Accepted Manuscript
Multicentre experience using daclatasvir and sofosbuvir to treat hepatitis C re-currence after liver transplantation - The CO23 ANRS CUPILT study
Audrey Coilly, Claire Fougerou-Leurent, Victor de Ledinghen, PaulineHoussel-Debry, Christophe Duvoux, Vincent Di Martino, Sylvie Radenne,Nassim Kamar, Louis D’Alteroche, Vincent Leroy, Valérie Canva, PascalLebray, Christophe Moreno, Jérôme Dumortier, Christine Silvain, CamilleBesch, Philippe Perre, Danielle Botta-Fridlund, Rodolphe Anty, Claire Francoz,Armando Abergel, Maryline Debette-Gratien, Filomena Conti, FrançoisHabersetzer, Alexandra Rohel, Emilie Rossignol, Hélène Danjou, Anne-MarieRoque-Afonso, Didier Samuel, Jean-Charles Duclos-Vallee, Georges-PhilippePageaux, for the ANRS C023 CUPILT study group,
PII: S0168-8278(16)30253-7DOI: http://dx.doi.org/10.1016/j.jhep.2016.05.039Reference: JHEPAT 6137
To appear in: Journal of Hepatology
Received Date: 27 November 2015Revised Date: 19 May 2016Accepted Date: 23 May 2016
Please cite this article as: Coilly, A., Fougerou-Leurent, C., de Ledinghen, V., Houssel-Debry, P., Duvoux, C., DiMartino, V., Radenne, S., Kamar, N., D’Alteroche, L., Leroy, V., Canva, V., Lebray, P., Moreno, C., Dumortier,J., Silvain, C., Besch, C., Perre, P., Botta-Fridlund, D., Anty, R., Francoz, C., Abergel, A., Debette-Gratien, M.,Conti, F., Habersetzer, F., Rohel, A., Rossignol, E., Danjou, H., Roque-Afonso, A-M., Samuel, D., Duclos-Vallee,J-C., Pageaux, G-P., for the ANRS C023 CUPILT study group, Multicentre experience using daclatasvir andsofosbuvir to treat hepatitis C recurrence after liver transplantation - The CO23 ANRS CUPILT study, Journal ofHepatology (2016), doi: http://dx.doi.org/10.1016/j.jhep.2016.05.039
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Multicentre experience using daclatasvir and sofosbuvir to treat hepatitis C recurrence after
liver transplantation - The CO23 ANRS CUPILT study
Audrey Coilly1-4
, Claire Fougerou-Leurent5,6
, Victor de Ledinghen7, Pauline Houssel-Debry
8,
Christophe Duvoux9, Vincent Di Martino
10, Sylvie Radenne
11, Nassim Kamar
12, Louis D'Alteroche
13,
Vincent Leroy14
, Valérie Canva15
, Pascal Lebray16
, Christophe Moreno17
, Jérôme Dumortier18
,
Christine Silvain19
, Camille Besch20
, Philippe Perre21
, Danielle Botta-Fridlund22
, Rodolphe Anty23
,
Claire Francoz24
, Armando Abergel25
, Maryline Debette-Gratien26
, Filomena Conti16
, François
Habersetzer27
, Alexandra Rohel28
, Emilie Rossignol5,6
, Hélène Danjou5,6
, Anne-Marie Roque-
Afonso29,2-4
, Didier Samuel1-4
, Jean-Charles Duclos-Vallee1-4
, Georges-Philippe Pageaux30
, for the
ANRS C023 CUPILT study group.
Affiliations:
1. AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif F-94800, France;
2. Université Paris-Sud, Université Paris Sud-Saclay, UMR-S 1193, Villejuif F-94800, France;
3. INSERM, Unité 1193, Villejuif F-94800, France;
4. DHU Hepatinov, Villejuif F-94800, France;
5. Hôpital Universitaire de Pontchaillou, Service de Pharmacologie, Rennes, France;
6. INSERM, CIC 1414 Clinical Investigation Centre, Rennes, France;
7. Service d’Hépato-Gastroentérologie, Hôpital Haut-Lévêque, CHU Bordeaux, & INSERM
U1053, Bordeaux, France;
8. Hôpital Universitaire de Pontchaillou, Service d’Hépatologie et Transplantation Hépatique,
Rennes, France;
9. Service d’Hépatologie, Hôpital Henri-Mondor, AP–HP, 94000 Créteil, France;
2
10. Service d’Hépatologie, CHRU Jean Minjoz et Université de Franche-Comté, Besançon,
France;
11. Service d’Hépatologie, HCL, Hôpital de la Croix-Rousse, 69205 Lyon, France;
12. Département de Néphrologie et Transplantation d’Organes, CHU Rangueil, INSERM U1043,
IFR–BMT, Université Paul Sabatier, Toulouse, France;
13. Service Hépato-gastro-entérologie, CHU Tours, France;
14. Clinique Universitaire d’Hépato-Gastroentérologie, Pôle Digidune, CHU de Grenoble, France;
15. CHRU de Lille, Service d’Hépatologie, Hôpital Huriez, CHRU Lille, 59037 Lille;
16. Service d’Hépatologie et de Transplantation Hépatique, AP-HP, Groupe Hospitalier Pitié-
Salpêtrière, Paris, France;
17. Département de Gastroenterologie, d’Hépatopancréatologie et Cancérologie Digestive, CUB
Hôpital Erasme, Université Libre de Bruxelles, Bruxelles, Belgique;
18. Unité de Transplantation Hépatique, Fédération des Spécialités Digestives, Hôpital Edouard
Herriot, Hospices Civils de Lyon et Université Claude Bernard Lyon 1, Lyon;
19. Service Hépato-gastro-entérologie, CHU Poitiers, France;
20. Centre de Chirurgie Digestive et Transplantation Hépatique, Université de Strasbourg, France;
21. Service de MPU Infectiologie CHD Vendée, 85925, La Roche sur Yon, France;
22. CHU Timone, Service d’Hépato-gastroentérologie, Marseille F-13005, France;
23. Hôpital universitaire de Nice, Service d’Hépato-gastroentérologie; INSERM, U1065, Equipe 8,
Université de Nice-Sophia-Antipolis, Faculté de Médecine, Nice, F-06107, Cedex 2, France;
24. Service d'Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy,
France;
3
25. Service d’Hépato-gastroentérologie, CHU Estaing Clermont-Ferrand, Clermont-Ferrand,
France;
26. Service d'Hépato-gastroentérologie, CHU Limoges, Limoges, France ;
27. Hôpitaux Universitaires de Strasbourg, Inserm U 1110, LabEx HepSYS, Université de
Strasbourg, Strasbourg, France;
28. Unité de recherché Clinique et Fondamentale sur les Hépatites Virales, Agence Nationale de
Recherche sur le Sida et les Hépatites Virales, Paris, France;
29. AP-HP Hôpital Paul-Brousse, Service de Virologie, Villejuif F-94800, France;
30. Département d’Hépato-gastroentérologie et de Transplantation Hépatique, CHU Saint-Eloi,
Université de Montpellier, Montpellier F-34295, France;
Corresponding author: Audrey Coilly, MD
Centre Hépato-Biliaire
Hôpital Paul-Brousse
12-14 avenue Paul-Vaillant Couturier
94800 Villejuif
FRANCE
Tel.: 00 33 1 45 59 66 36 Fax: 00 33 1 45 59 38 57
