Excellent outcome of direct antiviral treatment for chronic hepatitis C in Switzerland

Bachofner Jacqueline A.a, Valli Piero V.a, Bergamin Irinae, Kröger Arnea, Künzler Patriziae, Baserga Adrianad, Braun Dominique L.bc, Seifert Burkhardtf, Moncsek Anjaa, Fehr Janb, Semela Davide, Magenta Lorenzod, Müllhaupt Beata, Beretta-Piccoli Benedetta Terzirolid, Mertens Joachim C.a, the Swiss Hepatitis C Cohort Study a Division of Gastroenterology and Hepatology, University Hospital Zürich, Switzerland and Swiss HPB Centre b Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich, Switzerland c Institute of Medical Virology, University of Zurich, Switzerland d Epatocentro Ticino, Lugano, Switzerland e Division of Gastroenterology and Hepatology, Hospital St Gallen, Switzerland f Department of Biostatistics and Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Switzerland


Introduction
Interferon-free direct antiviral agents (DAAs) for the treatment of chronic hepatitis C (CHC) became available in Switzerland in December 2013.In large registration studies, DAA treatment resulted in sustained virological response (SVR) rates of more than 90% in many patient populations with minimal side effects [1][2][3].Based on these registration studies, recommendations of the major national and international societies quickly adopted the novel treatment regimens for most patients, rendering previous pegylated-interferon (PEG-IFN)-based regimens obsolete (summarised in the EASL and AASLD guidelines on the treatment of chronic hepatitis C virus [HCV] infection) [4,5].With the widespread use of DAA in diverse clinical settings and patient populations, initial registration study results have been challenged by so-called "real life" data that, in several cases, were clearly inferior to the SVR rates expected on the basis of phase III trials [6,7].These data remain controversial, with other studies finding SVR rates similar to registration trials (e.g., treatment in age >65 [8] or human immunodeficiency virus [HIV] co-infected [9]).Given the significant cost and burden to healthcare systems due to the high large number of CHC patients and the high costs of DAA, the success rate and performance of these novel drugs in a clinical situation outside of registration studies is of major interest.Furthermore, it allows for the evaluation of recommended treatment regimens as well as critical evaluation of current local access to medication and reimbursement restrictions.The aim of this study was to assess treatment regimens and success rates of patients with CHC in Switzerland, and to review access and reimbursement limitations with regards to treatment outcome.

Study design
This was an observational study assessing treatment regimens and treatment outcome of a patient cohort suffering from CHC. Reporting of data follows the STROBE Statement (Strengthening the Reporting of Observational studies in Epidemiology) for observational epidemiological studies [10].

Setting
The present study was conducted at three Swiss tertiary care centres (University Hospital Zurich, Kantonsspital St Gallen, Epatocentro Ticino, Lugano).Data collection was performed retrospectively as well as prospectively.Data were analysed per intention-to-treat (ITT) analysis, and per modified ITT analysis with respect to HCV genotype, regimen of DAA therapy, treatment outcome as well as retreatment in patients who did not achieve SVR after the first course of DAA.Patients were recruited between November 2013 and June 2016.Most patients are participants in the Swiss Hepatitis C Cohort Study [11].

Participants
Five hundred and eighty-five patients with CHC undergoing DAA treatment between November 2013 and June 2016 were evaluated.DAA treatment regimens were chosen according to current recommendations of the European Association for the study of the Liver (EASL), Swiss expert opinion statement and/or treatment according to availability, and reimbursement limitations of the Swiss health authorities.Inclusion criteria were (1) age older than 18 years (2), a documented HCV infection (3), a DAA-based therapy for CHC (4), available data on HCV treatment including laboratory data and documented HCV viral load (HCV RNA by PCR [COBAS 4800; Roche Diagnostics, Rotkreuz, Schweiz]), and (5) patient informed consent.Patients not meeting these criteria were not included in the study (see fig. 1).Concomitant liver diseases and co-infections were recorded if available.

Variables
Patients were divided into five groups according to HCV genotype and subtype (1a, 1b, 2-4).Patients with HCV genotype 1 were divided into the subgroups 1a and 1b, since the treatment regimen differs for the two subtypes.In contrast, the other HCV genotypes (2, 3 and 4) were treated with a genotype-specific regimen regardless of subtype.Because of the scarcity of these genotypes in Switzerland, no patients with HCV genotype 5 or 6 infection were included in the study.Successful treatment was defined as negative HCV-PCR 12 weeks after end of treatment (SVR12).Treatment failure was defined as again positive HCV-PCR during antiviral therapy (breakthrough) or after end of treatment (relapse).

