Abstract
Introduction
Pegylated interferon-based therapy for hepatitis C virus (HCV) negatively impacts nutritional state and patient-reported outcomes (PROs) such as health-related quality of life (HRQL). Clinical trials with direct-acting antivirals (DAAs) report significant PRO improvement but real-world data are still scarce.
Methods
Prospective cohort study recruiting HCV patients treated with DAAs in 2015–2016. Data at baseline, end of treatment (EOT) and 12 weeks thereafter (FU12) included: patient-reported medication adherence; SF-36; Karnofsky Performance Status; paid labour productivity; physical exercise level; nutritional state [by body mass index (BMI) and Jamar hand grip strength (HGS)] and Beliefs about Medicines Questionnaire. Potential factors predicting these PROs were evaluated with multiple regression analysis.
Results
A total of 68 patients were enrolled: 85% male, median age 57 years, 80% genotype 1, 40% cirrhotics, 46% haemophilia. Both cure rate and patient-reported adherence were 97%. SF-36 Physical Component Summary did not change (43.2 ± 11.9, 44.9 ± 10.3 and 44.7 ± 10.9 at baseline, EOT and FU12, p = 0.71). In contrast, SF-36 mental component summary (MCS) decreased transiently during therapy (49.2 ± 11.9, 44.6 ± 10.3 and 49.9 ± 12.6 at baseline, EOT and FU12, p < 0.01). Concomitant ribavirin-use was the only independent predictor of decreased SF-36 MCS. BMI (25.7 ± 4.5 and 25.6 ± 4.4 at baseline and EOT, p = 0.8) and Jamar HGS (39.7 ± 13.0, 37.4 ± 11.9 and 37.9 ± 13.8 at baseline, EOT and FU12, p = 0.56) did not change.
Conclusion
Our study reveals concomitant ribavirin as the only independent predictor of transient decrease in SF-36 mental HRQL during DAA therapy. In contrast to interferon-based therapy, DAAs do not affect BMI or Jamar HGS.
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Introduction
Patient-reported outcomes (PROs) have taken centre stage in the assessment of quality provision in hepatitis C virus (HCV) care [1]. While the main goal of HCV antiviral therapy is to achieve a sustained virological response (SVR), which is considered a surrogate marker for favourable long-term hepatic and extra-hepatic clinical outcomes [2], PROs can demonstrate immediate change in patient’s perceived health condition.
A wide variety of PROs such as health-related quality of life (HRQL), labour productivity and physical exercise level are negatively impacted by chronic HCV infection [3,4,5]. Even HCV patients with an early fibrosis stage often report impaired HRQL, predominantly attributable to fatigue or depression [4]. Advanced hepatic disease such as cirrhosis is associated with further HRQL impairment [6]. Interferon- and ribavirin-containing regimens also temporarily compromise patient HRQL perception and may lead to a detrimental nutritional state [7], poor therapy adherence and early treatment discontinuation [8]. On the other hand, HCV patients who accomplished successful viral eradication with an interferon-based regimen exhibited improved HRQL following treatment compared to non-responders [9]. The novel direct-acting antivirals (DAAs) significantly reduce patient treatment burden because of shorter therapy courses and a superior side effect profile compared to interferon-containing regimens. The favourable qualities of second-generation DAAs even resulted in PRO improvement as early as 2 weeks after treatment initiation in clinical trials [10]. However, real-world data on PROs in HCV patients on DAA therapy are still scarce. The current study describes a variety of PROs in a real-world cohort of chronic HCV patients who received DAA treatment.
Methods
Patient Selection and Study Design
All consecutive patients with chronic HCV who received anti-viral treatment with an all-oral DAA regimen at the Department of Gastroenterology of the University Medical Center Utrecht in 2015–2016 were eligible for inclusion in this observational prospective cohort study. Patients with no comprehension of Dutch or English languages and with either HBV or HIV coinfection were excluded.
