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.

Abstract and Introduction

Abstract

Background & Aims: There is scant data on use of sofosbuvir containing directly acting antiviral (DAA) regimens in chronic kidney disease (CKD) patients. Recently generic versions of DAAs have become available in low-income countries including India. The aim of this study was to study the efficacy and safety of generic sofosbuvir in combination with generic ribavirin, ledipasvir or daclatasvir in HCV-infected patients with CKD including patients with advanced CKD (CKD stage 4 or 5 with an estimated glomerular filtration rate (GFR) <30 mL/min or those on dialysis).

Methods: Seventy-one CKD patients (76% male, 84.5% on maintenance haemodialysis, 23.9% cirrhosis) with HCV infection were included in the study. Full-dose sofosbuvir was used in combination with ribavirin (n = 26, for 24 weeks, 69.2% genotype 1, 30.8% genotype 3), ledipasvir (n = 26, for 12 weeks, all genotype 1) and daclatasvir (n = 19, for 12 weeks, all genotype 3).

Results: Sustained virological response (SVR) (HCV RNA <12 IU/mL) at 12 weeks after stopping treatment was seen in 100% of the patients in all the 3 groups. At 24-week follow-up after end of therapy, 1 patient in sofosbuvir plus ledipasvir group relapsed. At 48-week follow-up after end of therapy, 1 more patient in sofosbuvir plus ribavirin group relapsed.

Conclusion: Full-dose sofosbuvir-based DAA therapy using generics is highly effective for individuals with HCV infection and CKD including advanced CKD (CKD stage 4 or 5 with an e-GFR <30 mL/min or those on dialysis).

