KDIGO 2018 Clinical Practice Guideline for the Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C in Chronic Kidney Disease

  • Kidney Disease: Improving Global Outcomes (KDIGO) Hepatitis C Work Group

      Table of Contents

      Figure thumbnail fx1
      Tabled 1
      KDIGO 2018 Clinical Practice Guideline for the Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C in Chronic Kidney Disease
      93Tables, figures, algorithms, and supplementary material
      95KDIGO executive committee
      96Reference keys
      97CKD nomenclature
      98Conversion factors
      99Abbreviations and acronyms
      100Notice
      101Foreword
      102Work Group membership
      103Abstract
      104Summary of recommendation statements
      108Chapter 1: Detection and evaluation of HCV in CKD
      114Chapter 2: Treatment of HCV infection in patients with CKD
      121Chapter 3: Preventing HCV transmission in hemodialysis units
      130Chapter 4: Management of HCV-infected patients before and after kidney transplantation
      137Chapter 5: Diagnosis and management of kidney diseases associated with HCV infection
      142Methods for guideline development
      151Biographic and disclosure information
      157Acknowledgments
      158References
      The development and publication of this guideline were supported by KDIGO. The opinions or views expressed in this professional education supplement are those of the authors and do not necessarily reflect the opinions or recommendations of the International Society of Nephrology or Elsevier. Dosages, indications, and methods of use for products that are referred to in the supplement by the authors may reflect their clinical experience or may be derived from the professional literature or other clinical sources. Because of the differences between in vitro and in vivo systems and between laboratory animal models and clinical data in humans, in vitro and animal data may not necessarily correlate with clinical results.

      Tables

      Tabled 1
      106Table 1. Infection control practices (“hygienic precautions”) particularly relevant in preventing HCV transmission
      122Table 2. Recent reported HCV prevalence in hemodialysis patients
      122Table 3. Factors and lapses in infection control practices associated with transmission of HCV infection in dialysis units
      125Table 4. Hygienic precautions for hemodialysis (dialysis machines)
      127Table 5. Steps to initiate concurrently and undertake following identification of a new HCV infection in a hemodialysis patient
      127Table 6. Strategies to support adherence to infection control recommendations in hemodialysis centers
      128Table 7. Key hygienic precautions for hemodialysis staff
      143Table 8. Systematic review topics and screening criteria
      144Table 9. Hierarchy of outcomes
      145Table 10. Work products for the guideline
      146Table 11. Classification of study quality
      146Table 12. GRADE system for grading quality of evidence
      146Table 13. Final grade for overall quality of evidence
      147Table 14. Balance of benefits and harms
      147Table 15. KDIGO nomenclature and description for grading recommendations
      147Table 16. Determinants of strength of recommendation
      148Table 17. The Conference on Guideline Standardization (COGS) checklist for reporting clinical practice guidelines

      Figures

      Tabled 1
      105Figure 1. Recommended DAA treatment regimens for patients with CKD G4–G5D and kidney transplant recipients, by HCV genotype
      144Figure 2. Search yield

      Algorithms

      Tabled 1
      118Algorithm 1. Treatment scheme for CKD G1–G5D
      119Algorithm 2. Treatment scheme for kidney transplant recipients
      132Algorithm 3. Proposed strategy in an HCV-infected kidney transplant candidate

      Supplementary Material

      Tabled 1
      Appendix A. Search strategies
      Appendix B. Concurrence with Institute of Medicine standards for systematic reviews and for guidelines
      Table S1. Summary table: diagnostic testing for liver fibrosis (by biopsy)
      Table S2. Evidence profile: diagnostic testing for liver fibrosis (by biopsy)
      Table S3. Summary table: HCV infection as independent predictor of CKD progression
      Table S4. Evidence profile: HCV infection as independent predictor of CKD progression
      Table S5. Summary table: treatment with direct-acting antiviral regimens in chronic HCV-infected CKD patients
      Table S6. Evidence profile: treatment with direct-acting antiviral regimens in chronic HCV-infected CKD patients
      Table S7. Summary table: treatment with direct-acting antiviral regimens in kidney transplant recipients with chronic HCV infection
      Table S8. Evidence profile: treatment with direct-acting antiviral regimens in kidney transplant recipients with chronic HCV infection
      Table S9. Summary table: isolation of HCV patients receiving hemodialysis
      Table S10. Evidence profile: isolation of HCV patients receiving hemodialysis
      Table S11. Summary table: transplantation versus waitlist among patients with HCV infection
      Table S12. Evidence profile: transplantation versus waitlist among patients with HCV infection
      Table S13. Summary table: HCV infection as predictor of death among kidney transplant recipients
      Table S14. Evidence profile: HCV infection as predictor of death and graft loss among kidney transplant recipients
      Table S15. Summary table: clinical outcomes of HCV-positive kidney transplant recipients from HCV-positive donors
      Table S16. Summary table: induction and immunosuppression in kidney transplant recipients with HCV infection
      Table S17. Summary table: HCV treatment of HCV-associated glomerular disease
      Table S18. Evidence profile: HCV treatment of HCV-associated glomerular disease
      Supplementary material is linked to the online version of the article at www.kisupplements.org.

      KDIGO Executive Committee

      Tabled 1
      Garabed Eknoyan, MD

      Norbert Lameire, MD, PhD

      Founding KDIGO Co-Chairs
      Bertram L. Kasiske, MD

      Immediate Past Co-Chair
      David C. Wheeler, MD, FRCP

      KDIGO Co-Chair
      Wolfgang C. Winkelmayer, MD, MPH, ScD

      KDIGO Co-Chair
      Ali K. Abu-Alfa, MD

      Geoffrey A. Block, MD

      Jürgen Floege, MD

      John S. Gill, MD, MS

      Kunitoshi Iseki, MD

      Zhi-Hong Liu, MD, PhD

      Magdalena Madero, MD

      Ziad A. Massy, MD, PhD
      Ikechi G. Okpechi, MBBS, FWACP, PhD

      Brian J.G. Pereira, MBBS, MD, MBA

      Rukshana Shroff, MD, FRCPCH, PhD

      Paul E. Stevens, MB, FRCP

      Marcello A. Tonelli, MD, SM, FRCPC

      Suzanne Watnick, MD

      Angela C. Webster, MBBS, MM (Clin Epi), PhD

      Christina M. Wyatt, MD
      KDIGO Staff

      John Davis, Chief Executive Officer

      Danielle Green, Executive Director

      Michael Cheung, Chief Scientific Officer

      Tanya Green, Communications Director

      Melissa Thompson, Implementation Director

      Reference keys

       Nomenclature and Description for Rating Guideline Recommendations

      Within each recommendation, the strength of recommendation is indicated as Level 1, Level 2, or not graded, and the quality of the supporting evidence is shown as A, B, C, or D.
      Tabled 1
      Grade
      The additional category “not graded” is used, typically, to provide guidance based on common sense or where the topic does not allow adequate application of evidence. The most common examples include recommendations regarding monitoring intervals, counseling, and referral to other clinical specialists. The ungraded recommendations are generally written as simple declarative statements. They should not be interpreted as being weaker recommendations than Level 1 or 2 recommendations.
      Implications
      PatientsCliniciansPolicy
      Level 1

      “We recommend”
      Most people in your situation would want the recommended course of action, and only a small proportion would not.Most patients should receive the recommended course of action.The recommendation can be evaluated as a candidate for developing a policy or a performance measure.
      Level 2

      “We suggest”
      The majority of people in your situation would want the recommended course of action, but many would not.Different choices will be appropriate for different patients. Each patient needs help to arrive at a management decision consistent with her or his values and preferences.The recommendation is likely to require substantial debate and involvement of stakeholders before policy can be determined.
      a The additional category “not graded” is used, typically, to provide guidance based on common sense or where the topic does not allow adequate application of evidence. The most common examples include recommendations regarding monitoring intervals, counseling, and referral to other clinical specialists. The ungraded recommendations are generally written as simple declarative statements. They should not be interpreted as being weaker recommendations than Level 1 or 2 recommendations.
      Tabled 1
      GradeQuality of evidenceMeaning
      AHighWe are confident that the true effect lies close to the estimate of the effect.
      BModerateThe true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
      CLowThe true effect may be substantially different from the estimate of the effect.
      DVery lowThe estimate of effect is very uncertain, and often will be far from the truth.

       Current Chronic Kidney Disease (CKD) Nomenclature Used by KDIGO

      CKD is defined as abnormalities of kidney structure or function, present for >3 months, with implications for health. CKD is classified based on cause, GFR category (G1–G5), and albuminuria category (A1–A3), abbreviated as CGA.
      Figure thumbnail fx2
      Prognosis of CKD by GFR and albuminuria category

       Conversion Factors of Conventional Units to SI Units

      Tabled 1
      Conventional unitConversion factorSI unit
      Creatininemg/dl88.4μmol/l
      Note: conventional unit × conversion factor = SI unit.

       Albuminuria Categories in CKD

      Tabled 1
      CategoryAER (mg/24 h)ACR (approximate equivalent)Terms
      (mg/mmol)(mg/g)
      A1<30<3<30Normal to mildly increased
      A230–3003–3030–300Moderately increased
      Relative to young adult level.
      A3>300>30>300Severely increased
      Including nephrotic syndrome (albumin excretion usually > 2200 mg/24 h [ACR > 2200 mg/g; > 220 mg/mmol]).
      ACR, albumin-to-creatinine ratio; AER, albumin excretion rate; CKD, chronic kidney disease.
      a Relative to young adult level.
      b Including nephrotic syndrome (albumin excretion usually > 2200 mg/24 h [ACR > 2200 mg/g; > 220 mg/mmol]).

       Interpretation of HCV Assays

      Tabled 1
      Anti-HCVHCV-NATInterpretation
      PositivePositiveAcute or chronic HCV infection depending on the clinical context
      PositiveNegativeResolution of HCV infection (i.e., successfully treated or spontaneously cleared)
      NegativePositiveEarly acute HCV infection; chronic HCV in the setting of immunosuppressed state; false anti-HCV negative or false HCV-NAT positive
      NegativeNegativeAbsence of HCV infection
      Anti-HCV, HCV antibody; HCV, hepatitis C virus; NAT, nucleic acid testing.

      Abbreviations and acronyms

      Tabled 1
      AASLDAmerican Association for the Study of Liver Diseases
      ALTalanine aminotransferase
      Anti-HCVHCV antibody
      APRIaspartate aminotransferase–platelet ratio index
      ASNAmerican Society of Nephrology
      AUCarea under the curve
      BSIbloodstream infection
      CDCCenters for Disease Control and Prevention
      CIconfidence interval
      CKDchronic kidney disease
      CKD G4 CKD G5chronic kidney disease GFR category 4 chronic kidney disease GFR category 5
      CKD-EPIChronic Kidney Disease Epidemiology Collaboration
      CNIcalcineurin inhibitor
      CPGclinical practice guideline
      CrClcreatinine clearance
      DAAdirect-acting antiviral
      DOPPSDialysis Outcomes and Practice Patterns Study
      EASLEuropean Association for the Study of the Liver
      eGFRestimated glomerular filtration rate
      ERTevidence review team
      ESKDend-stage kidney disease
      FDAFood and Drug Administration
      GFRglomerular filtration rate
      GNglomerulonephritis
      GRADEGrading of Recommendations Assessment, Development and Evaluation
      GTgenotype
      HAVhepatitis A virus
      HBcAbantibody to hepatitis B core antigen
      HBsAbantibody to hepatitis B surface antigen
      HBsAghepatitis B surface antigen
      HBVhepatitis B virus
      HCChepatocellular carcinoma
      HCVhepatitis C virus
      HIVhuman immunodeficiency virus
      HRhazard ratio
      IFNinterferon
      IUinternational unit
      KDIGOKidney Disease: Improving Global Outcomes
      MMFmycophenolate mofetil
      MNmembranous nephropathy
      MPGNmembranoproliferative glomerulonephritis
      NATnucleic acid test(ing)
      NS5Anonstructural protein 5A
      NS5Bnonstructural protein 5B
      ORodds ratio
      PrOD (3D regimen)paritaprevir/ritonavir/ombitasvir and dasabuvir
      RBVribavirin
      RCTrandomized controlled trial
      RRrelative risk
      SVR (weeks)sustained virologic response (at stated weeks)
      USUnited States

      Notice

       Section I: Use of the Clinical Practice Guideline

      This Clinical Practice Guideline document is based upon literature searches last conducted in May 2017, supplemented with additional evidence through July 2018. It is designed to assist decision making. It is not intended to define a standard of care, and should not be interpreted as prescribing an exclusive course of management. Variations in practice will inevitably and appropriately occur when clinicians consider the needs of individual patients, available resources, and limitations unique to an institution or type of practice. Health care professionals using these recommendations should decide how to apply them to their own clinical practice.

       Section II: Disclosure

      Kidney Disease: Improving Global Outcomes (KDIGO) makes every effort to avoid any actual or reasonably perceived conflicts of interest that may arise from an outside relationship or a personal, professional, or business interest of a member of the Work Group. All members of the Work Group are required to complete, sign, and submit a disclosure and attestation form showing all such relationships that might be perceived as or are actual conflicts of interest. This document is updated annually and information is adjusted accordingly. All reported information is published in its entirety at the end of this document in the Work Group members’ Biographic and Disclosure section, and is kept on file at KDIGO.
      Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the US Centers for Disease Control and Prevention.
      Copyright © 2018, KDIGO. Published by Elsevier on behalf of the International Society of Nephrology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
      Single copies may be made for personal use as allowed by national copyright laws. Special rates are available for educational institutions that wish to make photocopies for nonprofit educational use. No part of this publication may be reproduced, amended, or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without explicit permission in writing from KDIGO. Details on how to seek reprints, permission for reproduction or translation, and further information about KDIGO’s permissions policies can be obtained by contacting Danielle Green, Executive Director, at [email protected] .
      To the fullest extent of the law, neither KDIGO, Kidney International Supplements, nor the authors, contributors, or editors assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

      Foreword

      With the growing awareness that chronic kidney disease (CKD) is an international health problem, Kidney Disease: Improving Global Outcomes (KDIGO) was established in 2003 with its stated mission to “improve the care and outcomes of kidney disease patients worldwide through promoting coordination, collaboration, and integration of initiatives to develop and implement clinical practice guidelines.”
      The high prevalence of hepatitis C virus (HCV) in the CKD population was recognized once diagnostic testing became available in the early 1990s, as was its transmission within dialysis units. A series of publications subsequently identified the adverse consequences of HCV infection in the CKD population as well as its detrimental effect on recipient and graft outcomes following kidney transplantation. Although screening of blood products for HCV reduced its acquisition by blood transfusion, the unique aspects of its epidemiology in the CKD population were apparent. Studies also established that transmission was frequent in dialysis patients and typically reflected insufficient attention to body fluid precautions. Also confounding the management of HCV in the CKD population was an absence of biochemical liver dysfunction in most HCV-infected hemodialysis patients, which contributed to the lack of recognition of its presence and clinical significance. An additional difficulty was the lack of effective and tolerable antiviral agents to treat HCV in patients with CKD because interferon, especially in combination with ribavirin, had considerable toxicity. Furthermore, interferon was implicated in graft dysfunction in kidney transplant recipients.
      KDIGO convened a group of experts in this area to develop guideline recommendations for the prevention, diagnosis, and management of HCV in CKD a decade ago, which resulted in the publication of the very first KDIGO guideline in 2008. Since then there have been major advances in HCV management, particularly in antiviral therapy. As a result, much of the hesitancy in advising therapy for HCV-infected patients with CKD and following kidney transplant has now disappeared. In addition, diagnostic testing has evolved in chronic liver disease to the extent that fibrosis can now be assessed with noninvasive techniques such as transient elastography. Because of these advances in diagnostics and therapeutics, it was deemed appropriate to undertake a comprehensive review and update of the KDIGO HCV guideline in patients with kidney disease. It has been KDIGO’s philosophy to provide recommendations based on the best available clinical evidence without direct consideration of costs, as they vary widely across countries. The recent Lancet Commission on Essential Medicines articulated the importance and challenges of providing access to safe, effective, and affordable essential medicines, including treatments for combating HCV.
      • Wirtz V.J.
      • Hogerzeil H.V.
      • Gray A.L.
      • et al.
      Essential medicines for universal health coverage.
      In this vein, the World Health Organization has issued its first global report to offer practical steps to expand access for such treatments.
      The Lancet Gastroenterology Hepatology
      Access to HCV treatments: hurdles not barriers.
      We thank Michel Jadoul, MD, and Paul Martin, MD, for leading this important initiative, and we are especially grateful to the Work Group members who provided their time and expertise to this endeavor. In addition, this Work Group was ably assisted by colleagues from the independent evidence review team led by Ethan Balk, MD, MPH, Craig Gordon, MD, MS, Amy Earley, BS, and Mengyang Di, MD, PhD, who made this guideline possible.
      In keeping with KDIGO’s policy for transparency and rigorous public review during the guideline development process, its scope and the draft guideline were both made available for open commenting. The feedback received was carefully considered by the Work Group members who critically reviewed the public input and revised the guideline as appropriate for the final publication.
      David C. Wheeler, MD, FRCP
      Wolfgang C. Winkelmayer, MD, ScD
      KDIGO Co-Chairs

      Work Group membership

      Tabled 1
      Work Group Co-chairs
      Michel Jadoul, MD

      Cliniques Universitaires Saint Luc

      Université Catholique de Louvain

      Brussels, Belgium
      Paul Martin, MD

      Miller School of Medicine

      University of Miami

      Miami, FL, USA
      Work Group
      Marina C. Berenguer, MD

      La Fe University Hospital, IIS La Fe

      University of Valencia-CIBERehd

      Valencia, Spain
      Bertram L. Kasiske, MD, FACP

      Hennepin County Medical Center

      Minneapolis, MN, USA
      Wahid Doss, MD

      National Hepatology and Tropical Medicine Research Institute

      Cairo, Egypt
      Ching-Lung Lai, MD, FRCP, FRACP, FHKAM (Med), FHKCP, FAASLD

      University of Hong Kong

      Hong Kong, China
      Fabrizio Fabrizi, MD

      Maggiore Hospital and IRCCS Foundation

      Milan, Italy
      José M. Morales, MD, PhD

      Hospital Universitario 12 de Octubre

      Madrid, Spain
      Jacques Izopet, PharmD, PhD

      Centre de Physiopathologie de Toulouse Purpan

      Toulouse, France
      Priti R. Patel, MD, MPH

      Centers for Disease Control and Prevention

      Atlanta, GA, USA
      Vivekanand Jha, MBBS, MD, DM, FRCP, FRCP (Edin), FAMS

      The George Institute for Global Health

      New Delhi, India
      Stanislas Pol, MD, PhD

      Hôpital Cochin

      Paris, France
      Nassim Kamar, MD, PhD

      CHU Rangueil

      Toulouse, France
      Marcelo O. Silva, MD

      Hospital Universitario Austral

      Pilar, Argentina
      Evidence Review Team

      Center for Evidence Synthesis in Health, Brown University School of Public Health

      Providence, RI, USA

      Ethan M. Balk, MD, MPH, Project Director, Evidence Review Team Director

      Craig E. Gordon, MD, MS, Assistant Project Director, Evidence Review Team Associate Director

      Amy Earley, BS, Research Associate

      Mengyang Di, MD, PhD, Physician Researcher

      Abstract

      The Kidney Disease: Improving Global Outcomes (KDIGO) 2018 Clinical Practice Guideline for the Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C in Chronic Kidney Disease represents a complete update of the prior guideline published in 2008. This guideline is intended to assist the practitioner caring for patients with hepatitis C virus (HCV) and chronic kidney disease (CKD), including those who are on chronic dialysis therapy and individuals with a kidney transplant. Specifically, the topic areas for which new recommendations are issued include detection and evaluation of HCV in CKD; treatment of HCV infection in patients with CKD; management of HCV-infected patients before and after kidney transplantation; prevention of HCV transmission in hemodialysis units; and diagnosis and management of kidney diseases associated with HCV infection. Development of this guideline update followed an explicit process of evidence review and appraisal. Treatment approaches and guideline recommendations are based on systematic reviews of relevant studies, and appraisal of the quality of the evidence and the strength of recommendations followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Limitations of the evidence are discussed, with areas of future research also presented.
      Keywords: chronic kidney disease; cryoglobulinemia; dialysis; direct-acting antivirals; glomerular diseases; hemodialysis; hepatitis C virus; infection control; guideline; KDIGO; kidney transplantation; liver testing; nosocomial transmission; screening; systematic review
      CITATION
      In citing this document, the following format should be used: Kidney Disease: Improving Global Outcomes (KDIGO) Hepatitis C Work Group. KDIGO 2018 Clinical Practice Guideline for the Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C in Chronic Kidney Disease. Kidney Int Suppl. 2018;8:91–165.

