- Email: [email protected]
Efficacy and safety of sofosbuvir-based triple therapy in hepatitis C genotype 4 infection
Accepted Manuscript Title: Efficacy and safety of sofosbuvir-based triple therapy in hepatitis C genotype 4 infection Author: Malte H. Wehmeyer Sabine Jordan Stefan L¨uth Johannes Hartl Albrecht Stoehr Christiane Eißing Ansgar W. Lohse J¨org Petersen Peter Buggisch Julian Schulze zur Wiesch PII: DOI: Reference:
S1590-8658(15)00347-3 http://dx.doi.org/doi:10.1016/j.dld.2015.05.018 YDLD 2899
To appear in:
Digestive and Liver Disease
Received date: Revised date: Accepted date:
25-2-2015 20-4-2015 18-5-2015
Please cite this article as: Wehmeyer MH, Jordan S, L¨uth S, Hartl J, Stoehr A, Eißing C, Lohse AW, Petersen J, Buggisch P, Wiesch JS, Efficacy and safety of sofosbuvir-based triple therapy in hepatitis C genotype 4 infection, Digestive and Liver Disease (2015), http://dx.doi.org/10.1016/j.dld.2015.05.018 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 Efficacy and safety of sofosbuvir-based triple therapy in hepatitis C genotype 4 infection
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Dr. Malte H. Wehmeyer1*, Dr. Sabine Jordan1*, Prof. Stefan Lüth1, Dr. Johannes Hartl1, Dr. Albrecht Stoehr2, Ms. Christiane Eißing1, Prof. Ansgar W. Lohse1,3, Prof.
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Jörg Petersen2, Dr. Peter Buggisch2, PD Dr. Julian Schulze zur Wiesch1,3
us
(1) I. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf,
an
Martinistraße 52, 20246 Hamburg, Germany
(2) Institut für Interdisziplinäre Medizin an der Asklepios Klinik St. Georg,
M
Lohmühlenstraße 5 / Haus L, 20099 Hamburg, Germany
(3) German Center for Infection Research (DZIF), Hamburg site
Corresponding author
te
d
* = contributed equally
Ac ce p
Julian Schulze zur Wiesch, MD
I. Medizinische Klinik und Poliklinik Universitätsklinikum Hamburg-Eppendorf Martinistr. 52
20246 Hamburg, Germany
Phone: ++49 – 40 – 7410-52831 Fax: ++49 – 40 – 7410-55128 e-mail: [email protected] Word count: 1444; Abstract word count: 147 Funding: Julian Schulze zur Wiesch and Ansgar W. Lohse are supported by the Deutsche Forschungsgemeinschaft (DFG, SFB841). Page 1 of 16
2 Abstract Background: There are only limited data on sofosbuvir-based treatment regimens in hepatitis C virus (HCV) genotype 4-infected patients.
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Aims: To evaluate safety and efficacy of sofosbuvir-based triple-therapy in HCV genotype 4 infection.
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Methods: All HCV genotype 4-infected patients who started sofosbuvir-based tripletherapy at our two centres between January and June 2014 were prospectively
us
included (N=24) and compared to genotype 4 patients treated with
an
peginterferon/ribavirin between January 2001 and December 2012 (N=63). Results: The demographics in the sofosbuvir group and the controls were
M
comparable (males 87.5% and 82.5%; mean age 46.7±9.0 years and 42.0±9.8 years, respectively). Sustained virological response was achieved in 83.3% in the sofosbuvir
d
group and in 47.6% of controls (P=0.003). Fatigue (P=0.007), flu-like (P=0.015),
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gastrointestinal (P<0.001), dermatologic (P<0.001) and psychiatric symptoms (P=0.022) were more common in the control group.
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Conclusions: In our real-life cohort, sofosbuvir-based triple therapy confirmed its high efficacy and safety for chronic genotype 4 hepatitis C.
Keywords: direct acting antivirals; HCV; sustained virological response; SVR
Page 2 of 16
4 Introduction Until recently, dual therapy with peginterferon-alpha (PEG-IFNα) and ribavirin (PR) was the standard of care for chronic hepatitis C virus genotype 4 (HCV4) infection.
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The novel NS5B polymerase inhibitor sofosbuvir (SOF) has pangenotypic efficacy and displays a favourable safety profile [1,2]. Recently, 24 weeks of SOF/ribavirin
cr
was proven to be superior to 12 weeks with SOF/ribavirin in HCV4 infection in a phase II trial (sustained virological response [SVR] 93% vs. 68%) [3]. While the
us
results of this trial are clearly impressive, ideally this study would have benefitted
an
from incorporating a control arm with a peginterferon-containing regimen. Importantly, HCV4 is endemic to low income regions, such as the Middle East or Northern Africa
M
[4], and a 24-week treatment with sofosbuvir outside special treatment programmes is a very costly. Here, we would like to provide further data to the ongoing discussion
Ac ce p
Patients and Methods
te
a “real-life” setting.