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Table 1. Demographic characteristics of the patients at baseline
Characteristic	All patients	Sofosbuvir plus ribavirin	Sofosbuvir plus ledipasvir	Sofosbuvir plus daclatasvir
Number of patients	71	26	26	19
Age (Y), median (range)	42.0 (22.0–80.0)	49.0 (26.0–60.0)	38.0 (27.0–73.0)	40.0 (22.0–80.0)
Age <50 y, no. (%)	49 (69%)	15 (57.7%)	19 (73.1%)	15 (78.9%)
Male sex, no. (%)	54 (76.1)	21 (80.8)	19 (73.1)	14 (73.7)
CKD Stage, no. (%) 2/3/4/5	1 (1.4)//6 (8.5)/4 (5.6)/60 (84.5)	0 (0)/3 (11.5)/2 (7.7)/21 (80.8)	0 (0)/1 (3.8)/0 (0)/25 (96.2)	1 (5.3)/2 (10.5)/2 (10.5)/14 (73.7)
On dialysis, no.(%)	11 (15.5)	5 (19.2)	1 (3.8)	5 (26.3)
Duration of dialysis (mo), median (range)	38.0 (5.0–240.0)	38.0 (19.0–240.0)	47.0 (5.0–132.0)	37.0 (6.0–96.0)
e-GFR, mL/min/1.73 m2, median (range) [For patients not on dialysis]	34.0 (21.0–63.0)	34.0 (24.0–59.0)	44	33.0 (21.0–63.0)
History of Diabetes, no. (%)	15 (21.1)	4 (15.4)	7 (26.9)	4 (21.1)
Bilirubin (mg/dL), median (range)	0.8 (0.3–4.5)	0.7 (0.3–2.4)	0.9 (0.4–1.3)	0.8 (0.3–4.5)
AST (IU/L), median (range)	40.0 (8.0–668.0)	35.0 (8.0–80.0)	34.0 (14.0–119.0)	55.0 (18.0–668.0)
ALT (IU/L), median (range)	35.0 (7.0–1002.0)	31.0 (7.0–185.0)	29.5 (11.0–201.0)	51.0 (19.0–1002)
Alkaline phosphatase (IU/L), median (range)	169.0 (16.0–981.0)	225.0 (45.0–981.0)	164.0 (72.0–949.0)	135.0 (16.0–716.0)
Albumin (g/L), median (range)	3.5 (1.8–4.6)	3.4 (1.8–4.2)	3.5 (2.4–4.6)	3.4 (1.9–4.3)
Haemoglobin (g/dL), median (range)	10.4 (8.5–15.6)	10.8 (9.0–15.6)	10.4 (7.9–15.3)	10.4 (8.0–13.9)
Platelet count (10⁹/L), median (range)	165.0 (64.0–379.0)	172.0 (64.0–312.00	154.0 (100.0–379.0)	165.0 (75.0–322.0)
TLC (×1000 per cu mm), median (range)	6.1 (2.6–12.8)	5.8 (3.1–9.4)	6.6 (2.6–11.1)	6.0 (2.6–12.8)
HCV RNA [log10 IU/mL], median (range)	6.12 (3.0–7.84)	6.17 (3.0–7.80)	6.36 (3.59–7.67)	5.67 (3.0–7.84)
HCV RNA <6 log10 IU/mL, no. (%)	34 (47.9%)	12 (46.2%)	10 (38.5%)	12 (63.2%)
HCV Genotype, no. (%)
1/1a/1b	44 (62)/39 (54.9)/5 (7.1)	18 (69.2)/17 (65.4)/1 (3.8)	16 (100)/22 (84.6)/4 (15.4)	0/0/0
3/3a/3b	27 (38)/24 (33.8)/3 (4.2)	8 (30.8)/7 (27.0)/1 (3.8)	0/0/0	19 (100)/17 (89.5)/2 (10.5)
No cirrhosis, no. (%)	54 (76.1)	22 (84.6)	20 (76.9)	12 (63.2)
Compensated cirrhosis, no. (%)	17 (23.9)	4 (15.4)	6 (23.1)	7 (36.8)
Decompensated cirrhosis, no. (%)	0 (0)	0 (0)	0 (0)	0 (0)
Previous HCV treatment, no.(%)
No	58 (81.7)	19 (73.1)	23 (88.5)	16 (84.2)
Yes (Peg-interferon and ribavirin)	13 (18.3)	7 (26.9)	3 (11.5)	3 (15.8)
Follow-up after stopping treatment (wk), no. (%)
Up to 12 wk	71 (100)	26 (100)	26 (100)	19 (100)
Up to 24 wk	71 (100)	26 (100)	26 (100)	19 (100)
Up to 48 wk	67 (94.4)	26 (100)	24 (92.3)	17 (89.5)
Up to 72 wk	35 (49.3)	24 (92.3)	6 (23.1)	5 (26.3)
Starting dose of ribavirin (mg per week), median (range)	NA	600 (600–600)	Not applicable	Not applicable
Maximum tolerated dose of ribavirin during treatment (mg), median (range)		500 (200–1400)

ALT, Alanine transaminase; AST, Aspartate transaminase; CKD, Chronic kidney disease; e-GFR, Estimated glomerular filtration rate; HCV, Hepatitis C virus; TLC, Total leucocyte count.

