Executive Summary Of The KDIGO 2022 Clinical Practice Guideline For The Prevention, Diagnosis, Evaluation, And Treatment Of Hepatitis C in Chronic Kidney Disease
Sep 19, 2023
Infection with the hepatitis C virus (HCV) has adverse liver, kidney, and cardiovascular consequences in patients with chronic kidney disease (CKD), including those on dialysis therapy or with a kidney transplant. Since the publication of the Kidney Disease: Improving Global Outcomes (KDIGO) HCV Guideline in 2018, advances in HCV management, particularly in the field of antiviral therapy and treatment of HCV-associated glomerular diseases, coupled with increased usage of HCV-positive kidney grafts, have prompted a reexamination of the 2018 guideline. As a result, the Work Group performed a comprehensive review and revised the 2018 guidance. This Executive Summary highlights key aspects of the updated guideline recommendations for 3 chapters: Chapter 2: Treatment of HCV infection in patients with CKD; Chapter 4: Management of HCV-infected patients before and after kidney transplantation; and Chapter 5: Diagnosis and management of kidney diseases associated with HCV infection.
Hepatitis C virus (HCV) infection in the chronic kidney disease (CKD) population has presented some unique challenges. These include its high prevalence among dialysis patients, transmission within dialysis units and by infected grafts, and the resultant increased risk of progressive liver disease in chronically infected patients who remain on dialysis, as well as in kidney transplant recipients. Additional challenges in these populations previously included potentially reduced tolerance of antiviral therapy and choice of appropriate regimen. In 2008, Kidney Disease: Improving Global Outcomes (KDIGO) published a guideline1 addressing HCV management in CKD, and in 2018, a complete update of the guideline was produced that encompassed the major advances in HCV management that had occurred in the preceding decade,2 such as noninvasive methods for evaluating liver-disease severity and the availability of oral direct-acting antiviral (DAA) therapies. Since the 2018 guideline was published, additional DAA regimens have been used in the CKD population and kidney transplant recipients. In addition, the increasing experience with the use of organs from HCV-infected donors has expanded allograft access in kidney transplantation. The role of antiviral therapy in treating glomerulonephritis due to HCV infection has also been more clearly defined. As a result of these advances, we undertook an update on portions of the 2018 guideline focusing on these evolving areas in Chapters 2, 4, and 5. Chapters 1 and 3, addressing the detection and evaluation of HCV in CKD, and prevention of its transmission in hemodialysis units, respectively, remain current and did not warrant any substantive revision; thus, they remain unchanged from the 2018 guideline. This Executive Summary presents the revised recommendations and highlights the rationale for the revisions to Chapters 2, 4, and 5.3 These recommendations fully replace all recommendations from the equivalent chapters in the 2018 guideline.
Chapter 2: Treatment of HCV infection in patients with CKD DAA therapy is highly effective and well-tolerated (with rare serious adverse events) in patients across all stages of CKD, including in patients undergoing dialysis and following kidney transplantation. Sustained virologic response rates 12 weeks after treatment (SVR12) range from 92%–100% in all stages of CKD and across a variety of DAA regimens. Serious adverse event rates attributed to DAA generally are reported in fewer than 1% of treated patients. As a result, interferon-based therapy is no longer used in HCV. With the introduction of several DAA regimens active against all HCV genotypes (pan-genotypic), awareness of HCV genotype is less of a concern in antiviral therapy. However, in some countries, genotype-specific DAA regimens are more readily accessible, and the use of these regimens thus requires ascertainment of HCV genotype prior to treatment.
Multiple pangenotypic and genotype-specific DAA regimens have been investigated in CKD G4–G5ND (ND, non-dialysis), G5D (D, dialysis), and in kidney transplant recipients, and they are consistently highly effective and welltolerated. Since the publication of the KDIGO 2018 HCV guideline, evidence has mounted that sofosbuvir, a key component of several regimens, is safe for all stages of CKD, including for individuals with low glomerular filtration rate (GFR) or undergoing dialysis. This development is important because in many nations, the only available DAA regimens are those that are sofosbuvir-based. Additionally, protease inhibitors (“-previrs” such as simeprevir, paritaprevir, and grazoprevir) are contraindicated in patients with Child-Pugh B and C cirrhosis.
In patients with normal kidney function, DAA therapy arrests the progression of liver disease and reduces its complications, while improving patient survival with acceptable toxicity. Additionally, evidence exists for improvement in cardiovascular disease following anti-HCV therapy in the general population. These benefits of DAA therapy potentially translate to patients with CKD as well. The KDIGO HCV Work Group agreed with other specialty guidelines, including the American Association for the Study of Liver Diseases/Infectious Diseases Society of America Guideline [AASLD/IDSA]), that HCV treatment should be withheld in patients with a very limited life expectancy
CKD G1–G5ND. As shown in Figure 1, a number of pan-genotypic regimens can be used, irrespective of GFR. If a nonpangenotypic regimen is contemplated, identification of a specific genotype is necessary to determine its efficacy. Dose adjustment of DAA is not required in CKD G1–G5ND. Treatment duration varies by regimen (but currently is typically 12 weeks), presence of cirrhosis, and prior DAA therapy. The most recent recommendations should be confirmed by consulting the latest AASLD/IDSA guidelines (https://www.hcvguidelines.org) or the European Association for the Study of the Liver (EASL) guidelines
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CKD G5D. Similar to CKD G1–G5ND, multiple pan-genotypic as well as genotype-specific regimens are available for patients with CKD G5D (Figure 1), with treatment durations varying based on DAA regimen as well as the presence or absence of cirrhosis and/or prior HCV treatment. DAA dose adjustment is also not required for patients with CKD G5D. The most recent recommendations should be confirmed by consulting the latest AASLD/IDSA or EASL guidelines on HCV therapy. The majority of data on DAA therapy in CKD G5D derives from patients undergoing hemodialysis with limited information on the safety and efficacy of DAA in patients undergoing peritoneal dialysis.