      Summary of recommendation statements

       Chapter 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).
        • 1.1.2: We recommend screening all patients for HCV infection upon initiation of in-center hemodialysis or upon transfer from another dialysis facility or modality (1A).
          • 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 hemodialysis (2D).
        • 1.1.4: We recommend screening all patients for HCV infection at the time of evaluation for kidney transplantation (1A).
      1.2 Follow-up HCV screening of in-center hemodialysis patients
      • 1.2.1: We recommend screening for HCV infection with immunoassay or NAT in in-center hemodialysis patients every 6 months (1B).
        • 1.2.1.1: Report any new HCV infection identified in a hemodialysis 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 be increased (1A).
        • 1.2.1.3: We recommend that hemodialysis patients with resolved HCV infection undergo repeat testing every 6 months using NAT to detect possible re-infection (1B).
      • 1.2.2: We suggest that patients have serum alanine aminotransferase (ALT) level checked upon initiation of in-center hemodialysis or upon transfer from another facility (2B).
        • 1.2.2.1: We suggest that hemodialysis patients have ALT level checked monthly (2B).
      1.3 Liver testing in patients with CKD and HCV infection
      • 1.3.1: We recommend assessing HCV-infected patients with CKD for liver fibrosis (1A).
      • 1.3.2: We recommend an initial noninvasive evaluation of liver fibrosis (1B).
      • 1.3.3: When the cause of liver disease is uncertain or noninvasive testing results are discordant, consider liver biopsy (Not Graded).
      • 1.3.4: We recommend assessment for portal hypertension in CKD patients with suspected advanced fibrosis (F3–4) (1A).
      1.4 Other testing of patients with HCV infection
      • 1.4.1: We recommend assessing all patients for kidney disease at the time of HCV infection diagnosis (1A).
        • 1.4.1.1: Screen for kidney disease with urinalysis and estimated glomerular filtration rate (eGFR) (Not Graded).
      • 1.4.2: If there is no evidence of kidney disease at initial evaluation, patients who remain NAT-positive should undergo repeat screening for kidney disease (Not Graded).
      • 1.4.3: We recommend that all CKD patients with a history of HCV infection, whether NAT-positive or not, be followed up regularly to assess progression of kidney disease (1A).
      • 1.4.4: We recommend that all CKD patients with a history of HCV infection, whether NAT-positive or not, be screened and, if appropriate, vaccinated against hepatitis A virus (HAV) and hepatitis B virus (HBV), and screened for human immunodeficiency virus (HIV) (1A).

       Chapter 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).
      • 2.2: We recommend that patients with GFR ≥ 30 ml/min per 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 per 1.73 m2 (CKD G4–G5D) should be treated with a ribavirin-free DAA-based regimen as outlined in Figure 1.
        Figure thumbnail gr1
        Figure 1Recommended direct-acting antiviral (DAA) treatment regimens for patients with chronic kidney disease (CKD) G4–G5D and kidney transplant recipients (KTRs), by hepatitis C virus (HCV) genotypea. Duration of therapy for all above regimens is usually 12 weeks but readers should consult Association for the Study of Liver Diseases (AASLD) or European Association for the Study of the Liver guidelines for latest guidance. aWe recommend that CKD patients with glomerular filtration rates (GFRs) ≥ 30 ml/min per 1.73 m2 (CKD G1T–G3bT) be treated with any licensed DAA regimen. bThere is little published evidence to guide treatment regimens in KTRs with GFR < 30 ml/min per 1.73 m2 (CKD G4T–G5T). Regimens in KTRs should be selected to avoid drug–drug interactions, particularly with calcineurin inhibitors. cBased on Reau et al.

        Reau N, Kwo PY, Rhee S, et al. Glecaprevir/pibrentasvir treatment in liver or kidney transplant patients with hepatitis C virus infection [e-pub ahead of print]. Hepatology. https://doi.org/10.1002/hep.30046. Accessed July 25, 2018.

        dAs suggested in AASLD guidelines (https://www.hcvguidelines.org/). CKD G, chronic kidney disease (GFR category); HD, hemodialysis; n/a, no data or evidence available; PD, peritoneal dialysis.
      • 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 as outlined in Figure 1 (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).
        • 2.4.4: 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).
          • 2.4.4.1: We recommend that calcineurin inhibitor levels be monitored during and after DAA treatment (1B).
      • 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).

       Chapter 3: Preventing HCV transmission in hemodialysis units

      • 3.1: We recommend that hemodialysis facilities adhere to standard infection control procedures including hygienic precautions that effectively prevent transfer of blood and blood-contaminated fluids between patients to prevent transmission of blood-borne pathogens (see Table 1) (1A).
        • 3.1.1: We recommend regular observational audits of infection control procedures in hemodialysis units (1C).
        • 3.1.2: We recommend not using dedicated dialysis machines for HCV-infected patients (1D).
        • 3.1.3: We suggest not isolating HCV-infected hemodialysis patients (2C).
        • 3.1.4: We suggest that the dialyzers of HCV-infected patients can be reused if there is adherence to standard infection control procedures (2D).
        Table 1Infection control practices (“hygienic precautions”) particularly relevant for preventing HCV transmission
        • Proper hand hygiene and glove changes, especially between patient contacts, before invasive procedures, and after contact with blood and potentially blood-contaminated surfaces/supplies
        • Proper injectable medication preparation practices following aseptic techniques and in an appropriate clean area, and proper injectable medication administration practice
        • Thorough cleaning and disinfection of surfaces at the dialysis station, especially high-touch surfaces
        • Adequate separation of clean supplies from contaminated materials and equipment
      • 3.2: We recommend that hemodialysis centers examine and track all HCV test results to identify new cases of HCV infections in their patients (1B).
        • 3.2.1: We recommend that aggressive measures be taken to improve hand hygiene (and proper glove use), injection safety, and environmental cleaning and disinfection when a new case of HCV is identified that is likely to be dialysis-related (1A).
      • 3.3: Strategies to prevent HCV transmission within hemodialysis units should prioritize adherence to standard infection control practices and should not primarily rely upon the treatment of HCV-infected patients (Not Graded).

       Chapter 4: Management of HCV-infected patients before and after kidney transplantation

      4.1 Evaluation and management of kidney transplant candidates regarding HCV infection
      • 4.1.1: We recommend kidney transplantation as the best therapeutic option for patients with CKD G5 irrespective of presence of HCV infection (1A).
      • 4.1.2: We suggest that all HCV-infected kidney transplant candidates be evaluated for severity of liver disease and presence of portal hypertension (if indicated) prior to acceptance for kidney transplantation (2D).
        • 4.1.2.1: We recommend that HCV-infected patients with compensated cirrhosis (without portal hypertension) undergo isolated kidney transplantation (1B).
        • 4.1.2.2: We recommend referring HCV-infected patients with decompensated cirrhosis for combined liver-kidney transplantation (1B) and deferring HCV treatment until after transplantation (1D).
      • 4.1.3: Timing of HCV treatment in relation to kidney transplantation (before vs. after) should be based on donor type (living vs. deceased donor), wait-list times by donor type, center-specific policies governing the use of kidneys from HCV-infected deceased donors, HCV genotype, and severity of liver fibrosis (Not Graded).
        • 4.1.3.1: We recommend that all HCV-infected patients who are candidates for kidney transplantation be considered for DAA therapy, either before or after transplantation (1A).
        • 4.1.3.2: We suggest that HCV-infected kidney transplant candidates with a living kidney donor can be considered for treatment before or after transplantation according to HCV genotype and anticipated timing of transplantation (2B).
        • 4.1.3.3: We suggest that if receiving a kidney from an HCV-positive donor improves the chances for transplantation, the HCV NAT–positive patient can undergo transplantation with an HCV-positive kidney and be treated for HCV infection after transplantation (2B).
      4.2 Use of kidneys from HCV-infected donors
      • 4.2.1: We recommend that all kidney donors be screened for HCV infection with both immunoassay and NAT (if NAT is available) (1A).
      • 4.2.2: We recommend that transplantation of kidneys from HCV NAT-positive donors be directed to recipients with positive NAT (1A).
      • 4.2.3: After the assessment of liver fibrosis, HCV-positive potential living kidney donors who do not have cirrhosis should undergo HCV treatment before donation; they can be accepted for donation if they achieve sustained virologic response (SVR) and remain otherwise eligible to be a donor (Not Graded).
      4.3 Use of maintenance immunosuppressive regimens
      • 4.3.1: We suggest that all conventional current induction and maintenance immunosuppressive regimens can be used in HCV-infected kidney transplant recipients (2C).
      4.4 Management of HCV-related complications in kidney transplant recipients
      • 4.4.1: We recommend that patients previously infected with HCV who achieved SVR before transplantation be tested by NAT 3 months after transplantation or if liver dysfunction occurs (1D).
      • 4.4.2: Untreated HCV-positive kidney transplant recipients should have the same liver disease follow-up as HCV-positive non-transplant patients, as outlined in the American Association for the Study of Liver Diseases (AASLD) guidelines (Not Graded).
      • 4.4.3: HCV-infected kidney transplant recipients should be tested at least every 6 months for proteinuria (Not Graded).
        • 4.4.3.1: We suggest that patients who develop new-onset proteinuria (either urine protein-to-creatinine ratio > 1 g/g or 24-hour urine protein > 1 g on 2 or more occasions) have an allograft biopsy with immunofluorescence and electron microscopy included in the analysis (2D).
      • 4.4.4: We recommend treatment with a DAA regimen in patients with post-transplant HCV-associated glomerulonephritis (1D).

       Chapter 5: Diagnosis and management of kidney diseases associated with HCV infection

      • 5.1: We recommend that a kidney biopsy be performed in HCV-infected patients with clinical evidence of glomerular disease (Not Graded).
      • 5.2: We recommend that patients with HCV-associated glomerular disease be treated for HCV (1A).
        • 5.2.1: We recommend that patients with HCV-related glomerular disease showing stable kidney function and/or non-nephrotic proteinuria be treated initially with DAA (1C).
        • 5.2.2: We recommend that patients with cryoglobulinemic flare, nephrotic syndrome, or rapidly progressive kidney failure be treated, in addition to DAA treatment, with immunosuppressive agents with or without plasma exchange (1C).
        • 5.2.3: We recommend immunosuppressive therapy in patients with histologically active HCV-associated glomerular disease who do not respond to antiviral therapy, particularly those with cryoglobulinemic kidney disease (1B).
          • 5.2.3.1: We recommend rituximab as the first-line immunosuppressive treatment (1C).

       Chapter 1: Detection and evaluation of HCV in CKD

       1.1 Screening patients with CKD for HCV infection

      Patients receiving maintenance hemodialysis and subgroups of CKD patients not yet on dialysis are known to have a high prevalence of HCV infection. The reasons for testing CKD patients for HCV infection include early detection and treatment of HCV infection, diagnostic evaluation of the cause of CKD, identification of infection control lapses in hemodialysis centers, and guidance on decisions surrounding kidney transplantation care.
      • 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).
      • 1.1.2: We recommend screening all patients for HCV infection upon initiation of in-center hemodialysis or upon transfer from another dialysis facility or modality (1A).
        • 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 hemodialysis (2D).
      • 1.1.4: We recommend screening all patients for HCV infection at the time of evaluation for kidney transplantation (1A).

       Rationale

      • 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).
      Any CKD patient who has a risk factor for HCV infection should be tested.

      World Health Organization. Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection. July 2018. Available at: http://www.who.int/hepatitis/publications/hepatitis-c-guidelines-2018/en/. Accessed July 27, 2018.

      Additionally, HCV testing is warranted for the evaluation of CKD because: (i) the prevalence of HCV infection may be higher in patients with CKD not yet on dialysis than in the general population;
      • Bergman S.
      • Accortt N.
      • Turner A.
      • et al.
      Hepatitis C infection is acquired pre-ESRD.
      • Iwasa Y.
      • Otsubo S.
      • Sugi O.
      • et al.
      Patterns in the prevalence of hepatitis C virus infection at the start of hemodialysis in Japan.
      (ii) HCV infection increases the risk of developing CKD;
      • Fabrizi F.
      • Verdesca S.
      • Messa P.
      • et al.
      Hepatitis C virus infection increases the risk of developing chronic kidney disease: a systematic review and meta-analysis.
      and (iii) HCV infection can accelerate progression of CKD.
      • Crook E.D.
      • Penumalee S.
      • Gavini B.
      • et al.
      Hepatitis C is a predictor of poorer renal survival in diabetic patients.
      • Noureddine L.A.
      • Usman S.A.
      • Yu Z.
      • et al.
      Hepatitis C increases the risk of progression of chronic kidney disease in patients with glomerulonephritis.
      • Wyatt C.M.
      • Malvestutto C.
      • Coca S.G.
      • et al.
      The impact of hepatitis C virus coinfection on HIV-related kidney disease: a systematic review and meta-analysis.
      Diagnosis of HCV infection relies on various assays.
      • Easterbrook P.J.
      Who to test and how to test for chronic hepatitis C infection - 2016 WHO testing guidance for low- and middle-income countries.
      • Kamili S.
      • Drobeniuc J.
      • Araujo A.C.
      • et al.
      Laboratory diagnostics for hepatitis C virus infection.
      Serological assays that detect HCV antibody (anti-HCV) are based on enzyme immunoassays or chemoluminescence immunoassays. Anti-HCV tests are unable to distinguish between resolved HCV infection and current HCV infection. Detection of HCV viremia relies on NAT technologies. Qualitative and quantitative HCV RNA methods are available and have similar limits of detection (10–20 international units [IU]/ml). HCV antigen tests that detect core antigen alone or in combination with other HCV proteins have the potential to be less costly than NAT, but their limit of detection is higher (equivalent to about 150–3000 IU/ml).
      • Easterbrook P.J.
      Who to test and how to test for chronic hepatitis C infection - 2016 WHO testing guidance for low- and middle-income countries.
      • Cresswell F.V.
      • Fisher M.
      • Hughes D.J.
      • et al.
      Hepatitis C core antigen testing: a reliable, quick, and potentially cost-effective alternative to hepatitis C polymerase chain reaction in diagnosing acute hepatitis C virus infection.
      • Hu K.Q.
      • Cui W.
      A highly specific and sensitive hepatitis C virus antigen enzyme immunoassay for One-step diagnosis of viremic hepatitis C virus infection.
      • Miedouge M.
      • Saune K.
      • Kamar N.
      • et al.
      Analytical evaluation of HCV core antigen and interest for HCV screening in haemodialysis patients.
      The most usual strategy for diagnosis of HCV infection consists of initial screening with an inexpensive serological assay and, if the assay is positive, subsequent NAT. However, in high prevalence settings or very high risk groups, immediate NAT is an appropriate alternative.
      • 1.1.2: We recommend screening all patients for HCV infection upon initiation of in-center hemodialysis or upon transfer from another dialysis facility or modality (1A).
        • 1.1.2.1: We recommend using NAT alone or an immunoassay followed by NAT if immunoassay is positive (1A).
      The prevalence of HCV infection in patients undergoing hemodialysis (CKD G5 on dialysis) is higher than in the general population
      • Fissell R.B.
      • Bragg-Gresham J.L.
      • Woods J.D.
      • et al.
      Patterns of hepatitis C prevalence and seroconversion in hemodialysis units from three continents: the DOPPS.
      • Saune K.
      • Kamar N.
      • Miedouge M.
      • et al.
      Decreased prevalence and incidence of HCV markers in haemodialysis units: a multicentric French survey.
      and has been associated with the number of years one has been on hemodialysis. Patient-to-patient transmission of HCV infection in outpatient hemodialysis centers has occurred repeatedly despite widespread knowledge of this risk and published guidelines for prevention. Identification of HCV transmission within a dialysis facility should prompt immediate reevaluation of infection control practices and determination of appropriate corrective action (see Chapter 3).
      • Hmaied F.
      • Ben Mamou M.
      • Saune-Sandres K.
      • et al.
      Hepatitis C virus infection among dialysis patients in Tunisia: incidence and molecular evidence for nosocomial transmission.
      • Izopet J.
      • Sandres-Saune K.
      • Kamar N.
      • et al.
      Incidence of HCV infection in French hemodialysis units: a prospective study.
      • Mbaeyi C.
      • Thompson N.D.
      Hepatitis C virus screening and management of seroconversions in hemodialysis facilities.
      • Nguyen D.B.
      • Gutowski J.
      • Ghiselli M.
      • et al.
      A large outbreak of hepatitis C virus infections in a hemodialysis clinic.
      • Savey A.
      • Simon F.
      • Izopet J.
      • et al.
      A large nosocomial outbreak of hepatitis C virus infections at a hemodialysis center.
      The majority of persons with HCV infection are asymptomatic, making screening necessary to detect infection in high-risk populations, particularly in hemodialysis patients in whom signs or symptoms of acute HCV infection are rarely recognized. Screening of maintenance hemodialysis patients for HCV infection is recommended by the United States (US) Centers for Disease Control and Prevention (CDC) and also the US Preventive Services Task Force.
      Recommendations for preventing transmission of infections among chronic hemodialysis patients.
      • Moyer V.A.
      Screening for hepatitis C virus infection in adults: U.S. Preventive Services Task Force recommendation statement.
      Goals of screening in this patient population include early detection of HCV infection, treatment of infection, and detection of dialysis-related transmission. HCV screening is indicated in patients starting in-center maintenance hemodialysis and also in patients who transfer from another dialysis facility or modality. In dialysis units with a high prevalence of HCV, initial testing with NAT should be considered. An anti-HCV–negative, HCV RNA–positive (i.e., NAT-positive) profile strongly suggests acute HCV infection.
      Samples collected to test for HCV by NAT should be drawn before dialysis, because hemodialysis sessions reduce viremia level, although the mechanism remains unclear.
      • Barril G.
      • Bartolome J.
      • Sanz P.
      • et al.
      Effect of hemodialysis schedules and membranes on hepatocyte growth factor and hepatitis C virus RNA levels.
      • 1.1.3: We suggest screening all patients for HCV infection upon initiation of peritoneal dialysis or home hemodialysis (2D).
      HCV transmission has typically been described in the context of in-center hemodialysis. In this setting, blood contamination on the hands of staff members or of medications, supplies, and equipment can contribute to HCV transmission. The current risk of health care–related HCV infection among patients who receive peritoneal dialysis or home hemodialysis has not been quantified. Many of these patients will require in-center hemodialysis at some point during their care, and may be at risk of acquiring HCV infection during that time. Screening of peritoneal dialysis and home hemodialysis patients should be considered upon initiation of dialysis to document baseline HCV infection status. If these patients transiently receive in-center hemodialysis, they should undergo HCV infection screening as per the recommendations for in-center hemodialysis patients, with consideration of continued screening until 6 months after the completion of in-center hemodialysis (and transition to a different modality).
      • 1.1.4: We recommend screening all patients for HCV infection at the time of evaluation for kidney transplantation (1A).
      Kidney transplantation candidates should be tested for HCV infection during evaluation for transplantation. Determination of HCV status in recipients is essential for optimal management and potentially for acceptance of kidneys from HCV-infected donors (see Chapter 4).

       1.2 Follow-up HCV screening of in-center hemodialysis patients

      • 1.2.1: We recommend screening for HCV infection with immunoassay or NAT in in-center hemodialysis patients every 6 months (1B).
        • 1.2.1.1: Report any new HCV infection identified in a hemodialysis 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 be increased (1A).
        • 1.2.1.3: We recommend that hemodialysis patients with resolved HCV infection undergo repeat testing every 6 months using NAT to detect possible re-infection (1B).
      • 1.2.2: We suggest that patients have serum alanine aminotransferase (ALT) level checked upon initiation of in-center hemodialysis or upon transfer from another facility (2B).
        • 1.2.2.1: We suggest that hemodialysis patients have ALT level checked monthly (2B).