Table 2. Response during and after treatment according to treatment regimens
Response	All Patients	Sofosbuvir plus Ribavirin	Sofosbuvir plus Ledipasvir	Sofosbuvir plus Daclatasvir
Number of patients	71	26	26	19
HCV RNA <12 IU/mL, at wk 4, no. (%)
Any genotype	62/71 (87.3)	23/26 (88.5)	23/26 (88.5)	16/19 (84.2)
Genotype 1a	35/39 (89.7)	15/17 (88.2)	20/22 (90.9)	Not applicable
Genotype 1b	4/5 (80.0)	1/1 (100.0)	3/4 (75.0)	Not applicable
Genotype 3a	20/24 (83.3)	6/7 (85.7)	Not applicable	14/17 (82.3)
Genotype 3b	3/3 (100.0)	1/1 (100.0)	Not applicable	2/2
HCV RNA <12 IU/mL, at end of treatment, no. (%)
Any genotype	71/71 (100.0)	26/26 (100.0)	26/26 (100.0)	19/19 (100.0)
Genotype 1a	39/39 (100.0)	17/17 (100.0)	22/22 (100.0)	Not applicable
Genotype 1b	5/5 (100.0)	1/1 (100.0)	4/4 (100.0)	Not applicable
Genotype 3a	24/24 (100.0)	7/7 (100.0)	Not applicable	17/17 (100.0)
Genotype 3b	3/3 (100.0)	1/1 (100.0)	Not applicable	2/2 (100.0)
HCV RNA <12 IU/mL, at 12 wk after stopping treatment, no. (%)
Any genotype	71/71 (100.0)	26/26 (100.0)	26/26 (100.0)	19/19 (100.0)
Genotype 1a	39/39 (100.0)	17/17 (100.0)	22/22 (100.0)	Not applicable
Genotype 1b	5/5 (100.0)	1/1 (100.0)	4/4 (100.0)	Not applicable
Genotype 3a	24/24 (100.0)	7/7 (100.0)	Not applicable	17/17 (100.0)
Genotype 3b	3/3 (100.0)	1/1 (100.0)	Not applicable	2/2 (100.0)
HCV RNA <12 IU/mL, at 24 wk after stopping treatment, no. (%)
Any genotype	70/71 (98.5)	26/26 (100.0)	25/26 (96.1)	19/19 (100.0)
Genotype 1a	38/39 (97.4)	17/17 (100.0)	21/22 (95.4)	Not applicable
Genotype 1b	5/5 (100.0)	1/1 (100.0)	4/4 (100.0)	Not applicable
Genotype 3a	24/24 (100.0)	7/7 (100.0)	Not applicable	17/17 (100.0)
Genotype 3b	3/3 (100.0)	1/1 (100.0)	Not applicable	2/2 (100.0)
HCV RNA <12 IU/mL, at 48 wk after stopping treatment, no. (%)
Any genotype	65/67 (97.0)	25/26 (96.1)	23/24 (95.8)	17/17 (100.0)
Genotype 1a	36/38 (94.7)	16/17 (94.1)	20/21 (95.2)	Not applicable
Genotype 1b	4/4 (100.0)	1/1 (100.0)	3/3	Not applicable
Genotype 3a	22/22 (100.0)	7/7 (100.0)	Not applicable	15/15 (100.0)
Genotype 3b	3/3 (100.0)	1/1 (100.0)	Not applicable	2/2 (100)
HCV RNA <12 IU/mL, at 72 wk after stopping treatment, no. (%)
Any genotype	33/35 (94.3)	23/24 (95.8)	5/6	5/5 (100)
Genotype 1a	20/22 (90.9)	15/16 (93.8)	5/6	Not applicable
Genotype 1b	1/1	1/1	0	Not applicable
Genotype 3a	11/11 (100.0)	6/6 (100.0)	Not applicable	5/5 (100)
Genotype 3b	1/1 (100.0)	1/1 (100.0)	Not applicable	0
Underwent kidney transplantation, n (%)	14 (19.7)	7 (26.9)	3 (11.5)	4 (21.0)