d
by describing the results of a small investigator initiated study of SOF/PR for HCV4 in
Data of 24 consecutive HCV4 patients who received therapy with SOF/PR for 12 weeks between January and June 2014 were prospectively collected at our two tertiary care centres for viral hepatitis in Hamburg, Germany. Results were then compared to a historic cohort of 63 consecutive HCV4 patients who had received conventional dual PR therapy for 48 weeks between January 2001 and December 2012. Additional analysis was conducted using a matched control group of 24/63 patients after propensity score analysis for different cofactors. The patients in both groups received bodyweight-adapted dose of ribavirin and either PEG-IFNα-2a (180 µg/week) or -2b (bodyweight-adapted). Patients in the SOF/PR group additionally received SOF 400 mg once daily. The primary endpoint was SVR 12 weeks after end Page 3 of 16
5 of treatment. Secondary endpoints included rapid virological response (RVR), end of treatment response (EOTR) and appearance of adverse events (AE). Univariate analysis (Fisher’s exact test, t-test and Mann-Whitney-U-Test, each were applicable)
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and propensity score analysis were performed using SPSS Version 22. A Pvalue<0.05 was considered statistically significant. The tolerance for differences in
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the propensity score in the matching process was 0.1. The study was approved by
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the local ethics board (Ethikkommission der Ärztekammer Hamburg; PV3939).
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Results
The baseline characteristics and data on treatment outcome of the SOF/PR group
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and the historic controls are presented in Table 1. In SOF/PR patients mean age was 46.7±9.0 years, in PR patients mean age was 42.0±0.8 years (P=0.039). Median viral
d
load at baseline was 5.74 log UI/ml (range 2.01-6.71) in the SOF/PR group and 4.85
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log UI/ml (range 2.70-6.30) in controls (P<0.001). Among SOF/PR patients, 13/24 were treatment-experienced (54.2%) compared to 10/63 in the PR group (15.9%,
Ac ce p
P<0.001). F3 or F4 fibrosis was diagnosed 50% of SOF/PR patients vs. 12.7% in the control group (P=0.073). All cirrhotic patients were Child-Pugh class A (N=5 in the SOF/PR group and N=8 in the PR group). SOF/PR patients had a higher rate of RVR and EOTR as compared to controls (77.3% vs. 41.5% P=0.006; 95.8% and 66.7%, P=0.005; respectively). In an intention to treat analysis, we found 12 weeks of SOF/PR superior to 48 weeks PR with SVR12 in 20/24 patients (83.3%) and 30/63 patients, respectively (47.6%; P=0.003). Three SOF/PR patients experienced a virological failure (relapse in two patients, breakthrough in one patient) and one patient was lost to follow-up. Figure 1 displays the SVR rates in SOF/PR and PR patients in the different subgroups. As analysed per protocol, SVR was achieved in 20/23 SOF/PR patients (87.0%) and in 30/57 Page 4 of 16
6 control patients (52.6%; P=0.005). Patients with a history of non-response or breakthrough (N=6) in the SOF/PR group were at increased risk for virological failure (P=0.001), whereas all treatment naïve patients (N=11) and patients with a previous
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relapse (N=7) achieved a SVR. Furthermore, low baseline platelet counts (median: 122x109/L [range 104x109 – 184x109] vs. 218x109/L [136x109 – 350x109]) and
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advanced age (mean 44.9±8.1 years vs. 55.8±8.2 years) were associated with
treatment failure in the SOF/PR group (P=0.005 and 0.023, respectively). Other
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variables were not associated with SVR12 in the SOF/PR group in our small cohort
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(Table 2).
In the preparation of the additional analysis with matched controls, a propensity score
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was calculated for all patients incorporating sex, age, cirrhosis status, viral load and treatment experience as possible confounders. However, by using a maximum
d
tolerance of 0.1 propensity score difference between matched-pairs of patients, only
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18/24 patients in the SOF/PR group had a sufficient control (panel A in Supplementary Figure S1). Therefore, we reduced the cofactors included in the
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logistic regression model to determine the propensity scores to 3 (sex, age, cirrhosis status; panel B in Supplementary Figure S1). The results of the second analysis with the matched control group largely mirrored the original analysis, details can be found in Supplementary Table S1. An overview and the comparison of adverse events in both groups is provided in Figure 2. Ribavirin dose reduction was necessary in 6/24 SOF/PR patients (25%) and in 18/63 patients of the controls (28.6%; P=0.795). Only 1 patient in the SOF/PR group (4.2%) had to reduce the PEG-IFNα dose compared to 17 patients in the control group (27.0%; P=0.019; Table 1). No differences were observed regarding anaemia (12.5% in SOF/PR patients vs. 14.3% in the control group, P=1.0); thrombocytopenia (4.2% vs. 15.9%, respectively; P=0.174); leukopenia (12.5% vs. Page 5 of 16
7 17.5%, respectively; P=0.749, Figure 2). Supplementary Table S1 summarizes the adverse events in the matched-pairs analysis. No SOF/PR patient and two controls experienced serious adverse events (one patient with exacerbation of neurosyphilis
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and one patient with acute on chronic liver failure; both patients recovered).
