Management of Hepatitis C in Advanced Chronic Kidney Disease

Risk and Impact of HCV Infection in CKD

Introduction

Hepatitis C virus (HCV) remains a public health challenge. HCV is typically asymptomatic until

major complications supervene. Detection had been based on screening patients with

acknowledged risk factors, but more recently the focus has been on screening individuals born

between 1945 - 1965 given the high prevalence of HCV infection in this age group. The advent

of highly effective and well tolerated HCV therapies has made virological cure feasible for the

vast majority of HCV infected patients, including those with chronic kidney disease (CKD).

Prevalence and Associations of HCV and CKD

HCV persists as the most common chronic blood-borne infection in the United States (U.S.). An

estimated 2.7 - 3.9 million people in the United States have chronic HCV infection, which is

associated with increased risk of liver fibrosis or cirrhosis, development of hepatocellular

carcinoma, and is a common indication for liver transplant in the U.S.1,2 The majority (75% -

85%) of newly infected individuals will develop chronic infection. The incidence of HCV infection

is likely under-reported; most people infected are asymptomatic and it is estimated that only

half of those infected have been tested and diagnosed.3

HCV infection is a potentially life-threatening condition. The number of HCV-associated deaths

increased 10.9% from 2011 through 2014 and decreased 0.2% in 2015.4 Approximately one-half

of all deaths in 2015 occurred among persons aged 55 - 64 years.4 An observational cohort

study of mortality data showed that 19% of decedents had HCV listed on the death certificate,

despite 63% having medical record evidence of chronic liver disease, suggesting that HCV is

under-reported even in people with liver disease.5

In addition to hepatic complications (i.e., cirrhosis, hepatocellular carcinoma), HCV infection has

been implicated in other extrahepatic manifestations, including cardiovascular disease,

diabetes, neurocognitive dysfunction, systemic vasculitis, and B cell non-Hodgkin lymphoma

(Figure 1).6,7,8,9,10,11 HCV infection has also been linked to higher incidence and faster

progression of CKD as well as higher rates of end-stage renal disease (ESRD, also known as

kidney failure).

Figure 1: Extrahepatic Manifestations of Chronic HCV Infection

HCV is more prevalent among patients with CKD than in the general population.12,13 HCV

infection is a recognized cause of progression to kidney failure, and is associated with reduced

survival in the CKD population.14,15 A study by Molnar et al found that HCV infection is

associated with a higher mortality risk, incidence of decreased kidney function, and progressive

loss of kidney function (Figure 2).16 Multivariate adjusted models showed HCV infection

independently was associated with a 2.2 - fold higher mortality (adjusted hazard ratio (aHR),

95% confidence interval (CI): 2.13; 2.21), and a 15% higher incidence of decreased kidney

function (aHR, 95% CI: 1.12; 1.17).

Figure 2: Associations with HCV Infection, Mortality, and Decreased Kidney Function

A 6-year cohort study by Chen et al compared individuals newly diagnosed with HCV without

traditional CKD risk factors to randomly selected matched controls without HCV infection.17

HCV-infected patients had a significantly higher rate of CKD compared with the control group

(aHR 3.42 vs 2.48 per 1,000 person-years, P = 0.02) and had a significantly greater risk for CKD

(aHR 1.75, 95% CI: 1.25; 2.43, P=0.0009). The authors concluded that this association between

HCV and CKD may indicate a causative role for HCV in kidney injury.

The prevalence of HCV infection is higher among CKD patients of all stages compared with rates

in the general population, but is particularly high among patients receiving hemodialysis.18,19,20

A study by Goodkin et al evaluated data from the Dialysis Outcomes and Practice Patterns

Study (DOPPS).20 The study reviewed the HCV status of 76,689 adults enrolled between 1996 –

2015 and found that 7.5% of patients were HCV-positive at enrollment. HCV infection among

patients receiving hemodialysis was associated with higher risk of death, hospitalization, and

worse quality-of life scores. Cardiovascular and infectious hospitalizations are also greater

among patients infected with Hepatitis C.20 A meta-analysis of 14 observational studies by