Table 3. Adverse events, haematologic abnormalities and discontinuations
Event	All patients	Sofosbuvir plus Ribavirin	Sofosbuvir plus Ledipasvir	Sofosbuvir plus Daclatasvir
Number of patients	71	26	26	19
Common adverse events
Fatigue	32 (45.1)	19 (73.1)	7 (26.9)	6 (31.6)
Headache	16 (22.5)	7 (26.9)	5 (19.2)	4 (21.1)
Insomnia	11 (15.5)	5 (19.2)	4 (15.4)	2 (10.5)
Nausea	13 (18.3)	6 (23.1)	4 (15.4)	3 (15.8)
Diarrhoea	15 (21.2)	7 (26.9)	4 (15.4)	4 (21.1)
Haematologic event
Anaemia, n (%)	21 (29.6)	17 (65.4)	2 (7.7)	2 (10.5)
Required transfusion(s)	8 (11.3)	8 (30.8)	0 (0)	0 (0)
Reduction in ribavirin dose because of anaemia^a, n (%)	17/26 (65.4)	17 (65.4)	NA	NA
Erythropoietin stimulating drugs started or dose increased, n (%)	19 (26.7)	15 (57.7)	2 (7.7)	2 (10.5)
Ribavirin stoppage^a, n (%)	8/26(30.8)	8 (30.8)	NA	NA
Any serious adverse events, n (%)	0 (0)	0 (0)	0 (0)	0 (0)
Cardiac serious adverse events, n (%)	0 (0)	0 (0)	0 (0)	0 (0)
Death, n (%)	0 (0)	0 (0)	0 (0)	0 (0)

^aAmong patients receiving ribavirin.

Table 4. Changes in e-GFR during follow-up among patients not on maintenance dialysis
e-GFR	All patients*	Sofosbuvir plus Ribavirin**	Sofosbuvir plus Ledipasvir	Sofosbuvir plus Daclatasvir***
Number of patients	11	5	1	5
e-GFR, baseline mL/min/1.73 m², median (range)	34.0 (21.0–63.0)	34.0 (24.0–59.00	44.0	33.0 (21.0–63.0)
Number of patients	11	5	1	5
e-GFR, at end of treatment mL/min/1.73 m², median (range)	35 (16.0–69.0)	24.0 (16.0–61.0)	38.0	35.0 (20.0–69.0)
Creatinine increase of >0.3 mg/dL from baseline, n (%)	2/11 (18.1)	2/5 (40.0)	0 (0.0)	0 (0.0)
Number of patients	11	5	1	5
e-GFR, at 12 wk after stopping treatment mL/min/1.73 m², median (range)	34.0 (11.0–64.0)	36.0 (11.0–58.0)	34.0	31.0 (21.0–64.0)

e-GFR, estimated glomerular filtration rate.
*P value = .092.
**P value = .368.
***P value = .331.

