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Transjugular Intrahepatic Portosystemic Shunt: A Possible Risk Factor for Direct‐Acting Antiviral Treatment Failure in Patients With Hepatitis C?

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Direct‐acting antiviral (DAA) therapies have revolutionized the treatment of chronic hepatitis C virus infection, achieving sustained virological response (SVR) rates of >90% even in patients with advanced liver cirrhosis. Having observed an unusual case of repeated DAA therapy failures in a patient with a transjugular intrahepatic portosystemic shunt (TIPS), we assessed a possible association between prior TIPS placement and DAA failure. A structured search of our clinical database revealed 10 patients who had received DAA therapy after TIPS placement. At the time of therapy, most patients (8; 80%) presented with a Child‐Pugh score B, and the following DAA regimens were used: sofosbuvir/ledipasvir ± ribavirin (5 patients), sofosbuvir/daclatasvir ± ribavirin (3), sofosbuvir/velpatasvir (2), and sofosbuvir/velpatasvir/voxilaprevir (1). In total, 5 patients (50%) achieved an SVR, whereas a virological relapse occurred in the other half of the cases, including 2 patients with multiple relapses. In this patient cohort, SVR rates were unusually low for all regimens: sofosbuvir/ledipasvir ± ribavirin, 3/5 (60%); sofosbuvir/daclatasvir ± ribavirin, 2/3 (66%); sofosbuvir/velpatasvir, 0/2 (0%); and sofosbuvir/velpatasvir/voxilaprevir, 0/1 (0%), and patients with a TIPS made up a relevant proportion of DAA failures in patients with cirrhosis at our center: sofosbuvir/ledipasvir, 2/18 (11%); sofosbuvir/daclatasvir, 1/4 (25%); sofosbuvir/velpatasvir, 2/3 (66%); and sofosbuvir/velpatasvir/voxilaprevir, 1/1 (100%). Conclusion: We observed a high rate of virological relapse in patients with a TIPS who received DAA treatment and therefore postulate that TIPS placement may be a possible risk factor for DAA failure due to the profound hemodynamic changes evoked by the intervention. Longer treatment duration or addition of ribavirin might be warranted in these patients.
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HEPATOLOGY COMMUNICATIONS, VOL. 0, NO. 0, 2019
Transjugular Intrahepatic Portosystemic
Shunt: A Possible Risk Factor for
Direct-Acting Antiviral Treatment
Failure in Patients With Hepatitis C?
Felix Piecha,1 Jan-Michael Gänßler,1 Sabine Jordan,1 Can Ergen,1 Harald Ittrich,2 Johannes Kluwe,1 Sven Pischke,1
Ansgar W. Lohse,1,3 and Julian Schulze zur Wiesch1,3
Direct-acting antiviral (DAA) therapies have revolutionized the treatment of chronic hepatitis C virus infection,
achieving sustained virological response (SVR) rates of >90% even in patients with advanced liver cirrhosis. Having
observed an unusual case of repeated DAA therapy failures in a patient with a transjugular intrahepatic portosys-
temic shunt (TIPS), we assessed a possible association between prior TIPS placement and DAA failure. A struc-
tured search of our clinical database revealed 10 patients who had received DAA therapy after TIPS placement. At
the time of therapy, most patients (8; 80%) presented with a Child-Pugh score B, and the following DAA regimens
were used: sofosbuvir/ledipasvir ± ribavirin (5 patients), sofosbuvir/daclatasvir ± ribavirin (3), sofosbuvir/velpatasvir
(2), and sofosbuvir/velpatasvir/voxilaprevir (1). In total, 5 patients (50%) achieved an SVR, whereas a virological
relapse occurred in the other half of the cases, including 2 patients with multiple relapses. In this patient cohort,
SVR rates were unusually low for all regimens: sofosbuvir/ledipasvir ± ribavirin, 3/5 (60%); sofosbuvir/daclatasvir ±
ribavirin, 2/3 (66%); sofosbuvir/velpatasvir, 0/2 (0%); and sofosbuvir/velpatasvir/voxilaprevir, 0/1 (0%), and patients
with a TIPS made up a relevant proportion of DAA failures in patients with cirrhosis at our center: sofosbuvir/le-
dipasvir, 2/18 (11%); sofosbuvir/daclatasvir, 1/4 (25%); sofosbuvir/velpatasvir, 2/3 (66%); and sofosbuvir/velpatasvir/
voxilaprevir, 1/1 (100%). Conclusion: We observed a high rate of virological relapse in patients with a TIPS who
received DAA treatment and therefore postulate that TIPS placement may be a possible risk factor for DAA failure
due to the profound hemodynamic changes evoked by the intervention. Longer treatment duration or addition of
ribavirin might be warranted in these patients. (Hepatology Communications 2019;0:1-6).
Since the advent of direct-acting antiviral (DAA)
therapies for the treatment of chronic hepatitis
C virus (HCV) infection, sustained virological
response (SVR) rates have steadily increased from ini-
tially 60% in interferon-based DAA treatment reg-
imens(1) to >90% for currently used DAA regimens,
Abbreviations: CPS, Child-Pugh score; DA A, direct-acting antiviral; GT, genotype; HCV, hepatitis C virus; LTFU, lost to follow-up; MELD,
Model for End-Stage Liver Disease; RAS , resistance-associated substitutions; SVR, sustained virological response; T IPS, transjugular intrahepatic
portosystemic shunt.