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Discussion
Here, we present data of a “real-life” cohort of patients who were treated for chronic
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HCV4 infection with 12 weeks SOF/PR compared to a historic cohort of patients
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(“controls”) treated with PR for 48 weeks. Data of SOF/PR in HCV4 are limited, as only 28 treatment-naïve patients with HCV4 infection were enrolled in the appropriate
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phase III trial [1]. In previous “real-life” studies SVR rates were remarkably lower than those of the respective phase III trials, e.g. in telaprevir- or boceprevir-based
d
treatment regimens [5]. However, our study largely confirms the results from the
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NEUTRINO trial with a frequency of SVR12 of 96.4% in treatment naïve patients infected with HCV4 [1] compared to 100% in our cohort for patients receiving
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SOF/PR. The subgroup analysis revealed that treatment experienced patients with a history of non-response to PR treatment and patients with advanced fibrosis were at increased risk for a virological failure, although the study is limited by the small number of enrolled patients in each subgroup. Our results also indicate that 12 weeks of SOF/PR are significantly more tolerable than 48 weeks of PR. On the one hand, the frequency of severe anaemia, thrombocytopenia and leukopenia, as well as the need for ribavirin dose adjustment was comparable between both groups. On the other hand, PEG-IFNα dose reduction was more common during 48 weeks of PR compared to the shorter 12-week SOF/PR treatment regimen, which indicates the impact of the reduced time-span of PEG-IFNα toxicity in SOF-based triple therapy.
Page 6 of 16
8 Furthermore, efficacy of SOF/PR in HCV4 infected patients is comparable to daclatasvir/PR and superior to simeprevir/PR or 12 weeks of SOF/ribavirin [3,6,7]. Clinical data on other interferon-free regimens such as 12 weeks of SOF/simeprevir,
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SOF/ledipasvir, ombitasvir/paritaprevir/ritonavir/ribavirin, daclatasvir/asunaprevir/beclabuvir or 24 weeks of SOF/ribavirin for HCV4-infection
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are limited, but promising [3,8-10]. Importantly, 31% of the patients in the 24-week
SOF/ribavirin arm in the study of Ruane et al. [3] had to decrease ribavirin dose due
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to adverse effects, Therefore, the need to monitor the patients who receive 24-week
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dual therapy with SOF/ribavirin is not necessarily less intensive than a 12-week course of SOF/PR.
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We are aware of the limitations of our study, in particular, the small and heterogeneous cohort, the lack of data on HCV4 subtypes and the comparison of
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SOF/PR to a historical control group treated with PR. Furthermore, we provide only
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limited data about IL28B polymorphism rs12979860, which has been shown to be an important predictor of SVR in HCV4 infected patients [11].
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However, overall our data supports the alternative strategy of using 12 weeks SOF/PR in treatment of HCV4-infected patients rather than 24 weeks of SOF/ribavirin, at least in treatment-naïve patients or previous relapsers. Given an acceptable tolerability of 12 weeks SOF/PR, this regimen remains a reasonable option, if all-oral therapy is not accessible due to budgetary concerns.
Page 7 of 16
9 References 1. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013;368:1878-1887.
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2. Jacobsen IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med
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2013;368:1867-1877.
3. Ruane PJ, Ain D, Stryker R, et al. Sofosbuvir plus ribavirin for the treatment of
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chronic genotype 4 hepatitis C virus infection in patients of Egyptian ancestry.
an
J Hepatol 2014 Nov 5; doi:10.1016/j.jhep.2014.10.044 [Epub ahead of print]. 4. Wantuck JM, Ahmed A, Nguyen MH. Review article: the epidemiology and
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therapy of chronic hepatitis C genotypes 4, 5 and 6. Aliment Pharmacol Ther 2014;39:137-147.
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5. Wehmeyer MH, Eißing F, Jordan S, et al. Safety and efficacy of protease
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inhibitor based combination therapy in a single-center “real-life” cohort of 110 patients with chronic hepatitis C genotype 1 infection. BMC Gastroenterology
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2014;14:87.
6. Hezode C, Hirschfield GM, Ghesquiere W, et al. Daclatasvir plus peginterferon alfa and ribavirin for treatment-naive chronic hepatitis C genotype 1 or 4 infection: a randomised study. Gut 2014. doi:10.1136/gutjnl-2014-307498 [Epub ahead of print].
7. Moreno C, Hezode C, Marcellin P, et al. Efficacy and safety of simeprevir with pegIFN/ribavirin in naïve or experienced patients infected with chronic HCV genotype 4. J Hepatol 2015. doi:10.1016/j.hep.2014.12.031 [Epub ahead of print]. 8. Hezode C, Asselah T, Reddy KR, et al. Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naïve and treatment-experienced Page 8 of 16
10 patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial. Lancet 2015; doi:10.1016/S01406736(15)60159-3 [Epub ahead of print].
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9. Kapoor R, Kohli A, Sidharthan A, et al. All oral treatment for genotype 4 chronic hepatitis C infection with sofosbuvir and ledipasvir: interim results from
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the NIAID SYNERGY trial. Hepatology 2014;60:321A (abstract).
10. Hassanein T, Sims KD, Bennett M, et al. A randomized trial of daclatasvir in
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combination with asunaprevir and beclabuvir in patients with chronic hepatitis
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C virus genotype 4 infection. J Hepatol 2015; doi:10.1016/j.hep.2014.12.025 [Epub ahead of print].
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11. Ragheb MM, Nemr NA, Kishk RM, et al. Strong prediction of of virological response to combination therapy by IL28B gene variants rs12979860 and
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te
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rs8099917 in chronic hepatitis C genotype 4. Liver int 2014;34:890-895.
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11 Figure legends Figure 1. Frequency of sustained virological response in the different subgroups. Sofosbuvir-based triple-therapy was compared with controls using
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Fisher’s exact test. Stage of fibrosis was assessed according to METAVIR. SOF, sofosbuvir; PR, peginterferon/ribavirin; RVR, rapid virological response; NR/BT,
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non-response/breakthrough]
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Figure 2. Frequency of adverse events in sofosbuvir based triple-therapy
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patients compared to controls.
