Generic Sofosbuvir-based Direct-acting Antivirals in Hepatitis C Virus-infected Patients With Chronic Kidney Disease

Manoj Kumar; Suman L. Nayak; Ekta Gupta; Ashish Kataria; Shiv K. Sarin


Liver International. 2018;38(12):2137-2148. 

In This Article


Chronic hepatitis C virus (HCV) infection worsens outcomes in patients at every stage of chronic kidney disease (CKD).[1] In addition, clearing HCV in this population may improve their quality of life and would decrease the risk of nosocomial transmission in dialysis units.[2]

Recently, there have been major advancements in the treatment of HCV with the development of new direct-acting antivirals (DAAs). Among the currently approved DAAs, sofosbuvir, an NS5B polymerase inhibitor, is the only DAA which has significant renal elimination. The other currently approved DAAs, simeprevir, ledipasvir, daclatasvir, paritaprevir/ritonavir, ombitasvir, dasabuvir, grazoprevir and elbasvir are not renally eliminated and thus do not need dose adjustment in advanced chronic kidney disease (CKD stage 4 or 5 with an e-GFR <30 mL/min or those on dialysis).

Sofosbuvir requires no dosage adjustments are suggested for mild to moderate renal impairment. In 1 single 400 mg sofosbuvir study in non-HCV-infected patients, the area under curve (AUC) for sofosbuvir and its inactive metabolite GS-331007 was 171% and 451% higher in patients with severe renal impairment.[3,4] The potential toxicity of these elevated drug and metabolite levels in humans remains unknown; however, premarket animal testing has raised concerns regarding cardiovascular and hepatobiliary toxicity at higher levels of sofosbuvir dosing.[3]

However, a reduced adjusted dose based on renal clearance might also lead to subtherapeutic exposure for risk of treatment failure.

There is scant clinical data on use of sofosbuvir in HCV patients with severe kidney impairment (estimated GFR <30 mL/min) or those on intermittent haemodialysis There have been a few case reports and series on use of sofosbuvir-based therapy (in combination with ribavirin, ribavirin and peg-interferon, simeprevir, simeprevir and ribavirin, ledipasvir or daclatasvir), with varying doses of sofosbuvir (including 400 mg daily, 400 mg alternate day, 400 mg thrice weekly or 200 mg daily).[6–15]

Generic sofosbuvir was approved in India in March 2015. Generic sofosbuvir and ledipasvir combination, and daclatasvir were approved in India in December 2015. There has been some controversy concerning the bioequivalence of generics when compared to brand name agents[16,17] and the safety and efficacy data for generic DAAs are scanty and inconclusive,[18–20] with no data in CKD patients.

The aim of this study was to study the efficacy and safety of full-dose sofosbuvir in combination with ribavirin, ledipasvir or daclatasvir, using generic versions, in HCV-infected patients with CKD including patients with advanced CKD (CKD stage 4 or 5 with an estimated GFR <30 mL/min or those on dialysis).