Email: [email protected]
4
Disclosures
1. Audrey Coilly has been a clinical investigator, speaker and/or consultant for Astellas, Bristol-
Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Novartis, Merck Sharp & Dohme
and Abbvie;
2. Claire Fougerou-Leurent has nothing to disclose;
3. Victor De Ledinghen has been a clinical investigator, speaker and/or consultant for Abbvie,
Bristol-Myers Squibb, Gilead Sciences, Jansen Pharmaceuticals, Merck Sharp & Dohme;
4. Pauline Houssel-Debry has been speaker and/or consultant for Astellas, Novartis and Gilead
Sciences;
5. Christophe Duvoux has nothing to disclose;
6. Vincent Di Martino has been a clinical investigator, speaker and/or consultant for Abbvie,
Bristol-Myers Squibb, Gilead Sciences, Jansen Pharmaceuticals, Merck Sharp & Dohme;
7. Sylvie Radenne has nothing to disclose;
8. Nassim Kamar has been a clinical investigator, speaker and/or consultant for Astellas, Bristol-
Myers Squibb, Gilead Sciences, Merck Sharp & Dohme, Novartis, Alexion, Fresenius, Amgen
and Roche;
9. Louis D’Alteroche has nothing to disclose;
10. Vincent Leroy has been a clinical investigator, speaker and/or consultant for Abbvie, Bristol-
Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Merck Sharp & Dohme, and
Roche;
11. Valerie Canva has nothing to disclose;
12. Pascal Lebray has been a clinical investigator, speaker and/or consultant for Bristol-Myers
Squibb, Gilead Sciences, Jansen Pharmaceuticals, Biotest and Merck Sharp & Dohme;
13. Christophe Moreno has nothing to disclose;
14. Jérôme Dumortier has been a clinical investigator, speaker and/or consultant for Astellas,
Gilead Sciences, Janssen Pharmaceuticals, Novartis and Roche;
15. Christine Silvain has been a clinical investigator, speaker for Abbvie, Bristol-Myers Squibb,
Gilead Sciences, Jansen Pharmaceuticals, Astellas;
16. Camille Besch has nothing to disclose;
17. Philippe Perré has nothing to disclose;
5
18. Danielle Botta-Fridlund has been a clinical investigator, speaker and/or consultant for Abbvie,
Bristol-Myers Squibb, Janssen, Gilead and Roche;
19. Rodolphe Anty has nothing to disclose;
20. Claire Francoz has nothing to disclose;
21. Armando Abergel has nothing to disclose;
22. Maryline Debette-Gratien has nothing to disclose;
23. Filomena Conti has nothing to disclose;
24. François Habersetzer has nothing to disclose;
25. Alexandra Rohel has nothing to disclose;
26. Emily Rossignol has nothing to disclose;
27. Hélène Danjou has nothing to disclose;
28. Didier Samuel has been a clinical investigator, speaker and/or consultant for Astellas, Bristol-
Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Abbvie, Novartis, Merck Sharp &
Dohme and Roche.
29. Jean-Charles Duclos-Vallée has been a clinical investigator, speaker and/or consultant for
Astellas, Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Abbvie, Novartis
and Roche;
30. Georges-Philippe Pageaux has been a clinical investigator, speaker and/or consultant for
Astellas, Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Merck Sharp &
Dohme, Novartis and Roche.
6
Abbreviations:
AE: Adverse events
DAAs: Direct-acting antiviral agents
DCV: Daclatasvir
EOT: End of treatment
GFR: Glomerular filtration rate
HCV: Hepatitis C virus
HIV: Human immunodeficiency virus
IMS: Immunosuppressive
LLOQ: Lower limit of quantification
LT: Liver transplantation
MDRD: Modified Diet in Renal Disease
MELD: Model for End-stage Liver Disease
PEG-IFN: pegylated interferon
RBV: Ribavirin
SAE: Serious adverse events
SOF: Sofosbuvir
SVR: Sustained virological response
TBC: Trough blood concentration
W: Week
Keywords: daclatasvir, direct-acting antiviral agents, hepatitis C, liver transplantation, recurrence,
sofosbuvir.
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Abstract
Background & Aims: HCV recurrence remains a major issue in the liver transplant field, as it has a
negative impact on both graft and patient survival. The purpose of this study was to investigate the
efficacy and safety of treating HCV recurrence with sofosbuvir (SOF) and daclatasvir (DCV)
combination therapy.
Methods: From October 2013 to March 2015, 559 liver recipients were enrolled in the prospective
multicentre ANRS CUPILT cohort. We selected 137 patients with an HCV recurrence receiving SOF
and DCV, whatever the genotype or fibrosis stage. The use of ribavirin and the duration of therapy
were at the investigator’s discretion. The primary efficacy end point was a sustained virological
response (SVR) 12 weeks after the end of treatment.
Results: The SVR rate 12 weeks after completing treatment was 96% under the intention-to treat
analysis and 99% when excluding non-virological failures. Only two patients experienced a virological
failure. The serious adverse event (SAE) rate reached 17.5%. Four patients (3%) stopped their
treatment prematurely because of SAEs. Anaemia was the most common AE, with significantly more
cases in the ribavirin group (56% versus 18%; p<0.0001). A slight but significant reduction in
creatinine clearance was reported. No clinically relevant drug-drug interactions were noted, but 52% of
patients required a change to the dosage of immunosuppressive drugs.
Conclusion: Treatment with SOF plus DCV was associated with a high SVR12 and low rates of
serious adverse events among liver recipients with HCV recurrence.
Lay Summary
The recurrence of hepatitis C used to be the first cause of graft failure in infected liver transplanted
recipients. Our study demonstrates the great efficacy of one combination of new all-oral direct acting
antiviral, sofosbuvir and daclatasvir, to treat the recurrence of hepatitis C on the graft. Ninety-six per
cent of recipients were cured. The safety profile of this combination seemed to be good, especially no
relevant drug-drug interaction with immunosuppressive drugs.
