Managing Hepatitis C and CKD: A Clinical Update

> Introduction > Associations Between HCV and CKD > Overview of HCV Evaluation > New Options in HCV Management > Summary Introduction Overview of HCV Evaluation Hepatitis C virus (HCV) is the most common Diagnostic tests consist of two broad categories: chronic blood-borne infection in the United States (1) serologic assays that detect antibodies to HCV, (U.S.) and is more prevalent among patients with and (2) molecular assays that detect or quantify chronic kidney disease (CKD) than in the general HCV RNA.12 The Centers for Disease Control and population.1,2,3 HCV is usually asymptomatic, and Prevention (CDC) recommends a testing sequence detection requires screening patients with risk for identifying current HCV infection, consisting factors and testing for serum HCV antibodies or HCV of initial HCV antibody testing (either rapid or RNA (viral load). The field of HCV has dramatically laboratory-conducted assay) followed by an HCV changed in recent years with the advent of direct- RNA assay for all positive antibody tests.4,13 acting antivirals (DAAs) and multi-class drug Several organizations have provided guidelines for combinations. These newer therapies have been which individuals should be tested. All guidelines the focus of clinical research in recent years for their generally recommend screening patients at improved efficacy (90-100% sustained viral response increased risk for HCV (Table 1).4,13,14 Testing of (SVR) in most cases), with improved side effect patients with CKD should be considered in all profiles and better tolerability. Recently approved patients on dialysis and in CKD patients with DAA regimens can safely and effectively treat unexplained proteinuria, microscopic hematuria, patients with CKD and patients on dialysis. increased aminotransferase levels, or other known risk factors for HCV acquisition.6,15 Associations Between HCV and CKD An estimated 2.7-3.9 million people in the U.S. have chronic HCV infection, which is associated 4,14 with increased risk of liver fibrosis or cirrhosis, Table 1: Risk Factors for HCV Testing development of hepatocellular carcinoma, and is the leading indication for liver transplants in the • Born from 1945 through 1965 U.S.4 HCV infection is prevalent in patients with kidney disease; it is associated with progression to • Injected illicit drugs kidney failure, and with reduced survival in the CKD population.4,5,6,7 A study by Molnar et al. found that • Clotting factor concentrates made HCV infection is associated with higher mortality prior to 1987 risk, incidence of decreased kidney function, and progressive loss of kidney function.8 Multivariate • Blood transfusions or solid organ adjusted models showed HCV infection was transplants prior to July 1992 associated with a 2.2-fold higher mortality (fully • Long-term hemodialysis treatment adjusted hazard ratio (aHR), 95%CI: 2.17(2.13-2.21)), and a 15% higher incidence of decreased kidney • Healthcare-related exposure to function (aHR, 95%CI: 1.15(1.12-1.17)). HCV-infected blood

Patients with CKD often have compromised • Recipients of blood or organs from a immune systems and can be at increased risk for donor later testing HCV positive acquiring HCV infection. For example, patients receiving dialysis potentially have percutaneous • HIV infection HCV exposure from intravenous administration of treatments and potential for needle stick injury. • Signs or symptoms of liver disease Transplant recipients are at higher risk of infection (e.g., abnormal liver enzyme tests) from immunosuppression regimens used to prevent • Children born to HCV-positive mothers allograft rejection. Risk is also influenced by other factors that are not directly related to CKD, but (test after age 18 months of birth) individual characteristics (Table 1). • Receiving a tattoo in an unregulated There has been a strong and likely causal association setting between chronic HCV infection and glomerular • Incarceration diseases, including mixed cryoglobulinemia, membranoproliferative glomerulonephritis (MPGN), membranous nephropathy, and polyarteritis nodosa (PAN).9,10,11

