International Urology and Nephrology

https://doi.org/10.1007/s11255-020-02656-y

NEPHROLOGY - ORIGINAL PAPER

The effect of anemia on the efficacy and safety of treating chronic

hepatitis C infection with direct‑acting antivirals in patients
with chronic kidney disease
Ahmed Yahia Elmowafy1 · Mohamed Hamed Abbas1 · Ahmed Abdelfattah Denewar1 · Mohamed Elsayed Mashaly1 ·
Gamal Shiha2 · Salwa Mahmoud El Wasif1 · Lionel Rostaing3,4 · Mohamed Adel Bakr1

Received: 28 April 2020 / Accepted: 14 September 2020

© Springer Nature B.V. 2020

Abstract
Background/Aim Chronic hepatitis-C infection is a great health burden in Egypt. The effect of anemia on the efficacy and
safety of direct-acting anti-viral (DAA) therapies for those with chronic-kidney disease (CKD) has not been evaluated.
Patients/Methods This single-center retrospective study included 235 renal patients: i.e., 70-CKD patients not on hemo-
dialysis (42 with anemia, 28 without); 40 hemodialysis patients (16 anemic; 24 non-anemic), and 125 kidney-transplant
(KTx) recipients (40 anemic; 85 non-anemic). Anemia was defined by a hemoglobin level < 10.5 g/dL. Hemodialysis
patients received ritonavir-boosted paritaprevir/ombitasvir. KTx patients received sofosbuvir/daclatasvir. CKD patients
with eGFR > 30 mL/min/1.73 ­m2 received sofosbuvir/daclatasvir. Those with eGFR < 30 mL/min/1.73 m ­ 2 received ritonavir-
boosted paritaprevir/ombitasvir; 64 non-anemic patients also received ribavirin therapy.
Results Mean age of CKDs was 49.1 years, 43.2 years for HDs, and 45.2 years for KTx patients. Most were male; body-
mass index was ~ 23.8. Anemia did not affect the efficacy of DAAs in hemodialysis, CKD, or KTx patients. Most patients
achieved a rapid virologic response (RVR), and a 12- and 24-week sustained viral response. Worsening of anemia among
the non-anemic group was mostly related to ribavirin therapy in hemodialysis patients (11/16 patients). Acute kidney injury
in CKDs occurred more frequently within the anemic group (59.5%) compared to the non-anemic group (32.1%). For KTx,
graft impairment was more common among the anemic group (7/40) compared to the non-anemic group (2/85).
Conclusion Hemoglobin levels of < 10.5 g/dL prior to DAA treatment did not affect the virological response in renal patients
but was associated with increased serum creatinine among KTx and those with CKD.

Keywords Chronic kidney disease · HCV infection · Sofosbuvir · Daclatasvir · Anemia · Kidney transplantation ·
Hemodialysis · DAA therapy

Introduction

Hepatitis C virus (HCV) infection is strongly associated with

Lionel Rostaing and Mohamed Adel Bakr contributed equally to
this manuscript. chronic kidney disease (CKD), an independent risk factor
for developing CKD. HCV significantly increases morbidity
* Lionel Rostaing and mortality in patients with CKD [1]. In addition, HCV
lrostaing@chu‑grenoble.fr
may accelerate the progressive loss of kidney function and
1
Urology and Nephrology Center, Mansoura University, is associated with a more than two-fold risk of developing
Mansoura, Egypt end-stage renal disease (ESRD) [2]. Moreover, chronic HCV
2
Egyptian Liver Research Institute and Hospital, Mansoura, infection increases the mortality rates of dialysis patients [3].
Egypt HCV sero-positivity is also associated with a higher risk of
3
Université Grenoble Alpes, Grenoble, France mortality in kidney-transplant recipients (KTx), [4].
4 Treating patients with HCV and severely impaired renal
Service de Néphrologie, Hémodialyse, Aphérèses et
Transplantation Rénale, CHU Grenoble-Alpes, CS 10217, function can be challenging. There is a risk of increased
38043 Grenoble Cedex 09, France exposure to drugs that undergo significant renal elimination.

