Executive Summary of the KDIGO 2022 Clinical Practice Guideline for the Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C in Chronic Kidney Disease

Abstract

Infection with the hepatitis C virus (HCV) has adverse liver, kidney, and cardiovascular consequences in patients with chronic kidney disease (CKD), including those on dialysis therapy or with a kidney transplant. Since the publication of the Kidney Disease: Improving Global Outcomes (KDIGO) HCV Guideline in 2018, advances in HCV management, particularly in the field of antiviral therapy and treatment of HCV-associated glomerular diseases, coupled with increased usage of HCV-positive kidney grafts, have prompted a reexamination of the 2018 guideline. As a result, the Work Group performed a comprehensive review and revised the 2018 guidance. This Executive Summary highlights key aspects of the updated guideline recommendations for 3 chapters: Chapter 2: Treatment of HCV infection in patients with CKD; Chapter 4: Management of HCV-infected patients before and after kidney transplantation; and Chapter 5: Diagnosis and management of kidney diseases associated with HCV infection. Infection with the hepatitis C virus (HCV) has adverse liver, kidney, and cardiovascular consequences in patients with chronic kidney disease (CKD), including those on dialysis therapy or with a kidney transplant. Since the publication of the Kidney Disease: Improving Global Outcomes (KDIGO) HCV Guideline in 2018, advances in HCV management, particularly in the field of antiviral therapy and treatment of HCV-associated glomerular diseases, coupled with increased usage of HCV-positive kidney grafts, have prompted a reexamination of the 2018 guideline. As a result, the Work Group performed a comprehensive review and revised the 2018 guidance. This Executive Summary highlights key aspects of the updated guideline recommendations for 3 chapters: Chapter 2: Treatment of HCV infection in patients with CKD; Chapter 4: Management of HCV-infected patients before and after kidney transplantation; and Chapter 5: Diagnosis and management of kidney diseases associated with HCV infection. Hepatitis C virus (HCV) infection in the chronic kidney disease (CKD) population has presented some unique challenges. These include its high prevalence among dialysis patients, transmission within dialysis units and by infected grafts, and the resultant increased risk of progressive liver disease in chronically infected patients who remain on dialysis, as well as in kidney transplant recipients. Additional challenges in these populations previously included potentially reduced tolerance of antiviral therapy and choice of appropriate regimen. In 2008, Kidney Disease: Improving Global Outcomes (KDIGO) published a guideline1Kidney Disease: Improving Global Outcomes (KDIGO)KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease.Kidney Int Suppl. 2008; 73: S1-S99Abstract Full Text Full Text PDF Google Scholar addressing HCV management in CKD, and in 2018, a complete update of the guideline was produced that encompassed the major advances in HCV management that had occurred in the preceding decade,2Kidney Disease: Improving Global Outcomes (KDIGO) Hepatitis C Work GroupKDIGO 2018 clinical practice guideline for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease.Kidney Int Suppl. 2018; 8: 91-165Abstract Full Text Full Text PDF Scopus (131) Google Scholar such as noninvasive methods for evaluating liver-disease severity and the availability of oral direct-acting antiviral (DAA) therapies. Since the 2018 guideline was published, additional DAA regimens are being used in the CKD population and kidney transplant recipients. In addition, the increasing experience with the use of organs from HCV-infected donors has expanded allograft access in kidney transplantation. The role of antiviral therapy in treating glomerulonephritis due to HCV infection has also been more clearly defined. As a result of these advances, we undertook an update on portions of the 2018 guideline focusing on these evolving areas in Chapters 2, 4, and 5. Chapters 1 and 3, addressing detection and evaluation of HCV in CKD, and prevention of its transmission in hemodialysis units, respectively, remain current and did not warrant any substantive revision; thus, they remain unchanged from the 2018 guideline. This Executive Summary presents the revised recommendations and highlights the rationale for the revisions to Chapters 2, 4, and 5.3Kidney Disease: Improving Global Outcomes (KDIGO) Hepatitis C Work GroupKDIGO 2022 clinical practice guideline for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease.Kidney Int. 2022; 102: S129-S205Scopus (10) Google Scholar These recommendations fully replace all recommendations from the equivalent chapters in the 2018 guideline.2Kidney Disease: Improving Global Outcomes (KDIGO) Hepatitis C Work GroupKDIGO 2018 clinical practice guideline for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease.Kidney Int Suppl. 