close

Вход

Забыли?

вход по аккаунту

?

s40620-017-0446-2

код для вставкиСкачать
J Nephrol
DOI 10.1007/s40620-017-0446-2
POSITION PAPERS AND GUIDELINES
Recommendations for the treatment of hepatitis C virus infection
in chronic kidney disease: a position statement by the Spanish
association of the liver and the kidney
Sami Aoufi‑Rabih1 · Rebeca García‑Agudo2 · María‑Carlota Londoño3 ·
María‑Dolores Fraga‑Fuentes4 · Guillermina Barril‑Cuadrado5 · On behalf on the
Spanish Association of the Liver and the Kidney (AEHR)
Received: 10 July 2017 / Accepted: 18 September 2017
© Italian Society of Nephrology 2017
Abstract Hepatitis C virus (HCV) infection is one of the
main causes of liver cirrhosis worldwide. The long-term
impact of HCV infection is highly variable, ranging from
minimal histological changes to extensive fibrosis with
hepatocellular carcinoma. The development of HCV drugs
has increased dramatically in recent years, even in special
populations such as chronic kidney disease patients. Classical treatment of chronic hepatitis C was based on the administration of interferon and ribavirin for 24–48 weeks, which
was associated with a poor viral response and a high rate of
side effects, especially in patients with a lower estimated
glomerular filtration rate. The current high availability of
the new direct-acting antivirals renders the classification of
these agents for this special population necessary. The Spanish Association of the Liver and the Kidney has produced
a position statement on the treatment of HCV infection in
chronic kidney disease patients since the evidence to guide
this treatment is scant and what evidence does exist is weak.
* Rebeca García‑Agudo
rgarciaagudo@aehr.es
1
Hepatorenal Unit, Department of Gastroenterology
and Hepatology, Hospital General La Mancha-Centro,
Avda. de la Constitución, 3, 13600 Alcázar de San Juan,
Ciudad Real, Spain
2
Hepatorenal Unit, Department of Nephrology, Hospital
General La Mancha-Centro, Avda de la Constitución, 3,
13600 Alcázar de San Juan, Ciudad Real, Spain
3
Hepatology Unit, Hospital Clínic, Carrer de Villarroel, 170,
08036 Barcelona, Spain
4
Department of Pharmacy, Hospital General La
Mancha-Centro, Avda de la Constitución, 3,
13600 Alcázar de San Juan, Ciudad Real, Spain
5
Department of Nephrology, Hospital Universitario La
Princesa, Diego de León, 62, 28006 Madrid, Spain
The recommendations are based on the results of clinical
trials and controlled studies conducted to date, with data
published hitherto by the authors of these studies. Since the
indications for treatment have been evaluated by other societies or are dependent on internal clinical protocols, the main
goal of this position statement is to assist in decision-making
when choosing a therapeutic option.
Keywords Hepatitis C virus · Chronic kidney disease ·
Cirrhosis · Direct-acting antiviral
Introduction
Hepatitis C virus (HCV) infection in chronic kidney disease
(CKD) stage 5 patients is greater than in the general population. In hemodialysis, the prevalence is 13% with a high
variability (1–70%) [1] even among hemodialysis units in
the same country [2]: it is below 5% in the north of Europe,
around 10% in the south of Europe and the US and between
10 and 15% and up to 70% in many developing countries,
including certain areas of Asia, Latin America and the north
of Africa [3–5]. The incidence of HCV infection has been
reduced to less than 1–2% in developed countries [1, 2, 6].
In Spain, the SHECTS study, with 187 participating sites
and 12,472 screened patients, placed the prevalence of HCV
infection in hemodialysis at 5.6% in 2011 [7]. In renal transplantation, the prevalence of HCV infection varies between
7 and 40%, and also presents a broad geographic and demographic variability [1, 6, 8, 9].
HCV is an independent mortality factor in hemodialysis
for both hepatic and cardiovascular reasons [10]. In kidney
transplant recipients, HCV infection is the main cause of
post-kidney transplantation liver dysfunction and the fourth
cause of mortality in this population [10, 11]. HCV behaves
13
Vol.:(0123456789)
as an independent risk factor for the onset of proteinuria [12,
13], it increases the risk of developing post-transplantation
diabetes [14–16], de novo glomerulonephritis [17–20] or
chronic graft nephropathy, of aggravating liver disease and
of causing a greater number of infections [21]. Moreover,
immunosuppression in renal transplantation predisposes
to a reactivation of HCV. An increase in fibrosis and the
frequency of fibrosing cholestatic hepatitis has also been
described which, together with an accelerated evolution to
cirrhosis, may significantly increase morbidity and mortality
and require a liver transplantation [22, 23].
Despite the existing evidence on the benefits of antiviral
treatment in patients with pre-transplantation chronic hepatitis due to HCV and CKD [24, 25], only some renal transplantation protocols impose the treatment of HCV, which is
not usually classified as a pre-transplantation criterion but
rather as a recommendation [26–28]. Epidemiological data
and the natural history of the disease suggest that all patients
should be treated. The main justification is the elimination of
the viral reservoir to reduce the risk of contagion and disease
progression. This, in turn, involves a reduction in the need
to use medical resources in these patients and a resulting
reduction in healthcare expenditure.
Multidisciplinary work is required between nephrologists and hepatologists to detect infected patients and initiate
treatment jointly and early in order to avoid the progression
of CKD and liver disease-derived complications and to manage treatment-associated adverse events (AE).
The Spanish Association of the Liver and the Kidney
(AEHR) has produced a position statement on the treatment
of HCV infection in CKD, since insufficient evidence is currently available to guide this treatment and the evidence that
does exist is weak. These recommendations are based on the
results of the clinical trials and controlled studies performed
to date, with the data published hitherto by the authors of
these studies. Since the treatment indications have been
evaluated by other societies or are dependent upon internal
clinical protocols, the fundamental objective of this position statement is to provide support in therapeutic option
decision-making. This position statement does not purport
to become a clinical practice guideline, but rather is intended
as an assistance tool based on expert opinion, clinical experience and the evidence from clinical trials and studies already
conducted.
Treatment options in chronic hepatitis C
The classical treatment of chronic hepatitis C is based on
the administration of subcutaneous interferon (IFN) alpha
and oral ribavirin (RBV) for 24–48 weeks. This treatment
has been associated with a poor sustained viral response
(SVR) (30–50%) and a high rate of side effects [29]. In
13
J Nephrol
2011, a notable change took place in the therapeutic panorama of hepatitis C with the marketing of boceprevir and
telaprevir, the first generation of selective and reversible
NS3 protease inhibitors for the treatment of IFN ± RBV
(naïve) patients infected with HCV genotype 1 and nonresponders to this therapy. Since this treatment is combined with pegylated IFN alpha and RBV (triple therapy),
SVR rates increased to up to 70% in some patient subpopulations [30], permitting a reduction in treatment duration
from 48 to 24 weeks in some cases. However, the toxicological profile of the treatment was even greater than
with biotherapy, rendering it necessary to interrupt treatment in a much higher percentage of patients than in those
treated only with pegylated IFN alpha and RBV. Moreover,
it presented a broad range of pharmacological interactions
which, combined with the complexity of the treatment, left
a substantial margin for improvement.
This first generation of protease inhibitors was followed
in 2014 by a new wave of agents with superior pharmacodynamic, pharmacokinetic and toxicological properties:
simeprevir (dual NS3/NS4A inhibitor), daclatasvir (NS5A
inhibitor) and sofosbuvir (NS5B inhibitor). They were all
authorized by the European Medicines Agency (EMA)
through an accelerated procedure in view of the relevance
of their therapeutic contribution.
The combination of ledipasvir (NS5A inhibitor) and
sofosbuvir was subsequently authorized and marketed, yielding excellent results in HCV genotype 1 patients with SVR
rates of above 95% and on 12- and 24-week treatments, in
both naïve and treatment-experienced and cirrhotic patients
[31], reducing treatment duration to 8 weeks in special cases.
Paritaprevir, ombitasvir and dasabuvir inhibit the NS3,
NS5A and NS5B proteases, respectively. Paritaprevir and
ombitasvir have been included in a single formulation combined with ritonavir (2D combination), whereas dasabuvir
is formulated independently with the mixture of both (3D
combination). The 3D combination has yielded SVR rates
of 90% in patients with CKD stages 4–5, non-cirrhotic with
HCV genotype 1 treated for 12 weeks independently of
the use of RBV [32]. In compensated non-renal cirrhotic
patients, the response rate was 92 and 96% in naïve patients
with genotypes 1a and 1b treated for 12 and 24 weeks,
respectively, and 80% in non-responders to bitherapy, albeit
with 24 weeks of treatment [33].