2 New Options in HCV Management discontinuation rate of 25%.17 Issues of suboptimal efficacy and tolerability have also been reported in Research has led to a greater understanding of the non-dialysis CKD patients.18,19 HCV structure and life cycle. The HCV genome is a single-stranded, positive sense RNA strand with a A greater understanding of the of the HCV genome nucleotide length of 9.6 kb, and encodes for a single and proteins, coupled with ongoing unmet needs, polypeptide. (Figure 1).16 The virus is transmitted has led to the discovery of multiple therapeutic through blood and infects hepatocytes by interacting targets. This, in turn has led to the development of with co-receptors that results in its endocytosis, a host of newer therapies known as direct-acting followed by fusion of the viral genome with the antivirals (DAAs), which are medications targeted endosome and uncoating of its RNA, which is then at specific steps within the HCV life cycle. Typically, cleaved into 10 viral proteins (3 structural and 7 multiple classes are used in combination. nonstructural). There are at least six HCV genotypes Single-class DAAs include simeprevir, sofosbuvir, and (GT 1 - 6). Of the six genotypes, HCV GT 1-4 are the daclatasvir. Simeprevir is a macrocyclic noncovalent most commonly encountered clinically and HCV GT NS3/NS4A protease inhibitor for use in combination 1 is the most prevalent. Assessment of viral load and with IFN/RBV in HCV GT 1 infection. Sofosbuvir is a genotyping have been important determinants of nucleotide analog NS5B polymerase inhibitor, for successful therapeutic response to therapy. the treatment of HCV infection subtypes GT 1-4 as Historically, therapy was based on interferon (IFN), part of a regimen with RBV or IFN/RBV. Daclatasvir pegylated interferon (pegIFN), and/or ribavirin (RBV). is a NS5A inhibitor, for use with sofosbuvir (with These therapies can be effective, but have been or without RBV) for the treatment of patients with associated with lower SVR rates (compared to newer chronic HCV GT 1 or 3 infection. therapies), multiple side effects, and poor tolerability. Multi-class combination antiviral medications for IFN causes flu-like symptoms, autoimmune HCV infection include elbasvir-grazoprevir, phenomenon, and psychiatric side effects. RBV glecaprevir-pibrentasvir, ledipasvir-sofosbuvir, causes hemolytic anemia, nausea, and fatigue. A ombitasvir-paritaprevir-ritonavir and dasabuvir, meta-analysis by Fabrizi et al studying IFN/RBV in ombitasvir-paritaprevir-ritonavir, sofosbuvir- HCV-infected patients receiving hemodialysis velpatasvir, and sofosbuvir-velpatasvir-voxilaprevir showed a summary SVR rate of 56% and (Table 2).

Figure 1: HCV Genomic RNA16

IRES

1 Cleaved by host or virus proteases 3000 NS4 Core E1 E2 NS2 NS3 A B NS5A NS5B p7 Structural proteins Non-structural proteins

Nucleocapsid Lipid bilayer Core protein Viral (-) RNA Virus replication complex

HCV RNA Viral (+) RNA Spike E1 HCV viral particle proteins E2 Viral (+) RNA

Structure of HCV. HCV RNA encodes a polyprotein composed of about 3,000 amino acids. The core protein, and two envelope proteins are classified as structural proteins, while NS2, NS3, NS4A, NS4B, NS5A, and NS5B are non-structural proteins.