SOF, sofosbuvir; PR, peginterferon/ribavirin; GI, gastrointestinal; anaemia, Hb < 10g/dL; thrombocytopenia, platelet count < 75 x109/L; leukopenia, white blood cell
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count < 2 x109/L
Page 10 of 16
12 Table 1. Characteristics and treatment outcome of patients receiving sofosbuvirbased triple-therapy compared to historical controls PR
N (%)
N (%)
24
63
21 (87.5%)
52 (82.5%)
46.7± 9.0
42.0± 9.8
Mean age (years) Fibrosis stage (METAVIR)
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Male gender
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N
P-Value
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SOF/PR
0.749
0.039* 0.073
12 (50%)
F3-4
12 (50%)
17 (27.0%)
5 (20.8%)
8 (12.7%)
0.335
53 (84.1%)
<0.001*
7 (29.2%)
3 (4.8%)
0.004*
Non-response
5 (20.8%)
6 (9.5%)
0.279
Breakthrough
1 (4.2%)
1 (1.6%)
1
5.74
4.85
<0.001*
(2.01 – 6.71)
(2.70 – 6.30)
15.1
15.0
(11.8 – 17.2)
(11.5 – 18.3)
200.5
214
(104 – 350)
(59 – 392)
6.8
6.5
(3 – 10.6)
(2.5 – 15.6)
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Cirrhosis (F4) Treatment naïve
11 (45.8%)
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Treatment experienced
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Relapse
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46 (73.0%)
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F0-2
Baseline laboratory
Median Viral load [log IU/ml]
Medina Haemoglobin [g/dL]
Median Platelet count [x109/L]
Median Leucocyte count [x109/L]
0.803
0.948
0.480
Page 11 of 16
13 63
(25 – 538)
(11 – 346)
6 (25%)
18 (28.6%)
0.795
8050
7000
0.095
(4200 – 8400)
(2015 – 11200)
1 (4.2%)
17 (27.0%)
Median Ribavirin dose (mg/week)
PEG-IFNα dose reduction Median PEG-IFNα-2a dose (µg/
N = 18
N = 44
180 (180 – 180)
180 (97 – 180)
N=6
N = 19
0.019*
0.022*
0.869
week)
110 (80 – 150)
118 (50 – 150)
RVR (N = 78)
17/22 (77.3%)
22/53 (41.5%)
0.006*
EOTR
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an
Mean PEG-IFNα-2b dose (µg/
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week)
0.169
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Ribavirin dose reduction
87.5
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Median ALT [U/L]
23 (95.8%)
42 (66.7%)
0.005*
20 (83.3%)
30 (47.6%)
0.003*
* P < 0.05
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SVR12 (SOF/PR) / SVR24 (PR)
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SOF, sofosbuvir; PR, peginterferon/ribavirin; ALT, Alanine aminotransferase; PEGIFNα, peginterferon alpha; RVR, rapid virological response; EOTR, end of treatment response; SVR12/24, sustained virological response 12/24 weeks after treatment completion;
Page 12 of 16
14 Table 2. Characteristics of 24 patients treated with sofosbuvir-based triple-therapy by treatment outcome SVR12
Treatment failure
N (%)
N (%)
20 (83.3%)
4 (16.7%)
Breakthrough
n/a
1 (24%)
Relapse
n/a
2 (50%)
0
1 (24%)
17 (85%)
Mean Age (years)
44.9±8.1)
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4 (100%)
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Male gender
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Lost to follow-up
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Number of patients
P-Value
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Fibrosis stage (METAVIR) F0-2
2 (50%)
10 (50%)
2 (50%)
4 (20%)
1 (25%)
1
11 (55%)
0
0.098
Relapse
7 (31.8%)
0
0.283
Non-response
2 (9.1%)
3 (75%)
0.018*
Breakthrough
0
1 (25%)
0.167
C/C
7
1 (100%)
1
C/T
3
0
1
T/T
3
0
1
14/19 (73.7%)
3/3 (100%)
0.558
Treatment naïve
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Treatment experienced
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Cirrhosis (F4)
0.023* 1
10 (50%)
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F3-4
55.8±8.2)
1
IL28B-haplotype (N = 14)
RVR (N = 22) Baseline laboratory
Page 13 of 16
15 5.81
5.39
(2.01 – 6.71)
(4.75 – 5.95)
Median Haemoglobin [g/dL]
15.1 (11.8-17.2)
15.7 (13.4-16.6)
0.723
Median Thrombocyte count
217.5 (136-350)
122 (104-184)
0.005*
3.1 (1.1-7.3)
2.4 (1.1-3.9)
74 (25-538)
134 (56-189)
0.337
1 (25%)
1 0.912
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[x109/L] Median Leukocyte count
5 (25%)
Cumulative median ribavirin
100800
93800
dose (mg)
(50400-100800)
(84000-100800)
PEG-IFNα
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Ribavirin dose reduction
M
us
[x109/L] Median ALT [U/l]
0.346
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Median Viral load [log IU/ml]
1 3 (75%)
5 (25%)
1 (25%)
PEG-IFNα dose reduction
1 (5%)
0
1
Cumulative median PEG-
2160
2160
1
(2160-2160)
(2160-2160)
1440
960
(1000-1800)
(960-960)
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te
2b
15 (75%)
d
2a
0.264
IFNα-2a dose (µg)
Cumulative median PEG-IFNα 2b dose [µg]
0.333
*P < 0.05
SVR12, sustained virological response 12 weeks after treatment completion; IL28B, interleukin 28B polymorphism; RVR, rapid virological response; ALT, Alanine aminotransferase; PEG-IFNα, peginterferon alpha
Page 14 of 16
e Ac c
Page 15 of 16
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Page 16 of 16
S1590-8658(15)00347-3 http://dx.doi.org/doi:10.1016/j.dld.2015.05.018 YDLD 2899
To appear in:
Digestive and Liver Disease
Received date: Revised date: Accepted date:
25-2-2015 20-4-2015 18-5-2015
Please cite this article as: Wehmeyer MH, Jordan S, L¨uth S, Hartl J, Stoehr A, Eißing C, Lohse AW, Petersen J, Buggisch P, Wiesch JS, Efficacy and safety of sofosbuvir-based triple therapy in hepatitis C genotype 4 infection, Digestive and Liver Disease (2015), http://dx.doi.org/10.1016/j.dld.2015.05.018 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 Efficacy and safety of sofosbuvir-based triple therapy in hepatitis C genotype 4 infection
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Dr. Malte H. Wehmeyer1*, Dr. Sabine Jordan1*, Prof. Stefan Lüth1, Dr. Johannes Hartl1, Dr. Albrecht Stoehr2, Ms. Christiane Eißing1, Prof. Ansgar W. Lohse1,3, Prof.