2018; 8: 91-165Abstract Full Text Full Text PDF Scopus (131) Google Scholar DAA therapy is highly effective and well-tolerated (with rare serious adverse events) in patients across all stages of CKD, including in patients undergoing dialysis and following kidney transplantation. Sustained virologic response rates 12 weeks after treatment (SVR12) range from 92%–100% in all stages of CKD and across a variety of DAA regimens. Serious adverse event rates attributed to DAA generally are reported in fewer than 1% of treated patients. As a result, interferon-based therapy is no longer used in HCV. With the introduction of several DAA regimens active against all HCV genotypes (pangenotypic), awareness of HCV genotype is less of a concern in antiviral therapy. However, in some countries, genotype-specific DAA regimens are more readily accessible, and use of these regimens thus requires ascertainment of HCV genotype prior to treatment. Multiple pangenotypic and genotype-specific DAA regimens have been investigated in CKD G4–G5ND (ND, non-dialysis), G5D (D, dialysis), and in kidney transplant recipients, and they are consistently highly effective and well-tolerated. Since the publication of the KDIGO 2018 HCV guideline, evidence has mounted that sofosbuvir, a key component of several regimens, is safe for all stages of CKD, including for individuals with low glomerular filtration rate (GFR) or undergoing dialysis. This development is important because in many nations, the only available DAA regimens are those that are sofosbuvir-based. Additionally, protease inhibitors (“-previrs” such as simeprevir, paritaprevir, and grazoprevir) are contraindicated in patients with Child-Pugh B and C cirrhosis. In patients with normal kidney function, DAA therapy arrests progression of liver disease and reduces its complications, while improving patient survival with acceptable toxicity. Additionally, evidence exists for improvement in cardiovascular disease following anti-HCV therapy in the general population. These benefits of DAA therapy potentially translate to patients with CKD as well. The KDIGO HCV Work Group agreed with other specialty guidelines, including the American Association for the Study of Liver Diseases/Infectious Diseases Society of America Guideline [AASLD/IDSA]), that HCV treatment should be withheld in patients with a very limited life expectancy (https://www.hcvguidelines.org/evaluate/when-whom). As shown in Figure 1, a number of pangenotypic regimens can be used, irrespective of GFR. If a non-pangenotypic regimen is contemplated, identification of specific genotype is necessary to determine its efficacy. Dose adjustment of DAA is not required in CKD G1–G5ND. Treatment duration varies by regimen (but currently is typically 12 weeks), presence of cirrhosis, and prior DAA therapy. The most recent recommendations should be confirmed by consulting the latest AASLD/IDSA guidelines (https://www.hcvguidelines.org) or the European Association for the Study of the Liver (EASL) guidelines (http://www.easl.eu/research/our-contributions/clinical-practice-guidelines) on HCV therapy. Similar to CKD G1–G5ND, multiple pangenotypic as well as genotype-specific regimens are available for patients with CKD G5D (Figure 1), with treatment durations varying based on DAA regimen as well as the presence or absence of cirrhosis and/or prior HCV treatment. DAA dose adjustment is also not required for patients with CKD G5D. The most recent recommendations should be confirmed by consulting the latest AASLD/IDSA or EASL guidelines on HCV therapy. The majority of data on DAA therapy in CKD G5D derives from patients undergoing hemodialysis with limited information on the safety and efficacy of DAA in patients undergoing peritoneal dialysis. Pangenotypic regimens, as well as genotype-specific regimens, are safe and effective in kidney transplant recipients. Most of the data for DAA use in kidney transplant recipients derive from individuals with GFR ≥30 ml/min per 1.73 m2 (CKD G1T–G3T; Figure 1). Limited information on high efficacy and safety of DAA can be extrapolated from DAA use in the highly selected population of HCV-uninfected recipients of kidneys from HCV-infected donors who at least initially have low GFR. The major concern about DAA use in kidney transplantation is the potential for drug–drug interactions that could occur