Impact of successful treatment with direct-acting antiviral agents on health-related quality of life in chronic hepatitis C patients
Regina Juanbeltz ,
Iván Martínez-Baz,
Ramón San Miguel,
Silvia Goñi-Esarte,
Juan Manuel Cabasés,
Jesús Castilla
Published: October 9, 2018
https://doi.org/10.1371/journal.pone.0205277
Abstract
Background
Direct-acting antivirals (DAA) have demonstrated high efficacy to achieve sustained virological response (SVR) in chronic hepatitis C patients. We aim to assess the change in health-related quality of life (HRQoL) among patients successfully treated, and to identify predictors of this variation.
Methods
In a prospective observational study, patients with chronic hepatitis C who started DAA therapy between May 2016 and April 2017 completed the EQ-5D-5L questionnaire at baseline and 12 weeks after the end of therapy before knowing the virological result. Analysis included all patients with SVR.
Results
Median baseline EQ-5D-5L scores of the 206 enrolled patients were 0.857 utility and 70.0 visual analogue scale (VAS). Following SVR, a reduction occurred in the proportion of patients with mobility problems (35% vs 24%, p = 0.012), pain/discomfort (60% vs 42%, p<0.001) and anxiety/depression (57% vs 44%, p = 0.012), with an increase in utility (+0.053, p<0.001) and VAS (+10, p<0.001). Score improvements were also observed in cirrhotic (+0.048 utility, p = 0.027; +15 VAS, p<0.001) and HIV co-infected patients (+0.039 utility, p = 0.036; +5 VAS, p = 0.002). In multivariate analyses, middle age (45–64 years) and baseline anxiety/depression were associated to greater improvement in utility after SVR, and moderate-advanced liver fibrosis and cirrhosis to greater increase in VAS score. Low baseline values were associated to greater improvements in utility value and VAS score.
Conclusions
The cure of chronic hepatitis C infection with DAA has a short term positive impact on HRQoL with improvement in mobility, pain/discomfort, anxiety/depression, utility value and VAS score. Patients with poor baseline HRQoL were the most beneficed.
Successful treatment with DAA on health-related quality of life in patients with chronic hepatitis C was associated to significant improvement in the majority of HRQoL domains measured by the EQ-5D-5L instrument. Improvement of HRQoL started shortly after the initiation of therapy and enhanced after achieving SVR, including cirrhotic and HIV co-infected patients, classically considered “difficult to treat” populations. Main improvements occurred in mobility, pain/discomfort and anxiety/depression dimensions, as well as in the health utility and VAS score. Although evidence from “real life” setting is lacking [
23], patient reporting outcomes with DAA in clinical trials also suggest benefit after treatment [
33–
36]. Relationship between SVR and HRQoL improvement has not been elucidated, but viral clearance has been suggested to result in cytokines and inflammatory biomarkers reduction in periphery and central nervous system, leading to a positively impact on patients’ experience [
37,
38]. The improvement observed in the well-being of patients cured with DAA reinforces the idea that chronic HCV infection, far from being a purely hepatic disease, presents a clearly systemic component and impaires HRQoL [
39,
40]. According the Spanish National Health Survey 2011/12 [
41], the general population aged 45–54 years referred a VAS score of 77.2 and utility value of 0.928, being higher figures than those referred by our patients before treatment, 70.0 and 0.875, respectively. Lower scores in our patients suggest a HRQoL impairment associated to chronic hepatitis C infection [
7,
29].
In the first 4 weeks of treatment, the median VAS score increased 5 points and improved health dimensions that were negatively affected with interferon treatments [
42]. This early improvement in HRQoL has been described for DAA [
35], contrary to what happened with peg-IFN + RBV and triple therapy with boceprevir or telaprevir [
10,
17,
43,
44], which seems to relate HRQoL deterioration during treatment to interferon and not to second generation DAA. The use of RBV was not associated with significant disutility, a fact that suggests a lower impact of side effects such as anaemia and pruritus, when administered in combination with DAA compared to when administered with interferon. This aspect reinforces the idea of the good tolerability of DAA in real life conditions [
45,
46].