cr
Jörg Petersen2, Dr. Peter Buggisch2, PD Dr. Julian Schulze zur Wiesch1,3
us
(1) I. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf,
an
Martinistraße 52, 20246 Hamburg, Germany
(2) Institut für Interdisziplinäre Medizin an der Asklepios Klinik St. Georg,
M
Lohmühlenstraße 5 / Haus L, 20099 Hamburg, Germany
(3) German Center for Infection Research (DZIF), Hamburg site
Corresponding author
te
d
* = contributed equally
Ac ce p
Julian Schulze zur Wiesch, MD
I. Medizinische Klinik und Poliklinik Universitätsklinikum Hamburg-Eppendorf Martinistr. 52
20246 Hamburg, Germany
Phone: ++49 – 40 – 7410-52831 Fax: ++49 – 40 – 7410-55128 e-mail: [email protected] Word count: 1444; Abstract word count: 147 Funding: Julian Schulze zur Wiesch and Ansgar W. Lohse are supported by the Deutsche Forschungsgemeinschaft (DFG, SFB841). Page 1 of 16
2 Abstract Background: There are only limited data on sofosbuvir-based treatment regimens in hepatitis C virus (HCV) genotype 4-infected patients.
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Aims: To evaluate safety and efficacy of sofosbuvir-based triple-therapy in HCV genotype 4 infection.
cr
Methods: All HCV genotype 4-infected patients who started sofosbuvir-based tripletherapy at our two centres between January and June 2014 were prospectively
us
included (N=24) and compared to genotype 4 patients treated with
an
peginterferon/ribavirin between January 2001 and December 2012 (N=63). Results: The demographics in the sofosbuvir group and the controls were
M
comparable (males 87.5% and 82.5%; mean age 46.7±9.0 years and 42.0±9.8 years, respectively). Sustained virological response was achieved in 83.3% in the sofosbuvir
d
group and in 47.6% of controls (P=0.003). Fatigue (P=0.007), flu-like (P=0.015),
te
gastrointestinal (P<0.001), dermatologic (P<0.001) and psychiatric symptoms (P=0.022) were more common in the control group.
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Conclusions: In our real-life cohort, sofosbuvir-based triple therapy confirmed its high efficacy and safety for chronic genotype 4 hepatitis C.
Keywords: direct acting antivirals; HCV; sustained virological response; SVR
Page 2 of 16
4 Introduction Until recently, dual therapy with peginterferon-alpha (PEG-IFNα) and ribavirin (PR) was the standard of care for chronic hepatitis C virus genotype 4 (HCV4) infection.
ip t
The novel NS5B polymerase inhibitor sofosbuvir (SOF) has pangenotypic efficacy and displays a favourable safety profile [1,2]. Recently, 24 weeks of SOF/ribavirin
cr
was proven to be superior to 12 weeks with SOF/ribavirin in HCV4 infection in a phase II trial (sustained virological response [SVR] 93% vs. 68%) [3]. While the
us
results of this trial are clearly impressive, ideally this study would have benefitted
an
from incorporating a control arm with a peginterferon-containing regimen. Importantly, HCV4 is endemic to low income regions, such as the Middle East or Northern Africa
M
[4], and a 24-week treatment with sofosbuvir outside special treatment programmes is a very costly. Here, we would like to provide further data to the ongoing discussion
Ac ce p
Patients and Methods
te
a “real-life” setting.
d
by describing the results of a small investigator initiated study of SOF/PR for HCV4 in
Data of 24 consecutive HCV4 patients who received therapy with SOF/PR for 12 weeks between January and June 2014 were prospectively collected at our two tertiary care centres for viral hepatitis in Hamburg, Germany. Results were then compared to a historic cohort of 63 consecutive HCV4 patients who had received conventional dual PR therapy for 48 weeks between January 2001 and December 2012. Additional analysis was conducted using a matched control group of 24/63 patients after propensity score analysis for different cofactors. The patients in both groups received bodyweight-adapted dose of ribavirin and either PEG-IFNα-2a (180 µg/week) or -2b (bodyweight-adapted). Patients in the SOF/PR group additionally received SOF 400 mg once daily. The primary endpoint was SVR 12 weeks after end Page 3 of 16
5 of treatment. Secondary endpoints included rapid virological response (RVR), end of treatment response (EOTR) and appearance of adverse events (AE). Univariate analysis (Fisher’s exact test, t-test and Mann-Whitney-U-Test, each were applicable)
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and propensity score analysis were performed using SPSS Version 22. A Pvalue<0.05 was considered statistically significant. The tolerance for differences in
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the propensity score in the matching process was 0.1. The study was approved by
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the local ethics board (Ethikkommission der Ärztekammer Hamburg; PV3939).