with concomitant use of immunosuppressive agents such as calcineurin and mTOR inhibitors. The most recent recommendations should be confirmed by consulting the latest AASLD/IDSA or EASL guidelines on HCV therapy as well as the University of Liverpool Hepatitis Drug Interactions website (http://www.hep-druginteractions.org). With suppression of HCV replication, reactivation of HBV replication may occur in patients with current or prior HBV infection. Testing for markers of HBV infection including hepatitis B surface antigen (HBsAg), total core antibody (anti-HBc antibody), and antibody to hepatitis B surface antigen (anti-HBs antibody) is indicated prior to DAA therapy. HBV antiviral therapy should be administered prior to DAA therapy if criteria for HBV treatment in accordance with AASLD or EASL are met.4European Association for the Study of the Liver (EASL)EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection.J Hepatol. 2017; 67: 370-398Abstract Full Text Full Text PDF PubMed Scopus (3395) Google Scholar,5Terrault N.A. Lok A.S.F. McMahon B.J. et al.Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.Hepatology. 2018; 67: 1560-1599Crossref PubMed Scopus (2219) Google Scholar If HBsAg is absent but markers of prior HBV infection (HBcAb-positive with or without HBsAb) are detected, HBV antiviral therapy is not required prior to DAA therapy, but aminotransferase levels should be checked regularly and HBV DNA testing should be performed if levels of liver function tests rise during DAA therapy. If HBV viremia is present, confirming reactivation as the reason for the rise in aminotransferases, therapy for HBV should be started. If left untreated, HCV infection decreases patient survival and allograft survival following kidney transplantation. However, for patients with CKD G5 or G5D and HCV infection, survival is still improved by kidney transplantation compared to remaining on chronic dialysis. DAA therapy has also been shown to be effective and well-tolerated in kidney transplant recipients.Chapter 2: Treatment of HCV Infection in Patients With CKD2.1:We recommend that all patients with CKD (G1-G5), on dialysis (G5D), and kidney transplant recipients (G1T-G5T) with HCV be evaluated for direct-acting antiviral (DAA)-based therapy as outlined in Figure 1 (1A).2.1.1:We recommend that the choice of specific regimen be based on prior treatment history, drug–drug interactions, glomerular filtration rate (GFR), stage of hepatic fibrosis, kidney and liver transplant candidacy, and comorbidities (1A). If pangenotypic regimens are not available, HCV genotype (and subtype) should guide the choice of treatment (Figure 1).2.1.2:Treat kidney transplant candidates in collaboration with the transplant center to optimize timing of therapy (Not Graded).2.1.3:We recommend pre-treatment assessment for drug–drug interactions between the DAA-based regimen and other concomitant medications including immunosuppressive drugs in kidney transplant recipients (1A).2.1.4:We recommend that calcineurin inhibitor levels be monitored during and after DAA treatment in kidney transplant recipients (1B).2.2:All patients with CKD (G1-G5), on dialysis (G5D), and kidney transplant recipients (G1T-G5T) with HCV should undergo testing for hepatitis B virus (HBV) infection prior to DAA therapy (Not Graded).2.2.1:If hepatitis B surface antigen [HBsAg] is present, the patient should undergo assessment for HBV therapy (Not Graded).2.2.2:If HBsAg is absent but markers of prior HBV infection (HBcAb-positive with or without HBsAb) are detected, exclude HBV reactivation with HBV DNA testing if levels of liver function tests rise during DAA therapy (Not Graded). 2.1:We recommend that all patients with CKD (G1-G5), on dialysis (G5D), and kidney transplant recipients (G1T-G5T) with HCV be evaluated for direct-acting antiviral (DAA)-based therapy as outlined in Figure 1 (1A).2.1.1:We recommend that the choice of specific regimen be based on prior treatment history, drug–drug interactions, glomerular filtration rate (GFR), stage of hepatic fibrosis, kidney and liver transplant candidacy, and comorbidities (1A). If pangenotypic regimens are not available, HCV genotype (and subtype) should guide the choice of treatment (Figure 1).2.1.2:Treat kidney transplant candidates in collaboration with the transplant center to optimize timing of therapy (Not Graded).2.1.3:We recommend pre-treatment assessment for drug–drug interactions between the DAA-based regimen and other concomitant medications including immunosuppressive drugs in kidney transplant recipients (1A).2.1.4:We recommend that calcineurin inhibitor levels be monitored during and after DAA treatment in kidney