Two new combinations were marketed in 2016. Grazoprevir (NS3 protease inhibitor) and elbasvir (NS5A
inhibitor) have the pivotal trial with the greatest number
of patients with CKD, reporting an SVR rate of 87–90%
in 12 weeks of treatment with hardly any AE [34]. Moreover, sofosbuvir and velpatasvir (NS5A inhibitor) have the
advantage of being pangenotypic and of having been used
in decompensated cirrhotic patients [35]. Besides the aforementioned drugs, there is a broad range of direct-acting
J Nephrol
antiviral drugs that are active against HCV currently in the
development stage.
Table 1 lists the drugs authorized by the EMA for the
treatment of HCV infection and their dosage in CKD
patients [36].
Preliminary considerations prior to the position
statement
Since the advent of the new and direct-acting antivirals
(DAA), there is no justification for prescribing an IFN- and
RBV-based therapy in any stage of CKD due to its lower
efficacy and high rate of AE, unless no other options are
available. Therefore, the treatment decision must be based
on genotype, as in non-renal patients, although not all the
new antivirals have been tested in patients with CKD. The
pharmacokinetics of the antiviral will determine its use,
according to the degree of kidney failure.
1. There is no justification for prescribing an IFN- and
RBV-based therapy in any stage of CKD due to its lower
efficacy and high rate of AE unless no other options are
available. The combination of IFN and RBV yields SVR
rates (56%) with a very high frequency of AE (26% anemia and 9% heart failure), rendering treatment interruption necessary in a considerable percentage of patients
(25%) [29].
2. The treatment decision must be based on genotype, as
in non-renal patients. The new DAA have brought several treatment options, even for the same genotype, and
genotype is indispensable in choosing the most effective
therapy in each case.
3. Not all the new DAA have been tested in clinical trials for patients with CKD. It is important to emphasize that there are some drugs that have been tested in
CKD patients in clinical trials and others that have not,
hence it is necessary to extrapolate from clinical trials
in non-renal patients when there is no other option with
a greater level of evidence.
4. The pharmacokinetics of the antiviral will determine its
use, depending on the degree of kidney failure. This is
particularly significant in patients with CKD stages 4–5.
Table 1 Drugs authorized by the EMA and their dosage in patients with CKD (adapted) [36]
Drug
eGFR/CrCl (ml/min)
50–80
30–50
15–30
< 15 (dialysis)
PEG-IFN
PEG-IFN (2a) 180 µg;
PEG-IFN (2b) 1.5 µg/kg
PEG-IFN (2a) 180 µg;
PEG-IFN (2b) 1 µg/kg
(25% reduction)
PEG-IFN (2a) 135 µg;
PEG-IFN (2b) 1 µg/kg
(50% reduction)
RBV (elimination: liver,
urine)
No dose titration required
200 mg/day
Sofosbuvir (elimination:
urine 80%; feces 14%;
exhaled air 2.5%)
Ledipasvir (elimination:
bile; urine 1%)
Daclatasvir (elimination:
feces 88%; urine 6.6%)
Ombitasvir (elimination:
feces 90%; urine 2%)
Dasabuvir (elimination:
bile 95%; urine 2%)
Paritaprevir (elimination:
feces 88%; urine 8%)
Simeprevir (elimination:
feces 91%; urine < 1%)
Grazoprevir/elbasvir
(elimination: feces;
urine < 1%)
Velpatasvir (elimination:
feces 94%; urine 0.4%)
No dose titration has been
established
Alternating doses of
200 mg and 400 mg
every second day
No dose titration has been
established
PEG-IFN (2a) 135 µg/week
or PEG-IFN (2b) 1 µg/
kg/week or standard IFN
3 mU 3x/week
200 mg/day
Risk of impaired renal
function
Risk of impaired renal
function
No dose titration required
No dose titration required
No data available
No data available
No dose titration required
No dose titration required
No dose titration required
No dose titration required
No dose titration required
No dose titration required
No dose titration required
No dose titration required
No dose titration required
No dose titration required
No dose titration required
No dose titration required
No dose titration required
No dose titration required
No dose titration required
No dose titration required
No dose titration required
No dose titration required
No dose titration required
Limited data available
No dose titration required
No dose titration required
No dose titration required
No dose titration required
No dose titration required
No dose titration required
No data available
No data available
eGFR estimated glomerular filtration rate, CrCl creatinine clearance, PEG-IFN peginterferon, RBV ribavirin
13
5. Patients with CKD stages 1–3 will be treated like nonrenal patients. The pharmacokinetics of the new DAA
means that no dose titration is required in patients with
an estimated glomerular filtration rate (eGFR) greater
than 30 ml/min/1.73 m2.
6. For the moment, sofosbuvir and velpatasvir are the
only marketed pangenotypic DAA. Since the TARGET
trial with sofosbuvir yielded a lower viral response rate
(82–83%) [37], the combination with velpatasvir must
be considered in the treatment of genotypes that do not
have sufficient evidence with other DAA.
Treatment of chronic hepatitis C in CKD
Genotype 1
1. Grazoprevir/elbasvir for 12 weeks [34] (16 weeks
if criteria are unfavorable) [37]
Grazoprevir/elbasvir is the treatment for HCV genotype 1
with the greatest evidence in patients at any stage of CKD,
based on the C-SURFER [34] phase III, randomized, double-blind, parallel-group, placebo-controlled, multicenter
and international clinical trial that evaluated treatment
with grazoprevir (100 mg) and elbasvir (50 mg) in patients
with chronic HCV genotype 1 infection and with CKD
stages 4–5, including patients on hemodialysis (76%), with
liver cirrhosis (6%) or without cirrhosis, after 12 weeks
of treatment. The patients included were naïve and nonresponders or relapsers to IFN with or without RBV. The
224 patients were divided into 2 groups: one immediate
treatment group (ITG) grazoprevir plus elbasvir (blind)
once a day for 12 weeks (n = 111) and a deferred treatment
group (DTG) (initially the control group with placebo for
12 weeks, subsequently a 4-week follow-up period and
then treatment with grazoprevir plus elbasvir (open-label)
once a day for 12 weeks, n = 113). The trial included an
open arm with 11 patients that were given grazoprevir and
elbasvir once a day for 12 weeks with intensive pharmacokinetic sampling. SVR was observed in 99% (115/116)
of the patients after 12 weeks. One IFN-intolerant patient
with genotype 1b, non-cirrhotic, presented viral relapse at
week 12 post-treatment. None of the ITG group patients
interrupted treatment for AE, whereas 4.4% (5/113) of
the patients in the placebo phase of the DTG group interrupted treatment for AE. The serious AE rates were 14.4%
(16/111) in the ITG and 16.8% (19/113) in the placebocontrol DTG group. The most common treatment-related
AE in the ITG and DTG (placebo) groups were: headache
(17.1 vs. 16.8%), nausea (15.3 vs. 15.9%) and fatigue (9.9
vs. 15%), respectively.
13
J Nephrol
2. 3D combination for 12 weeks in genotype 1b [32]
a) + RBV for 12 weeks if genotype 1a [32]
b) + RBV for 24 weeks if genotype 1a with cirrhosis [33,
38].
RUBY-I [32] is the second-most important study in the
treatment of kidney and hepatitis C patients with DAA. It is
a phase III, open-label, multicenter, national study that evaluated the efficacy and safety of the 3D combination (12.5 mg
of ombitasvir plus 75 mg of paritaprevir/50 mg of ritonavir
and 250 mg of dasabuvir) in 20 naïve or IFN-treatment experienced patients, with RBV (200 mg/24 h) in genotype 1a
and without RBV in genotype 1b for 12 weeks of treatment,
and 24 weeks post-treatment. The patients had HCV-related
chronic hepatitis without cirrhosis and CKD stages 4–5,
including patients on hemodialysis or on peritoneal dialysis. SVR was observed in 95% of the patients after 12 weeks
and one of them relapsed due to a suspected lack of treatment adherence. One patient died at the end of treatment for
unrelated causes. The majority of AE were mild-moderate
and serious in four patients, the most frequent ones being (in
more than 20%): anemia, fatigue, diarrhea, nausea, dizziness
and headache. In no case was treatment suspended, RBV
was interrupted in 9 patients for anemization (reduction in
hemoglobin levels above 2 g/dl for a period of 4 weeks or
with a hemoglobin value below 10 g/dl at any time) and four
were given erythropoiesis-stimulating agents. One patient
presented hemoglobin below 8 g/dl and required hospitalization, although no blood transfusions were performed.
The data from the RUBY-I cohort 2, corresponding to
cirrhotic patients, have not yet been published. The indication of the 3D plus RBV combination in cirrhotic patients
is therefore extrapolated from studies in non-renal patients.