13
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Patients that require dialysis can be additionally affected by
drug exposure and clearance [5].
Sofosbuvir, the foundation of many current direct-act-
ing antivirals (DAA), is not recommended for patients that
have CKD stage 4 or those with ESRD due to the ~ 20-fold
increased exposure to the sofosbuvir metabolite, GS-331007,
which is renally eliminated [6]. Instead, the American Asso-
ciation for the Study of Liver Disease (AASLD)/Infectious
Diseases Society of America (IDSA) currently recommends
12 weeks of treatment with elbasvir/grazoprevir (HCV geno-
type (GT) 1a, GT1b or GT4) or 8–16-week treatment with
glecaprevir/pibrentasvir (GT1–6) [7].
The combination of three DAAs: i.e., ombitasvir (an
NS5A inhibitor), ritonavir-boosted paritaprevir (an NS3/4A
serine protease inhibitor), and dasabuvir (an NS5B non-
nucleoside polymerase inhibitor), administered with and
without ribavirin, is another treatment option for patients
with HCV genotype 1 (GT1) or GT4 infection, including
those with mild, moderate, or severe renal impairment and
those on dialysis [8].
Patients with ESRD can develop progressive anemia due
to low endogenous erythropoietin (EPO) production by the
kidneys. Fortunately, therapy with exogenous EPO can pre-
vent/treat debilitating anemia, aiming at hemoglobin (Hb)
levels between 10 and 11.5 g/dL. Those with low (< 10 g/
dL) and high hemoglobin levels (> 11.5 g/dL) are associated
with increased cardiovascular events and death [9].
Anemia is also a commonly observed complication in
patients treated for HCV, especially with a ribavirin regi-
men: drug discontinuation or dose modification is then rec-
ommended [10].
The aim of our single-center study was to assess whether
the management of anemia in CKD patients affected the
efficacy and safety of the DAAs used to treat chronic HCV
infections.
Patients and methods
Study design and setting
This single-center, retrospective, cohort study was con-
ducted in the Urology and Nephrology Center, Mansoura
University, Egypt.
Participants and eligibility criteria
All the HCV RNA-positive hemodialysis and HCV RNA-
positive kidney transplant patients in our center were
included in our study: they all received direct-acting anti-
viral between 2016 to 2019. In addition, HCV RNA(+)
CKD patients followed-up at our outpatient clinic from
2016 to 2019 and who received DAAs were also included.
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International Urology and Nephrology
All available patients were included to avoid selection
bias. The sample size was calculated using prevalence of
anemia among CKD patients reported by Ryu et al. [11]
using G. power program with α. Error = 0.05 and power
80% then the calculated sample size is approximately 235
patients (see Tables 1, 2, 3).
• Group I: 70 patients with CKD (not yet on hemodialy-
sis).
• Group II: 40 hemodialysis (HD) patients.
• Group III: 125 KTx patients.
All patients received direct-acting anti-virals (DAAs)
with or without ribavirin to treat chronic HCV infection.
Each group was subdivided into two subgroups accord-
ing to hemoglobin level prior to starting anti-HCV treat-
ment. Even though anemia related to CKD is diagnosed
when hemoglobin level is < 11 g/dL because erythropoietin
therapy is only reimbursed in Egypt if Hb level is < 10.5 g/
dL we decided (for our study) to choose a hemoglobin level
of < 10.5 g/dL as the cut-off value for anemia. The anemic
groups had Hb levels of < 10.5 g/dL and the non-anemic
groups had Hb levels ≥ 10.5 g/dL. Thus, the prevalence of
anemia was 60%, 40%, and 32% in CKD, HD, and KTx
patients, respectively.
Before treatment
All patients underwent a clinical examination, laboratory
investigations [serum creatinine, estimated glomerular-filtra-
tion rate (eGFR) according to the MDRD formula, hepatic
transaminase levels, i.e., aspartate (AST) and alanine (ALT)
aminotransferases, bilirubin, albuminemia, total cholesterol,
prothrombin time, complete blood counts, immunosuppres-
sive-drug trough levels for KTx patients, and HCV RNA
viral load] and radiological assessment (a liver ultrasound
and a fibroscan). All patient’s maintenance medications were
revised for drug interactions with DAAs using the Liverpool
HEP drug checker website (https:​ //www.hep-drugin​ terac​ tion​
s.org/). Diagnosis of the severity of cirrhosis was based on
the Child–Pugh score, which depends on the presence of
hepatic encephalopathy, ascites, the level of bilirubin and
albumin, and prothrombin time [12]. The degree of liver
fibrosis was diagnosed based on the METAVIR score, using
fibroscan [13].
During treatment
All patients were followed up monthly at the out-patient
clinic. The follow-up included a clinical examination and
the previously listed laboratory investigations.
International Urology and Nephrology

Table 1  Baseline characteristics Anemic group (n = 42) Non-anemic group (n = 28) p value
of patients with chronic kidney
disease Age (years) 49.6 ± 11.1 49.2 ± 14.3 0.89
Gender (male) 26 (61.9%) 21 (75%) 0.37
BMI (kg/m2) 26.3 ± 3.2 25.43 ± 2.8 0.55
Hypertension [yes; n (%)] 22 (52.4%) 16 (57.1%) 0.88
Diabetes [yes; n (%)] 13 (30.9%) 9 (32.1%) 0.87
Hepatitis B virus co-infection 0 1 (3.57%) 0.4
Previous treatment with α-IFN 7 (16.67%) 3 (10.71%) 0.72
Liver ultrasound findings 0.633
Normal 21 (50%) 16 (57.14%)
Enlarged 18 (42.85%) 9 (32.14%)
Cirrhotic 3 (7.14%) 3 (10.71%)
Fibroscan: F0 11 (26.2%) 4 (14.28%) 0.44
F1 15 (35.7%) 13 (46.42%)
F2 13 (30.95%) 7 (25%)
F3 3 (12.6%) 4 (14.28%)
HCV genotype (4 vs .1) 38 (90.5%) vs. 4 (9.5%) 26 (92.8%) vs. 2 (7.2%) 0.3
HCV RNA (IU/L) 1,685,347 ± 753,282 1,587,665 ± 698,743 0.6
Serum creatinine (mg/dL) 4.07 ± 1.6 3.4 ± 1.6 0.125
eGFR (mL/min) 26.7 ± 11.8 33.4 ± 16.2 0.04
Alanine aminotransferase (IU/L) 41.8 ± 19.2 49.5 ± 19.4 0.108
Aspartate aminotransferase (IU/L) 41.1 ± 18 35.1 ± 16.2 0.155
Serum bilirubin (mg/dL) 0.5 ± 0.2 0.48 ± 0.1 0.862
Hemoglobin (g/dL) 9.1 ± 0.78 11.25 ± 1.16 0.0001
Platelets (/mm3) 210.2 ± 84.7 249.6 ± 80.2 0.58

eGFR estimated glomerular filtration rate according to MDRD formula; BMI body mass index, IFN inter-
feron; F fibrosis

