clinical trial www.kidney-international.

org

Grazoprevir plus elbasvir in HCV genotype-1

or -4 infected patients with stage 4/5 severe see commentary on page 18
chronic kidney disease is safe and effective
Laurent Alric1, Isabelle Ollivier-Hourmand2, Emilie Bérard3, Sophie Hillaire4, Maeva Guillaume5,
Anais Vallet-Pichard6, Brigitte Bernard-Chabert7, Veronique Loustaud-Ratti8, Marc Bourlière9,
Victor de Ledinghen10, Isabelle Fouchard-Hubert11, Valerie Canva12, Anne Minello13, Eric Nguyen-Khac14,
Vincent Leroy15, David Saadoun16, Dominique Trias17, Stanislas Pol6 and Nassim Kamar18
1
Department of Internal Medicine and Digestive Diseases, CHU Purpan, UMR 152 Pharma Dev, IRD Toulouse 3 University, Toulouse,
France; 2Digestive Department, CHU, Caen, France; 3Department of Epidemiology, Health Economics and Public Health, UMR-1027
INSERM-Toulouse University Hospital (CHU), Toulouse, France; 4Digestive Department, Hopital Foch, Suresnes, France; 5Digestive
Department, CHU Purpan, Toulouse, France; 6Hepatology Department, Hopital Cochin, Université Paris Descartes, Inserm U-1223, Institut
Pasteur, Paris, France; 7Digestive Department, CHU, Reims, France; 8Digestive Department, CHU, Limoges, France; 9Digestive Department,
Hopital Saint Joseph, Marseille, France; 10Digestive Department, CHU, Bordeaux, France; 11Digestive Department, CHU, Angers, France;
12
Digestive Department, CHU, Lille, France; 13Digestive Department, CHU, Dijon France; 14Digestive Department, CHU Amiens, France;
15
Digestive Department, CHU, Grenoble, France; 16Department of Internal Medicine and Clinical Immunology, Sorbonne University,
INSERM, UMR 959, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; 17MSD, Paris, France; and 18Departments of Nephrology and
Organ Transplantation, CHU Rangueil, INSERM U1043, IFR–BMT, Université Paul Sabatier, Toulouse, France

Patients with advanced chronic kidney disease who receive Kidney International (2018) 94, 206–213; https://doi.org/10.1016/
direct-acting antiviral drugs require special consideration j.kint.2018.02.019
regarding comorbid conditions. Here we assessed KEYWORDS: chronic kidney disease; DAA; elbasvir; grazoprevir; HCV;
hemodialysis
the efficacy and safety of grazoprevir plus elbasvir in
Copyright ª 2018, International Society of Nephrology. Published by
93 patients infected with HCV genotype 1 or 4 and with
Elsevier Inc. All rights reserved.
advanced chronic kidney disease in a non-randomized,
multicenter, nationwide observational survey. Twenty
patients with HCV genotype 1a, 51 patients with 1b, four

unclassified genotype 1, 17 with genotype 4 and one with
genotype 6 received grazoprevir plus elbasvir (100/50 mg)
once daily. All patients had severe chronic kidney disease
with 70 patients stage G5, including patients on
hemodialysis (74.2%), and 23 were stage G4 chronic kidney
disease. Severe liver disease (Metavir F3/F4) was found in
33 patients. A sustained virologic response 12 weeks after
the end of therapy was achieved in 87 of 90 patients. Two
patients had a virologic breakthrough and one had a
relapse after treatment withdrawal. Most patients received
many concomitant medications (mean 7.7) related to
comorbid conditions. Serious adverse events occurred in
six patients, including three deaths while on grazoprevir
plus elbasvir, not related to this therapy. Thus, once-daily
grazoprevir plus elbasvir was highly effective with a low
rate of adverse events in this advanced chronic kidney
disease difficult-to-treat population with an HCV genotype
1 or 4 infection.
Correspondence: Laurent Alric, Department of Internal Medicine and
Digestive Diseases, Pavillon Dieulafoy, CHU Purpan, 31059 Toulouse Cedex 9,
France. E-mail: alric.l@chu-toulouse.fr
Received 17 November 2017; revised 17 January 2018; accepted 1
February 2018; published online 5 May 2018
T
he prevalence of hepatitis C virus (HCV) infection in
patients with end-stage renal disease (ESRD), despite
its prevalence declining over time, remains 4 times
greater in dialysis patients and kidney-transplant recipients
than in the general population.1–4 In the general population,
apart from its impact on the liver, chronic HCV infection is
associated with increased global mortality related to higher
rates of diabetes, neurologic stroke, and cardiovascular dis-
ease. In addition, HCV infection increases the risk of chronic
kidney disease (CKD), leading to ESRD.5 After renal trans-
plantation, HCV infection is an independent factor for global
mortality and the loss of the kidney graft.6 This worse prog-
nosis in HCV-infected kidney recipients is usually thought to
be caused in part by a more rapid progression of liver fibrosis
and an increased risk of de novo transplant glomerulopathy.7,8
Currently, direct-acting antiviral drugs (DAAs) are the gold
standard for treating HCV infection.9 There are numerous types
of DAAs, and the combination of at least 2 different classes
results in a high sustained virologic response, as defined by an
undetectable HCV RNA 12 weeks after the end of therapy
(SVR12). Sofosbuvir was the first pan-genotypic DAA to
become available. A second wave of DAAs that are active against
HCV genotypes 1, 2, 3, 4, 5, and 6 were subsequently approved.
A combination of these drugs, with or without ribavirin, has
been shown to be effective and well tolerated in treatment-naïve

