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


In this study, we report our experience of full-dose sofosbuvir-based antiviral therapies using generics in HCV-infected patients with CKD including advanced CKD (CKD stage 4 or 5 with an e-GFR <30 mL/min or those on dialysis).

In this study, we found that SVR at 12 weeks was seen in 100% of the patients in all the 3 groups (sofosbuvir plus ribavirin for 6 months for both genotype 1 and 3, sofosbuvir plus ledipasvir for 3 months for genotype 1, and sofosbuvir plus daclatasvir for 3 months for genotype 3). At 24 weeks of follow-up after end of therapy, 1 patient in sofosbuvir plus ledipasvir group became HCV RNA positive; and at 48 weeks of follow-up after end of therapy, 1 patient in sofosbuvir plus ribavirin group became HCV RNA positive. Whether this late reappearance of HCV RNA represents relapse or reinfection is difficult to ascertain [although the patient on sofosbuvir and ribavirin was on regular dialysis after stopping treatment, whereas the other patients was not on dialysis after stopping of treatment], given the lack of sequence analysis data [although the genotype was same as pretreatment in both the patients]. There are reports suggesting that reappearance of HCV RNA years after a SVR can be from relapse of the initial viral infection rather than reinfection from a different virus.[22,23]

There are few published full length papers on the use of sofosbuvir based therapy in HCV in CKD including patients with advanced CKD (CKD stage 4 or 5 with an e-GFR <30 mL/min or those on dialysis) (Table 5).

In our study, sofosbuvir-ribavirin regimen was as efficacious as sofosbuvir/ledipasvir or sofosbuvir/daclatasvir regimens. This may be because of the fact that our cohort of patients treated with sofosbuvir and ribavirin had factors predictive of good SVR. Prior studies have identified female sex, absence of cirrhosis, younger age (age<50 years) and a low viral load at baseline (less than 6 log10 IU per millilitre) as predictors of a sustained virologic response to both sofosbuvir-ribavirin regimens and interferon-based treatment.[24,25] In our study, in the sofosbuvir plus ribvirin group, 84.6% of patients did not have cirrhosis, 46.2% had HCV RNA less than 6 log10 IU per millilitre and 57.7% had age less than 50 years.

In this study, overall there was no significant change in median e-GFR up to 12 weeks after stopping therapy among the 11 patients who were not on maintenance haemodialysis. In 2 patients (both treated with sofosbuvir and ribavirin for 24 weeks), there was increase in serum creatinine of >0.3 mg/dL at end of therapy from the baseline. In 1 patient there were other precipitating factors, while in other one, there was no clear precipitating factor. Previous studies have reported heterogeneous results as regards to worsening of renal function during use of sofosbuvir containing regimens in CKD patients with HCV infection. In the study by Saxena et al, in which sofosbuvir was used in full dose (in combination with ribavirin, or ribavirin and pegylated interferon, or simprevir, or simeprevir and ribvirin) 11 of 73 (15%) developed worsening of renal function among patients with e-GFR ≤45 as compared to 18 of 1716 (1%) among patients with e-GFR >45.[8] In another study of 6 patients with baseline e-GFR ≤30 mL/min/1.73 m2 undergoing treatment with full-dose sofosbuvir (in combination with simeprevir or ribavirin], 1 patient (17%) experienced worsening renal function that was deemed unrelated to treatment.[12] Two other studies using full-dose sofosbuvir in CKD patients (in combination with ribavirin, or ribavirin and peg-interferon, or daclatasvir, or daclatasvir and ribavirin, or simeprevir, or simeprevir and ribavirin), kidney function remained stable among patients not on dialysis.[9,14] However, the concern still remains whether sofosbuvir could worsen the renal function in ESRD patients, given the limited number of not dialysed cases and the absence of a control group (ESDR patients treated with regimens not containing sofosbuvir) in our study.

This study used generic versions of all the 3 drug combinations (sofosbuvir/ribavirin, sofosbuvir/ledipasvir and sofosbuvur/daclatasvir) and showed excellent SVRs. In September 2014, U.S. drug maker Gilead Sciences Inc had licensed its hepatitis C drug sofosbuvir (Sovaldi) to 7 India-based drugmakers.[26] Sofosbuvir/ledipasvir combination and daclatasvir was approved for use by the Drug Controller General of India (DCGI) in December 2015. List pricing of generic versions of sofosbuvir is around 825 US$ for 12 weeks supply in India (vs US$ 50 368 in UK and US$ 84 000 in the USA).[27] In India, the list price is also much lower for generic versions of sofosbuvir/ledispasvir combination (1152 US$ for 12 weeks supply vs US$ 56 123 in UK and US$ 94,500 in the US),[27] and daclatsvir (275 US$ for 12 weeks supply vs 63 000 US$ in USA and 13000 US$ in UK.[28,29]

There have been some studies on use of generic DAAs in HCV-infected patients, but none in CKD patients. In the recent Australian REDEMPTION study (n = 412) using DAA HCV therapy in non-CKD patients, accessed through the Fix HepC website, outcomes were equivalent to those using branded treatments at one-hundredth the cost.[20] In another study from China in non-CKD patients, 63 cirrhotic (group 1) and 65 non-cirrhotic (group 2) patients were administered generic ledipasvir-sofosbuvir plus 1000-1200 mg of ribavirin daily for 12 and 8 weeks respectively; and 64 non-cirrhotic patients (group 3) received ledipasvir-sofosbuvir for 8 weeks. Intention-to-treat analysis revealed excellent SVR 12 rates [96.8% (61/63), 96.9% (63/65) and 96.9% (62/64) in groups 1, 2 and 3 respectively].[18] However, in 1 study from Qatar in non-CKD patients, 399 patients were treated (with sofosbuvir/ribavirin, sofosbuvir/daclatasvir, sofosbuvir/simeprevir or sofosbuvir/peg-interferon/ribavirin) and 33.1% were treated with branded and 66.9% with the generic drugs. The overall response was slightly inferior for generic (72%) compared to the branded (87%).[19] In another recent study among 616 HCV-infected patients, reporting on efficacy of generic versions of sofosbuvir, ledipasvir and daclatasvir from suppliers in India, Bangladesh, China and Egypt via 3 buyers' clubs (Australian buyers' clubs, South-east Asian buyers' clubs and an Eastern European buyers' club), found SVR12 in 99% of patients evaluated to date.[30]

Despite promising results, our study has few limitations. The first one is that evaluation of patient subgroups according to fibrosis stage was not done. Although liver stiffness was measured (using Fibroscan) in these patients (data not shown), this method has not been validated in CKD patients including ESRD. Also, whether sofosbuvir containing regimens lead to decline in renal function in patients who are not on maintenance dialysis, could not be answered; as such a question needs a randomized controlled trial among CKD patients not on maintenance dialysis treated with sofosbuvir-containing and sofosbuvir-free regimens. Also levels of sofosbuvir and its metabolites were not measured in this study.