Fabrizi et al observed an independent and significant relationship between anti-HCV

seropositivity in patients receiving hemodialysis and mortality risk (relative risk (RR) 1.35; 95%

CI, 1.25; 1.47).21

Mortality in HCV-infected patients receiving hemodialysis is most often related to progression

of liver disease (RR 3.82; 95% CI, 1.92; 7.61), with the cause of death attributed to cirrhosis and

hepatocellular carcinoma in most cases.21 HCV was also associated with increased risk for

cardiovascular mortality in patients receiving hemodialysis (RR 1.26; 95% CI, 1.10; 1.45).21 The

role of HCV in cardiovascular risk is believed to be related to inflammation of chronic disease

and atherogenesis mediated by the metabolic syndrome and dyslipidemia.9

Patients with CKD can be at increased risk for acquiring HCV infection due to factors directly

related to the treatment of their renal disease. For example, patients receiving hemodialysis are

at elevated risk for acquiring HCV due to their increased exposure to factors implicated in viral

transmission. Risk factors that relate to HCV risk among patients receiving hemodialysis include

duration and mode of dialysis, and prevalence of HCV in the hemodialysis unit.22 In 2016 a

report by the Centers for Disease Control and Prevention (CDC), highlighted an increased

number of reports of newly acquired HCV infection in patients on maintenance hemodialysis.23

Additional risks factors include intravenous drug use and a history of kidney transplantation.24

HCV infection is a concern in kidney transplantation, as it has been implicated in diminished

patient and graft survival. A meta-analysis by Fabrizi et al showed that HCV-positive patients

after kidney transplantation have an increased risk of mortality and graft loss.25 The study

identified 18 observational studies (n=133,530) of kidney transplant recipients. The summary

estimate for adjusted relative risk (aRR) of all-cause mortality was 1.85 (95% CI, 1.49; 2.31, P <

0.0001) and; for all-cause graft loss was 1.76 (95% CI, 1.46; 2.11, P < 0.0001).25 HCV infection

also increases the likelihood of posttransplant diabetes in kidney transplant recipients.26

There is an association between chronic HCV infection and glomerular diseases, including mixed

cryoglobulinemia, membranoproliferative glomerulonephritis (MPGN), membranous

nephropathy, and polyarteritis nodosa (PAN).27,28,29 Among patients with HCV-related

glomerulonephritis, rapid deterioration in kidney function has been observed in 20% - 25% of

patients, moderate renal insufficiency in 50% of patients, and hypertension in 80% of

patients.29 When biopsied, patients most often are found to have a MPGN pattern of injury on

light microscopy with immunofluorescence microscopy demonstrating granular staining for IgG,

IgM, C3 and C1q. Electron microscopy shows electron dense deposits in subendothelial

locations.30

Pathogenesis of HCV

The HCV genome is a single-stranded, RNA virus (Figure 3).31 The virus is transmitted

predominantly through blood and infects hepatocytes by interacting with co-receptors that

results in its endocytosis, followed by fusion of the viral genome with the endosome and

uncoating of its RNA, which is then cleaved into 10 viral proteins (3 structural and 7

nonstructural). The nonstructural HCV proteins (P7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B)

are processed by both viral and host proteases, and are essential in the HCV life cycle.32,33,34

There are at least six HCV genotypes (GT 1 - 6). Of the six genotypes, HCV GT 1 is the most

prevalent in the U.S.35,36,37 Viral treatment responses to interferon-based therapies have varied

based on genotype.

Figure 3: Structure of HCV

Several mechanisms have been implicated in the pathogenesis of kidney disease in patients

with HCV infection. HCV may have direct cytopathic effects on renal parenchyma associated

with HCV binding on the cell surface and undergoing endocytosis.38 Research has identified a

role for immune-mediated responses to HCV infection in the development of

glomerulonephritis, including an innate immune response mediated by increased expression of

toll-like receptors (TLRs) in glomeruli and a systemic immune response via cryoglobulins and the

formation of HCV-antibody immune complexes.38,39

Patients infected with HCV and with renal disease often have additional comorbidities that are

recognized risk factors for CKD, including diabetes mellitus, hypertension, hyperlipidemia,

