[Editor’s note: This review and commentary includes study data presented at the 53rd Congress of the European Renal Association-European Dialysis & Transplant Association (ERA-EDTA 2016) in Vienna, Austria, May 21-24. 2016, and reflects discussions that took place at the congress.]
Infection with the hepatitis C virus (HCV) affects more than 170 million people worldwide. After acute infection, 80% to 85% of individuals do not clear the virus and progress to chronic infection and its associated complications.1 The risk of liver-related complications such as cirrhosis and hepatocellular carcinoma is well known, but it has become apparent that HCV is also associated with extra-hepatic complications, including chronic kidney disease (CKD).
HCV and chronic kidney disease
According to a recent systematic review and meta-analysis, individuals who are seropositive for anti-HCV antibodies (HCV+) have a significant 23% greater relative risk of having and/or developing CKD compared with uninfected individuals.2 At the 53rd Congress of the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) in Vienna, I advised delegates that chronic HCV infection should be seen as a metabolic disease that causes chronic systemic inflammation through direct viral effects on the vasculature and indirect effects via the immune system and the liver. The result is a pro-inflammatory state that increases the risk of atherosclerosis, cardiovascular disease, the metabolic syndrome, and diabetes.3 These are known risk factors for CKD in the general population, but a large cohort study in Taiwan concluded that there is a significant and independent association between HCV and CKD in the absence of traditional CKD risk factors.4
It is now well recognized that HCV is associated with glomerular disease, most commonly membranoproliferative glomerulonephritis with or without cryoglobulinemia. Other reported lesions include membranous nephropathy, focal segmental glomerulosclerosis, fibrillary or immunotactoid glomerulopathies, and thrombotic microangiopathy.5 HCV is thought to cause renal injury through the action of cryoglobulins, HCV-antibody immune complexes, and direct cytopathic effects, including endotheliitis, mesangial inflammation and podocyte injury.6
Worldwide, diabetes mellitus is the most common cause of end-stage renal disease (ESRD),7 and HCV adds to the risk in these patients. In a study, the risk of ESRD was 44% greater in patients with both diabetes and HCV patients than in those without HCV (HCV−). The risk was 2.0 and 1.8 times as great for patients younger than 50 years and those infected within 4 years of their diabetes diagnosis, respectively.8 The presence of diabetes may therefore be a strong indication for antiviral treatment. A study from Taiwan demonstrated that patients treated for HCV infection had a significant 84% reduction in the risk of ESRD, a significant 47% reduction in the risk of ischemic stroke, and a non-significant 36% reduction in the risk of acute coronary syndromes.9
HCV and hemodialysis
HCV has long been a challenge for nephrologists because of the risk of transmission of this blood-borne virus in hemodialysis (HD) centers. HCV prevalence among HD patients has been falling in many countries, but overall it remains higher than in the general population. Prevalence also varies across the world: from less than 5% in northern Europe, Canada, Australia and New Zealand, to 8% to 16% in the United States, Southern Europe, and Japan, and up to 70% in some African, South American, and Asian countries.10, 11
One explanation for the decline in nosocomial HCV transmission is the implementation by dialysis centers of universal infection control precautions, as recommended by Kidney Disease Improving Global Outcomes (KDIGO) guidelines.12 During ERA-EDTA 2016, Nejra Prohić, MD, of University Clinical Centre, Sarajevo, Bosnia and Herzegovina, reported that strict adherence to infection control procedures resulted in a decline in the incidence of HCV among in-center dialysis patients, from 0.55% in 2006 to 0.15% in 2015.13 A second study presented during ERA-EDTA 2016 by Boris Bikbov, MD, of the A.I. Evdokimov Moscow State University of Medicine and Dentistry, Moscow, Russian Federation, also reported a fall in seroconversion rates in patients starting dialysis, from 2.7 events per 100 patient-years in 2004–2008 to 2.2 events per 100 patient-years in 2009–2013.14
HD patients are at increased risk of death compared with the age-matched general population,15 and chronic HCV infection worsens this already poor prognosis. A meta-analysis of 14 studies concluded that HCV infection independently predicts a significant 1.35, 1.26, and 3.82 times increased relative risk for all-cause mortality, cardiovascular death, and liver disease-related death, respectively, in adjusted analyses.16 These adverse outcomes are most likely due to HCV-associated inflammation and the cumulative cardiovascular effects of the combination of ESRD and HCV.