Patients received DAA therapy in agreement with international guidelines [11, 12]. Medication was dispensed according to usual medical practice and all DAAs were fully reimbursed by the health care insurance (with the exception of the obligatory deductible excess) [11, 12]. Follow-up visits during therapy with the treating physician were at baseline, after 2 and 4 weeks, and thereafter at 4-week intervals. Both PROs and routine laboratory test results were collected at baseline, end of treatment (EOT) and at 12 weeks after treatment completion (FU12). It was aimed to offer support for the patient in cases of any marked decrease in one of the selected PROs (e.g. severe weight loss). The Beliefs About Medicines Questionnaire (BMQ) [13] was collected at baseline and FU12. HCV RNA was assessed using the Cobas Ampliprep and Cobas TaqMan HCV test, Roche (lower limit of detection 15 IU/mL). Sustained virological response (SVR) was defined as negative serum HCV RNA 12 weeks post-treatment. Cirrhosis was defined as either Fibroscan® ≥ 12.5 kPa) [14] or liver histology with METAVIR classification of F4.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional (Medical Ethical Committee of the University Medical Center Utrecht) and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.
Patient-Reported Outcomes
Health-Related Quality of Life and Performance Status
The HRQL was assessed using a validated Dutch version of the Short Form-36 (SF-36) [15]. This questionnaire quantifies HRQL with scores ranging from 0 (lowest) to 100 (highest) using eight subscales consisting of: physical functioning (PF), bodily pain (BP), role physical (RP), general health (GH), role emotional (RE), vitality (VT), social functioning (SF) and mental health (MH). The subscales of SF-36 are summarised as physical component summary (PCS) and mental component summary (MCS). Minimal clinically important difference (MCID) for PCS and MCS was defined as a change of ≥ 5%, in accordance with previous literature [16].
The Karnofsky performance status (KPS) scale, which ranges from 0 to 100, was used to evaluate performance status [17].
Beliefs about Medicines Questionnaire and Treatment Adherence
Patients’ attitude towards medicines was measured at baseline and FU12 using the BMQ [13], which consists of two sections: the BMQ-general and the BMQ-specific which are both scored on a 5-point Likert scale. The BMQ-general assesses beliefs about the harmfulness and overuse of medicine in general. The BMQ-specific assesses patients’ beliefs about the necessity of the prescribed DAAs for controlling their illness and their concerns about the potential adverse consequences of taking it. Mean scores for each subscale are computed and higher scores indicate stronger agreement. Additionally, the BMQ-specific is categorised into four different groups: “accepting”, i.e. necessity score ≥ 2.5 (high) and concerns score < 2.5 (low), “ambivalent” i.e. necessity score ≥ 2.5 (high) and concerns score ≥ 2.5 (high), “indifferent”, i.e. necessity < 2.5 (low) and concerns < 2.5 (low), and “skeptical”, i.e. necessity score < 2.5 (low) and concerns score ≥ 2.5 (high).
Patients’ self-reported medication adherence was registered at each visit. Patient-reported treatment adherence was expressed in percentages which were calculated using the following formula: (the number of pills taken during the treatment period divided by the number of pills prescribed by the physician) × 100.
Nutritional State
Nutritional state was assessed with the voluntary hand grip strength (HGS) according to Jamar. This parameter is a measure of nutritional state [18] and an independent predictor of complications in patients with cirrhosis [19]. The HGS was measured in the dominant hand with a calibrated Jamar dynamometer (Biometrics, Almere, The Netherlands) adjusted for sex, age, and height and compared to a healthy reference population [20,21,22,23]. The best of three consecutive measurements was recorded (1 min recovery time between attempts). In addition, data on weight and body mass index (BMI) were collected at baseline and EOT.
Paid Labour Productivity
For the assessment of paid labour productivity (PLP) patients were asked to provide information on their productivity status. The PLP was defined as full time (≥ 36 h/week), part time (< 36 h/week) or none, and further categorised as either white collar (physically inactive) or blue collar (physically active) labour. Work impairment was defined as any decrease in working hours during or after DAA therapy.
Physical Exercise
At each study visit, patients indicated their level of leisure physical exercise (with exclusion of exercise during paid labour working hours). Patients were divided into the following categories according to their physical exercise activity per week: (1) no significant physical exercise (< 60 min of exercise); (2) 60–150 min of low-intensity exercise; (3) > 150 min of low-intensity exercise; (4) 60–150 min of high-intensity exercise; (5) > 150 min of high-intensity exercise. Low-intensity exercise was defined as walking and leisure cycling. High-intensity exercise was defined as strength training, running and intense cycling.