Received December 20, 2018; accepted February 24, 2019.
Additional Supporting Information may be found at onlinelibrary.wiley.com/doi/10.1002/hep4.1337/suppinfo.
Supported by the Dr. Liselotte and Dr. Karl-Robert Brauns Foundation (Dr. Liselotte Brauns Research Award for Internal Medicine 2018 to
F.P. and J.K.), the German Research Agency (SFB 841 to H.I., A.W.L., and J.S.z.W.), and the German Center for Infection Research (DZIF
05.809 to A.W.L. and J.S.z.W.).
© 2019 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of
Liver Diseases. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which
permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or
adaptations are made.
View this article online at wileyonlinelibrary.com.
DOI 10.1002/hep 4.1337
Potential conflict of interest: Dr. Kluwe consults for Novartis. Dr. Pischke consults for MSD and AbbVie. Dr. Schulze sur Wiesch is on the
speakers’ bureau for and received grants from Gilead and is on the speakers’ bureau for MSD and AbbVie. The other authors have nothing to report.
HEPATOLOGY COMMUNICATIONS, Month 2019PIECHA ET AL.
2
even in patients with liver cirrhosis.(2) However,
several factors are associated with increased rates of
treatment failure, including previous DAA treatment
experience, advanced liver cirrhosis,(2) the presence of
resistance-associated substitutions (RAS),(3) and con-
ditions that have an impact on the bioavailability of
the drugs, such as prior gastric surgery.(4,5)
In patients with decompensated liver cirrhosis,
the implantation of a transjugular intrahepatic por-
tosystemic shunt (TIPS) has become the treatment
of choice for portal-hypertensive complications of
end-stage liver disease, such as esophageal varices or
refractory ascites.(6) Although the primary aim of this
intervention is to decrease portal pressure, it has also a
profound effect on hepatic hemodynamics, including
an increase in hepatic arterial perfusion(7) and changes
on tissue stiffness.(8) An unusual case of repeated
DAA therapy failures in a patient who had previously
been treated with a TIPS led us to analyze our clinical
database for a possible association between TIPS and
DAA failure in a structured way.
Patients and Methods
Patients with HCV-associated liver cirrhosis
receiving a TIPS between January 2009 and January
2018 at the Medical Center Hamburg-Eppendorf
were identified by chart review. Standard labora-
tory results, including calculation of the Child-Pugh
score (CPS), the Model for End-Stage Liver Disease
(MELD) score, and flow rates on Doppler ultrasound
prior to the first DAA therapy, were retrospectively
assessed in patients who underwent DAA therapy
after TIPS placement. The proportion of patients
with a TIPS who experienced a virological relapse in
comparison with the overall SVR rate was calculated
by retrospective analysis of the treatment response of
all patients who received sofosbuvir/ledipasvir, sofos-
buvir/daclatasvir, sofosbuvir/velpatasvir, and sofos-
buvir/velpatasvir/voxilaprevir between January 2014
and February 2018 at our center. SVR was defined
as documented negative HCV-polymerase chain reac-
tion 12 weeks after the end of treatment, whereas a
virological relapse was defined as the renewed detec-
tion of viral RNA after HCV treatment (and after
intermittent complete viral control of HCV viremia).
Patients who had initiated an antiviral DAA therapy
but did not have a documented control of viremia at
least 12 weeks after the end of treatment were defined
as lost to follow-up (LTFU). The study protocol was
approved by the local ethics committee in accordance
with the Declaration of Helsinki.
STATISTICAL ANALYSIS
Categorical data are given in percentages. Mean or
median values with the corresponding SD or inter-
quartile range were calculated for continuous data
using Excel 2016 (Microsoft, Inc., Redmond, WA)
and SPSS Statistics version 25 (IBM Corp., Armonk,
NY). SVR rates were calculated using a per-protocol
analysis. Comparison of flow velocities for the group
of patients with relapse or SVR was carried out using
a Mann-Whitney U test; P < 0.05 was considered sta-
tistically significant.
Results
PATIENT COHORT
A total of 74 patients with HCV-associated liver
cirrhosis and TIPS were identified by review of our
ARTICLE INFORMATION:
From the 1 I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 2 Depar t ment of
Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Hamburg,
Germa ny; 3 German Center for Infection Research, Par tner Site Hamburg-Lübeck-Borstel-Riems, Germany.
ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Julian Schulze zur Wiesch, M.D.
I. Department of Medicine
University Medical Center Hamburg-Eppendorf
Martinistraße 52
D-20246 Hamburg, Germany
E-mail: j.schulze-zur-wiesch@uke.de
Tel.: +49 40 7410 53910
HEPATOLOGY COMMUNICATIONS, Vol. 0, No. 0, 2019 PIECHA ET AL.
3
clinical database. Of these 74 patients, 38 patients
(51%) remained without HCV therapy, 16 patients
(22%) were treated before TIPS placement, and 7
patients (9%) received treatment after liver transplan-
tation. DAA treatment was initiated in 13 patients
after TIPS placement, including 2 patients who
underwent liver transplantation during therapy and
1 patient who was LTFU, leaving 10 cases of DAA
therapy after TIPS placement for detailed analysis
(Fig. 1).
