Special populations: treatment of HCV in people with renal impairment
Hepatitis C is associated with intrinsic renal disease, including cryoglobulinaemia and glomerulonephritis.101 People with renal impairment should be investigated to determine the underlying cause and managed appropriately. Those with severe acute vasculitic manifestations may require immunosup- pressive 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. 102,103 People with moderate–severe renal impairment (eGFR < 50 mL/min/1.73 m 2 ) should be referred to specialist centres for consideration of antiviral therapy.
People with mild–moderate renal impairment (eGFR, 30–80 mL/min/1.73 m 2)
For people with mild to moderate renal impairment (eGFR, 30–80 mL/min/1.73 m 2 ), no dose adjustment is required for sofosbuvir, ledipasvir, paritaprevir– ritonavir, ombitasvir, dasabuvir, daclatasvir, elbasvir or grazoprevir. Ribavirin is renally excreted and can- not be removed by dialysis. Ribavirin accumulates in the setting of renal impairment with creatinine clearance < 50 mL/min and can cause severe anaemia.104 The product information recommends that ribavirin should not be used in individuals with an eGFR < 50 mL/min/1.73 m 2 . In specialist centres, ribavirin-containing regimens may be considered for those with an eGFR < 50 mL/min/1.73 m 2 . 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 m 2 , no dose adjustment; 30–50 mL/min/1.73 m 2 , alternating doses of 200 m and 400 mg every other day; < 30 mL/min/1.73 m 2 , 200 mg daily; haemodialysis, 200 mg pre-dialysis.
People with severe renal impairment (eGFR < 30 mL/min/1.73 m 2 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. Sofosbuvir is renally excreted and there are limited safety data on its use in people with severe renal impairment. 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, in people with an eGFR < 30 mL/min/1.73 m2. Sofosbuvir is not recommended in people with an eGFR < 30 mL/min/1.73 m2. As noted above, severe renal impairment necessitates a significant dose reduction for ribavirin. Ribavirin should only be used in this setting under the supervision of a specialist with experience in treating HCV infection in people with severe renal impairment.
Elbasvir and grazoprevir are cleared by hepatic metabolism and can be used in people with severe renal impairment. The efficacy of this regimen in people with chronic kidney disease (eGFR < 30 mL/min/1.73 m2, with or without haemodialysis requirements) was evaluated in a large Phase III randomised study,45 in which 224 people with chronic Gt 1 HCV infection were randomly assigned to immediate or deferred therapy with elbasvir and grazoprevir. The deferred treatment arm provided a placebo comparator to the immediate treatment arm. Ribavirin was not used, despite 52% of the cohort being infected with Gt 1a HCV. In the immediate treatment arm, the SVR rate was 94.3% in the full analysis set. The SVR rate was 99.1% in a modified analysis set that excluded patients who discontinued treatment for reasons that were not related to virological failure. Adverse events were frequent in this population with significant comorbidities, but were comparable between the immediate and deferred treatment groups (76% v 84%). People with Gt 1a or Gt 1b HCV, as well as those with Gt 4 HCV infection, who have severe renal impairment (eGFR < 30 mL/min/1.73 m2) or end-stage renal disease, including patients receiving dialysis, should be treated with elbasvir plus grazoprevir without ribavirin.45
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-I 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).105 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. More recent data from the RUBY-II study suggest that ribavirin is not necessary in people with Gt 1a HCV and severe renal impairment who are treated with PrOD. In 13 patients treated for 12 weeks with PrOD and no ribavirin, the SVR rate was 100%.40
Daclatasvir is also hepatically cleared,106 but is used in combination with sofosbuvir and therefore cannot be recommended.
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 mg weekly and further reduced to 90 mg 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. For people with Gt 2, 3 or 6 HCV infection, therapy should be deferred pending the availability of these regimens.