Statistical Analysis
Continuous data are reported as means with standard deviations (SD) or, in cases of a non-Gaussian distribution, as medians with interquartile range (IQR). Discrete variables are described as absolute and relative frequencies. Differences between subgroups were tested for statistical significance by independent t test or Mann–Whitney U test, as appropriate.
Paired-samples t test or, in cases of a non-Gaussian distribution, the Wilcoxon signed rank test was used to analyse within-group changes between two different time points. In cases of three different time points, a repeated measure ANOVA or a Friedman Test was used in combination with post hoc analysis with Bonferroni correction for multiple testing. Associations between changes from baseline of different continuous outcomes were evaluated with Pearson’s correlation coefficient. Univariable and multivariable linear regression analyses were conducted to identify potential factors predicting changes in KPS and SF-36 Summary scores at EOT and FU12 compared to baseline scores. Potential predictors that were analysed, predominantly based on previous literature, included: gender, age, BMI, prior treatment exposure, use of ribavirin, presence of cirrhosis or concomitant haemophilia [10, 24, 25]. Factors with a p value < 0.2 in univariable analysis were included in subsequent multivariable analysis. Adjusted Beta coefficients with their 95% confidence intervals (CIs) were calculated. A two-sided p value < 0.05 was considered statistically significant. SPSS v.4.0 (IBM, Armonk, NY, USA) was used for statistical analyses and GraphPad Prism v.6.0 (GraphPad Software, La Jolla, CA, USA) for creating graphics.
Results
Patients
A total of 72 consecutive HCV patients who received a DAA regimen were considered for inclusion in this study. Four patients were excluded because of language barriers. The remaining 68 participants (Table 1) were predominantly male (85%) with a median age of 57 years. Genotypes 1a and 1b were the most prevalent (31% and 49%, respectively) and 40% of patients had compensated cirrhosis. Extrahepatic HCV manifestations such as haematologic, auto-immune or dermatologic conditions were not present in the study population. Concomitant inherited bleeding disorders (haemophilia A or B) were present in 46%. The DAA regimens were sofosbuvir-based in 85% and ombitasvir/paritaprevir/ritonavir/dasabuvir (3D)-based in 15%. In total, 63% of all patients received treatment with ribavirin. On average, haemoglobin concentration declined with 1.2 mmol/L during DAA treatment and haemoglobin concentration had recovered completely to baseline levels at FU12. Seven patients (10%) had a history of a depressive disorder of which two were on long-term antidepressant treatment. One patient stopped taking the mood stabiliser during DAA therapy due to resolution of symptoms. During the study period, two patients used antidepressants for reasons other than depression such as attention deficit hyperactivity disorder and neuropathic pain. All patients completed the entire treatment period with follow-up 12 weeks post-treatment available. Adherence was 100% for 66 patients (97%). The remaining two patients missed one and three doses, respectively, but still achieved a SVR. Total SVR rate was 97%. Two genotype 1b patients with mild fibrosis (F0–F1) exhibited positive HCV RNA within 3–6 months after completion of a 3D-based regimen. One case was classified as a relapse and the other as a re-infection with a genotype switch to 1a.
Health-Related Quality of Life and Performance Status
At baseline, the physical component summary (PCS) was impaired in comparison with the general Dutch population [15]; however, there was no subsequent change in PCS during or after DAA therapy (43.2 ± 11.9, 44.9 ± 10.3, and 44.7 ± 10.9 at baseline, EOT and FU12, respectively, p = 0.71) (Table 2). Patients with an inherited bleeding disorder tended to have lower PCS at baseline than those without an inherited bleeding disorder (40.7 ± 10.5 vs. 45.5 ± 9.6, p = 0.06), and this discrepancy was also observed during and after DAA treatment. In multivariable analysis, higher BMI was found predictive for increase of PCS score at EOT compared to baseline (p < 0.05).
