Presentation: HCV in dialysis

Hepatitis C Virus Infection in
Patients with Kidney Disease:
a Roadmap for Nephrologists
By
Salwa Elwasif, MD Mohammed Elhadidy
Rasha Kamal Ahmed Yahiya
Nour Elbialy

• a bimonthly publication
• Edited by Prof. Richard A Sherman from
Rutgers University, New Jersey.
• It focuses exclusively on cutting-edge clinical
aspects of dialysis therapy.
• It publishes review articles by the most
respected names in the field of dialysis

Introduction
12 articles
Diagnostic test and
prognosis
HCV as a systemic
disease
HCV ttt in dialysis
Transmission
Coinfection with
HIV
Treatment , how,
when and why?
In advanced
kidney disease
Epidemiology
Pharmacokinetics
DAA
HCV ttt in tx
Management and
ttt
Donor with HCV

hepatitis C virus infection as a systemic disease
• Cardiovascular disease:
• Metabolic diseases:
• Renal Insufficiency:
• Cryoglobulinemia vasculitis:
• B‐cell lymphoproliferative diseases
• Arthralgia and myalgia:
• Sicca syndrome

Cardiovascular disease:
• Major adverse cardiovascular events (MACE)
(stroke, coronary artery disease, heart failure,
peripheral arterial disease) are currently recognized
as important comorbidities in patients with chronic
HCV infection.
(Negro et al, 2014)

Cardiovascular disease:
• HCV seropositivity is associated with high
rates of carotid artery plaques, increasing
cerebrovascular disease risk.
• Patients with sustained virological response
showed an improvement in myocardial
perfusion defects whereas relapsing patients
exhibited a worsening following a transient
improvement

Metabolic diseases:
Diabetes and insulin resistance occur with an
increased incidence in patients with chronic
HCV infection.
(Taskoparan et al, 2011)

Metabolic diseases:
• The mechanisms through which hepatitis C
induces type 2 diabetes involve direct viral effects,
insulin resistance, release of proinflammatory
cytokines and other immunemediated processes.
(Serfaty et al, 2009)

Renal Insufficiency:
• Cryoglobulinemic vasculitis
• Membranoproliferative glomerulonephritis
(MPGN) .
(Cacoub and Comarmond, 2019)

Renal Insufficiency:
• patients with chronic HCV infection appear
to have more rapid progression of CKD and
an almost twofold increased risk of
developing end‐stage renal disease
(Molnar et al, 2015)

Renal biopsy
• Type I MPGN in more than 70% of patients
• (Less frequent)
– focal segmental glomerulosclerosis
– Membranous glomerulopathy.
– crescentic GN, necrotizing vasculitis, interstitial inflammation,
– capillary luminal cryoglobulin thrombi
• Immunofluorescence study:
– IgG, IgM, and C3 within most of the cryoglobulin deposits present
in capillary loops;
– C1q was present in about one‐third of the patients.
(Cacoub and Comarmond, 2019)

Cryoglobulinemia vasculitis:
• Circulating mixed cryoglobulins in 40%‐60% of patients
chronically infected with HCV
• Overt CryoVas develops in only approximately 15% of
patients. (dermatologic, neurologic, and renal
involvement)
(Serfaty et al, 2009)

1) Dermatologic manifestations:
• Purpura, chronic cutaneous ulcers, Raynaud's
phenomenon, acrocyanosis, and digital ulcerations)
2) Neurologic manifestations:
• distal sensory or sensory‐motor polyneuropathy
• painful asymmetric paresthesia.
• Multiple mononeuropathy (less frequent)
(Cacoub et al, 2015)

treatment
• Initial control of disease with rituximab, with or without
plasmapheresis, is recommended along with DAA treatment.
• Low‐dose corticosteroids for inflammatory findings but are
not adequate alone in cases of major organ involvement.
• Immunosuppressants should be given only in cases of
refractory forms of CryoVas, which are frequently associated
with underlying B‐cell lymphoma.
(Saadoun et al, 2009)

B‐cell lymphoproliferative diseases
• HCV‐related lymphoproliferative diseases appear to
be the result of multiple events, including sustained
B‐cells activation, an aberrant B‐cell survival,
genetic/epigenetic, and environmental factors.
(Zignego et al, 2012)

B‐cell lymphoproliferative diseases
• Patients with SVR, low incidence of B-NHL and
regression of already diagnosed one.
• Patients with recurrent viremia , , relapse of B-NHL.
(Kawamura et al, 2007)

Arthralgia and myalgia:
• in 30%‐70% with mixed cryoglobulin
syndrome.
• O/E:
bilateral, symmetric, nondeforming joint
pains involving mainly the knees and
hands.
(Cacoub et al, 2015)

Sicca syndrome
• in 20%‐ 30% of HCV‐infected patients
• Sjögren's syndrome (less than 5% ).
(Verbaanet al, 1999)

Evolution of diagnostic tests in HCV
Laboratory blood tests:
General testing for liver disease:
LFT
HCV‐specific tests:
HCV Antibody (Ab), not protective
• can also be performed using oral fluid or
buccal swab and the sensitivity is slightly
lower at 98.1%.