206 Kidney International (2018) 94, 206–213

L Alric et al.: Grazoprevir and elbasvir in HCV chronic kidney disease clinical trial

and treatment-experienced patients with HCV infection.
Indeed, >90% of HCV patients can be cured of the infection,
and an SVR is generally associated with resolution of liver
fibrosis in patients without cirrhosis.9 Because sofosbuvir is
primarily eliminated by the kidney,10 its use is not recom-
mended for patients with ESRD, including patients with an
estimated glomerular filtration rate (eGFR) <30 ml/min per
1.73 m2 or those receiving hemodialysis. Consequently, the
safety and efficacy of sofosbuvir-containing regimens have not
been clearly established in such patients. In addition, therapy
with DAAs given to CKD patients requires special consideration
regarding comorbid conditions and drug-to-drug in-
teractions.10–12 Phase 2 and 3 trials using grazoprevir (GZR), an
NS3/4A protease inhibitor, and elbasvir (EBR), an NS5A protein
inhibitor of HCV, have shown very good results against HCV
genotype 1 and 4 infections.13,14 Less than 1% of GZRþEBR is
renally excreted; thus, dose adjustments of GZRþEBR are not
needed for patients with nondialysis-dependent stage 4/5 CKD
or those who are dialysis dependent. C-Surfer15 was the first
randomized, placebo-controlled phase 3 study to evaluate an
all-oral, ribavirin-free regimen in HCV genotype 1–infected
patients, with stage 4 or 5 advanced CKD, including subjects on
hemodialysis. Once-daily GZRþEBR was highly effective, with
a low rate of adverse events in patients with advanced CKD and
a HCV genotype 1 infection. Taking into account the results of
the C-Surfer study, GZRþEBR is a good therapy option for this
specific population.
In 2015, the French National Agency for Medicine and
Health-Product Safety granted nominative temporary
authorization (ATUn) for the use of GZRþEBR, which is an
early-access program that gives patients access to a medica-
tion before it is authorized for marketing. Patients were
mainly CKD stage 4/5, infected with HCV genotype 1 or 4,
sometimes with a history of kidney or liver transplantation or
on a transplantation list, were treatment-naïve or experi-
enced, regardless of fibrosis stage or comorbid conditions.
Most of these patients had been excluded from phase 2 or 3
trials.
The aims of this multicenter cohort study were to report,
in real-life clinical practice, the efficacy and safety of GZR þ
EBR-based therapy given to HCV-infected patients with
advanced CKD and differing clinical profiles.
RESULTS
Characteristics of patients at baseline
As shown in Figure 1, 93 patients with CKD were included in
the study. They were enrolled at 28 centers, and 90 patients
reached week 12 of the follow-up after GZR þ EBR with-
drawal. Three patients died while receiving GZR þ EBR; thus,
SVR12 was not assessed. The baseline demographic and dis-
ease characteristics are shown in Table 1. Most patients were
on hemodialysis (69/93, 74.2%). All patients had severe CKD:
70 (75.3%) were stage G5 and 23 (24.7%) were stage G4. The
duration of hemodialysis before GZR þ EBR treatment was
27.5  3.5 months. Previous anti-HCV treatment with
pegylated interferon þ ribavirin failed in 37 patients (39.8%).
Most patients were HCV genotype 1b (54.8%); the prevalence
of HCV genotype 1a (21.5%) or genotype 4 (18.3%) was
substantial. At baseline, liver fibrosis was mild in 53 patients
(57.0%), and severe liver disease (METAVIR F3/F4) was
observed in 33 patients (35.5%); 19 patients (20.4%) were
METAVIR F3. Fourteen patients (15.1%) had compensated
cirrhosis. Most of the patients (76.3%) received GZR þ EBR
for 12 weeks, 16.1% for 16 weeks, and only 1 patient for 24
weeks (Table 1). This extended duration of antiviral therapy
was for patients with HCV genotype 1a infection or those
with cirrhosis. Six patients (6.5%) were treated for <12 weeks
due to adverse events or because the patient requested that
treatment was stopped. Only 3 patients (3.2%) received
GZR þ EBR in association with ribavirin: at a low dose of 200
mg/day for 2 patients, and 600 mg/d for 1 patient.
Viral efficacy
Of the 90 patients who received GZR þ EBR and completed
the 12-week follow-up after treatment withdrawal, a virologic
response at the end of antiviral therapy was observed in

97 patients screened

4 screening failures
(included in another trial)

93 treated with
grazoprevir + elbasvir

3 deaths
(discontinued treatment quickly and not
analyzable for SVR12)
4 patients discontinued treatment
but continued follow-up:
2 breakthroughs, 1 serious
adverse event, 1 patient’s
decision
90 completed follow-up 12 weeks after
treatment withdrawal

Figure 1 | Flowchart. SVR12, sustained virologic response at week 12 of follow-up after grazoprevir þ elbasvir withdrawal.