GENERAL CHARACTERISTICS
Most patients in this cohort were male adults (8/10;
80%), and the mean age was 52.8 ± 11.7 years. At the
time of DAA therapy, 2 patients presented with CPS
A, whereas most patients were CPS B (8/10; 80%)
(Table 1). The most prevalent genotype (GT) was
GT 1a (5/10; 50%), followed by GT 3 (3/10; 30%)
and GT 1b (2/10; 20%). Further cofactors with a
potential impact on treatment response were present
in 5 patients (50%), including HCV-associated mem-
branoproliferative glomerulonephritis (2/10; 20%),
baseline RAS (2/10; 20%), and coinfection with the
human immunodeficiency virus (1/10; 10%).
TREATMENT RESPONSES IN
PATIENTS WITH A TIPS
Treatment was well tolerated and completed in all
patients with a TIPS. However, 5 patients (50%) had
a virological relapse after DAA therapy. In 2 patients,
a virological relapse occurred after two or even three
consecutive DAA treatment courses. Both virological
responses or relapses were observed in patients receiv-
ing the combination sofosbuvir/ledipasvir ± ribavirin
(three responses, two relapses; 60% SVR) or sofosbu-
vir/daclatasvir ± ribavirin (two responses, one relapse;
66% SVR), whereas all patients with a TIPS who had
received sofosbuvir/velpatasvir (2; 0% SVR) or sofos-
buvir/velpatasvir/voxilaprevir (1; 0% SVR) showed a
relapse.
VIROLOGICAL RELAPSE AFTER
TIPS PLACEMENT COMPARED TO
GENER AL SVR RATES
The high percentage of virological relapses in
patients with HCV and TIPS became even more evi-
dent when compared to the “real life” SVR data of
patients treated with DAA at our center. In patients
with a documented 12-week follow-up, SVR rates
were high for sofosbuvir/ledipasvir in all patients
(366/390; 94%) and also in the subgroup of patients
with liver cirrhosis (69/87; 79%). The same was true
for sofosbuvir/daclatasvir (all patients, 24/30 [80%
SVR]; patients with cirrhosis, 16/20 [80% SVR]),
sofosbuvir/velpatasvir (all patients, 91/94 [97% SVR];
patients with cirrhosis, 21/24 [88% SVR]), and sofos-
buvir/velpatasvir/voxilaprevir (all patients, 12/13 [92%
SVR]; patients with cirrhosis, 6/7 [86% SVR]), result-
ing in an overall high SVR rate of 112/138 (81%)
in patients with liver cirrhosis receiving one of the
above-mentioned DAA regimens. Therefore, patients
with a TIPS made up a relevant proportion of
patients with cirrhosis that experienced a virological
relapse (6/26; 23%); this was true even for the recently
approved “next-generation DAA regimens (sofosbuvir/
ledipasvir, 2/18 [11%]; sofosbuvir/daclatasvir, 1/4
FIG. 1. Flow chart of the database analysis to identify patients
with DAA treatment post-TIPS. Interestingly, all 7 patients
receiving DAA treatment after liver transplantation and the 2
patients undergoing liver transplantation while being treated
cleared the virus, whereas only 50% of patients with a TIPS
reached an SVR. Abbreviation: LT, liver transplantation.
Internal database analysis: TIPS procedure and
HCV infection from 01/01/09 to 01/01/18
74 patients identified
13 patients with DAA therapy post-TIPS placement
10 cases analyzed in detail
5relapses 5 SVR
38 without therapy
16 with therapy pre-TIPS
7 with therapy
post-LT (100% SVR)
2 LT under therapy (100% SVR)
1 LTFU
HEPATOLOGY COMMUNICATIONS, Month 2019PIECHA ET AL.
4
TABLE 1. GENER AL CHARACTER ISTICS AND TREATMENT R ESPONSES OF 10 PATIENTS WHO RECEIVED DAA THERAPY POSTTIPS
General Characteristics
Viral
Parameters First DAA Therapy Second DAA Therapy Third DAA Therapy
Patient Age Sex
Indication
for TIPS
IFN
experi-
enced Cofactors GT RAS
CPS
(points) MELD
Albumin
(g/ L) INR
Viral load
(IU/mL)
DAA
therapy Outcome
CPS
(points) MELD
Viral
load
(IU/mL)
DAA
therapy Outcome
CPS
(points) MELD
Viral load
(IU/mL)
DAA
therapy Outcome
162 Male Variceal
bleeding
No None 1a NS3: Q80K ,
D168 D/E ;
NS5A:
L31V,
Y93N
B (7) 13 22 1.4 6 4,000,000 SOF/SM V/
RBV (16
wee ks)
Relapse B (7) 12 370,000 SOF/LDV
(24
wee ks)
Relapse B (7) 9 83,800,000 SOF/VEL/
VOX
(12
wee ks)
Relapse
250 Male Refractory
ascites
Yes MPGN 1a None B (7) 9 20 1100,000 SOF/RBV/
IFN (12
wee ks)
Relapse B (8) 10 222,000 SOF/LDV/
RBV
(24
wee ks)
Relapse
344 Male Refractory
ascites
No MPGN 3N/A B (9) 912 0.97 500,000 SOF/DAC
(24
wee ks)
SVR
461 Female Refrac tory
ascites
Yes None 3N/A B (7) 9 27 1.06 500,000 SOF/DAC
(24
wee ks)
Relapse
546 Male Variceal
bleeding
No None 3N/A B (7) 10 24 1.3 4 236,800 SOF/DAC/
RBV (24
wee ks)
SVR
640 Male Refractory
ascites
No None 1a N/A A (6) 632 0 .99 190,000 SOF/LDV
(12
wee ks)
SVR
753 Male Variceal
bleeding
Yes HIV
coinfec-
tion
1a N/A B (7) 12 30 1.23 367,000 SOF/LDV
(24
wee ks)
SVR
876 Female Variceal
bleeding
No None 1b N/A A (6) 928 1.1 320,000 SOF/LDV/
RBV (12
wee ks)
SVR
958 Male Refractory
ascites
No None 1b N/A B (7) 9 26 1. 3 149,000 SOF/VEL
(12
wee ks)
Relapse
10 38 Male Variceal
bleeding
No Surgery
under
therapy
1a NS5A: Q30 R,
L31L /M
B (7) 9 27 1. 2 347,000 SOF/ VEL
(12
wee ks)
Relapse
At the time of treatment, most patients presented with Child-Pugh B liver cirrhosis and low MELD scores ranging from 6 to 13 points.