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Introduction
Hepatitis C virus (HCV) represents a major healthcare issue, in that some 170 million people are
chronically infected worldwide [1]. When patients develop end-stage liver disease or hepatocellular
carcinoma, liver transplantation (LT) remains the only curative option. In France, more than 20% of
candidates for LT are infected with HCV [2]. Among patients with a positive viral load, a recurrence of
HCV infection on the graft is constant and constituted a challenge in the past because fibrosis
progression may be accelerated when compared to the situation in non-transplant patients. Twenty to
30% of HCV-infected recipients develop graft cirrhosis within 5 years of LT [3]
. This results in poorer
graft and patient survival rates compared to those of recipients transplanted for another indication [4].
The clearance of HCV is the only way to improve the outcome of these patients. The standard of care
for treating HCV recurrence used to be 48 weeks of peg-interferon (PEG-IFN) with ribavirin (RBV),
although this was only effective in 30% of patients, mainly because of poor tolerance which led to
premature treatment discontinuation in 30% of cases. The combination of a first-generation protease
inhibitor (telaprevir or boceprevir) with PEG-IFN and RBV subsequently improved sustained virological
response (SVR) rates to 50%-65% in genotype 1 HCV-infected recipients, but at the cost of an even
poorer safety profile and potent drug-drug interactions [5, 6]. Although feasible, these regimens
required close monitoring and considerable clinical expertise.
In 2013, two second-generation direct-acting antiviral agents (DAAs), the nucleotide analogue NS5B
polymerase inhibitor sofosbuvir (SOF), and the nucleotide analogue NS5A polymerase inhibitor
daclatasvir (DCV), became available through an early access programme and were then approved by
the French Agency for the Safety of Medicines and Healthcare Products (ANSM). Although limited, the
preliminary data on the combined use of SOF and DCV with or without RBV have shown high SVR
rates of >90%, with minimal side effects in non-transplant patients [7]. Consequently, access to this
combination was available from the outset for the sickest patients, including those undergoing a liver
transplant.
Initial experience using SOF plus DCV in the transplant setting took the form of a case report [8]. Our
group then reported on the efficacy and safety of this type of combination in the most urgent and
difficult-to-treat patients. Among 15 patients suffering from fibrosing cholestatic hepatitis, a significant
clinical improvement was achieved, with an SVR12 of 96% [9]. Recently, the open-label ALLY-1 study
9
assessed the safety and efficacy of the SOF and DCV combination plus RBV to treat HCV infection in
the context of advanced cirrhosis or post-LT recurrence in 53 patients [10]. SVR was achieved by 95%
and 91% of patients with genotype 1 and 3 infections, respectively. We report here on our multicentre
experience including a large number of patients who received SOF and DCV, with or without RBV, to
treat an HCV recurrence of varying degrees of severity following liver transplantation.
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Patients and Methods
Study design and patients
The ANRS C023 “Compassionate use of Protease Inhibitors in viral C Liver Transplantation” (CUPILT)
study is a multicentre prospective cohort being implemented in 24 French and one Belgian LT centre
(ClinicalTrials.gov number NCT01944527). It is being funded and sponsored by ANRS (France
REcherche Nord&Sud Sida-hiv Hépatites). To be enrolled in this cohort, patients must have (1)
received a liver transplant for an HCV infection, (2) experienced an HCV recurrence whatever the
stage of fibrosis, (3) been treated with second-generation DAAs, and (4) given their written informed
consent. At enrolment, fibrosis stage was established based on a histological assessment (according
to the METAVIR scoring system [11]) and/or elastometry (such as F3 ≥9.5 kPa and F4 ≥14.5kPa). The
protocol has been carried out in accordance with the Declaration of Helsinki and French laws on
biomedical research, and was approved by the "South Mediterranean Ethics Committee” (France).
Exclusion criteria were an age under 18 and pregnancy.
Between October 2013 and March 2015, 559 liver recipients were enrolled. For the present study, we
selected patients receiving both SOF and DCV who were followed for at least 12 weeks after
treatment discontinuation. Patients were excluded if they were co-infected with the human
immunodeficiency virus (HIV) or diagnosed with fibrosing cholestatic hepatitis (such as previously
defined [9]).
This study is observational so that the type of treatment, dosing of drugs and duration of treatment are
at the discretion of each investigator. However, the CUPILT Scientific Committee (Supplemental
Appendix 1) issues treatment recommendations every 6 months. Patients receive SOF and DCV at a
once-daily dose of 400 mg and 60 mg, respectively. When used, the RBV dose is adjusted by
considering body weight, potential ribavirin-related haematological toxicity and renal function in the LT
recipients. Treatment duration was initially planned for 12 or 24 weeks, but the investigators are
allowed to extend this period if they deem this clinically necessary.
Efficacy assessments
For this study, plasma HCV RNA levels were quantified using the Abbott Real Time HCV PCR assay
(lower limit of quantification (LLOQ) of 12 IU/mL, Abbott Diagnostics®, USA) or COBAS AmpliPrep®
11
or COBAS TaqMan® (LLOQ of 15 IU/mL, Roche Molecular Systems, Pleasanton, California).
Hepatitis C virus RNA was monitored at baseline, during scheduled visits throughout treatment (1, 2,
3, 4, 6, 8, 12, and if applicable 16, 20 and 24 W) and then at 4, 12, 24, 48 W after the completion of
treatment. The primary endpoint was the proportion of patients who achieved undetected HCV RNA
levels or an SVR at W12 after treatment discontinuation (SVR12). Secondary endpoints included viral
kinetics, and on-treatment (W4) and end-of-treatment (EOT) response rates. Virological failures were
also reported. Viral breakthrough and relapse were defined as plasma HCV RNA levels higher than
the LLOQ after achieving a level lower than the LLOQ, during treatment and after the end of treatment,
respectively. When a virological failure occurred, baseline and relapse resistance-associated viral
(RAV) mutations in the NS3/A4, NS5A and NS5B regions were obtained by population sequencing
using in-house methods. RAVs were defined according to the Geno2Pheno algorithm
(http://hcv.geno2pheno.org/), developed by the Max-Planck-Institut für Informatik, Saarbrücken,
Germany.
Another secondary endpoint was an improvement in liver function. Clinical evaluations, including
clinical signs of decompensated liver disease (ascites, hepatic encephalopathy) and laboratory tests
were performed by applying a similar visit timetable as that used for virological assessments; i.e. at
baseline, during scheduled visits throughout the treatment (1, 2, 3, 4, 6, 8, 12, and if applicable 16, 20
and 24 W) and then at weeks 4, 12, 24 and 48 after the completion of treatment.