• if HCV antibody is positive, the presence of
active infection should be confirmed using HCV
Ribonucleic acid (HCV RNA)

• HCV RNA test needs to be performed even if
HCV antibody is negative, In immunosuppressed
patients or those with HCV infection during the
“window” period.
• A study on 2796 HD patients, reported an overall
prevalence of 0.8% of HCV RNA positive
subjects although HCV antibody was negative

Laboratory blood tests:
HCV has seven different genotypes 1 to 7 and
67 subtypes
HCV virus is capable of mutating within the
same host, with the production of different
genetic variants and quasispecies.

• HCV genotype testing
is recommended if the patient has detectable
HCV viremia to personalize the treatment
options.
• HIV and HBV infection:
should be ruled out in all HCV positive patients
before starting DAAs

IMAGING STUDIES:
• Ultrasound (US): liver architecture, spleen size,
• Doppler US: portal vein diameter and flow
• Computed tomography(CT) & magnetic
resonance imaging(MRI): iron deposition, liver
lesions and concomitant biliary diseases.

Liver fibrosis assessment:
Liver biopsy
• KDIGO-2008: liver biopsy as clinical standard to
assess liver fibrosis
• KDIGO-2018: use non‐invasive markers of liver
fibrosis as first line, and liver biopsy only if non
invasive markers are not concordant or to rule out
other liver‐related comorbidities

Serum markers of liver fibrosis:
• Directly involved in the remodeling and
turnover of the liver matrix
– hyaluronic acid, human cartilage glycoprotein
• indirect biomarkers that reflect the liver cell
damage
– AST, ALT, albumin, bilirubin,

• The aminotransferase‐to‐platelet ratio index
(APRI) is an indirect score system calculated
as [(AST level/ULN)/PLT] × 100.
• APRI score is by far the most reliable and
accurate in identifying advanced liver fibrosis

• Fib‐4 is a biomarker panel calculated as [age
(years) x AST]/PLT X
ALT

• Fibrosure/Fibrotest gender, age, total bilirubin,
haptoglobin, ALT, GGT, alfa2‐macroglobulin,
and apolipoproteinA1.
• no data are available for the ESRD patients.

Limitations:
• AST levels are usually normal or mildly
elevated in HD patients and both APRI and
Fib‐4
• Heparin use during HD sessions may cause
possible thrombocytopenia, negatively
affecting the accuracy of APRI and Fib‐4.

Elastography techniques for assessment of liver
fibrosis (fibroscan):
• Diagnostic accuracy of TE was better than
APRI for fibrosis.

Hepatic venous pressure gradient (HVPG):

HCV and progression of ESRD
• HCV infection accelerate the progression of
CKD and the development of ESRD. even in
other renal diseases, including diabetic
nephropathy, HIV, and chronic GN

HCV and progression of ESRD
• treatment with interferon‐based therapy resulted
in a 58% reduction in incident CKD and an 84%
decreased risk of ESRD.
• HCV‐infected liver transplant recipients, antiviral
treatment, and SVR improved kidney function in
those with mild CKD.

• The incidence of chronic HCV infection is between
64 and 103 million among people worldwide.
• Globally, HCV infection is still common in CKD
patients despite the advent of serologic screening and
better adherence to infection control.

• Evidence regarding the epidemiology of HCV in
CKD patients predialysis is much less abundant.
HCV is considered now a systemic disease associated
with both hepatic and extrahepatic manifestations.

• A large body of epidemiological evidence
regarding HCV infection among patients
undergoing maintenance dialysis in the
developed countries, prevalence rates have
been shown to range between 1.4% and 28.3%.

• the epidemiology of HCV infection among
patients on chronic dialysis in developing
countries is partly explained by fewer studies ,
most of which have limited sample sizes .
prevalence rates between 4.7% and 41.9%

• The adoption of several preventive measures has given way to
the possibility of reducing the prevalence of HCV infection
among patients on maintenance hemodialysis in the developed
world.
• HCV remains prevalent in the dialysis population, and
outbreaks of HCV infection continue to occur within dialysis
units.
• antiviral therapy of HCV is able to improve patient survival
and reduce the risk of dialysis in patients with advanced CKD.

