In the 2018 update of the Kidney Disease: Improving Global Outcome (KDIGO) guidelines, updates have been made for screening, detection, and treatment recommendations for patients with hepatitis C virus (HCV) and chronic kidney disease (CKD). A narrative review summarizing the most recent guideline updates has been published in Clinical Gastroenterology and Hepatology.1

HCV prevalence in patients with CKD undergoing hemodialysis is still higher than in the general population, despite a decrease over the past 2 decades.1 In the Using Dialysis Outcomes and Practice Patterns Study (DOPPS), researchers found that HCV diagnosis in this patient population was nearly 10% between 2012 and 2015.2 Currently, an estimated 4.8% of hemodialysis patients on the transplant waitlist are seropositive for hepatitis C.3 In examining the prevalence of HCV positivity at the onset of hemodialysis, the DOPPS study found a roughly 5% prevalence of HCV, a figure “that hardly changed over the last 2 decades.”2

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Given the outlined relationship between HCV and CKD, all patients with CKD, including those undergoing hemodialysis, peritoneal dialysis, or transplant evaluation, should be screened for HCV. Regardless of glomerular filtration rate, a 1-time screening “needs to be performed by the physician who initially diagnoses CKD,” according to Ahmed Awan, MD, of the Selzman Institute for Kidney Health at Baylor College of Medicine in Houston, Texas, and colleagues.1

“Detection of anti-HCV antibody by screening immunoassays (enzyme or chemoluminescence) with infection confirmed by nucleic acid testing (NAT) is required to make a diagnosis,” the researchers wrote. In hemodialysis units with high HCV presence, initial NAT testing should be considered, with NAT samples drawn prior to hemodialysis to avoid reduced viremia level.

Multiple methods are available to confirm the presence of HCV viremia; however, many antigen tests that have a higher detection limit (150-3000 IU/ml) are not commonly used despite their lower cost. However, serum alanine aminotransferase (ALT) monitoring is an inexpensive HCV surveillance method that is recommended for patients who either initiate in-center hemodialysis or get transferred from another facility.1

According to Dr Awan and colleagues, most reported HCV outbreaks have been associated with “multiple deficiencies in infection control,” such as lapses in hand hygiene or glove use, handling of injectable medication, and environmental surface disinfection.1 “Regular assessment and adherence to evidence-based interventions should be reinforced through observational studies,” the researchers noted, adding that guidelines do not recommend either the isolation of HCV infected patients during hemodialysis or the use of dedicated dialysis machines for this patient population.

Patients should, however, be screened for HCV monthly via ALT level and every 6 months via HCV immunoassay or NAT. If newly acquired HCV is detected, all patients in the hemodialysis center should be tested, and subsequent testing frequency should be increased. HCV seroconversions for HCV suspected to be acquired through hemodialysis should be reported to the appropriate public health authorities.1

According to Dr Awan and colleagues, all patients with HCV should be considered for treatment, “given the significant liver, cardiovascular, and kidney benefits of achieving [sustained viral response] in [patients] with CKD with HCV infection.”

Researchers of numerous studies have identified an association between sustained viral response and mortality reduction in the general population, 34 including the renal benefits associated with a sustained viral response, mitigation of “other extra-hepatic manifestations,”1 a reduction in vascular events, and an improvement in cryoglobulinemic vasculitis.”1,5,6

Interferon-based therapy has been found to have “limited use” in the CKD population due to poor tolerability, low efficacy, and concern about graft rejection in transplant recipients.1 Similarly, ribavirin therapy is limited due to the likelihood of severe anemia.

In terms of viable treatments, NS3/4A protease inhibitors were approved in 2011; since then, numerous direct-acting antivirals (DAAs) have been developed. Other options include NS5A replication complex inhibitors and non-nucleoside NS5B polymerase inhibitors, which do not require dose adjustments during the later stages of CKD.

All patients should be screened for HBV infection before therapy initiation. If HBV surface antigen is detected, antiviral therapy should be initiated to prevent reactivation of HBV as a consequence of DAA therapy.1

CKD G1-G3b: For patients in this group, both KDIGO and the European Association for the Study of the Liver7 recommend using any available DAA based on viral load, HCV genotype, fibrosis degree, and treatment history. No dose modification is necessary for these combination drug regimens. Note that velpatasvir has not been approved for use in this population “in some jurisdictions,” and sofosbuvir is approved for use only in patients with estimated glomerular filtration rate (eGFR) >30 mL/min/1.73m2.1 Typical treatments for this population include combination sofosbuvir-velpatasvir, ledipasvir-sofosbuvir, glecaprevir-pibrentasvir, or grazoprevir-elbasvir.