The most significant study is the one by Poordad et al. [33],
a phase III clinical trial conducted in 380 genotype 1 cirrhotic patients who were randomly assigned to the 3D and
RBV combination for 12 or 24 weeks with an SVR of 91.8
vs. 95.9%, respectively. The most frequent AE were: fatigue
(32.7 vs. 46.5%), headache (27.9 vs. 30.8%) and nausea
(17.8 vs. 20.3%). The level of hemoglobin below 10 g/dl
was present in 7.2 vs. 11%. In 2.1% of the patients, treatment
was interrupted due to AE.
Although it is a retrospective study [38], there is a multicenter experience with the 3D combination for 12 weeks
in 46 patients with CKD stages 4–5, 36.9% of whom were
cirrhotic. The SVR12 rate in the intention-to-treat population was 95.7%. Twenty-one patients (45.6%) received RBV,
which was discontinued in two (9.5%). Anemia (hemoglobin < 10 g/dl) occurred in 12 patients (57.1%) with RBV
vs. 10 (40.0%) without RBV. Renal function remained stable
during antiviral therapy. Nine patients (19.5%) experienced
serious AE unrelated to antiviral therapy. Concomitant
J Nephrol
medication was discontinued or modified in 41.3% of
patients.
The German Registry [39] showed a 100% of SVR12 in
34 severe-renal impairment patients with genotype 1 and
4. Ponziani et al. [40] published a case series about the
safety and effectiveness of a 3D combination in 10 patients
on hemodialysis with genotype 1a, 1b or 4 HCV infection
who had predictors of unfavorable response such as compensated cirrhosis (7) or advanced fibrosis and failure of
previous therapy (3). The treatment, with or without RBV,
was administered daily for 12 or 24 weeks and achieved a
SVR of 100%; 80% of patients had at least one AE (fatigue,
mild anemia and one episode of moderate liver decompensation). Sato et al. [41] treated four patients on hemodialysis,
who had a genotype 1 infection and achieved a SVR of 75%.
3. Regimen with sofosbuvir for 12 weeks (+ simeprevir,
ledipasvir or daclatasvir) + RBV if cirrhosis is present [42,
43] (not in CKD stages 4–5)
There are no clinical trials that endorse this indication—
only observational studies are available. The possibility of
a worsening renal function with sofosbuvir and the lack of
scientific evidence do not permit its indication in patients
with CKD stages 4–5. Each center should evaluate the treatment including sofosbuvir in the absence of other options,
always with close monitoring of renal function in patients
not on dialysis and of anemia in patients on dialysis.
The most relevant study is the TARGET observational,
longitudinal, multicenter and international study by Saxena
et al. [42], which evaluated the efficacy and safety of a regimen based on a standard dose of sofosbuvir in a total of 1893
CKD patients of any genotype, 82 of whom had an eGFR
below 45 ml/min (66 with genotype 1). The treatment was
completed by 83% of these patients, while 6% interrupted it
early and 11% were excluded from the analysis because they
were still on treatment when the study was published. The
following treatment options were included: sofosbuvir plus
pegylated IFN and RBV, sofosbuvir plus RBV, sofosbuvir
plus simeprevir and sofosbuvir plus simeprevir and RBV.
AE were more frequent in the renal patients: anemia (30
vs. 16%), transfusion requirements (10 vs. 2%), the use of
erythropoiesis-stimulating agents (12 vs. 4%), suspension
of RBV (12 vs. 1%), worsening renal function (15 vs. 1%),
and hospitalization (22 vs. 6%). Overall SVR was similar
in all treatment, genotype and renal function groups (83%
in the renal patients vs. 82%). In the renal patients, the
regimen with the highest SVR was sofosbuvir plus simeprevir and RBV (100%), followed by sofosbuvir plus RBV
(86%), sofosbuvir plus simeprevir (80%) and sofosbuvir plus
pegylated IFN and RBV (50%). Being male, black, having
renal dysfunction, previous HCV treatment, cirrhosis and the
RBV-free regimen were related to a poorer SVR.
Desnoyer et al. [43] performed an observational, prospective, multicenter study to evaluate the pharmacokinetics,
safety and efficacy of a regimen of sofosbuvir in 12 patients
on dialysis with chronic hepatitis C, with (10) or without
cirrhosis (2), 11 with genotype 1 and one with genotype 2.
The patients took 400 mg of sofosbuvir a day (7 patients) or
three times a week (5 patients) with simeprevir, daclatasvir,
ledipasvir or RBV after dialysis, for 12 or 24 weeks depending on the case. The concentrations of sofosbuvir in plasma
were not accumulated with any sofosbuvir regimen; it had a
longer half-life (38 h) in one patient. Ten patients obtained
SVR and two had a relapse, both of them from the threetimes weekly regimen. The AE were mild or moderate; three
patients presented anemia, although the need for treatment
interruption, the use of erythropoiesis-stimulating agents or
blood transfusion was not specified.
4. Sofosbuvir + velpatasvir for 12 weeks [44] (not in CKD
stages 4–5) (extrapolated from non‑renal patients)
There are only studies in non-renal patients for this indication. This combination is not recommended in patients with
CKD stages 4–5, due to the risk of worsening their renal
function and the absence of scientific evidence endorsing
this indication. Feld et al. [44] conducted a phase III, doubleblind, placebo-controlled study to treat 624 patients with
HCV genotypes 1 (328), 2 (104), 4 (100), 5 (97) and 6 (41),
naïve and non-responders, without cirrhosis or with compensated cirrhosis. The patients with genotypes 1, 2, 4 and
6 were randomized to receive sofosbuvir and velpatasvir or
placebo for 12 weeks. The patients with genotype 5 received
the treatment without placebo group, due to the low prevalence of this genotype. The global SVR following treatment
was 99% (98% in genotype 1a and 99% in 1b). Two patients
with genotype 1 (less than 1%) had a relapse. One patient
interrupted treatment due to an anxiety crisis on day 13 of
treatment. Serious AE were observed in 2% of the patients
(hypertransaminasemia). One patient died in their sleep on
day 8 after finishing treatment, having a background of dyslipidemia treated with simvastatin and ezetimibe, although
the cause of death was not determined.
Genotype 2
There are no studies on the treatment of chronic hepatitis C
genotype 2 in renal patients, hence the data must be extrapolated from studies in patients without CKD. Sofosbuvir
is contraindicated in patients with CKD stages 4–5, unless
there is no alternative, for which reason consideration must
be given to either treating while accepting the risk of worsening renal function or waiting to treat until after the patient
has undergone the kidney transplantation.
13
1. Sofosbuvir + velpatasvir for 12 weeks [44, 45]
(extrapolated from non‑renal patients) (not in CKD stages
4–5)
The study by Feld et al. [44], with a total of 624 treated
patients (104 with genotype 2) with sofosbuvir and velpatasvir vs. placebo for 12 weeks, is described in genotype
1. The global SVR was 99% (100% in genotype 2). Foster et al. [45] conducted two phase III, open-label, randomized clinical trials (ASTRAL 2 and 3) in patients with
HCV genotype 2 and 3, naïve and treatment-experienced,
without and with cirrhosis. The patients with genotype 2
were randomized to receive sofosbuvir and velpatasvir (134)
or RBV for 12 weeks. The SVR in patients with genotype
2 treated with sofosbuvir and velpatasvir was 99 vs. 94%
in the RBV-treated group. One patient on treatment with
velpatasvir interrupted the treatment due to AE. Other serious AE described were pneumonia and abdominal enteritis
(with velpatasvir) and arthralgia and depression (with RBV).
Two patients died in the velpatasvir group during the posttreatment follow-up: one due to heart failure 131 days after
the end of treatment and another from complications related
to metastatic lung cancer 112 days later.
2. Sofosbuvir + daclatasvir for 12 weeks [46] (extrapolated
from non‑renal patients) (not in CKD stages 4–5)
There are no clinical trials available. Mangia et al. [46] performed a prospective observational study in 106 patients
with HCV genotype 2, naïve or with contraindication for
the use of ribavirin, without or with cirrhosis (58%), compensated and decompensated, and with comorbidity. Two
patients were kidney transplant recipients. Four patients had
a creatinine clearance (CrCl) of 30–50 ml/min. The patients
were assigned to receive sofosbuvir and daclatasvir for 12
or 24 weeks. All patients reached SVR irrespective of treatment duration. The treatment was not suspended due to AE,
which amounted to 17.9%, most of them mild and consisting
of headache, nausea, or irritability, and which were most
frequent in the cirrhotic patients. Saxena et al. [42] carried
out the TARGET study, described in genotype 1. It evaluated the efficacy and safety of a sofosbuvir-based regimen in
CKD patients of any genotype. Of the 1893 patients treated,
82 had an eGFR below 45 ml/min (15 with genotype 2).
Overall SVR was similar in all groups (83% in the renal
patients vs. 82%).