cardiovascular disease, and liver cirrhosis. Several of these can be directly mediated by HCV and

not just comorbid conditions. For example, HCV may directly inhibit insulin signaling and

increase oxidative stress, thereby leading to endothelial dysfunction in CKD and progression of

kidney disease.40,41

Evaluation and Prevention Strategies for HCV Infection in Advanced CKD

Recognition of Risk Factors

Blood transfusions and the sharing of used needles and syringes had been the commonest

route of HCV spread in the U.S.42 Following introduction of routine blood screening for HCV

during 1991 - 1992, transfusion-related HCV infection has virtually disappeared. Injection drug

use is now the most common risk factor for HCV transmission. A needle-stick accident in the

healthcare setting is another significant risk factor.42 People with high-risk sexual behavior,

multiple partners, and sexually transmitted diseases are also at increased risk.42

Society guidelines recommend screening patients at increased risk for HCV.1,45,43 The American

Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America

(IDSA) guidelines on testing, managing, and treating HCV provide recommendations on HCV risk

factors that should prompt at least one-time testing for HCV in the general population (Figure

4).43 These include birth between 1945 and 1965, current or previous injection or intranasal

illicit drug use, receiving a tattoo in an unregulated setting, incarceration, healthcare-related

exposure to HCV-infected blood, being a recipient of an organ transplantation or blood

transfusion prior to 1992, and undergoing long-term hemodialysis, among others (Figures 4 and

5).

Figure 4: HCV Screening

Figure 5: HCV Screening Continued

Screening and Testing

Screening for HCV in CKD patients is justified for a number of reasons, including the high

prevalence of HCV infection in CKD patients.6 In addition, regular monitoring of kidney function

in HCV-infected patients is also important, including evaluation of proteinuria, hematuria and

serum creatinine. As a result of decreased muscle mass, serum creatinine values may be low in

patients with severe liver disease, so estimates of glomerular filtration rate (eGFR) should be

interpreted with this in mind.6

HCV infection can be asymptomatic, or may cause abdominal pain, gastrointestinal bleeding,

bloating, nausea, fatigue, fever, loss of appetite, weight loss, or jaundice. Because HCV is

asymptomatic in many cases, detection usually requires screening patients with risk factors and

confirming viremia in seropositive patients.

Diagnostic tests consist of two broad categories: (1) serologic assays that detect antibodies to

HCV and (2) molecular assays that detect or quantify HCV RNA. Other diagnostic modalities

(e.g., genotype testing, serum fibrosis panels, and liver biopsy) can help predict prognosis and

help select the optimal treatment regimen.44 The CDC and 2008 Kidney Disease: Improving

Global Outcomes (KDIGO) guidelines on Hepatitis C and CKD recommend a testing sequence for

identifying current HCV infection, consisting of initial HCV antibody testing (either rapid or

laboratory-conducted assay) followed by an HCV RNA assay for all positive antibody tests.1,15,45

Alanine aminotransferase (ALT) is a nonspecific marker of liver damage.46 HCV infection results

in an increase in serum ALT. However, spuriously “normal” ALT levels have been often reported

in HCV infected patients with advanced CKD, including patients receiving hemodialysis.14,47 Liver

biopsy, increasingly replaced by non-invasive transient elastography, can provide prognostic

information on extent of fibrosis in HCV-associated hepatic disease, but requires caution in

advanced CKD because of the low, but still potential, risk of bleeding complications.14

HCV testing of patients with CKD should be performed in patients with unexplained proteinuria,

microscopic hematuria, increased ALT levels, or other known risk factors for HCV

acquisition.15,48 All transplant candidates are also tested. Serologic testing to detect HCV

antibodies is suggested for non-dialysis CKD and hemodialysis in units with low prevalence of

HCV. A positive result should be followed by molecular testing to detect HCV RNA in the

blood―qualitative testing to detect the presence of HCV RNA, and quantitative testing to

detect the viral load.

Prevention

In general, primary prevention strategies for HCV include screening and testing blood donors,

inactivating HCV in plasma-derived products, testing and risk-reduction counseling for at-risk

patients, and vigilant infection control in health-care settings.