transplant recipients (1B). patients with CKD (G1-G5), on dialysis (G5D), and kidney transplant recipients (G1T-G5T) with HCV should undergo testing for hepatitis B virus (HBV) infection prior to DAA therapy (Not Graded).2.2.1:If hepatitis B surface antigen [HBsAg] is present, the patient should undergo assessment for HBV therapy (Not Graded).2.2.2:If HBsAg is absent but markers of prior HBV infection (HBcAb-positive with or without HBsAb) are detected, exclude HBV reactivation with HBV DNA testing if levels of liver function tests rise during DAA therapy (Not Graded). to the evaluation and management of HCV-infected kidney transplant candidates is presented in Figure patients who are anti-HCV of viremia and evaluation of the severity of liver disease and of fibrosis, typically by noninvasive is also as outlined in Chapter If cirrhosis is based on clinical or after assessment of liver fibrosis, additional evaluation is to determine if is hepatic is with Patients with clinical evidence of cirrhosis or other clinical such as or hepatic among or should be evaluated for transplant if they have (Figure In HCV-infected patients with cirrhosis without or in those without evidence of cirrhosis, kidney transplantation is as DAA therapy can progression of liver disease (Figure DAA therapy should be administered to all HCV-infected kidney transplant before or after transplantation. timing of HCV treatment after kidney include by severity of hepatic fibrosis, and of the patient and to an from an HCV-infected In a patient with cirrhosis or no cirrhosis for transplant is to be than DAA therapy can be administered prior to transplant to treatment of 12 weeks duration with of 12 weeks after its (Figure HCV-infected kidney transplant candidates with an kidney can be treated for HCV before or after transplantation on the timing of transplantation. of kidneys from HCV-infected and donors the and use should be kidneys from HCV-infected donors only to HCV-infected recipients, reduced for transplantation without a on patient In DAA therapy should be administered to progression of liver disease and other of and management of kidney transplant candidates HCV recommend kidney transplantation as the for patients with CKD G5 irrespective of presence of HCV infection that all kidney transplant candidates with HCV be evaluated for severity of liver disease and presence of prior to for kidney transplantation recommend that patients with cirrhosis, and no undergo kidney transplantation and that patients with cirrhosis or hepatic or evidence of on or undergo a transplantation (1B). Treatment of those with should be on a recommend patients with HCV and cirrhosis for transplantation of HCV treatment in to kidney transplantation should be based on by the use of kidneys from HCV-infected and severity of liver (Not recommend that all kidney transplant candidates with HCV be for DAA therapy, before or after transplantation that HCV-infected kidney transplant candidates with a kidney be for treatment before or after transplantation on the timing of transplantation and management of kidney transplant candidates HCV recommend kidney transplantation as the for patients with CKD G5 irrespective of presence of HCV infection that all kidney transplant candidates with HCV be evaluated for severity of liver disease and presence of prior to for kidney transplantation recommend that patients with cirrhosis, and no undergo kidney transplantation and that patients with cirrhosis or hepatic or evidence of on or undergo a transplantation (1B). Treatment of those with should be on a recommend patients with HCV and cirrhosis for transplantation of HCV treatment in to kidney transplantation should be based on by the use of kidneys from HCV-infected and severity of liver (Not recommend that all kidney transplant candidates with HCV be for DAA therapy, before or after transplantation that HCV-infected kidney transplant candidates with a kidney be for treatment before or after transplantation on the timing of transplantation kidneys from HCV-infected donors have been HCV-uninfected recipients. these patients, DAA therapy administered at the of transplant or is safe and effective to of HCV infection in the DAA regimens and timing of DAA treatment for weeks has been associated with rates of (SVR12) as well as allograft function and with patient survival rates at 1 following transplant. treatment duration have been more associated with thus, a treatment is should be to HCV of kidneys from HCV-infected recommend that all kidney donors be for HCV infection with and testing is assessment of liver fibrosis, HCV-infected potential kidney donors who not have cirrhosis should