3. Sofosbuvir + RBV for 12 weeks [47] or 16 weeks
if cirrhosis is present [48, 49] (extrapolated from non‑renal
patients) (not in CKD stages 4–5)
There are several studies on the combination of sofosbuvir
and RBV, the most outstanding one by Zeuzem et al. [47], a
13
J Nephrol
phase III, multicenter and randomized trial with sofosbuvir
and RBV vs. placebo in 419 patients with HCV genotype
2 for 12 weeks and genotype 3 for 24 weeks, naïve or IFN
treatment-experienced (58%), without and with cirrhosis
(21%). The patients treated with placebo were subsequently
treated with sofosbuvir and RBV in another clinical trial.
SVR was reached in 93% of the patients with genotype 2 and
85% of the patients with genotype 3, in whom the SVR was
notably lower in the patients with cirrhosis (68 vs. 91%). In
genotype 3, relapses were observed in 45% of the patients
who were treated for 12 weeks as opposed to 13% of those
who were treated for 24 weeks. The most frequent AE were
headache, fatigue and pruritus. Three patients interrupted the
treatment due to AE: hypertransaminasemia in one patient
treated with placebo, malaise, and headache in one genotype
3 patient on treatment for 12 weeks and attempted suicide in
one genotype 3 patient on treatment for 24 weeks. Diarrhea
and irritability were more frequent in the 24-week group.
Jacobson et al. [48] conducted two randomized, phase 3
studies involving patients with chronic HCV genotype 2 or 3
infection, who were treated with sofosbuvir and RBV (207)
or matching placebo (71) for 12 weeks and with sofosbuvir
and RBV (103) or matching placebo (98) for 16 weeks. In
previously treated patients or those with cirrhosis, 16 weeks
of therapy was significantly more effective than 12 weeks
(73 vs. 50%). Welzel et al. [49] performed a prospective
observational study (HCV-TARGET) to evaluate clinical
practice data with the treatment of sofosbuvir and RBV
for 12 weeks (283 patients) or 16 weeks (38). In cirrhotic
patients, SVR was 91% after 12 weeks and 92.9% after
16 weeks. In patients with cirrhosis treated, SVR was 79%
after 12 weeks and 83% after 16 weeks.
Genotype 3
1. Sofosbuvir + daclatasvir for 12 weeks [50] (+ RBV
for 12 weeks if cirrhosis is present or 24 weeks
if previously treated) [47, 51] (not in CKD stages 4–5)
There are no studies in the renal population with HCV genotype 3, hence the data must be extrapolated from non-renal
patients.
Nelson et al. [50] performed a phase III study (ALLY-3)
with sofosbuvir and daclatasvir for 12 weeks in 152 patients
with HCV genotype 3, naïve (101) or treatment-experienced (51), with or without cirrhosis. The SVR was 90%
in the naïve patients and 86% in the treatment-experienced
patients. There were substantial differences in cirrhotic
patients, with an SVR of 63 vs. 96%. One patient interrupted
treatment at week 8 for pregnancy, reaching SVR. Sixteen
patients (9 naïve and 7 experienced) had a relapse, 11 of
whom were cirrhotic patients. The most common AE were
headache, fatigue and nausea. One patient had one serious
J Nephrol
AE consisting of gastrointestinal hemorrhage, which was
not treatment-related.
The study by Zeuzem et al. [47] with sofosbuvir and RBV
was dealt with under genotype 2. The initial protocol was
designed for 12 weeks in genotype 3 and was modified to
24 weeks after the findings of the FUSION study became
known. The patients treated with placebo were subsequently
treated with sofosbuvir and RBV in another clinical trial.
SVR was reached in 93% of the patients with genotype 2 and
85% of the patients with genotype 3, in whom the SVR was
notably lower in the patients with cirrhosis (68 vs. 91%). In
genotype 3, relapses were observed in 45% of the patients
that had done only 12 weeks as opposed to 13% of those that
had done 24 weeks. The most frequent AE were headache,
fatigue and pruritus. Three patients interrupted the treatment
due to AE: hypertransaminasemia in one patient treated with
placebo, malaise, and headache in one genotype 3 patient
on treatment for 12 weeks and attempted suicide in one
genotype 3 patient on treatment for 24 weeks. Diarrhea and
irritability were more frequent in the 24-week group. These
data support the recommendation of extending the duration
of treatment with sofosbuvir and RBV in HCV genotype 3
patients to 24 weeks.
Leroy et al. [51] conducted the ALLY-3 + study in 50
patients with HCV genotype 3 with advanced fibrosis (14)
or compensated cirrhosis (36), naïve (13) or experienced
(37) who received sofosbuvir, daclatasvir and RBV for 12
or 16 weeks. The global SVR was 90%, with 88% in the
12-week group and 92% in the 16-week group. The SVR
was 100% in the patients with advanced fibrosis and 86% in
patients with cirrhosis (83% in the 12-week group and 89%
in the 16-week group); in treatment-experienced patients
with cirrhosis, these values were 88 and 86%, respectively.
Four patients (two from each group) had a relapse. No
patient interrupted the treatment for AE, the most frequent
ones being: insomnia, fatigue, headache, irritability, asthenia, diarrhea and dyspnea.
2. Sofosbuvir + velpatasvir for 12 weeks [45] (not in CKD
stages 4–5)
This indication was dealt with under genotype 2. Foster et al.
[45] conducted two phase III, open-label, randomized clinical trials (ASTRAL 2 and 3) in patients with HCV genotype 2 and 3, naïve and experienced, without and with cirrhosis. The patients with genotype 3 were randomized to
receive sofosbuvir and velpatasvir for 12 weeks (277) or
RBV for 24 weeks. The genotype 3 patients had an SVR of
95 vs. 80%. Nine patients with genotype 3 interrupted treatment due to AE on treatment with RBV. Other serious AE
described were pneumonia and abdominal enteritis (with
velpatasvir) and arthralgia and depression (with RBV).
Genotype 4
There is no scientific evidence in renal patients, hence the
data must be extrapolated from non-renal patients.
1. Grazoprevir/elbasvir for 12 weeks [34] (+ RBV
for 16 weeks if there are unfavorable criteria)
(extrapolated from genotype 1)
This indication was addressed in genotype 1.
2. Combination 2D ± RBV for 12 weeks [52] or 24 weeks
if cirrhosis is present [33] (extrapolated from genotype 1)
Hézode et al. [52] conducted the PEARL-I multicenter,
phase 2b, open-label, randomized clinical trial in 105
patients with HCV genotype 4 without cirrhosis, who were
assigned to receive, for 12 weeks, the 2D combination with
or without RBV if they were naïve and with RBV if they
had been previously treated with IFN and RBV. The SVR
was 90.9% in the naïve patients without RBV and 100% in
the RBV group. Two relapses and one breakthrough were
observed in the patients without RBV. The most frequent
AE was headache, which was even greater in naïve patients.
No patient interrupted the medication on account of AE.
Seven percent of the patients treated with RBV required a
dose titration for anemia.
The data from the cirrhotic patients with genotype 1 are
extrapolated to genotype 4. In this regard, the most relevant
study is the one by Poordad et al. [33], a phase III clinical trial conducted in 380 genotype 1 cirrhotic patients who
were randomly assigned to the 3D and RBV combination for
12 or 24 weeks with an SVR of 91.8 vs. 95.9%, respectively.
The most frequent AE were: fatigue (32.7 vs. 46.5%), headache (27.9 vs. 30.8%) and nausea (17.8 vs. 20.3%). The level
of hemoglobin below 10 g/dl was present in 7.2 vs. 11%.
Treatment was interrupted in 2.1% of the patients due to AE.
3. Sofosbuvir + simeprevir [42], velpatasvir [44]
or ledipasvir [53] for 12 weeks (not in CKD stages 4–5)
Although there is scientific evidence in renal patients with
this indication, the risk of worsening renal function and the
contraindication for prescribing sofosbuvir in CKD stages
4–5 make it the last alternative. The three indications are
within the same line of recommendation, as they are sofosbuvir-based regimens with similar efficacy and safety results.
The observational, longitudinal, multicenter and international TARGET study by Saxena et al. [42], already
addressed in genotype 1, evaluated the efficacy and safety
of sofosbuvir-based regimens in CKD patients of any genotype with renal dysfunction, in a total of 1893 patients,
82 of whom had an eGFR below 45 ml/min. In the renal
13
patients, the regimen with the highest SVR was sofosbuvir
plus simeprevir and RBV (100%), followed by sofosbuvir
plus RBV (86%), sofosbuvir plus simeprevir (80%) and
sofosbuvir plus pegylated IFN and RBV (50%). Being male,
black, having renal dysfunction, previous HCV treatment,
cirrhosis and the RBV-free regimen were related to a poorer
SVR. The study by Feld et al. [44], conducted on a total of
624 treated patients (100 with genotype 4) with sofosbuvir and velpatasvir vs. placebo for 12 weeks, is described
in genotype 1. The global SVR was 99%. Kohli et al. [53]
performed a phase IIa, open-label, single-center trial in 21
patients with HCV genotype 4, naïve or IFN-experienced,
with and without cirrhosis, who were treated with sofosbuvir
and ledipasvir for 12 weeks, with an SVR of 95%. No patient
interrupted the treatment due to AE, which were most frequently diarrhea, fatigue, nausea and upper respiratory tract
treatment infections.