Safety assessments
Data on the following adverse events were collected: serious adverse events (SAE), as defined in
Supplemental Appendix 2, clinical and laboratory grade 3 or 4 adverse events (assessed using the
INSERM-ANRS scale to score the severity of adverse events, v6 dated 9 September 2003 and given
in Supplemental Appendix 3) and adverse events of any grade related to neutrophils, platelets,
prothrombin values, bilirubin, creatinine, haemoglobin or infections.
Decisions to reduce, interrupt, or discontinue ribavirin doses because of toxic effects were based on
the drug manufacturer's labelling. The investigators were encouraged to manage all AE according to
the guidelines issued by the French Association for the Study of the Liver (AFEF) [12]. The glomerular
filtration rate (GFR) was calculated using the Modified Diet in Renal Disease (MDRD)-6 equation [13].
12
During treatment, the trough blood concentration (TBC) of calcineurin inhibitors was monitored. The
TBC targeted depended on the past medical history of the patients. Changes to the dosage of
immunosuppressive drugs were made accordingly, at the investigators’ discretion.
Statistical Analysis
Analyses were performed in the modified intention-to-treat population, which included all patients who
had received at least one dose of treatment. In the case of a non-normal distribution, continuous
variables were expressed by median and inter-quartile ranges, and in case of a normal distribution,
continuous variables were expressed by mean and standard deviation. Categorical variables were
expressed in terms of the number of patients and percentages. Differences in baseline characteristics
between the four groups, as reflected by the duration of therapy and RBV use, were evaluated using
Kruskall-Wallis test for continuous data and the chi-square test or Fisher's exact test for categorical
data. To test for changes over time (i.e W0 and EOT) in continuous variables, a paired t-test was used
in the case of a normal distribution and a Wilcoxon signed rank sum test for a non-normal distribution.
All statistical tests and 95% confidence intervals had a significance level of 0.05. SAS software,
Version 9.4 (SAS Institute Inc., Cary, NC, USA) was used.
13
Results
Baseline demographic and clinical characteristics
One hundred thirty-seven liver transplant recipients treated with SOF plus DCV were selected for the
present study between October 2013 and March 2015 (Figure 1). The baseline characteristics of these
patients are presented in Table 1. There was a majority of men (77.4%), with a median age of 59.0
[53.0–65.0] years. Most patients were infected with HCV genotype 1 (n=109; 79.6%), mainly of the 1b
type (n=62; 45.3%). Although 69 patients (50.4%) were treatment-naive, when treated, a majority of
patients were proved to be non-responders (19.0%). The median MELD score at baseline was 10 [7–
13] (Supplemental Table 1). Forty-six patients (33.6%) experienced cirrhosis on the graft. The
characteristics of cirrhotic patients are detailed in Supplemental Table 1. The median period elapsing
between LT and treatment initiation was 72.3 months [24.6–123.8]. Eighty-nine patients (65.0%)
received SOF and DCV without RBV. The treatment duration was 12 or 24 weeks for 21 and 68
patients, respectively. Forty-eight patients (35.0%) were treated with SOF and DCV plus RBV (four for
12 weeks and 44 for 24 weeks). In this latter group, the median baseline RBV dosage was 800 [600–
1000] mg/day.
Treatment efficacy
By W4 of treatment, HCV RNA levels had fallen below the LLOQ in 71 patients (53%). The median
time required to achieve undetectability was 4 weeks [3–8]. Concerning viral kinetics during treatment,
there were no differences regarding the use of RBV or fibrosis stage at baseline (Supplemental Figure
1). As for the primary endpoint, 132 out of 137 patients (96.4%) had a sustained virological response
at post-treatment W12 (Figure 2). Among the five patients who did not achieve an SVR12, one was
lost to follow-up and two died between EOT and SVR 12. Excluding non-virological failures, the
SVR12 rate thus reached 98.5% (132/134). Two patients in the study population therefore
experienced a virological failure. One was a 55-year old treatment-naive man who experienced a
recurrence of genotype 1a HCV and fibrosis stage ≤2 on the graft, and a virological breakthrough at
W11. He was receiving SOF+DCV with RBV for a planned treatment duration of 12 weeks.
Retrospectively, we investigated his resistance mutations both at baseline and after this failure: no
mutation was found in the NS5B regions but one de novo Q30R mutation in the NS5A region
14
appeared after breakthrough. The other patient was a 49-year old man who had previously not
responded to PEG-IFN/RBV, was infected with genotype 4 and had cirrhosis on the graft (baseline
MELD score of 19). He relapsed four weeks after completion of a 24-week course of SOF+DCV. As
previously, no mutation was found in the NS5B regions but one pre-existing mutation in the NS5A
region (Q30R) was observed at baseline and another was found after the relapse (Y93H). No factors
were found to influence SVR12 rates with respect to genotype, fibrosis stage or previous response to
therapy (Supplemental Figure 2). Patients with cirrhosis responded remarkably well, with an SVR12
rate of 96%.
Clinical improvement
All clinical and biological parameters reflecting liver function and general status improved significantly
during treatment (Table 2). In the overall population, the mean reduction in the MELD score between
baseline and EOT was 0±2 [-10-5]. However, among potential candidates for a re-transplantation with
a MELD score at baseline over 15, 65% improved, the MELD score falling by between 1 and 10 points
(Figure 3). Among the four patients with refractory ascites at baseline, only one (relapser) still had
ascites at EOT. Ascites disappeared in three of the five patients with mild or moderate ascites at
baseline. No hepatic encephalopathy was reported at EOT.
Safety
Adverse events were common, affecting 105 patients (77%), although the majority were mild to
moderate in severity (Table 3). The most common AE was anaemia, which increased significantly with
the use of RBV (18.0% versus 56.3%, P<0.0001). In 17 patients (35%) treated with RBV, it was
necessary to reduce the RBV dosage during treatment, and a discontinuation was required in seven
patients (15%). A serious AE was reported in 17.5% of patients. Two patients (1.5%) died during the
study period. The first experienced a severe decompensation of diabetes mellitus, leading to
hyperosmolar coma then multi-organ failure one week after treatment initiation. No relationship
between treatment initiation and this event was determined (in accordance with the mandatory
declaration procedure under the early access programme when it was applicable). The second patient
experienced a recurrence of hepatocellular carcinoma after treatment initiation and finally died 8
weeks after treatment completion. One patient (0.01%) prematurely discontinued his therapy following
the investigator's decision due to severe flare-up of psoriasis. Two patients suffered from biopsy-
15
proven acute graft rejection at W8 and W9 of treatment, respectively, but recovered fully after an
increase in their immunosuppressive therapy. A severe infection occurred in 4 patients (2.9%), with
favourable outcomes. Eighty-six patients (62.8%) developed or experienced a worsening of renal
insufficiency during treatment, with an estimated GFR ≤60ml/min. Figure 4 represents the kinetics of
GFR during therapy. In the overall population, there was a moderate but significant decrease in GFR
values between baseline and EOT, from 70.1±27.1 to 64.5±25.0 mL/min (P<0.0001). There were no
differences regarding the use of RBV, the fibrosis stage at baseline or combined liver-kidney
transplant status (n=2) (data not shown).