       Rationale

      • 1.2.1: We recommend screening for HCV infection with immunoassay or NAT in in-center hemodialysis patients every 6 months (1B).
        • 1.2.1.1: Report any new HCV infection identified in a hemodialysis 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 be increased (1A).
        • 1.2.1.3: We recommend that hemodialysis patients with resolved HCV infection undergo repeat testing every 6 months using NAT to detect possible re-infection (1B).
      Patients who are not infected with HCV should be screened for presence of new infection every 6 months.
      Recommendations for preventing transmission of infections among chronic hemodialysis patients.
      This recommendation includes anti-HCV–negative patients and anti-HCV–positive, HCV RNA–negative patients screened initially by immunoassay, as well as HCV RNA–negative patients screened initially by NAT. Patients who are anti-HCV–positive and HCV RNA–negative (i.e., NAT-negative) have resolved infection but remain at risk for re-infection if exposed.
      • Midgard H.
      • Weir A.
      • Palmateer N.
      • et al.
      HCV epidemiology in high-risk groups and the risk of reinfection.
      Therefore, these patients should also undergo repeat screening. For dialysis patients who are anti-HCV–positive and HCV NAT–negative, screening for HCV reinfection should be conducted every 6 months using NAT.
      The purpose of the repeat screening is to identify new infections (i.e., newly acquired infections) that could represent transmission within the dialysis center. The baseline HCV testing results should be reviewed for any patient who has a positive HCV screening test result to determine whether there was a change in infection status indicating a new infection, and results must be communicated to the patient. Any patient with a current infection, whether new or pre-existing, should be linked to HCV care and considered for antiviral therapy.
      Acute HCV infection in a hemodialysis patient should be reported to the appropriate public health authority. Reporting may be mandated by law, as in the US, where a documented negative HCV antibody or NAT laboratory test result followed within 12 months by a positive HCV test result (test conversion) must be reported to public health authorities.
      Centers for Disease Control and Prevention
      Hepatitis C, Acute 2016: Case Definition.
      Acute HCV infection in a hemodialysis patient should be investigated and considered health care–related until proven otherwise.
      Centers for Disease Control and Prevention Health Alert Network
      CDC urging dialysis providers and facilities to assess and improve infection control practices to stop hepatitis C transmission in patients undergoing hemodialysis.
      Behavioral risk factors, along with dialysis and nondialysis health care exposures, should be evaluated by public health authorities. Molecular sequencing of HCV RNA from other patients in the facility may help to identify a source.
      • Savey A.
      • Simon F.
      • Izopet J.
      • et al.
      A large nosocomial outbreak of hepatitis C virus infections at a hemodialysis center.
      • Allander T.
      • Medin C.
      • Jacobson S.H.
      • et al.
      Hepatitis C transmission in a hemodialysis unit: molecular evidence for spread of virus among patients not sharing equipment.
      • Hmaied F.
      • Ben Mamou M.
      • Dubois M.
      • et al.
      Determining the source of nosocomial transmission in hemodialysis units in Tunisia by sequencing NS5B and E2 sequences of HCV.
      • Izopet J.
      • Pasquier C.
      • Sandres K.
      • et al.
      Molecular evidence for nosocomial transmission of hepatitis C virus in a French hemodialysis unit.
      Acute HCV infection should also prompt immediate evaluation of all other patients in the same facility to identify additional cases. The status of all patients should be reviewed at the time a new infection is identified, and all patients previously known to be uninfected should be retested for HCV infection. The frequency of repeat screening should also be increased for a limited time: for example, monthly testing for 3 months, followed by testing again in 3 months, and then resumption of screening every 6 months if no additional infections are identified.
      • Mbaeyi C.
      • Thompson N.D.
      Hepatitis C virus screening and management of seroconversions in hemodialysis facilities.
      Recommendations for preventing transmission of infections among chronic hemodialysis patients.
      This strategy can help to identify delayed seroconversions (from the same exposure period as the index case) or other cases resulting from recurrent breaches. Use of this strategy has led to the detection of additional new cases in several reported outbreaks.
      • Savey A.
      • Simon F.
      • Izopet J.
      • et al.
      A large nosocomial outbreak of hepatitis C virus infections at a hemodialysis center.
      • Kokubo S.
      • Horii T.
      • Yonekawa O.
      • et al.
      A phylogenetic-tree analysis elucidating nosocomial transmission of hepatitis C virus in a haemodialysis unit.
      For anti-HCV–positive patients with chronic HCV infection who become HCV NAT–negative with a sustained virologic response (SVR) to HCV therapy, initiate NAT screening 6 months after documentation of SVR. SVR is determined based on results of NAT testing ≥ 12 weeks after the conclusion of therapy.
      For patients with spontaneous resolution of acute HCV infection as documented by a negative test for HCV RNA at ≥ 6 months after the onset of acute infection, NAT screening should begin 6 months after documented resolution of infection.
      • 1.2.2: We suggest that patients have serum alanine aminotransferase (ALT) level checked upon initiation of in-center hemodialysis or upon transfer from another facility (2B).
        • 1.2.2.1: We suggest that hemodialysis patients have ALT level checked monthly (2B).
      A baseline serum ALT test, followed by monthly testing, in susceptible patients has been recommended to enable early detection of new HCV infection in hemodialysis patients.
      Recommendations for preventing transmission of infections among chronic hemodialysis patients.
      Newly infected patients may have an increase in ALT levels prior to antibody conversion, which should prompt additional evaluation. If an unexplained elevation (i.e., to greater than upper-limit normal) of ALT occurs, the patient should be tested for HCV infection. The exact predictive value of ALT screening for detection of HCV infection has been assessed in a single study and found to be moderate.
      • Saab S.
      • Martin P.
      • Brezina M.
      • et al.
      Serum alanine aminotransferase in hepatitis C screening of patients on hemodialysis.
      However, ALT monitoring is an inexpensive way to ensure that hemodialysis patients are assessed for possible acquisition of infection between regular antibody or NAT screenings. Because few hemodialysis patients with a new HCV infection report symptoms or have symptoms documented in their dialysis medical records, ALT levels are also often used retrospectively to define the likely exposure period for patients who acquired infection. Thus, monthly ALT levels are valuable to help narrow the focus of an HCV case investigation to the most likely exposure and source. The value of monthly ALT testing in patients who have resolved HCV infection has not been studied.

       1.3 Liver testing in patients with CKD and HCV infection

      • 1.3.1: We recommend assessing HCV-infected patients with CKD for liver fibrosis (1A).
      • 1.3.2: We recommend an initial noninvasive evaluation of liver fibrosis (1B).
      • 1.3.3: When the cause of liver disease is uncertain or noninvasive testing results are discordant, consider liver biopsy (Not Graded).
      • 1.3.4: We recommend assessment for portal hypertension in CKD patients with suspected advanced fibrosis (F3–4) (1A).

       Rationale

       Evaluation of liver fibrosis in HCV-infected patients with CKD

      In the prior Kidney Disease: Improving Global Outcomes (KDIGO) HCV guideline published in 2008,
      KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease.
      liver biopsy had been considered the gold standard to assess liver fibrosis in patients with CKD, including candidates for transplantation and transplant recipients. The primary objective of liver biopsy in patients with advanced CKD had been to diagnose cirrhosis. Because of the risk of liver-related mortality after kidney transplantation, cirrhosis had been considered a contraindication to kidney transplantation alone and led to consideration of combined liver-kidney transplantation.
      Current evidence suggests that biochemical noninvasive markers (FibroTest/FibroMeter, aspartate aminotransferase–platelet ratio index [APRI], Forns, or FIB-4 index) and morphological evaluation (liver stiffness by elastography) may have comparable accuracy in evaluating liver fibrosis in patients with CKD G4–5 as in the general population.
      • Liu C.H.
      • Liang C.C.
      • Huang K.W.
      • et al.
      Transient elastography to assess hepatic fibrosis in hemodialysis chronic hepatitis C patients.
      Noninvasive methods, especially elastography, are sufficiently reliable to detect extensive fibrosis and/or cirrhosis (F3–F4)
      • Jadoul M.
      • Horsmans Y.
      Impact of liver fibrosis staging in hepatitis C virus (HCV) patients with kidney failure.
      KDIGO clinical practice guideline for the care of kidney transplant recipients.
      though noninvasive tests other than elastography may be less accurate (Supplementary Tables S1 and S2). Furthermore, although serious complications of liver biopsy are uncommon, patients are often reluctant to consider it, and its validity may be diminished by sampling as well as interpretation errors. Liver biopsy use in HCV-infected patients generally has declined.
      Because SVR can now be anticipated in the vast majority of patients treated for HCV, the management of the HCV-infected kidney transplant candidate, even with cirrhosis, has evolved. SVR is associated with sustained and long-lasting suppression of necroinflammation and may even result in regression of cirrhosis, potentially resulting in decreased disease-related morbidity and improved survival.
      • Serpaggi J.
      • Carnot F.
      • Nalpas B.
      • et al.
      Direct and indirect evidence for the reversibility of cirrhosis.
      Even in the absence of regression of cirrhosis, kidney transplantation alone is feasible in the absence of major complications of portal hypertension, just like in patients with hepatitis B virus (HBV)–related cirrhosis.
      EASL clinical practice guidelines: Management of chronic hepatitis B virus infection.
      Thus, the role of liver biopsy in evaluation of liver fibrosis in HCV-infected patients with CKD G4–5 will evolve given the high SVR rates obtained with current DAA regimens. Defining the severity of cirrhosis involves assessment for clinically significant portal hypertension (hepatic-vein wedge-pressure gradient of ≥ 10 mm Hg).
      • Garcia-Tsao G.
      • Abraldes J.G.
      • Berzigotti A.
      • et al.
      Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases.
      Methods include upper endoscopy, noninvasive radiological evaluation, or direct portal pressure measurement. Based on the Baveno VI consensus,
      • de Franchis R.
      Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension.
      portal hypertension is very unlikely (and hence an upper endoscopy can be avoided with > 90% reliability) in patients with compensated cirrhosis but elastography < 20 kPa and platelet count > 150,000/mm3. Whether this approach is also valid for patients on hemodialysis remains unknown.
      In summary, all HCV-infected patients with kidney failure should undergo a noninvasive biochemical and/or morphological evaluation to stage fibrosis and determine the role of antiviral therapies (see Chapter 2) and to facilitate the choice of kidney or combined liver-kidney transplantation in cirrhotic patients. When results between biochemical and morphological evaluation are discordant or when liver comorbidities are suspected, liver biopsy is suggested.

      European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C 2018. J Hepatol. 2018;69:461–511.

       1.4 Other testing of patients with HCV infection

      Although HCV infection predominantly causes liver disease, it is also associated with extrahepatic manifestations including kidney disease.
      • Zampino R.
      • Marrone A.
      • Restivo L.
      • et al.
      Chronic HCV infection and inflammation: clinical impact on hepatic and extra-hepatic manifestations.
      HCV has been shown to infect both hepatocytes and lymphocytes; thus, lymphoproliferative disorders such as lymphoma and mixed cryoglobulinemia are linked to HCV infection.
      • Cacoub P.
      • Comarmond C.
      • Domont F.
      • et al.
      Extrahepatic manifestations of chronic hepatitis C virus infection.
      HCV has also been implicated in derangements of multiple organ systems including cardiovascular, endocrine, muscular, nervous, ocular, respiratory, skeletal, cutaneous, and urinary systems. In addition, HCV can have a deleterious impact on psychosocial status.
      • Goodkin D.
      • Bieber B.
      • Jadoul M.
      • et al.
      Mortality, hospitalization, and quality of life among patients with hepatitis C infection on hemodialysis.
      The relationship between HCV infection and CKD is complex. HCV infection and CKD are prevalent in the general population and associated in various ways: patients on chronic hemodialysis are at increased risk of acquiring HCV, and some types of kidney disease are precipitated by HCV infection. Conventional risk factors for CKD such as aging, diabetes, hypertension, and metabolic syndrome do not fully explain the current frequency of CKD in the adult general population of developed countries. In addition to these conventional risk factors, accumulating evidence in the last decade has implicated HCV infection as a cause of kidney disease. HCV co-infection has also been implicated as a risk factor for CKD in HIV-infected patients.
      • Lucas G.M.
      • Ross M.J.
      • Stock P.G.
      • et al.
      Clinical practice guideline for the management of chronic kidney disease in patients infected with HIV: 2014 update by the HIV Medicine Association of the Infectious Diseases Society of America.
      A meta-analysis
      • Fabrizi F.
      • Verdesca S.
      • Messa P.
      • et al.
      Hepatitis C virus infection increases the risk of developing chronic kidney disease: a systematic review and meta-analysis.
      of observational studies
      • Asrani S.K.
      • Buchanan P.
      • Pinsky B.
      • et al.
      Lack of association between hepatitis C infection and chronic kidney disease.
      • Butt A.A.
      • Wang X.
      • Fried L.F.
      HCV infection and the incidence of CKD.
      • Chen Y.C.
      • Lin H.Y.
      • Li C.Y.
      • et al.
      A nationwide cohort study suggests that hepatitis C virus infection is associated with increased risk of chronic kidney disease.
      • Hofmann J.N.
      • Torner A.
      • Chow W.H.
      • et al.
      Risk of kidney cancer and chronic kidney disease in relation to hepatitis C virus infection: a nationwide register-based cohort study in Sweden.
      • Lee J.J.
      • Lin M.Y.
      • Chang J.S.
      • et al.
      Hepatitis C virus infection increases risk of developing end-stage renal disease using competing risk analysis.
      • Moe S.M.
      • Pampalone A.J.
      • Ofner S.
      • et al.
      Association of hepatitis C virus infection with prevalence and development of kidney disease.
      • Molnar M.Z.
      • Alhourani H.M.
      • Wall B.M.
      • et al.
      Association of hepatitis C viral infection with incidence and progression of chronic kidney disease in a large cohort of US veterans.
      • Su F.H.
      • Su C.T.
      • Chang S.N.
      • et al.
      Association of hepatitis C virus infection with risk of ESRD: a population-based study.
      • Tsui J.I.
      • Vittinghoff E.
      • Shlipak M.G.
      • et al.
      Association of hepatitis C seropositivity with increased risk for developing end-stage renal disease.
      demonstrated a relationship between anti-HCV–positive serologic status and an increased incidence of CKD in the adult general population, with an adjusted hazard ratio (HR) of 1.43 (95% confidence interval [CI]: 1.23–1.63). Based on current information, patients with HCV infection should be regarded as being at increased risk of CKD, regardless of the presence of conventional risk factors for kidney disease.
      • 1.4.1: We recommend assessing all patients for kidney disease at the time of HCV infection diagnosis (1A).
        • 1.4.1.1: Screen for kidney disease with urinalysis and estimated glomerular filtration rate (eGFR) (Not Graded).
      • 1.4.2: If there is no evidence of kidney disease at initial evaluation, patients who remain NAT-positive should undergo repeat screening for kidney disease (Not Graded).
      • 1.4.3: We recommend that all CKD patients with a history of HCV infection, whether NAT-positive or not, be followed up regularly to assess progression of kidney disease (1A).
      • 1.4.4: We recommend that all CKD patients with a history of HCV infection, whether NAT-positive or not, be screened and, if appropriate, vaccinated against hepatitis A virus (HAV) and hepatitis B virus (HBV), and screened for human immunodeficiency virus (HIV) (1A).

       Rationale

      • 1.4.1: We recommend assessing all patients for kidney disease at the time of HCV infection diagnosis (1A).
        • 1.4.1.1: Screen for kidney disease with urinalysis and estimated glomerular filtration rate (eGFR) (Not Graded).
      The prevalence of CKD, defined by a reduction in eGFR and/or increased urinary albumin excretion,
      Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease.
      exceeds 10% in the adult general population, according to numerous population-based studies. The prevalence of low GFR alone is around 5% to 6% but increases sharply with older age. Testing for CKD appears logical in HCV-infected individuals, as many authors have suggested a potential role of HCV infection as a cause of CKD. However, epidemiologic supporting data regarding the prevalence of CKD in HCV-infected patients were until recently limited and used variable criteria for the definition of CKD; the demographic/clinical characteristics of the representative patient population were variable as well. According to 3 studies performed in the US,
      • Asrani S.K.
      • Buchanan P.
      • Pinsky B.
      • et al.
      Lack of association between hepatitis C infection and chronic kidney disease.
      • Moe S.M.
      • Pampalone A.J.
      • Ofner S.
      • et al.
      Association of hepatitis C virus infection with prevalence and development of kidney disease.
      • Tsui J.I.
      • Vittinghoff E.
      • Shlipak M.G.
      • et al.
      Association of hepatitis C seropositivity with increased risk for developing end-stage renal disease.
      the unadjusted prevalence of low GFR (<60 ml/min per 1.73 m2) ranged at baseline between 5.1% and 8.0% among middle-aged anti-HCV–seropositive individuals. The unadjusted prevalence of renal insufficiency (serum creatinine >1.5 mg/dl [>133 μmol/l]) in one large study of anti-HCV-seropositive veterans from the US was 4.8%.
      • Dalrymple L.S.
      • Koepsell T.
      • Sampson J.
      • et al.
      Hepatitis C virus infection and the prevalence of renal insufficiency.
      In another large cohort of HCV-positive, HIV-positive patients from North America, the unadjusted frequency of low GFR (<60 ml/min per 1.73 m2) at baseline ranged between 3.7% and 4.0%.
      • Lucas G.M.
      • Jing Y.
      • Sulkowski M.
      • et al.
      Hepatitis C viremia and the risk of chronic kidney disease in HIV-infected individuals.
      Kidney involvement in HCV infection was first recognized more than 2 decades ago; however, the association between HCV and CKD (low GFR or presence of proteinuria) in the adult general population was controversial until a few years ago. An increasing body of evidence has recently highlighted the detrimental impact of HCV infection on the risk of CKD (Supplementary Tables S3 and S4). One meta-analysis
      • Fabrizi F.
      • Verdesca S.
      • Messa P.
      • et al.
      Hepatitis C virus infection increases the risk of developing chronic kidney disease: a systematic review and meta-analysis.
      reported an HR of 1.43 (95% CI: 1.23–1.63) between positive HCV serologic status and increased incidence for CKD, while another recent study

      Park H, Chen C, Wang W, et al. Chronic hepatitis C virus (HCV) increases the risk of chronic kidney disease (CKD) while effective HCV treatment decreases the incidence of CKD [e-pub ahead of print]. Hepatology. https://doi.org/10.1002/hep.29505.