Data sources/measurement
HCV genotyping was performed by a line probe assay (Versant HCV Genotype 2.0 Assay, Siemens/Realtime HCV Genotype II, Abbott) and assessment of viral load was performed by a PCR-based test (COBAS 4800; Roche Diagnostics, Rotkreuz, Schweiz).SVR was defined as undetectable HCV RNA by PCR at week 12 after treatment.The lower limit of detection of the HCV-PCR assay was 10 IU/ml at University Hospital Zurich and 15 IU/ml at Kantosspital St Gallen and Epatocentro Ticino.Liver fibrosis was assessed histologically by means of liver biopsy or non-invasively by transient elastography (Fibroscan ® ).Results were graded according to Metavir F stages with transient elastography values of >9.5 kPa corresponding to Metavir F3 while transient elastography values >12.5 equalling Metavir F4 [12].If both biopsy and transient elastography results were available, transient elastography values were only used for analysis if more recent than biopsy.

Bias
To control for a selection bias, the study had defined inclusion and exclusion criteria, which reflects the Swiss CHC population undergoing antiviral treatment.

Study size
All patients with CHC undergoing DAA treatment between November 2013 and June 2016 from three tertiary Swiss hepatology centres were screened for study participation.

Statistical methods
Statistical analysis was performed using SPSS 22.0 (IBM Corp, Armonk, NY USA).Graphs were generated using PowerPoint (Version 14.6.9,Microsoft PowerPoint Mac OS X 2011).Patients lost to follow-up were excluded before performing statistical evaluations (see fig. 1).

Ethics statement
The study protocol was designed according to the ethical guidelines of the 1975 Helsinki Declaration.The ethics committee of the Canton of Zurich (BASEC 2016-00341) and the ethics committees of the participating centres (BASEC 2016-00171) approved the present study.Written informed consent of all patients was obtained.For the statistical analysis all clinical data were anonymised.

Patient and treatment characteristics
A total of 584 patients from three centres undergoing DAA treatment for CHC were evaluated.Eighteen patients did not meet inclusion criteria and were therefore excluded from further analysis (fig.1).The 565 remaining patients that underwent DAA treatment with a minimal post-treatment follow-up of 12 weeks were included and a modified ITT analysis was performed.Characteristics of the cohort are shown in table 1. Seventy-one percent (403 of 565, 71.3%) of patients had Metavir F3 or F4 fibrosis as determined by biopsy or transient elastography.Two hundred and fifty-seven patients in our study suffered from liver cirrhosis (liver fibrosis stage F4).Among those cirrhotic patients there were 197 patients with Child-Pugh Class A (197 of 257, 77%) and 18 patients with Child-Pugh Class B (18 of 257, 7%).There was no cirrhotic patient with Child-Pugh Class C. Five-hundred-twelve patients received an interferon-free DAA combination ± ribavirin (512 of 565, 90.6%) and 53 patients a combination of PEG-IFN, ribavirin and sofosbuvir (53 of 565, 9.4%).Mean treatment duration for all patients was 15 weeks.Overall SVR rate was 94% (530 of 565, 93.8%, 95% CI 92-96%) for all patients treated (fig.2).Of the patients without cirrhosis (fibrosis stage F1-F3), 95% reached SVR (286 of 300, 95% CI 93-97%).SVR rate in patients with liver cirrhosis (fibrosis stage F4) was lower (236 of 259, 92%, 95% CI 88-94%).Cirrhotic patients with Child-Pugh Class A reached SVR in 91% (179 of 197, 95% CI 87-95%) and cirrhotic patients with Child-Pugh Class B reached SVR in 83% (15 of 18, 95% CI 65-100%]) of cases.Fifty-five percent of all patients were treatment naïve (310 of 565, 54.9%), 46 patients had a concomitant HIV infection (46 of 565, 8.1%), 6 patients had a hepatitis B virus (HBV) infection (6 of 565, 1%) and 2 patients suffered from HIV and HBV co-infection (2 of 565, 0.4%).There was one case of each of the following: primary biliary cholangitis, primary sclerosing cholangitis, haemochromatosis, autoimmune hepatitis and Wilson's disease (1 of 565, 0.2%).Reasons for exclusion from the final analysis were liver transplantation during the course of therapy (5 of 584, 0.9%), change in HCV treatment (2 of 584, 0.3%) and missing data (2 of 584, 0.3%).One patient stopped the treatment because of reasons other than adverse events (1 of 584, 0.2%).There were no SVR data for five patients at the time of analysis (5 of 584, 0.9%) and four patients (4 of 584, 0.7%) were lost to follow-up.Reporting SVR results by ITT analysis, overall SVR rates were (530 of 575, 92%, 95% CI 90-94%).In this analysis the following 10 patients are included: one patient who stopped the treatment (1 of 10, 10%), five patients who had no SVR value (5 of 10, 50%) and four patients who were lost to follow-up (4 of 10, 40%).The following results on treatment outcome are from a modified ITT from which the previously mentioned 10 patients were excluded.).This is in concordance with international studies on RAS incidence [13][14][15] Re-treatment of this group was successful in a large proportion of patients (fig.3).Of 16 patients that did receive re-treatment, 14 patients achieved SVR (88%).For several patients, reimbursement of re-treatment is currently under revision.Only one patient did not have any further treatment options based on his RAS profile.