Abbreviations: DAC, daclatasvir; HIV, human immunodeficiency virus; IFN, interferon; LDV, ledipasvir; MPGN, membranoproliferative glomerulonephritis; N/A, not applicable; RBV, ribavirin;
SOF, sofosbuvir; SMV, simeprevir; VEL, velpatasvir; VOX, voxilaprevir.
HEPATOLOGY COMMUNICATIONS, Vol. 0, No. 0, 2019 PIECHA ET AL.
5
[25%]; sofosbuvir/velpatasvir, 2/3 [66%]; and sofosbu-
vir/velpatasvir/voxilaprevir, 1/1 [100%]). Additionally,
even in the difficult to treat subgroup of patients with
advanced liver cirrhosis CPS B (32) or C (2), the over-
all SVR rate was substantially higher (27/34; 79%) in
patients without a TIPS compared to patients under-
going HCV treatment after TIPS placement, especially
when comparing sofosbuvir/velpatasvir (4/4, 100%
SVR in patients without a TIPS versus 0/2, 0% SVR
in patients with a TIPS) and sofosbuvir/velpatasvir/
voxilaprevir (3/3, 100% SVR in patients without a
TIPS versus 0/1, 0% SVR in patients with a TIPS).
FLOW VELOCITIES WITH
DOPPLER ULTRASOUND ARE
COMPARABLE BETWEEN GROUPS
Doppler ultrasound results of individual patients
achieving an SVR or experiencing a relapse were sim-
ilar. Accordingly, portal venous flow was antegrade
toward the liver, whereas the intrahepatic portal venous
flow was retrogradely directed toward the TIPS in all
patients. In patients with a DAA treatment relapse,
the median portal venous flow velocity was lower
(22.9 versus 37.0 cm/second), albeit not statistically
significant (P = 0.310). Furthermore, the intra-TIPS
flow velocity was comparable between the groups,
with a median flow velocity of 105.0 cm/second
in patients with relapse and 100.0 cm/second in
patients achieving an SVR (Table 2).
Discussion
Here, we present the HCV DAA treatment results
of a small cohort of patients with cirrhosis previously
treated with TIPS and in whom an unusually high rate
of DAA treatment failure was observed. Even though
the reasons for treatment failure are manifold, we
hypothesize that TIPS placement could be a possible
contributing factor. From a pathophysiological point
of view, a TIPS placement reduces portal pressure by
shunting blood from the portal to the hepatic vein,
leading to sustained changes in hepatic perfusion and
biomechanical properties, such as tissue stiffness,(8)
including an intrahepatic retrograde flow toward the
TIPS as also seen in this cohort. All our patients
received a sofosbuvir-based treatment regimen, a pro-
drug that is activated intrahepatically. Additionally,
ledipasvir, velpatasvir, and voxilaprevir are metabolized
by enzymes of the cytochrome family and subject to
biliary excretion. Therefore, the changes in hepatic
perfusion caused by a TIPS placement might also
have an impact on the pharmacokinetic and pharma-
codynamic properties of these drugs. In this context,
higher rates of treatment failures after a gastric bypass
TABLE 2. FLOW VELOCITIES ON DOPPLER ULTRASOUND PRIOR TO THE FIRST DA A THERAPY
Patient
Portal Venous
Flow (cm/second)
Intra-TIPS Flow
(cm/second)
Intrahepatic Portal Venous
Flow (cm/second)
Hepatic Arterial
Flow (cm/second) Outcome
148.8 105.0 −21. 5 47.1 Relapse
222.9 10 6.7 −28.4 62.4 Relapse
325.0 100.0 −10. 5 N/A SVR
437. 0 98.1 −13 .2 4 4.1 Relapse
537. 0 93.7 −12.1 N/A SVR
635.0 132 .0 −25.7 N/A SVR
738.2 116 .0 −10.9 N/A SVR
846.0 92.9 −13.8 79.7 SVR
921.7 74.0 −13 .6 N/A Relapse
10 22.0 126 .7 Retrograde N/A Relapse
Median flow velocities according to
outcome (range)
Patients with relapse 22.9 (21.9- 42.9) 105.0 (86.1-116.7) −17.6 (−26.7 to −13.3)
Patients achieving SVR 37.0 (30.0-42.1) 100.0 (93.3-124.0) −12.1 (−19.8 to −10.7 )
Before DAA treatment, flow velocities of the hepatic vessels and intra-TIPS flow rates were similar among individual patients. Portal
venous flow was orthograde, whereas intrahepatic portal flow was retrogradely directed toward the TIPS in all patients. Median flow
velocities were not signif icantly different bet ween the groups (Mann-Whitney U test; P = 0.310). The upper portion of the table shows
individual patient data, whereas the lower part shows median flow velocities with the corresponding range.