Table 5. Summary of efficacy outcomes in studies published as full length paper of sofosbuvir-based therapy for chronic HCV infection with CKD including advanced CKD (CKD stage 4 or 5 with an e-GFR <30 mL/min or those on dialysis)
Author, Year [Ref]	No of patients	HCV genotypes, n [%]	Cirrhosis, n [%]	Treatment experienced, n [%]	Treatment regimen with duration	ETR, n [%] SVR 12, n [%]	Side effects, n [%]
Singh T, 2016⁷	Total = 8, All on HD	Total = 8 G1a = 3 G1b = 3 G3 = 1 G4 = 1	3 (37%), All compensated	1 (12.5%)	4 = SOF 400 mg/SMV 150 mg, 12 wk 4 = SOF 400 mg/LDV 90 mg, 12 wk	ETR=8/8 (100%) SVR 12 = 7/7 (100%)	Total=4 [50%] Dose reduction or discontinuation because of side effects=0 1 = nausea, vomiting 1 = headache 1 = insomnia 1 = Hb drop> 2 g/dL
Saxena v, 2016⁸	Total = 73 e-GFR≤45 ml/min = 73 e-GFR≤30 ml/min = 17 On HD = 5 HIV co-infection = 3 Prior LT = 36 Prior Kidney transplant = 6	Total = 73 G1a = 33 G1b = 15 G1-ns = 8 G2 = 11 G3 = 4 G4 = 1 Other = 1	47 (64%) History of decompensation = 34 HCC = 1	39 (53%)	5 = SOF 400 mg/PEG-RBV, 12 wk 16 = SOF 400 mg/RBV, 12 wk 39 = SOF 400 mg/SMV, 12 wk 13 = SOF 400 mg/SMV/RBV, 12 wk	SVR 12 = Overall 53/64 (83%) 2/4 (50%) 12/14 (86%) 28/35 (80%) 11/11 (100%)	Early treatment discontinuation = 5 (7%) Discontinuation because of side effects = 3 (4%) Anaemia = 22 (30%) Required transfusion(s) = 10 (20%) Needed Erythropoietin stimulating drugs = 9 (12%) Reduction in RBV because of anaemia = 11/34 (32%) RBV discontinuation = 4/34 (12%) Worsening renal function = 11 (15%) Fatigue = 22 (30%) Headache = 10 (14%) Nausea = 11 (15% Any serious adverse events = 16 (22%) Cardiac serious adverse events = 3 (4%) Death = 1 (1%) [Post-LT patient with worsening renal function and liver decompensation]
Dumortier J, 2016⁹	Total = 50 e-GFR<35 ml/min = 35; On HD = 15 Prior LT = 11 Prior Kidney transplant = 17	Total = 50 G1a = 7 G1b = 21 G2 = 6 G3 = 5 G4 = 9 G5 = 2	27 [54%]	36 [72%]	A reduced dose of SOF (400 mg 3 times a week patients and 400 mg/d in non-HD patients was used 4 = SOF/RBV, 12 wk 3 = SOF/RBV, 24 wk 2 = SOF/RBV/PEG-IFN, 12 wk 19 = SOF/DCV, 12 wk 8 = SOF/DCV, 24 wk 1 = SOF/DCV/RBV, 12 wk 2 = SOF/DCV/RBV, 24 wk 1 = SOF/SMV/RBV, 12 wk 10 = SOF/SMV, 12 wk	ETR=48/50 (96%, 1 patient died before week 12, 1 patient received liver/kidney transplantation before week 12). SVR 12 = 43/50 (86%).	Discontinuation because of side effects = 0 Hb<8 g/dL = 3 (6%) Required transfusion(s) = 2 (4%) Reduction in RBV because of anaemia = 2 (16.7%) Headache = 16 (32%) Asthenia = 14 (28%) Digestive discomfort (ie, diarrhoea or nausea) = 10 (20%) Insomnia = 8 (16%) In non-HD patients, median e-GFR not significantly modified during treatment
Nazario HE, 2016¹⁰	Total = 17 e-GFR<30 mL/min = 2 On HD = 15	Total = 17 G1a = 13 G1b = 4	8 (47%); Decompensated = 2	3 (18%)	SOF 400 mg/SMV 150 mg, 12 wks	ETR=16/17 (94%); 1 pt did not get end of treatment testing SVR 12 wk = 17/17 (100%)	Discontinuation because of side effects = 0 Insomnia = 2 (12%) Nausea = 1 (5%); Headache = 1 (5%) Anaemia = 1 (5%); received BT
