Over the last few years, the management of hepatitis C has been revolutionized by the advent of direct antiviral agents (DAA). This has arguably been one of the most impactful advancements in medicine over the last decade, potentially affecting 70-plus million people worldwide who are afflicted with chronic hepatitis C virus (HCV). Ten years ago, Kidney Disease: Improving Global Outcomes (KDIGO) published a guideline for the Prevention, Diagnosis, Evaluation and Treatment of Hepatitis C in Chronic Kidney Disease (CKD). It was clearly time for an update, and KDIGO aptly responded with a 2018 version (and provided an 11-page Executive Summary here).

HCV is not only a leading cause of liver disease and cirrhosis worldwide, but is also linked to cardiovascular disease, diabetes, and kidney disease, among others. This infection is of special importance to nephrologists not only as a cause of glomerular disease, but also because of its high prevalence in our patient population. Traditionally, HCV has been associated with inferior outcomes in both dialysis and transplant patients compared to non-infected counterparts. Most of this data comes from the interferon (IFN) era where cure rates in the end-stage renal disease (ESRD) population were less than 40%.

Coupled with the poor tolerability of IFN due to side effects, there was understandably a blunted enthusiasm for treating HCV in ESRD and advanced CKD. For example, in a DOPPS study of a cohort of dialysis patients in 12 countries from 1996-2011, only 1% of HCV-infected patients received IFN or ribavirin based on prescription data. Even among those who were waitlisted for transplant, only 4% received treatment. Post-transplantation, patients with HCV could not be treated due to the high risk of acute rejection associated with IFN and treatment was reserved for those who developed life-threatening complications such as fibrosing cholestatic hepatitis.

Fast-forward to the modern era of DAA therapy where cure rates are now reported to be greater than 95% with a 12-week course of an oral agent. Several regimens are approved for use in patients with an estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m² including those on dialysis. More recently, a regimen that is effective against all genotypes has become available. In general, DAAs have been reported to be well-tolerated, with only mild side effects. DAA treatment post-transplantation has also been reported to be very effective, with few adverse events. Given the efficacy and tolerability that have been demonstrated with DAAs, the impetus to screen, diagnose, and treat our patients is now arguably much higher, with a potential for markedly improving patient outcomes. 

The 2018 KDIGO guideline aims to provide the nephrologist with recommendations on clinical decision-making while recognizing that care should remain individualized to patients’ needs and institutional resources. The guideline, organized into the same five sections found in the 2008 version, is notably more exhaustive, with stronger recommendations based on higher quality evidence. The guideline sections are listed below along with a few highlights:

1. Detection and evaluation of HCV in CKD. Changes from 2008 – Guideline 1 provides more specific and detailed recommendations compared to the previous version.

• Patients should be screened at time of initial evaluation, initiation of dialysis, and at kidney transplant evaluation utilizing immunoassay and nucleic acid testing (NAT), if the immunoassay is positive. For patients initiating dialysis in HD units, proceeding directly to NAT testing is also an option.
• Non-invasive testing is recommended to evaluate for liver fibrosis, with a liver biopsy as a second-line test if non-invasive testing is inconclusive or the cause of liver disease is uncertain.

2. Treatment of HCV infection in patients with CKD. Changes from 2008 – Guideline 2 does away with any recommendation of utilizing interferon for treatment, which was previously a weak recommendation. This guideline also highlights the ability to treat hepatitis C post-transplantation, which was not possible in 2008.

• All patients should be evaluated for antiviral, interferon-free therapy.
• Specific regimens should be tailored to the clinical scenario such as genotype, eGFR, prior treatment history, and drug-drug interactions. For patients with eGFR less than 30 mL/min/1.73 m² (CKD stages 4-5), the DAA regimen should be ribavirin-free.
• Algorithms 1 and 2 summarize recommended DAA regimens based on genotype and eGFR in CKD and kidney transplant recipients, respectively.

Algorithm 1 | Treatment 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. Reproduced from KDIGO under a CC BY-NC-ND license.

Algorithm 2 | Treatment 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. Reproduced from KDIGO under a CC BY-NC-ND license.

3. Preventing HCV transmission in hemodialysis units. Guideline 3 is essentially unchanged from 2008.

• The importance of standard infection control procedures and hygiene precautions is emphasized.
• Using dedicated HD machines is not recommended.
• It is suggested that isolating hepatitis C-infected patients is not necessary and that dialyzers can be reused.

4. Management of HCV-infected patients before and after kidney transplantation. Changes from 2008 – Guideline 4 has been completely overhauled. KDIGO recommends DAA treatment before or after kidney transplantation depending on the clinical scenario.

• Patients with compensated cirrhosis are recommended to undergo isolated kidney transplantation while those with decompensated cirrhosis should be evaluated for combined liver-kidney transplantation while deferring HCV treatment until after transplantation.
• Kidneys from HCV-infected donors should be directed towards HCV-infected recipients.
• Timing of DAA treatment in kidney transplant candidates should be determined on a case-by-case basis, with consideration of treating post transplantation if this improves a patient’s chances of receiving a transplant. This is shown in algorithm 3.

Algorithm 3 | Proposed strategy in a hepatitis C virus (HCV)-infected kidney transplant candidate. SKLT, simultaneous kidney-liver transplantation. Reproduced from KDIGO under a CC BY-NC-ND license.

5. Diagnosis and management of kidney diseases associated with HCV infection. Guideline 5 offers 1C recommendations in treating HCV-associated glomerular disease.

• Treat HCV-associated kidney disease with DAAs as first-line therapy and add immunosuppressive agents with or without plasma exchange if with cryoglobulinemic flare, nephrotic syndrome, or rapidly progressive kidney failure.

Overall, the KDIGO 2018 Guideline proves to be a useful HCV overview for nephrologists, especially with regards to treatment. However, with the relatively rapid pace in which new DAA regimens are being introduced into the market and the changes occurring with regards to transplant center policies, this guideline will likely need constant updating in the years to come. It is notable that the evidence for the recommendations provided in this guideline is much stronger than 10 years ago. We can only expect more data-driven recommendations in the future as we learn about the impact of DAA therapy on patient outcomes.

Undoubtedly, one of the biggest barriers that remain is the high cost of DAA therapy, with a 12-week regimen costing up to $75,000. KDIGO admittedly did not address this issue and elected to provide recommendations based on “…best available evidence without direct considerations of costs, as they vary widely across countries.” Despite data showing cost-effectiveness of treatment, access to DAAs continues to be a challenge, particularly for those with limited insurance coverage or those in low-income countries. We hope that with improved access to this care, the utility and impact of these guidelines will increase with time.

For more on the past, present, and future of HCV and kidney transplantation, see these blog posts from 2017: Part 1 and Part 2.

– Post prepared by Beatrice Concepcion, AJKD Social Media Advisory Board member. Follow her @KidneyBea_n.