HEPATOLOGY COMMUNICATIONS, Month 2019PIECHA ET AL.
6
and therefore possible changes in the bioavailability
of the drugs have been reported.(5) Another possi-
ble explanation could be that, due to the changes in
hepatic hemodynamics, parts of the liver tissue are
no longer adequately perfused, leading to reservoirs
where the virus is safely harbored.
However, this retrospective study has several lim-
itations, first and foremost due to the limited sample
size, which made further statistical validation not fea-
sible, including matching of patients with versus with-
out a TIPS according to HCV genotype, Child-Pugh
and MELD score, and type and duration of treatment
regimen used. Furthermore, although not documented
in the files, compliance issues in patients with a TIPS
because of episodes of hepatic encephalopathy can-
not be completely excluded due to the retrospective
study design. Additionally, other possible reasons for a
relapse were present in some patients, including RAS,
and 1 patient with relapse received a treatment that
would not be considered optimal today (sofosbuvir/
daclatasvir), even though 2 other patients cleared the
virus with this regimen. Even though most patients
failed to highly potent DAA regimens (sofosbuvir/
ledipasvir, sofosbuvir/velpatasvir, and sofosbuvir/
velpatasvir/voxilaprevir), it could be argued that the
additional use of ribavirin in all cases as recommended
by current guidelines in patients with Child-Pugh
B(2) liver cirrhosis might have prevented some of the
relapses. Furthermore, the only regimen that has been
specifically approved for the treatment of patients
with a virological relapse (sofosbuvir/velpatasvir/
voxilaprevir)(9) was used off-label in 1 patient of this
current cohort because it contains a protease inhibitor,
which is not recommended to be used in patients with
Child-Pugh B liver cirrhosis.
Although larger studies will have to evaluate
whether longer or more intensified treatment reg-
imens are warranted in these patients, our prelim-
inary data suggest that treatment should be carried
out under optimized conditions (e.g., taking RAS
baseline testing into account, addition of ribavirin
or extension of treatment duration) or should even
postponed until after liver transplantation if feasi-
ble. In this context, a detailed evaluation of DAA
treatment results in patients with decompensated
liver cirrhosis and large portosystemic shunts also
merits further research because altered hepatic
hemodynamics are also conceivable under these
circumstances.
In summary, we present a case series of HCV
DAA therapy in a cohort of patients with cirrho-
sis who have previously been treated with a TIPS.
Although the DAA therapy was safely tolerated
by all patients, we observed a strikingly high rate
of virological relapses. Therefore, we postulate that
TIPS placement may pose a possible risk factor
for DAA failure due to the hemodynamic changes
and alterations in liver perfusion evoked by the
intervention.
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Supporting Information
Additional Supporting Information may be found at
onlinelibrary.wiley.com/doi/10.1002/hep4.1337/suppinfo.
... A small retrospective study found that SVR was achieved in 3/3 patients treated with SOF/VEL/VOX without a TIPS versus 0/1 patients treated with SOF/VEL/VOX with a TIPS. 29 Posttransplant patient studies are lacking; however, one case report showed successful SVR in a post-liver transplant, DAA-experienced patient with genotype 3 HCV. 30 This patient was treated for 16 weeks with SOF/VEL/VOX along with the addition of ribavirin starting at 8 weeks. ...
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The treatment of chronic hepatitis C has been revolutionized with the introduction of direct-acting antivirals (DAAs). However, some patients are not cured with first-line treatment. Sofosbuvir/velpatasvir/voxilaprevir is a fixed-dose combination of a polymerase inhibitor, an NS5A inhibitor, and a protease inhibitor with activity against strains of the hepatitis C virus that show resistance to other first-line antiviral regimens. Sofosbuvir/velpatasvir/voxilaprevir has been studied in four Phase III randomized trials: POLARIS-1, -2, -3, and -4, which enrolled both treatment naïve and experienced patients with and without compensated cirrhosis. In these trials, at least 95% of patients treated with sofosbuvir/velpatasvir/voxilaprevir achieved sustained virological response (SVR). This includes favorable treatment outcomes in patients who had previously failed a regimen containing sofosbuvir or an NS5A inhibitor. Patient-reported outcomes also improved during and after treatment with sofosbuvir/velpatasvir/voxilaprevir. Treatment with sofosbuvir/velpatasvir/voxilaprevir is well tolerated, with the most commonly reported adverse events being headache, fatigue, diarrhea, and nausea. The approval of sofosbuvir/velpatasvir/voxilaprevir allows a treatment option for patients who have failed treatment with certain DAA regimens.
... Furthermore, only two patients failed more than two DAA treatment courses, of which one patient received treatment after placement of a transjugular intrahepatic portosystemic shunt (TIPS). Therefore, we hypothesize that failing multiple treatments might be limited to a certain subgroup of patients with a combination of unfavorable baseline characteristics like decompensated liver cirrhosis, extensive RAS or previous TIPS placement [25]. Therefore, an individualized treatment concept that takes all individual risk factors into account is warranted in these patients. ...