3 Elbasvir-grazoprevir is a once-daily tablet, which Ombitasvir-paritaprevir-ritonavir is indicated in consists of a NS3/4A protease inhibitor (grazoprevir) combination with RBV for the treatment of patients and a NS5A replication complex inhibitor (elbasvir), with HCV GT 4 infection without cirrhosis or with approved for the treatment of chronic HCV GT 1 or compensated cirrhosis. 4 infections with or without RBV in adult patients. Glecaprevir-pibrentasvir is a multi-class DAA for The Phase II/III C-SURFER trial evaluated elbasvir- the treatment of HCV GT 1-6 without cirrhosis grazoprevir in patients with HCV GT 1 infection and or with compensated cirrhosis. Glecaprevir is an advanced CKD (stages 4 and 5, including patients NS3/4A protease inhibitor and pibrentasvir is an on hemodialysis) with or without liver cirrhosis. NS5A inhibitor. Data from the EXPEDITION-4 study The study showed that elbasvir-grazoprevir showed that glecaprevir-pibrentasvir achieved an achieved an SVR12 in 94% of patients in the primary SVR12 of 98% (primary ITT) in HCV-infected patients intent-to-treat (ITT) analysis, supporting the use with advanced CKD and on dialysis.30 The study of elbasvir-grazoprevir in patients with severely included treatment-naive and -experienced patients compromised kidney function.14,20,21 (previous IFN or pegIFN ± RBV, or sofosbuvir and Ledipasvir-sofosbuvir is a multi-class DAA for the ribavirin ± pegIFN) with CKD stage 4 or 5 (including treatment of HCV GT 1, 4, 5, or 6, without cirrhosis hemodialysis). The study supports the efficacy and or with compensated cirrhosis, or in combination safety of glecaprevir-pibrentasvir in patients with with RBV in patients with decompensated cirrhosis. CKD and ESRD.14,30 The recommended duration Ledipasvir is a NS5A inhibitor. Sofosbuvir-velpatasvir of therapy is similar for patients without CKD. The is another DAA combination for the treatment of MAGELLAN-2 study, which included liver (n=80) adult patients with chronic HCV GT 1-6 infection, and kidney (n=20) transplant recipients, showed without cirrhosis or with compensated cirrhosis, an SVR12 achieved in 99% of patients receiving or in combination with RBV in patients with glecaprevir-pibrentasvir.31 decompensated cirrhosis. Velpatasvir is a NS5A inhibitor. No dosage recommendation can be given Summary for patients with severe renal impairment (eGFR <30 mL/min/1.73m2) or with ESRD due to higher HCV infection has been associated with multiple exposures (up to 20-fold) of the predominant adverse outcomes and increased risk in CKD sofosbuvir metabolite.22 Published reports have and HCV progression. Newer treatment options examined the use of sofosbuvir-based regimens are closing unmet medical needs, including in hemodialysis.23,24,25, Data from HCV-TARGET, a pan-genotypic, multi-class combination DAAs, and multicenter, longitudinal treatment cohort, showed offer the opportunity to manage HCV infection that SVR12 rates of 82% - 83% were similar across more effectively. eGFR groups (<30 mL/min; 31-45 mL/min; 46-60 However, ongoing issues remain. For example, mL/min; and >60 mL/min).26 Patients with eGFR testing for HBV prior to starting therapy is generally ≤45 mL/min more frequently experienced anemia, recommended for DAAs, and protease inhibitors worsening renal function and serious adverse generally should be avoided in patients with events, suggesting the need for close monitoring of decompensated cirrhosis.14,32,33,34 The U.S. Food and these patients.14,26 Studies have indicated successful Drug Administration (FDA) required a Boxed Warning use of sofosbuvir-containing regimens in kidney about the risk of HBV reactivation to be added transplant recipients, with dose reductions in some to the drug labels of DAAs directing health care cases.27,28 professionals to screen and monitor for HBV in all 33 Paritaprevir-ritonavir-dasabuvir-ombitasvir is a patients receiving DAA treatment. The presence of multi-class DAA for the treatment of HCV GT1. resistance-associated variants of HCV can attenuate 35 Ombitasvir is a NS5A inhibitor, paritaprevir is a the efficacy of DAAs. NS5A resistance variants NS3/4A protease inhibitor, and ritonavir is a can alter the length of therapy and necessitate the CYP3A inhibitor. These three therapies are addition of RBV. combined as a fixed-dose tablet and dasabuvir Other areas that require further study include the (NS5B inhibitor) is a separate tablet. A single-arm, optimal timing of DAA therapy and impact on multicenter study showed an SVR12 of 90% in long-term outcomes (e.g., morbidity, mortality, HCV GT1-infected patients with CKD stage 4/5 quality-of-life) within the CKD population. However, (including hemodialysis) treated with overall recent data suggests that HCV-infected CKD paritaprevir-ritonavir-dasabuvir-ombitasvir.29 patients can be effectively treated.