Discussion
This Swiss data for novel DAA treatment of CHC shows SVR rates very similar to those from the registration trials [1][2][3]16].This is in accordance with other studies that also reproduce the generally excellent SVR rates, especially among patients with genotype 1 CHC [17][18][19].For the observed time period between 2014 and mid-2016, genotypes 2 and especially 4 had limited treatment options.The data reported here do not take into account the introduction of novel DAAs such as elbasvir/grazoprevir (April 2016) and sofosbuvir/velpatasvir (January 2017) that were licensed after this study and should significantly improve the SVR rates in these patient groups [20,21] Most relapses were detected early in the post-treatment period, usually within the first 4 weeks.Fortunately, re-treatment was successful in most patients.Access to DAA treatment and reimbursement of the very high therapy costs is a worldwide challenge for HCV patients as well as for healthcare systems [22][23][24][25].Limitations of access and reimbursement have been introduced in many countries [26].Beginning in 2014, the reimbursement of DAA therapies in Switzerland was limited to patients that had histologically verified advanced fibrosis or cirrhosis (Metavir F3 or F4) or showed transient elastography values >9.5 kPa in two consecutive measurements with a minimum interval of 3 months [27].Moreover, several of the recommended therapeutics were not approved or reimbursed.This made modifications and deviations from the treatment recommendations by EASL necessary in 2014 and early 2015.Thirty percent of patients that did suffer a relapse were not treated according to international guidelines due to limitations of availability or reimbursement.Until the market introduction of paritaprevir/ritonavir/ombitasvir plus ribavirin, and grazoprevir/elbasvir in mid-2016, there was no approved interferon-free treatment regimen for HCV genotype 4 available in Switzerland, and alternative treatments required case-by-case approval of reimbursement by health insurance providers.
Since the analysis of our data, several pan-genotypic treatments have been approved that show high efficacy and SVR rates.Moreover, limitation for treatment reimbursement according to fibrosis grade has been lifted mean-

Original article
while.These new circumstances expand the population of HCV patients that will be treated.Future studies will need to include data on these new patient populations and medications.This study highlights the importance of the early adoption of internationally accepted treatment guidelines, if possible.Moreover, approved but suboptimal treatment regimens that did comply with national drug availability and reimbursement limitations may have generated excessive costs for the healthcare system.
Our study has limitations.Patients were only included from three referral centres in this non-randomised observational study with a retro-and prospective follow-up.Therefore, the study population might not reflect the standard Swiss HCV population.But at the same time, patients with advanced fibrosis and cirrhosis might be overrepresented in this tertiary care population.As we have shown, the SVR rate in this population is lower, and therefore these excellent SVR results might nevertheless be representative for Switzerland.Finally, the median follow-up period is relatively short, but it is well documented that late relapses are extremely uncommon [28].Accordingly, this short follow-up has no relevant impact on the SVR reported in this study In summary, data from Switzerland for DAA treatment in CHC confirm the excellent efficacy of these drugs.These results are novel and have not been reported for Switzerland so far.They are in line with other national and international studies reporting excellent overall outcomes for DAA in a post-approval real-life setting.Patients who do suffer a relapse can in most cases be successfully re-treated.Limitations of access prevented optimal therapy in some patients.

Figure 1 :
Figure 1: Flow chart of patient recruitment.

Figure 2 :
Figure 2: Overall SVR rate and SVR rates for individual HCV genotypes.Eight patients with not further specified genotype 1 are not included in this figure.