Sofosbuvir–Velpatasvir Fixed Drug Combination for the Treatment of Chronic Hepatitis C Infection in Patients With End-Stage Renal Disease and Kidney Transplantation

Abstract

Introduction

India is witnessing high hepatitis C virus (HCV) infection burden in patients of chronic kidney disease. Due to unavailability of costly Kidney Disease Improving Global Outcomes-recommended directly acting antiviral drugs, a widely available pan-genotypic combination of Sofosbuvir and Velpatasvir can become an economical option. Data regarding treatment experience of sofosbuvir–velpatasvir combination in chronic kidney disease is scarce. No data from India have been published in patients on renal replacement therapies till now.

Methods

This retrospective analysis included all patients of end-stage renal disease on maintenance hemodialysis with treatment-naïve chronic HCV infection treated with sofosbuvir (400 mg) and velpatasvir (100 mg) fixed-dose combination. Pretreatment routine investigations were performed, which included HCV viral load, genotype, fibro scan, endoscopy for esophageal varices, and portal vein Doppler. The patients were followed up with HCV viral load to declare sustained virologic response.

Result

patients were included with a mean age of 39.8 ± 10.8 years, and 77.4% were male. Genotype 1 was found to be most prevalent (67.7%), with a median viral load of 10⁶copies/ml. Six (19.3%) patients had hepatitis B virus co-infection. Three (9.7%) patients had cirrhosis. Sustained virologic response (SVR12) was achieved in 30 (96.8%) patients, and one (3.2%) patient had relapse. Furthermore, 14 (45.2%) patients underwent renal transplantation, and none of them had relapsed. Dyspepsia (9.7%) was the most common side effect observed with no major adverse effect.

Conclusion

Our study showed excellent efficacy with the safety profile of this drug combination in end-stage renal disease patients. However, larger prospective studies and multicenter randomized controlled trials are needed for further confirmation.

Hepatitis C virus (HCV) infection is emerging as a major public health problem since its discovery in 1989. The prevalence of HCV infection in the general population has reached to more than 180 million people worldwide (approximately 2.8% of the global population).¹ Dialysis Outcomes and Practice Patterns Study (DOPPS) noted 13.5% of the end-stage renal disease (ESRD) patients on hemodialysis were infected with HCV.² The prevalence varies from 2.6 to 22.9% between the United States, Europe, and Asia.² The estimated prevalence of HCV infection in India is about 0.5–1.5%.³ A study from New Delhi reported a prevalence of HCV RNA positivity to be 27.7% among patients undergoing hemodialysis.⁴ Another recent study reported a prevalence of 33.5% in a north Indian dialysis center.⁵ Chronic HCV infection not only can lead to liver cirrhosis, hepatic decompensation, and hepatocellular carcinoma in chronic kidney disease (CKD), but also accelerates renal deterioration, increases morbidity, mortality and cardiovascular risk.⁶ Post-renal transplant HCV infection raises the risk of mortality, post-transplant diabetes mellitus, de-novo or recurrent glomerulonephritis, sepsis, and malignancy.⁷ Therefore, treatment of chronic HCV infection is necessary

With the arrival of new directly acting antiviral (DAA) drugs, a revolutionary change is being observed in the treatment of chronic HCV infection. In developing countries like India, unavailability of newer drugs (grazoprevir/elbasvir and glecaprevir/pibrentasvir) recommended by the American Association for the Study of Liver Diseases⁸ and Kidney Disease Improving Global Outcomes⁹ for HCV treatment in dialysis-dependent CKD patients compels us to use more economical pan-genotypic DAA.

Velpatasvir, a novel, pan-genotypic NS5a inhibitor, and sofosbuvir, a pan-genotypic NS5b polymerase inhibitor, the fixed-dose combination of the two has shown high rates of sustained virologic response among both previously treated and untreated patients infected with HCV genotype 1, 2,3, 4, 5, or 6, including those with compensated cirrhosis.^10,11 In CKD patients(GFR < 30 ml/min), the experience is limited with this drug combination.

In this study, we are sharing our experience with this drug combination in patients with ESRD on maintenance hemodialysis.

Material and methods

Patients and Treatment Protocol

This retrospective analysis included all patients of ESRD on maintenance hemodialysis with treatment-naïve chronic HCV infection treated with sofosbuvir (400 mg) and velpatasvir (100 mg) fixed-dose combination to be taken daily, between July 2017 and June 2018, in the Department of Nephrology at our center, a tertiary-care teaching institute situated in the north Indian city of Jaipur.

Clinical and Laboratory Assessment

Data were collected from patient's hospital records, pretransplant workup records, and patients were interviewed for history, associated comorbidities, and experienced adverse effects during the treatment course.