undergo HCV treatment before if the is they can be for if they virologic response and remain to be a (Not recommend that kidneys from HCV-infected donors be of HCV of potential kidney transplant recipients kidneys from HCV-infected donors HCV-uninfected recipients, transplant that patients and are in with information to Patients should be of the and benefits of transplantation with an HCV-infected kidney, including the for DAA treatment (Not kidneys from HCV-infected donors HCV-uninfected recipients, transplant should availability of for in the (Not Graded). of kidneys from HCV-infected recommend that all kidney donors be for HCV infection with and testing is assessment of liver fibrosis, HCV-infected potential kidney donors who not have cirrhosis should undergo HCV treatment before if the is they can be for if they virologic response and remain to be a (Not recommend that kidneys from HCV-infected donors be of HCV of potential kidney transplant recipients kidneys from HCV-infected donors HCV-uninfected recipients, transplant that patients and are in with information to Patients should be of the and benefits of transplantation with an HCV-infected kidney, including the for DAA treatment (Not kidneys from HCV-infected donors HCV-uninfected recipients, transplant should availability of for in the (Not Graded). kidney donors should undergo HCV testing as well as testing If a potential kidney is an evaluation for severity of liver disease and should be and should be after DAA therapy in the and are can if evaluation of the hepatic of immunosuppressive recommend that kidney transplant recipients being treated with be evaluated for the for dose of concomitant of immunosuppressive recommend that kidney transplant recipients being treated with be evaluated for the for dose of concomitant HCV following kidney transplantation due to not DAA therapy. interactions are an important to DAA regimens are used in kidney transplant recipients due to to This is particularly in kidney transplant recipients treated with calcineurin and mTOR inhibitors. The Hepatitis Drug Interactions website is a for potential drug–drug interactions of in kidney transplant that patients previously infected with HCV who before transplantation undergo testing by 3 after transplantation or if liver transplant recipients with cirrhosis should have the liver disease as patients, as outlined in the American Association for the Study of Liver Diseases guidelines (Not kidney transplant recipients should be at least for (Not that patients who 1 or 1 on or more have an allograft with and included in the recommend treatment with a DAA regimen in patients with HCV-associated glomerulonephritis of in kidney transplant that patients previously infected with HCV who before transplantation undergo testing by 3 after transplantation or if liver transplant recipients with cirrhosis should have the liver disease as patients, as outlined in the American Association for the Study of Liver Diseases guidelines (Not kidney transplant recipients should be at least for (Not that patients who 1 or 1 on or more have an allograft with and included in the recommend treatment with a DAA regimen in patients with HCV-associated glomerulonephritis antiviral therapy progression of liver disease and allograft due to HCV infection. is but if is evidence of hepatic HCV and HBV reactivation or should be As in any for and other of HCV and liver disease is following kidney transplantation of HCV-infected patients, as outlined in the AASLD and EASL patients with prior HCV infection should be monitored for and GFR. allograft is by in these in HCV recipients and should allograft including and of HCV-associated glomerulonephritis is an additional for DAA 5: Diagnosis and management of kidney diseases associated with HCV patients with a of glomerulonephritis can be without a kidney However, a may be indicated in clinical (Figure (Not recommend that patients with HCV-associated glomerulonephritis antiviral therapy recommend that patients with HCV-associated kidney function, and without be treated with prior to other recommend that patients with or progressive glomerulonephritis be treated with and immunosuppressive agents with or without to use immunosuppressive agents in patients with should be (Not recommend immunosuppressive therapy in patients with active HCV-associated glomerulonephritis who not to antiviral therapy, particularly those with kidney disease recommend as the immunosuppressive treatment patients with a of glomerulonephritis can be without a kidney However, a may be indicated in clinical (Figure (Not Graded). recommend that patients with HCV-associated glomerulonephritis antiviral