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Hepatitis C and end-stage renal disease

Issue: July 2015

ByCatherine T. Frenette, MD

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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.

It has been well-shown that HCV positive patients with end-stage renal disease (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 for death, especially with coexisting diabetes. After kidney transplantation, the risk for 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 for graft rejection and potential graft loss. Sustained virologic response (SVR) rates for interferon-based therapies in this patient population have been reported ranging from 13% to 75%.

The use of new direct-acting antivirals (DAA) in the setting of severe renal disease, ESRD and hemodialysis is currently under investigation. Currently, 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.

Simeprevir

The elimination of Olysio (simeprevir, 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/minute or in patients on hemodialysis.

Sofosbuvir

Sovaldi (Sofosbuvir, 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 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/minute 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/minute. In clinical trials, it appears that dosing is also unchanged for patients on hemodialysis.

DAAs not approved yet

Studies are ongoing for daclatasvir/asunaprevir/beclabuvir (Bristol Myers Squibb), GS-5816 (Gilead Sciences) and grazoprevir/elbasvir (Merck). As of now, it appears that dose adjustments will not be required for GS-5816 or grazoprevir/elbasvir in patients with severe renal impairment or on dialysis. For the daclatasvir/asunaprevir/beclabuvir combination, patients on hemodialysis will likely require daily dosing rather than twice-daily dosing. Daclatasvir as a single compound can be given to patients with renal failure with standard dosing.

EASL 2015 data

At the European Association for the Study of the Liver Annual Meeting in April, Paul J. Pockros, MD, director of the Liver Disease Center of the division of gastroenterology/hepatology at Scripps Clinic, presented the RUBY-1 data, where 14 patients with severe renal impairment or ESRD were treated with ombitasvir, paritaprevir/ritonavir and dasabuvir for 12 weeks, in combination with ribavirin dosed at 200 mg daily in patients with genotype 1a. Genotype 1b patients received the three DAAs without ribavirin. All patients were treatment naive, and no patients with cirrhosis were enrolled in this cohort. Patients also had to have a hemoglobin of at least 10 g/dL. Preliminary safety results were presented. Ribavirin was dosed 4 hours prior to the start of hemodialysis, and hemoglobin was checked weekly for the first month. Ribavirin was interrupted for a decrease of hemoglobin greater than 2 g/dL in less than 4 weeks or a hemoglobin value less than 10 g/dL. The patients (mean age, 60 years) were 85% men, 70% black, with a median viral load of 6.6 log10 IU/mL. Sixty-five percent were genotype 1a, and 65% were on dialysis, with the remaining having a CrCl of 15 mL/minute to 30 mL/minute.

No serious adverse events occurred that were related to the renal system. Two patients experienced serious adverse events: one with diskitis and respiratory failure, and the other with a small bowel obstruction. Neither of these serious adverse events was deemed to be treatment related. There were no study drug discontinuations. Eight of 13 patients required ribavirin interruption while on treatment, and one patient had a hemoglobin less than 8 g/dL, but no patients required blood transfusion. All patients rapidly suppressed viral loads on treatment, with only three of 14 having detectable virus by week 4, and all patients were viral-negative by week 8. Ten patients so far have reached week 4 post treatment, and all patients achieved SVR4. Two patients have reached SVR12 thus far.

Sofosbuvir plus simeprevir

Two abstracts at EASL reported treatment with sofosbuvir/simeprevir in patients with severe renal impairment or on dialysis.

Frank Czul, MD, of the University of Miami Miller School of Medicine, and colleagues treated 18 patients with genotype 1 HCV (n = 11, 1a; n = 7, 1b) who were on dialysis (n = 15) or who had CrCl less than 30 mL/minute (n = 3). Ten patients had cirrhosis. Seventeen received 12 weeks of treatment, and one was extended to 24 weeks of therapy because of low-level viremia at week 4. All patients received full-dose simeprevir. Sofosbuvir was reduced to 200 mg daily in 15 patients and 400 mg every other day in three patients. Sixteen patients were HCV RNA negative at week 4, and all patients were negative by week 8.