Effective infection control programs are an important part of providing high-quality health care

in multiple clinical settings, particularly in hemodialysis facilities. Certain components are

important parts of a successful program, including HCV surveillance through periodic testing of

ALT and HCV enzyme immunoassay (EIA), engaging of hemodialysis personnel into preventing

transmission of blood-borne pathogens, and implementation of clinical practice guidelines

related to HCV transmission.15,49 Surveillance of staff practices related to blood-borne

pathogens allows hemodialysis units the opportunity to understand specific problems with

hygienic precautions, monitor changes and outcomes over time, and assess the effects of

interventions or changes in protocols. Hemodialysis staff should be allowed sufficient

opportunity and time to perform the required responsibilities without compromising standard

hygienic precautions. These functions should be performed separate from other clinical duties,

in order to maintain focus on infection control measures. Staff should also undergo

appropriate, structured, and ongoing training on infection control policies and practices.

Infection control requirements and procedures within hemodialysis facilities should include all

standard precautions adopted in multiple healthcare settings, to prevent transmission of blood-

borne pathogens, such as HCV.49

Infection control techniques to prevent HCV transmission in dialysis facilities have mainly

included safe injection and hygiene practices.49 Activities to help reduce the risk of infection

include preparing single-use medications for patients in a clean area separate from dialysis

stations, avoidance of using common medication carts to deliver medications to patients,

cleaning and disinfecting stations between patients, and appropriate use of hand hygiene

before and after patient contact.49,50 Items taken into a dialysis station for individual patients

(e.g., supplies, medications, equipment) should be either cleaned or disinfected between

patients, or disposed of if they cannot be cleaned or disinfected.

Management of HCV and CKD: A Clinical Update

Interferon-Based Therapy

The goal of treatment is to achieve sustained virologic response (SVR) (defined as undetectable

HCV RNA 12 weeks post-treatment). Optimal treatment for HCV-infected CKD patients should

consider the HCV genotype, extent of liver damage, CKD stage, transplant candidacy, prior HCV

treatment, patient comorbidities, and the benefits and risks of antiviral treatment itself.15

Historically, identifying the specific HCV genotype and determining the viral load through

nucleic acid testing (NAT) allowed stratification about the likelihood of achieving sustained

virologic response (SVR) following treatment and determined treatment duration with IFN-

based regimens.

IFN is a naturally occurring nonglycosylated serum protein produced by immune cells in

response to foreign antigen exposure; pegylated IFN (pegIFN) is a long acting polymer

formulation of IFN. Ribavirin (RBV) is a nucleoside analog. These therapies can be effective, but

have also have been associated with suboptimal SVR rates, multiple side effects, and poor

tolerability. Infections with HCV can be less responsive to IFN therapy and may require up to 48

weeks of treatment. A meta-analysis of 10 clinical studies by Fabrizi et al studying IFN/RBV in

HCV-infected patients receiving hemodialysis showed a summary SVR rate of 56% and

discontinuation rate of 25%.51 Antiviral therapy for HCV infection had been difficult in patients

with CKD due to the generally poor tolerance of IFN and RBV based regimens in patients that

often have with multiple comorbidities including anemia.52 The possible hemolytic anemia

induced by ribavirin can be hazardous in patients with CKD in whom baseline anemia is typical.

Importantly, RBV is not efficiently dialyzed and thus the associated anemia can be long lasting.53

IFN-based HCV therapy post-kidney transplant generally has not been advised due to concerns

about risk of precipitating graft rejection.54

The advent of direct-acting antivirals (DAAs) has dramatically changed the approach to HCV

genotype and viral load. For example, SVR rates generally exceed 90% in most subpopulations

with DAAs. Determining HCV genotype is still a part of defining the Hepatitis C treatment

regimen for a patient, as the efficacy of several DAAs can vary by genotype. With the recent

arrival of several pan-genotypic DAAs, it is possible that determining genotype may have a

lesser role in planning HCV treatment in the future.