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Background Re-treatment in patients with a chronic hepatitis C virus (HCV) infection and a previous failure to direct-acting antiviral (DAA) treatment remains a challenge. Therefore, we investigated the success rate of treatment and re-treatment regimens used at our center from October 2011 to March 2018. Methods A retrospective analysis of DAA-based HCV therapies of 1096 patients was conducted. Factors associated with a virological relapse were identified by univariable and multivariable logistic regression, treatment success of the re-treatment regimens was evaluated by an analysis of sustained virological response (SVR) rates in patients with a documented follow-up 12 weeks after the end of treatment. Results Of 1096 patients treated with DAA-based regimens, 91 patients (8%) were lost to follow-up, 892 of the remaining 1005 patients (89%) achieved an SVR12. Most patients (65/113, 58%) who experienced a virological relapse received an interferon-based DAA regimen. SVR rates were comparable in special cohorts like liver transplant recipients (53/61, 87%) and people with a human immunodeficiency virus (HIV) coinfection (41/45, 91%). On multivariable analysis, interferon-based DAA therapy was associated with treatment failure (odds ratio 0.111, 95%-confidence interval 0.054–0.218) among others. One hundred seventeen patients with multiple DAA treatment courses were identified, of which 97 patients (83%) experienced a single relapse, but further relapses after two (18/117, 15%) or even three (2/117, 2%) treatment courses were also observed. Eighty-two of 96 (85%) re-treatment attempts with all-oral DAA regimens were successful after an initial treatment failure. Conclusion Overall, DAA re-treatments were highly effective in this real-world cohort and only a minority of patients failed more than two treatment courses. Switching to–or addition of–a new drug class seem to be valid options for the re-treatment of patients especially after failure of an interferon-based regimen.
... prospective, randomized trial comparing TIPS to LVP 8 in patients with only recurrent ascites and a limited paracentesis frequency, which demonstrated a survival benefit in TIPS-treated patients. Therefore, we suggest that a TIPS should be considered early in patients with a stable underlying liver disease whose kidney function is beginning to be impaired, whereas in patients with an HCV-associated liver cirrhosis, treatment of the underlying disease with direct-acting antivirals should be considered first 31 to improve liver function. Furthermore, our data clearly indicate that patients with persistent ascites after TIPS have a decreased transplant-free survival. ...
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Background & aims: Refractory ascites is the main reason for the implantation of a transjugular intrahepatic portosystemic shunt (TIPS) in liver cirrhosis, but ascites control by TIPS fails in a relevant proportion of cases. Here, we investigated whether routine parameters pre-TIPS can predict persistent ascites after TIPS implantation and whether persistent ascites predicts long-term clinical outcome. Methods: A detailed retrospective analysis of 128 patients receiving expanded polytetrafluoroethylene-covered stents for the treatment of refractory ascites was performed. Persistent ascites post-TIPS was defined as the prolonged need for paracentesis >3 months after TIPS. The influence of demographics, laboratory results, pre-TIPS heart and liver ultrasound results, and invasive hemodynamic parameters on persistent ascites was evaluated by univariable and multivariable logistic regression. Predictors of the composite endpoint liver transplantation/death were analyzed using a multivariable Cox regression. Results: Ascites control post-TIPS was achieved in 95/128 patients (74%), whereas ascites remained persistent in 33/128 cases (26%). On multivariable analysis, a lower paracentesis frequency pre-TIPS (odds ratio 1.672; 95% CI 1.253-2.355) and lower baseline creatinine levels (odds ratio 2.640; CI 1.201-6.607) were associated with ascites control. Patients with persistent ascites post-TIPS had and impaired transplant-free survival (median 10.0 vs. 25.8 months), for which persistent ascites was the only independent predictor (hazard ratio 5.654; CI 3.019-10.59). Conclusion: TIPS-placement in patients with lower paracentesis frequency and creatinine levels is associated with superior ascites control. Thus, TIPS implantation should be considered in moderate decompensation and not as a last resort. Persistent ascites post-TIPS seems to be the only predictor of liver transplantation and death. Lay summary: The insertion of a transjugular intrahepatic portosystemic shunt (TIPS) in patients with refractory ascites should be considered in patients with moderate decompensation and not as a last resort, as lower paracentesis frequency and creatinine levels pre-TIPS are associated with superior ascites control. In turn, failure to control ascites seems to be the only predictor of liver transplantation and death.
Article
Objective Baseline liver stiffness (LS) is prognostically relevant in patients with chronic hepatitis C virus (HCV) infection but may change after successful HCV eradication. Data on post-treatment LS for a further risk stratification remain scarce. Here, we study the kinetics of LS and laboratory parameters in patients undergoing HCV treatment and analyze the association of post-treatment LS with outcome parameters. Methods In a cohort of 1011 chronic HCV patients undergoing DAA treatment, we identified 404 patients with sequential LS and laboratory assessments with or without viral eradication. Additionally, outcome parameters were correlated with post-treatment LS after successful HCV therapy. Results LS significantly decreased from a median of 8.8 to 6.1 kPa in 346 patients after HCV eradication, but significantly increased from a median of 10.5 to 11.9 kPa in 58 patients without viral clearance. In 78 patients with two sequential post-treatment measurements, LS decreased from 12.6 to 8.7 kPa after a median 344 d, with a further decrease to 7.0 kPa after a median of 986 d after end of treatment (EoT). In 400 patients with a post-treatment LS assessment after viral eradication, only 9 liver-related events occurred over a median follow-up (FU) of 23 months. All events were observed in patients with a post-treatment LS >20 kPa. Conclusions After successful HCV eradication, LS improves sequentially, suggesting an initial phase of necroinflammation regression followed by a second phase of true fibrosis regression. Overall, liver-related events were rarely observed and seem to be limited to patients with a post-treatment LS >20 kPa, so that these patients require a closer clinical monitoring.