Treatment details Outcomes

Patients with CKD and an eGFR > 30 mL/min/1.73 ­m2
received a 3-month course of sofosbuvir (400 mg daily)
and daclatasvir (60 mg daily). CKD patients with an
eGFR < 30 mL/min/1.73 ­m 2 received daily two tablets
of ritonavir-boosted paritaprevir and ombitasvir (OMV/
PTV/RTV: 12.5 mg/75 mg/50 mg) for 3 months. Hemo-
dialysis patients received a 3-month course of ritonavir-
boosted paritaprevir and ombitasvir (two tablets daily of
OMV/PTV/RTV: 12.5 mg/75 mg/50 mg). KTx recipients
received a 6-month course of sofosbuvir (400 mg daily) and
daclatasvir (60 mg daily). In addition, non-anemic CKD and
HD patients (n = 44) and 20 non-anemic KTx received riba-
virin therapy. Ribavirin dose for CKDs was 200 mg/day;
hemodialysis patients received 200 mg/48 h; KTx recipients
received 900–1200 mg/day. A rapid virological response was
defined as viral clearance within 3 weeks of initiating treat-
ment. A sustained virological response (SVR) was defined
as viral clearance at 12 weeks after completing therapy. A
relapse was defined as the reappearance of viral load after
an initial recovery after treatment [14]. The follow-up period
was 12 months after completing treatment.
They included (1) rapid virological response (RVR), i.e.,
viral clearance within 3 weeks of treatment initiation), (2)
12- and 24-week sustained virological response (SVR), i.e.,
persisting viral clearance at 12 and 24 weeks after com-
pletion of DAA therapy, (3) ALT, AST, hemoglobin levels
during and after DAA therapy, (4) hepatic decompensation
during and after DAA therapy, (5) serum creatinine, eGFR,
and proteinuria during and after DAA therapy for CKD and
kidney-transplant patients, and (6) tacrolimus trough levels
during and after DAA therapy for kidney-transplant patients.
Statistical analyses
All data were tabulated using an SPSS sheet. Descriptive
measures were used for demographic and pre-treatment data.
Repeat-measure ANOVA tests for parametric data and the
Friedman test for non-parametric data were used to compare
the laboratory findings before, during, and after treatment.
The chi-square test was used to calculate the relative risk
factors and the log-rank test was used to determine kidney
survival among those with and without anemia, and with

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 International Urology and Nephrology

Table 2  Baseline characteristics Anemic patients (n = 24) Non-anemia patients (n = 16) p value
of patients receiving
hemodialysis Age (years) 50.2 ± 13.9 45.3 ± 12.9 0.34
Gender (male) 11 (68.7%) 16 (66.6%) 0.5
BMI (kg/m2) 22.3 ± 3.2 21.43 ± 2.8 0.55
Hypertension 8 6 0.7
Diabetes 4 3 0.3
Hepatitis B virus co-infection 1 1 1
Previous treatment with α-IFN 2 0 0.5
Liver ultrasound findings 0.95
Normal 15 10
Enlarged 8 6
Cirrhotic 1 0
Fibroscan 0.9
F0 10 8
F1 10 7
F2 3 1
F3 1 0
HCV genotype (4 vs .1) 22 (91.7%) vs. 2 (8.3%) 15 (93.75%) vs. 1 (6.25%) 0.3
HCV RNA (IU/L) 987,632 ± 423,877 976,667 ± 445,787 0.8
Alanine aminotransferase (IU/L) 57.3 ± 23.9 36.1 ± 15.7 0.005
Aspartate aminotransferase (IU/L) 56.5 ± 21.4 43.4 ± 13.4 0.07
Hemoglobin (g/dL) 9.3 ± 0.36 11.3 ± 0.6 0.0001

BMI body mass index, IFN interferon; F fibrosis

CKD. A result was considered statistically significant if the
p value was ≤ 0.05.
Results
Baseline characteristics
Of our 235 renal patients, only 22 had previously received
alpha-interferon (αIFN) (14 patients had a relapse after a
primary response to αIFN and 8 did not tolerate α-IFN due
to severe anemia, leucopenia, or recurrent infection). Seven
patients had been co-infected with hepatitis B virus; how-
ever, all patients were cleared of the virus prior to HCV
treatment and were maintained life-long on Entecavir
(0.5 mg/day). In addition, ten patients had cirrhosis; of
which five were anemic.
Drug efficacy
All patients, with or without anemia, achieved an RVR (viral
clearance within 3 weeks of treatment initiation).
For CKD patients, the 12- and 24-week SVRs were 94.3%
and 77.1%, respectively, with no difference between anemic
and non-anemic groups; there was no statistical difference
across the two groups. Overall, there were 16 relapses, i.e.,
22.8%. Four of the 16 patients (25%) had a relapse within
12 weeks after completing DAA treatment and 12 patients
had a relapse beyond that time (75%). Eleven relapsers then
received a 3-month ritonavir-boosted regimen and five cases
received a 3-month sofosbuvir-based regimen. Five cases
of relapse in the non-anemia group also received ribavi-
rin, which was suspended after 1 month due to a drop in
hemoglobin. The possibility that re-infection was related to
hemodialysis-related nosocomial transmission occurred in
three patients from group I, i.e., they had poor renal function
during the first DAA treatment, and subsequently lost renal
function and had to begin hemodialysis.
There was no statistical difference between the groups
regarding hepatic transaminases either before treatment,
during, or after completing DAA treatment. However, ALT
levels significantly improved after treatment was completed:
i.e., ALT levels before, during, and after in the non-anemic
group were 49.5 ± 19.4, 41 ± 0.1, and 30 ± 16, respectively
(p = 0.018); whereas ALT levels before, during, and after
treatment in the anemic group were 41.8 ± 19.2, 35.1 ± 16.2,
and 35.1 ± 16.2, respectively (p = 0.007).
For hemodialysis patients, the 12- and 24-SVRs were
100% and 95%, respectively, with one relapse in each group.
Both cases received a 3-month ritonavir-boosted regimen.
One case also received ribavirin (200 mg every other day)
for 1 month, which was then suspended due to a drop in
hemoglobin (10.8 g/dL before treatment to 8.8 g/dL after
treatment). Both cases had a relapse by 3 months after

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International Urology and Nephrology