The mental component summary (MCS) was similar to the general population at baseline but decreased transiently during therapy (49.2 ± 11.9, 44.6 ± 10.3 and 49.9 ± 12.6 at baseline, EOT and FU12 respectively, p < 0.05) (Table 2). At baseline, patients with an inherited bleeding disorder had substantially higher MCS score in comparison with the non-haemophilic patients (54.7 ± 10.1 vs. 44.1 ± 11.1, p < 0.05). In contrast, cirrhotic patients had significantly lower MCS scores at baseline (45.3 ± 12.8 vs. 51.9 ± 10.6, p < 0.05) than those without cirrhosis. In the multivariable analysis, concomitant ribavirin use was the only independent predictor of decreased MCS during therapy (p < 0.05) (Table 3). Although ribavirin recipients experienced a greater decline in haemoglobin concentration than those treated with ribavirin-free regimens (− 1.7 vs. − 0.4 mmol/L, p < 0.05), the haemoglobin decline was not correlated with the decrease in MSC during DAA treatment (r = 0.14, p = 0.31). Patients not receiving ribavirin had stable MCS levels during treatment (53.2 ± 10.8, 50.3 ± 11.0 and 52.9 ± 11.2 at baseline, EOT and FU12 respectively, p = 0.28).
The eight SF-36 subscales generally decreased during treatment with improvement 12 weeks after end of therapy (Fig. 1). The SF-36 vitality scale, (considered the most affected component of SF-36 in HCV patients[16]), was the only subscale that demonstrated significant improvement at FU12 compared to baseline (+ 5.9, CI 1.2–10.0, p < 0.05).
The overall Karnofsky performance status (KPS) score at baseline was high (92.3 ± 11.7) although patients with cirrhosis had a considerable lower KPS level than non-cirrhotics (87.0 ± 13.8 vs. 96.1 ± 7.7, p < 0.05). Similar to the SF-36 MCS score, KPS showed a significant transient decrease during treatment with subsequent recovery (92.3 ± 11.7, 84.2 ± 13.7 and 90.3 ± 11.8 at baseline, EOT and FU12 respectively, p < 0.05). No predictive factors were identified for decline in KPS during treatment in multiple regression analysis.
Beliefs About Medicines
Paired BMQ results at baseline and 3 months after end of therapy were available for 49 patients (72%). According to the BMQ-specific questionnaire, 37% of all patients had an ‘accepting’ attitude towards DAA therapy which increased to 55% at FU12 (Table 4). This can be explained by a decrease in the proportion of patients with ‘high concerns’ about the potential adverse consequences of taking DAAs from 56% at baseline to 25% at EOT. Overall, changes in attitude towards DAA at FU12 compared to baseline did not reach significance (p = 0.10). When considering beliefs about medication in general, treatment with DAAs had no significant impact on the beliefs about harmfulness (2.3 ± 0.7 and 2.3 ± 0.6 at baseline and FU12, p = 0.65) and overuse (2.5 ± 0.6 and 2.6 ± 0.8 at baseline and FU12, p = 0.51).
Nutritional State
Baseline BMI indicated normal weight (BMI 18.5–25 kg/m2), overweight (BMI > 25–30 kg/m2) and obesity (BMI > 30 kg/m2) in 44%, 40% and 16% of patients, respectively. Overall, no substantial BMI change was observed during therapy (25.7 ± 4.5 and 25.6 ± 4.4 at baseline and EOT, respectively, p = 0.78) and severe weight loss (i.e. ≥ 10% of basal values) did not occur.
In 36 patients, hand grip strength (HGS) measurements according to Jamar were available at baseline, EOT and/or FU12. At baseline, HGS was sufficient in 52–88% of the group, depending on reference values that were used, and this ranged between 40% and 78% at both EOT and at FU12 [21, 23]. Mean HGS during antiviral therapy did not change (39.7 ± 13.0, 37.4 ± 11.9 and 37.9 ± 13.8 at baseline, EOT and FU12 respectively, p = 0.56). A total of 5 patients experienced a reduction of greater than 10% in HGS at EOT; however, this returned to baseline levels for all but one patient at FU12 (Fig. 2).
Paid Labour Productivity and Physical Exercise
Data on paid labour productivity, physical exercise and performance status are given in Table 5. At baseline, paid labour was performed by 50% (54% full time white collar, 6% full time blue collar, 32% part-time white collar and 8% part-time blue collar).
After therapy completion, complete loss of labour and work impairment were reported by 8% and 19% of all patients with paid labour at baseline, respectively. All three patients with complete loss of labour had an inherited bleeding disorder. At FU12, two of these three had returned to working the same hours as before treatment initiation.