Immunosuppression
At baseline, 120 patients (88%) were receiving a calcineurin inhibitor-based regimen, mainly
tacrolimus (in 85 patients (62%)). The immunosuppressive drug regimens are detailed in Figure 5.
Changes to immunosuppressive drug dosages were required in 52%, 49%, 58% and 7% of patients
treated with tacrolimus, cyclosporine, everolimus and mycophenolate mofetil, respectively. The degree
of these changes was moderate, but greater for patients treated with tacrolimus. Between baseline
and W4, the tacrolimus and cyclosporine dosages needed to be increased by 19% and 4%,
respectively. Between baseline and EOT, the tacrolimus and everolimus dosages needed to be
increased by 34% and 9%, respectively, whereas the variations were minor with cyclosporine and
mycophenolate mofetil (2% and 0%, respectively).
16
Discussion
In this study, we describe our multicentre experience in treating HCV recurrence in LT recipients using
an all-oral, interferon-free, antiviral regimen including DCV and SOF, with or without RBV, for 12 or 24
weeks. The SVR rate 12 weeks after completing treatment was 96% under the intention-to treat
analysis and 99% when excluding non-virological failures. This combination therapy was very well
tolerated, although SAE rates reached 17.5%. Two patients (1.5%) stopped their treatment
prematurely due to SAE; both patients died, but their deaths were not related to the antiviral drugs
under investigation.
Earlier studies had shown that overall graft and patient survival rates were lower among liver
transplant recipients with HCV infection than in those transplanted for other indications, because of
universal HCV reinfection of the graft and an accelerated progression of fibrosis in immuno-
compromised patients [14]. Among liver transplant recipients, studies of PEG-IFN/RBV or first-
generation protease inhibitors (boceprevir or telaprevir) in combination with this dual therapy produced
low SVR rates (from 20% to 60%), and high rates of potentially life-threatening SAEs [5, 6, 15-17].
Furthermore, drug-drug interactions were potent between first generation protease inhibitors and
immunosuppressive drugs [18]. Experience of treating liver transplant recipients using an all-oral,
interferon-free, antiviral regimen is currently emerging. In a phase II study, SOF and RBV for 24 weeks
resulted in an SVR12 rate of 70% [19]. During a recent randomised study, 34 liver transplant recipients
infected with genotype 1 under ombitasvir/paritaprevir/ritonavir/dasabuvir (OPRB) and RBV for 24
weeks achieved an SVR12 of 97% [20], although these patients were only infected with HCV genotype
1 and had no or mild fibrosis on the graft. In another recent multicentre study, an SVR12 was achieved
in 90% of 123 liver transplant recipients infected with genotype 1 treated with SOF plus simeprevir
(SIM), with or without RBV, for 12 weeks [21]. During a recent phase II open-label study, Charlton et
al. reported on their experience of combining SOF plus ledipasvir with RBV for 12 or 24 weeks in order
to treat genotypes 1 or 4 cirrhotic or liver transplant patients [22]. Among the graft recipients, SVR12
rates ranged from 96% to 98% among 227 patients. Recently, the combination of SOF plus DCV with
RBV was studied during a phase II open-label study. In 53 liver transplant patients, an SVR12 was
achieved by 95% and 91% of patients with G1 and G3 infection, respectively [10]. Our study is the
only one to have reported on real-life liver transplant patients, regardless of genotype and fibrosis
stage at baseline. Despite this, our excellent SVR12 rate of 96% demonstrated the considerable
17
efficacy of the SOF plus DCV combination in treating liver transplant recipients. These results were
particularly impressive in the patients most difficult to treat, such as cirrhotic patients, with a SVR12
rate of 96%. These data thus confirm the findings of several recent publications regarding this latter
population whose prognosis has been dramatically modified [9, 23].
There are many advantages to using a combination of NS5A and NS5B inhibitors to treat liver
transplant recipients. These drugs are both pangenotypic, with a high barrier of resistance. To date,
NS5B inhibitors such as SOF have usually been the backbone of interferon-free antiviral regimens.
Thanks to their renal metabolism, these inhibitors can be used in patients with severe hepatic
impairment. On the other hand, no drug-drug interactions have been described with
immunosuppressive drugs22
. Based on the findings of pharmacokinetic studies, NS5A inhibitors such
as DCV are also convenient in the context of LT [24]. Unlike protease inhibitors, trough blood
concentrations (TBC) of DCV remain stable, even in the event of severe hepatic impairment. As for
drug-drug interactions, the concomitant administration of SMV may decrease the TBC of tacrolimus.
Using SMV and cyclosporine together is not recommended, as the TBC of both drugs are increased
when in combination [25]. The dosage of calcineurin inhibitors still requires adjustment when a
combination of OPRD is used in a liver transplant recipient [20]. During our study, no significant drug-
drug interactions were highlighted. However, an adjustment of immunosuppressive regimens was
required in more than a half of our study population (52%, 49%, 58% and 7% of patients treated with
tacrolimus, cyclosporine, everolimus and mycophenolate mofetil, respectively). Most changes were
necessary four weeks after treatment initiation, probably as a result of improved hepatic function under
therapy. All these factors imply a need to closely monitor the TBC of immunosuppressive drugs during
antiviral therapy in liver transplant patients.
One limitation of our study consisted in the problem of comparing efficacy according to the duration of
treatment or the use of RBV. However, the use of RBV does not appear to be mandatory in light of the
SVR12 rates of 100% and 97% achieved under SOF plus DCV without RBV for 12 and 24 weeks,
respectively. RBV is known to be responsible for several AEs, and particularly haematological toxicity
[26]. Although a reduction in the RBV dosage was required in 35% of the patients in our study,
anaemia remained the most common AE, leading to a significant increase in erythropoietin use among
patients receiving RBV. Not using RBV in the context of LT would improve tolerance, but its withdrawal
18
could have a deleterious impact on efficacy. In our study, patients treated without RBV for 12 weeks
achieved a SVR12 rate of 100%, but their number was too small to draw any definitive conclusions
(n=21). The majority of the patients were treated with 24 weeks of therapy and thus we cannot make a
recommendation on duration and/or use of ribavirin based on our results. Overall all groups had a high
SVR rate.