Table 3  Baseline characteristics Anemic patients (n = 40) Non-anemic patients (n = 85) p value
of kidney-transplant recipients
Age (years) 47.12 ± 13.9 43.25 ± 11.7 0.1
Gender (male) 23 (57.5%) 68 (80%) 0.008
BMI (kg/m2) 21.9 ± 2.9 21.7 ± 2.6 0.7
Hypertension [yes (%)] 33 (82.5%) 71 (83.5%) 0.8
Diabetes [yes (%)] 7 (17.5%) 12 (14.5%) 0.6
Kidney-transplant duration (years) 13.6 ± 6.7 14.2 ± 6.9 0.7
Hepatitis B virus co-infection 2 (5%) 2 (2.3%) 0.6
Previous treatment with α-IFN 4 (10%) 6 (7.05%) 0.5
Liver ultrasound findings 0.9
Normal 30 64
Enlarged 9 19
Cirrhotic 1 2
Fibroscan 0.8
F0 22 46
F1 11 28
F2 5 8
F3 2 3
HCV genotype (4 vs .1) 36 (90.0%) vs. 4 (10%) 77 (90.6%) vs. 8 (9.4%) 0.3
HCV RNA (IU/L) 887,369 ± 36,789 989,798 ± 45,876 0.54
Baseline serum creatinine (mg/dL) 1.7 ± 0.7 1.3 ± 0.6 0.001
Baseline eGFR (mL/min) 56.4 ± 12.3 63.9 ± 15.6 0.008
Alanine aminotransferase (IU/L) 50.3 ± 20.1 48.21 ± 16.3 0.45
Aspartate aminotransferase (IU/L) 48.3 ± 18.6 46.78 ± 13.7 0.6
Hemoglobin (g/dl) mean ± SD 10.1 ± 0.24 12.2 ± 1.6 0.0001
Trough levels:
Tacrolimus (ng/mL) 4.4 ± 1.3 4.3 ± 1.1 0.65
Cyclosporine (ng/mL) 95.3 ± 25.3 90.1 ± 24.4 0.27

eGFR estimated glomerular filtration rate according to MDRD formula; BMI body mass index; IFN inter-
feron; F fibrosis

completing treatment and had an initial response. There
was no statistical difference between the two groups regard-
ing baseline AST, bilirubin, or albumin. However, baseline
ALT was significantly higher among the anemic group, i.e.,
57.3 ± 23.9 IU/L compared to the non-anemic group, i.e.,
36.1 ± 15.7 IU/L (p = 0.005). There was significant improve-
ment in ALT in both groups: the anemic group had ALT
levels before, at 1 month, and at 3 months after complet-
ing treatment of 57.3 ± 23.9, 49.4 ± 22.3, 39.9 ± 19.8 IU/L,
respectively (p = 0.009). The non-anemic group had
ALT before, at 1 month, and at 3 months after complet-
ing treatment of 36.1 ± 15.7, 29.6 ± 13.3, 24.4 ± 11.9 IU/L
(p = 0.001).
All KTRs achieved an RVR and an SVR except for
one patient (in the anemic group). Liver-enzyme levels
were significantly improved in both groups: in the anemic
group, ALT levels before, during, and after treatment were
50.3 ± 20.1, 38.2 ± 18.3, 35.7 ± 13.2 IU/L; p = 0.001; in non-
anemic group, ALT levels before, during, and after treatment
were 48.21 ± 19.8, 38.6 ± 17.9, 34.9 ± 12.9 IU/L; p = 0.001.
One patient had a relapse after receiving a 6-month sofosbu-
vir-based regimen; relapse occurred 3 months after complet-
ing treatment. He was not re-treated because he died from a
cardiovascular event.
Drug tolerability
Overall, the drop in hemoglobin level was greater in the
non-anemic group than the anemic group across the three
types of patients. In addition, the drop in hemoglobin levels
between, before and at 1 month after treatment was greater
in the non-anemic group compared to the anemic group (i.e.,
CKD patients: 3.15 ± 0.1 vs. 0.4 ± 0.02 g/dL, respectively;
p = 0.0001; hemodialysis patients: 2.15 ± 0.2 vs. 0.2 ± 0.01 g/
dL; p = 0.0001; KTx: 3.2 ± 0.3 vs. 0.1 ± 0.02 g/dL; p-value:
0.0001). CKD patients without anemia had hemoglobin lev-
els before and at 1 month after starting DAA treatment of
11.52 ± 1.16, and 8.1 ± 1.06 g/dL, respectively (p = 0.0001).
Hemodialysis patients without anemia had hemoglobin lev-
els before and at 1 month after starting DAA treatment of