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Background The combination of boceprevir or telaprevir with peginterferon-alfa and ribavirin for the treatment of patients infected with HCV genotype 1 has led to significantly increased rates of sustained virological response (SVR) in phase III trials. There is only limited data regarding the safety and efficacy in a “real-life” cohort. Methods We analyzed a cohort of 110 unselected HCV patients who started triple therapy from September 2011 to February 2013 by chart review with focus on the individual course of treatment, complications and outcome. We excluded 8 patients from analysis because of HIV-coinfection (N = 6) or status post liver transplant (N = 2). Importantly, 41 patients displayed F3 or F4 fibrosis, 10 patients had a history of treatment with protease/polymerase inhibitors and 15 patients were prior partial- or null-responder. Results SVR12 was achieved in 62 of the 102 patients (60.8%). A high rate of serious adverse events (N = 30) was observed in 22 patients including 2 fatalities in cirrhotic diabetes patients. Age >50 years, liver cirrhosis, bilirubin >1.1 mg/dl (P < 0.01, each), platelets <100,000/μl (P = 0.01), ASAT >100 U/l (P = 0.03) and albumin ≤35 g/l (P = 0.04) at baseline were associated with occurence of a SAE. Conclusions The frequency of SVR in a “real-life” treatment setting is slightly lower as compared to the results of the phase III trials for telaprevir or boceprevir. Importantly, we observed a high frequency of SAE in triple therapy, especially in patients with liver cirrhosis.
Article
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, with approximately 71 million chronically infected individuals worldwide. Clinical care for patients with HCV-related liver disease has advanced considerably thanks to an enhanced understanding of the pathophysiology of the disease, and because of developments in diagnostic procedures and improvements in therapy and prevention. These European Association for the Study of the Liver Recommendations on Treatment of Hepatitis C describe the optimal management of patients with acute and chronic HCV infections in 2018 and onwards.
Article
Background & aims: Little is known about substitutions that mediate resistance of HCV to direct-acting antivirals (DAAs), due to the small number of patients with treatment failure in approval studies. It is important to identify resistance patterns to select effective salvage treatments. Methods: We performed a comprehensive analysis for resistance-associated substitutions (RASs) in HCV genes (NS3, NS5A, NS5B) targeted by DAAs. We compared NS3, NS5A, and NS5B sequences from 626 patients in Europe with DAA failure with sequences from 2322 DAA-naïve patients, infected with HCV genotypes 1-4. We considered RASs to be relevant if they were associated with DAA failure in patients or conferred a greater than 2-fold changed in susceptibility compared with a reference strain in in vitro replicon assays. Data were collected on pretreatment status, DAA regimen, the treatment initiation date and duration, and virologic response. Patients who received at least 4 weeks antiviral treatment were included in the analysis. Results: RASs in NS3 associated with simeprevir or paritaprevir failure include R155K and D168E/V. In addition, several RASs were specifically associated with failure of simeprevir (Q80K/R in patients with genotype 1a or 4) or paritaprevir (Y56H in combination with D168V in patients with genotype 1b). Y93H in NS5A was the RAS most frequently associated with failure of daclatasvir, ledipasvir, or ombitasvir in patients with genotype 1b infection, and L31M was associated with failure of daclatasvir or ledipasvir, but not ombitasvir. RASs in NS5A were heterogeneous among patients with HCV genotype 1a or genotype 4 infections. In patients with HCV genotype 3, Y93H was associated with resistance to daclatasvir, but no RASs were associated with ledipasvir failure, pointing to a limited efficacy of ledipasvir in patients with genotype 3. Among patients failed by sofosbuvir-containing regimens, L159F was enriched in patients with genotype 1b (together with C316N) or genotype 3 infection, whereas the RAS S282T was rarely observed. Conclusions: We compared RASs in NS3, NS5A, and NS5B among patients failed by DAA therapy. Theses varied with the HCV genotype and subtype, and the different drug classes. These findings might be used to select salvage therapies.
Article
Liver stiffness (LS) as measured by transient elastography is widely used to screen for liver fibrosis. However, LS also increases in response to pressure changes like congestion but no data on portal pressure are available. We here study the effect of rapid portal pressure changes on LS. Therefore, LS was assessed directly prior and after ligation of esophageal varices (n=11) as well as TIPS implantation in patients with established cirrhosis (n=14). Additionally, we retrospectively analyzed changes in LS and variceal size in patients with sequential gastroscopic monitoring and LS measurements (n=14). To study LS and portal pressure in healthy livers, LS (µFibroscan, Echosens, Paris) and invasive pressures (Powerlab, AD Instruments, New Zealand) were assessed in male Wistar rats after ligation of single liver lobes. Ligation of esophageal varices caused an immediate and significant increase of LS from 40.3±19.0 to 56.1±21.5 kPa. Likewise, LS decreased significantly from 53.1±16.6 to 43.8±17.3 kPa after TIPS placement which correlated significantly with portal pressure (r=0.558). In the retrospective cohort, the significant LS decrease from 54.9±23.5 to 47.9±23.8 kPa over a mean observation interval of 4.3±3 months was significantly correlated with a concomitant increase of variceal size (r=-0.605). In the animal model, LS and portal pressure increased significantly after single lobe ligation without changes of arterial or central venous pressure. In conclusion, rapid changes of portal pressure are a strong modulator of LS in healthy and cirrhotic organs. In patients with stable cirrhosis according to MELD, a decrease of LS may be indicative for enlarging varices.