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clinical trial L Alric et al.: Grazoprevir and elbasvir in HCV chronic kidney disease

Table 1 | Baseline clinical characteristics of the patients 88 patients (97.8%) (Table 2). The primary endpoint
Grazoprevir D elbasvir (i.e., SVR12), was achieved in 87 patients (96.7%) (95%
(N [ 93) confidence interval 0.91–0.99). A virologic breakthrough was
Sex, N (%) observed in 2 patients and a relapse in 1 patient (Table 2). Of
Male 55 (59.1) the 87 patients who achieved an SVR12, 2 patients dis-
Female 38 (40.9) continued treatment prematurely at 5 and 8 weeks, with no
Age, mean  SD (range), y 58.6  12.7 (24–90)
Race, N (%)
effect on virologic response. The first patient stopped treat-
French European 56 (60.2) ment because of an adverse event, and 1 patient decided to
Caribbean Island 6 (6.5) stop treatment.
African 18 (19.3) We observed only 3 treatment failures with GZR þ EBR
Asian 5 (5.4)
East European 4 (4.3) therapy. Of these, 2 patients had a virologic breakthrough:
North African 4 (4.3) 1 was on hemodialysis and had mild liver fibrosis, whereas
HCV genotype, N (%) the second patient was cirrhotic and not on hemodialysis.
1a 20 (21.5)
1b 51 (54.8) The breakthrough occurred after 4 and 8 weeks, respectively,
1 undetermined 4 (4.3) of therapy, and both patients were infected by HCV geno-
4 17 (18.3) type 4d. NS5A resistance–associated substitutions were
6 1 (1.1)
Hepatitis fibrosis stage, N (%)
detected in both patients; these were L28G and L28S. Only 1
F0–F2 53 (57.0) relapse was observed; this occurred in a cirrhotic patient
F3 19 (20.4) receiving hemodialysis with an HCV genotype 1b infection.
F4 14 (15.1) He had a complete virologic response at 4 weeks after
Undetermined 7 (7.5)
Baseline HCV RNA, N (%) completing the treatment, but then a relapse occurred at 8
#800,000 IU/ml 49 (52.7) weeks after treatment withdrawal, and no resistance-
>800,000 IU/ml 39 (41.9) associated substitutions were identified. No clinical differ-
Missing 5 (5.4)
HCV treatment history, N (%) ence in SVR12 was observed in patients with or without
Treatment naïve 56 (60.2) cirrhosis (98.1% and 93.5% for METAVIR F0/F2 and
Previous HCV treatment 37 (39.8) METAVIR F3/F4, respectively), for HCV genotype 1 or 4
Treatment duration, wk, N (%)
12 71 (76.3)
(98.6% vs. 87.5%), for HCV subtype 1b or 1a (98% vs.
16 15 (16.1) 100%), or with >800,000 IU/ml or <800,000 IU/ml of HCV
24 1 (1.1) RNA at baseline (92.3% vs. 100%). Moreover, a virologic
Other 6 (6.5) response was not influenced by hemodialysis. Patients who
Combination with ribavirin, N (%) 3 (3.2)
Chronic kidney disease stage, N (%) were not undergoing hemodialysis had a mean eGFR of 20.5
Stage G4 23 (24.7)  8.5 ml/min per 1.73 m2.
Stage G5, not receiving hemodialysis 1 (1)
Stage G5, receiving hemodialysis 69 (69.8)
Previous renal transplantation, N (%) 16 (17.2) Safety
Patients with functioning kidney allograft, N (%) 12 (12.9) Most patients included in the cohort had numerous co-
Main cause of kidney disease, N (%)
Genetic disease 6 (6.5)
morbid conditions (Table 1). In our cohort, the number of
Glomerulonephritis 16 (17.2) concomitant therapies for each patient before GZR þ EBR
Tubulointerstitial nephritis 7 (7.5) (Table 3) was high (7.7  4.4). Most patients were receiving
Cryoglobulinemia 11 (11.8) antihypertensive therapy (Table 3), as well as statins (21.1%)
Diabetes 8 (8.6)
Hypertension and nephroangiosclerosis 5 (5.4) or proton pump inhibitors (45.6%). During GZRþEBV
Othera 22 (23.7) treatment, few patients stopped their regular concomitant
Undetermined 18 (19.3)
Comorbidities, N (%)
Liver transplanted 4 (4.3) Table 2 | Virological response
HIV coinfected 7 (7.5)
Grazoprevir D elbasvir treatment
Diabetes 22 (23.7)
Hypertension 67 (72.0) On Not on
Dyslipidemia 23 (24.7) hemodialysis hemodialysis Total
Cardiac disease 35 (37.6) (N [ 67) (N [ 23) (N [ 90)a
Vascular disease 7 (7.5)
Respiratory disease 4 (4.3) SVR (HCV RNA <LLoQ)
Alcohol uptake 11 (11.8) End of treatment, N (%) 66 (98.5) 22 (95.6) 88 (97.7)
i.v drug addiction 1 (1.1) Follow-up week 12, N 65 (97) 22 (95.7) 87 (96.7)
Cancer 7 (7.5) (%)
Other (not listed) 31 (33.3) Relapse 1 0 1
Breakthrough 1 1 2
HCV, hepatitis C virus.
Data are N (%) or mean  SD (range). HCV, hepatitis C virus; LLoQ, lower limit of quantification (HCV RNA is detected
a
Vascular nephropathy, tubulointerstitial nephropathy, lupus, hyperoxaluria type 2, but <15 mIU/ml); SVR, sustained virological response.
cardiorenal syndrome, oligomeganephronic, nephropathy of vesicoureteral reflux, Data are N (%).
segmental and focal hyalinosis, thrombotic microangiopathy, Henoch-Schönlein a
Death occurred in 3 of 93 patients before the end of grazoprevir þ elbasvir therapy:
purpura. 90 patients were analyzed for SVR12.