13

11.35 ± 0.63 and 9.2 ± 0.9 g/dL, respectively (p = 0.001.
However, hemoglobin levels improved significantly in the
non-anemic group after the 2nd month of treatment, mostly
due to stopping ribavirin in 51 of 64 patients (79.7%). Hemo-
globin levels at 1 month after starting and at 1 month after
stopping ribavirin were as follows: CKD patients: 8.1 ± 1.06
vs. 8.88 ± 0.63 g/dL (p = 0.004); hemodialysis patients had
9.2 ± 0.9 vs.10.5 ± 0.44 g/dL (p = 0.0001); and KTx had
9.8 ± 0.9 vs.11.5 ± 1.23 g/dL, respectively (p = 0.0001).
Twenty KTx patients without anemia that received riba-
virin had a significant drop in hemoglobin (11.8 ± 0.8 g/
dL at baseline vs. 8.06 ± 0.9 g/dL at 4 weeks after starting
treatment; p = 0.001). As a consequence, we greatly reduced
ribavirin dose, i.e., from 900 mg/day at the start of therapy to
200 mg/day at 1 month after initiating treatment. This ena-
bled hemoglobin to increase to 10.4 ± 0.86 g/dL by 1 month
later, i.e., during the 2nd month of DAA therapy.
An increase in serum creatinine among CKD, and KTx
patients was a major side effect. Regarding CKD patients,
baseline eGFR was less in those with anemia compared to
those without anemia (26.7 ± 11.8 vs. 33.4 ± 16.2 mL/min;
p = 0.04).
CKD patients had a deterioration in kidney func-
tion within 1 month of starting DAAs; this was observed
in 59.5% of anemic patients vs. 32.15% of non-anemic
patients (p = 0.024). Thus, in the anemic group, eGFR was
26.7 ± 11.8 mL/min at baseline vs. 21.28 ± 13 mL/min at
1 month later (p = 0.014); in the non-anemic group, eGFR at
baseline was 33.4 ± 16.2 vs. 29.2 ± 17.2 mL/min at 1 month
later (p = 0.33). More of the anemic group (38.1%) needed
hemodialysis, i.e., 16 (3 transient, 13 definitive) vs. 4 cases
(14.3%; p = 0.03) in the non-anemic group (3 transient, 1
definitive). Figure 1 shows Kaplan–Meyer kidney-survival
analysis among patients with CKD and with or without ane-
mia (Tables 4, 5, 6).
Regarding KTx, graft impairment during treatment
occurred more frequently amongst the anemic group,
100
80
Kidney Survival (%)
60
40
20
Duraon (months)
0
0 2 4 6 8 10 12 14 16
Anemia group No-anemia group
Fig. 1  Kaplan–Meier curve for kidney function survival amongst
patients with chronic kidney disease, and with or without anemia
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International Urology and Nephrology
i.e., 7 of 40 KTx (17.5%) compared to 2 of 85 KTx
(2.35%) in the non-anemic group (p = 0.004). Baseline
eGFR was significantly lower in the anemic group vs. the
non-anemic group (56.4 ± 12.3 mL/min vs. 63.9 ± 15.6;
p = 0.008). Graft biopsies were performed in the nine
patients that had deteriorating allograft function during
DAA therapy. In the anemic group, three (7.5%) of the
40 KTx were diagnosed with acute rejection: three (7.5%)
biopsies revealed acute tubular injury (ATI) with nega-
tive C4d staining and no vasculitis, whereas, one patient’s
(2.5%) biopsy revealed chronic transplant glomerulopa-
thy. One (1.2%) of the 85 KTx in the non-anemic group
experienced an acute rejection and one had ATI. Table 7
illustrates the details of the nine patients that experienced
impaired graft function during DAA therapy.
Tacrolimus trough level at the time of acute-rejection epi-
sodes was 4.3 ± 1.6 ng/mL and cyclosporine trough level was
94.4 ± 22.8 ng/mL. Acute-rejection episodes were treated
with pulses of methylprednisolone (10 mg/kg for 5 days):
responses varied from partial recovery (3 KTx) to complete
recovery (1 KTx). The four cases of ATI responded well to
good hydration and to lowering the tacrolimus trough-level
to ~ 4 ng/mL. The case of chronic rejection was managed by
increasing basal immunosuppression. We also observed that
a sofosbuvir-based regimen did not affect immunosuppres-
sive-drug trough levels (Table 7).
In a univariate analysis we analyzed the risk factors for
developing a rise in serum creatinine during DAA therapy
amongst patients with CKD or KTx patients (see Table 8).
Only anemia was statistically associated as a risk factor (RR:
7.4, p value: 0.01).
Of the 235 patients, 14 (6%) (of which 10 already had
cirrhosis) presented within 3 months after DAA therapy
with hepatic decompensation (12 patients with anemia and 2
patients without anemia; p = 0.0016). Most cases (12 cases)
occurred amongst those with CKD. Hepatic decompensation
was diagnosed clinically by the development of ascites and
lower-limb edema associated with a rise in liver enzymes
and a decrease in serum-albumin levels. Hepatic decompen-
sation was associated with a HCV RNA relapse in only three
cases; two of these patients died.
Discussion
To the best of our knowledge, this is the first study to evalu-
ate the effect of CKD -related anemia on the efficacy and
safety of DAAs in a large cohort of HCV-positive CKD
18 Egyptian patients. Our results show that (1) anemia did not
affect the response to DAAs; (2) the addition of ribavirin
therapy for non-anemic CKD patients caused a decline in
hemoglobin levels; and (3) that DAA-treated anemic CKD
International Urology and Nephrology

Table 4  Efficacy and adverse events among patients with chronic kidney disease
Anemic patients Non-anemia (n = 28) p value
(n = 42)

DAA treatment
Sofosbuvir/Daclatasvir 11 (26.2%) 9 (32.1%) 0.07
OMV/PTV/RTV 31 (73.8%) 19 (67.8%) 0.07
Add-on Ribavirin 9 (21.4%) 23 (82.1%) 0.0001
RVR: N (%) 42 (100%) 28 (100%) 0.9
12-week SVR: N (%) 39 (92.8%) 27 (96.4%) 0.9
24-week SVR: N (%) 31 (74%) 23 (83%) 0.7
Alanine aminotransferase 1 month after beginning DAA (IU/L) 35.1 ± 16.2 41 ± 0.1 0.15
Alanine aminotransferase at the end of DAA therapy (IU/L) 35.1 ± 16.2 30 ± 16 0.9
Relapse: N (%) 11 (28.57%) 5 (21.42%) 0.7
Hepatic decompensation: N (%) 10 (23.8%) 2 (7.14%) 0.07
Hepatocellular carcinoma 0 0 1
Worsening of anemia: N (%) 14 (33.3%) 20 (71.4%) 0.001
Hemoglobin (g/dL) 1 month after starting DAA 8.7 ± 0.76 8.1 ± 1.06 0.004
Hemoglobin (g/d/L) 1 month after ribavirin cessation 8.8 ± 0.6 8.9 ± 0.9 0.56
Hemoglobin (g/dL) at the end of DAA therapy 9.4 ± 0.8 10.4 ± 0.9 0.004
Rise of serum creatinine: 25 (59.5%) 9 (32.1%) 0.02
AKI/CKD (recovered) 12 (28.6%) 8 (28.6%) 0.7
Progression to ESRD 13 (30.9%) 1 (3.6%) 0.005
Need for hemodialysis: N (%) 16 (38.1%) 4 (14.3) 0.03
Serum creatinine (mg/dL) 5.9 ± 2.3 4. ± 2.1 0.03
eGFR (mL/min) 21.3 ± 13 29.3 ± 17.2 0.02
DAA interruption
Sofosbuvir/daclatasvir 6 (14.3%) 3 (10.7%) 0.6
OMV/PTV/RTV 19 (45.2%) 6 (21.4%) 0.04
Ribavirin 14 (13.3%) 20 (71.4%) 0.001

eGFR estimated glomerular filtration rate according to MDRD formula; DAA direct-acting antiviral; OMV/PTV/RTV, Ombitasvir/Paritaprevir/
Ritonavir; RVR rapid virologic response; SVR sustained virologic response; AKI acute kidney injury; CKD chronic kidney disease; ESDR end-
stage renal disease

