Only partial improvement in health- related quality of life after treatment of chronic hepatitis C virus infection with direct acting antivirals in a real- world setting— results from the German Hepatitis C- Registry (DHC- R)

Improvement of health- related quality of life (HRQoL) is frequently reported as a benefit when treating hepatitis C virus infection (HCV) with direct acting antivirals (DAA). As most of the available data were obtained from clinical trials, limited generalizability to the real- world population might exist. This study aimed to investigate the impact of DAA therapy on changes in HRQoL in a real- world setting. HRQoL of


| INTRODUC TI ON
With an approximate prevalence of 1% (71 million people) worldwide, chronic hepatitis C virus (HCV) infection represents one of the major global health issues. 1 HCV is commonly known as a hepatotropic virus. Liver-associated complications of HCV infection comprise the development of cirrhosis in up to 30% of cases, with an annual risk of hepatocellular carcinoma (HCC) of 2%-4%. 2 However, in up to 75% of patients, extrahepatic manifestations are present, 3 for example lymphoproliferative disorders, type II diabetes mellitus or dermatological diseases. 4 Importantly, up to 50% of HCV-infected patients develop neuropsychiatric symptoms such as fatigue, depression or cognitive disorders, which occur independently of the severity of liver disease and may even represent the clinically predominant problem. 4,5 To evaluate the comprehensive consequences of chronic HCV infection, assessment of patient-reported outcomes (PRO), for example the self-reported health-related quality of life (HRQoL), has become of increasing importance. Not surprisingly, an impairment of HRQoL is commonly reported in patients with chronic HCV infection. 6 -8 Concerns about transmitting the infection to contact persons may deteriorate physical and mental well-being.
Also, the medical condition of the liver disease (eg chronic hepatitis, liver cirrhosis) as well as virus-induced neuropsychiatric extrahepatic manifestations are supposed to contribute to reduced HRQoL. 9,10 Antiviral treatment of chronic HCV infection was revolutionized in 2011 with the approval of the first direct acting antivirals (DAA).
Modern DAA regimens are endowed with SVR rates >95% and very moderate side effects. 11 Achievement of SVR is associated with normalization of liver enzymes, regression of fibrosis and reduced risk for HCC and all-cause mortality. 12 Next to liver-related benefits, 13 SVR is regularly reported to be linked to an overall improvement of PRO's, including HRQoL 14 as well as extrahepatic complications including neuropsychological symptoms. 15 In some patients with moderate liver disease but a high prevalence of neuropsychological symptoms and/or a low HRQoL (eg drug/alcohol users and/or patients suffering from depression), this may represent the leading motivation to start antiviral treatment.
However, most of the recently available data investigating alterations in self-reported HRQoL under modern DAA combinations were obtained from clinical trials and might have limited generalizability compared to the real-world populations. Especially, population subgroups with a known higher HCV prevalence compared to the general population (eg active substance users 16 ), are regularly excluded from clinical trials. 17 Thereby, in patients with active drug usage, HIV coinfection, opioid substitution therapy (OST) or significant alcohol consumption, an impaired HRQoL is & Co. KG; Deutsches Zentrum für Infektionsforschung scores (MCS and PCS) were defined as a minimal clinical important difference (MCID).
Potential predictors of HRQoL changes were analysed. Overall, a statistically significant increase in HRQoL after DAA therapy was observed, that was robust among various subgroups. However, roughly half of all patients failed to achieve a clinically important improvement in MCS and PCS. Low MCS (p < .001, OR = 0.925) and PCS (p < .001, OR = 0.899) BL levels were identified as predictors for achieving a clinically important improvement. In contrast, presence of fatigue (p = .023, OR = 1.518), increased GPT levels (p = .005, OR = 0.626) and RBV containing therapy regimens (p = .001, OR = 1.692) were associated with a clinically important decline in HRQoL after DAA therapy. In conclusion, DAA treatment is associated with an overall increase of HRQoL in HCV-infected patients. Nevertheless, roughly half of the patients fail to achieve a clinically important improvement. Especially patients with a low HRQoL seem to benefit most from the modern therapeutic options. Importantly, in our study, roughly half of the patients failed to achieve a clinically important improvement in HRQoL.
Various risk factors for an absent improvement in HRQoL were evaluated. commonly reported independently of concomitant HCV infection and therefore, effects of HCV treatment on HRQoL might be partially masked. 14,18,19 This study aimed to investigate the association of DAA therapy on the likelihood for clinically important improvements of HRQoL in a real-world setting. A particular focus of the analysis was put on subgroups of patients for whom a change in HRQoL was considered to be of particular relevance. Therefore, we longitudinally assessed Short-Form 36 (SF-36) scores before and after DAA treatment within the German Hepatitis C-Registry. Baseline (BL) factors associated with clinically important changes in HRQoL after HCV treatment were sought to be identified.