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L Alric et al.: Grazoprevir and elbasvir in HCV chronic kidney disease clinical trial

medications, and almost all patients remained on the same Table 4 | Safety and adverse events
treatment during the follow-up (Table 3). No significant Grazoprevir D
drug-to-drug interactions were observed between GZR þ elbasvir (N [ 93)
EBR and other therapies. Table 4 shows the safety profiles for Any adverse eventa 32 (34.4)
GZR þ EBR therapy. A high incidence of adverse events Headache 5 (5.4)
(N ¼ 32, 34.4%) was observed during follow-up. These Nausea 3 (3.2)
adverse events, such as asthenia (17.2%), were of low in- Asthenia 16 (17.2)
Insomnia 2 (2.1)
tensity and not obviously associated with the antiviral Irritability 1 (1.1)
therapy, particularly in those on hemodialysis. Of the 3 pa- Diarrhea 3 (3.2)
tients who received ribavirin, only the patient who received Pruritus 3 (3.2)
600 mg/day had anemia that required the dose to be Otherb 10 (10.8)
Drug-related adverse event 22 (23.7)
decreased to 400 mg/day. No patient required GZR þ EBR Serious adverse event 6 (6.45)
therapy to be stopped. The dose of erythropoietin- Drug-related serious adverse event 1 (1.1)
stimulating agent was unchanged. Discontinuation due to an adverse event 2 (2.1)
Deaths 3 (3.2)
Data regarding change in proteinuria with antiviral therapy
Lowest hemoglobin on treatmentc
were not available in these patients, most of whom were on 8.5–11.0 g/dl 10 (10.8)
hemodialysis. Kidney function became impaired between the <8.5 g/dl 2 (2.1)
screening and the initiation of therapy in 8 patients who Alanine aminotransferasec
1.5–2.5  baseline 2 (2.2)
required starting hemodialysis rapidly. This was unrelated to >2.5  baseline 0 (0)
GZR þ EBR. With respect to the 24 nonhemodialysis pa- >5  baseline 0 (0)
tients, only 2 (8.3%) had a severe worsening of kidney Aspartate aminotransferasec
function during antiviral therapy (Table 4). Three patients 1.5–2.5  baseline 1 (1.1)
>2.5  baseline 1 (1.1)
(12.5%) had an improvement in eGFR (>10 ml/min) >5  baseline 0 (0)
compared with pretreatment values. Overall, the mean eGFR Bilirubinc
remained unchanged (i.e., 20.5  8.5 ml/min per 1.73 m2 at >2.5–5  baseline 1 (1.1)
the initiation of therapy and 21.4  6.9 ml/min per 1.73 m2 at >5.0–10.0  baseline 0 (0)
Creatininec
the end of the therapy. >2.5  baseline 2 (2.1)
No other significant changes in other blood test results
Data are n (%).
were observed during GZR þ EBR treatment (Table 4). a
Incidence during the initial treatment period and for 30 days after the completion
Serious adverse events occurred in 6 of 93 patients of treatment (all patients treated).
b
Back pain, weakness of the legs, abdominal pain, hypercalcemia, arthralgia,
(6.45%), leading to early discontinuation of GZR þ EBR in 2 amenorrhea, hair loss, and decreased libido.
of 90 patients (2.2%). A 41-year-old woman with a previous c
Data presented for patients with >1.0 change from baseline.
renal transplantation and cirrhosis had a first episode of as-
cites during GZRþEBR therapy, but rapidly recovered with diuretics without recurrence. One woman had severe anemia
(7.5 g/dl) that required a blood transfusion; she was not on
Table 3 | Therapeutics classes used during HCV treatment hemodialysis and was noncirrhotic. She did not receive
ribavirin. Hepatocellular carcinoma developed in a cirrhotic
Before to start At the end of
grazoprevir D grazoprevir D 64-year-old woman during antiviral therapy that was treated
elbasvir (N [ 90) elbasvir (N [ 90) by radiofrequency ablation, but GZR þ EBR was not stopped.
No. of concomitant treatmenta 7.7  4.4 (0–28) 7.6  4.5 (0–30)
All 3 patients achieved SVR12. Of the 6 serious adverse
Diuretics 34 (37.8) 34 (37.8) events, deaths occurred in 3 of 93 patients (3.2%) during the
Angiotensin-converting- 17 (18.9) 15 (16.7) course of GZR þ EBR. A 78-year-old man died of a brain
enzyme inhibitors hemorrhage after 38 days of antiviral therapy. A second
Proton pump inhibitors 41 (45.6) 41 (45.6)
Beta-blockers 39 (43.3) 39 (43.3) cirrhotic patient with diabetes who was 58 years old died of
Platelet aggregation inhibitors 29 (32.2) 29 (32.2) severe hypoglycemia followed by multiorgan failure 19 days
Benzodiazepines-hypnotics 15 (16.7) 16 (17.8) after GZR þ EBR initiation. The last death was a 78-year-old
Statins 19 (21.1) 19 (21.1) man who died of septic shock a few days after withdrawal of
Insulin 13 (14.4) 13 (14.4)
Oral antidiabetic agents 6 (6.7) 5 (5.6) antiviral therapy. These 3 deaths seemed to be more related to
Gout treatment 11 (12.2) 11 (12.2) comorbid conditions than to the GZR þ EBR therapy.
Corticoids 20 (22.2) 19 (21.1) Because the 3 patients died during GZR þ EBR therapy, HCV
Othersb 69 (76.7) 69 (76.7)
RNA was not available at 12 weeks after antiviral therapy
HCV, hepatitis C virus. withdrawal.
a
Data are N (%) or mean  SD (range).
b
Thyroid hormones, mineral, nutritional, vitamin and protein supplements, hyper-
kalemia or hyperphosphatemia therapy, antacids, anti-inflammatory, laxative, iron DISCUSSION
chelator, antihistamine, biphosphonate, antiasthmatic, opioid substitution therapy,
estrogen therapy, muscle relaxants, new oral anticoagulants, low molecular weight
Our study confirms that once-daily GZRþEBR is highly
heparin, antineoplastic agents, antibiotics, and antiretroviral therapy. effective and has a low rate of adverse events in a real-life