HCV may also be a factor in the cognitive impairment that occurs more frequently in HD patients than in the general population.17 In a study presented during ERA-EDTA 2016, severe impairment on the Mini-Mental State Examination was more frequent in HCV+ HD patients compared with matched HCV- controls: 10 of 22 (45.4%) versus 3 of 23 (13%). HCV+ patients also had significantly greater impairment on visual attention and psychomotor speed scores, and borderline significant impairment on working memory scores. According to Mohammed Ibrahim, MD, of Ain Shams University in Cairo, Egypt, these findings may reflect subclinical encephalopathy in HCV+ HD patients, suggesting that treatment to clear the virus should be initiated early after the infection is detected.18
HCV and kidney transplantation
HCV eradication is recommended before kidney transplantation, but few waitlisted patients currently receive treatment,10 and they are consequently at higher risk of death and graft loss after transplantation. In a Swedish study that includes 571 kidney and kidney-transplant recipients, HCV significantly reduced patient and graft survival. HCV remained an independent risk factor for lower patient and graft survival after adjusting for sex, previous transplant history, and time in RRT.19 Although cardiovascular disease was the main cause of death in this study, post-transplant immunosuppression also adversely influenced viremia, increasing the risks of infection and septicemia.
Another reason for the lower patient and graft survival seen in HCV+ recipients may be their increased risk of new-onset glomerulonephritis after transplantation. In a study, this complication developed in 15 (34%) HCV+ patients at a mean of 47 months compared with only 8 (6.6%) of 121 HCV− patients at a mean of 60 months, a significant difference between the groups. The HCV+ group also had significantly impaired graft survival. In contrast, the incidence of recurrent primary glomeronephritides was significantly higher in HCV− patients (29% vs. 6.8% in HCV+ patients).20
HCV after transplantation is also associated with a higher risk of post-transplant diabetes mellitus (PTDM), a well-recognised risk factor for reduced patient and graft survival.21 A systemic review of 10 studies in which the adjusted odds ratio of PTDM in HCV+ patients was 3.97.22 While no prospective study has investigated the impact of pre-transplant HCV clearance on the incidence of PTDM, retrospective reports suggest that treatment could reduce the risk of this potentially serious complication.23,24
During a presentation at ERA-EDTA 2016, I reminded delegates that, compared with remaining on the waiting list, kidney transplantation improves survival in HCV+ patients.25 Therefore, HCV has not been seen as a contraindication to kidney transplantation although treatment options were limited especially after transplantation. Recent advances in treatment have changed this as it is potentially feasible to eradicate the virus after transplantation in nearly all patients.
Over the last 20 years, there has been a dramatic improvement in sustained virologic response (SVR) or cure rates of HCV, rising from 7%–10% with interferon to 40%–50% with pegylated interferon and ribavirin, and to more than 90% with interferon-free combinations of direct-acting antiviral drugs (DAAs). As a result, HCV has become the first chronic viral infection to be cured by medical therapy in most patients.1 According to David Roth, MD, of the University of Miami Miller School of Medicine, despite advances in treatment, there remains a high unmet need among HCV+ renal patients. Of the 49,762 HD patients included in the international Dialysis Outcomes and Practice Patterns (DOPPS) study, 9.5% were HCV+, but only 1% of 4,589 patients with prescription data and 3.7% of waitlisted patients were receiving antiviral medication.10
Dr Roth explained that SVR rates reported in recent clinical trials in the general population have been achieved by targeting different parts of the HCV genome with fixed-dose DAA combinations, such as elbasvir-grazoprevir, ledipasvir-sofosbuvir, and paritaprevir-ombitasvir-ritonavir (with or without dasabuvir). With the exception of sofosbuvir, these drugs are cleared by the liver. In the observational, prospective HCV-TARGET study, sofosbuvir-containing regimens achieved SVR in 82% to 83% of patients with an estimated glomerular filtration rate (eGFR) of 45 mL/min/1.73 m2 or less and HCV genotype 1 regardless of renal function. However, anemia, worsening renal function, and serious adverse events (AEs) occurred more frequently regardless of ribavirin use.26
Although paritaprevir has not been well studied in patients with an eGFR below 15 mL/min/1.73 m2 and in HD patients, no dosage adjustments are recommended in mild to severe renal impairment.27 Dr Roth reported that in the open-label RUBY-1 trial, paritaprevir-ombitasvir-dasabuvir (with ribavirin in HCV genotype 1a and without ribavirin in HCV genotype 1b) achieved SVR in 18 of 20 patients with an eGFR of 30 mL/min/1.73 m2 or less. AEs were primarily mild or moderate, and no patient discontinued treatment due to an AE. Ribavirin therapy was interrupted due to anemia in 9 patients, 4 of whom received erythropoietin.28
Renal function does not influence the dosage of the fully oral, ribavirin-free combination of elbasvir-grazoprevir. The prospective C-SURFER trial randomized 224 patients with an eGFR below 30 mL/min/1.73 m2 and HCV genotype 1 to receive either immediate treatment with elbasvir-grazoprevir (111 patients) or deferred treatment (113 patients), with 11 patients assigned to intensive pharmacokinetic investigation. Dr Roth commented that C-SURFER patients were typical of those seen in clinical practice: 76% were HD dependent, 52% had HCV genotype 1a, 80% were HCV-treatment naïve, and 6% had cirrhosis. After 12 weeks treatment, SVR was 99% in the combined immediate-treatment and intensive pharmacokinetic group, with 1 relapse 12 weeks after the end of treatment. The most common AEs were headache, nausea, and fatigue, which occurred at similar frequencies in patients receiving active treatment and placebo.29