4 Table 2: Multi-Class Combination Direct Acting Antivirals36

Name Class/Description Genotype* Primary Metabolic Recommendations for Pathway CKD (per Package Insert)

Elbasvir- - Elbasvir: NS5A HCV GT 1 - Elbasvir: Hepatic No restrictions/dose Grazoprevir inhibitor or 4 - Grazoprevir: Hepatic adjustments - Grazoprevir: NS3/4A protease inhibitor

Glecaprevir- - Glecaprevir: NS3/4A HCV GT 1-6 - Glecaprevir: Hepatic No restrictions/dose Pibrentasvir protease inhibitor - Pibrentasvir: Hepatic adjustments - Pibrentasvir: NS5A inhibitor

Ledipasvir- - Ledipasvir: NS5A HCV GT 1,4,5, - Ledipasvir: Hepatic No dosage Sofosbuvir inhibitor or 6 - Sofosbuvir: Renal recommendation for - Sofosbuvir: NS5B patients with severe renal polymerase inhibitor impairment (eGFR <30 mL/min) or with ESRD

Ombitasvir- - Ombitasvir: NS5A Chronic HCV - Ombitasvir: Hepatic No restrictions/dose Paritaprevir- inhibitor GT 1 - Paritaprevir: Hepatic adjustments Ritonavir - Paritaprevir: NS3/4A - Ritonavir: Hepatic and protease inhibitor - Dasabuvir: Hepatic Dasabuvir - Ritonavir: CYP3A inhibitor - Dasabuvir: NS5B polymerase inhibitor

Ombitasvir- - Ombitasvir: NS5A HCV GT 4 - Ombitasvir: Hepatic No restrictions/dose Paritaprevir- inhibitor - Paritaprevir: Hepatic adjustments Ritonavir - Paritaprevir: NS3/4A - Ritonavir: Hepatic protease inhibitor - Ritonavir: CYP3A inhibitor

Sofosbuvir- - Sofosbuvir: NS5B HCV GT 1-6 - Sofosbuvir: Renal No dosage Velpatasvir polymerase inhibitor - Velpatasvir: Hepatic recommendation for - Velpatasvir: NS5A patients with severe renal inhibitor impairment (eGFR <30 mL/min) or with ESRD

Sofosbuvir- - Sofosbuvir: NS5B HCV GT 1-6 - Sofosbuvir: Renal No dosage Velpatasvir- polymerase inhibitor - Velpatasvir: Hepatic recommendation for Voxilaprevir - Velpatasvir: NS5A - Voxilaprevir: Hepatic patients with severe renal inhibitor impairment (eGFR <30 - Voxilaprevir: NS3/4A mL/min) or with ESRD protease inhibitor

* Consult Package Insert for specific indications. CKD, chronic kidney disease; ESRD, end-stage renal disease; GFR, glomerular filtration rate; HCV, Hepatitis C virus

Disclaimer: Information contained in this National Kidney Foundation educational resource is based upon current data available at the time of publication. Information is intended to help clinicians become aware of new scientific findings and developments. This educational resource is not intended to set out a preferred standard of care and should not be construed as one. Neither should the information be interpreted as prescribing an exclusive course of management. 5 References 1 Centers for Disease Control and Prevention (CDC). Blood safety: 20 Roth D, Nelson D, Bruchfeld A, et al. Grazoprevir plus elbasvir in diseases and organisms. Available at: https://www.cdc.gov/ treatment-naive and treatment-experienced patients with Hepatitis bloodsafety/bbp/diseases-organisms.html. Accessed September C virus genotype 1 infection and stage 4-5 chronic kidney disease 29, 2017. (The C-SURFER Study): a combination phase 3 study. Lancet. 2 Ladino M, Pedraza F, Roth D. 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