CKD G4-G5, including patients on dialysis (G5D): For patients in this group, low eGFR and viral genotype are the primary determinants of DAA choice. A combination elbasvir and grazoprevir regimen is recommended for use in HCV genotypes 1 and 4.1 The C-SURFER trial found that coadministration of CYP3A4 inducers, including rifampin, phenytoin, and St. John’s wart, is contraindicated as they may reduce the antiviral activity of these agents.1 Similarly, coadministration of OATP1B1/3 inhibitors, such as enalapril, statins, digoxin, and some angiotensin-receptor blockers, may cause hyperbilirubinemia.

Regardless of HCV genotype, pangenotypic glecaprevir-pibrentasvir combination therapy is an option in CKD G4-G5D, and can be used in patients with cirrhosis and in patients who failed treatment with interferon-based therapy.1

Kidney transplant recipients: Due to various immunologic and nonimmunologic mechanisms, kidney transplant recipients have baseline CKD, classified as G1T to G5T. As with patients with CKD, transplant recipients with GFR >30 ml/min/1.73 m2 (CKD G1T-G3bT) and HCV genotypes 1 and 4 can be treated with either pibrentasvir-glecaprevir or a sofosbuvir-based regimen. Combination pibrentasvir-glecaprevir is recommended for genotypes 2, 3, 5, and 6. For patients with eGFR <30 ml/min/1.73m2, “the same regiments are recommended as used for CKD G4-G5D.”1 In addition, interferon-free regimens are recommended for kidney transplant recipients, while DAAs — including sofosbuvir-based regimens — require dose adjustment of immunosuppressive medications.

In kidney transplant recipients, drug-drug interactions are an important consideration. For example, DAA therapies can lead to “elevated or suppressed levels of immunosuppressive medications, resulting in graft rejection or toxicity.”1 Protease inhibitors have been associated with a significant risk for interaction with calcineurin inhibitors, while NS5A and NS5B inhibitors are associated with a lower interaction risk. Concurrent elbasvir-grazoprevir and cyclosporine use is not recommended.

Regardless of HCV status, the best treatment for patients with end-stage kidney disease is kidney transplantation, based on significant survival advantages. Despite potential issues with patient and graft survival in patients with persistent HCV replication after transplant, survival is overall better compared with patients who remain on dialysis.1

HCV infection in potential transplant recipients can be treated either before or after transplantation, and often depends on donor type, waitlist times, “center-specific policies regarding the use [of] HCV-infected deceased donors,” HCV genotype, and liver fibrosis severity.1 HCV treatment can be deferred if a living kidney transplantation is anticipated without a long wait. With wait times longer than 24 weeks, there is sufficient time for treatment and confirmation of sustained viral response.

In the United States alone, approximately 100,000 patients yearly are waitlisted for kidney transplantations, with wait times in excess of 3 to 5 years.8,9 Despite a “substantial need” for organs, more than 800 kidneys from donors with HCV were discarded in 2016.5,6

KDIGO guidelines strongly recommend that when using deceased donors, HCV NAT-positive donors “should be directed to recipients with positive NAT.”1

“If acceptance of a graft from an HCV-positive donor reduces the wait time for transplantation, a patient can undergo transplantation with an HCV-positive kidney and get treatment for HCV infection after transplant,” Dr Awan and colleagues noted. However, this approach requires patients to provide informed consent.

Although waitlist times can vary, they are typically shorter for those who receive HCV-positive organs. HCV treatment can be initiated once the patient is on a stable immunosuppressive regimen.1

For living donors, those who are HCV NAT-positive should be treated, with sustained viral response confirmed prior to transplantation. If a donor is anti-HCV positive but NAT-negative, an HCV-negative recipient may safely receive the transplant. Kidney transplantation results from HCV NAT-positive donors to HCV-positive recipients treated with DAAs after transplantation are “reassuring,” although the safety of transplanting these kidneys into HCV-negative recipients is still being researched.1

Viral loads increase after transplantation and result in an increased risk for death from infection in the 6 months following transplantation.10 This risk drops at 6 months, and, according to Dr Awan and colleagues, “studies have suggested that antibody induction has no detrimental effect on long-term survival in HCV-positive patients.”1 Mycophenolate mofetil (MMF) has not been found to increase serum HCV ribonucleic acid concentration, and both MMF and tacrolimus can be used in patients regardless of HCV status.1

Transplant recipients with HCV infection who are treated before transplantation should undergo NAT testing 3 months post-transplantation. This population should also be tested for proteinuria every 6 months, with the development of proteinuria triggering a kidney biopsy.