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Results
The baseline characteristics and data on treatment outcome of the SOF/PR group
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and the historic controls are presented in Table 1. In SOF/PR patients mean age was 46.7±9.0 years, in PR patients mean age was 42.0±0.8 years (P=0.039). Median viral
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load at baseline was 5.74 log UI/ml (range 2.01-6.71) in the SOF/PR group and 4.85
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log UI/ml (range 2.70-6.30) in controls (P<0.001). Among SOF/PR patients, 13/24 were treatment-experienced (54.2%) compared to 10/63 in the PR group (15.9%,
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P<0.001). F3 or F4 fibrosis was diagnosed 50% of SOF/PR patients vs. 12.7% in the control group (P=0.073). All cirrhotic patients were Child-Pugh class A (N=5 in the SOF/PR group and N=8 in the PR group). SOF/PR patients had a higher rate of RVR and EOTR as compared to controls (77.3% vs. 41.5% P=0.006; 95.8% and 66.7%, P=0.005; respectively). In an intention to treat analysis, we found 12 weeks of SOF/PR superior to 48 weeks PR with SVR12 in 20/24 patients (83.3%) and 30/63 patients, respectively (47.6%; P=0.003). Three SOF/PR patients experienced a virological failure (relapse in two patients, breakthrough in one patient) and one patient was lost to follow-up. Figure 1 displays the SVR rates in SOF/PR and PR patients in the different subgroups. As analysed per protocol, SVR was achieved in 20/23 SOF/PR patients (87.0%) and in 30/57 Page 4 of 16
6 control patients (52.6%; P=0.005). Patients with a history of non-response or breakthrough (N=6) in the SOF/PR group were at increased risk for virological failure (P=0.001), whereas all treatment naïve patients (N=11) and patients with a previous
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relapse (N=7) achieved a SVR. Furthermore, low baseline platelet counts (median: 122x109/L [range 104x109 – 184x109] vs. 218x109/L [136x109 – 350x109]) and
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advanced age (mean 44.9±8.1 years vs. 55.8±8.2 years) were associated with
treatment failure in the SOF/PR group (P=0.005 and 0.023, respectively). Other
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variables were not associated with SVR12 in the SOF/PR group in our small cohort
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(Table 2).
In the preparation of the additional analysis with matched controls, a propensity score
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was calculated for all patients incorporating sex, age, cirrhosis status, viral load and treatment experience as possible confounders. However, by using a maximum
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tolerance of 0.1 propensity score difference between matched-pairs of patients, only
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18/24 patients in the SOF/PR group had a sufficient control (panel A in Supplementary Figure S1). Therefore, we reduced the cofactors included in the
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logistic regression model to determine the propensity scores to 3 (sex, age, cirrhosis status; panel B in Supplementary Figure S1). The results of the second analysis with the matched control group largely mirrored the original analysis, details can be found in Supplementary Table S1. An overview and the comparison of adverse events in both groups is provided in Figure 2. Ribavirin dose reduction was necessary in 6/24 SOF/PR patients (25%) and in 18/63 patients of the controls (28.6%; P=0.795). Only 1 patient in the SOF/PR group (4.2%) had to reduce the PEG-IFNα dose compared to 17 patients in the control group (27.0%; P=0.019; Table 1). No differences were observed regarding anaemia (12.5% in SOF/PR patients vs. 14.3% in the control group, P=1.0); thrombocytopenia (4.2% vs. 15.9%, respectively; P=0.174); leukopenia (12.5% vs. Page 5 of 16
7 17.5%, respectively; P=0.749, Figure 2). Supplementary Table S1 summarizes the adverse events in the matched-pairs analysis. No SOF/PR patient and two controls experienced serious adverse events (one patient with exacerbation of neurosyphilis
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and one patient with acute on chronic liver failure; both patients recovered).
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Discussion
Here, we present data of a “real-life” cohort of patients who were treated for chronic
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HCV4 infection with 12 weeks SOF/PR compared to a historic cohort of patients
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(“controls”) treated with PR for 48 weeks. Data of SOF/PR in HCV4 are limited, as only 28 treatment-naïve patients with HCV4 infection were enrolled in the appropriate
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phase III trial [1]. In previous “real-life” studies SVR rates were remarkably lower than those of the respective phase III trials, e.g. in telaprevir- or boceprevir-based
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treatment regimens [5]. However, our study largely confirms the results from the
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NEUTRINO trial with a frequency of SVR12 of 96.4% in treatment naïve patients infected with HCV4 [1] compared to 100% in our cohort for patients receiving
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SOF/PR. The subgroup analysis revealed that treatment experienced patients with a history of non-response to PR treatment and patients with advanced fibrosis were at increased risk for a virological failure, although the study is limited by the small number of enrolled patients in each subgroup. Our results also indicate that 12 weeks of SOF/PR are significantly more tolerable than 48 weeks of PR. On the one hand, the frequency of severe anaemia, thrombocytopenia and leukopenia, as well as the need for ribavirin dose adjustment was comparable between both groups. On the other hand, PEG-IFNα dose reduction was more common during 48 weeks of PR compared to the shorter 12-week SOF/PR treatment regimen, which indicates the impact of the reduced time-span of PEG-IFNα toxicity in SOF-based triple therapy.