Direct-Acting Antivirals

A greater understanding of the HCV genome and proteins has led to the discovery of multiple

therapeutic targets and the development of a host of DAAs, which target non-structural parts of

the HCV genome (Figure 6).55,56 These therapies include NS3/4A protease inhibitors, nucleotide

analog NS5B polymerase inhibitors, NS5A inhibitors, and multi-class combination antiviral

medications. Examples include simeprevir, sofosbuvir, and daclatasvir. Simeprevir is a

macrocyclic noncovalent NS3/NS4A protease inhibitor for use in combination with IFN/RBV in

HCV GT 1 infection. Sofosbuvir is a nucleotide analog NS5B polymerase inhibitor, for the

treatment of HCV infection subtypes GT 1-4. Daclatasvir is a NS5A inhibitor, for use with

sofosbuvir (with or without RBV) for the treatment of patients with chronic HCV GT 1 or 3

infection. The advent of DAAs has dramatically changed the field of Hepatitis C. These newer

therapies have been the focus of clinical research in recent years for their improved efficacy.

Figure 6: HCV Life Cycle and Potential Targets for Direct-Acting Antivirals

Typically, multiple DAAs are used in combination, NS5A or NS5B inhibitor with a protease

inhibitor, to target the different aspects of the HCV genome. Multi-class combination antiviral

medications for HCV infection are summarized in Figure 7.

Figure 7: Multi-Class Combination Direct-Acting Antivirals Elbasvir-grazoprevir is a once-daily tablet, which consists of a NS3/4A protease inhibitor

(grazoprevir) and a NS5A replication complex inhibitor (elbasvir), approved for the treatment of

chronic HCV GT 1 or 4 infections with or without RBV in adult patients. No dosage adjustment

of elbasvir-grazoprevir is required in patients with any degree of renal impairment including

patients on hemodialysis.57

The Phase II/III C-SURFER trial evaluated elbasvir-grazoprevir in patients with HCV GT 1

infection and advanced CKD (stages 4 and 5 (eGFR <30 mL/min/1.73m2)), including patients on

hemodialysis) with or without liver cirrhosis. The study compared 12 weeks of the daily fixed-

dose combination of elbasvir (50 mg)/grazoprevir (100 mg) versus placebo.58 Of the 224

patients in the study, 179 were hemodialysis-dependent. The SVR12 rates (primary intention-

to-treat [ITT] and modified intention-to-treat [mITT] analysis) were 94% and 99%, respectively,

supporting the use of elbasvir-grazoprevir in patients with severely compromised kidney

function.43,58,59

Paritaprevir-ritonavir-dasabuvir-ombitasvir is a multi-class DAA for the treatment of HCV GT1.

Ombitasvir is a NS5A inhibitor, paritaprevir is a NS3/4A protease inhibitor, and ritonavir is a

CYP3A inhibitor. These three therapies are combined as a fixed-dose tablet and dasabuvir

(NS5B inhibitor) is a separate tablet. Ombitasvir-paritaprevir-ritonavir is indicated in

combination with RBV for the treatment of patients with HCV GT 4 infection without cirrhosis

or with compensated cirrhosis.

Due to ritonavir boosting this combination has significant drug-drug interactions with

calcineurin inhibitors, requiring dose adjustments and careful monitoring in transplant

recipients.

A single-arm, multicenter study by Pockros et al examined the use of paritaprevir-ritonavir-

dasabuvir-ombitasvir (with or without RBV) in the treatment-naïve adult patients (n=25) with

HCV GT 1 infection, without cirrhosis and with CKD stage 4 or 5 (including hemodialysis).60

Patients with HCV GT 1a also received RBV, while those with HCV GT1b did not receive RBV. The

study showed an SVR12 of 90% in patients treated with paritaprevir-ritonavir- dasabuvir-

ombitasvir. Overall, the treatments were well-tolerated, although use of RBV may require a

reduction or interruption to manage anemia.