• There are currently 13 (FDA) approved DAAs
products for the treatment of HCV either as a single
agent or in combination with each other.
• Patients with CKD and an estimated GFR (eGFR) >
30 mL/min/1.73 m2 can be treated with any of these
regimens.

There are Four regimens used in patients with GFR
≤ 30 mL/min.:
• paritaprevir/ritonavir/ombitasvir/dasabuvir (PrOD)
• paritaprevir/ritonavir/ombitasvir (PRO)
• grazoprevir/ elbasvir (GZR/ELB)
• glecaprevir/pibrentasvir (G/P)

SOFOSBUVIR‐BASED STUDIES IN CKD
• The low GFR group had a significantly higher rate of
cirrhosis, anemia and renal dysfunction.
• Viral response was high irrespective of eGFR, and
notably patients on hemodialysis had a sustained
virologic response (SVR12) also.

SOFOSBUVIR‐BASED STUDIES IN CKD
• The current AASLD and recently published KDIGO
guidelines: sofosbuvir‐based regimens are not
recommended in patients with an eGFR below 30
mL/min/1.73 m2.

PROD‐BASED (PARITAPREVIR/RITONAVIR/OMBITASVIR
+ DASABUVIR)STUDIES IN CKD
In stage 4 or 5 CKD, including those on hemodialysis.
• . The sustained virologic response rate was 90%.
• The SVR rate without RBV was also high, even in
genotype 1a patients.
• data from the ERCHIVES study demonstrating high SVR
rates, lower incidence of GFR decline with PrOD
regimen as compared with sofusbuvir‐based treatment.

GRAZOPREVIR AND ELBASVIR COMBINATION THERAPY
FOR HCVINFECTED CKD PATIENTS
• data using EBR/GZR for 12 weeks in a nonrandomized,
multicenter, nationwide observational survey in France
demonstrated high efficacy in HCV genotype‐1 or ‐4
infected patients with stage 4/5 CKD.

GLECAPREVIR AND PIBRENTASVIRCOMBINATION
TREATMENT IN CKD
• the EXPEDITION‐4 open label, single‐arm study the
clinical efficacy and safety of the pan‐genotypic
combination glecaprevir and pibrentasvir. for 12 weeks
was investigated in 104 treatment‐naïve and ‐experienced
patients HCV‐infected stage 4‐5 CKD patients.
• This regimen achieved an SVR12 rate of 98%.29 Adverse
events included fatigue (14%), and nausea (12%) which
was similar to the C‐SURFER trial.

• For advanced stage CKD patients with HCV strains
with viral resistance who do not achieve SVR12,
treatment options are currently limited. However, a
recent report suggested that the recently approved
pangenotypic glecaprevir/pibrentasvir combination is
a potentially useful salvage treatment for patients who
have failed prior DAA regimens.

Epidemiology Of HCV Transmission Among HD Patients:
 HD setting facilitates transmission of HCV through risk of blood
contamination of surfaces, objects and devices, treatment
simultaneously in a shared space.
 The reported seroconversion rates are between 1.1% and 3.6%
per 100 patient‐years.
 For all outbreaks, epidemiologic investigations must be
performed.
 Investigations include (Usually, multiple findings are present):
 interviews of dialysis facility staff.
 Interviews of patients for HCV risk factors.
 Review of patient charts.
 Review and observation of infection control practices at the facilities

Factors Associated With HCV Transmission In
Dialysis Facilities

Recommendations For Prevention Of HCV Transmission
In Dialysis Facilities
 Screening all patients for HCV AB upon admission.
 HCV PCR for positive anti-body patients.
 Positive HCV PCR to be referred for treatment.
 Negative HCV AB to be screened every 6 months.
 Negative HCV AB to be monitored for ALT monthly
and any unexplained rise should warrant HCV testing.
 Any new HCV infections should be reported to local
public health agencies and steps be taken to prevent
further transmission of the virus.

DAAs STUDIED IN ESRD PATIENTS
1. Sofosbuvir‐based regimens:
• Desnoyer et al.,: neither the parent drug nor its main
metabolite accumulated in patients treated with either daily
or three times a week dosing schedules; however, they did
find that the half‐life of the primary metabolite was
increased (38 vs 27 hours).
Nazario et al.,HCV-TARGET study
15 hemodialysis patients82 patients (Crcl: <45
ml/min)
Sample size
Sofosbuvir-based+ RBVSofosbuvir-based+ RBVTreatment used
100%85-90%SVR-12
015%Rise of serum creatinine
MinorCommonAnemia

• Simprevir/ Ledipasvir/ Velpatasvir :
 Should be combined with sofosvubir.
 Limited data.
 Several case series (Effective, minimal adverse events).
 More deterioration of kidney function with Ledipasvir.
• Daclatasvir:
 Common combination with sofosbuvir.
 Hepatic metabolism.
• Because sofosbuvir is cleared by the kidneys,
it is contraindicated in hemodialysis.