Finally, in our cohort, we observed a small but significant reduction in the GFR during treatment (from
70.1±27.1 to 64.5±25.0 mL/min. between baseline and EOT). This could not be attributed to the use of
RBV, because a similar decrease was seen in the arm without RBV. This finding was only possible
because we enrolled real-life patients, regardless of any previous renal impairment. Renal function is a
major prognostic factor following liver transplantation, and further studies are necessary to investigate
predictive factors for renal impairment during antiviral therapy. Longer term follow-up would also be
useful, in order to determine whether this decline persists over time. Other studies coming from the
ANRS CO23 CUPILT cohort and investigating pharmacokinetic changes and renal function are
currently on-going. A final report on the entire cohort will be also published.
In conclusion, we found that the combination of DCV and SOF, with or without RBV, administered for
12 or 24 weeks, enabled an SVR12 rate of 96% among LT recipients. Overall, this regimen was safe
and well tolerated. The combination of DCV and SOF could become the gold standard for the
treatment of HCV recurrence after LT, allowing us to treat patients earlier, before the development of
fibrosis on the graft. It would help to eradicate HCV infection in a specific population at high risk of
severe liver disease and life threatening events, for whom treatment guidelines are still awaited.
19
ACKNOWLEDGEMENTS:
We would like to thank all the patients and their families, and all the co-investigators of the CUPILT
study in France and Belgium for their support and for making this study feasible. Our particular thanks
go to Laurent Alric, Teresa Maria Antonini, Ellada Ayvazyan, Eleonora De Martin, Djamel Elaribi,
Laure Esposito, Stéphanie Faure, Joelle Guitard, Stéphanie Haïm Boukobza, Laurence Lavayssière,
Sophie Metivier, Gilles Pelletier, Bruno Roche, Lionel Rostaing, Faouzi Saliba, Rodolphe Sobesky,
Maria Grazia Tateo, Albert Tran who participated actively in the study. We also acknowledge the
assistance provided by the clinical research associates: Mustapha Ahmim, Neila Bouchard, Alain
Caro, Selma El Andaloussi, Anne Laligant, Khellaf Ouamara, Julie Raimon, Régine Thierry and
Aurélie Veislinger. Finally, we thank all the staff at the ANRS (France REcherche Nord&Sud Sida-hiv
Hépatites) who were responsible for this study, and notably Professor Jean-François Delfraissy, Inga
Bertucci, Alexandra Rohel, Alpha Diallo and Ventzislava Petrov-Sanchez.
20
Figures and Tables
Figure 1: Breakdown of patient details
Patients were selected between October 2013 and March 2015. Two patients were excluded: one who
did not meet the inclusion criteria and one who did not start treatment.
Figure 2: Virological responses according to treatment duration and RBV use
Two virological failures were observed: one virological breakthrough (in the group receiving
SOF+DCV+RBV for 12 weeks) and one relapse (in the group receiving SOF+DCV for 24 weeks). One
patient was lost to follow-up between EOT and SVR12 (in the SOF+DCV 24 weeks group). Two
patients died in the SOF+DCV+RBV 24 weeks group.
Figure 3: Changes to MELD score between baseline and EOT among the 23 patients with a
baseline MELD score >15
Each bar represents one patient. Above the line, 7 patients correspond to an increase in the MELD
score (4 in SOF+DCV and 3 in SOF+DCV+RBV) and thus a worsening of their condition, while one
patient remained stable. The majority of patients (65%) improved during treatment.
Figure 4: Kinetics of creatinine clearance according to RBV use (A) and IMS use (B)
Creatinine clearance was estimated according to the MDRD6 formula. Results are given as medians
according to time. A small but significant decrease in creatinine clearance during treatment was
observed (from 70.1 ± 27.1 to 64.5 ± 25 mL/min between baseline and EOT). There was no difference
regarding the use of RBV.
Figure 5: Immunosuppressive regimens and their management during the study
(A) The Table shows the breakdown of immunosuppressive drugs at baseline, week 4 and EOT (B)
The graph represents the intensity and direction of dosage changes, between baseline and week 4,
and baseline and EOT, for each immunosuppressive drug.
21
Table 1: Baseline characteristics of the study population
Table 2: Evolution of clinical and biological liver function parameters during the study
Table 3: Adverse events and laboratory abnormalities during treatment
Supplemental Table 1: Parameters assessing the severity of liver disease in the study population
Supplemental Figure 1: Virological kinetics during treatment according to RBV use (A), cirrhotic status (B) and with the intended duration extended (n=3) (C)
Supplemental Figure 2: Virological responses according to previous response to therapy, genotype and fibrosis stage
Supplemental Appendix 1: Scientific committee of the ANRS C023 CUPILT Study
Supplemental Appendix 2: Definitions of adverse events and serious adverse events
Supplemental Appendix 3: ANRS scale used to grade the severity of adverse events in adults
22
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23
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Author names in bold designate first author or shared co-first authorship.