      demonstrated that patients with HCV had a 27% increased risk of CKD compared with patients without HCV. This study also revealed that HCV-positive patients experienced a 2-fold higher risk of membranoproliferative glomerulonephritis (MPGN) and a nearly 17-fold higher risk of cryoglobulinemia. Effective antiviral treatments have been shown to reduce risk for development of CKD by 30%. Cohort studies performed in patients with HIV and HCV co-infection,
      • Wyatt C.M.
      • Malvestutto C.
      • Coca S.G.
      • et al.
      The impact of hepatitis C virus coinfection on HIV-related kidney disease: a systematic review and meta-analysis.
      patients with diabetes,
      • Crook E.D.
      • Penumalee S.
      • Gavini B.
      • et al.
      Hepatitis C is a predictor of poorer renal survival in diabetic patients.
      • Soma J.
      • Saito T.
      • Taguma Y.
      • et al.
      High prevalence and adverse effect of hepatitis C virus infection in type II diabetic-related nephropathy.
      and patients with biopsy-proven chronic glomerulonephritis (GN)
      • Noureddine L.A.
      • Usman S.A.
      • Yu Z.
      • et al.
      Hepatitis C increases the risk of progression of chronic kidney disease in patients with glomerulonephritis.
      have confirmed a significant relationship between anti-HCV–positive serologic status and accelerated progression of CKD. The prevalence of anti-HCV in serum was significantly greater in patients with CKD before reaching end-stage kidney disease (ESKD) than in a healthy population.
      • Bergman S.
      • Accortt N.
      • Turner A.
      • et al.
      Hepatitis C infection is acquired pre-ESRD.
      • Iwasa Y.
      • Otsubo S.
      • Sugi O.
      • et al.
      Patterns in the prevalence of hepatitis C virus infection at the start of hemodialysis in Japan.
      Among liver transplant recipients infected with HCV who were treated with antiviral therapy, SVR led to improved eGFR in those with CKD G2 (GFR 60–89 ml/min per 1.73 m2) before treatment.
      • Ble M.
      • Aguilera V.
      • Rubin A.
      • et al.
      Improved renal function in liver transplant recipients treated for hepatitis C virus with a sustained virological response and mild chronic kidney disease.
      HCV co-infection is a risk factor for increased health care resource utilization in HIV-infected individuals in the US; a multivariate Poisson model showed that HCV co-infection was associated with higher frequency of emergency department visits: adjusted relative risk (RR) 2.07 (95% CI: 1.49–2.89). In particular, emergency department visits related to kidney disease were much more common among co-infected patients (37%) than among those with HIV infection alone (10%).
      • Norton B.L.
      • Park L.
      • McGrath L.J.
      • et al.
      Health care utilization in HIV-infected patients: assessing the burden of hepatitis C virus coinfection.
      Another meta-analysis of observational studies
      • Fabrizi F.
      • Dixit V.
      • Martin P.
      • et al.
      Hepatitis C virus increases the risk of kidney disease among HIV-positive patients: Systematic review and meta-analysis.
      reported a relationship between positive anti-HCV serologic status and an increased risk of reduced GFR among HIV-infected individuals, with an adjusted HR of 1.64 (95% CI: 1.28–2.0), compared with those having HIV infection alone.
      • 1.4.2: If there is no evidence of kidney disease at initial evaluation, patients who remain NAT-positive should undergo repeat screening for kidney disease (Not Graded).
      The recommendation to repeat testing for proteinuria or GFR in anti-HCV–positive, HCV NAT–positive patients comes from epidemiologic data. In one study, serial measurements of eGFR and proteinuria were obtained in a large cohort of US metropolitan residents. The prevalence of CKD was greater among anti-HCV–positive, HCV NAT–positive patients compared with matched anti-HCV–negative controls (9.1% vs. 5.1%, P = 0.04).
      • Satapathy S.K.
      • Lingisetty C.S.
      • Williams S.
      Higher prevalence of chronic kidney disease and shorter renal survival in patients with chronic hepatitis C virus infection.
      In addition, using data from the Third National Health and Nutrition Examination Survey, at least 2 studies have observed an increased risk of albuminuria in patients with HCV.
      • Liangpunsakul S.
      • Chalasani N.
      Relationship between hepatitis C and microalbuminuria: results from the NHANES III.
      • Tsui J.I.
      • Vittinghoff E.
      • Shlipak M.G.
      • et al.
      Relationship between hepatitis C and chronic kidney disease: results from the Third National Health and Nutrition Examination Survey.
      Classically, HCV infection predisposes to cryoglobulinemic MPGN; however, HCV-positive individuals may also be at risk for kidney injury related to decompensated cirrhosis, injection drug use, and HIV or HBV co-infection. Overall, multiple studies have now shown that HCV infection is associated with an increased risk of developing CKD, as summarized in a recent meta-analysis.
      • Fabrizi F.
      • Verdesca S.
      • Messa P.
      • et al.
      Hepatitis C virus infection increases the risk of developing chronic kidney disease: a systematic review and meta-analysis.
      It is possible that accelerated atherosclerosis also contributes to the increased risk of developing kidney disease among HCV-infected individuals.
      • Petta S.
      • Adinolfi L.E.
      • Fracanzani A.L.
      • et al.
      Hepatitis C virus eradication by direct-acting antiviral agents improves carotid atherosclerosis in patients with severe liver fibrosis.
      • 1.4.3: We recommend that all CKD patients with a history of HCV infection, whether NAT-positive or not, be followed up regularly to assess for progression of kidney disease (1A).
      Although studies are heterogeneous and some controversy persists,
      • Rogal S.S.
      • Yan P.
      • Rimland D.
      • et al.
      Incidence and Progression of Chronic Kidney Disease After Hepatitis C Seroconversion: Results from ERCHIVES.
      overall, HCV-infected patients appear to be at greater risk for incidence and progression of kidney disease and require monitoring as outlined in the KDIGO CKD guideline.
      Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease.
      In the Women’s Interagency HIV study, anti-HCV–positive serologic status was independently associated with a net decrease in eGFR of approximately 5% per year (95% CI: 3.2–7.2) compared with women who were seronegative.
      • Tsui J.
      • Vittinghoff E.
      • Anastos K.
      • et al.
      Hepatitis C seropositivity and kidney function decline among women with HIV: data from the Women's Interagency HIV Study.
      Of note, antiviral therapy for HCV significantly improves hepatic and extrahepatic outcomes in the general population
      • Hsu C.S.
      • Kao J.H.
      • Chao Y.C.
      • et al.
      Interferon-based therapy reduces risk of stroke in chronic hepatitis C patients: a population-based cohort study in Taiwan.
      • van der Meer A.J.
      • Berenguer M.
      Reversion of disease manifestations after HCV eradication.
      and among patients co-infected with HIV and HCV.
      • Berenguer J.
      • Rodriguez E.
      • Miralles P.
      • et al.
      Sustained virological response to interferon plus ribavirin reduces non-liver-related mortality in patients coinfected with HIV and Hepatitis C virus.
      Six studies have addressed the impact of interferon (IFN)-based regimens on the progression of CKD.
      • Satapathy S.K.
      • Lingisetty C.S.
      • Williams S.
      Higher prevalence of chronic kidney disease and shorter renal survival in patients with chronic hepatitis C virus infection.
      • Arase Y.
      • Suzuki F.
      • Kawamura Y.
      • et al.
      Development rate of chronic kidney disease in hepatitis C virus patients with advanced fibrosis after interferon therapy.
      • Chen Y.C.
      • Hwang S.J.
      • Li C.Y.
      • et al.
      A Taiwanese nationwide cohort study shows interferon-based therapy for chronic hepatitis C reduces the risk of chronic kidney disease.
      • Hsu Y.C.
      • Ho H.J.
      • Huang Y.T.
      • et al.
      Association between antiviral treatment and extrahepatic outcomes in patients with hepatitis C virus infection.
      • Hsu Y.C.
      • Lin J.T.
      • Ho H.J.
      • et al.
      Antiviral treatment for hepatitis C virus infection is associated with improved renal and cardiovascular outcomes in diabetic patients.
      • Leone S.
      • Prosperi M.
      • Costarelli S.
      • et al.
      Incidence and predictors of cardiovascular disease, chronic kidney disease, and diabetes in HIV/HCV-coinfected patients who achieved sustained virological response.
      Five multivariate analyses
      • Satapathy S.K.
      • Lingisetty C.S.
      • Williams S.
      Higher prevalence of chronic kidney disease and shorter renal survival in patients with chronic hepatitis C virus infection.
      • Arase Y.
      • Suzuki F.
      • Kawamura Y.
      • et al.
      Development rate of chronic kidney disease in hepatitis C virus patients with advanced fibrosis after interferon therapy.
      • Chen Y.C.
      • Hwang S.J.
      • Li C.Y.
      • et al.
      A Taiwanese nationwide cohort study shows interferon-based therapy for chronic hepatitis C reduces the risk of chronic kidney disease.
      • Hsu Y.C.
      • Ho H.J.
      • Huang Y.T.
      • et al.
      Association between antiviral treatment and extrahepatic outcomes in patients with hepatitis C virus infection.
      • Hsu Y.C.
      • Lin J.T.
      • Ho H.J.
      • et al.
      Antiviral treatment for hepatitis C virus infection is associated with improved renal and cardiovascular outcomes in diabetic patients.
      suggested that treatment of HCV infection may improve renal survival per se. In a nationwide cohort study from Taiwan, patients who had received antiviral treatment (pegylated IFN plus ribavirin [RBV]) had a calculated 8-year cumulative incidence of ESKD of 0.15% versus 1.32% in untreated patients (P < 0.001).
      • Hsu Y.C.
      • Ho H.J.
      • Huang Y.T.
      • et al.
      Association between antiviral treatment and extrahepatic outcomes in patients with hepatitis C virus infection.
      Multivariate-adjusted Cox regression revealed that antiviral treatment was associated with lower risks of ESKD (HR: 0.15; 95% CI: 0.07–0.31). Antiviral treatment was also associated with an adjusted HR of 0.77 (95% CI: 0.62–0.97) for acute coronary syndrome, and 0.62 (95% CI: 0.46–0.83) for ischemic stroke.
      • Hsu Y.C.
      • Ho H.J.
      • Huang Y.T.
      • et al.
      Association between antiviral treatment and extrahepatic outcomes in patients with hepatitis C virus infection.
      These favorable associations were not observed in patients treated for less than 16 weeks, suggesting that shorter-duration therapy was inadequate.
      In a study on 650 Japanese patients with liver cirrhosis,
      • Arase Y.
      • Suzuki F.
      • Kawamura Y.
      • et al.
      Development rate of chronic kidney disease in hepatitis C virus patients with advanced fibrosis after interferon therapy.
      multivariate Cox proportional hazards analysis showed that failure to achieve SVR was a predictor of development of CKD, with an adjusted HR of 2.67 (95% CI:1.34–5.32). In a hospital-based study from the US, 552 HCV-infected patients were evaluated, and 159 received IFN therapy during a 7-year follow-up. Multivariate logistic regression indicated that a history of IFN treatment was a significant independent negative predictor for CKD (odds ratio [OR]: 0.18; 95% CI: 0.06–0.56).
      • Satapathy S.K.
      • Lingisetty C.S.
      • Williams S.
      Higher prevalence of chronic kidney disease and shorter renal survival in patients with chronic hepatitis C virus infection.
      Finally, a recent meta-analysis of controlled and uncontrolled studies (11 studies; n = 225 patients) that evaluated efficacy and safety of antiviral treatment for HCV-related glomerular disease found that the summary estimate of the mean decrease in serum creatinine levels was 0.23 mg/dl (20 μmol/l) (95% CI: 0.02–0.44) after IFNα-based therapy.
      • Feng B.
      • Eknoyan G.
      • Guo Z.S.
      • et al.
      Effect of interferon-alpha-based antiviral therapy on hepatitis C virus-associated glomerulonephritis: a meta-analysis.
      • 1.4.4: We recommend that all CKD patients with a history of HCV infection, whether NAT-positive or not, be screened and, if appropriate, vaccinated against HAV and HBV, and screened for human immunodeficiency virus (HIV) (1A).
      HCV is a blood-borne pathogen and shares routes of transmission with HBV and HIV. Although hepatitis A virus (HAV) infection is frequently mild in healthy individuals, superinfection with HAV and HBV in patients with liver disease (including chronic HCV) may result in significant morbidity and mortality.
      • Reiss G.
      • Keeffe E.B.
      Review article: hepatitis vaccination in patients with chronic liver disease.
      Thus, as HAV
      • Tung J.
      • Carlisle E.
      • Smieja M.
      • et al.
      A randomized clinical trial of immunization with combined hepatitis A and B versus hepatitis B alone for hepatitis B seroprotection in hemodialysis patients.
      and HBV
      • Fabrizi F.
      • Martin P.
      • Messa P.
      Novel perspectives on the hepatitis B virus vaccine in the chronic kidney disease population.
      are vaccine-preventable infections, appropriate vaccination should be encouraged, although response rates to vaccination are diminished in patients with advanced CKD.

       Research recommendations

      • Studies are needed to examine HCV antigen testing as an alternative to NAT to diagnose HCV viremic infection.
      • The clinical utility of HCV antigen immunoassays and antigen and antibody combination assays should be determined.
      • The predictive value of different levels of ALT for identifying HCV infection and the additive value of ALT screening to the current generation of immunoassays or NAT testing should be investigated. Data should already exist to address this question among dialysis providers that perform routine screening of their patients. The utility of ALT testing after resolved HCV infection should be studied.
      • With the availability of effective treatments for HCV, the role of DAAs in preventing and slowing the progression of CKD in HCV-infected population should be assessed.

       Chapter 2: Treatment of HCV infection in patients with CKD

      The recommendations are presented below by GFR category. GFR can be measured GFR or estimated GFR. If eGFR is used, we suggest using the creatinine-based Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula or the creatinine and cystatin C-based CKD-EPI formula.
      • Inker L.A.
      • Schmid C.H.
      • Tighiouart H.
      • et al.
      Estimating glomerular filtration rate from serum creatinine and cystatin C.
      Because multiple studies from the general population have found a strong correlation between mortality and SVR,
      • Simmons B.
      • Saleem J.
      • Hill A.
      • et al.
      Risk of late relapse or reinfection with hepatitis C virus after achieving a sustained virological response: a systematic review and meta-analysis.
      regulatory agencies such as the US Food and Drug Administration (FDA) have generally accepted SVR response as a surrogate endpoint for trials used in their drug approval process.

      Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Chronic hepatitis C virus infection: developing direct-acting antiviral drugs for treatment. Guidance for industry. 2017. Available at: https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm225333.pdf. Accessed March 23, 2018.

      The FDA recently replaced SVR at 24 weeks after cessation of therapy (SVR24) with SVR at 12 weeks (SVR12). Although there are no data demonstrating that SVR12 reduces mortality in CKD, a meta-analysis showed that SVR24 predicted mortality not only in the general population, but also in patients with cirrhosis and patients with HIV co-infection.
      • Simmons B.
      • Saleem J.
      • Heath K.
      • et al.
      Long-term treatment outcomes of patients infected with hepatitis C virus: a systematic review and meta-analysis of the survival benefit of achieving a sustained virological response.
      Currently, duration of therapy for DAA regimens is usually 12 weeks but may change in the future.
      For most CKD patients, as in the general population, the potential benefits of antiviral treatment outweigh potential harms.
      • Falade-Nwulia O.
      • Suarez-Cuervo C.
      • Nelson D.R.
      • et al.
      Oral direct-acting agent therapy for hepatitis C virus infection: a systematic review.
      However, some patients may not be expected to live long enough to benefit from therapy (e.g., those with metastatic cancer). The Work Group was hesitant to specify a minimum life expectancy that would justify treatment, given the inaccuracy of predictions and the need to individualize this decision. However, as noted in the American Association for the Study of Liver Diseases/Infectious Diseases Society of America (AASLD/IDSA) guidance, little evidence exists to support initiation of HCV treatment in patients with a limited life expectancy (<12 months).

      AASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C. Available at: http://www.hcvguidelines.org. Accessed June 12, 2018.

      IFN is often poorly tolerated in advanced CKD (CKD G4–G5) patients who have prolonged IFN exposure due to decreased renal clearance. RBV is also associated with adverse events. Hemolytic anemia induced by RBV is especially common in patients with CKD G3b–G5 and can be severe. The RBV dose needs to be reduced in patients with advanced CKD, but dose reductions can only be approximated. An initial starting dose of 200 mg daily is typical but does not preclude development of anemia, despite initiation or increased dosing of erythropoiesis stimulating agents (ESAs). Because DAAs are effective, well-tolerated, and often do not require dose reductions in those with CKD, it is clearly desirable to avoid IFN completely in all patients and to minimize use of RBV in patients with advanced 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).
      • 2.2: We recommend that patients with GFR ≥ 30 ml/min per 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 per 1.73 m2 (CKD G4–G5D) should be treated with a ribavirin-free DAA-based regimen as outlined in Figure 1.
      • 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 as outlined in Figure 1 (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).
        • 2.4.4: 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).
          • 2.4.4.1: We recommend that calcineurin inhibitor levels be monitored during and after DAA treatment (1B).
      • 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).

       Rationale

       CKD G1–G3b (GFR ≥ 30 ml/min per 1.73 m2)

      For mild to moderate decreases in kidney function, patients with CKD can generally be treated as per evidence-based guidelines for the general population. Currently in the US, the AASLD/IDSA guidelines recommend few dosage modifications for people with mild to moderate reductions in GFR. For CKD G1–G3b (GFR ≥ 30 ml/min per 1.73 m2), no dosage adjustment is required when using daclatasvir (60 mg); daily fixed-dose combination of elbasvir (50 mg) and grazoprevir (100 mg); daily fixed dose combination of glecaprevir (300 mg) and pibrentasvir (120 mg); fixed dose combination of sofosbuvir (400 mg) with either ledipasvir (90 mg) or velpatasvir (100 mg); simprevir (150 mg); fixed-dose combination of sofosbuvir (400 mg), velpatasvir (100 mg), and voxilaprevir (100 mg); or sofosbuvir (400 mg). At the time of publication, regimens including velpatasvir have not been formally approved for use in patients with CKD G1–G3 in some jurisdictions, however.
      The 2018 European Association for the Study of the Liver (EASL) guideline

      European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C 2018. J Hepatol. 2018;69:461–511.

      also recommends no dosage modifications of DAAs for CKD G1–G3 patients, but recommends that these patients should be carefully monitored.
      In summary, for patients with CKD G1–G3 the choice of DAA is not restricted. However, it must be stressed that recommended drugs and dosage are constantly evolving, and clinicians should consult the latest guidelines from AASLD (https://www.hcvguidelines.org/unique-populations/renal-impairment) or EASL (http://www.easl.eu/research/our-contributions/clinical-practice-guidelines) for the most up-to-date treatment information.

       CKD G4–G5 and G5D (Advanced CKD: GFR < 30 ml/min per 1.73 m2 and those on hemodialysis)

      DAAs have variable renal elimination; thus, advanced CKD, if present, is an important determinant in the choice of agent. Until recently, patients with advanced CKD had limited options for HCV therapy. Importantly sofosbuvir, which had been the cornerstone of most DAA regimens, is predominantly renally cleared (80%) and is licensed for use only in individuals with GFR ≥ 30 ml/min per 1.73 m2 (CKD G1–G3b).
      A regimen combining a nonstructural protein 5A (NS5A) replication complex inhibitor (elbasvir) and a new-generation nonstructural protein NS3/4A protease inhibitor (grazoprevir) has been licensed for patients infected with HCV genotypes (GTs) 1 and 4, with safety and efficacy data available in patients with advanced CKD. Both agents are metabolized by CYP3A and primarily (>90%) excreted in feces with minimal renal clearance (<1%). Although pharmacokinetic analyses show that area under the curves (AUCs) are higher in individuals with advanced CKD requiring hemodialysis (up to 46% higher compared with individuals with normal kidney function), these changes in exposure to the drugs are not considered clinically relevant.
      • Gamal N.
      • Andreone P.
      Grazoprevir/elbasvir fixed-dose combination for hepatitis C.
      Of note, Reddy et al.
      • Reddy K.R.
      • Roth D.
      • Bruchfeld A.
      • et al.
      Elbasvir/grazoprevir does not worsen renal function in patients with hepatitis C virus infection and pre-existing renal disease.
      identified 32 patients with CKD G3a/G3b included in trials with grazoprevir and elbasvir and found no evidence of deterioration of kidney function as a result of treatment with these agents.
      Grazoprevir is a substrate of OATP1B1/3, and co-administration with drugs that inhibit OATP1B1/3 (such as enalapril, statins, digoxin, some angiotensin-receptor blockers) may result in increased levels of grazoprevir that may lead to clinically significant hyperbilirubinemia. Elbasvir and grazoprevir are substrates of CYP3A, and co-administration with strong CYP3A inducers (such as rifampin, phenytoin, and St John’s wort) is contraindicated, as it may result in decreased plasma concentrations and potentially reduced antiviral activity of both agents. The Hepatitis Drug Interactions website from the University of Liverpool (http://www.hep-druginteractions.org) or another reliable expert source should be accessed to determine the risk and management recommendations for drug–drug interactions.
      In contrast to sofosbuvir, agents such as grazoprevir-elbasvir, paritaprevir-ritonavir-ombitasvir with or without dasabuvir, simeprevir, daclatasvir as well as glecaprevir/pibrentasvir can be safely used in CKD G4 and G5 patients (Supplementary Tables S5 and S6). Data on several regimens have been published in patients with advanced CKD (CKD G4–G5D). In the C-SURFER trial, a phase 3 placebo-controlled, randomized, multicenter trial, 12-week treatment with grazoprevir and elbasvir was evaluated in HCV GT1–infected patients with advanced CKD (81% with eGFR < 15 ml/min per 1.73 m2 [CKD G5] and 76% on hemodialysis [CKD G5D]), including 6% of patients with cirrhosis).
      • Roth D.
      • Nelson D.R.
      • Bruchfeld A.
      • et al.
      Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study.
      The majority of them were infected with GT1a (52%), and 80% were treatment-naïve. SVR12 was 99% (95% CI: 95.3–100.0; 115 of 116), with 1 relapse 12 weeks after end of treatment with no significant difference between GTs 1a and 1b, nor between those undergoing hemodialysis and those with advanced CKD not on dialysis therapy. Tolerability was excellent. The most common adverse events (≥10% frequency) were headache, nausea, and fatigue, and were comparable in the treatment versus control arms. The frequencies of hemoglobin levels < 8.5 g/dl (< 85 g/l) were also comparable between treated and untreated groups (4.5% and 4.4%, respectively), and similar proportions of patients in both groups required treatment with ESAs. Renal events such as a rise in serum creatinine and/or blood urea nitrogen, change in eGFR, and need to start hemodialysis were comparable between both groups.
      • Roth D.
      • Nelson D.R.
      • Bruchfeld A.
      • et al.
      Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study.
      • Bruchfeld A.
      • Roth D.
      • Martin P.
      • et al.
      Elbasvir plus grazoprevir in patients with hepatitis C virus infection and stage 4-5 chronic kidney disease: clinical, virological, and health-related quality-of-life outcomes from a phase 3, multicentre, randomised, double-blind, placebo-controlled trial.
      These RCT results have recently been confirmed in a real-world French cohort study.
      • Alric L.
      • Ollivier-Hourmand I.
      • Berard E.
      • et al.
      Grazoprevir plus elbasvir in HCV genotype-1 or -4 infected patients with stage 4/5 severe chronic kidney disease is safe and effective.
      The combination of ritonavir-boosted paritaprevir with ombitasvir and dasabuvir (“PrOD” or 3D regimen) has been evaluated in a small single-arm study as well as in observational cohorts demonstrating excellent efficacy in patients infected with HCV GT1 and CKD G4 and G5.
      • Munoz-Gomez R.
      • Rincon D.
      • Ahumada A.
      • et al.
      Therapy with ombitasvir/paritaprevir/ritonavir plus dasabuvir is effective and safe for the treatment of genotype 1 and 4 hepatitis C virus infection (HCV) in patients with severe renal impairment: a multicenter experience.
      RBV may be required when using the PrOD regimen in patients infected with HCV GT1a. However, even with a reduced dose of 200 mg RBV daily, further dosing reduction was required in half of the treated patients despite the use of ESAs.
      • Pockros P.J.
      • Reddy K.R.
      • Mantry P.S.
      • et al.
      Efficacy of direct-acting antiviral combination for patients with hepatitis C virus genotype 1 infection and severe renal impairment or end-stage renal disease.
      Virological factors that may impact response to HCV therapy especially in GT1a-infected patients include the presence of resistance-associated variants.
      • Sarrazin C.
      The importance of resistance to direct antiviral drugs in HCV infection in clinical practice.
      Resistance testing may not be available in some centers, and if use of RBV is not feasible due to baseline anemia, extension of therapy with grazoprevir/elbasvir to 16 weeks for patients infected with HCV GT1a should be considered. In HCV GT1a patients with high viral load (>800,000 IU/ml), prolonging duration of therapy to 16 weeks and the use of RBV, if possible, to avoid a reduction in SVR12 (from 99% with RBV to 88% without in 1 study) is suggested.