therapy recommend that patients with HCV-associated kidney function, and without be treated with prior to other recommend that patients with or progressive glomerulonephritis be treated with and immunosuppressive agents with or without to use immunosuppressive agents in patients with should be (Not recommend immunosuppressive therapy in patients with active HCV-associated glomerulonephritis who not to antiviral therapy, particularly those with kidney disease recommend as the immunosuppressive treatment glomerulonephritis is a of HCV infection. This can occur with or without evidence of In an HCV-infected patient with a of glomerulonephritis (Figure and DAA therapy can be without kidney In the event that GFR or following or if immunosuppressive therapy is being kidney should be Patients with and those with evidence of progressive glomerulonephritis or should undergo kidney In patients with progressive in GFR due to active glomerulonephritis or a concomitant immunosuppressive therapy should be If treatment with DAA not result in an improvement in immunosuppressive therapy is If is present, treatment should be based on including severity of kidney and of immunosuppressive treatment is is generally used as the The efficacy and safety of DAA has the of HCV management in patients with CKD and an update to the KDIGO 2018 guideline on HCV in The key to HCV in CKD are outlined in The most are the of safety and efficacy of in patients with CKD and G5D an additional pangenotypic to the DAA and that can be in patients with cirrhosis. the field of kidney transplantation from individuals to recipients has major advances the publication of the 2018 guideline, with to the timing and duration of treatment and additional information on clinical associated with the role of and immunosuppressive agents for HCV-associated glomerulonephritis to with an about patients kidney before therapy, can be treated with DAA and immunosuppressive with of key from KDIGO 2022 HCV Guideline are highly effective and well-tolerated for treatment of HCV in patients across all CKD including those undergoing dialysis therapy and kidney transplant recipients, with no for dose DAA regimens, including regimens, and genotype-specific regimens are safe and effective for CKD (CKD or and for kidney transplant recipients, and can be selected based on and availability of specific pangenotypic regimens are not available, genotypes should be prior to DAA inhibitors (“-previrs” such as simeprevir, paritaprevir, and grazoprevir) are contraindicated in patients with Child-Pugh B and C with DAA agents should be in kidney transplant recipients the potential drug–drug interactions with immunosuppressive agents such as calcineurin and mTOR inhibitors. should of about HBV reactivation DAA testing for HBV markers hepatitis B surface antigen total core antibody and antibody to HBV surface antigen should be performed prior to HCV treatment with DAA HBsAg is present, the patient should undergo assessment for HBV therapy. If HBsAg is absent but markers of prior HBV infection (HBcAb-positive with or without HBsAb) are detected, HBV reactivation should be with HBV DNA testing if levels of liver function tests rise during DAA transplant candidates with HCV should be evaluated for severity of liver disease and presence of prior to for kidney transplantation. from assessment guide the of kidney transplantation therapy should be administered to all HCV-infected kidney transplant before or after of DAA treatment for kidney transplantation candidates after should be based on by the use of kidneys from HCV-positive and severity of liver kidney donors should be for HCV infection with and if from HCV-infected donors can be to potential recipients of HCV that or and transplantation from HCV-infected donors to recipients with or DAA treatment is associated with and patient kidneys from HCV-infected donors HCV-uninfected recipients, transplant that recipients and are in with information to Patients should be of the and benefits of transplantation with an HCV-positive kidney, including the for DAA treatment. should availability of to be administered to recipients in the patients with a of glomerulonephritis can be without a kidney However, a should be if is of GFR or or if immunosuppressive therapy is patients with chronic HCV and glomerulonephritis should be treated with as those without with or progressive glomerulonephritis can be treated with and immunosuppressive with or without is generally used as the immunosuppressive should also be in progressive chronic kidney direct-acting glomerular filtration hepatitis B hepatitis C of in a

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