The most frequent form of renal involvement in HCV is membranoproliferative glomerulonephritis, typically due to cryoglobulinemic vasculitis, with membranous nephropathy appearing less frequently. A kidney biopsy can be used to establish a diagnosis and exclude etiologies such as diabetic nephropathy, a “not infrequent” complication in patients with HCV.1 DAAs can be used to treat patients with HCV-associated glomerular disease.

Among patients with rapidly progressing kidney failure, acute cryoglobulinemic flare, or nephrotic syndrome, immunosuppression with first-line rituximab, with or without plasma exchange, should be considered prior to initiation of DAAs. A recent prospective study of rituximab in 16 patients with diffuse membranoproliferative glomerulonephritis found that this treatment was associated with nephropathy improvement during the second month after rituximab administration.11 However, rituximab can lead to HBV reactivation, resulting in a black box warning from the US Food and Drug Administration.12

“The role of DAAs in preventing and slowing the progression of CKD in the HCV infected population is not clear and needs to be evaluated,” Dr Awan and colleagues wrote, adding that the optimal timing of antiviral therapy either before or after kidney transplantation should be clarified, along with the use of HCV-positive donors in HCV-negative recipients.

“Significant strides have been made in the treatment of HCV infection,” Dr Awan and colleagues concluded. “However, financial concerns and lack of referral to hepatologists for treatment remain significant obstacles towards complete elimination of HCV. Promoting access to DAAs and reducing [the] risk of HCV transmission in dialysis centers, along with universal immunization for HBV, can make it possible to eliminate viral hepatitis within the next decade as a global health problem.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

References

1. Awan AA, Jadoul M, Martin P. Hepatitis C in chronic kidney disease—an overview of the KDIGO Guideline [published online July 31, 2019]. Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2019.07.050

2. Jadoul M, Bieber BA, Martin P, et al. Prevalence, incidence, and risk factors for hepatitis C virus infection in hemodialysis patients. Kidney Int. 2019;95(4):939-947.

3. Goodkin DA, Bieber B. International prevalence of hepatitis C positivity among hemodialysis patients awaiting transplantation. Kidney Int. 2018;93(5):1249.

4. 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 (2011). 2018;8(3):91-165.

5. Cacoub P, Desbois AC, Comarmond C, Saadoun D. Impact of sustained virological response on the extrahepatic manifestations of chronic hepatitis C: A meta-analysis. Gut. 2018;67(11):2025-2034.

6. Agnello V, Mecucci V, Casato M. Regression of splenic lymphoma after treatment of hepatitis C virus infection. N Engl J Med. 2002;347(26):2168-2170.

7. European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C 2018. J Hepatol. 2018;69(2):461-511.

8. Hart A, Smith JM, Skeans MA, et al. OPTN/SRTR 2016 annual data report: kidney. Am J Transplant. 2018;18 Suppl 1:18-113.

9. US Department of Health and Human Services. Organ Procurement and Transplantation Network. https://optn.transplant.hrsa.gov/ Accessed September 3, 2019.

10. Roth D, Gaynor JJ, Reddy KR, et al. Effect of kidney transplantation on outcomes among patients with hepatitis C. J Am Soc Nephrol. 2011;22(6):1152-1160.

11. Roccatello D, Sciascia S, Baldovino S, et al. Improved (4 plus 2) rituximab protocol for severe cases of mixed cryoglobulinemia: a 6-year observational study. Am J Nephrol. 2016;43(4):251-260.

12. US Food and Drug Administration. FDA Drug Safety Communication: Boxed Warning and new recommendations to decrease risk of hepatitis B reactivation with the immune-suppressing anti-cancer drugs Arzerra (ofatumumab) and Rituxan (rituximab). https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-boxed-warning-and-new-recommendations-decrease-risk-hepatitis-b. Published February 29, 2016. Accessed September 3, 2019.