Presenting further C-SURFER data during the ERA-EDTA congress, I reported that at entry to the study, 11.7% of patients with HCV genotype 1a had NS5A resistance-associated variants (RAVs). These are known to impair treatment response in regimens that include an NS5A inhibitor such as elbasvir, but the effect on SVR was modest at 84.5% versus 100% in patients without baseline RAVs. Pharmacokinetic analysis confirmed that elbasvir-grazoprevir does not require dose adjustment in HD patients. Compared with placebo, active treatment had a generally positive effect on health-related quality of life, with trends towards improvements from baseline in physical component summary and health domain scores. The exception was social functioning, role limitations: emotional and mental component summary.30
Current KDIGO HCV guidelines, published in 2008, do not take into account the availability of DAA combinations. Dr Roth advised delegates that treatment recommendations for HCV+ patients with renal impairment are available from the American Association for the Study of Liver Disease (AASLD). Depending on HCV genotype, elbasvir-grazoprevir, paritaprevir-ombitasvir-dasabuvir or pegylated interferon and dose-adjusted ribavirin are recommended for patients with creatinine clearance less than 30 mL/min for whom the urgency to treat is high and kidney transplantation is not an immediate option.31
The latest guidelines from the European Association for the Study of the Liver (EASL) recommend an interferon-free and preferably ribavirin-free regimen, which should if possible be given to potential kidney transplant candidates before wait listing.32 According to Dr Roth, the differences between the US and European guidelines reflect the availability of DAAs: while elbasvir-grazoprevir is approved in the United States, it not yet available in Europe (though the European Medicines Agency issued a positive opinion in May 2016). However, both the AASLD and EASL strongly recommend HCV eradication in transplant candidates to avoid the surge in viral replication in patients receiving induction therapy and potent maintenance immunosuppression.
In a recent statement, the ERA-EDTA described patients with CKD stages 4–5 as a priority group for treatment with DAAs, but suggested that in the DAA era, treatment could be postponed until after transplantation if this enables earlier transplantation with an HCV+ donor kidney.33 Dr Roth agreed that a deceased-donor HCV+ kidney transplant could significantly reduce waiting time—for example, from 3 to 5 years to a few months at his own center—and avoid the AEs that an HCV+ kidney recipient would experience by remaining on dialysis. However, HCV+ patients are at higher risk of complications in the early post-transplant period. Vigilant and frequent post-transplant monitoring by nephrologists is also essential because of potentially serious drug-drug interactions between DAAs and immunosuppressant drugs, especially the calcineurin inhibitors.
Dr Roth advised delegates that, based on published experience in liver transplantation, the first consideration in HCV+ kidney transplant candidates is an accurate assessment of the extent of their liver disease. If the patient does not have cirrhosis and has a living donor, it may be appropriate to eradicate HCV before transplantation. In the absence of a living donor, patients have the choice of receiving an HCV+ kidney following post-transplant treatment to achieve SVR or of undergoing HCV eradication before transplantation and accepting the longer waiting time for an HCV− donor kidney.34
In Dr Roth’s opinion, the DAA era raises important questions for nephrologists. There is accumulating evidence that DAAs effectively eradicate HCV after kidney transplantation,35 but the logistics of identifying HCV genotype in an RNA-positive donor might be challenging for some transplant centres. The outcomes of HCV+ transplantation compared with receiving a non-infected donor kidney are not well studied, and there is potential for super-infection if the recipient has a different HCV genotype from that of the donor. The latter risk may, however, be reduced by limiting HCV+ donor organs to recipients with the majority genotype within the local population; for example, genotype 1 in Europe and the US.36 There are also ethical issues, especially if an HCV+ kidney is offered to an HCV− recipient. Nephrologists must be confident that they will be able to cure HCV post-transplant and, to ensure fully informed consent, patients must be educated about the risks as well as benefits.
The availability of DAAs offers the opportunity for successful eradication of HCV in renal patients before and after kidney transplantation, but this raises important questions for nephrologists, transplant centers, and healthcare systems. There has been criticism of the acquisition costs of curative DAA therapy, but Dr Roth noted that these are comparable to the costs of novel palliative oncology therapies, and DAAs have been judged cost effective in health technology assessment.37 New KDIGO HCV guidelines are urgently needed, but in the meantime, given the potential benefits for renal patients of HCV eradication, nephrologists must become involved in decisions about patient selection for DAA therapy.
Annette Bruchfeld, MD, PhD, is Associate Professor, Karolinska Institute, Department of Renal Medicine, Karolinska University Hospital, Sweden, and Scientific Secretary, Swedish Society of Nephrology . Sue Lyon, a freelance medical writer in London, UK, assisted in the preparation of the manuscript.
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