      Jacobson IM, Asante-Appiah E, Wong P, et al. Prevalence and impact of baseline NSA resistance associated variants (RAVs) on the efficacy of elbasvir/grazoprevir (EBR/GZR) against GT1a infection [Abstract LB-22]. In: 66th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), November 13-17, 2015. San Francisco, CA; 2015.

      In the RUBY II trial presented at the 2016 AASLD Annual Meeting, dialysis patients with HCV GT1a were treated with ritonavir-boosted paritaprevir, ombitasvir, and dasabuvir, and those infected with GT4 were treated with the first 2 agents without dasabuvir. RBV was not included in the regimen. Of the 13 treated subjects, 12 achieved SVR (92%). The remaining patient who discontinued antiviral therapy elected to undergo kidney transplantation.
      • Gane E.J.
      • Solà R.
      • Cohen E.
      • et al.
      RUBY-II: Efficacy and Safety of a Ribavirin-free Ombitasvir/Paritaprevir/Ritonavir ± Dasabuvir Regimen in Patients with Severe Renal Impairment or End-Stage Renal Disease and HCV Genotypes 1a or 4 Infection.
      All components of the combination regimen containing ombitasvir, paritaprevir, ritonavir, and dasabuvir (used in GT1 and without dasabuvir in GT4) are predominantly excreted in the feces, with <11% renal clearance; thus, pharmacokinetics are not significantly altered in advanced CKD (CKD G4–G5), and no dose adjustment is recommended. In a single-arm, multicenter study of treatment-naïve adults with HCV GT1 infection without cirrhosis and with CKD G4 or G5, 20 patients were treated with this regimen for 12 weeks. Patients with HCV GT1a infection also received RBV (n = 13), whereas those with GT1b infection did not (n = 7). Eighteen of the 20 patients achieved SVR12 (90%; 95% CI: 69.9–97.2), but 1 treatment failure was nonvirological (death after the end of the treatment unrelated to the treatment). The only patient who relapsed was a GT1-infected patient with advanced liver fibrosis on hemodialysis. Adverse events were primarily mild or moderate, and no patient discontinued treatment due to an adverse event. RBV therapy was interrupted in nine patients due to anemia; 4 received ESAs. No blood transfusions were required.
      • Pockros P.J.
      • Reddy K.R.
      • Mantry P.S.
      • et al.
      Efficacy of direct-acting antiviral combination for patients with hepatitis C virus genotype 1 infection and severe renal impairment or end-stage renal disease.
      Similar to other protease inhibitors (simeprevir and paritaprevir), grazoprevir is contraindicated in decompensated patients with Child-Turcotte-Pugh class B or C due to diminished hepatic metabolism and risk of adverse event, particularly hepatic toxicity.
      In practice, no dose adjustment for kidney function is needed with NS5A inhibitors such as daclatasvir and protease inhibitors such as simeprevir.
      Prior to the recent introduction of glecaprevir-pibrentasvir, a sofosbuvir-based regimen had been the only option for patients with CKD G4 and G5 infected with HCV GTs 2, 3, 5, and 6, particularly those with cirrhosis and those with a history of prior nonresponse to IFN-based therapies. However, the glecaprevir-pibrentasvir regimen is pan-genotypic, with no dose reduction necessary for diminished GFR. In the EXPEDITION-4 trial, which included 104 patients with CKD G4–G5 and HCV GTs 1–6 of whom 82% were receiving hemodialysis therapy,
      • Gane E.
      • Lawitz E.
      • Pugatch D.
      • et al.
      Glecaprevir and pibrentasvir in patients with HCV and severe renal impairment.
      subjects received the combination of glecaprevir, a protease inhibitor, and pibrentasvir, an NS5A inhibitor, for 12 weeks. Forty-two percent of subjects had been treated previously, including 2 who had received sofosbuvir-based therapy; 19% of patients had compensated cirrhosis. SVR12 was 98%; of the 2 patients who did not achieve SVR, 1 received only 4 weeks of therapy and the other died of an unrelated cause shortly after completion of therapy. Detection of resistance-associated variants, present in 29% of subjects, did not impact SVR, although HCV GT 3 patients with prior therapy failure had been excluded from inclusion.
      We recognize that preferred regimens such as grazoprevir-elbasvir and glecaprevir-pibrentasvir for CKD G4–G5D patients may not be available in some countries or regions, and sofosbuvir-based regimens may be all that is available despite the fact that they are not licensed for use in CKD G4–G5D patients. Sofosbuvir undergoes extensive hepatic metabolism and is biotransformed to the pharmacologically active nucleotide analog uridine-triphosphate (SOF-007TP) which, once dephosphorylated, results in the formation of the predominant sofosbuvir inactive metabolite GS-331007 (SOF-007). SOF-007 is mainly eliminated through the renal route, and the 4-hour hemodialysis extraction ratio is about 53%.
      • Kirby B.J.
      • Symonds W.T.
      • Kearney B.P.
      • et al.
      Pharmacokinetic, pharmacodynamic, and drug-interaction profile of the hepatitis C virus NS5B polymerase inhibitor sofosbuvir.
      For creatinine clearance (CrCl) < 30 ml/min, pharmacokinetics data showed marked plasma overexposure of sofosbuvir (AUC0-IFN 171% higher), and particularly SOF-007 (AUC0-IFN 451% higher) after a single dose of 400 mg, as compared with subjects with normal kidney function.
      • Gane E.J.
      • Robson R.A.
      • Bonacini
      • et al.
      Safety, anti-viral efficacy and pharmacokinetics (PK) of sofosbuvir (SOF) in patients with severe renal impairment. [Abstract 966].
      Despite these pharmacokinetics studies, there are preliminary data with sofosbuvir-based regimen in CKD patients suggesting that sofosbuvir with a daily or 3-times weekly regimen is safe and well tolerated in HCV-infected patients, most with cirrhosis, who require hemodialysis.
      • Gane E.J.
      • Robson R.A.
      • Bonacini
      • et al.
      Safety, anti-viral efficacy and pharmacokinetics (PK) of sofosbuvir (SOF) in patients with severe renal impairment. [Abstract 966].
      • Czul F.
      • Schiff E.
      • Peyton C.
      • et al.
      First ribavirin-free sofosbuvir and simeprevir treatment of Hepatitis C genotype 1 patients with severe renal impairment (GFR <30 ml/min or dialysis). [Abstract P0878].
      • Nazario H.E.
      • Ndungu M.
      • Modi A.
      Safety and efficacy of sofosbuvir + simeprevir without ribavirin in hepatitis C genotype 1-infected patients with end-stage renal disease or GFR <30 ml/min. [Abstract P0802].
      • Perumpail R.B.
      • Wong R.J.
      • Pham E.A.
      • et al.
      A new standard of care? standard dose sofosbuvir in an HCV-infected liver transplant recipient undergoing hemodialysis.
      • Perumpail R.B.
      • Wong R.J.
      • Ha L.D.
      • et al.
      Sofosbuvir and simeprevir combination therapy in the setting of liver transplantation and hemodialysis.
      • Desnoyer A.
      • Pospai D.
      • Le M.P.
      • et al.
      Pharmacokinetics, safety and efficacy of a full dose sofosbuvir-based regimen given daily in hemodialysis patients with chronic hepatitis C.
      • Bhamidimarri K.R.
      • Czul F.
      • Peyton A.
      • et al.
      Safety, efficacy and tolerability of half-dose sofosbuvir plus simeprevir in treatment of Hepatitis C in patients with end stage renal disease.
      • Saxena V.
      • Koraishy F.M.
      • Sise M.E.
      • et al.
      Safety and efficacy of sofosbuvir-containing regimens in hepatitis C-infected patients with impaired renal function.
      In a recent prospective study, 2 dosing regimens, sofosbuvir full dose (400 mg daily, n = 7) and 3 times a week (n = 5) after hemodialysis with simeprevir, daclatasvir, ledipasvir, or RBV, were compared in hemodialysis patients.
      • Desnoyer A.
      • Pospai D.
      • Le M.P.
      • et al.
      Pharmacokinetics, safety and efficacy of a full dose sofosbuvir-based regimen given daily in hemodialysis patients with chronic hepatitis C.
      While both groups showed higher SOF-007 plasma concentrations than those previously reported in patients with normal kidney function, plasma concentrations of sofosbuvir or its inactive metabolite SOF-007 did not accumulate with either regimen between hemodialysis sessions or throughout the treatment course.
      Additional experience with reduced sofosbuvir doses, such as 200 mg daily or 400 mg 3 times weekly, suggests that while very well tolerated, these suboptimal doses may lead to inferior SVR rates. In one study, Gane et al. presented results for 10 patients with advanced CKD (9 infected with HCV GT1 and 1 with HCV GT3, all with CrCl < 30 ml/min) receiving sofosbuvir, 200 mg daily, combined with RBV, 200 mg daily.
      • Gane E.J.
      • Robson R.A.
      • Bonacini
      • et al.
      Safety, anti-viral efficacy and pharmacokinetics (PK) of sofosbuvir (SOF) in patients with severe renal impairment. [Abstract 966].
      This schedule resulted in 6 relapses in HCV GT1-infected patients. In 2 case reports, Perumpail et al. reported the successful treatment of 2 liver transplant patients on hemodialysis therapy who received sofosbuvir, 200 mg and 400 mg daily, respectively, with simeprevir at standard dose.
      • Perumpail R.B.
      • Wong R.J.
      • Pham E.A.
      • et al.
      A new standard of care? standard dose sofosbuvir in an HCV-infected liver transplant recipient undergoing hemodialysis.
      • Perumpail R.B.
      • Wong R.J.
      • Ha L.D.
      • et al.
      Sofosbuvir and simeprevir combination therapy in the setting of liver transplantation and hemodialysis.
      Bhamidimarri et al.
      • Bhamidimarri K.R.
      • Czul F.
      • Peyton A.
      • et al.
      Safety, efficacy and tolerability of half-dose sofosbuvir plus simeprevir in treatment of Hepatitis C in patients with end stage renal disease.
      evaluated 2 different schedules in 15 patients with advanced CKD (n = 3) or requiring hemodialysis (n = 12). Eleven patients received sofosbuvir, 200 mg daily, and 4 patients received sofosbuvir, 400 mg 3 times weekly, all with simeprevir at a standard dose. Two relapses occurred, one in each group. Finally, preliminary results from another case series in 11 patients requiring hemodialysis receiving sofosbuvir, 400 mg daily, and simeprevir reported no relapse.
      • Nazario H.E.
      • Ndungu M.
      • Modi A.
      Safety and efficacy of sofosbuvir + simeprevir without ribavirin in hepatitis C genotype 1-infected patients with end-stage renal disease or GFR <30 ml/min. [Abstract P0802].
      Very recently, a larger study (n = 50) also suggested that sofosbuvir-based antiviral therapy, with a reduced dose of sofosbuvir, is reasonably safe and effective for the treatment of HCV patients with ESKD, including hemodialysis patients.
      • Dumortier J.
      • Bailly F.
      • Pageaux G.P.
      • et al.
      Sofosbuvir-based antiviral therapy in hepatitis C virus patients with severe renal failure.
      Use of full-dose off-label use of sofosbuvir daily has been reported in HCV patients on dialysis and in those at high risk of treatment failure such as those with cirrhosis, previously pretreated or nonresponders and those infected with GT3. Such patients should be closely monitored, with clinical, biological, and cardiac assessment.
      • Li T.
      • Qu Y.
      • Guo Y.
      • et al.
      Efficacy and safety of direct-acting antivirals-based antiviral therapies for hepatitis C virus patients with stage 4-5 chronic kidney disease: a meta-analysis.
      A related and unresolved issue is whether use of sofosbuvir in patients with advanced CKD may accelerate its progression. Most of the studies that examined this issue were conducted in patients with moderate CKD. Gonzalez-Parra and colleagues

      Gonzalez-Parra E, Soledad PS, et al. Renal function evolution in patients infected with HCV and basal estimated glomerular filtration rate (GFRE) between 30-60 ml/min/1.73 m2 treated with ombitasvir/paritaprevir/ritonavir and dasabuvir (3D) vs regimens based on sofosbuvir (SOF). EASL Special Conference, September 23-24, 2016. Available at: http://www.easloffice.eu/office/paris2016/mobile/index.html#p=172. Accessed February 25, 2018.

      observed a significant mean decrease in GFR of 9 ml/min per 1.73 m2 in 35 patients treated with a sofosbuvir-based regimen with a baseline GFR of 30 to 60 ml/min per 1.73 m2, whereas no significant decline in GFR occurred in 8 patients treated with the PrOD regimen. Rosenblatt et al.
      • Rosenblatt R.
      • Mehta A.
      • Wagner M.
      • Kumar S.
      Baseline creatinine clearance is a predictor of worsening renal function while on HCV treatment with sofosbuvir-ledipasvir.
      also reported that in a series of 90 patients, a baseline CrCl < 60 ml/min predicted a decline in kidney function with sofosbuvir therapy. Saxena et al. also observed a decline in kidney function in 73 patients with a baseline eGFR ≤ 45 ml/min per 1.73 m2 treated with sofosbuvir.
      • Saxena V.
      • Koraishy F.M.
      • Sise M.E.
      • et al.
      Safety and efficacy of sofosbuvir-containing regimens in hepatitis C-infected patients with impaired renal function.
      Mallet et al.,
      • Mallet V.
      • Parlati L.
      • Dorval O.
      • et al.
      Estimated glomerular filtration rate variations and direct acting antivirals treatment for chronic hepatitis C: a retrospective longitudinal study.
      in a retrospective study of 814 HCV patients mostly with baseline eGFR ≥ 60 ml/min per 1.73 m2, reported a mean eGFR decrease of 2.6 and 1.7 ml/min per 1.73 m2 over a maximum of 37 months in patients treated with sofosbuvir-based and non–sofosbuvir-based regimens, respectively. In contrast, Sise et al.
      • Sise M.E.
      • Backman E.
      • Ortiz G.A.
      • et al.
      Effect of sofosbuvir-based hepatitis C virus therapy on kidney function in patients with CKD.
      recently reported that in patients with CKD G3a–G3b who received sofosbuvir-based regimens, HCV cure was associated with a 9.3 ml/min per 1.73 m2 improvement in eGFR during the 6-month post-treatment follow-up period. Despite these conflicting findings, if a sofosbuvir-based regimen is selected, monitoring of kidney function should be performed with serial serum creatinine measurements during therapy, although it is unclear whether dose reduction or withdrawal is indicated if GFR declines further.
      Algorithm 1 summarizes the recommended choice of DAAs according to the level of kidney function and HCV GT. The Work Group recognizes that not all preferred regimens are available in all jurisdictions, and as such we have also recommended alternate regimens to provide further potential treatment options. There is no evidence to support specific DAA regimens in patients on peritoneal dialysis, but it is reasonable to follow guidance for patients on hemodialysis.
      • Stark J.E.
      • Cole J.
      Successful treatment of chronic hepatitis C virus infection in a patient receiving daily peritoneal dialysis.
      Figure thumbnail gr3
      Algorithm 1Treatment scheme for chronic kidney disease (CKD) G1–G5D. Recommendation grading is provided for each specific treatment regimen and hepatitis C virus (HCV) genotype. CKD G, chronic kidney disease, GFR category; DAA, direct-acting antiviral; GFR, glomerular filtration rate; NAT, nucleic acid testing.
      In summary, we recommend that patients with CKD G4–G5 and G5D be treated with a RBV-free DAA-based regimen. Glecaprevir-pibrentasvir has pan-genotypic efficacy including in patients with prior sofosbuvir treatment and cirrhosis. Grazoprevir-elbasvir and the PrOD regimen are also approved for use in CKD G4–G5 and G5D patients with GTs 1 and 4. Although there are studies reporting the use of sofosbuvir in patients with CKD G4–G5D, in jurisdictions where there is availability of well-tolerated regimens (i.e., grazoprevir-elbasvir and glecaprevir-pibrentasvir), its use is not recommended given the limited information about its safety in this population. Our guidance is in general concordance with those provided by AASLD (https://www.hcvguidelines.org/unique-populations/renal-impairment) and EASL (http://www.easl.eu/research/our-contributions/clinical-practice-guidelines), but given that recommended drugs and dosage are constantly evolving, clinicians should consult these resources for the most up-to-date treatment information.

       Kidney transplant recipients: CKD G1T–G5T (see also Chapter 4)

      Although published data on DAAs in kidney transplant recipients are less abundant,
      • Lin M.V.
      • Sise M.E.
      • Pavlakis M.
      • et al.
      Safety and efficacy of novel antivirals in kidney transplant recipients with chronic hepatitis C virus (HCV) infection. [Abstract LP42].
      the study results seem as satisfactory as those observed in liver transplant recipients (Supplementary Tables S7 and S8). In a recent trial comparing 12 and 24 weeks of sofosbuvir and ledipasvir in 114 kidney transplant recipients infected with HCV GTs 1 and 4 (96% GT1) with an eGFR of 40 ml/min per 1.73 m2 or greater (median eGFR 56 ml/min per 1.73 m2), the therapy was very well tolerated, and SVR rates were close to 100% without differences between arms, suggesting that a 12-week regimen is also indicated in kidney transplant recipients.
      • Colombo M.
      • Aghemo A.
      • Liu H.
      • et al.
      Treatment with ledipasvir-sofosbuvir for 12 or 24 weeks in kidney transplant recipients with chronic hepatitis C virus genotype 1 or 4 infection: a randomized trial.
      Smaller cohort studies recently also reported excellent results in kidney transplant recipients with sofosbuvir-based regimens.
      • Fernandez I.
      • Munoz-Gomez R.
      • Pascasio J.M.
      • et al.
      Efficacy and tolerability of interferon-free antiviral therapy in kidney transplant recipients with chronic hepatitis C.
      • Kamar N.
      • Marion O.
      • Rostaing L.
      • et al.
      Efficacy and safety of sofosbuvir-based antiviral therapy to treat hepatitis C virus infection after kidney transplantation.
      • Sawinski D.
      • Kaur N.
      • Ajeti A.
      • et al.
      Successful treatment of hepatitis C in renal transplant recipients with direct-acting antiviral agents.
      Sofosbuvir/velpatasvir has also been shown to be highly effective and well tolerated in liver transplant recipients with GTs 1–4 and may be considered for kidney transplant recipients in the future, although at the present, efficacy and safety data for the latter group are lacking.

      Agarwal K, Castells L, Mullhaupt B, et al. Sofosbuvir/velpatasvir for 12 weeks in genotype 1-4 HCV-infected liver transplant recipients [e-pub ahead of print]. J Hepatol. https://doi.org/10.1016/j.jhep.2018.05.039. Accessed July 28, 2018.

      Reau et al.