24
Table 1: Baseline characteristics of the study population
Continuous variables are expressed as median (IQR)
Overall population SOF+DCV SOF+DCV+RBV SOF+DCV SOF+DCV+RBV
P 12 weeks 12 weeks 24 weeks 24 weeks
(n=137) (n=21) (n=4) (n=68) (n=44)
Age (years) 59.0 (53.0 - 65.0) 64.0 (57.0 - 71.0) 59.5 (53.5 - 69.5) 59.5 (52.0 - 64.0) 58.5 (53.0 - 64.0) 0.43
Gender (M) – n (%) 106 (77.4) 16 (76.2) 4 (100.0) 52 (76.5) 34 (77.3) 0.91
Body Mass Index (Kg/m2) 24.1 (21.8 - 27.2) 23.5 (21.4 - 25.1) 27.4 (24.1 - 28.1) 25.3 (22.2 - 28.1) 23.6 (21.3 - 26.2) 0.15
Indication for LT – n (%)
0.24
End-stage liver disease 58 (42.3) 7 (33.3) 2 (50.0) 35 (51.5) 14 (31.8)
HCC 67 (48.9) 13 (61.9) 2 (50.0) 29 (42.6) 23 (52.3)
HCV ReLT 12 (8.8) 1 (4.8) 0 (0.0) 4 (5.9) 7 (15.9)
Previous treatment response post-LT – n (%)
0.64
Treatment-naïve patients 69 (50.4) 14 (66.7) 2 (50.0) 36 (52.9) 17 (38.6)
Non-responders 26 (19.0) 3 (14.3) 0 (0.0) 12 (17.6) 11 (25.0)
Relapsers 5 (3.6) 0 (0.0) 0 (0.0) 2 (2.9) 3 (6.8)
Virological breakthroughs 16 (11.7) 2 (9.5) 1 (25.0) 6 (8.8) 7 (15.9)
Intolerance 21 (15.3) 2 (9.5) 1 (25.0) 12 (17.6) 6 (13.6)
Exposure to previous regimens – n (%)
0.39
PEG-IFN/RBV 56 (40.9) 7 (33.3) 2 (50.0) 25 (36.8) 22 (50.0)
First generation PI 11 (8.0) 0 (0.0) 0 (0.0) 7 (10.3) 4 (9.1)
25
SOF based regimen 1 (0.7) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.3)
Interval between LT and antiviral therapy (months)
72.3 (24.6 - 123.8) 76.5 (45.4 - 152.3) 94.8 (40.1 - 153.7) 72.7 (24.8 -
125.3) 61.4 (19.6 -
111.4) 0.67
Overall population SOF+DCV SOF+DCV+RBV SOF+DCV SOF+DCV+RBV
P 12 weeks 12 weeks 24 weeks 24 weeks
(n=137) (n=21) (n=4) (n=68) (n=44)
HCV Genotype – n (%)
N/A
1a 11 (8.0) 2 (9.5) 0 (0.0) 7 (10.3) 2 (4.5)
1b 36 (26.3) 6 (28.6) 2 (50.0) 15 (22.1) 13 (29.5)
1 62 (45.3) 10 (47.6) 1 (25.0) 33 (48.5) 18 (40.9)
3 15 (10.9) 2 (9.5) 1 (25.0) 5 (7.4) 7 (15.9)
4 12 (8.8) 1 (4.8) 0 (0.0) 7 (10.3) 4 (9.1)
5 1 (0.7) 0 (0.0) 0 (0.0) 1 (1.5) 0 (0.0)
Fibrosis stage – n (%)
0.91
≤F2 60 (43.8) 10 (47.6) 3 (75.0) 29 (42.6) 18 (40.9)
F3 31 (22.6) 5 (23.8) 0 (0.0) 17 (25.0) 9 (20.5)
F4 46 (33.6) 6 (28.6) 1 (25.0) 22 (32.4) 17 (38.6)
MELD score 10 (7 - 13) 8 (6 - 13) 9 (7 - 10) 9 (8 - 13) 11 (7 - 15) 0.14
Total bilirubin (µmol/L) 13.2 (8.6 - 20.0) 12.0 (10.5 - 17.5) 10.5 (8.0 - 17.5) 13.9 (8.6 - 19.5) 14.0 (8.0 - 26.5) 0.88
ALT (IU/L) 67 (43 - 107) 60 (31 - 117) 45 (37 - 85) 73 (44 - 105) 74 (40 - 108) 0.67
Albuminemia (g/L) 37.9 (34.1 - 42.0) 35.5 (33.4 - 41.0) 37.2 (34.7 - 41.5) 38.0 (35.0 - 42.1) 38.0 (33.6 - 39.5) 0.69
Creatinine clearance (mL/min) 68.6 (50.5 - 88.8) 80.9 (45.4 - 92.5) 66.0 (61.6 - 77.6) 68.6 (50.7 - 89.1) 65.4 (48.8 - 89.1) 0.96
Haemoglobin (g/dL) 13.2 (11.7 - 14.7) 13.0 (11.8 - 14.2) 15.2 (14.6 - 15.9) 13.2 (10.9 - 14.6) 13.4 (12.0 - 14.7) 0.13
Neutrophil count (G/L) 2.73 (1.96 - 3.86) 3.10 (2.36 - 4.17) 2.97 (2.25 - 5.57) 2.61 (1.98 - 3.73) 2.68 (1.73 - 3.91) 0.44
Platelet count (G/L) 131 (89 - 172) 145 (101 - 172) 192 (107 - 250) 128 (88 - 171) 128 (88 - 169) 0.62
26
HCV viral load (log10 IU/mL) 6.32 (6.01 - 6.74) 6.23 (5.77 - 6.53) 6.17 (6.00 - 6.37) 6.35 (6.01 - 6.72) 6.43 (6.13 - 6.83) 0.36
Abbreviations: IQR: inter-quartile ranges; HCC: hepatocellular carcinoma; HCV: hepatitis C virus; DCV: daclatasvir; M: male; n: number; LT: liver transplantation; PEG-IFN: pegylated interferon; PI: protease inhibitor; RBV: ribavirin; SOF: sofosbuvir
Table 2: Evolution of clinical and biological liver function parameters during the study
Results are given in mean ± standard deviation.
Baseline EOT Follow-up week
12 P*
Body mass index (Kg/m2) 24.6 ± 4.4 25.5 ± 5.0 25.2 ± 4.5 < 0.0001
ALT (IU/L) 87 ± 78 24 ± 12 30 ± 52 < 0.0001
γGT (IU/L) 292 ± 370 80 ± 105 81 ± 114 < 0.0001
Total Bilirubin level (µmol/L) 19.2 ± 23.1 13.5 ± 9.5 12.3 ± 7.8 0.0008
Albumin level (g/L) 37.6 ± 5.2 39.7 ± 4.3 40.8 ± 4.3 < 0.0001
Platelet count (G/L) 137 ± 65 155 ± 72 154 ± 69 < 0.0001
MELD score 11 ± 4 11 ± 4 11 ± 5 0.3197
CHILD score in cirrhotic patients** 6 (5 - 7) 5 (5 - 6) 5 (5 - 6) 0.0011
* P was evaluated for the difference between baseline and Follow-up week 12.