Table 5  Efficacy and adverse Anemic patients Non-anemic p value

events among hemodialysis (n = 24) patients (n = 16)
patients
RVR: n (%) 24 (100) 16 (100) 0.9
12-week SVR: n (%) 24 (100) 16 (100) 0.9
24-week SVR: n (%) 23 (95.8) 15 (93.75) 0.4
Relapse: n (%) 1 (4.16%) 1 (6.25%) 0.4
Hepatic decompensation: n (%) 1 (4.16%) 0 0.4
Hepatocarcinoma: n (%) 2 (8.32%) 0 0.15
Worsening of anemia: n (%) 3 (12.5%) 11 (68.75% 0.0002
DAA interruption
OMV/PTV/RTV 0 0 0.9
Ribavirin 0 11 0.0001
Hemoglobin (g/dL) 1 month after starting DAA 9.1 ± 0.3 9.2 ± 0.9 0.6
Hemoglobin (g/dL) 1 month after stopping ribavirin 9.1 ± 0.6 10.5 ± 0.4 0.001

DAA direct-acting antivirals; RVR rapid virological response; SVR sustained virological response; OMV/
PTV/RTV Ombitasvir/Paritaprevir/Ritonavir

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 International Urology and Nephrology

Table 6  Efficacy and adverse Anemic Non-anemic p value

events among kidney-transplant patients patients (n = 85)
recipients (n = 40)

RVR: n (%) 40 (100%) 85 (100%) 1

12-week SVR: n (%) 40 (100%) 85 (100%) 1
24-week SVR: n (%) 39 (97.5%) 85 (100%) 0.3
Alanine aminotransferase (IU/mL) 1 month after starting DAA 38.2 ± 18.3 35.7 ± 13 0.4
Alanine aminotransferase (IU/L) at the end of DAA therapy 38.6 ± 17.9 34.9 ± 12.9 0.2
Relapse: n (%) 1 (2.5%) 0 0.3
Hepatic decompensation: n (%) 1 (2.5%) 0 0.3
Hepatocellular carcinoma 0 0 1
Worsening of anemia: n (%) 3 (7.5%) 20 (23.5%) 0.03
Hemoglobin (g/dL) 1 month after starting DAA 10 ± 0.2 9.8 ± 0.9 0.48
Hemoglobin (g/dL) 1 month after ceasing ribavirin 10.2 ± 0.5 11.5 ± 1.2 0.0001
Hemoglobin (g/dL) at the end of DAA therapy 10.3 ± 0.9 11.8 ± 0.8 0.0001
Rise in serum creatinine: n (%) 7 (17.5%) 2 (2.3%) 0.004
Acute rejection: n (%) 3 (7.5%) 1 (1.2%) 0.06
Acute tubular injury 3 (7.5%) 1 (1.2%) 0.06
Chronic transplant glomerulopathy: n (%) 1 (2.5%) 0 0.32
Serum creatinine (mg/dL) 1.95 ± 0.8 1.34 ± 0.6 0.0001
eGFR (mL/min) mean ± SD 54.36 ± 23.6 61.99 ± 20.87 0.07
Trough level 1 month after DAA initiation:
Tacrolimus (ng/mL) 4.9 ± 1.6 4.7 ± 1.3 0.6
Cyclosporine (ng/mL) 96.4 ± 25.1 91.3 ± 22.3 0.3

DAA direct-acting antivirals; RVR rapid virological response; SVR sustained virological response; eGFR
estimated glomerular filtration rate according to MDRD formula

Table 7  Kidney-transplant recipients presenting with impaired graft function during DAA therapy
Case Baseline CNI trough Timing of Peak of CNI trough Kidney Treatment Last serum Days of DAA
serum creati- level (ng/ graft function serum creati- level (ng/ biopsy creatinine interruption
nine (mg/dL) mL) impairment nine (mg/dL) mL) at peak results (mg/dL) (days)
serum creati-
nine

KTr 1 1.9 4.3 Day 14 2.1 4.8 ATI Conservative 1.9 14

KTr 2 1.7 4.9 Day 14 2.1 5.6 ATI Conservative 1.8 10
KTr 3 1.2 4.1 Day 28 1.6 4.2 ACR​ Steroid 1.3 8
pulses
KTr 4 1.4 5.1 Day 28 1.8 5 ACR​ Steroid 1.6 7
pulses
KTr 5 0.9 3.9 Day 28 1.4 4.8 ACR​ Steroid 0.9 7
pulses
KTr 6 1.7 5.5 Day 14 2.5 7 ATI Conservative 1.7 10
KTr ­7a 1.6 95 Day 28 2.6 110 ATI Conservative 1.8 21
KTr 8 a 1.6 91 Day 28 2.0 105 ACR​ Steroid 1.7 10
pulses
KTr 9 1.9 84 Day 14 2.6 88 CTG​ Conservative 2.4 14

KTr kidney transplant recipient; ATI acute tubular injury; ACR​acute cellular rejection, CTG​chronic transplant glomerulopathy
a
KTr 7 and 8 belong to the non-anemic group whereas the other patients were within the anemic group

and KTx patients developed impaired renal function more The prevalence of HCV infection remains higher in CKD
frequently than non-anemic CKD and KTx. and HD patients than in the general population (i.e., 5–10%
in Europe and USA). In addition, in Egypt, the prevalence

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International Urology and Nephrology