      Reau N, Kwo PY, Rhee S, et al. Glecaprevir/pibrentasvir treatment in liver or kidney transplant patients with hepatitis C virus infection [e-pub ahead of print]. Hepatology. https://doi.org/10.1002/hep.30046. Accessed July 25, 2018.

      have recently described the use of glecapravir/pibrentasvir in 100 organ transplant recipients, 20 of whom had received a kidney transplant with high SVR and excellent tolerability.
      In transplant recipients, drug–drug interactions with immunosuppressive agents may result in increased or diminished plasma levels of immunosuppressive agents, with consequent risk of toxicity or graft rejection, respectively. For instance, concurrent use of elbasvir-grazoprevir and cyclosporine is not recommended, as it results in a 15-fold increase in grazoprevir AUC and 2-fold increase in elbasvir AUC. Elbasvir-grazoprevir increases levels of tacrolimus by 43%; thus, close monitoring of levels is indicated, and dose reductions of tacrolimus may be needed. Other protease inhibitors such as simeprevir and paritaprevir have similar drug–drug interactions with cyclosporine, tacrolimus, and everolimus. There are no significant drug–drug interactions with these protease inhibitors and mycophenolate mofetil (MMF). No significant interactions between NS5A and polymerase inhibitors such as sofosbuvir and calcineurin inhibitors (CNIs) have been described, but close monitoring of immunosuppressive drugs is mandatory because changes in liver metabolism concurrent with HCV eradication may require modification of immunosuppressive drug doses.
      Overall, drug–drug interactions are an important factor in the choice of a DAA regimen. Protease inhibitors are associated with significant risk for drug–drug interactions, particularly in patients who are treated with immunosuppressive agents such as CNIs and mTOR inhibitors.
      • Munoz-Gomez R.
      • Rincon D.
      • Ahumada A.
      • et al.
      Therapy with ombitasvir/paritaprevir/ritonavir plus dasabuvir is effective and safe for the treatment of genotype 1 and 4 hepatitis C virus infection (HCV) in patients with severe renal impairment: a multicenter experience.
      • Morelle J.
      • Goffin E.
      • Wallemacq P.
      • et al.
      Extended release tacrolimus and antiretroviral therapy in a renal transplant recipient: so extended!.
      Nonstructural protein 5B (NS5B) inhibitors such as sofosbuvir or NS5A inhibitors such as ledipasvir and daclatasvir are associated with a low risk of drug–drug interaction with CNIs and mTOR inhibitors, but may have interactions with other concomitant medications. The Hepatitis Drug Interactions website from the University of Liverpool (http://www.hep-druginteractions.org) or another reliable expert source should be accessed to determine the risk and management recommendations for drug–drug interactions.
      Waiting times for deceased donor kidney transplantation are very long in many parts of the world, and many transplant candidates die while waiting for a deceased donor transplant. (see Chapter 4). Survival after transplantation is generally better than survival on dialysis including for HCV-infected patients. With access to DAA, it may be better to receive a kidney transplant from an HCV-positive donor than to face a long wait for an HCV-negative kidney. It has been suggested that an HCV-positive transplant candidate should forego treatment of HCV until after kidney transplantation, to allow receipt of a kidney transplant from an HCV-positive deceased donor. Adoption of this strategy would expand the deceased donor organ pool as well as diminish wait times as suggested by Kucirka et al.
      • Kucirka L.M.
      • Singer A.L.
      • Ros R.L.
      • et al.
      Underutilization of hepatitis C-positive kidneys for hepatitis C-positive recipients.
      If an HCV-negative transplant candidate has a potential living donor who is HCV NAT–positive, then it seems reasonable for the donor to be treated for HCV, and donate the kidney after SVR has been achieved. Because the probability of SVR is very high, and the time it takes to achieve SVR is only 12 weeks, this strategy makes intuitive sense even if there are no supporting data. The potential donor also requires careful evaluation of severity of liver disease. Another consideration is the use of a kidney from an HCV NAT–positive donor in an HCV-negative recipient with prompt DAA treatment after transplant, as recently reported by Goldberg et al.
      • Goldberg D.S.
      • Abt P.L.
      • Blumberg E.A.
      • et al.
      Trial of transplantation of HCV-infected kidneys into uninfected recipients.
      and Durand et al.
      • Durand C.M.
      • Bowring M.G.
      • Brown D.M.
      • et al.
      Direct-acting antiviral prophylaxis in kidney transplantation from hepatitis C virus-infected donors to noninfected recipients: an open-label nonrandomized trial.
      in 2 encouraging small case series. This approach requires further study before it can be endorsed.
      In summary, kidney transplant recipients with GFR ≥ 30 ml/min per 1.73 m2 (CKD G1T–G3bT) and HCV GTs 1 or 4 can utilize sofosbuvir-based regimens and glecaprevir-pibrentasvir. For those with HCV GTs 2, 3, 5, and 6, we recommend glecaprevir-pibrentasvir. For kidney transplant recipients with GFR < 30 ml/min per 1.73 m2 (CKD G4T–G5T), the same regimens proposed for patients with CKD G4–G5D apply (i.e., grazoprevir-elbasvir for GTs 1 and 4 and glecaprevir-pibrentasvir for all GTs). Our guidance is in general concordance with those provided by AASLD (https://www.hcvguidelines.org/unique-populations/kidney-transplant) and EASL (http://www.easl.eu/research/our-contributions/clinical-practice-guidelines), but given that recommended drugs and dosage are constantly evolving, clinicians should consult these resources for the most up-to-date treatment information. Algorithm 2 summarizes the recommended choice of DAAs for kidney transplant recipients according to the level of kidney function and HCV GT.
      Figure thumbnail gr4
      Algorithm 2Treatment scheme for kidney transplant recipients (KTRs). Recommendation grading is provided for each specific treatment regimen and hepatitis C virus (HCV) genotype. Chronic kidney disease (CKD) G, CKD glomerular filtration rate (GFR) category (suffix T denotes transplant recipient); NAT, nucleic acid testing.

       Reactivation of HBV infection after DAA therapy

      A number of reports have recently described apparent reactivation of HBV infection in individuals following successful therapy of HCV infection with DAA-based therapy.
      • Chen G.
      • Wang C.
      • Chen J.
      • et al.
      Hepatitis B reactivation in hepatitis B and C coinfected patients treated with antiviral agents: a systematic review and meta-analysis.
      • Mucke M.M.
      • Backus L.I.
      • Mucke V.T.
      • et al.
      Hepatitis B virus reactivation during direct-acting antiviral therapy for hepatitis C: a systematic review and meta-analysis.
      This has prompted an FDA warning.
      • Bersoff-Matcha S.J.
      • Cao K.
      • Jason M.
      • et al.
      Hepatitis B virus reactivation associated with direct-acting antiviral therapy for chronic hepatitis C virus: a review of cases reported to the U.S. Food and Drug administration adverse event reporting system.
      As part of routine evaluation of patients with HCV and CKD, serum markers of HBV infection (i.e., hepatitis B surface antigen [HBsAg) and HBV DNA) should be obtained prior to antiviral therapy. Initiation of therapy with an oral HBV suppressive agent is recommended if criteria for HBV therapy are met, based on initial testing prior to HCV therapy or during follow-up after HCV. If HBsAg is initially absent but markers of prior HBV infection (positive antibody to hepatitis B core antigen [HBcAb-positive] with or without antibody to hepatitis B surface antigen [HBsAb]) are detected, patients should be monitored for HBV reactivation with serial HBV DNA and liver function tests during DAA therapy (see also https://www.hcvguidelines.org/evaluate/monitoring).

       Research recommendations

      • Further studies should be conducted on whether RBV is required after kidney transplantation in some specific groups such as prior nonresponders infected with HCV GT1a. Treatment of NS5A-resistant variants after kidney transplantation should also be evaluated.
      • Optimal timing of antiviral therapy before or after transplantation in candidates for kidney transplantation should be clarified. Because the time to transplantation with kidneys from deceased donors is unpredictable, delaying treatment carries higher vascular, metabolic, and malignancy risks as well as the risk of drug–drug interactions with CNIs after transplantation. As such, treatment before transplantation may be more appropriate. However, in regions where the prevalence of anti-HCV–positive donors is high, post-kidney transplant therapy should be considered.
      • Use of organs from HCV-positive donors for HCV-negative recipients with DAA therapy needs to be further explored.
      • The impact of treating HCV infection on CKD progression should be further investigated.

       Chapter 3: Preventing HCV transmission in hemodialysis units

      • 3.1: We recommend that hemodialysis facilities adhere to standard infection control procedures including hygienic precautions that effectively prevent transfer of blood and blood-contaminated fluids between patients to prevent transmission of blood-borne pathogens (see Table 1) (1A).
        • 3.1.1: We recommend regular observational audits of infection control procedures in hemodialysis units (1C).
        • 3.1.2: We recommend not using dedicated dialysis machines for HCV-infected patients (1D).
        • 3.1.3: We suggest not isolating HCV-infected hemodialysis patients (2C).
        • 3.1.4: We suggest that the dialyzers of HCV-infected patients can be reused if there is adherence to standard infection control procedures (2D).
      • 3.2: We recommend that hemodialysis centers examine and track all HCV test results to identify new cases of HCV infections in their patients (1B).
        • 3.2.1: We recommend that aggressive measures be taken to improve hand hygiene (and proper glove use), injection safety, and environmental cleaning and disinfection when a new case of HCV is identified that is likely to be dialysis-related (1A).
      • 3.3: Strategies to prevent HCV transmission within hemodialysis units should prioritize adherence to standard infection control practices and should not primarily rely upon the treatment of HCV-infected patients (Not Graded).

       Rationale

      The prevalence of HCV infection in hemodialysis patients is usually higher than in the general population.
      • Fabrizi F.
      • Martin P.
      • Dixit V.
      • et al.
      Hepatitis C virus infection and kidney disease: a meta-analysis.
      HCV prevalence rates range from about 4%–9% in most high-income countries, but is significantly higher in other countries, particularly those in the Middle East, North and Sub-Sahara Africa, Asia, and Eastern Europe
      • Fissell R.B.
      • Bragg-Gresham J.L.
      • Woods J.D.
      • et al.
      Patterns of hepatitis C prevalence and seroconversion in hemodialysis units from three continents: the DOPPS.
      • Schneeberger P.M.
      • Keur I.
      • van Loon A.M.
      • et al.
      The prevalence and incidence of hepatitis C virus infections among dialysis patients in the Netherlands: a nationwide prospective study.
      • Vladutiu D.S.
      • Cosa A.
      • Neamtu A.
      • et al.
      Infections with hepatitis B and C viruses in patients on maintenance dialysis in Romania and in former communist countries: yellow spots on a blank map?.
      • Sun J.
      • Yu R.
      • Zhu B.
      • et al.
      Hepatitis C infection and related factors in hemodialysis patients in China: systematic review and meta-analysis.
      (Table 2). Rates also vary during times of social crisis, war, or economic downturn.
      • Voiculescu M.
      • Iliescu L.
      • Ionescu C.
      • et al.
      A cross-sectional epidemiological study of HBV, HCV, HDV and HEV prevalence in the SubCarpathian and South-Eastern regions of Romania.
      • Selm S.B.
      Prevalence of hepatitis C virus infection among hemodialysis patients in a single center in Yemen.
      • Ali I.
      • Siddique L.
      • Rehman L.U.
      • et al.
      Prevalence of HCV among the high risk groups in Khyber Pakhtunkhwa.
      According to a recent systematic review of studies in hemodialysis patients based on data up to 2006, the overall global incidence rate of HCV infection was 1.47 per 100 patient-years: 4.44 per 100 patient-years in low- to middle-income countries, and 0.99 per 100 patient-years in high-income countries.
      • Su Y.
      • Norris J.L.
      • Zang C.
      • et al.
      Incidence of hepatitis C virus infection in patients on hemodialysis: a systematic review and meta-analysis.
      HCV is easily transmitted parenterally, primarily through percutaneous exposure to blood. Dramatic reductions were noted in the incidence following introduction of screening for HCV in blood donors and reduction in blood transfusion requirements following introduction of ESAs,
      • Marwaha N.
      • Sachdev S.
      Current testing strategies for hepatitis C virus infection in blood donors and the way forward.
      leaving nosocomial transmission as the main method of spread of HCV in dialysis units. Several studies have confirmed nosocomial transmission in dialysis units using epidemiologic and phylogenetic data obtained by viral sequencing.
      • Nguyen D.B.
      • Gutowski J.
      • Ghiselli M.
      • et al.
      A large outbreak of hepatitis C virus infections in a hemodialysis clinic.
      KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease.
      • Thompson N.D.
      • Novak R.T.
      • White-Comstock M.B.
      • et al.
      Patient-to-patient hepatitis C virus transmissions associated with infection control breaches in a hemodialysis unit.
      • Aho-Glele L.S.
      • Giraudon H.
      • Astruc K.
      • et al.
      Investigation of a case of genotype 5a hepatitis C virus transmission in a french hemodialysis unit using epidemiologic data and deep sequencing.
      • Thompson N.D.
      • Novak R.T.
      • Datta D.
      • et al.
      Hepatitis C virus transmission in hemodialysis units: importance of infection control practices and aseptic technique.
      • Fabrizi F.
      • Messa P.
      Transmission of hepatitis C virus in dialysis units: a systematic review of reports on outbreaks.
      These data are further supported by the observation of decline in infection rates following routine implementation of infection control practices and virological follow-up to detect anti-HCV using sensitive, specific new-generation serological tests.
      • Saune K.
      • Kamar N.
      • Miedouge M.
      • et al.
      Decreased prevalence and incidence of HCV markers in haemodialysis units: a multicentric French survey.
      • Jadoul M.
      • Poignet J.L.
      • Geddes C.
      • et al.
      The changing epidemiology of hepatitis C virus (HCV) infection in haemodialysis: European multicentre study.
      A multicenter survey revealed that prevalence of anti-HCV positivity for a Belgian cohort of hemodialysis patients (n = 1710) dropped steadily from 13.5% in 1991 to 6.8% in 2000, and the same survey revealed significant drops in other European countries including France (42% to 30%), Italy (28% to 16%), and Sweden (16% to 9%).
      • Jadoul M.
      • Poignet J.L.
      • Geddes C.
      • et al.
      The changing epidemiology of hepatitis C virus (HCV) infection in haemodialysis: European multicentre study.
      Table 2 provides an overview of HCV prevalence in hemodialysis patients as summarized from some recent studies.
      Table 2Recent reported HCV prevalence in hemodialysis patients
      CountryNYear of testingHCV prevalence (%)Source
      Australia-New Zealand39320123.8DOPPS 5
      • Bieber B.
      • Goodkin D.A.
      • Nwankwo C.
      • et al.
      Hepatitis C prevalence and clinical outcomes in the Dialysis Outcomes and Practice Patterns Study.
      Belgium48520124.0DOPPS 5
      • Bieber B.
      • Goodkin D.A.
      • Nwankwo C.
      • et al.
      Hepatitis C prevalence and clinical outcomes in the Dialysis Outcomes and Practice Patterns Study.
      Brazil79820118.4Rodrigues de Freitas
      • de Jesus Rodrigues de Freitas M.
      • Fecury A.A.
      • de Almeida M.K.
      • et al.
      Prevalence of hepatitis C virus infection and genotypes in patient with chronic kidney disease undergoing hemodialysis.
      Canada45720124.1DOPPS 5
      • Bieber B.
      • Goodkin D.A.
      • Nwankwo C.
      • et al.
      Hepatitis C prevalence and clinical outcomes in the Dialysis Outcomes and Practice Patterns Study.
      China118920129.9DOPPS 5
      • Bieber B.
      • Goodkin D.A.
      • Nwankwo C.
      • et al.
      Hepatitis C prevalence and clinical outcomes in the Dialysis Outcomes and Practice Patterns Study.
      Cuba274200976Santana
      • Santana R.R.
      • Martínez Z.
      • Martínez M.T.
      • Mato J.
      Hepatitis C virus present in hemodialysis units from Cuban western region.
      Egypt2007–201650Ashkani-Esfahan
      • Ashkani-Esfahani S.
      • Alavian S.M.
      • Salehi-Marzijarani M.
      Prevalence of hepatitis C virus infection among hemodialysis patients in the Middle-East: a systematic review and meta-analysis.
      France50120126.9DOPPS 4
      • Bieber B.
      • Goodkin D.A.
      • Nwankwo C.
      • et al.
      Hepatitis C prevalence and clinical outcomes in the Dialysis Outcomes and Practice Patterns Study.
      Germany58420124.5DOPPS 5
      • Bieber B.
      • Goodkin D.A.
      • Nwankwo C.
      • et al.
      Hepatitis C prevalence and clinical outcomes in the Dialysis Outcomes and Practice Patterns Study.
      Gulf Cooperation Council910201219.3DOPPS 5
      • Bieber B.
      • Goodkin D.A.
      • Nwankwo C.
      • et al.
      Hepatitis C prevalence and clinical outcomes in the Dialysis Outcomes and Practice Patterns Study.
      India216201216NephroPlus
      1050201311
      306820148
      Iran2006–201512Ashkani-Esfahan
      • Ashkani-Esfahani S.
      • Alavian S.M.
      • Salehi-Marzijarani M.
      Prevalence of hepatitis C virus infection among hemodialysis patients in the Middle-East: a systematic review and meta-analysis.
      Iraq2008–201520Ashkani-Esfahan
      • Ashkani-Esfahani S.
      • Alavian S.M.
      • Salehi-Marzijarani M.
      Prevalence of hepatitis C virus infection among hemodialysis patients in the Middle-East: a systematic review and meta-analysis.
      7122201510
      767320169
      Italy485201211.5DOPPS 5
      • Bieber B.
      • Goodkin D.A.
      • Nwankwo C.
      • et al.
      Hepatitis C prevalence and clinical outcomes in the Dialysis Outcomes and Practice Patterns Study.
      Japan1609201211.0DOPPS 5
      • Bieber B.
      • Goodkin D.A.
      • Nwankwo C.
      • et al.
      Hepatitis C prevalence and clinical outcomes in the Dialysis Outcomes and Practice Patterns Study.
      Jordan2007–201535Ashkani-Esfahan
      • Ashkani-Esfahani S.
      • Alavian S.M.
      • Salehi-Marzijarani M.
      Prevalence of hepatitis C virus infection among hemodialysis patients in the Middle-East: a systematic review and meta-analysis.
      Lebanon37692010–20124.7Abou Rached
      • Abou Rached A.
      • El Khoury L.
      • El Imad T.
      • et al.
      Incidence and prevalence of hepatitis B and hepatitis C viruses in hemodialysis patients in Lebanon.
      Libya23822009–201031.1Alashek
      • Alashek W.A.
      • McIntyre C.W.
      • Taal M.W.
      Hepatitis B and C infection in haemodialysis patients in Libya: prevalence, incidence and risk factors.
      Nigeria100201415Ummate
      • Ummate I.
      • Denue B.A.
      • Kida I.M.
      • et al.
      Risk factors for hepatitis C virus sero-positivity among haemodialysis patients receiving care at kidney centre in a tertiary health facility in Maiduguri, Nigeria.
      Palestine2010–201618Ashkani-Esfahan
      • Ashkani-Esfahani S.
      • Alavian S.M.
      • Salehi-Marzijarani M.
      Prevalence of hepatitis C virus infection among hemodialysis patients in the Middle-East: a systematic review and meta-analysis.
      Romania600201027.3Schiller
      • Schiller A.
      • Timar R.
      • Siriopol D.
      • et al.
      Hepatitis B and C virus infection in the hemodialysis population from three romanian regions.
      Russia486201214.0DOPPS 5
      • Bieber B.
      • Goodkin D.A.
      • Nwankwo C.
      • et al.
      Hepatitis C prevalence and clinical outcomes in the Dialysis Outcomes and Practice Patterns Study.
      Saudi Arabia200719Ashkani-Esfahan
      • Ashkani-Esfahani S.
      • Alavian S.M.
      • Salehi-Marzijarani M.
      Prevalence of hepatitis C virus infection among hemodialysis patients in the Middle-East: a systematic review and meta-analysis.
      Senegal10620115.6Seck
      • Seck S.M.
      • Dahaba M.
      • Gueye S.
      • et al.
      Trends in hepatitis C infection among hemodialysis patients in Senegal: results of a decade of prevention.
      Syria200954Ashkani-Esfahan
      • Ashkani-Esfahani S.
      • Alavian S.M.
      • Salehi-Marzijarani M.
      Prevalence of hepatitis C virus infection among hemodialysis patients in the Middle-East: a systematic review and meta-analysis.
      Spain61320128.9DOPPS 5
      • Bieber B.
      • Goodkin D.A.
      • Nwankwo C.
      • et al.
      Hepatitis C prevalence and clinical outcomes in the Dialysis Outcomes and Practice Patterns Study.
      Sweden42620126.0DOPPS 5
      • Bieber B.
      • Goodkin D.A.
      • Nwankwo C.
      • et al.
      Hepatitis C prevalence and clinical outcomes in the Dialysis Outcomes and Practice Patterns Study.
      Turkey38320127.0DOPPS 5
      • Bieber B.
      • Goodkin D.A.
      • Nwankwo C.
      • et al.
      Hepatitis C prevalence and clinical outcomes in the Dialysis Outcomes and Practice Patterns Study.
      United Kingdom39720124.6DOPPS 5
      • Bieber B.
      • Goodkin D.A.
      • Nwankwo C.
      • et al.
      Hepatitis C prevalence and clinical outcomes in the Dialysis Outcomes and Practice Patterns Study.
      United States297720127.3DOPPS 5
      • Bieber B.
      • Goodkin D.A.
      • Nwankwo C.
      • et al.
      Hepatitis C prevalence and clinical outcomes in the Dialysis Outcomes and Practice Patterns Study.
      DOPPS, Dialysis Outcomes and Practice Patterns Study; HCV, hepatitis C virus.
      Nevertheless, more than 50% of all health care–associated HCV outbreaks from 2008 to 2015 reported to the CDC occurred in hemodialysis settings.
      Centers for Disease Control and Prevention
      Healthcare-associated hepatitis B and C outbreaks reported to the Centers for Disease Control and Prevention, 2008-2015.
      As a result, the CDC recently provided guidance on improving infection control practices to stop HCV transmission in dialysis units.
      The Centers for Disease Control and Prevention
      CDC urging dialysis providers and facilities to assess and improve infection control practices to stop hepatitis C virus transmission in patients undergoing hemodialysis.