Article
Background Patients who are chronically infected with hepatitis C virus (HCV) and who do not have a sustained virologic response after treatment with regimens containing direct-acting antiviral agents (DAAs) have limited retreatment options. Methods We conducted two phase 3 trials involving patients who had been previously treated with a DAA-containing regimen. In POLARIS-1, patients with HCV genotype 1 infection who had previously received a regimen containing an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive either the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the protease inhibitor voxilaprevir (150 patients) or matching placebo (150 patients) once daily for 12 weeks. Patients who were infected with HCV of other genotypes (114 patients) were enrolled in the sofosbuvir–velpatasvir–voxilaprevir group. In POLARIS-4, patients with HCV genotype 1, 2, or 3 infection who had previously received a DAA regimen but not an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive sofosbuvir–velpatasvir–voxilaprevir (163 patients) or sofosbuvir–velpatasvir (151 patients) for 12 weeks. An additional 19 patients with HCV genotype 4 infection were enrolled in the sofosbuvir–velpatasvir–voxilaprevir group. Results In the three active-treatment groups, 46% of the patients had compensated cirrhosis. In POLARIS-1, the rate of sustained virologic response was 96% with sofosbuvir–velpatasvir–voxilaprevir, as compared with 0% with placebo. In POLARIS-4, the rate of response was 98% with sofosbuvir–velpatasvir–voxilaprevir and 90% with sofosbuvir–velpatasvir. The most common adverse events were headache, fatigue, diarrhea, and nausea. In the active-treatment groups in both trials, the percentage of patients who discontinued treatment owing to adverse events was 1% or lower. Conclusions Sofosbuvir–velpatasvir–voxilaprevir taken for 12 weeks provided high rates of sustained virologic response among patients across HCV genotypes in whom treatment with a DAA regimen had previously failed. (Funded by Gilead Sciences; POLARIS-1 and POLARIS-4 ClinicalTrials.gov numbers, NCT02607735 and NCT02639247.)
Article
What is already known about this subject: Changes to oral drug bioavailability have been observed post bariatric surgery. However, the magnitude and the direction of changes have not been assessed systematically to provide insights into the parameters governing the observed trends. Understanding these can help with dose adjustments. What this study adds: Analysis of drug characteristics based on a biopharmaceutical classification system is not adequate to explain observed trends in altered oral drug bioavailability following bariatric surgery, although the findings suggest solubility to play an important role. Aims: To identify the most commonly prescribed drugs in a bariatric surgery population and to assess existing evidence regarding trends in oral drug bioavailability post bariatric surgery. Methods: A retrospective audit was undertaken to document commonly prescribed drugs amongst patients undergoing bariatric surgery in an NHS hospital in the UK and to assess practice for drug administration following bariatric surgery. The available literature was examined for trends relating to drug permeability and solubility with regards to the Biopharmaceutics Classification System (BCS) and main route of elimination. Results: No significant difference in the 'post/pre surgery oral drug exposure ratio' (ppR) was apparent between BCS class I to IV drugs, with regards to dose number (Do) or main route of elimination. Drugs classified as 'solubility limited' displayed an overall reduction as compared with 'freely soluble' compounds, as well as an unaltered and increased ppR. Conclusion: Clinical studies establishing guidelines for commonly prescribed drugs, and the monitoring of drugs exhibiting a narrow therapeutic window or without a readily assessed clinical endpoint, are warranted. Using mechanistically based pharmacokinetic modelling for simulating the multivariate nature of changes in drug exposure may serve as a useful tool in the further understanding of postoperative trends in oral drug exposure and in developing practical clinical guidance.
Article
Hepatic arterial buffer response (HABR) is considered an important compensatory mechanism to maintain perfusion of the liver by hepatic arterial vasodilation on reduction of portal venous perfusion. HABR has been suggested to be impaired in patients with advanced cirrhosis. In patients with hepatopetal portal flow, placement of a transjugular intrahepatic portosystemic shunt (TIPS) reduces portal venous liver perfusion. Accordingly, patients with severe cirrhosis should have impaired HABR after TIPS implantation. Therefore, the aim of this study was to investigate the effect of TIPS on HABR as reflected by changes in resistance index (RI) of the hepatic artery. A total of 366 patients with cirrhosis (Child-Pugh class A, 106; class B, 168; class C, 92) underwent duplex Doppler ultrasonographic examination with determination of RI and maximal flow velocity in the portal vein before and 1 month after TIPS placement. Portosystemic pressure gradient was determined before and after TIPS placement. In 29 patients with hepatofugal portal blood flow, RI was significantly lower than in 337 patients with hepatopetal flow (0.63 plus minus 0.02 vs. 0.69 plus minus 0.01; P <.001). TIPS induced a significant decrease of the RI in patients with hepatopetal flow (RI, 0.69 plus minus 0.01 before vs. 0.64 plus minus 0.01 after TIPS; P =.001) but not in patients with hepatofugal flow (RI, 0.63 plus minus 0.02 before vs. 0.63 plus minus 0.02 after TIPS; NS). This response was not dependent on the Child-Pugh class. In conclusion, our results suggest that some degree of HABR is preserved even in patients with advanced cirrhosis with significant portal hypertension.
European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C 2018
European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C 2018. J Hepatol 2018;69:461-511.