Table 8  Univariate analysis to Chronic kidney disease Kidney-transplant recipients

determine the risk factors for
eGFR decline across chronic Relative risk 95% CI p value Relative risk 95% CI p value
kidney disease and kidney-
transplant recipients receiving Gender (male) 1.35 0.76–2.4 0.29 0.74 0.19–2.8 0.66
DAAs Hypertension 1.28 0.82–2.02 0.26 1.57 0.2–11.94 0.66
Diabetes 0.7 0.42–1.2 0.23 2.97 0.8–10.8 0.09
Hepatitis B 0.5 0.05–6.6 0.67 3.78 0.6–23.44 0.15
Previous alpha-interferon therapy 0.8 0.35–1.35 0.58 3.31 0.79–13.88 0.1
Liver cirrhosis 1.4 0.76–2.65 0.26 1.6 0.11–23.22 0.72
Baseline eGFR < 30 mL/min 1.1 0.63–1.94 0.71 – – –
Baseline eGFR ≥ 30 mL/min 0.9 0.515–1.57 0.7 – – –
Baseline proteinuria ≥ 4 g/day 1.5 0.92–2.4 0.09 1.9 0.51–7.1 0.33
Baseline ALT > 30 Iu/L 1.12 0.67–1.84 0.67 1.85 0.42–5.94 0.49
Baseline hemoglobin < 10.5 g/dL 1.85 1.023–3.35 0.04 7.4 1.61–34.2 0.01
Sofosbuvir-based 0.9 0.515–1.57 0.7 – – –
OMV/PTV/RTV 1.1 0.63–1.94 0.71 – – –

DAA direct antiviral agents; eGFR estimated glomerular filtration rate; ALT alanine aminotransferase;
OMV/PTV/RTV Ombitasvir/Paritaprevir/Ritonavir

of HCV infection in the general population is the world’s
highest [15].
A variety of measures have reduced the prevalence of
HCV infection in CKD patients [16]. Recently, the Dialysis
Outcomes and Practice Patterns Study (DOPPS, 1996–2015)
assessed trends in the prevalence, incidence, and risk factors
for HCV infection, as defined by a documented diagnosis
or antibody positivity in hemodialysis patients. They found
that, among prevalent hemodialysis patients, the prevalence
of HCV was nearly 10% in 2012–2015, ranging from 4% in
Belgium to as high as 20% in the Middle East, with interme-
diate prevalences in China, Japan, Italy, Spain, and Russia.
However, the prevalence of HCV has decreased over time in
most countries that have participated in more than one phase
of DOPPS; its prevalence was ~ 5% among patients that had
recently (< 4 months) initiated dialysis. The incidence of
HCV infection has also decreased from 2.9 to 1.2 per 100
patient-years in countries participating in the initial phase
of DOPPS.
CKD patients continue to experience unique challenges
in HCV management, such as concerns about progressive
liver disease and graft injury following renal transplanta-
tion [17]. HCV often has a negative impact on the survival
of post renal-transplant patients due to the increased risk
of graft loss caused by chronic rejection and HCV-related
de novo glomerulopathies, post-transplant diabetes, de novo
cancer, including hepatocarcinoma, and the rapid progres-
sion of liver fibrosis [18–20]. The advent of a well-tolerated
oral regimens for HCV infection has expanded treatment
options for patients with severe CKD and HD. Although
ribavirin was envisioned to become obsolete with the advent
of DAAs, it continues to play an adjunct role in some regi-
mens, particularly in real-life settings in Egypt [21].
Until recently, data for the use of oral regimens given to
patients with severe CKD or on dialysis have been limited.
This is reflected in the HCV guidelines, which formerly
endorsed the use of initially available DAA regimens only
for patients with a GFR of > 30 mL/min, which clearly pre-
cluded HD patients from therapy [22]. Among the currently
approved DAAs, sofosbuvir, an NS5B polymerase inhibitor,
is the only DAA that is renally eliminated. Therefore, there
is no recommended dose for sofosbuvir in cases of severe
renal insufficiency or for those on dialysis. A few pharma-
cokinetic and clinical data report on the use of sofosbuvir
in the setting of HD [23, 24]. Desnoyer et al. reported on
a multicenter, prospective, and observational study of HD
patients that received sofosbuvir [400 mg once daily (n = 7)
or 3 times a week (n = 5)], after hemodialysis with sime-
previr, daclatasvir, ledipasvir, or ribavirin. They reported
that plasma concentrations of sofosbuvir or its inactive
metabolite GS-331007 did not accumulate within hemo-
dialysis sessions or throughout the treatment course [25].
The other currently approved DAAs (simeprevir, ledipas-
vir, daclatasvir, paritaprevir/ritonavir, ombitasvir, dasabuvir,
grazoprevir, and elbasvir) are not eliminated renally and thus
do not need dose adjustment in cases of severe CKD or in a
HD setting [25].
In Egypt, for KTX, HD, and CKD HCV genotype
4-infected patients, we recently reported on the efficacy of a
sofosbuvir-based regimen if eGFR was > 30 mL/min or with
a ritonavir-boosted paritaprevir/ombitasvir-based regimen if
eGFR was < 30 mL/min. Ribavirin was only added and given
to patients that were non-anemic [26–28]. A cure for HCV
infection was obtainable for the majority of HD and KTx
patients [27, 28], whereas this was not the case for CKD
patients where there was a high rate of acute kidney injury