Kidney International (2018) 94, 206–213 209

clinical trial
population with ESRD and HCV genotype 1 or 4 infection.
Extensive treatment of HCV-infected patients with advanced
CKD stage 4/5 is a very important issue for many reasons.
HCV-infected patients with advanced CKD have an increased
risk of all-cause death and liver-related diseases; and the
decline of kidney function is also accelerated.4 In addition,
HCV infection decreases patient and graft survival after kid-
ney transplantation.1,4 The reported prevalence of HCV
infection in patients with ESRD varies between 5% and
15%.2,3 DOPPS (Dialysis Outcomes and Practice Patterns
Study),2 which provided data on 49,762 dialyzed patients,
reported a mean prevalence of HCV infection of 9.5%, and
only 1% of HCV-infected patients received antiviral therapy.
Among 617 HCV-infected patients on a waiting list for renal
transplantation, only 3.7% received antiviral therapy.2 Com-
bined therapy of pegylated interferon-a  ribavirin was the
first demonstrably effective treatment for HCV infection, but
was poorly tolerated in ESRD.16 This explains the low rate of
anti-HCV therapy given to patients with CKD. However,
HCV therapy can reduce the progression of liver fibrosis and
extrahepatic manifestations in patients with CKD.17,18
Currently, DAAs are the gold-standard treatment for HCV
infection. DAAs result in a high SVR with very good safety in
the general population.9,19 Most studies using DAAs have
excluded patients with stage 4 to 5 CKD. Indeed, many DAAs
have kidney elimination,10 need potential dose adjustments,
and are associated with the risk of drug-to-drug interactions.
The few data available on patients with severe kidney disease
and treated with current regimens are often from small
sample sizes.20–24 Sofosbuvir-based therapies have dramati-
cally improved the prognosis of HCV infection. However,
sofosbuvir is metabolized into GS-331007, the active
form.10,23 The kidney is the major organ involved in elimi-
nating sofosbuvir and its metabolites. In patients with severe
renal impairment, the pharmacokinetics of sofosbuvir and
GS-331007 were 171% and 451% higher, respectively, than in
patients with normal renal function.23 There was no evidence
of clinically relevant consequences from sofosbuvir
toxicity.20–23 The HCV TARGET study reported on the safety
and efficacy of sofosbuvir-based therapies given to 1789 pa-
tients with various renal impairments.22 However, only 18
patients had an eGFR <30 ml/min per 1.73 m2, and only 5
patients were on hemodialysis. Another observational cohort
recently reported that sofosbuvir-based therapy was safe and
effective with a stability of kidney function under DAA
therapy.20 However, all patients included in this cohort20 only
had stages 1 to 3 CKD, and they were very different from
our patients with ESRD stage 4/5. In addition, in the study by
Sise et al.,20 7 patients had an increased creatinine
level associated with sofosbuvir-based therapy. No data are
available on the new combination of sofosbuvir þ
ledipasvir þ voxilaprevir in ESRD.24 Thus, questions remain
regarding the use of sofosbuvir-based therapies for cases of
severe renal failure and the consequences of metabolite
accumulation or toxicity in patients with ESRD. Another
study25 reported the efficacy of a sofosbuvir-free combination
210
L Alric et al.: Grazoprevir and elbasvir in HCV chronic kidney disease
of ombitasvir þ paritaprevir þ ritonavir þ dasabuvir therapy
in 20 patients with ESRD. Despite very low urinary elimina-
tion of this combination of DAAs, without sofosbuvir, the use
of ritonavir (a CYP3A inhibitor) or ribavirin in patients with
ESRD remains problematic.
The C-Surfer study15 was the first large, randomized,
placebo-controlled, phase 3 study to evaluate an all-oral
ribavirin-free regimen in patients infected with HCV geno-
type 1, and stage 4 or 5 advanced CKD. SVR12 was partic-
ularly high: 98.6% on a modified intention-to-treat basis. The
primary route of elimination of GZR þ EBR is via feces
compared with <1% via urine.10 Taking into account the
results of the C-Surfer study, in this specific population, the
French National Agency for Medicine and Health-Product
Safety granted ATUn for HCV genotype 1– or 4–infected
patients with CKD stage 4/5, whatever the profile or
comorbidities of the patients. Our cohort is a large national
study on real-life utilization of GZR þ EBR in HCV genotype