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8 Furthermore, efficacy of SOF/PR in HCV4 infected patients is comparable to daclatasvir/PR and superior to simeprevir/PR or 12 weeks of SOF/ribavirin [3,6,7]. Clinical data on other interferon-free regimens such as 12 weeks of SOF/simeprevir,
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SOF/ledipasvir, ombitasvir/paritaprevir/ritonavir/ribavirin, daclatasvir/asunaprevir/beclabuvir or 24 weeks of SOF/ribavirin for HCV4-infection
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are limited, but promising [3,8-10]. Importantly, 31% of the patients in the 24-week
SOF/ribavirin arm in the study of Ruane et al. [3] had to decrease ribavirin dose due
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to adverse effects, Therefore, the need to monitor the patients who receive 24-week
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dual therapy with SOF/ribavirin is not necessarily less intensive than a 12-week course of SOF/PR.
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We are aware of the limitations of our study, in particular, the small and heterogeneous cohort, the lack of data on HCV4 subtypes and the comparison of
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SOF/PR to a historical control group treated with PR. Furthermore, we provide only
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limited data about IL28B polymorphism rs12979860, which has been shown to be an important predictor of SVR in HCV4 infected patients [11].
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However, overall our data supports the alternative strategy of using 12 weeks SOF/PR in treatment of HCV4-infected patients rather than 24 weeks of SOF/ribavirin, at least in treatment-naïve patients or previous relapsers. Given an acceptable tolerability of 12 weeks SOF/PR, this regimen remains a reasonable option, if all-oral therapy is not accessible due to budgetary concerns.
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9 References 1. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013;368:1878-1887.
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2. Jacobsen IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med
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2013;368:1867-1877.
3. Ruane PJ, Ain D, Stryker R, et al. Sofosbuvir plus ribavirin for the treatment of
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chronic genotype 4 hepatitis C virus infection in patients of Egyptian ancestry.
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J Hepatol 2014 Nov 5; doi:10.1016/j.jhep.2014.10.044 [Epub ahead of print]. 4. Wantuck JM, Ahmed A, Nguyen MH. Review article: the epidemiology and
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therapy of chronic hepatitis C genotypes 4, 5 and 6. Aliment Pharmacol Ther 2014;39:137-147.
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5. Wehmeyer MH, Eißing F, Jordan S, et al. Safety and efficacy of protease
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inhibitor based combination therapy in a single-center “real-life” cohort of 110 patients with chronic hepatitis C genotype 1 infection. BMC Gastroenterology
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2014;14:87.
6. Hezode C, Hirschfield GM, Ghesquiere W, et al. Daclatasvir plus peginterferon alfa and ribavirin for treatment-naive chronic hepatitis C genotype 1 or 4 infection: a randomised study. Gut 2014. doi:10.1136/gutjnl-2014-307498 [Epub ahead of print].
7. Moreno C, Hezode C, Marcellin P, et al. Efficacy and safety of simeprevir with pegIFN/ribavirin in naïve or experienced patients infected with chronic HCV genotype 4. J Hepatol 2015. doi:10.1016/j.hep.2014.12.031 [Epub ahead of print]. 8. Hezode C, Asselah T, Reddy KR, et al. Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naïve and treatment-experienced Page 8 of 16
10 patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial. Lancet 2015; doi:10.1016/S01406736(15)60159-3 [Epub ahead of print].
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9. Kapoor R, Kohli A, Sidharthan A, et al. All oral treatment for genotype 4 chronic hepatitis C infection with sofosbuvir and ledipasvir: interim results from
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the NIAID SYNERGY trial. Hepatology 2014;60:321A (abstract).
10. Hassanein T, Sims KD, Bennett M, et al. A randomized trial of daclatasvir in
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combination with asunaprevir and beclabuvir in patients with chronic hepatitis
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C virus genotype 4 infection. J Hepatol 2015; doi:10.1016/j.hep.2014.12.025 [Epub ahead of print].
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11. Ragheb MM, Nemr NA, Kishk RM, et al. Strong prediction of of virological response to combination therapy by IL28B gene variants rs12979860 and
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te
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rs8099917 in chronic hepatitis C genotype 4. Liver int 2014;34:890-895.
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11 Figure legends Figure 1. Frequency of sustained virological response in the different subgroups. Sofosbuvir-based triple-therapy was compared with controls using
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Fisher’s exact test. Stage of fibrosis was assessed according to METAVIR. SOF, sofosbuvir; PR, peginterferon/ribavirin; RVR, rapid virological response; NR/BT,
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non-response/breakthrough]
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Figure 2. Frequency of adverse events in sofosbuvir based triple-therapy
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patients compared to controls.