Glecaprevir-pibrentasvir is a multi-class DAA for the treatment of HCV GT 1 - 6 without cirrhosis

or with compensated cirrhosis. Glecaprevir is an NS3/4A protease inhibitor and pibrentasvir is

an NS5A inhibitor. No dosage adjustment of glecaprevir-pibrentasvir is required in patients with

mild, moderate or severe renal impairment, including those on dialysis.61

The EXPEDITION-4 study evaluated treatment of glecaprevir-pibrentasvir in patients infected

with HCV GT 1 - 6. The study included treatment-naive and -experienced patients (previous IFN

or pegIFN ± RBV, or sofosbuvir and ribavirin ± pegIFN) with CKD stage 4 or 5 (including

hemodialysis). The daily fixed-dose combination of glecaprevir (300 mg)-pibrentasvir (120mg)

was administered as three 100 mg-40 mg fixed-dose combination pills. The study showed that

glecaprevir-pibrentasvir achieved an SVR12 of 98% (primary ITT) in HCV-infected patients with

advanced CKD and on dialysis, across all major HCV genotypes.62 A modified ITT (excluding

subjects who did not achieve SVR for reasons other than virologic failure), showed an SVR 12 of

100%. The study supports the efficacy and safety of glecaprevir-pibrentasvir in patients with

CKD and ESRD.43,62 The recommended duration of therapy is similar for patients without CKD.

MAGELLAN-2 was a phase III, open-label, single arm study that evaluated treatment of

glecaprevir-pibrentasvir in liver (n=80) or kidney (n=20) transplant recipients with HCV GT 1-6

infection (≥3 months posttransplant). The study included patients without cirrhosis who were

HCV treatment naïve, or treatment experienced with IFN, pegIFN ± RBV or sofosbuvir with RBV

± pegIFN (except for HCV GT 3 patients). Glecaprevir-pibrentasvir (300mg – 120 mg) was

administered for 12 weeks. The study showed an SVR12 achieved in 99% of patients receiving

glecaprevir-pibrentasvir.63

Ledipasvir-sofosbuvir is a multi-class DAA for the treatment of HCV GT 1, 4, 5, or 6, without

cirrhosis or with compensated cirrhosis, or in combination with RBV in patients with

decompensated cirrhosis. Ledipasvir is a NS5A inhibitor. Sofosbuvir-velpatasvir is another DAA

combination for the treatment of adult patients with chronic HCV GT 1-6 infection, without

cirrhosis or with compensated cirrhosis, or in combination with RBV in patients with

decompensated cirrhosis. Velpatasvir is a NS5A inhibitor. No dosage recommendation can be

given for patients with severe renal impairment (eGFR <30 mL/min/1.73m2) or with ESRD due

to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite.64,65 In general,

this consideration applies to multi-class combination therapies that contain sofosbuvir.

Studies have evaluated the use of sofosbuvir-containing regimens in hemodialysis.66,67,68 A

study of 15 HCV GT 1- infected patients with advanced CKD (eGFR <30 mL/min/1.73m2), 11 of

which received hemodialysis, showed that SVR at week four and 12 were documented to be

93% and 87%, respectively, in patients treated with half-dose sofosbuvir plus full-dose

simeprevir.68 Data from HCV-TARGET, a multicenter, longitudinal treatment cohort, showed

that SVR12 rates of 82% - 83% were similar across eGFR groups (<30 mL/min; 31-45 mL/min;

46-60 mL/min; and >60 mL/min) in patients receiving a sofosbuvir-containing regimen.69

However, patients with eGFR ≤45 mL/min/1.73m2 more frequently experienced anemia,

worsening renal function and serious adverse events.43,69

Studies have indicated successful use of sofosbuvir-containing regimens in kidney transplant

recipients, with dose reductions in some cases.70,71,72 A study by Sawinski et al evaluated 20

kidney transplant recipients, 88% of which were infected with HCV GT 1. The study showed use

of sofosbuvir-containing regimens achieved 100% SVR without major toxicity and with

adjustment of immunosuppression necessary in less than half of patients. The most commonly

used regimen was sofosbuvir 400 mg daily in combination with simeprevir 150 mg daily.70 A

study by Columbo et al evaluated the use of 90 mg ledipasvir with 400 mg sofosbuvir in kidney

transplant recipients (n=114) with chronic HCV GT 1 or 4 infection (with or without

compensated cirrhosis), and an eGFR ≥40 mL/min/1.73m2.72 The study showed 100% of

patients achieved SVR12. Most studies in kidney transplant recipients have enrolled patients

with eGFR >30 mL/min/1.73m2, allowing the use of sofosbuvir-based regimens.