1 and, for the first time, genotype 4 infected patients with
advanced CKD, and accessibility to few alternative DAA
therapies. Our patients had many comorbid conditions. Pa-
tients with HCV genotype 4, HIV coinfection, or transplant
recipients were not included in C-Surfer study. Thus,
although our patients were more difficult to treat than those
included in the C-Surfer study, we observed an excellent
SVR12 rate of 96.7% compared with 94% in the C-Surfer
study. We encountered only 3 failures to GZR þ EBR therapy.
Both patients with a virologic breakthrough were infected by
HCV genotype 4 and resistance-associated substitutions were
found. Only 1 patient with HCV genotype 1b infection had a
relapse, and resistance-associated substitutions were not
identified. SVR12 was not influenced by HCV genotype, viral
load at baseline, cirrhosis, or hemodialysis. Interestingly, all
patients with an HCV genotype 1a infection had SVR12. Most
of our patients had undergone many concomitant therapies
before GZR þ EBR treatment. Interestingly, statins or proton
pump inhibitors were taken, respectively, by 21.1% and
45.6% of our patients. These drugs have been reported to
negatively influence the efficacy of DAAs,9 and most phase 2
or 3 studies on DAAs require that these drugs be stopped or
the patient excluded from the trial. In our real-life study, few
patients stopped their regular concomitant treatments. No
significant drug-to-drug interactions on safety or efficacy
were observed between GZR þ EBR and other therapies.
Among our 93 patients treated with GZR þ EBR, 3 died
prematurely. The deaths were not related to GZR þ EBR
therapy. Because the deaths occurred before the end of
GZR þ EBR therapy, it was impossible to assess the virologic
response of these patients. Thus, they were excluded from the
efficacy analysis. The safety profiles were good, and there were
only 3 treatment discontinuations. These 3 patients obtained
a SVR12. These very good safety and efficacy results may have
been biased because physicians followed each ESRD patient
very carefully, with additional oversight from the French
National Agency for Medicine and Health-Product Safety.
Another limitation of our study is related to the selection of
Kidney International (2018) 94, 206–213
L Alric et al.: Grazoprevir and elbasvir in HCV chronic kidney disease
patients. To limit inclusion bias, all consecutive patients
receiving GZR þ EBR during the period of ATUn were
included. The main strength of our study is that it provides a
comprehensive evaluation of real-life antiviral treatment and
the different profiles of ESRD with HCV infection.
HCV therapies with DAAs are being constantly improved.
Very recently, a new combination of glecaprevir þ pibren-
tasvir has shown pan-genotypic HCV activity with negligible
renal excretion.26 Of 104 patients with ESRD, glecaprevir þ
pibrentasvir, 3 pills administered orally once daily for 12
weeks, resulted in 98% of cases achieving a SVR12. Safety was
good, although new emerging adverse events, such as pru-
ritus in 20% of patients, have been reported compared with
3.2% in our study. These very interesting results in a single-
arm, open-label, uncontrolled trial are very similar to those
of patients given GZR þ EBR for a HCV genotype 1 or 4
infection. The new combination of glecaprevir þ pibrentasvir
is a promising option for ESRD patients with a HCV geno-
type 2 or 3 infection that is not covered by GZR þ EBR.26
However, the results from this phase 3 study need to be
confirmed in real life. In our network, 4 centers had the
ability to include ESRD patients in the international trial
using glecaprevir þ pibrentasvir. Among our 97 patients who
had obtained an ATUn, 4 did not receive GZR þ EBR therapy
because they had the opportunity to receive treatment in the
international trial with glecaprevir þ pibrentasvir. For the
remaining 93 patients treated with GZR þ EBR, >50% did
not meet the eligibility criteria to be included in the
glecaprevir þ pibrentasvir clinical trial because of comorbid
conditions or concomitant medications. Real-world clinical
practice is required to gather efficacy and safety data. Real-life
studies can identify any emerging safety and efficacy signals
not seen in phase 2 or 3 trials because the latter are per-
formed in carefully selected patients who are followed by
extremely competent physicians doing clinical research.