Desnoyer A. 2016⁶	Total 12 on HD 2 = HIV co-infection 1 = prior renal transplant	Total = 12 G1a = 3 G1b = 5 G1na = 3 G2 = 1	10/12 (83.3%)	6/12 (50%)	SOF 400 mg QD or TIW was used 1 = SOF QD/SMV QD, 12 wk 1 = SOF QD/SMVQD, 24 wk 1 = SOF QD/LDV QD, 12 wk 1 = SOF QD/DCV QD, 12 wk 2 = SOF QD/DCV QD, 24 wk 3 = SOF TIW/DCV QD, 12 wk 2 = SOF TIW/DCV QD, 24 wk 1 = SOF TIW/RBV BID, 12 wk	SVR 12 wk = 10 Relapse = 2	Discontinuation because of side effects = 0 Anaemia = 3; headache = 2; Sepsis (unrelated to drug) = 1
Bhamidimarri KR. 2015¹¹	Total = 15 e-GFR≤30 mL/min = 15 On dialysis = 12	Total = 15 G1a = 10 G1b = 5	9/15 (60%) 1 = decompensated	9/15 (60%)	Half dose SOF was used 14 = SOF/SMV, 12 weeks 1 = SOF/SMV, 24 weeks	ETR = 15/15 (100%) SVR 12 = 13/15 (87%)	Discontinuation or dose adjustment because of side effects = 0 Anaemia = 13%; Fatigue = 20% Rash/itching = 13%; Loss of appetite = 7%
Hundemer GL. 2015¹²	Total = 6 e-GFR≤30 mL/min = 6 On HD = 2 Prior LT = 1 Prior Kidney transplant = 1	Total = 6 G1a = 3 G1b = 1 G1na = 2	3/6 (50%)	3/6 (50%)	SO F400 mg daily was used 3 = SOF/SMV 150 mg daily, 12 wk 2 = SOF/RBV 200 mg twice daily, 24 wk 1 = SOF/RBV 600 mg twice daily/PEG-IFN 180 μg weekly, 12 wk	ETR=6/6 (100%) SVR12 = 4/6 (66.6%)	Discontinuation because of side effects = 1 (IFN regimen) Anaemia = 3 Leucopenia = 1 AKI (Lupus like immune complex diseases) = 1
Vionnet J. 2016¹³	Total = 2 e-GFR≤30 mL/min = 2 On HD = 1 Prior LT = 1 Prior Kidney transplant = 1t HBV co-infection = 1	Total = 2 G1a = 2	1/2 (50%)	1/2 (50%)	1 = SOF 400 mg every other day/DCV 60 mg daily, 24 wk 1 = SOF 200 mg daily/DCV 60 mg daily, 24 wk	ETR = 2/2 (100%) SVR 12 = 2/2 (100%)	Discontinuation because of side effects = 0 Atrial fibrillation at wk 14 = 1 Superior mesenteric vein thrombosis 4 wk after EOT = 1
Beinhardt S. 2016¹⁴	Total = 25 On dialysis = 10	Total = 25 G1a = 4 G1b = 12 G3a = 4 G4 = 4 G1b/3a = 1	12/25 (48%) Decompensated = 6	10/25 (40%)	SOF 400 mg daily was used 1 = SOF/PEG/RBV 1 = SOF/LDV 8 = SOF+SMV 13 = SOF+DCV 1 = SOF+RBV 1 = DCV/SMV	SVR 12 = 24/25 (96%)	Severe adverse reactions = 6 SOF dose reduction = 1 (sepsis induced pancytopenia) RBV dose reduction = 1 Anaemia = 1 Thrombocytopenia = 2 Hepatic encephalopathy = 1 Pneumonia = 1 Peritonitis (Patient on PD) = 1 Kidney function remained stable patients not on dialysis
Agarwal SK, 2017¹⁵	Total = 62 On HD = 62	Total = 62 G1 = 40 G2 = 1 G3 = 18 G4 = 2 G6 = 1	0 (0)	0 (0)	All patients treated for 12 wk 39 = SOF 400 mg A/D/RBV 200 mg/d 2 = SOF 400 mg/d/RBV 200 mg/d 6 = SOF 400 mg A/D/DCV 60 mg/d 15 = SOF 400 mg/d/DCV 60 mg/d	SVR 12 = Overall = 59/62 (95.2%) 37/39 (94.8%) 2/2 (100%) 6/6 (100%) 14/15 (93.3%)	Dyspepsia = 23 (37%) Increase in erythropoietin dose among ribavirin treated = 23/41 (56%) 4 = Tuberculosis 3 = Bacterial pneumonia

A/D, Alternate day; DCV, Daclatasvir; e-GFR, estimated glomerular filtration rate; ETR, end of therapy response; HD, haemodialysis; HCC, hepatocellular carcinoma; LDV, ledipasvir; LT, liver transplantation; PD, peritoneal dialysis; PEG, pegylated interferon; QD, per day; RBV, ribavirin; SOF, sofosbuvir; SMV, simeprevir; SVR 12, sustained virological response at 12 week after end of therapy; TIW, thrice weekly.