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