       Infection control

      Infection control lapses responsible for HCV transmission contribute to transmission of other pathogens; hence implementation of improvement efforts will have broader salutary effects. Most importantly, HCV transmission can be prevented effectively through adherence to currently recommended infection control practices. There are no reports of transmission of HCV in dialysis units that had all infection control practices in place. Publication bias is unlikely to explain this observation. Additionally, in the experience of the authors, centers that have had HCV transmission identified and that subsequently responded with increased attention to appropriate infection control practices have not had continued transmission. This observation applies to unpublished outbreaks and transmission events.
      Three systematic reviews have examined the reasons behind transmission of HCV in hemodialysis units.
      KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease.
      • Fabrizi F.
      • Messa P.
      Transmission of hepatitis C virus in dialysis units: a systematic review of reports on outbreaks.
      • Thompson N.D.
      • Perz J.F.
      • Moorman A.C.
      • et al.
      Nonhospital health care-associated hepatitis B and C virus transmission: United States, 1998-2008.
      Root cause analysis of confirmed nosocomial outbreaks
      • Savey A.
      • Simon F.
      • Izopet J.
      • et al.
      A large nosocomial outbreak of hepatitis C virus infections at a hemodialysis center.
      • Allander T.
      • Medin C.
      • Jacobson S.H.
      • et al.
      Hepatitis C transmission in a hemodialysis unit: molecular evidence for spread of virus among patients not sharing equipment.
      • Izopet J.
      • Pasquier C.
      • Sandres K.
      • et al.
      Molecular evidence for nosocomial transmission of hepatitis C virus in a French hemodialysis unit.
      • de Lamballerie X.
      • Olmer M.
      • Bouchouareb D.
      • et al.
      Nosocomial transmission of hepatitis C virus in haemodialysis patients.
      • McLaughlin K.J.
      • Cameron S.O.
      • Good T.
      • et al.
      Nosocomial transmission of hepatitis C virus within a British dialysis centre.
      has revealed lapses in infection control to be associated with transmission of HCV infection between patients in dialysis units. For several reasons, including the long latency period of HCV infection, the number of dialysis treatments occurring during a patient’s likely exposure period (based on multiple treatments per week), and sparse documentation of details in the dialysis treatment record, retrospective investigation to determine an exact cause of dialysis-related HCV acquisition is challenging. Rarely, the exact cause can be surmised using epidemiologic and molecular virology data. More often, transmission is documented among patients in the same clinic, who lack other common exposures and/or risk factors, and lapses in infection control are identified in the clinic that could logically lead to transmission (Table 3). Other causes of infection such as undergoing dialysis during travel to developing countries, and nondialysis health care exposures (e.g., procedures performed in a common vascular access surgical center) can occur and are considered before concluding that transmission occurred in the dialysis unit.
      Table 3Factors and lapses in infection control practices associated with transmission of HCV infection in dialysis units
      • Preparation of injections in a contaminated environment (including at patient treatment station)
      • Reuse of single-dose medication vial for more than 1 patient
      • Use of mobile cart to transport supplies or medications to patients
      • Inadequate cleaning or disinfection of shared environmental surfaces between patients
      • Failure to separate clean and contaminated areas
      • Failure to change gloves and perform hand hygiene between tasks or patients
      • Hurried change-over processes
      • Low staff-to-patient ratio
      HCV, hepatitis C virus.
      Mishandling of parenteral medications has been implicated frequently in transmission. Medication vials can become contaminated with HCV when accessed with used needles or syringes, or through environmental or touch contamination of the vial diaphragm by health care personnel hands. The US CDC’s One & Only Campaign on safe injection practices (http://www.oneandonlycampaign.org/) should help address the former issue by promoting single use of syringes. The latter issue concerning contamination is more likely to occur when medications are stored or prepared in contaminated areas and blood-contaminated items are handled in close proximity. Sharing of multidose heparin or other medication vials or spring-triggered devices for glucose monitoring can lead to transmission. Inadequate cleaning and disinfection of shared environmental surfaces also increases risk of transmission. This may include failure to adequately clean and disinfect external surfaces of hemodialysis machines, treatment chairs, and other surfaces in the treatment station, and failure to clean blood spills.
      It should be emphasized that blood contamination of environmental surfaces and equipment both at the patient treatment station and outside the immediate treatment area can be present, even in the absence of visible blood. HCV RNA has been detected on external surfaces of dialysis machines, a dialysate connector, on a shared waste cart, and in hand washings of dialysis personnel.
      • Alfurayh O.
      • Sabeel A.
      • Al Ahdal M.N.
      • et al.
      Hand contamination with hepatitis C virus in staff looking after hepatitis C-positive hemodialysis patients.
      • Bergervoet P.W.
      • van Riessen N.
      • Sebens F.W.
      • et al.
      Application of the forensic Luminol for blood in infection control.
      • Caramelo C.
      • de Sequera P.
      • Lopez M.D.
      • et al.
      Hand-borne mechanisms of dissemination of hepatitis C virus in dialysis units: basis for new addenda to the present preventive strategies.
      • Froio N.
      • Nicastri E.
      • Comandini U.V.
      • et al.
      Contamination by hepatitis B and C viruses in the dialysis setting.
      • Girou E.
      • Chevaliez S.
      • Challine D.
      • et al.
      Determinant roles of environmental contamination and noncompliance with standard precautions in the risk of hepatitis C virus transmission in a hemodialysis unit.
      • Kamili S.
      • Krawczynski K.
      • McCaustland K.
      • et al.
      Infectivity of hepatitis C virus in plasma after drying and storing at room temperature.
      • Patel P.R.
      • Thompson N.D.
      • Kallen A.J.
      • et al.
      Epidemiology, surveillance, and prevention of hepatitis C virus infections in hemodialysis patients.
      Blood that is visible or not visible to the naked eye, as evidenced by chemical tests, has also been detected on dialysis treatment station surfaces that underwent routine cleaning procedures following an outbreak of HCV.
      • Nguyen D.B.
      • Gutowski J.
      • Ghiselli M.
      • et al.
      A large outbreak of hepatitis C virus infections in a hemodialysis clinic.
      HCV can persist in an infectious state for at least 16 hours, and potentially much longer, on surfaces at room temperature.
      • Kamili S.
      • Krawczynski K.
      • McCaustland K.
      • et al.
      Infectivity of hepatitis C virus in plasma after drying and storing at room temperature.
      • Paintsil E.
      • Binka M.
      • Patel A.
      • et al.
      Hepatitis C virus maintains infectivity for weeks after drying on inanimate surfaces at room temperature: implications for risks of transmission.
      Hand hygiene also plays an important role in prevention of nosocomial transmission.
      • Laporte F.
      • Tap G.
      • Jaafar A.
      • et al.
      Mathematical modeling of hepatitis C virus transmission in hemodialysis.
      Lack of adherence to standard practices, such as hand-washing and glove use and removal practices, has been documented in several audits. In most HCV outbreaks in US hemodialysis centers reported to the CDC, multiple lapses in infection control were identified, involving practices such as hand hygiene and glove use, injectable medication handling, and environmental surface disinfection.
      Centers for Disease Control and Prevention
      Healthcare-associated hepatitis B and C outbreaks reported to the Centers for Disease Control and Prevention, 2008-2015.
      Petrosillo et al.
      • Petrosillo N.
      • Gilli P.
      • Serraino D.
      • et al.
      Prevalence of infected patients and understaffing have a role in hepatitis C virus transmission in dialysis.
      conducted a multicenter study in 58 Italian hemodialysis centers and found that the adjusted risk of transmission was correlated with dialysis in units with a high prevalence of HCV-infected patients at baseline and those with a low personnel-patient ratio. A study of 87 US hemodialysis centers similarly found that baseline HCV prevalence of greater than 10%, low staff-to-patient ratio, and ≥2-year duration of treatment in the facility were independently associated with frequency of HCV infections that were likely to be acquired in the facility.
      • Shimokura G.
      • Chai F.
      • Weber D.J.
      • et al.
      Patient-care practices associated with an increased prevalence of hepatitis C virus infection among chronic hemodialysis patients.
      Implementation of infection control practices can be advanced by establishing a list of evidence-based interventions, such as those recommended by the CDC, and regularly assessing and reinforcing adherence to practice through observational audits. Infection control practices that may be most critical to improve (based upon observation of breaches in outbreak situations that are likely to transmit HCV) are shown in Table 1. The CDC has checklists and audit tools to assist facilities in implementing and assessing many of these practices.
      Centers for Disease Control and Prevention
      Dialysis safety audit tools and checklists.

       Isolation

      Isolating HCV-infected patients (or patients awaiting HCV screening results) during hemodialysis is defined as physical segregation from others for the express purpose of limiting direct or indirect transmission of HCV. The traditional definition of contact isolation is that used for HBV infections in hemodialysis centers (i.e., dedicated room, machine, equipment, gowns, and personnel). However, “isolation” as considered for HCV control has involved multiple varied approaches and policies, including the use of a dedicated dialysis machine, personnel, room, or shift, and/or other barrier precautions (e.g., aprons, gowns, or gloves) by health care professionals attending these patients.
      Whereas the complete isolation of HBV-infected patients (by room, thus including machine, equipment, and staff) has proven invaluable in halting the nosocomial transmission of HBV within hemodialysis units,
      • Labriola L.
      • Jadoul M.
      The decades-long fight against HBV transmission to dialysis patients: slow but definite progress.
      there are multiple reasons that argue against recommending isolation of HCV-positive patients:
      • Jadoul M.
      Should hemodialysis patients with hepatitis C virus antibodies be isolated?.
      • (i)
        Isolation purely for HCV will have no impact on transmission of other infections. Segregation of patients can create a false sense of reassurance around practices that could easily result in bloodstream infections (BSIs) or transmission of multi-drug resistant organisms or other blood-borne pathogens.
      • (ii)
        Segregating patients on the basis of HBV and HCV would create four separate cohorts, which creates a significant logistic challenge. The treatment of HCV infection in dialysis patients raises an additional logistical difficulty of how to cohort patients undergoing therapy.
      • (iii)
        Isolating only on HCV infection status may expose the isolated patient to infection with a second HCV GT.
      • (iv)
        HCV seroconversion may be delayed for several months in newly infected hemodialysis patients and serological testing cannot be relied on to exclude recent infection.
        • Sypsa V.
        • Psichogiou M.
        • Katsoulidou A.
        • et al.
        Incidence and patterns of hepatitis C virus seroconversion in a cohort of hemodialysis patients.
      • (v)
        Starting and maintaining isolation is likely to impose large costs on already expensive dialysis programs.
      The evidence for the use of isolation of HCV-infected patients during hemodialysis is weak, based on very low-quality evidence (Supplementary Tables S9 and S10). The KDIGO 2008 HCV guideline
      KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease.
      stated that hemodialysis units should ensure implementation of and adherence to strict infection control procedures designed to prevent transmission of blood-borne pathogens, including HCV, but isolation of HCV-infected patients was not recommended as an alternative to strict infection control procedures (unless in cases of continued health care–acquired transmission, where a local isolation policy may be deemed necessary).
      A recent Cochrane review
      • Bravo Zuniga J.I.
      • Loza Munarriz C.
      • Lopez-Alcalde J.
      Isolation as a strategy for controlling the transmission of hepatitis C virus (HCV) infection in haemodialysis units.
      examined the impact of isolation as a strategy for controlling transmission of HCV infection in hemodialysis units. Of the 123 full-text articles identified, the authors could find only 1 randomized controlled trial (RCT).
      • Shamshirsaz A.A.
      • Kamgar M.
      • Bekheirnia M.R.
      • et al.
      The role of hemodialysis machines dedication in reducing Hepatitis C transmission in the dialysis setting in Iran: a multicenter prospective interventional study.
      This cluster RCT included a total of 12 hemodialysis centers (593 patients) assigned to either dedicated hemodialysis machines for HCV-infected patients or no dedicated machines. Two follow-up periods were included in the study, and each was 9 months long. Staff was educated on standard infection control practices. Although the original article reported a significant reduction in the proportion of new infections in the second follow-up period among the facilities using dedicated versus nondedicated machines (calculated using chi-square test), based on a more standard risk ratio analysis, the Cochrane review concluded that the use of dialysis machines dedicated for HCV-infected individuals, as compared with the use of nondedicated machines made no difference in terms of reducing the incidence of HCV infection during the follow-up period. In addition, the quality of evidence was rated as “very low” due to several methodological issues.
      Other studies examining isolation as a means of reducing HCV transmission reported a reduction of transmission, but they were observational and had very poor-quality evidence with methodological challenges.
      • Karkar A.
      • Abdelrahman M.
      • Ghacha R.
      • et al.
      Prevention of viral transmission in HD units: the value of isolation.
      • Harmankaya O.
      • Cetin B.
      • Erimez D.
      • et al.
      Patient isolation prevents the transmission of hepatitis C virus infection in hemodialysis units.
      • Dzekova-Vidimliski P.
      • Pavleska-Kuzmanovska S.
      • Trajceska L.
      • et al.
      Decreasing prevalence of hepatitis C virus infection in hemodialysis patients: Following KDIGO guidelines.
      The isolation policies studied included implementing the isolation or cohorting of infected patients in a separate room; using exclusive machines; or employing dedicated machines, room, and staff. Most studies have adopted a “before-and-after” design, and compared their results with their own historical controls.
      • Agarwal S.K.
      • Dash S.C.
      • Gupta S.
      • et al.
      Hepatitis C virus infection in haemodialysis: the 'no-isolation' policy should not be generalized.
      • Gallego E.
      • Lopez A.
      • Perez J.
      • et al.
      Effect of isolation measures on the incidence and prevalence of hepatitis C virus infection in hemodialysis.
      • Shebeb A.M.
      • Kotkat A.M.
      • Abd El Reheim S.M.
      • et al.
      An intervention study for prevention of HCV infection in some hemodialysis units in Alexandria.
      • Yang C.S.
      • Chang H.H.
      • Chou C.C.
      • et al.
      Isolation effectively prevents the transmission of hepatitis C virus in the hemodialysis unit.
      Thus, it is unclear whether the reported improvement resulted from the isolation policy or rather from the simultaneous raising of awareness and reinforcement of the application of hygienic precautions. Furthermore, in some studies, there might be other contributing factors such as changes in baseline prevalence and injection safety and hygienic practices over time.
      In contrast to these studies, a DOPPS (Dialysis Outcomes and Practice Patterns Study) multicenter study and an Italian multicenter study both concluded that isolation did not protect against transmission of HCV in hemodialysis patients,
      • Fissell R.B.
      • Bragg-Gresham J.L.
      • Woods J.D.
      • et al.
      Patterns of hepatitis C prevalence and seroconversion in hemodialysis units from three continents: the DOPPS.
      • Petrosillo N.
      • Gilli P.
      • Serraino D.
      • et al.
      Prevalence of infected patients and understaffing have a role in hepatitis C virus transmission in dialysis.
      and some prospective observational studies have shown reduction of transmission after adoption of universal precautions.
      • Schvarcz R.
      • Johansson B.
      • Nystrom B.
      • et al.
      Nosocomial transmission of hepatitis C virus.
      A prospective observational study showed a reduction in the annual incidence of HCV seroconversion from 1.4% to 0% after the reinforcement of basic hygienic precautions, without any isolation measures.
      • Jadoul M.
      • Cornu C.
      • van Ypersele de Strihou C.
      Universal precautions prevent hepatitis C virus transmission: a 54 month follow-up of the Belgian Multicenter Study. The Universitaires Cliniques St-Luc (UCL) Collaborative Group.
      The CDC does not recommend the isolation of HCV-infected patients in its infection-prevention guidelines.
      Recommendations for preventing transmission of infections among chronic hemodialysis patients.
      The UK Renal Association also states that patients with HCV do not need to be dialyzed in a segregated area; however, more experienced staff should be assigned. They further recommend that if nosocomial transmission continues to occur despite reinforcement and audit of the precautions, a local segregation policy may be deemed necessary.
      • Mactier R.
      • Davies S.
      • Dudley C.
      • et al.
      Summary of the 5th edition of the Renal Association Clinical Practice Guidelines (2009-2012).
      The European Best Practice Work Group considers implementation of universal hygienic measures to be the standard of care.
      European Best Practice Guidelines Expert Group on HemodialysisEuropean Renal Association
      Section VI. Haemodialysis-associated infection.
      Finally, several experts and guidelines acknowledge that because transmission can be effectively prevented by adherence to currently recommended practices, considering isolation of seropositive patients indicates a failure of adherence to the current standard and would have a negative impact on the implementation and reinforcement of basic hygienic measures in the unit as a whole.

       Dedicated dialysis machines

      Evidence of HCV transmission through internal pathways of the modern single-pass dialysis machine has not been demonstrated.
      KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease.
      Transmission would require the virion to cross the intact dialyzer membrane, migrate from the drain tubing to the fresh dialysate circuit, and pass again through the dialyzer membrane of a second patient. However, the virus does not cross the intact membrane, and even in the event of a blood leak, transmission would require HCV to reach fresh dialysate used for a subsequent patient and enter the blood compartment for that patient through back-filtration across the dialyzer membrane, a highly unlikely scenario. Almost all the studies included in the various systematic reviews have conclusively excluded transmission via the internal dialysis pathway. In a few cases, a role for the dialysis circuit could not be excluded, but the environmental surfaces are more likely to have contributed to transmission.
      • Nguyen D.B.
      • Gutowski J.
      • Ghiselli M.
      • et al.
      A large outbreak of hepatitis C virus infections in a hemodialysis clinic.
      Receiving dialysis next to, rather than sharing the same dialysis machine with, an HCV-infected patient has been found to be a risk factor for HCV acquisition.
      • Jadoul M.
      Transmission routes of HCV infection in dialysis.
      In outbreak investigations with phylogenetic viral sequencing analysis, transmission is sometimes documented from an infected patient to a subsequent patient treated at the same station on the next shift, and also from an infected patient to patients treated in nearby stations during the same or subsequent shifts, which indicates transmission independent of the machine. Hurried and incomplete disinfection of external machine surfaces and other surfaces at the station (e.g., side table, dialysis chair, blood pressure cuff, or prime waste container) are lapses commonly identified in these outbreaks. In some investigations, transmission involving the dialysis machine was essentially ruled out.
      • Thompson N.D.
      • Novak R.T.
      • White-Comstock M.B.
      • et al.
      Patient-to-patient hepatitis C virus transmissions associated with infection control breaches in a hemodialysis unit.
      In several studies included in the systematic reviews of HCV transmission, nosocomial spread was documented despite the existence of a policy of dedicated machines. Taken together, this information confirms that contamination of dialysis machine components cannot be the sole contributor to transmission, and may have little to no role in HCV spread. While contaminated external surfaces of dialysis machines might facilitate HCV spread, other surfaces in the dialysis treatment station are likely to have the same impact, diminishing the purported value of using dedicated machines. Similar to the concern about the risks of isolating dialysis patients with HCV, it should be stressed that using dedicated machines may trigger the perception that there is no longer a risk of nosocomial HCV transmission and thus reduce the attention devoted by hemodialysis staff members to body fluid precautions.

       Reuse

      During the reuse procedure, patient-to-patient transmission can take place if the dialyzers or blood port caps are switched between patients and not sterilized effectively or if there is spillage of contaminated blood or mixing of reused dialyzers during transport. These situations can be eliminated by adherence to standard hygienic precautions and appropriate labeling. Two large studies have not identified reuse as a risk factor for HCV transmission,
      • Jadoul M.
      • Cornu C.
      • van Ypersele de Strihou C.
      Universal precautions prevent hepatitis C virus transmission: a 54 month follow-up of the Belgian Multicenter Study. The Universitaires Cliniques St-Luc (UCL) Collaborative Group.
      • Finelli L.
      • Miller J.T.
      • Tokars J.I.
      • et al.
      National surveillance of dialysis-associated diseases in the United States, 2002.
      whereas a weak association was shown in 1 study, likely due to unmeasured confounders.
      • dos Santos J.P.
      • Loureiro A.
      • Cendoroglo Neto M.
      • et al.
      Impact of dialysis room and reuse strategies on the incidence of hepatitis C virus infection in haemodialysis units.