Prior to antiviral therapy, 32% of all patients performed no significant leisure physical exercise at all, and this proportion increased thereafter (52% and 59% at EOT and FU12, respectively). Before initiation of therapy, those HCV patients who performed exercise mostly trained at low intensity (76%) and a smaller proportion performed high-intensity exercise (24%). Abandonment of all significant physical exercise during DAA treatment occurred in 48% of those patients who exercised before DAA therapy. At FU12, exercise was reinitiated by 22% of these patients. There was no difference in haemoglobin concentration decline during treatment in patients who had stopped exercising compared to those who continued (− 1.3 vs. − 1.0 mmol/L, p = 0.40). Overall, the level of physical exercise during DAA treatment changed significantly (p < 0.05).
Discussion
In addition to efficacy and safety data, PROs are important in quantifying the impact and value of DAA therapy [26, 27]. Although clinical trial data suggest that PRO improvement in HCV patients can be accomplished even shortly after DAA treatment initiation [10], this has yet to be confirmed by real-world evidence.
The main finding of our study was that HRQL remained stable during and after DAA treatment when considering the PCS. Several previous clinical DAA trials demonstrate significant improvement of PCS at EOT and/or FU12 [28,29,30]. However, a temporary on-treatment decline in PCS during sofosbuvir/ribavirin treatment has also been reported [24]. Differences between our current study and previous trials could be related to a different patient selection. For instance, a large proportion of our patients had an inherited bleeding disorder and this subgroup exhibited lower PCS scores throughout the treatment and follow-up period compared to those without an inherited bleeding disorder. The mental component summary (MCS) revealed an important on-treatment decline in our patients with complete recovery at follow-up. Concomitant ribavirin was the only independent predictor of the temporary decline in MCS. Previous literature reports similar and reversible on-treatment declines in the MCS in HCV patients treated with a ribavirin-containing regimen. Of note, those patients who did not receive ribavirin in these clinical trials showed an early increase in the MCS after the start of DAA treatment [28, 31]. Patients in our study with a ribavirin-free regimen had no significant change in MCS level during therapy compared to baseline. With respect to the individual SF-36 domains, vitality demonstrated the most pronounced and clinically important improvement at FU12 compared to baseline (+ 5.9), which is in accordance with previous literature that describes vitality as one of the key SF-36 domains affected by HCV [16].
Patients with an inherited bleeding disorder comprise a large proportion of our cohort with excellent SVR-rates of 97%, which is in agreement with other studies in this patient category [32, 33]. To our knowledge, this is the first real-world report on PROs of HCV patients with an inherited bleeding disorder during DAA treatment. Patients with an inherited bleeding disorder had substantially lower PCS scores in comparison with the other patients. This could relate to the consequences of haemophilia (e.g. disabling arthropathy). In contrast, their MCS scores at each time-point during the study period were significantly higher than in the other patients. MCS scores in patients with haemophilia have previously been described to be relatively high in comparison with the country-specific normative scores [34, 35]. Since quality of life measurement expresses the patient’s subjective perception of their level of functioning compared to what they believe to be optimal, we hypothesise that the relatively high MSC scores in haemophiliacs in our study reflect a high degree of chronic disease acceptance in this well-adapted patient group.
It has been reported that patients’ beliefs about medicines as assessed with the BMQ is related to medication adherence in inflammatory bowel disease and depressive disorders [36, 37]. In this cohort, the selection of patients with an ‘accepting’ attitude towards DAAs improved from 37% at baseline to 55% at FU12. This was mainly due to a decrease in ‘high concerns’ about the potential adverse consequences of taking DAAs from 56% at baseline to 25%. At FU12, 76% of patients scored ‘high’ on beliefs about DAA necessity and 75% scored ‘low’ on concerns about DAAs, so both domains would have to be addressed equally to improve the overall patient acceptance of DAAs in the future. The relationship between patients’ attitude and adherence could not be investigated since 97% of this cohort reported perfect adherence (= 100%). This may be an overestimation of true adherence since adherence in this study was patient-reported and therefore subject to recall bias. Nevertheless, non-adherence does not appear a major problem in DAA therapy [38, 39].