Genotype 5
There is no scientific evidence in renal patients, hence the
data must be extrapolated from non-renal patients. Sofosbuvir is contraindicated in patients with CKD stages 4–5.
1. Sofosbuvir + ledipasvir [54] or velpatasvir [44]
for 12 weeks (not in stages 4–5 CKD)
Abergel et al. [54] conducted a phase II, single-arm, multicenter, open-label clinical trial in 41 patients with HCV
genotype 5, naïve (21) and experienced with an IFN-based
regimen (20), with (9) and without cirrhosis, who were
treated with sofosbuvir and ledipasvir for 12 weeks; 95%
of the patients and 89% of the cirrhotic patients reached
SVR. Two patients had relapses. One patient had a serious AE, consisting of a worsening of depression, which was
not treatment-related. The most frequent AE were asthenia,
headache and fatigue. The study by Feld et al. [44], in 624
treated patients (97 with genotype 5) with sofosbuvir and
velpatasvir vs. placebo for 12 weeks, is described in genotype 1. The global SVR following treatment was 99% (97%
in genotype 5).
Genotype 6
1. Sofosbuvir + ledipasvir ± RBV [55] or velpatasvir [44]
for 12 weeks (not in CKD stages 4–5)
This study by Gane et al. [55] was already addressed under
genotype 3, for its assessment of the efficacy of sofosbuvir and ledipasvir, with and without RBV, for 12 weeks in
patients with HCV genotype 3 (101) or 6 (25), naïve or experienced, in an open-label study. The patients with genotype
6, naïve or experienced, received sofosbuvir and ledipasvir,
13
J Nephrol
with an SVR of 96%. The most common AE were headache, upper respiratory tract infection, tiredness and nausea.
Six patients had serious AE; two of them were treatmentrelated and consisted of abdominal pain. The data of this
study point to the recommendation of adding RBV to the
sofosbuvir and ledipasvir regimen in patients with genotype
3 and CKD, although bitherapy would be an option if the AE
caused by RBV do not allow its use. The study by Feld et al.
[44], in a total of 624 treated patients (41 with genotype 6)
with sofosbuvir and velpatasvir vs. placebo for 12 weeks, is
described in genotype 1. The global SVR was 99% (100%
in genotype 6).
Although the drugs are not yet commercialized, Gane et al.
[56] presented the EXPEDITION-4 study at the American
Association for the Study of Liver Disease Meeting in 2016.
They treated 104 patients with CKD stages 4–5 and chronic
HCV genotypes 1–6 infection, with (19%) and without compensated cirrhosis, naïve (58%) or treatment-experienced, with
glecaprevir/pibrentasvir (300 mg/120 mg). Ninety-eight per
cent of patients achieved RVS after 12 weeks of treatment. AE
were present in 71% (serious AE in 24%, not drug-related).
Table 2 summarizes the recommendations for the treatment of chronic hepatitis C in CKD.
Treatment of chronic hepatitis C in renal
transplantation
Renal transplantation patients can only be given IFN-free
treatments due to the risk of rejection of the kidney graft and
for the same reasons as apply to other renal patients (risk of
worsening renal function and adverse events). Immunosuppressants in general do not interact significantly with DAA,
except for the combination of paritaprevir, ombitasvir and
dasabuvir [36, 57–60] (Table 3). The use of this combination
requires a careful titration of the doses of immunosuppressants, particularly the anticalcineurinics.
The concomitant use of simeprevir and cyclosporine is
totally advised against [57, 58], since the concentrations of
simeprevir increase due to the inhibition of cyclosporine on
the organic anion-carrying polypeptide 1B1, P-glycoprotein
1 and the cytochrome P450 3A4 (CYP3A4). Provisional
data from a phase II clinical trial [40] in nine liver transplantation patients with HCV demonstrated that the joint
administration of simeprevir (150 mg/24 h for 14 days) and
cyclosporine (tailored doses) increased the maximum concentration (Cmax) and the area under the curve (AUC) of
plasma concentrations of simeprevir 4.74- and 5.81-fold,
respectively. The joint administration of cyclosporine (a single dose of 100 mg) and simeprevir (150 mg/24 h for 7 days)
in 14 subjects increased the Cmax and AUC of cyclosporine
J Nephrol
Table 2 Recommendations
for the treatment of chronic
hepatitis C in CKD
Genotype
Treatment
1
Grazoprevir/elbasvir for 12 weeks (16 weeks if unfavorable criteria)
3D combination for 12 weeks if genotype 1b (+ RBV for 12 weeks if genotype 1a or
24 weeks if genotype 1a with cirrhosis)
Regimen with sofosbuvir for 12 weeks (+ simeprevir, ledipasvir or daclatasvir) + RBV if
cirrhosis is present (not in CKD stages 4–5)
Sofosbuvir + velpatasvir for 12 weeks (not in CKD stages 4–5)
Sofosbuvir + velpatasvir for 12 weeks (not in CKD stages 4–5)
Sofosbuvir + daclatasvir for 12 weeks (not in CKD stages 4–5)
Sofosbuvir + RBV for 12 weeks or 16 weeks if cirrhosis is present (not in CKD stages 4–5)
Sofosbuvir + daclatasvir for 12 weeks (+ RBV for 12 weeks if cirrhosis or 24 weeks if
previously treated) (not in CKD stages 4–5)
Sofosbuvir + velpatasvir for 12 weeks (not in CKD stages 4–5)
Grazoprevir + elbasvir for 12 weeks (+ RBV for 16 weeks if unfavorable criteria)
2D combination ± RBV for 12 weeks or 24 weeks if cirrhosis is present
Sofosbuvir + simeprevir, velpatasvir or ledipasvir for 12 weeks (not in CKD stages 4–5)
Sofosbuvir + ledipasvir or velpatasvir for 12 weeks (not in CKD stages 4–5)
Sofosbuvir + ledipasvir or velpatasvir for 12 weeks (not in CKD stages 4–5)
2
3
4
5
6
Table 3 Interaction of DAA with immunosuppressive drugs in kidney transplantation
Interactions
Azathioprine
Cyclosporine
Mycophenolate
Sirolimus
Tacrolimus
Grazoprevir + elbasvir
Daclatasvir
Ledipasvir + sofosbuvir
Ombitasvir + paritaprevir + ritonavir
Ombitasvir + paritaprevir + ritonavir + dasabuvir
Simeprevir
Sofosbuvir
No interaction
No interaction
No interaction
No interaction
Do not coadminister
No interaction
Potential interaction
Potential interaction
No interaction
No interaction
No interaction
Potential interaction
Potential interaction
No interaction
Potential interaction
Potential interaction
Potential interaction
No interaction
Potential interaction
Potential interaction
No interaction
Potential interaction
Potential interaction
Potential interaction
Potential interaction
No interaction
No interaction
Do not give jointly
No interaction
No interaction
No interaction
Potential interaction
No interaction
Potential interaction
No interaction
by 16 and 19%, respectively. The effects of simeprevir given
jointly with sirolimus have not been studied, but they translate into mild increases or reductions in sirolimus concentrations, hence monitoring is recommended. The use of simeprevir with tacrolimus results in an increase of simeprevir
plasma concentrations due to the inhibition of the organic
anion-carrying polypeptide 1B1.
The combination of ledipasvir and sofosbuvir with cyclosporine has not been studied. Cyclosporine is a substrate of
P-glycoprotein 1 and ledipasvir is a substrate and inhibitor
of P-glycoprotein 1. The joint administration of both could
increase their concentration. With regard to joint administration with sirolimus, although this has not been studied, an
increase in sirolimus might be expected due to the inhibition of P-glycoprotein 1 by ledipasvir. With regard to joint
administration with tacrolimus, although neither has this
been studied, sofosbuvir given alone is known to only reduce
the Cmax of tacrolimus by 27% [57].
In the joint administration of the 2D combination with
cyclosporine [58], the AUC increases fourfold, the minimum
concentration ­(Cmin) of cyclosporine increases 12-fold, ­Cmax
by 39%, AUC by 45% and the ­Cmin of paritaprevir by 18%.
When given jointly with mycophenolate, it increases exposure to mycophenolic acid by interacting with paritaprevir
and ritonavir, thus necessitating a dose reduction. It also
increases exposure to sirolimus, since the latter is a substrate
of CYP3A4 and ritonavir is an inhibitor of this enzyme. Tacrolimus is a substrate of CYP3A4 and, when given jointly,
­Cmax, AUC and ­Cmin increase 4-, 86- and 25-fold, respectively. The administration of 0.5 mg of tacrolimus once
weekly is recommended when it is given jointly with the
2D combination.