| Study design and study population
For this real-world study, data were obtained from the German Hepatitis C-Registry (DHC-R), a national real-world cohort of approximately 17,600 HCV-infected patients to date. Registry eligibility criteria include age ≥18 years and written informed consent to study participation and data usage. Collected data include BL sociodemographic information comprising age, sex and ethnicity.
Various laboratory variables were obtained at BL, including HC viral load (IU/ml) and HCV genotype.

| HRQoL instrument
The SF-36 health survey is an extensively used generic self-

| Characteristics of study population
A total of 1180 patients with obtained SF-36 data on BL, EoT and FU12/24 were considered for the analyses. Genotype 1 was the most prevalent genotype in our cohort (81.5%; n = 962/1180). The overall SVR rate (SVR12/24, ITT) was 97.7% (n = 1153/1180). Only 0.3% of patients discontinued DAA treatment. Detailed demographic and clinical characteristics of the study population are presented in Table 1.

| Changes in the values of HRQoL from baseline to FU12/24
Nine subgroups of patients were considered to be of particular interest when analysing changes in the HRQoL. These predefined subgroups were patients treated without RBV and achievement of SVR (I), as this is the most frequent group when using modern DAA regimens according to the current treatment guidelines, 28 Table S1. Analyses of the total study cohort result in a significant improvement of HRQoL from BL to FU12/24 as indicated by a significant increase in the mean values of PCS (48-50; p < .001) and MCS (40-45; p < .001).
Moreover, the significant increase in both summary scores was consistently documented over all eight selected subpopulations, with an exception in PCS increase with regard to HIV-infected patients (p = .056) and patients with significant alcohol intake (p = .400).
However, although statistically significant, absolute increase of PCS and MCS was rather low for some subpopulations. Among patients ≥65 years absolute mean improvement in MCS and PCS was only 3 (p < .001) and 2 (p = .001), respectively. Similarly, only very moderate but statistically significant changes were documented with regard to physical health in patients with active drug usage (p = .003), opioid substitution (p = .008) and patients with cirrhosis (p < .001).
Mean PCS improvement from BL to FU12/24 was only 2 in all three groups. Of note, MCS increase was particularly high in those with active drug use (37-44; p < .001). Considerable improvements of MCS were also documented in patients with alcohol consumption

| Baseline parameters associated with clinically important changes in HRQoL
We next aimed to identify predictive factors associated with clini- were no independent predictors for a further decline after DAA treatment in this subgroup. In contrast, PCS value at baseline was independently linked to MCS decline in these patients (Table S2a,b).  (Table S3).  (Table 5).   Parameters associated with absence of improvement or further decline in HRQoL were depression, absence of SVR, fatigue, increased GPT levels, ribavirin containing therapy regimens and obesity. Nevertheless, HRQoL is a multidimensional concept and therefore additional reasons, differential diagnosis and possible therapeutic concepts should be considered when a decline in HRQoL is recognized. Further research with longer follow-up is necessary to enhance the follow-up care for patients with a risk of long-term suffering even after clearance of the infection.

ACK N OWLED G EM ENTS
Data were derived from the German Hepatitis C-Registry (Deutsches and Roche Pharma AG (until 2017-07-14). We thank all study nurses and all study investigators. Statistical analyses were performed by Heike Pfeiffer-Vornkahl from e.factum GmbH.

CO N FLI C T O F I NTE R E S T
Valerie Ohlendorf has nothing to disclose. Arne Schäfer reports personal fees from Novo Nordisk and Amgen outside the submitted work.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.