Kidney transplant recipients. Pangenotypic regimens, as well as genotype-specific regimens, are safe and effective in kidney transplant recipients. Most of the data for DAA use in kidney transplant recipients derive from individuals with GFR $30 ml/min per 1.73 m2 (CKD G1T–G3T; Figure 1). Limited information on the high efficacy and safety of DAA can be extrapolated from DAA use in the highly selected population of HCV-uninfected recipients of kidneys from HCV-infected donors who at least initially have low GFR. The major concern about DAA use in kidney transplantation is the potential for drug–drug interactions that could occur with concomitant use of immunosuppressive agents such as calcineurin and mTOR inhibitors. The most recent recommendations should be confirmed by consulting the latest AASLD/IDSA or EASL guidelines on HCV therapy as well as the University of Liverpool Hepatitis Drug Interactions website (http://www.hep-druginteractions.org).
Reactivation of hepatitis B virus infection with DAA therapy. With suppression of HCV replication, reactivation of HBV replication may occur in patients with current or prior HBV infection. Testing for markers of HBV infection including hepatitis B surface antigen (HBsAg), total core antibody (anti-HBc antibody), and antibody to hepatitis B surface antigen (anti-HBs antibody) is indicated prior to DAA therapy. HBV antiviral therapy should be administered prior to DAA therapy if the criteria for HBV treatment in accordance with AASLD or EASL are met.4,5 If HBsAg is absent but markers of prior HBV infection (HBcAb-positive with or without HBsAb) are detected, HBV antiviral therapy is not required prior to DAA therapy, but aminotransferase levels should be checked regularly and HBV DNA testing should be performed if levels of liver function tests rise during DAA therapy. If HBV viremia is present, confirming reactivation as the reason for the rise in aminotransferases, therapy for HBV should be started.
CHAPTER 2: TREATMENT OF HCV INFECTION IN PATIENTS WITH CKD
2.1: We recommend that all patients with CKD (G1-G5), on dialysis (G5D), and kidney transplant recipients (G1TG5T) with HCV be evaluated for direct-acting antiviral (DAA)-based therapy as outlined in Figure 1 (1A).
2.1.1: We recommend that the choice of specific regimen be based on prior treatment history, drug–drug interactions, glomerular filtration rate (GFR), stage of hepatic fibrosis, kidney and liver transplant candidacy, and comorbidities (1A). If pangenotypic regimens are not available, HCV genotype (and subtype) should guide the choice of treatment (Figure 1).
Figure 1 | Direct-acting antiviral (DAA) regimens with evidence of effectiveness for various chronic kidney disease (CKD) populations. a The table includes only regimens that were evaluated by at least 2 studies in the specific CKD population and for which summary sustained virologic response at 12 weeks [wks] (SVR12) was >92%. Sofosbuvir monotherapy is excluded since current DAA regimens incorporate at least 2 agents. Other regimens may be appropriate for the above populations. Readers are encouraged to consult the Association for the Study of Liver Diseases (AASLD) or the European Association for the Study of the Liver (EASL) guidelines for the latest information on various regimens. The suggested durations of treatment are those most commonly employed by the relevant studies. Studies commonly extended treatment for patients with cirrhosis, prior DAA failure, or for some genotypes. Readers should consult the AASLD or EASL guidelines, as needed, to determine optimal treatment duration. b The order of hepatitis C virus (HCV) regimens does not indicate a ranking or preferential order of selection. The regimens are presented in order of the quality of evidence, then by HCV genotype, and then alphabetically. The differences in the quality of evidence primarily relate to the number of evaluated patients and small differences in the methodological quality of the underlying studies (see Guideline Supplementary Tables S5–S7). c Estimated glomerular filtration rate (eGFR) $30 ml/min per 1.73 m2 . d eGFR <30 ml/min per 1.73 m2 , not dialysis-dependent. e Regimens in kidney transplant recipients (KTRs) should be selected to avoid drug–drug interactions, particularly with calcineurin inhibitors. f Strength of evidence for CKD G4T-G5T is very low for all regimens. g Evidence primarily for patients on hemodialysis. Very few patients were on peritoneal dialysis. G, refers to the GFR category with suffix D denoting patients on dialysis and ND denoting patients not on dialysis; PrO D, ritonavir-boosted paritaprevir and ombitasvir with or without dasabuvir.
2.1.2: Treat kidney transplant candidates in collaboration with the transplant center to optimize the timing of therapy (Not Graded).
2.1.3: We recommend pre-treatment assessment for drug–drug interactions between the DAA-based regimen and other concomitant medications including immunosuppressive drugs in kidney transplant recipients (1A).
2.1.4: We recommend that calcineurin inhibitor levels be monitored during and after DAA treatment in kidney transplant recipients (1B).
2.2: All patients with CKD (G1-G5), on dialysis (G5D), and kidney transplant recipients (G1T-G5T) with HCV should undergo testing for hepatitis B virus (HBV) infection prior to DAA therapy (Not Graded). 2.2.1: If hepatitis B surface antigen [HBsAg] is present, the patient should undergo assessment for HBV therapy (Not Graded).
2.2.2: If HBsAg is absent but markers of prior HBV infection (HBcAb-positive with or without HBsAb) are detected, exclude HBV reactivation with HBV DNA testing if levels of liver function tests rise during DAA therapy (Not Graded).
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