In the case of the 3D combination, the same occurs as in
the previous case when it is given with cyclosporine [58],
with AUC and mean concentration increasing 5.8- and 15.8fold, respectively. A dose reduction is also necessary with
mycophenolate, since the latter interacts with paritaprevir
and ritonavir. A dose reduction is necessary with sirolimus,
since it is a substrate of CYP3A4, and also with tacrolimus
for the same reason, yielding, in joint administration, 4-,
13
57- and 16-fold increases in C
­ max, AUC and C
­ min of tacrolimus, respectively. Doses of tacrolimus of 0.5 mg/week are
recommended.
There are several studies in renal transplantation recipients with short patient series based on sofosbuvir regimens.
Colombo et al. [61] carried out the most significant clinical trial in kidney transplantation, a phase II multicenter,
randomized, parallel-group and open-label design study to
evaluate the efficacy, safety and tolerability of ledipasvir/
sofosbuvir in 114 kidney transplant patients. Treatmentnaïve (69%) or -experienced patients with chronic genotype 1 (91%) or 4 HCV infection, with (15%) or without
compensated cirrhosis, and with an eGFR of 40 ml/min or
greater were randomly assigned 1:1 to receive daily doses
of 90/400 mg for 12 or 24 weeks. One hundred percent of
patients achieved SVR after 12 weeks of treatment. Serious
AE were reported in 13 (11%): syncope (one patient discontinued due to this event), pulmonary embolism, creatinine
increase (treatment-related in three patients). The most frequent AE were headache (19%), asthenia (14%) and fatigue
(10%). Twenty-five patients (22%) had decreases to below
40 ml/min (4–< 30 ml/min). None of the 8 patients who had
CrCl less than 40 ml/min at baseline had a reduction in CrCl
to less than 30 ml/min during therapy. One patient temporarily stopped receiving the study drug because of a urinary
tract infection and an increased creatinine level. All but one
of the six patients with cirrhosis whose CrCl decreased to
below 40 ml/min continued study treatment without interruption; none permanently discontinued study treatment.
Twenty-one patients (18%) required an adjustment of their
immunosuppressant regimen: dosage reductions (7), dosage
increases (10), and both reductions and increases (4).
Kamar et al. [62] performed a pilot study to evaluate
the efficacy and safety of a sofosbuvir-based regimen: plus
RBV (6), daclatasvir (4), simeprevir ± RBV (10), ledipasvir ± RBV (9) and plus IFN ± RBV (1) for 12 or 24 weeks,
in 25 renal transplantation recipients who reached SVR.
Beinhardt et al. [63] evaluated regimens based on different
DAA in 25 patients with CKD, eight of whom were kidney
transplantation recipients, whereas seven had received a
dual liver and kidney transplantation. Barring one patient
who was treated with daclatasvir and simeprevir, the rest
received a regimen of sofosbuvir with simeprevir. The 25
patients were treated for 12 weeks, and in eight of them
(one kidney transplantation recipient and two liver-kidney
transplantation recipients), treatment was expanded to 24
weeks due to slow viral response, to 16 weeks in two, to 19
weeks in one and to 24 weeks in five (the situation regarding kidney transplantation is not specified). Two patients
with a dual transplantation presented unstable high blood
pressure at week 2 and 20, on treatment with sofosbuvir and simeprevir and with sofosbuvir and daclatasvir,
respectively, although their anti-hypertensive treatment
13
J Nephrol
did not need to be modified. One kidney transplantation
recipient had treatment-resistant ascites before beginning
sofosbuvir and daclatasvir due to a spontaneous bacterial
peritonitis and required multiple ambulatory paracenteses during the antiviral treatment. The dose of sofosbuvir
was reduced in three patients, one of whom was a kidney
transplantation recipient with general deterioration, refractory ascites and worsening of renal function (their baseline
creatinine of 2.98 mg/dl rose to 3.8 mg/dl in week 2). Of
all the patients recruited, 20 were taking immunosuppressants at the beginning of the antiviral treatment, five of
them on hemodialysis. Only one patient required titration
of the immunosuppressive dose (cyclosporine).
Other experiences have been carried out with sofosbuvir-based regimens in kidney recipients with chronic
HCV infection. Sawinski et al. [64] achieved an SVR12 of
100% in 20 kidney recipients treated with sofosbuvir and
simeprevir (9), RBV (3), ledipasvir (7) and daclatasvir (1).
The DAAs were well tolerated (one blood transfusion was
needed) and 45% of patients required calcineurin inhibitor dose adjustment during treatment. Lin et al. [65] in 24
kidney recipients treated with a sofosbuvir and simeprevir
(9 without and 3 patients with RBV) or ledipasvir (7 without and 1 with RBV) or RBV (4). The overall SVR12 was
91% and AE were reported in 46% of patients, who were
managed clinically without discontinuation of therapy.
Calcineurin inhibitor levels did not significantly change
during therapy.
The CORAL-I [66], multicenter, phase II, open-label
parallel group study in liver and kidney transplant patients
to evaluate the safety and efficacy of the 3D combination,
with or without RBV, in patients with HCV genotype 1 and
of the 2D combination, with RBV, in patients with HCV
genotype 4 study is currently ongoing. The trial consists
of multiple arms, two of them involving kidney transplant
patients: one arm in which patients are treated with the 3D
combination plus RBV for 12 weeks and another with the
3D combination for 12 weeks. The trial intends to recruit
195 patients. It began in February 2013, and the initial
and final results are expected to be available in 2017. For
the moment, only the results in 34 liver transplantation
patients have been published [67].
Acknowledgements Beatriz Proy Vega contributed to the investigation of this work.
Compliance with ethical standards Conflict of interest The authors declare that they have no conflict
of interest.
Research involving human participants or animals This article
does not contain any studies with human participants or animals performed by any of the authors.
J Nephrol
Informed consent For this type of study formal consent is not
required.
References
1. Fisell RB, Bragg-Gresaham JL, Woods JD, Jadoul M,
Gillespie B, Hedderwick SA et al (2004) Patterns of hepatitis
C prevalence and seroconversion in hemodialysis units from
three continents: the DOPPS. Kidney Int 65(6):2335–2342.
doi:10.1111/j.1523-1755.2004.00649.x
2. Sivapalasingam S, Malak SF, Sullivan JF, Lorch J, Sepkowitz KA
(2002) High prevalence of hepatitis C infection among patients
receiving hemodialysis at an urban dialysis center. Infect Control
Hosp Epidemiol 23(6):319–324. doi:10.1086/502058
3. Finelli L, Miller JT, Tokars JI, Alter MJ, Arduino
MJ (2005) National surveillance of dialysis associated diseases in the US, 2002. Semin Dial 18(1):52–61.
doi:10.1111/j.1525-139X.2005.18108.x
4. Espinosa M, Martín-Malo A, Ojeda R, Santamara R, Soriano S,
Aguera M et al (2004) Marked reduction in the prevalence of
hepatitis C virus infection in hemodialysis patients: causes and
consequences. Am J Kidney Dis 43(4):685–689 PMID: 15042545
5. Jadoul M, Poignet JL, Geddes C, Locatelli F, Medin C, Krajewska
M, HCV Collaborative Group et al (2004) The changing epidemiology of hepatitis C virus (HCV) infection in hemodialysis: European multicenter study. Nephrol Dial Transplant 19(4):904–909
6. Pereira BJ, Natov SN, Bouthot BA, Murthy BV, Ruthazer R,
Schmid CH et al (1998) Effects of hepatitis C infection and
renal transplantation on survival in end-stage renal disease. The
New England Organ Bank Hepatitis C Study Group. Kidney Int
53(5):1374–1381. doi:10.1046/j.1523-1755.1998.00883.x
7. García-Agudo R, Aoufi-Rabih S, Barril-Cuadrado G, Grupo de
Virus en Diálisis de la Sociedad Española de Nefrología (2013)
SHECTS multi-center Spanish study: liver situation of patients
with chronic hepatitis from HCV on renal replacement therapy
with hemodialysis. Nefrologia 33(2):188–195. doi:10.3265/Nefrologia.pre2012.Nov.11668
8. Hanafusa T, Ichikawa Y, Kishikawa H, Kyo M, Fukunishi T,
Kokado Y et al (1998) Retrospective study on the impact of hepatitis C virus infection on kidney transplant patients over 20 years.
