Treatment of HCV in people with renal impairment
Hepatitis C is associated with intrinsic renal disease, including cryoglobulinaemia and glomerulonephritis.88 People with renal impairment should be investigated to determine the underlying cause and managed appropriately. Those with severe acute vasculitic manifestations may require immunosuppressive therapy, including anti-CD20 antibody therapy and/or plasma exchange. In addition, the prevalence of anti-HCV antibodies is higher in patients requiring haemodialysis compared with the general population.
Management of HCV in individuals with renal impairment is complicated by renal clearance of drugs including sofosbuvir and ribavirin, as well as the complications and treatment of the intrinsic renal disease, including drug–drug interactions.89,90 People with moderate–severe renal impairment (eGFR < 50 mL/min/1.73 m2 ) should be referred to specialist centres for consideration of antiviral therapy.
People with mild–moderate renal impairment (eGFR, 30–80 mL/min/1.73 m2 )
For people with mild to moderate renal impairment (eGFR, 30–80 mL/min/1.73 m2 ), no dose adjustment is required for sofosbuvir, ledipasvir, paritaprevir–ritonavir, ombitasvir, dasabuvir or daclatasvir. Ribavirin is renally excreted and cannot be removed by dialysis. Ribavirin accumulates in the setting of renal impairment with creatinine clearance < 50 mL/min and can cause severe anaemia.91 The product information recommends that ribavirin should not be used in individuals with an eGFR < 50 mL/min/1.73 m2 . In specialist centres, ribavirin-containing regimens may be considered for those with an eGFR < 50 mL/min/1.73 m2 . In this setting, ribavirin therapy should be started at a low dose, with close monitoring of haemoglobin levels. Recommended ribavirin dose according to eGFR is: > 50 mL/min/1.73 m2 , no dose adjustment; 30–50 mL/min/1.73 m2 , alternating doses of 200 mg and 400 mg every other day; < 30 mL/min/1.73 m2 , 200 mg daily; haemodialysis, 200 mg pre-dialysis.
People with severe renal impairment (eGFR < 30 mL/min/1.73 m2 or haemodialysis)
Drugs that are primarily metabolised by the liver can be used in people with severe renal impairment and in those receiving haemodialysis; drugs excreted by the kidneys should be avoided or the dose regimen modified. Paritaprevir–ritonavir, ombitasvir and dasabuvir are all cleared by hepatic metabolism and can be used in individuals with severe renal disease. The efficacy of this regimen was demonstrated in the RUBY-1 study, a small, open-label, Phase IIIb study that enrolled 20 patients with Gt 1 HCV and no cirrhosis with an eGFR < 30 mL/min/1.73 m2 (including patients receiving haemodialysis).92 All patients had a baseline haemoglobin level > 100 g/L. People with Gt 1a HCV infection (n = 13) were treated with PrOD plus ribavirin (200 mg daily for patients not on haemodialysis; 200 mg 4 hours before dialysis for patients on haemodialysis), and people with Gt 1b HCV infection (n = 7) were treated with PrOD alone. Of 19 patients with post-treatment data, 18 (95%) achieved SVR. Overall, treatment was well tolerated, but ribavirin dose interruption was required for management of anaemia in most patients receiving ribavirin 200 mg daily.
Daclatasvir93 is also hepatically cleared, but is used in combination with sofosbuvir and therefore cannot be recommended. Sofosbuvir is renally excreted and there are limited safety data on its use in people with severe renal impairment. The registration studies for sofosbuvir-containing regimens excluded patients with an eGFR < 30 mL/min/1.73 m2 . Pharmacokinetic studies of a single 400 mg dose of sofosbuvir resulted in an increased area under the curve of 171% for sofosbuvir and 451% for its inactive metabolite (GS-331007), which is excreted exclusively by the kidneys. Studies in people with severe renal impairment or receiving haemodialysis are ongoing to determine dosing recommendations.
Clearance of pegIFN is reduced and overall exposure increased in proportion to the degree of renal dysfunction. Haemodialysis has little effect on clearance. In patients with an eGFR < 30 mL/min/1.73 m2 or receiving haemodialysis, the dose of peginterferon alfa-2a should be reduced to 135 μg weekly and further reduced to 90 μg weekly if adverse events occur.
The treatment of HCV continues to evolve. A number of sofosbuvir-free and ribavirin-free regimens are in clinical development for the treatment of people with moderate to severe renal impairment. The combination of the NS3 protease inhibitor grazoprevir and the NS5A inhibitor elbasvir has recently completed Phase III development. Both drugs are hepatically cleared. The C-SURFER study enrolled patients with Gt 1 HCV who had severe renal impairment (Stage 4 or 5), including 17% in whom treatment with pegIFN plus ribavirin had previously failed. A small number of people with cirrhosis were enrolled (n = 14 [6%]). SVR was 99% (115/116, modified full analysis set), and treatment was well tolerated.94 A TGA/PBAC application for this regimen has been submitted, and it is expected it will be listed on the PBS late in 2016. It is reasonable to consider deferring therapy pending the availability of this regimen for patients who would otherwise require treatment with a ribavirin-containing regimen.