Malnutrition can predict complications in patients with cirrhosis [19, 22] and severe weight loss (> 10%) during treatment often occurred in the interferon era [7]. To our knowledge, our study is the first report on nutritional state of HCV patients during all-DAA treatment. In our cohort, no significant changes in mean BMI and hand grip strength according to Jamar were found.
Infection with HCV imposes an economic burden with impaired work productivity [3, 40, 41]. Our study shows a high unemployment rate of 50% in patients with chronic HCV at baseline, which is in line with large international health surveys (7–74%) [3, 42, 43] and a previous study in the Netherlands (54%) [44]. Work impairment (i.e. decrease in working hours) in our cohort occurred in 15% during treatment which is lower than previously described (26–30%) [5, 42, 43]. However, actual work impairment may be higher as patients only reported on absenteeism and not presenteeism (i.e. being on the job but with diminished work productivity because of illness) which has been documented to be the predominant factor in work impairment in HCV patients receiving interferon-based therapy [5, 42, 43]. About one-third (32%) of all HCV patients performed no leisure physical exercise at baseline, comparable with previous literature (32–52%) [3, 43].
Our study has several strengths and limitations. First of all, it provides results on a wide range of validated PRO measures that were collected prospectively. Secondly, it contributes to the scarce knowledge on PROs in HCV patients with an inherited bleeding disorder. On the other hand, the inclusion of patients with an inherited bleeding disorder might cause somewhat diminished generalisability of the results. Of further note, patients with decompensated cirrhosis were not included in this study. Although we made efforts to minimise the amount of loss to follow-up, there are still some missing values in a number of outcomes variables which may have influenced our results. Finally, the relatively small number of patients may have prohibited us from demonstrating overall improvement in PROs and also precluded analysis of the potential effects of different DAA regimens on PRO values.
Conclusion
In conclusion, our real-world experience with DAAs reveals reversible decline of the SF-36 Mental Component Summary without change in the Physical Component Summary or the nutritional state. Concomitant ribavirin therapy was the only predictive factor for decreased Mental Component Summary.
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Acknowledgements
We thank all the participants of our study for their contribution and cooperation.
Funding
This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. No funding or sponsorship was received for the publication of this article.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authors’ Contributions
Andy I.M. Hoepelman: critical revision of the manuscript; Carina J.R. Verstraete: acquisition of data, critical revision of the manuscript; Eveline P. Mauser-Bunschoten: critical revision of the manuscript; Faydra I. Lieveld: acquisition of data, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript; Joop E. Arends: critical revision of the manuscript; Joep de Bruijne: critical revision of the manuscript; Karel J. van Erpecum: analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript; Linde M. Amelung: acquisition of data, analysis and interpretation of data, critical revision of the manuscript; Patricia A.M. Kracht: acquisition of data, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript; Peter D. Siersema: critical revision of the manuscript. All authors have read and approved the final article.
Disclosures
Andy I.M. Hoepelman: advisory boards: Abbvie, BMS, Gilead, Janssen, MSD; consultancy: AbbVie; financial support for HCV retrieval project from Abbvie, BMS, Gilead and MSD; Eveline P. Mauser-Bunschoten: has received unrestricted research/educational support from CSL Behring, Bayer, Baxter, Griffols, Novo Nordisk, Pfizer, Biotest, Roche and Sanquin; Joop E. Arends: advisory boards: Abbvie, BMS, Gilead, Janssen, MSD and ViiV; research grants: AbbVie, BMS; Karel J. van Erpecum: advisory boards: Abbvie, BMS, Gilead, Janssen-Cilag. Patricia A.M. Kracht, Faydra I. Lieveld, Linde Amelung, Carina J.R. Verstraete, Joep de Bruijne, and Peter D. Siersema have nothing to disclose.
Compliance with Ethics Guidelines
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional (Medical Ethical Committee of the University Medical Center Utrecht) and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.
Data Availability
The dataset analysed during the current study is available from the corresponding author on reasonable request.
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Kracht, P.A.M., Lieveld, F.I., Amelung, L.M. et al. The Impact of Hepatitis C Virus Direct-Acting Antivirals on Patient-Reported Outcomes: A Dutch Prospective Cohort Study. Infect Dis Ther 7, 373–385 (2018). https://doi.org/10.1007/s40121-018-0208-z
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DOI: https://doi.org/10.1007/s40121-018-0208-z