Postmarketing phase 4 studies on efficacy and safety become
outdated when completed in the context of rapidly advancing
HCV therapy. Thus, an observational real-life cohort can
expand our knowledge more rapidly. This point is particu-
larly important for specific populations that are underrep-
resented in clinical trials, such as patients with ESRD. The
ideal timing for HCV therapy initiation in CKD patients,
before or after kidney transplantation, is still debated.27,28
Finally, when discussing the appropriate time for antiviral
therapy in kidney transplant candidates, we should consider
that curing HCV can delay the time to transplantation due to
the potential loss of an opportunity to benefit from a kidney
from a HCV-viremic donor.
In conclusion, our cohort provides supportive evidence of
a good benefit-risk ratio to treat ESRD patients with HCV
genotype 1 or 4 infection and comorbid conditions with
GZR þ EBR in real life. This is an important issue for patients
with CKD around the world and will help physicians who
care for these patients. Of the different DAAs, GZR þ EBR,
and, in the near future, glecaprevir þ pibrentasvir are well
adapted to treat patients with ESRD and HCV infection.
Kidney International (2018) 94, 206–213
clinical trial
PATIENTS AND METHODS
Patients and study design
The French National Agency for Medicine and Health-Product
Safety granted an ATUn for GZR þ EBR for patients with HCV
and advanced CKD, defined as stage 4 (eGFR: 15–29 ml/min per 1.73
m2) or stage 5 (eGFR <15 ml/min per 1.73 m2), and including
patients on hemodialysis. Patients who had HCV genotype 1 or 4
infection could have been pretreated or not with pegylated interferon
and ribavirin. Twenty-eight French centers consecutively enrolled all
adult patients with advanced CKD and chronic HCV infection and
who had obtained an ATUn. Clinical and biological data for CKD
and HCV infections were collected when GZR þ EBR treatment had
been received. All events related to CKD or treatment of HCV and
outcomes were recorded during the follow-up period. Liver fibrosis
was evaluated by a liver biopsy or by measuring liver stiffness ac-
cording to the instructions from Fibroscan (Echosens, France).
The cohort (Figure 1) started treatment in July 2015, and the last
patient was included in December 2016. We included all 97
consecutive CKD patients with HCV infection who had obtained an
ATUn. Among the 97 patients enrolled in the study, 4 were excluded
because they were included in another trial and had not received
GZR þ EBR therapy. All 93 remaining patients received GZR 100
mg/mg þ EBR 50 mg/mg daily for 12, 16, or 24 weeks, following
ATUn allocation according to international labeled guidelines. The
GZR þ EBR regimen was associated with low-dose ribavirin (#600
mg/day) given to 3 patients.
The Toulouse University Hospital (CHU Toulouse) review board
approved the study. All patients provided informed consent. In-
vestigations were performed after approval from the Ethics Com-
mittee, according to the Jardé law. The study was conducted
according to the principles expressed in the Declaration of Helsinki.
The study is registered at clinical trials.gov (NCT03145623).
Efficacy
The primary efficacy endpoint of the trial was SVR12. Quantification
of HCV RNA level was performed at baseline, again during antiviral
therapy, and at 12 weeks after completing treatment using real-time
polymerase chain reaction (COBAS Amplicor/TaqMan, Roche Di-
agnostics, Basel, Switzerland) with a lower detection limit of 15 IU/ml.
The response to antiviral therapy was summarized as follows: end of
treatment virologic response (i.e., negative for HCV RNA at the end
of treatment); virologic breakthrough (i.e., detectable HCV RNA at
any time during antiviral therapy despite a significant initial viral
decline) SVR12, (i.e., negative for HCV RNA at 12 weeks after
the end of treatment); relapse: patients who achieved undetectable
HCV RNA levels at the end of antiviral therapy and then subse-
quently relapsed with positive HCV RNA after treatment was
completed.
Safety and adverse events
All patients were seen by their physician at baseline, every 2 weeks
during the first 2 months, every 4 weeks during the next phase of
therapy, and then every 4 and 12 weeks after completing treatment.
Adverse events were graded by investigators according to a modified
WHO grading system. Non–life-threatening adverse events and he-