There were two hospitalizations, one for hepatic encephalopathy and one for uncontrollable diarrhea. There were no treatment discontinuations. Sixteen patients completed treatment, and nine patients reached relevant milestones. SVR4 was seen in 91%, and SVR12 in 89%. One cirrhotic patient who was a prior protease inhibitor failure relapsed within 4 weeks after completion of the treatment.

Hector E. Nazario, MD, transplant hepatologist at Methodist Dallas Medical Center, also presented data on 12 patients treated with sofosbuvir/simeprevir with ESRD on hemodialysis (n = 11) or an estimated glomerular filtration rate (eGFR) less than 30 mL/minute (n = 1). All received sofosbuvir 400 mg daily (full dose) and simeprevir 150 mg daily, for 12 weeks. Of these, 58% had cirrhosis. Eight patients have completed the course of therapy. There were no treatment discontinuations or hospitalizations. Seven patients have achieved SVR4, which is 100% of patients who have reached that milestone, and five patients who have reached 12 weeks post-treatment have all achieved cure.

Ledipasvir plus sofosbuvir

No abstracts were presented using the combination of ledipasvir and sofosbuvir (Harvoni, Gilead Sciences) in patients with ESRD or on dialysis. However, the FDA recently approved a small pilot study of ledipasvir and sofosbuvir in 15 patients with an eGFR of less than 30 mL/minute.

Grazoprevir plus elbasvir

David B. Roth, MD, PhD, Simon Flexner Professor of Pathology and Laboratory Medicine at the University of Pennsylvania Perelman School of Medicine, presented the C-SURFER study, of grazoprevir and elbasvir in patients with chronic kidney disease or on dialysis. This large study enrolled 116 patients, of whom 75% were on dialysis and 83% were treatment naive. There were no significant treatment-related adverse events, and no patient discontinued treatment due to adverse events. After 12 weeks of treatment with these two DAAs, 99% achieved SVR. The FDA has recently awarded breakthrough status for this regimen for treatment of hepatitis C in patients with ESRD.

GS-5816

GS-5816 is a potent pangenotypic NS5A inhibitor that is still under investigation, but appears very promising as a shorter duration of treatment for patients with HCV. An abstract was presented of the pharmacokinetics of this compound in patients with severe renal impairment. Ten patients with CrCl less than 30 mL/minute received GS-5816 100 mg with subsequent pharmacokinetic sampling. There was a 50% increase in the AUC observed in patients with severe renal disease compared with healthy controls, and peak levels were similar. There was no change in protein binding observed. This compound appears to not require dose adjustments in patients with severe renal impairment.

Daclatasvir/asunaprevir/beclabuvir

Daclatasvir/asunaprevir/beclabuvir is a fixed-dose combination of three DAAs currently under phase 3 investigation. A pharmacokinetics study was presented in 41 patients with varying degrees of renal insufficiency and failure. In patients with CrCl greater than 30 mL/minute or in patients who are on hemodialysis, standard dosing of this compound did not result in any significant increase in the AUC, and dose adjustments are not required. In patients with CrCl less than 30 mL/minute but who are not yet on dialysis, dosing is recommended to be daily rather than twice daily. The compound was well tolerated, although one patient had to discontinue due to an increase in uric acid levels that were thought to be drug related.

Conclusions

Treatment of HCV in patients with severe renal failure or ESRD remains a difficult prospect. These patients are at increased risk for complications related to their hepatitis C, and treatment is imperative, especially for those patients who are waiting for kidney transplantation. All of the DAAs are being studied currently in this patient population, and hopefully we will have treatment options for these patients in the near future. Ribavirin remains difficult to use, but there remains promise that we will be able to offer SVR in this patient population with the same tolerability and efficacy as is seen in other populations.

• References:
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• For more information:
• Catherine T. Frenette, MD, is the medical director of liver transplantation at the Scripps Center for Organ Transplantation. She can be reached at Scripps Green Hospital, 10666 N. Torrey Pines Rd N200, La Jolla, CA 92037; email: Frenette.Catherine@scrippshealth.org.

Disclosure: Frenette reports she is on the speakers bureau for and owns stock in Gilead Sciences.