The Impact of Hepatitis C Virus Direct-Acting Antivirals on Patient-Reported Outcomes: A Dutch Prospective Cohort Study

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.

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.

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.

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.

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).

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).

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).