**Results are given in median (IQR)
IQR: inter-quartile ranges; ALT: alanine amino-transferase; EOT: end of treatment; GGT: gammaglutamyl-transferase; INR: international normalized ratio
Overall population SOF+DCV SOF+DCV+RBV
(n=137) (n=89) (n=48)
Serious AE – n (%) 24 (17.5) 15 (16.9) 9 (18.8)
Death – n (%) 2 (1.5) 0 (0.0) 2 (4.2)
Anaemia – n (%) 43 (31.4) 16 (18.0) 27 (56.3)
Grade 0 (but EPO) 6 (4.4) 1 (1.1) 5 (10.4)
Grade 1/2 (<10g/dL) 28 (20.4) 12 (13.5) 16 (33.3)
Grade 3/4 (<8 g/dL) 9 (6.6) 3 (3.4) 6 (12.5)
Erythropoietin use 23 (16.8) 10 (11.2) 13 (27.1)
Blood transfusion 7 (5.1) 3 (3.4) 4 (8.3)
RBV reduction for AE 17 (12.4) - 17 (35.4)
Discontinuation of RBV for AE 7 (5.1) - 7 (14.6)
Neutropenia – n (%) 26 (19.0) 12 (13.5) 14 (29.2) Grade 1/2 (<1.5G/L) 23 (16.8) 11 (12.4) 12 (25.0)
Grade 3/4 (<0.75G/L) 3 (2.2) 1 (1.1) 2 (4.2)
G-CSF use 1 (0.7) 1 (1.1) 0 (0.0)
Thrombocytopenia – n (%) 29 (21.2) 19 (21.3) 10 (20.8) Grade 1/2 (<99G/L) 24 (17.5) 15 (16.9) 9 (18.8)
Grade 3/4 (<50G/L) 5 (3.6) 4 (4.5) 1 (2.1)
Creatinine clearance (MDRD) – n (%) 86 (62.8) 56 (62.9) 30 (62.5)
Creatinine clearance ≤ 60 ml/min 71 (51.8) 43 (48.3) 28 (58.3)
Creatinine clearance ≤ 30 ml/min 11 (8.0) 10 (11.2) 1 (2.1)
Creatinine clearance ≤ 10 ml/min 4 (2.9)*** 3 (3.4) 1 (2.1)
Cardiac Disorders – n (%) 5 (3.6) 3 (3.4) 2 (4.2) Grade 1/2 0 (0.0) 0 (0.0) 0 (0.0)
Grade 3/4* 5 (3.6) 3 (3.4) 2 (4.2)
Infections – n (%) 30 (21.9) 13 (14.6) 17 (35.4)
Grade 1/2 26 (19.0) 11 (12.4) 15 (31.3)
Grade 3/4** 4 (2.9) 2 (2.2) 2 (4.2)
Biopsy proven acute rejection – n (%) 2 (1.5) 1 (1.1) 1 (2.1)
* 5 patients with cardiac disorders: 2 High Blood Pressure, 2 cardiac decompensations in patients with a past history of cardiomyopathy and 1 ischaemic heart disease
** 4 patients with severe infections: 2 abdominal infections (2 spontaneous bacterial peritonitis), 1 bronchopulmonary infection, 1 urinary tract infection, 2 other infections
*** Among the 4 patients with creatinine clearance ≤ 10 ml/min, SOF was adjusted to 400mg/2days in only one patient.
AE: adverse events; DCV: daclatasvir; EPO: erythropoietin use; G-CSF: granulocyte colony stimulating factor; n: number of patients; RBV: ribavirin; SOF: sofosbuvir.
Table 3: Adverse events and laboratory abnormalities during treatment
27
28
Figure 2: Virological responses according to treatment duration and RBV use
Two virological failures were observed: one virological breakthrough (in the group receiving SOF+DCV+RBV for 12 weeks) and one
relapse (in the group receiving SOF+DCV for 24 weeks). One patient was lost to follow-up between EOT and SVR12 (in the SOF+DCV 24 weeks group). Two patients died in the SOF+DCV+RBV 24 weeks group.
DCV: Daclatasvir; EOT: end of treatment response; RBV: ribavirin; SOF: sofosbuvir; SVR12: sustained virological response at 12
weeks after treatment discontinuation
Results are given in intention-to-treat.
100% 75% 100% 98%100% 75% 97% 95%
SOF+DCV (n=21) SOF+DCV+RBV (n= 4) SOF+DCV (n=68) SOF+DCV+RBV (n=44)
Week 12 Week 24
EOT SVR12
Figure 3: Changes to MELD score between baseline and EOT among the 23 patients with a baseline MELD score >15
Each bar represents one patient. Above the line, 7 patients correspond to an increase in the MELD score (4 in SOF+DCV and 3 in SOF+DCV+RBV) and thus a worsening of their condition, while one patient remained stable. The majority of patients (65%) improvedduring treatment.*For 2 patients, data were missing.
DCV: Daclatasvir; EOT: end of treatment response; RBV: ribavirin; SOF: sofosbuvir.
-14
-12
-10
-8
-6
-4
-2
0
2
4
6SOF+DCV, n=11*
n=1
-14
-12
-10
-8
-6
-4
-2
0
2
4
6SOF+DCV+RBV, n=12*
30
Figure 4: Kinetics of creatinine clearance according to RBV use (A) and IMS drugs (B)
Creatinine clearance was estimated according to the MDRD6 formula. Results are given as medians according to time. A small but significant decrease in creatinine clearance during treatment was observed (from 70.1 ± 27.1 to 64.5 ± 25 mL/min between baseline
and EOT). There was no difference regarding the use of RBV.
DCV: Daclatasvir; FUW: follow-up week X means X week after treatment completion; RBV: Ribavirin; SOF: Sofosbuvir; IMS:
Immunosuppressive
50
60
70
80
0 4 8 12 16 20 24 28 32Cre
ati
nin
e c
leara
nce
(m
l/m
in)
Weeks
SOF+DCV SOF+DCV+RBV
FUW4 FUW12
40
50
60
70
80
0 4 8 12 16 20 24 28 32Cre
ati
nin
e c
lea
ran
ce
(m
l/m
in)
Weeks
Cyclosporine Tacrolimus Others
FUW4 FUW12
A
B
31
Figure 5: Immunosuppressive regimens and their management during study
(A) The Table shows the breakdown of immunosuppressive drugs at baseline, week 4 and EOT (B) The graph represents the intensity and direction of dosage changes, between baseline and week 4, and baseline and EOT, for each immunosuppressive drug. DCV: Daclatasvir; EOT: end of treatment; MMF: Mycophenolate mofetil; N: Number of patients; RBV: Ribavirin; SOF: Sofosbuvir
Cyclosporine Tacrolimus Everolimus MMF
4%
19%
0% 2%2%
34%
9%
0%
Baseline/W4 Baseline/EOT
Cyclosporine Tacrolimus Everolimus MMF
At baseline
N (%) 35 (26%) 85 (62%) 11 (8%) 68 (50%)
Dosage (mg/d) 111 ± 51 2 ± 1 1 ± 1 1385 ± 678
Concentration (ng/mL) 76.3 ± 44.2 6.5 ± 3.3 - -
At week 4
N (%) 29 (21%) 75 (55%) 8 (6%) 63 (46%)
Dosage (mg/d) 106 ± 47 2 ± 1 1 ± 1 1396 ± 689
Concentration (ng/mL) 102.1 ± 66.4 4.4 ± 2.2 - -
At EOT
N (%) 31 (23%) 80 (58%) 10 (7%) 62 (45%)
Dosage (mg/d) 105 ± 45 2 ± 1 1 ± 0 1386 ± 702
Concentration (ng/mL) 82.3 ± 56.3 4.6 ± 2.1 - -
32
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