these professionals were existing clinical staff who closely worked together with the research nurses in management of the interventions and evaluations during the study period. For those eligible for HCV treatment, DAAs were administered by a nurse at OAT clinics/CCCs after a prescription from a consultant in infectious diseases. Contrary to standard HCV treatment, all HCV treatment and scheduled follow-ups during treatment were given in parallel with the observed intake of OAT medications and other care, in line with the study protocol. The number of deliveries of OAT and DAA medications per week was adapted to the level of functioning of each participant. For the most severely ill participants with the lowest level of daily functioning and high intake of multiple drugs, OAT medications and HCV treatment were usually dispensed daily in the OAT clinic, and intake was observed by a nurse. The multidisciplinary team planned assessments with participants, or drop-in approaches were applied.

Participants were evaluated prior to HCV treatment and EOT12 to record their health status, including fatigue level according to the FSS-9 score, sociodemographic data, current drug use, blood samples, transient elastography, and clinical examination. The health assessments were conducted by specialized research nurses in close collaboration with the clinics’ consultants in addiction medicine and infectious diseases. A medical team followed up with those who did not meet the criteria for inclusion in the study. Data from the health assessments prior to and after HCV treatment were defined as the study’s baseline and EOT12 (endpoint), respectively.

Selected participants were randomized at a 1:1 ratio using blocks of 10 stratified by city and assigned into integrated (n = 148) or standard treatment (n = 150) for the trial. Complete blinding was considered impractical and would have reduced external validity [21], although some masking measures were taken [20]. In short, randomization was disclosed to clinical staff providing treatment and follow-up. Participants were informed of key elements in the delivery of the respective intervention and follow-up to which they were assigned, but no information was shared on treatment and follow-up alternatives or the hypotheses for the study.

We assessed fatigue using the FSS-9, including items considering mental and physical functioning, motivation, carrying out duties, and interfering with work, family, or social life. The FSS-9 is a well-known questionnaire to quantify fatigue during the week prior to the assessment [22‐27], with high validity and reliability in people undergoing HCV treatment [28]. The FSS-9 items are answered on a Likert scale ranging from 1, no fatigue, to 7, worst fatigue, demonstrating the fatigue level. A high FSS-9 score indicates a high level of fatigue; a mean score greater than 4.0 reveals severe fatigue [27]. A nine-item fatigue severity scale sum score was calculated by summarizing the points generated by the nine items. The FSS-9 employed had been translated and back-translated from US-English into Norwegian by qualified native Norwegian-speaking translators (Additional file 2) [29].

We drew blood samples, including hepatitis B virus surface antigen, HIV antigen/antibodies, thrombocytes, and aspartate aminotransferase, as well as HCV antibodies and HCV polymerase chain reactions. Liver stiffness was measured by calculating the aspartate aminotransferase to platelet ratio index and performing transient elastography at baseline (Additional file 3). Transient elastography calculates liver stiffness using the median value of ten repeated measurements on an empty stomach [30, 31].

We used Stata SE version 17 (StataCorp, TX, USA) for descriptive analyses and linear mixed model analyses, and IBM SPSS version 26.0 for expectation–maximization calculation. The threshold for statistical significance was set to p < 0.05 for all analyses unless otherwise stated. All statistical analyses were conducted following CONSORT and SPIRIT guidelines [32, 33]. The sample size was calculated for the primary outcome of SVR in the INTRO-HCV trial [20].

We dealt with any missing values in FSS-9 scores at baseline and EOT12 as “missing at random” when running expectation–maximization algorithm [34, 35]. We identified missing values in 1.4% of FSS-9 scores at baseline and 29.9% at EOT12, and all were replaced with estimated values. The expectation–maximization algorithm for computing data iteratively performs maximum likelihood estimation in the presence of latent variables [36], recommended for optimizing the mixed models. Sensitivity analyses without estimated values were conducted in all regression models.

The FSS-9 sum scores at baseline and EOT12 were calculated as described above (“Measurement” section). We created Pen’s parades in which the FSS-9 sum score at baseline were in sorted order from lowest to highest values and spikes were performed to express changes in FSS-9 scores from baseline to EOT12 in the integrated and standard HCV treatment groups. Additionally, linear mixed models were applied to investigate whether the predictor variables of treatment groups (dichotomized as standard (0) versus integrated (1)), and SVR (dichotomized as no (0) versus yes (1)), defined as undetectable HCV RNA 12 weeks after HCV treatment completion, affected the ΔFSS-9 sum scores from baseline to EOT12. The linear mixed models were random intercept fixed slope regression models. The restricted maximum likelihood was set as the estimator [37, 38]. The full information of maximum likelihood ensured that all available FSS-9 sum scores were used. The linear mixed model analysis was performed as intention-to-treat and per-protocol analyses and as a sensitivity analysis without computed data. In addition, linear mixed model sensitivity analyses were performed to evaluate whether achieving SVR affected the FSS-9 sum score, adjusted for sex, age, educational attainment, injecting drug use, and drug use.

The median age was 44 years (interquartile range (IQR): 36–52) in the integrated HCV treatment group. Of those, 73% were male, and 58% had injected drugs recently. In the standard HCV treatment group, the median age was 42 years (IQR 34–49), 81% were male, and 64% had injected drugs recently. HCV genotype 3 was most prevalent, representing 65% of participants in the integrated HCV treatment group and 61% in the standard HCV treatment group.

At baseline, the mean FSS-9 sum score for participants on receiving integrated treatment was 46 (Standard deviation (SD): 15) and 41 (SD: 16) for those on standard treatment. The mean FSS-9 sum score in both groups was slightly left-skewed and tended toward a flattened distribution at baseline (Additional file 4). At EOT12, the mean FSS-9 sum score for participants receiving integrated treatment was 42 (SD: 15) and 40 (SD: 14) for those receiving standard treatment. For detailed information on the FSS-9 sum scores at baseline and EOT12, see Additional file 5.

Integrated HCV treatment did not reduce the FSS-9 sum score from baseline to EOT12 more than standard HCV treatment (ΔFSS-9 sum score: –3.0, 95% confidence interval (CI): –6.4; 0.4) (Table 2, Fig. 2) (intention to treat). Moreover, substantial intraindividual variations in FSS-9 sum scores over time were observed in both groups (Fig. 3). Likewise, per-protocol and sensitivity analyses without computed data showed similar results (Additional files 6, 7, 8, 9 and 10). Achieving SVR was not associated with changes in the FSS-9 sum score from baseline to EOT12, adjusted for sociodemographic factors, injecting drug use, and types of drugs used (Additional files 11 and 12).