13

[26]. However, in the setting of patients with impaired renal
function, DAA therapy has a very high SVR and slows a
rapid decline in eGFR associated with chronic HCV infec-
tion [29]. Therefore, in the era of DAAs, HCV infection may
be a reversible risk factor for CKD progression.
Beinhardt et al. reported that 96% of DAA-treated
patients with renal impairment achieved an SVR after 12
and 24 weeks of treatment-free follow-up [30]. Likewise,
other studies report that DAA therapy was highly effective
in the setting of renal transplantation, with 100% of patients
achieving viral clearance and similar SVR rates despite
receiving immunosuppression comprising a calcineurin-
inhibitor agent associated with, in most cases, low-dose ster-
oids and mycophenolic acid [31–33]. In addition, in these
studies, the viral response to DAAs was not affected by prior
failure of alpha-interferon-based therapy, the timing of DAA
therapy after transplantation, or the stage of liver fibrosis.
In our single-center, retrospective, cohort study, we tried
to assess the effect of anemia at pre-treatment as a predictor
for deleterious renal and extra-renal side effects of DAAs in
CKD, HD, and KTx patients. In general, the prevalence of
anemia is very high in the CKD population; indeed, when
present, it is corrected by iron and/or erythropoietin therapy
[34]. KDIGO guidelines state that anemia within CKD is
diagnosed when hemoglobin level is < 11 g/dL [35]. How-
ever, because of the reimbursement of erythropoietin policy
in Egypt, i.e., only when Hb level is < 10.5 g/L, we chose a
hemoglobin level of < 10.5 g/dL as the cut-off value. Thus,
of our 235 patients, 98 (41.7%) had anemia: of these, 60%,
40%, and 32% were CKD, HD, or KTx patients, respectively.
We found that DAA treatment was efficient, i.e., there was a
significant decrease in aminotransferase levels in both ane-
mic and non-anemic groups. It provided an SVR at 24 weeks
of > 95% for HD and KTx. Conversely, a 24-week SVR was
only obtained for 77.1% of CKD patients. However, being
anemic when initiating DAA therapy did not influence anti-
viral response across the three groups.
We found a significant drop in hemoglobin by 1 month
after starting DAA treatment in all non-anemic groups, i.e.,
CKD, HD, and KTx patients. This could be explained by
the use of ribavirin (200 mg/day) given to non-anemic CKD
and KTx patients and 200 mg given every other day to non-
anemic HD patients. Moreover, when ribavirin was stopped,
anemia was reversed. This runs parallel to results obtained
by other authors who report that ribavirin dose has to be re-
adjusted or stopped when associated with anemia [36–38].
For example, in the RUBY-1 trial ribavirin-related anemia
was common and led to its interruption in many patients
and the need to start erythropoietin plus a blood transfu-
sion, although this occurred more frequently in those with
baseline anemia [39].
Baseline eGFR was less in our anemic group compared to
the non-anemic group that had CKD or were KTx patients.
13
International Urology and Nephrology
This is concomitant with the fact that renal dysfunction is
associated with anemia. In the CKD group, the rise in serum
creatinine and the need for hemodialysis occurred signifi-
cantly more frequently among the anemic group (p = 0.02
and p = 0.03, respectively).
A change in serum creatinine between baseline and at
1 month after starting treatment was significantly higher
in the anemic group (compared to the non-anemic group:
i.e., + 1.89 ± 0.96 vs. + 0.59 ± 0.45 mg/dL; p = 0.0001). In
both groups, deterioration in renal function occurred more
frequently with a ritonavir-boosted regimen, especially in
the anemic group (p = 0.04). In both groups, DAAs was
suspended during the period of AKI. The period of suspen-
sion was extended from 3 weeks (7 patients) to 6 weeks (27
patients). Patients with an extended period of deteriorating
renal function and that required hemodialysis for more than
8 weeks after DAAs were interrupted were considered to be
end-stage renal-disease patients. As a consequence, we then
considered them to be HD patients and, thus, resumed DAA
therapy. The incidences of impaired graft function in KTx,
and those with acute tubular necrosis (ATN) and acute cel-
lular rejection were more frequent among our anemic group.
A change in serum creatinine at 1 month after treatment
(compared to baseline) was significantly greater among
the anemic group that the non-anemic group (+ 0.25 ± 0.1
vs. + 0.04 ± 0.01 mg/dL; p = 0.0001). Acute-rejection epi-
sodes were treated with pulses of IV methylprednisolone
(10 mg/kg for 5 days): responses varied from partial recov-
ery (three KTx) to complete recovery (one KTx).
Anemia itself is a risk factor for developing AKI [40,
41] and progressive CKD [42, 43]. In a normal physiologic
response, the kidney receives 20—25% of the blood from
cardiac output. This is the highest need throughout the body
in relation to organ weight. As a pathologic response, ane-
mia directly reduces the delivery of oxygen to the kidneys,
particularly to the medulla. Because AKI frequently devel-
ops under ischemic conditions, anemia can be a reason for
the high incidence of AKI [44, 45].
In a recent study that included 494 patients with advanced
chronic liver disease (ACLD) Scheiner et al. found that
two-thirds suffered from anemia; in addition, the degree
of hepatic dysfunction, portal hypertension, and episodes
of hepatic decompensation correlated with the severity of
anemia. Finally, anemic patients had worse overall 5-year
survival and increased 5-year liver-related mortality [46].
Post-treatment hepatic decompensation was more fre-
quent in our anemia group (12 cases vs. 2 cases). It was
diagnosed by the development of ascites and lower-limb
edema plus a concomitant rise in liver-enzyme levels and a
decrease in serum-albumin levels. All cases of decompensa-
tion were also associated with a relapse at some time point.
Most cases received a ritonavir-boosted regimen. They also
received supportive measures, including ursodeoxycholic
International Urology and Nephrology
acid, diuretics, and intravenous human albumin, when
needed.
Our study has the advantage of being the first to study
the effects of anemia on DAA efficacy and safety in CKD
patients. We also included patients with different stages of
CKD. The study also had a relatively large sample size.
However, lack of randomization, most patients were gen-
otype 4, and the study being retrospective are limitations to
our study. Also, we could not differentiate if deterioration in
kidney function in the anemic groups during DAA therapy
was related to anemia or to the already poor baseline kidney
function.
Conclusion
In conclusion, access to effective oral DAA therapy for renal
patients with HCV raises some logistical challenges; how-
ever, despite this concern, we now (finally) have safe and
effective all-oral DAA regimens that can reduce the burden
of HCV-related complications in renal populations. Correc-
tion of the associated medical disorders may improve the
outcomes of DAAs. Anemia is a common feature of both
renal and liver diseases; however, anemia did not affect DAA
efficacy. But anemia was associated with a rise in serum cre-
atinine among patients with CKD and KTx. Further studies
are needed to optimize the outcomes of HCV treatment in
renal patients.
Acknowledgements HCV working group (Urology and Nephrology
teams), Egyptian Liver Research Institute team and Egyptian Medical
insurance system for supplying the DAAs.
Funding Not funded.
Compliance with ethical standards
Conflict of interest All authors declared no conflicts of interest.
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