Overview of AASLD-IDSA Recommendations for DAAs in CKD

The most recent AASLD-IDSA guidelines issued recommendations for use of DAAs, as it relates

to patients with Hepatitis C and CKD.43 In HCV-infected patients with CKD Stage 1, 2, or 3, no

dose adjustment is required when using the following:43

Daclatasvir (60 mg, usually used in combination)

Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg)

Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg)

Fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg)

Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)

Simeprevir (150 mg, usually used in combination)

Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100

mg)

Sofosbuvir (400 mg, usually used in combination)

Recommended regimens for patients with CKD Stage 4 or 5 (eGFR <30 mL/min/1.73m2 or ESRD)

include 12 weeks of daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for

HCV GT 1 or GT 4. Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) is

recommended in CKD 4/5 for HCV GT 1-6 for 8-16 weeks. Duration of glecaprevir-pibrentasvir

should be based on presence of cirrhosis and prior treatment experience, and patients in this

group should be treated as would patients without CKD.43

In treatment-naive and -experienced kidney transplant patients with HCV GT 1 or 4 (with or

without compensated cirrhosis), daily fixed-dose combination of glecaprevir (300

mg)/pibrentasvir (120 mg) for 12 weeks is recommended. Daily fixed-dose combination of

ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks is also recommended for this patient

population.43

In treatment-naive and -experienced kidney transplant patients with HCV GT 2, 3, 5, or 6 (with

or without compensated cirrhosis), daily fixed-dose combination of glecaprevir (300

mg)/pibrentasvir (120 mg) for 12 weeks is recommended. Daily daclatasvir (60 mg) plus

sofosbuvir (400 mg) plus low initial dose of ribavirin (600 mg; increase as tolerated) for 12

weeks is an alternative regimen for this patient population.43

Additional Considerations for DAAs

Studies have shown that DAAs can be more effective compared to IFN-based regimens.

However, issues regarding their use need to be considered. For example, testing for HBV prior

to starting therapy is generally recommended for DAAs, and protease inhibitors generally

should be avoided in patients with decompensated cirrhosis.43,73,74,75 The presence of

resistance-associated variants of HCV can attenuate the efficacy of DAAs.76 NS5A resistance

variants can alter the length of therapy and necessitate the addition of RBV.

Drug interactions are also an important consideration for DAAs, thus, the Package Insert should

be reviewed for specific interactions, contraindications, and dose adjustments. Online

resources, such as https://www.hep-druginteractions.org/, are also available.77 Generally,

drugs/supplements to consider for potential interactions with certain DAAs can include statins,

proton pump inhibitors, St John’s wort, and other antiretroviral agents.43,55 Drug interactions

are also an important consideration in kidney transplant recipients. A summary of drug

interactions between calcineurin inhibitors and DAAs, along with AASLD-IDSA

recommendations in the setting of post liver transplantation, is provided in Figure 8.

Figure 8: DAA Interactions with Calcineurin Inhibitors

Summary

HCV infection has been associated with multiple adverse outcomes, increased risk in CKD, and

unmet medical needs. Effective prevention strategies, along with timely diagnosis and

treatment, are important components of Hepatitis C management. There are multiple areas of

research aimed at improving outcomes and addressing unmet medical needs, such as the utility

and safety of HCV positive donor organs, which have the potential to help broaden supply, and

thus, shorten wait times.78 Research has also focused on newer treatment options, including

pan-genotypic, multi-class combination DAAs. These newer therapies offer the opportunity to

manage HCV infection more effectively (Figure 9).13 Areas that require further study include the

optimal timing of therapy and impact on long-term outcomes (e.g., morbidity, mortality,

quality-of-life) within the CKD population. However, recent data on newer therapeutic options

suggests a greater opportunity to treat CKD patients with an HCV infection more effectively.

Figure 9: Hepatitis C Treatment in CKD: The KDIGO Perspective

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