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

Abstract

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.