SOF, sofosbuvir; PR, peginterferon/ribavirin; GI, gastrointestinal; anaemia, Hb < 10g/dL; thrombocytopenia, platelet count < 75 x109/L; leukopenia, white blood cell
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count < 2 x109/L
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12 Table 1. Characteristics and treatment outcome of patients receiving sofosbuvirbased triple-therapy compared to historical controls PR
N (%)
N (%)
24
63
21 (87.5%)
52 (82.5%)
46.7± 9.0
42.0± 9.8
Mean age (years) Fibrosis stage (METAVIR)
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Male gender
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N
P-Value
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SOF/PR
0.749
0.039* 0.073
12 (50%)
F3-4
12 (50%)
17 (27.0%)
5 (20.8%)
8 (12.7%)
0.335
53 (84.1%)
<0.001*
7 (29.2%)
3 (4.8%)
0.004*
Non-response
5 (20.8%)
6 (9.5%)
0.279
Breakthrough
1 (4.2%)
1 (1.6%)
1
5.74
4.85
<0.001*
(2.01 – 6.71)
(2.70 – 6.30)
15.1
15.0
(11.8 – 17.2)
(11.5 – 18.3)
200.5
214
(104 – 350)
(59 – 392)
6.8
6.5
(3 – 10.6)
(2.5 – 15.6)
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Cirrhosis (F4) Treatment naïve
11 (45.8%)
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Treatment experienced
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Relapse
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46 (73.0%)
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F0-2
Baseline laboratory
Median Viral load [log IU/ml]
Medina Haemoglobin [g/dL]
Median Platelet count [x109/L]
Median Leucocyte count [x109/L]
0.803
0.948
0.480
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13 63
(25 – 538)
(11 – 346)
6 (25%)
18 (28.6%)
0.795
8050
7000
0.095
(4200 – 8400)
(2015 – 11200)
1 (4.2%)
17 (27.0%)
Median Ribavirin dose (mg/week)
PEG-IFNα dose reduction Median PEG-IFNα-2a dose (µg/
N = 18
N = 44
180 (180 – 180)
180 (97 – 180)
N=6
N = 19
0.019*
0.022*
0.869
week)
110 (80 – 150)
118 (50 – 150)
RVR (N = 78)
17/22 (77.3%)
22/53 (41.5%)
0.006*
EOTR
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Mean PEG-IFNα-2b dose (µg/
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week)
0.169
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Ribavirin dose reduction
87.5
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Median ALT [U/L]
23 (95.8%)
42 (66.7%)
0.005*
20 (83.3%)
30 (47.6%)
0.003*
* P < 0.05
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SVR12 (SOF/PR) / SVR24 (PR)
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SOF, sofosbuvir; PR, peginterferon/ribavirin; ALT, Alanine aminotransferase; PEGIFNα, peginterferon alpha; RVR, rapid virological response; EOTR, end of treatment response; SVR12/24, sustained virological response 12/24 weeks after treatment completion;
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14 Table 2. Characteristics of 24 patients treated with sofosbuvir-based triple-therapy by treatment outcome SVR12
Treatment failure
N (%)
N (%)
20 (83.3%)
4 (16.7%)
Breakthrough
n/a
1 (24%)
Relapse
n/a
2 (50%)
0
1 (24%)
17 (85%)
Mean Age (years)
44.9±8.1)
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4 (100%)
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Male gender
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Lost to follow-up
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Number of patients
P-Value
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Fibrosis stage (METAVIR) F0-2
2 (50%)
10 (50%)
2 (50%)
4 (20%)
1 (25%)
1
11 (55%)
0
0.098
Relapse
7 (31.8%)
0
0.283
Non-response
2 (9.1%)
3 (75%)
0.018*
Breakthrough
0
1 (25%)
0.167
C/C
7
1 (100%)
1
C/T
3
0
1
T/T
3
0
1
14/19 (73.7%)
3/3 (100%)
0.558
Treatment naïve
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Treatment experienced
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Cirrhosis (F4)
0.023* 1
10 (50%)
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F3-4
55.8±8.2)
1
IL28B-haplotype (N = 14)
RVR (N = 22) Baseline laboratory
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15 5.81
5.39
(2.01 – 6.71)
(4.75 – 5.95)
Median Haemoglobin [g/dL]
15.1 (11.8-17.2)
15.7 (13.4-16.6)
0.723
Median Thrombocyte count
217.5 (136-350)
122 (104-184)
0.005*
3.1 (1.1-7.3)
2.4 (1.1-3.9)
74 (25-538)
134 (56-189)
0.337
1 (25%)
1 0.912
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[x109/L] Median Leukocyte count
5 (25%)
Cumulative median ribavirin
100800
93800
dose (mg)
(50400-100800)
(84000-100800)
PEG-IFNα
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Ribavirin dose reduction
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[x109/L] Median ALT [U/l]
0.346
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Median Viral load [log IU/ml]
1 3 (75%)
5 (25%)
1 (25%)
PEG-IFNα dose reduction
1 (5%)
0
1
Cumulative median PEG-
2160
2160
1
(2160-2160)
(2160-2160)
1440
960
(1000-1800)
(960-960)
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te
2b
15 (75%)
d
2a
0.264
IFNα-2a dose (µg)
Cumulative median PEG-IFNα 2b dose [µg]
0.333
*P < 0.05
SVR12, sustained virological response 12 weeks after treatment completion; IL28B, interleukin 28B polymorphism; RVR, rapid virological response; ALT, Alanine aminotransferase; PEG-IFNα, peginterferon alpha
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