In clinical practice, patient reporting outcomes constitute useful tools in the evaluation and monitoring of health interventions, since they provide information on patient perception and needs [
47]. Knowing the predictors of HRQoL improvement after the treatment of hepatitis C can help to strengthen patient adherence and motivation. Middle age, baseline anxiety-depression, advanced fibrosis and cirrhosis were found to be the most consistent predictors of HRQoL improvements after SVR. Precisely, those factors have been previously associated with impairment in HRQoL among chronic hepatitis C patients [
4,
29,
48] and appear to be key determinants for HRQoL deterioration prior to therapy [
14]. The high prevalence of depression and anxiety in HCV patients before treatment initiation [
49] would reinforce the need for psychosocial screening, even more when considering that a greater HRQoL improvement may occurs in those patients after SVR. In our study, patients with worse baseline HRQoL score showed more significant improvements, a common finding in all types of clinical trials [
50]. This result is consistent with the greater improvement in HRQoL in cirrhotic patients, with comorbidity or HIV co-infection, observed in the stratified analysis of the study.
This study provides useful information for cost-effectiveness analysis. Utility values allow to obtain quality adjusted life years, and to estimate incremental cost-utility ratios in pharmacoeconomic analysis. Since the advent of second-generation DAA, some cost-utility analyses have been published to assess their efficiency [
51–
54], with more or less favourable incremental cost-utility ratios depending on the degrees of liver fibrosis, the cost of the drugs and the previous treatment experience. More favourable treatment efficiency in patients with a high degree of fibrosis is derived from the potential more imminent progression to severe stages, associated with greater disutility and greater consumption of health resources [
51,
52]. According to our results, the more significant HRQoL improvement in cirrhotic patients after the SVR reinforces this idea. In any case, a decline in the cost of drugs and the possibility of currently treating patients with a low degree of liver fibrosis with short 8-week regimens, would reduce the incremental cost-utility ratios and improve the efficiency of treatment in all patient subpopulations.
This real-life prospective study included hepatitis C patients who received treatment in a regional reference hospital in northern Spain. Although the epidemiology of HCV infection and the introduction of DAA have been relatively homogeneous in Spain, we can not rule out some geographical differences which would affect representativeness of our study. However, patients were infected by all HCV genotypes with a distribution similar to that of the population in our environment [
55], in the different stages of the disease, treated with all available combinations of DAA and without excluding patients with comorbidity. The indication and choice of treatment was based on the same protocol, developed according to clinical and efficiency criteria. HRQoL was analysed including subpopulations of patients usually underrepresented in clinical trials, such as those with psychiatric disorders or persons co-infected with HIV [
23], which represent one third of the population in this study. All the interviews were carried out by the same investigator, in order to minimize the potential bias of the interviewer. The timing of the interview may affect the results. The post-12 interview was conducted in our study before knowing the SVR result, in order to avoid the possible overestimation on patient’s HRQoL self-assessment secondary to the euphoria experienced at that moment [
43,
56]. However, when patients know HCV become negative after treatment, the worry about the complications of the disease probably decrease and an improvement in the anxiety dimension could be greater than that observed in our study. A long-term evaluation of HRQoL after SVR would contribute to understand the effect of timing on HRQoL results.
Two possible shortcomings of our study need to be considered. First, the population size, although similar or greater than that of other observational studies [
35,
14,
57] was not large enough to obtain conclusive results in some subanalyses. In any case, the patients included accounted for 78% of the patients who received treatment successfully during the study period. Second, the EQ-5D-5L is a generic questionnaire. Although it has been used in many scenarios, including chronic hepatitis C and its treatment, its combination with a disease-specific questionnaire would have been desirable. Time-related limitations in terms of patient care in the consulting room and of personnel related to completing the interviews discouraged the use of other questionnaires. However, studies that use both types of tools for measurement of patient reporting outcomes in patients treated with DAA therapy obtained similar results and good correlation between the generic and HCV-specific questionnaires [
10,
35]. EQ-5D-5L version was used in this study, as it has demonstrated to be a valid extension of EQ-5D-3L, providing more precise measurement at both individual and group level [
58–
61]. Since no 5L value sets were yet available in Spain, the crosswalk value set was used in this study, as the EuroQol recommended [
31].
The new antivirals available recently seem to improve even more the treatment outcomes, being expected this same effect on quality of life.
Conclusions
In summary, this study shows a short-term positive impact of SVR on the HRQoL of patients with chronic hepatitis C treated with interferon-free DAA. The greatest impact was on health dimensions of mobility, pain/discomfort, anxiety/depression, and in utility values and the VAS of the EQ-5D-5L questionnaire. The treatment did not produce disutility, nor did the use of RBV. Predictors of greater improvements in HRQoL with SVR may be baseline depression, anxiety, moderate-advanced fibrosis and cirrhosis; which may help to give priority to patients for treatment. The results obtained provide the patient's perspective in the assessment of DAA and information on patient reporting outcomes to be incorporated in cost-utility studies.