Transplantation 66(4):471–476
9. Vosnides GG (1997) Hepatitis C in renal transplantation. Kidney
Int 52(3):843–861
10. Fabrizi F, Dixit V, Messa P (2012) Impact of hepatitis C on survival
in dialysis patients: a link with cardiovascular mortality? J Viral
Hepat 19(9):601–607. doi:10.1111/j.1365-2893.2012.01633.x
11. Maisonneuve P, Agodoa L, Gellert R, Stewar JH, Buccianti G,
Lowenfels AB et al (1999) Cancer in patients on dialysis for endstage renal disease: an international collaborative study. Lancet
354(9173):93–99
12. Morales JM, Domínguez-Gil B, Sanz-Guajardo D, Fernández J,
Escuin F (2004) The influence of hepatitis B and hepatitis C virus
infection in the recipient on late renal allograft failure. Nephrol
Dial Transpl 19 Suppl 3:iii72–iii76. doi:10.1093/ndt/gfh1020
13. Hestin D, Guillermin F, Castin N, Le Faou A, Champigneulles J,
Kessler M (1998) Pretransplant hepatitis C virus infection: a predictor of proteinuria after renal transplantation. Transplantation
65(5):741–744
14. Bloom RD, Rao V, Weng F, Grossman RA, Cohen D, Mange
KC (2002) Association of hepatitis C with posttransplant diabetes in renal transplant patients on tacrolimus. J Am Soc Nephrol
13(5):1374–1380
15. Kamar N, Mariat C, Delahousse M, Dantal J, al. Najjar A, Cassuto
E, Diapason Study Group, et al (2007) Diabetes mellitus after
kidney transplantation: a French multicenter observational study.
Nephrol Dial Transpl 22(7):1986–1993. doi:10.1093/ndt/gfm011
16. Fabrizi F, Martin P, Dixit V, Bunnapradist S, Kanwal F, Dulai G
(2005) Post-transplant diabetes mellitus and HCV seropositive
status after renal transplantation: meta-analysis of clinical studies.
Am J Transpl 5(19):2433–2440. doi:10.1093/ndt/gfm011
17. Roth D, Cirocco R, Zucker K, Ruiz P, Viciana A, Burke G et al
(1995) De novo membranoproliferative glomerulonephritis in
hepatitis C virus-infected renal allograft recipients. Transplantation 59(12):59:1676–1682
18. Floege J (2003) Recurrent glomerulonephritis following renal
transplantation: an update. Nephrol Dial Transpl 18(7):1260–1265
19. Choy BY, Chan TM, Lai KN (2006) Recurrent glomerulonephritis after kidney transplantation. Am J Transpl 6(11):2535–2542.
doi:10.1111/j.1600-6143.2006.01502.x
20. Kamar N, Izopet J, Alric L, Guilbeaud-Frugier C, Rostaing L
(2008) Hepatitis C virus-related kidney disease: an overview. Clin
Nephrol 69(3):149–160
21. Kidney Disease: Improving Global Outcomes (KDIGO) (2008)
Clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease. Kidney Int 73(Suppl 109):S53–S68. doi:10.1038/ki.2008.81
22. Kamar N, Ribes D, Izopet J, Rostaing L (2006) Treatment of
hepatitis C virus infection (HCV) after renal transplantation:
implications for HCV-positive dialysis patients awaiting a kidney transplant. Transplantation 82(7):853–856. doi:10.1097/01.
tp.0000238898.14393.c9
23. Toth CM, Pascual M, Chung RT, Graeme-Cook F, Dienstag JL,
Bhan AK et al (1998) Hepatitis C virus-associated fibrosing cholestatic hepatitis after renal transplantation: response to interferonalpha therapy. Transplantation 66(9):1254–1258
24. Hsu YC, Lin JT, Ho HJ, Kao YH, Huang YT, Hsiao NW et al
(2014) Antiviral treatment for hepatitis C virus infection is associated with improved renal and cardiovascular outcomes in diabetic
patients. Hepatology 59(4):1293–1302. doi:10.1002/hep.26892
25. Molnar MZ, Alhourani HM, Wall BM, Lu JL, Streja E, Kalantar-Zadeh K et al (2015) Association of hepatitis C viral infection with incidence and progression of chronic kidney disease
in a large cohort of US veterans. Hepatology 61(5):1495–1502.
doi:10.1002/hep.27664
26. García García M, Oppenheimer F, Valencia J (2006) Valoración y
seguimiento de inclusión en lista de espera para trasplante renal.
Nefrologia 26 Suppl 8:60–69
27. Campistol JM, Darnell A (2014) Trasplante renal: manejo clínico.
In: Protocolos del Servicio de Nefrología y Trasplante renal. Hospital Clínic de Barcelona. Euromedici, Badalona
28. Alonso Gil M (2016) Proceso asistencial integrado. Tratamiento sustitutivo de la IRC: diálisis y trasplante renal. Seville:
Consejería de Salud, Junta de Andalucía. http://www.juntadeandalucia.es/salud/sites/csalud/contenidos/Informacion_General/p_3_p_3_procesos_asistenciales_integrados/pai/
tratamiento_insuficiencia_renal_v3?perfil=org
29. Fabrizi F, Dixit V, Martin P, Messa P (2011) Combined antiviral therapy of hepatitis C virus in dialysis patients: metaanalysis of clinical trials. J Viral Hepat 18(7):e263-e269.
doi:10.1111/j.1365-2893.2010.01405.x
30. European Association for Study of the Liver (2015) EASL
recommendations on treatment of hepatitis C 2015. J Hepatol;63(1):199–236. doi:10.1016/j.jhep.2015.03.025
31. Kowdley KV, Gordon SC (2014) Ledipasvir and sofosbuvir for
8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med
370(20):1879–1888. doi:10.1056/NEJMoa1402355
32. Pockros PJ, Rajender Reddy K, Mantry PS, Cohen E, Bennett M, Sulkowski MS et al (2016) Efficacy of direct-acting
13
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
J Nephrol
antiviral combination for patients with hepatitis C virus genotype 1 infection and severe renal impairment or end-stage renal
disease. Gastroenterology 150(7):1590–1598. doi:10.1053/j.
gastro.2016.02.078
Poordad F, Herode C, Trinh R, Kowdley KV, Zeuzem S, Agarwal
K et al (2014) ABT-450/r-ombitasvir and dasabuvir with ribavirin
for hepatitis C with cirrhosis. N Engl J Med 370(21):1973–1982.
doi:10.1056/NEJMoa1402869
Roth D, Nelson DR, Bruchfeld A, Liapakis A, Silva M, Monsour
H Jr et al (2015) Grazoprevir plus elbasvir in treatment-naïve and
treatment-experienced patients with hepatitis C virus genotype 1
infection and stage 4–5 chronic kidney disease (the C-SURFER
study): a combination phase 3 study. Lancet 386(10003):1537–
1545. doi:10.1016/S0140-6736(15)00349-9
Curry MP, O’Leary JG, Bzowej N, Muir AJ, Korenblat KM,
Fenkel JM, ASTRAL-4 Investigators et al (2015) Sofosbuvir and
velpatasvir for HCV in patients with decompensated cirrhosis. N
Engl J Med 373(27):2618–2628. doi:10.1056/NEJMoa1512614
AASLD/IDSA HCV Guidance Panel (2015) Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing,
and treating adults infected with hepatitis C virus. Hepatology
62(3):932–954. doi:10.1002/hep.27950
Kwo P, Gane EJ, Peng CY, Pearlman B, Vierling JM, Serfaty L
et al (2017) Effectiveness of Elbasvir and Grazoprevir combination, with or without ribavirin, for treatment-experienced patients
with chronic hepatitis C infection. Gastroenterology 152(1):164–
175. doi:10.1053/j.gastro.2016.09.045
Munoz-Gomez R, Rincon D, Ahumada A, Hernandez E, Devesa
M, Izquierdo S et al (2017) Therapy with ombitasvir/paritaprevir/
ritonavir plus dasabuvir is effective and safe for the treatment
of genotypes 1 and 4 hepatitis C virus infection in patients with
severe renal impairment: a multicenter experience. J Viral Hepatol
24(6):464–471. doi:10.1111/jvh.12664
Welzel TM, Hinrichsen H, Sarrazin C, Buggisch P, Baumgarten A,
Christensen S et al (2017) Real-world experience with the all-oral,
interferon-free regimen of ombitasvir/paritaprevir/ritonavir and
dasabuvir for the treatment of chronic hepatitis C virus infection
in the German Hepatitis C Registry. J Viral Hepat. doi:10.1111/
jvh.12708 (Epub ahead of print)
Ponziani FR, Siciliano M, Lionetti R, Pasquazzi C, Gianserra L,
D’Offizi G et al (2017) Effectiveness of paritaprevir/ritonavir/
ombitasvir/dasabuvir in hemodialysis patients with hepatitis C
virus infection and advanced liver fibrosis: case reports. Am J
Kidney Dis 70(2):297–300. doi:10.1053/j.ajkd.2017.01.037
Sato K, Hosonuma K, Yamazaki Y, Kobayashi T, Takakusagi S,
Horiguchi N et al (2017) Combination therapy with ombitasvir/
paritaprevir/ritonavir for dialysis patients infected with hepatitis C
virus: a prospective multi-institutional study. Tohoku J Exp Med
241(1):45–53. doi:10.1620/tjem.241.45
Saxena V, Koraishy FM, Sise M, Lim JK, Schmidt M, Chung RT
(2016) Safety and efficacy of sofosbuvir-containing regimens in
hepatitis C-infected patients with impaired renal function. Liver
Int 36(6):807–816. doi:10.1111/liv.13102
Desnoyer A, Pospai D, Patric Le M, Gervais A, Heurgué-Berlot
A, Laradi A et al (2016) Pharmacokinetics, safety and efficacy
of a full dose sofosbuvir-based regimen given daily in hemodialysis patients with chronic hepatitis C. J Hepatol 65(1):40–47.
doi:10.1016/j.jhep.2016.02.044
Feld JJ, Jacobson IM, Hézode C, Asselah T, Ruane PJ, Gruener
N, ASTRAL-1 Investigators et al (2015) Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J
Med 373(27):2599–2607. doi:10.1056/NEJMoa1512610
Foster GR, Afdhal N, Roberts SK, Bräu N, Gane EJ, Pianko S,
ASTRAL-2 Investigators, ASTRAL-3 Investigators et al (2015)
Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection.