• 2. Ombitasvir‐paritaprevir‐ritonavir and dasabuvir:
• 3. Grazoprevir and elbasvir:
 Less than 1% is renal excretion.
 C‐SURFER trial: 235 (multi-center, double blinded), GT 1
 The combination of grazoprevir/elbasvir to treat HCV GT 1
infected advanced CKD patients has minimal side effects, high
SVR rates and excellent quality‐of‐life outcomes.
RUBY IIRUBY I
18 CKD patients20 CKD patientsSample size
OMV/PTV/RTV/DOMV/PTV/RTV/D+RTreatment used
1, 4, 51, 4, 5Genotype
100%90%SVR-12
UncommonUncommonRise of serum creatinine
UncommonCommon with RBVAnemia

• 4. Glecaprevir/pibrentasvir:
 EXPEDITION‐4 trial (multicenter, open-label, single arm)
proved the efficacy and safety of this combinations.
• AASLD and IDSA guidelines recommend one of the
following regimen to advanced renal impairment and
hemodialysis patients:
• Ombitasvir‐paritaprevir‐ritonavir and dasabuvir.
• Grazoprevir and elbasvir.
• Glecaprevir/pibrentasvir.

Epidemiology:
• >36 million world wide, 1.1 million American
residents.
• Increasing incidence among CKD, less than 1%
among HD.
• Co-infection with HCV among HIV, CKD
patients is common.

Risk factors for development of CKD among
HIV patients:
• Common with general population:
– African American race.
– Diabetes, hypertension, cardiovascular disease.
– Lower baseline GFR, and older age.
• Special for HIV patients:
– Unsuppressed HIV viral loads.
– Lower nadir CD4 count.
– Use of potentially nephrotoxic medications, such as
tenofovir.

HIV dialysis outcome
• American reports (Rodriguez et al., 2003) found short
survival of HIV patients especially if co-infected with
HCV.
• European reports (Tourret et al., 2006) and (Trullas t al.,
2011) showed better survival.
• The difference was explained by lower Africans among
European reports.
• Better outcome after the era of ART (Ahuja et al., 2011).
• Mono-infection is associated with better outcome than
combined infection (Swainski et al., 2018)

HIV kidney transplantation outcome
• The introduction of ART improved TX outcome (Kumar et
al., 2005).
• One-year graft and patient survival was the same among
HIV infected and HIV-free groups (Poland et al., 2008).
• Xia et al., performed “mate kidney” analysis: HIV/HCV
infection is associated with higher mortality than mono or
no infection.
• Despite inferior long‐term patient and allograft survival
among HIV/HCV coinfected recipients, when compared
with patients with HIV or HCV alone, kidney
transplantation provides a survival benefit over dialysis
(Locke et al., 2017)

HCV/HIV co-infection and liver disease:
• In HCV mono‐infected patients it takes several decades
for liver disease to progress to cirrhosis and end‐stage
liver disease (ESLD), but the time course is accelerated
in patients who have both HIV and HCV infection
(Thomson et al., 2011).

Liver assessment prior to treatment
• Transient elastography.
• Laboratory dependent scoring methods.

Treatment options for co-infection among hemodialysis
Timing for HIV treatmentHIV treatment optionHCV treatment option
After 3D completingRitonavir3D regimen
The same timeAtazanavir
Contraindicated (GIT upsets)Lopinavir
Contraindicated (prolonged QT interval)Rilpivirine
Drug interaction (CI)Any of the aboveElbasvir/grazoprevir
Contraindicated combinationsRitonavir, LopinavirGlecaprevir/pibrentasvir
HLEAtazanavir

Treatment options for co-infection among transplants
Timing for HIV treatmentHIV treatment optionHCV treatment option
Drug interaction with IS
(CI)
Any of them3D regimen
Increase Sof level (CI)RitonavirSofosbuvir
Increase Tenofovir level
(CI)
TenofovirSofosbuvir/velpatasvir
Monitor kidney functionTenofovirSofosbuvir/velpatasvir/voxilaprevir
Reduced Sof/Vel level (CI)Ritonavir
Dac dose adjustment
according to ART type
Any of themDaclatasvir

Summery and Guidelines
• The workgroup formulated guideline statements
that were rated as strong (level 1) or weak (level
2) based on the strength of evidence and other
considerations.
• The strength of the overall evidence that supports
each guideline statement was rated from high to
very low quality (A to D).

