Hepatitis C is a major cause of morbidity and mortality in patients with end stage renal disease and kidney transplant candidates. The prevalence of positive HCV antibody in patients on hemodialysis ranges from 5% to 60% in developed countries, depending on other risk factors. The spread of HCV in dialysis centers is declining, but hemodialysis remains a risk factor for viral hepatitis and is included in the CDC screening guidelines as a risk factor that warrants HCV screening.

Catherine T. Frenette

It has been well-shown that HCV positive patients with ESRD have increased liver-related mortality and all-cause mortality. Patients with HCV who are on the kidney transplant wait list also have increased risk of death, especially with coexisting diabetes. After kidney transplantation, the risk of death from liver disease in someone with hepatitis C is 21%, compared to 0% if patients are not infected with hepatitis C.

Treatment has historically been difficult in this patient population. Treatment prior to kidney transplant or while on hemodialysis reduces the likelihood of HCV-related complications and death. However, use of interferon in patients who are chronically ill is fraught with complications. In addition, ribavirin is predominantly cleared renally, and in patients with ESRD the use of ribavirin can be associated with significant anemia. Treatment after kidney transplant in the interferon era was associated with a high risk of graft rejection and potential graft loss. Sustained virologic response rates for interferon-based therapies in this patient population have been reported ranging from 13% to 75%.

The use of new direct-acting antivirals in the setting of severe renal disease, ESRD and hemodialysis is currently under investigation. As of now, most of the studies have been with patients on hemodialysis rather than peritoneal dialysis. Several abstracts have been presented at national and international meetings that address the need of dosing guidance for DAAs in the setting of renal disease.

DAA Metabolism and Use in Renal Failure

Simeprevir

The elimination of simeprevir (Olysio, Janssen) occurs via biliary excretion, and renal clearance plays an insignificant role in its elimination. No dose adjustment is required for mild, moderate or severe renal impairment. Per the package insert, the safety and efficacy has not been established in patients with creatinine clearance (CrCl) below 30 mL/min or in patients on hemodialysis.

Sofosbuvir

Sofosbuvir (Sovaldi, Gilead Sciences) is metabolized in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. Dephosphorylation of this moiety results in the formation of the nucleoside metabolite GS-331007, which has no antiviral activity. This metabolite GS-331007 is cleared in the urine, and thus dose adjustments may be required in patients with ESRD. The area under the curve (AUC) of sofosbuvir is 2.7-fold higher in patients with severe renal impairment (CrCl < 30), and the AUC of GS-331007 is 5.5-fold higher than in patients without renal impairment. Per the package insert, the safety and efficacy has not been established in patients with CrCl below 30 mL/min or in patients on hemodialysis.

Ledipasvir

No detectable metabolism of ledipasvir (Gilead Sciences) is observed by the cytochrome P450 enzymes. Evidence of slow oxidative metabolism via an unknown mechanism has been observed. Ledipasvir is predominantly excreted in the feces, with renal excretion being a minor pathway. In patients with severe renal impairment, no pharmacokinetic differences were observed.

Ombitasvir, Paritaprevir/Ritonavir, and Dasabuvir

Ombitasvir is predominantly metabolized by amide hydrolysis followed by oxidative metabolism, and paritaprevir/ritonavir, and dasabuvir are metabolized by the cytochrome P450 system (Viekira Pak, AbbVie). All of these medications are predominantly excreted into the feces, with minimal renal excretion. In the package insert, dosing is unchanged for patients with CrCl above 15 mL/min. In clinical trials, it appears that dosing is also unchanged for patients on hemodialysis.

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