N Engl J Med 373(27):2608–2617. doi:10.1056/NEJMoa1512612
13
46. Mangia A, Arleo A, Copetti M, Miscio M, Piazzolla V, Santoro
R et al (2016) The combination of daclatasvir and sofosbuvir for
curing genotype 2 patients who cannot tolerate ribavirin. Liver
Int 36(7):971–976. doi:10.1111/liv.13069
47. Zeuzem S, Dusheiko GM, Salupere R, Mangia A, Flisiak R,
Hyland RH, VALENCE Investigators et al (2014) Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med
370(21):1993–2001. doi:10.1056/NEJMoa1316145
48. Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, Sulkowski MS, POSITRON Study, FUSION
Study et al (2013) Sofosbuvir for hepatitis C genotype
2 or 3 in patients without treatment options. N Engl J Med
368(20):1867–1877. doi:10.1056/NEJMoa1214854
49. Welzel TM, Nelson DR, Morelli G, Di Bisceglie A, Reddy
RK, Kuo A HCV-TARGET Study Group et al (2016) Effectiveness and safety of sofosbuvir plus ribavirin for the treatment of HCV genotype 2 infection: results of the real-world,
clinical practice HCV-TARGET study. Gut 0:1–9. doi:10.1136/
gutjnl-2016-311609]
50. Nelson DR, Cooper JN, Lalezari JP, Lawitz E, Pockros PJ, Gitlin N, ALLY-3 Study Team et al (2015) All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C
virus genotype 3 infection: ALLY-3 phase III study. Hepatology
61(4);1127–1135. doi:10.1002/hep.27726
51. Leroy V, Angus P, Bronowicki JP, Dore GJ, Hezode C, Pianko S
et al (2016) Daclatasvir, sofosbuvir, and ribavirin for hepatitis C
virus genotype 3 and advanced liver disease: a randomized phase
III study (ALLY-3+). Hepatology 63(5):1430–1441. doi:10.1002/
hep.28473
52. Hézode C, Asselah T, Reddy KR, Hassanein T, Berenguer M,
Fleischer-Stepniewska K et al (2015) Ombitasvir plus paritaprevir
plus ritonavir with or without ribavirin in treatment-naïve and
treatment-experienced patients with genotype 4 chronic hepatitis
C virus infection (PEARL-I): a randomised, open-label trial. Lancet 385(9986):2502–2509. doi:10.1016/S0140-6736(15)60159-3
53. Kohli A, Kapoor R, Sims Z, Nelson A, Sidharthan S, Lam B
et al (2015) Ledipasvir and sofosbuvir for hepatitis C genotype 4: a proof-of-concept, single-center, open-label phase 2a
cohort study. Lancet Infect Dis 15(9):1049–1054. doi:10.1016/
S1473-3099(15)00157-7
54. Abergel A, Asselah T, Metivier S, Kersey K, Jiang D, Mo H, Pang
PS, Samuel D, Loustaud-Ratti V (2016) Ledipasvir-sofosbuvir
in patients with hepatitis C virus genotype 5 infection: an openlabel, multicenter, single-arm, phase 2 study. Lancet Infect Dis
16(4):459–464. doi:10.1016/S1473-3099(15)00529-0
55. Gane EJ, Hyland RH, An D, Svarovskaia E, Pang PS, Brainard
D (2015) Efficacy of ledipasvir and sofosbuvir, with or without
ribavirin, for 12 weeks in patients with HCV genotype 3 or 6
infection. Gastroenterology 149(6):1454–1461. doi:10.1053/j.
gastro.2015.07.063
56. Gane E, Lawitz E, Pugatch D, Papatheodoridis G, Bräu N, Brown
A et al. (2016) EXPEDITION-4: Efficacy and safety of glecaprevir/pibrentasvir (ABT-493/ABT-530) in patients with renal
impairment and chronic hepatitis C virus genotype 1–6 infection.
AASLD 2016 Nov 11–15 Boston, MA
57. Talavera Pons S, Boyer A, Lamblin G, Chennell P, Châtenet FT,
Nicolas C et al (2016) Managing drug-drug interactions with new
direct-acting antiviral agents in chronic hepatitis C. Br J Clin
Pharmacol 83(2):269–293. doi:10.1111/bcp.13095
58. Bradi P, Dutta S, Coakley E, Cohen D, Ding B, Podsadecki T
et al (2015) Pharmacokinetics and dose recommendations for
cyclosporine and tacrolimus when coadministered with ABT450, ombitasvir, and dasabuvir. Am J Transpl 15(5):1313–1322.
doi:10.1111/ajt.13111
59. HEP Drug interactions. University of Liverpool. http://www.hepdruginteractions.org
J Nephrol
60. Ouwerkerk-Mahadevan S, Vanwelkenhuysen I, Peeters M,
Simonts M, Ilsbroux I, Simion A et al (2015) P0834: Significant
drug–drug interaction between simeprevir and cyclosporine but
not tacrolimus in patients with recurrent chronic HCV infection
after orthotopic liver transplantation: the Saturn study. J Hepatol
62(Suppl 2):S650
61. Colombo M, Aghemo A, Liu H, Zhang J, Dvory-Sobol H, Hyland
R et al (2017) Treatment with ledipasvir-sofosbuvir for 12 or 24
weeks in kidney transplant recipients with chronic hepatitis C
virus genotype 1 or 4 infection: a randomized trial. Ann Intern
Med 166(2):109–117. doi:10.7326/M16-1205
62. Kamar N, Marion O, Rostaing L, Cointault O, Ribes D, Lavayssière L et al (2016) Efficacy and safety of sofosbuvir-based antiviral therapy to treat hepatitis C virus infection after kidney transplantation. Am J Transpl 16(5):1474–1479. doi:10.1111/ajt.13518
63. Beinhardt S, al. Zoairy R, Ferenci P, Kozbial K, Freissmuth C,
Stern R et al (2016) DAA-based antiviral treatment of patients
with chronic hepatitis C in the pre- and post-kidney transplantation setting. Transpl Int 29(9):999–1007. doi:10.1111/tri.12799
64. Sawinski D, Kaur N, Ajeti A, Trofe-Clark J, Lim M, Bleicher M
et al (2016) Successful treatment of hepatitis C in renal transplant
recipients with direct-acting antiviral agents. Am J Transpl
16:1588–1595. doi:10.1111/ajt.13620
65. Lin MV, Sise ME, Pavlakis M, Amundsen BM, Chute D, Rutherford AE et al (2016) Efficacy and safety of direct acting antivirals in kidney transplant recipients with chronic hepatitis C
virus infection. PLoS One 11(7):e0158431. doi:10.1371/journal.
pone.0158431
6 6. Open-Label, Phase 2 Study to Evaluate the Safety and Efficacy of the Combination of ABT-450/Ritonavir/ABT-267 With
ABT-333 and With or Without RBV in HCV Genotype 1 and
ABT-450/r/ABT-267 With RBV in HCV GT4-Infected Adult
Liver or Renal Transplant Recipients With Hepatitis C Virus
(HCV) Infection (CORAL-I). https://clinicaltrials.gov/ct2/show/
NCT01782495?term=CORAL-I&rank=1
67. Kwo PY, Mantry PS, Coakley E, Te HS, Vargas HE, Brown R
Jr et al (2014) An interferon-free antiviral regimen for HCV
after liver transplantation. N Engl J Med 371(25):2375–2382.
doi:10.1056/NEJMoa1408921
13
Документ
Категория
Без категории
Просмотров
0
Размер файла
793 Кб
Теги
017, 0446, s40620
1/--страниц
Пожаловаться на содержимое документа