Summery and Guidelines
• Ungraded statements were used for statements
that provided guidance based on common sense,
standards of care, reminders of the obvious, or
were otherwise not sufficiently specific to allow
for application of evidence to the issue and
therefore were not based on systematic evidence
review.

Guideline 1: Detection and Evaluation of HCV in CKD
1.1: Screening patients with CKD for HCV infection
• 1.1.1: We recommend screening all patients for
HCV infection at the time of initial evaluation of
CKD (1C).
• 1.1.1.1: We recommend using an immunoassay
followed by nucleic acid testing (NAT) if
immunoassay is positive (1A).
HCV infection upon initiation of in‐center
hemodialysis (HD) or upon transfer from another
dialysis facility or modality (1A).

1.1: Screening patients with CKD for HCV infection
• 1.1.2.1: We recommend using NAT alone or an
immunoassay followed by NAT if immunoassay is
positive (1A).
• 1.1.3: We suggest screening all patients for HCV
infection upon initiation of peritoneal dialysis or
home HD (2D).
HCV infection at the time of evaluation for kidney
transplantation (1A).

1.2: Follow‐up HCV screening of in‐center HD patients
• 1.2.1: We recommend screening for HCV infection with
immunoassay or NAT in in‐center HD patients every 6
months (1B).
• 1.2.1.1: Report any new HCV infection identified in a HD
patient to the appropriate public health authority (Not
Graded).
• 1.2.1.2: In units with a new HCV infection, we recommend
that all patients be tested for HCV infection and the
frequency of subsequent HCV testing is increased (1A).
• 1.2.1.3: We recommend that HD patients with resolved
HCV infection undergo repeated testing every 6 months
using NAT todetect possible reinfection (1B).

1.2: Follow‐up HCV screening of in‐center HD
patients
• 1.2.2: We suggest that patients have serum alanine
aminotransferase (ALT) level checked upon
initiation of in‐center HD or upon transfer from
another facility (2B).
• 1.2.2.1: We suggest that HD patients have ALT
level checked monthly (2B).

Guideline 2: Treatment of HCV infection in
patients with CKD
• 2.1: We recommend that all CKD patients infected
with HCV be evaluated for antiviral therapy (1A).
• 2.1.1: We recommend an interferon‐free regimen
(1A).
• 2.1.2: We recommend that the choice of specific
regimen be based on HCV genotype (and subtype),
viral load, prior treatment history, drug‐drug
interactions, glomerular filtration rate (GFR), stage
of hepatic fibrosis, kidney and liver transplant
candidacy, and comorbidities (1A).
• 2.1.3: Treat kidney transplant candidates in
collaboration with the transplant center to optimize
timing of therapy (Not Graded).

Guideline 2: Treatment of HCV infection in patients
with CKD
• 2.2: We recommend that patients with GFR ≥ 30
ml/min/1.73 m2 (CKD G1‐G3b) be treated with
any licensed direct‐acting antiviral (DAA)‐based
regimen (1A).
• 2.3: Patients with GFR < 30 ml/min/1.73 m2
(CKD G4‐G5D) should be treated with a
ribavirin‐free DAA‐based regimen

with CKD
• 2.4: We recommend that all kidney transplant
recipients infected with HCV be evaluated for
treatment (1A).
• 2.4.1: We recommend treatment with a DAA‐based
regimen (1A).
• 2.4.2: We recommend that the choice of regimen be
based on HCV genotype (and subtype), viral load,
prior treatment history, drug-drug interactions, GFR,
stage of hepatic fibrosis, liver transplant candidacy,
and comorbidities (1A).
• 2.4.3: We recommend avoiding treatment with
interferon (1A).

with CKD
• 2.4.4: We recommend pretreatment assessment for
drug‐drug interactions between the DAA‐based
regimen and other concomitant medications
including immunosuppressive drugs in kidney
transplant recipients (1A).
• 2.4.4.1: We recommend that calcineurin inhibitor
levels be monitored during and after DAA
treatment (1B).

with CKD
• 2.5: All treatment candidates should undergo
testing for HBV infection prior to therapy (Not
Graded).
• 2.5.1: If hepatitis B surface antigen [HBsAg] is
present, the patient should undergo assessment for
HBV therapy (Not Graded).
• 2.5.2: If HBsAg is absent but markers of prior
HBV infection (HBcAb‐positive with or without
HBsAb) are detected, monitor for HBV
reactivation with serial HBV DNA and liver
function tests during DAA therapy (Not Graded).

Presentation: HCV in dialysis

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