matological disorders were managed at the discretion of the
physician.
Statistical analysis
In order to describe an expected SVR12 equal to 94% with a 95%
confidence interval width of 10%, 95 subjects were required. Before
211
clinical trial
analysis, verification of missing, aberrant, or inconsistent data was
conducted. Analyses were performed on the locked database.
Descriptive statistics included mean  SD and range for continuous
variables and the number of observations with frequency (%) for
categorical variables. The primary endpoint (SVR12) was described
using the number of nonmissing observations and frequency (%)
together with the exact 95% confidence interval. Secondary end-
points for efficacy (others endpoints for response) and safety
(adverse events) were described using the number of nonmissing
observations and frequencies. Statistical analyses were performed
using STATA software 14.1 (StataCorp LP, College Station, TX [www.
stata.com]).
DISCLOSURE
LA is a consultant/speaker/investigator for AbbVie, Bristol-Myers
Squibb, Gilead, Janssen, and Merck. IO-H is a consultant, speaker, and
investigator for Bayer, Gilead, Daichi Sankyo, AbbVie, Intercept,
Boehringer Ingelheim, and Merck. MG is a speaker for Novonordisk,
AbbVie, Pfizer, and Intercept and an investigator for Intercept and
Inventiva. AV-P is a speaker for Gilead, Bristol-Myers Squibb, Merck,
AbbVie, and Janssen. BB-C is a speaker for AbbVie, Gilead, and Merck.
VL-R is a consultant, speaker, and investigator for AbbVie, Bristol-
Myers Squibb, Gilead, Janssen, and Merck. MB is an investigator,
speaker, and/or consultant for AbbVie, Boehringer Ingelheim, Bristol-
Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen Pharma-
ceuticals, Merck Sharp & Dohme, Roche, and Vertex. VdL is consultant,
speaker, and investigator for AbbVie, Bristol-Myers Squibb, Gilead,
Janssen, and Merck. IF-H is an investigator, consultant, and speaker for
Gilead, AbbVie, and Merck. EN-K is a consultant, speaker, and inves-
tigator for Bristol-Myers Squibb, AbbVie, Merck, Janssen, and Bayer.
VC is a consultant, speaker, and investigator for AbbVie, Bristol-Myers
Squibb, Gilead, Janssen, and Merck. AM is a consultant, speaker, and
investigator for Gilead, AbbVie, and Merck. VL is a speaker and
investigator for and has received a grant from Merck Sharp & Dohme,
Janssen, Gilead, Bristol-Myers Squibb, and Bayer. DS is an investigator,
speaker, and consultant for Medimmune, Roche, Servier, Gilead,
AstraZeneca, and GlaxoSmithKline. DT is a current employee of Merck.
SP is an investigator, consultant, and lecturer for Bristol-Myers Squibb,
Boehringer Ingelheim, Janssen, Gilead, Merck Sharp and Dohme,
Novartis, and AbbVie. NK is an investigator, speaker, and consultant
for AbbVie, Amgen, Astellas, Chiesi, Fresenius, Gilead, Merck Sharp &
Dohme, Neovii, Novartis, Roche, Sanofi, and Shire. The other authors
declared no competing interests.
ACKNOWLEDGMENTS
The study was promoted by Toulouse University Hospital France and
funded by a grant from Merck Sharp and Dohme. We thank Marie-
Elise Llau, Audrey Tomasik, Chloe Pomes, Virginie Sicart-Payssan,
Elodie Bedel, Rémy Morello, Caroline Bienvenu, and Amir Guidoun for
their technical assistance and the HEPATHER network: Hélène
Fontaine (Paris), Jean-Pierre Toudic (Caen), Faustine Wartel
(Valenciennes), Frédérique Prévost (Poitiers), Cédric Colin (Lyon),
Hatem Salloum (Meaux), Delphine Crampon (Clermont Ferrand),
Marie-Sophie Gavard (Le Havre), Jean-Baptiste Nousbaum (Brest),
Véronique Grando-Lemaire (Paris), Bruno Roche (Paris), Mariagrazia
Tateo (Paris), Christiane Stern (Paris), Karine Lacombe (Paris),
Dominique Batisse (Paris), Filomena Conti (Paris), Alina Pascale (Paris),
Si Nafa Si Ahmed (Orléans), Louis D’Alteroche (Tours), Jean-Pierre
Chabert (Reims), Pierre-Henri Bernard (Bordeaux), Moana Gelu-
Simeon (Pointe-à-Pitre), Ellada Anastasiadi-Ayvazyan (Nice),
Magdalena Meszaros (Narbonne), Armand Abergel (Clermont
Ferrand), Karim Aziz (Saint-Brieuc), Cathia Joseph-Reinette
(Argenteuil), Franck Audemar (Bayonne), Dominique Larrey
(Montpellier), Olivier Favre (La Réunion), Jean Pierre Bronowicki
212
L Alric et al.: Grazoprevir and elbasvir in HCV chronic kidney disease
(Nancy), Odile Goria (Rouen), Karine Clabault (Le Havre), Stephanie
Pennont (Fort de France), and Yvon Calmus (Paris).
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