       Management of a dialyzer membrane defect leading to blood leak

      As HCV is transmitted by percutaneous exposure to blood from an infected person, effective implementation of the dialysis precautions recommended in the 2008 KDIGO HCV guideline
      KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease.
      and by the CDC should prevent nosocomial transmission. The risk that the virus leaving the dialyzer could be trapped in the Hansen connector and transferred to the fresh dialysate side through accidental misconnection is vanishingly low, hence the CDC does not recommend disinfection of “single-pass” machines between treatments on the same day, even when a blood leak has occurred.
      Recommendations for preventing transmission of infections among chronic hemodialysis patients.
      The 2008 KDIGO HCV guideline, however, recommends disinfection of both the internal fluid pathways and the Hansen connectors before the next patient if a leak has occurred as a matter of abundant caution, and justified it based on the rarity of such events
      KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease.
      (Table 4). We reaffirm our previous recommendation.
      Table 4Hygienic precautions for hemodialysis (dialysis machines)
      Definitions
      • The “transducer protector” is a filter (normally a hydrophobic 0.2-μm filter) that is fitted between the pressure-monitoring line of the extracorporeal circuit and the pressure-monitoring port of the dialysis machine. The filter allows air to pass freely to the pressure transducer that gives the reading displayed by the machine, but it resists the passage of fluid. This protects the patient from microbiologic contamination (as the pressure-monitoring system is not disinfected) and the machine from ingress of blood or dialysate. An external transducer protector is normally fitted to each pressure-monitoring line in the blood circuit. A back-up filter is located inside the machine. Changing the internal filter is a technical job.
      • A “single-pass machine” is a machine that pumps the dialysate through the dialyzer and then to waste. In general, such machines do not allow fluid to flow between the drain pathway and the fresh pathway except during disinfection. “Recirculating” machines produce batches of fluid that can be passed through the dialyzer several times.
      Transducer protectors
      • External transducer protectors should be fitted to the pressure lines of the extracorporeal circuit.
      • Before commencing dialysis, staff should ensure that the connection between the transducer protectors and the pressure-monitoring ports is tight, as leaks can lead to wetting of the filter.
      • Transducer protectors should be replaced if the filter become wet, as the pressure reading may be affected. Using a syringe to clear the flooded line may damage the filter and increase the possibility of blood passing into the dialysis machine.
      • If wetting of the filter occurs after the patient has been connected, the line should be inspected carefully to see if any blood has passed through the filter. If any fluid is visible on the machine side, the machine should be taken out of service at the end of the session so that the internal filter can be changed and the housing disinfected.
      • Some blood tubing sets transmit pressure to the dialysis machine without a blood-air interface, thus eliminating the need for transducer protectors.
      External cleaning
      • After each session, the exterior of the dialysis machine and all surfaces in the dialysis treatment station should be cleaned with a low-level disinfectant if not visibly contaminated. Pay particular attention to high-touch surfaces that are likely to come into contact with the patient (e.g., arm rests or blood pressure cuff) or staff members’ hands (e.g., machine control panel).
      • Disinfection of external machine surfaces should not commence until the patient has left the dialysis treatment station. A complete (unit-wide) patient-free interval between shifts might facilitate more thorough cleaning and disinfection of the unit.
      • If a blood spillage has occurred, the exterior should be disinfected with a commercially available tuberculocidal germicide or a solution containing at least 500 p.p.m. hypochlorite (a 1:100 dilution of 5% household bleach) if this is not detrimental to the surface of dialysis machines. Advice on suitable disinfectants, and the concentration and contact time required, should be provided by the manufacturer.
      • If blood or fluid is thought to have seeped into inaccessible parts of the dialysis machine (e.g., between modules or behind the blood pump), the machine should be taken out of service until it can be dismantled and disinfected.
      Disinfection of the internal fluid pathways
      • It is not necessary for the internal pathways of a single-pass dialysis machines to be disinfected between patients, even in the event of a blood leak. Some facilities may still opt to disinfect the dialysate-to-dialyzer (Hansen) connectors before the next patient.
      • Machines with recirculating dialysate should always be put through an appropriate disinfection procedure between patients.

       Audits

      Audits and use of surveillance data to implement prevention steps are critical to any infection control program. Routine observational audits of various infection control practices, combined with feedback of results to clinical staff, allows for regular assessment of actual practices and identification of gaps. Data from audits can facilitate immediate interventions to correct practice and should also inform broader quality improvement efforts, including unit-wide staff education and retraining. In the US, most dialysis centers use infection control audit tools (including tools developed by the CDC or the dialysis company) as part of their continuous quality improvement process.
      Although there are no RCTs that examined the impact of audits on transmission of HCV infection in dialysis units, observational studies as part of quality improvement programs have shown reduction in the rates of BSIs following implementation of regular audits and an evidence-based intervention package. In a study from the US, 17 centers reported monthly event and denominator data to the National Healthcare Safety Network and received guidance from the CDC. The feedback included advice on chlorhexidine use for catheter exit site care, staff training and competency assessments focused on catheter care and aseptic technique, hand hygiene and vascular access care audits, and feedback of infection and adherence rates to staff. Modeled rates decreased 32% (P < 0.01) for BSIs and 54% (P < 0.001) for access-related BSIs.
      • Patel P.R.
      • Yi S.H.
      • Booth S.
      • et al.
      Bloodstream infection rates in outpatient hemodialysis facilities participating in a collaborative prevention effort: a quality improvement report.
      In a follow-up study, the reduction in access-related BSI rates was sustained for 4 years after the initial intervention implementation.
      • Yi S.H.
      • Kallen A.J.
      • Hess S.
      • et al.
      Sustained infection reduction in outpatient hemodialysis centers participating in a collaborative bloodstream infection prevention effort.
      The over-representation of hospital-based centers and lack of a control group limit generalization of these data. However, the ongoing simplification of audit tools for ease of reporting with the use of information technology—as used in this study—precludes the need of infection control professionals on site, and leaves little justification to not recommend implementation of audits. Moreover, the scope of such audits goes beyond measuring 1 particular outcome, such as HCV transmission, and permits wider implementation of infection control measures.
      Audits done in other dialysis center studies routinely show suboptimal adherence to hygienic practices. A Spanish study showed that gloves were used on 93% of occasions, and hands were washed only 36% of the time after patient contact and only 14% of the time before patient contact.
      • Arenas M.D.
      • Sanchez-Paya J.
      • Barril G.
      • et al.
      A multicentric survey of the practice of hand hygiene in haemodialysis units: factors affecting compliance.
      In a 2002 US survey, only 53% of US outpatient ESKD facilities reported preparing injected medications in a dedicated room or area separated from the treatment area; 25% prepared these medications at a medication cart or other location in the treatment area, and 4% prepared medications at the dialysis station.
      • Finelli L.
      • Miller J.T.
      • Tokars J.I.
      • et al.
      National surveillance of dialysis-associated diseases in the United States, 2002.
      A survey of 420 dialysis personnel from 45 facilities reported on hand hygiene practices and knowledge regarding HCV infection risk.
      • Shimokura G.
      • Weber D.J.
      • Miller W.C.
      • et al.
      Factors associated with personal protection equipment use and hand hygiene among hemodialysis staff.
      At these facilities, percentages of dialysis staff reported to always wash their hands and change gloves during the following activities were: 47% when going from one patient treatment station to another, 55% between administering intravenous medications to different patients, and 57% immediately before starting patients on dialysis. Other studies have shown similar findings.
      Observational audits of hygienic precautions that were carried out in outbreak investigations have identified a range of problems, including lack of basic hand hygiene, failure to change gloves when touching the machine interface, or when urgently required to deal with bleeding from a fistula; carrying contaminated blood circuits through the ward unbagged; lack of routine decontamination of the exterior of machines and other surfaces even when blood spillages had occurred; and failure to change the internal transducer protector when potentially contaminated. On the other hand, when hygienic practice was reviewed through interviewing staff after an outbreak rather than by observation, no obvious breaches in procedure could be identified.
      The frequency at which routine audits of infection control procedures should be carried out will depend on audit type, staff turnover and training, and on the results of previous audits. When setting up a new program, audits should be at intervals of no greater than 6 months to enable staff to gain experience with the process and ensure that any remedial actions taken have been effective. The CDC recommends that audits be performed as often as monthly to establish and constantly reinforce recommended practices. Observational audits should be conducted on various days of the week and different shifts to capture all staff, and should include particularly busy times of day such as shift changes. These factors and the number of opportunities (e.g., for hand hygiene) and procedures (e.g., injectable medication administration) observed will determine the representativeness of the results.
      The CDC website (http://www.cdc.gov/dialysis/prevention-tools/audit-tools.html) has a number of audit tools and checklists intended to promote CDC-recommended practices for infection prevention in hemodialysis facilities. The audit tools and checklists can be used by individuals when assessing staff practices. They can also be used by facility staff themselves to help guide their practices. In some centers, audit tools have been shared with patients, who are asked to assess staff practice as a means of engaging patients in the infection control efforts of the facility and improving the culture of safety in units.
      • Ball L.K.
      • George C.A.
      • Duval L.
      • et al.
      Reducing blood stream infection in patients on hemodialysis: Incorporating patient engagement into a quality improvement activity.
      Patients should be educated on correct practices and should feel empowered to speak up when they observe a breach in hand hygiene or other staff practice.
      It is known that hand hygiene practices improve when study participants are aware they are under observation. In one study, video monitoring of hand hygiene (performed via review of video surveillance footage) was shown to be a more accurate method than direct observation.
      • Sanchez-Carrillo L.A.
      • Rodriguez-Lopez J.M.
      • Galarza-Delgado D.A.
      • et al.
      Enhancement of hand hygiene compliance among health care workers from a hemodialysis unit using video-monitoring feedback.
      Video surveillance for hand hygiene adherence should be considered, and other innovative approaches to monitoring staff adherence to recommended infection control practices should be explored.

       Screening

      Screening for HCV infection is essential to identifying transmission in hemodialysis units. The CDC recommends that all maintenance hemodialysis patients be screened for anti-HCV and ALT level upon admission and that anti-HCV testing be repeated semiannually and ALT testing be repeated monthly for susceptible patients.
      CDC recommendations for preventing transmission of infections among chronic hemodialysis patients.
      This is discussed in Chapter 1. Detection of seroconversions should prompt an aggressive evaluation of infection control practices to correct lapses and prevent additional cases from occurring (Table 5).
      Centers for Disease Control and Prevention Health Alert Network
      CDC urging dialysis providers and facilities to assess and improve infection control practices to stop hepatitis C transmission in patients undergoing hemodialysis.
      Importantly, HCV screening should not be used as a substitute for regular infection control audits.
      Table 5Steps to initiate concurrently and undertake following identification of a new HCV infection in a hemodialysis patient (adapted from CDC Health Alert
      Centers for Disease Control and Prevention Health Alert Network
      CDC urging dialysis providers and facilities to assess and improve infection control practices to stop hepatitis C transmission in patients undergoing hemodialysis.
      )
      • A.
        Report the infection to appropriate public health authority.
        • Assess risk factors of the affected patient in conjunction with public health.
      • B.
        Determine HCV infection status of all patients in the hemodialysis unit.
        • Test all patients treated in the center for HCV infection (Chapter 1) unless they are already known to have active infection. Follow-up and testing of patients who were treated in the center and those subsequently transferred or discharged may be warranted.
      • C.
        Conduct a thorough root cause analysis of the infection and address infection control lapses.
        • Perform rigorous assessments of staff infection control practices to identify lapses. This should minimally include assessments of hand hygiene and glove change practices; injectable medication preparation, handling, and administration; and environmental cleaning and disinfection practices.
        • Share findings with all staff members and take action to address lapses. Staff education and retraining may be necessary.
        • Consider hiring a consultant with infection prevention expertise to provide recommendations for improvement of practices and work flow and/or to help implement actions to address identified lapses.
        • Conduct regular audits to ensure improved adherence to recommended practice.
        • Demonstrations of cleaning adequacy such as use of Glo Germ™ (Moab, UT) or luminol might be helpful for staff education.
      • D.
        Communicate openly with patients.
        • Inform all patients of the reason for additional HCV testing and the results of their HCV tests.
        • If transmission within the center is suspected or confirmed, inform all patients of this. Patients should also be made aware of steps being taken to assess and improve practices.
      CDC, Centers for Disease Control and Prevention; HCV, hepatitis C virus.

       Infrastructure requirements

      Audit data show that despite the existence of guidelines to prevent transmission of infections in hemodialysis units, their implementation remains suboptimal, leading to a large preventable burden of infections that not only adversely impacts clinical outcomes, but imposes large costs on the health care system. Experience from public health interventions shows that interventions that depend on behavior change require large effort, which can undermine their impact. In contrast, making systemwide changes, such as imposition of regulations and creating an environment that discourages unhealthy behavior, is likely to have greater impact. This impact has been shown in many fields such as smoking cessation and containing HIV infection.
      • Frieden T.R.
      A framework for public health action: the health impact pyramid.
      Examples in the dialysis field include endorsement of dialysis event BSI measure by the US National Quality Forum, and implementation of the Medicare Quality Initiative. Recommendation of uniform validated measures such as those used by the National Healthcare Safety Network are critical for comparisons and to facilitate interventions. Other systemwide changes that are likely to have a beneficial impact on infection prevention and control practices include increasing staff-to-patient ratios and instituting staff training and education requirements. Physical infrastructure changes to facilities might also be beneficial—for example, establishing minimum space requirements between treatment stations, creating walls around individual treatment stations to establish separate rooms instead of large open spaces, and using walls to separate clean and dirty processes (e.g., separate room for medication preparation). Such possibilities should be explored, along with strategies to improve work flow and reduce unnecessary staff maneuvers that add to the already substantial number of occasions during dialysis care when glove change and hand hygiene are warranted. As such, regulatory and accrediting agencies should issue and/or incorporate recommendations to favor compliance with basic infection control practices in dialysis units, and efforts to make the desired infection control behavior the simplest or most logical approach to care processes should be pursued (Table 6). Table 7 provides a summary of important hygienic precautions for hemodialysis center staff to follow.
      Table 6Strategies to support adherence to infection control recommendations in hemodialysis centers
      • It is important for the designers of dialysis units to create an environment that makes infection control procedures easy to implement. Adequate hand-washing facilities must be provided, and the machines and shared space should make it easy for staff to visualize individual treatment stations. Certain jurisdictions specify the area around a hemodialysis machine.
      • The unit should ensure that there is sufficient time between shifts for effective decontamination of the exterior of the machine and other shared surfaces.
      • The unit should locate supplies of gloves at enough strategic points to ensure that staff has no difficulty obtaining gloves in an emergency.
      • When selecting new equipment, ease of disinfection should be considered.
      • There are indications from the literature that the rate of failure to implement hygienic precautions increases with understaffing. Understaffing has been associated with hepatitis C outbreaks. Certain jurisdictions specify a specific nurse-to-patient ratio (e.g., 1:4 in France). Formal health care training of all staff should be required (e.g., in the US, technicians provide most direct hemodialysis care but lack standardized training). Dialysis units that are changing staff-to-patient ratios, or introducing a cohort of new staff, should review the implications on infection control procedures and educational requirements.
      • Resource problems should be handled by carrying out a risk assessment and developing local procedures. For example, if blood is suspected to have penetrated the pressure-monitoring system of a machine but the unit has no on-site technical support and no spare machines, an extra transducer protector can be inserted between the blood line and the contaminated system so that the dialysis can continue until a technician can attend to the problem.
      The following are useful CDC and WHO informational resources to improve hand hygiene, environmental cleaning and disinfection, and injection safety:
      CDC, Centers for Disease Control and Prevention; US, United States; WHO, World Health Organization.
      Table 7Key hygienic precautions for hemodialysis staff
      In addition to standard precautions.
      Definitions
      • A “dialysis station” is the space and equipment within a dialysis unit that is dedicated to an individual patient. This may take the form of a well-defined cubicle or room, but there is usually no material boundary separating dialysis stations from each other or from the shared areas of the dialysis unit.
      • A “potentially contaminated” surface is any item of equipment at the dialysis station that could have been contaminated with blood, or fluid containing blood, since it was last disinfected, even if there is no visual evidence of contamination.
      Education
      • A program of continuing education covering the mechanisms and prevention of crossinfection should be established for staff caring for hemodialysis patients.
      • Staff should demonstrate infection control competency for the tasks they are assigned. Infection control competencies (e.g., use of aseptic techniques) should be assessed upon hire and at least yearly thereafter.
      • Appropriate information on infection control should also be given to nonclinical staff, patients, caregivers, and visitors. Patients should be encouraged to speak up when they observe an infection control practice that is concerning to them.
      Hand hygiene
      • Staff should wash their hands with soap or an antiseptic hand-wash and water, before and after contact with a patient or any equipment at the dialysis station. An alcohol-based hand rub may be used instead when their hands are not visibly contaminated.
      • In addition to hand washing, staff should wear disposable gloves when caring for a patient or touching any potentially contaminated surfaces at the dialysis station. Gloves should always be removed when leaving the dialysis station.
      • Patients should also clean their hands with soap and water, or use an alcohol-based hand rub or sanitizer, when arriving at and leaving the dialysis station.
      Injection safety
      • Medication preparation should be done in a designated clean area.
      • All vials should be entered with a new needle and a new syringe, which should be discarded at point of use.
      • Medications should be administered aseptically, after wearing a disposable glove and disinfecting the injection port with an antiseptic.
      • Hand hygiene must be performed before and after administration of injection.
      • All single-dose vials must be discarded and multidose vials, if used, should not be stored or handled in the immediate patient care area.
      Equipment management (for management of the dialysis machine, see Table 4)
      • Single-use items required in the dialysis process should be disposed of after use on 1 patient.
      • Nondisposable items should be disinfected after use on 1 patient. Items that cannot be disinfected easily (e.g., adhesive tape and tourniquets) should be dedicated to a single patient and discarded after use.
      • The risks associated with use of physiologic monitoring equipment (e.g., blood pressure monitors, weight scales, and access flow monitors) for groups of patients should be assessed and minimized. Blood pressure cuffs should be dedicated to a single patient or made from a light-colored, wipe-clean fabric.
      • Medications and other supplies should not be moved between patients (e.g., on carts or by other means). Medications provided in multiple-use vials, and those requiring dilution using a multiple-use diluent vial, should be prepared in a dedicated central area and taken separately to each patient. Items that have been taken to the dialysis station should not be returned to the preparation area.
      • After each session, all potentially contaminated surfaces at the dialysis station should be wiped clean with a low-level disinfectant if not visibly contaminated. Surfaces that are visibly contaminated with blood or fluid should be disinfected with a commercially available tuberculocidal germicide or a solution containing at least 500 p.p.m. hypochlorite (a 1:100 dilution of 5% household bleach).
      Waste and specimen management
      • Needles should be disposed of in closed, unbreakable containers, which should not be overfilled. A “no-touch” technique should be used to drop the needle into the container, as it is likely to have a contaminated surface. If this is difficult due to the design of the container, staff should complete patient care before disposing of needles.
      • All blood and other biologic specimen handling should occur away from dedicated clean areas, medications, and clean supplies.
      • The used extracorporeal circuit should be sealed as effectively as possible before transporting it from the dialysis station in a fluid-tight waste bag or leak-proof container for disposal. Avoid draining or manipulating the used circuit. If it is necessary to drain the circuit to comply with local regulatory requirements, or to remove any components for reprocessing, this should be done in a dedicated area away from the treatment and preparation areas.
      a In addition to standard precautions.

       Treatment of HCV infection as a means for prevention of transmission

      With the availability of DAAs, there is a possibility that dialysis units might take recourse to starting HCV-infected patients on these agents with the hope that this will cure the infection and prevent transmission to uninfected patients. Several studies have shown that facility prevalence of HCV infection is associated with incidence of infection. Thus, it stands to reason that successful treatment of patients could reduce the likelihood of HCV spread in dialysis centers. However, it should be noted that transmission can occur even in centers with very low HCV prevalence.
      • Thompson N.D.
      • Novak R.T.
      • Datta D.
      • et al.
      Hepatitis C virus transmission in hemodialysis units: importance of infection control practices and aseptic technique.
      A study that modeled HCV transmission in hemodialysis centers found that HCV prevalence influenced incidence (as did staff-to-patient ratio), but the compliance rate with hand hygiene and glove change between patients was a much stronger determinant of transmission.
      • Laporte F.
      • Tap G.
      • Jaafar A.
      • et al.
      Mathematical modeling of hepatitis C virus transmission in hemodialysis.