As per the department policy, all new patients for maintenance hemodialysis were tested for anti-HCV antibody, aspartate transaminase (AST), and alanine transaminase (ALT). These tests were repeated in all patients on maintenance hemodialysis every three months. Patients with positive anti-HCV antibodies or those with unexplained altered liver functions but negative anti HCV antibodies were further investigated for their qualitative HCV RNA, HCV viral load, and HCV genotype if HCV RNA positive. The timing of HCV infection was taken as the time since the AST was high above the normal limit or anti-HCV was positive, whichever was earlier.

Patients were assessed for fibrosis using liver transient elastography. A cutoff value for the liver stiffness measurement >7.1 kPa F2 denoted significant fibrosis, and >12.5 kPa F4 was regarded as cirrhosis.¹² Upper gastrointestinal endoscopy and portal vein Doppler were performed in every patient to rule out portal hypertension. Portal hypertension was defined as hepatic venous pressure gradient (HVPG) of > 5 mm Hg; HVPG ≥ 10 mm Hg was considered clinically significant portal hypertension (CSPH); and severe portal hypertension was defined if HVPG ≥ 12 mm Hg¹³. Liver biopsy was not performed in any patient.

Follow-up

For the initial two weeks, all biochemical tests were repeated weekly; after that, tests were done as per clinical indications. Patients were followed weekly for the first month, biweekly in the second month, and then at the end of the third month. The quantitative HCV RNA was performed at fourth week, at the end of treatment, at 12th week after treatment completion to declare SVR12⁹ and repeated at 24th week after treatment completion to declare SVR24 (whenever follow-up duration permitted).

Outcomes SVR12 and SVR24 were defined as HCV RNA < the lower limit of quantitation (LLOQ) at 12 and 24 weeks, respectively, following the completion of treatment. As multiple studies have shown high concordance between SVR12 and SVR24 and have validated SVR12 as efficacy end point, we used SVR12 to declare cure. Relapse was defined as confirmed HCV RNA ≥ LLOQ during the post-treatment period having achieved HCV RNA < LLOQ at completion of treatment.¹⁴

As per the department policy, ESRD patients with HCV infection are considered for live renal transplantation after achievement of SVR12. On the other hand, deceased donor renal transplant can proceed irrespective of the SVR. All transplant patients receive triple immunosuppression, that is, corticosteroids, tacrolimus, and mycophenolate sodium, in standard doses. Induction therapy is given in high-risk cases (deceased donor and live unrelated donors) with basiliximab (20 mg intravenous infusion 4 h before the transplant surgery and on the 4th day post-transplant). Quantitative HCV RNA is performed at 12th week, post-transplant in all the patients or whenever there is a clinical indication (rise in SGOT and SGPT).

Statistical Analysis

Summary categorical statistics were expressed as a number (percentage). Summary continuous statistics were expressed as mean ± standard deviation if normally distributed, or median (inter-quartile range [IQR]) if not.

Ethical Clearance

Institute's Ethic Committee clearance was taken.

Results

In total, 31 treatment-naive patients received sofosbuvir (400 mg) and velpatasvir (100 mg) fixed-drug combination for chronic HCV infection. Table 1 shows the baseline characteristics of these patients. The mean age of the study population was 39.8 ± 10.8 years, 77.4% (N = 24) were males. All the patients were on maintenance hemodialysis with a mean duration of dialysis being 4.2 ± 2.7 years.

Table 1.

Baseline Characteristics of Patients on Maintenance Hemodialysis Treated With Sofosbuvir–Velpatasvir Fixed Drug Combination.

Characteristics	N = 31
Age (years) (mean ± SD)	39.8 ± 10.8
Male: Female	24 (77.5%):7(22.5%)
Duration of dialysis (years) (mean ± SD)	4.2 ± 2.7
Units of packed cell volume transfusion (mean ± SD)	3.8 ± 2.2
Basic kidney disease
Unclassified	23 (74.2%)
Diabetes	6 (19.3%)
IgA nephropathy	2 (6.4%)
HIV	0
HBsAg positive	6 (19.3%)
Anti HCV positive	26(83.8%)
Duration between diagnosis and start of therapy (mean ± SD)	1.1 ± 0.6
Hemoglobin (gm/dl)	9.0 ± 1.4
Total leucocyte count (/mm3) (mean ± SD)	6,832.3 ± 2075
Platelet count (lac/mm3) (mean (± SD)	2.16 ± 0.7
Total bilirubin (mg/dl) (mean ± SD)	1.19 ± 0.20
Direct bilirubin (mg/dl) (mean ± SD)	0.7 ± 0.2
ALT (U/L) (mean ± SD)	80.3 ± 25.6
AST (U/L) (mean ± SD)	44.9 ± 15.7
Serum protein	5.6 ± 0.5
Serum albumin (g/dl) (mean ± SD)	2.8 ± 0.5
Alpha fetoprotein (mg/dl)	3.4 ± 0.5
Genotype status
1	21 (67.7%)
3	10 (32.2%)
Quantitative RNA copies (median:interquartile range)	106 (105–107)
Fibrosis stage determined by TE (%)
F0–F1	23 (74.2%)
F2–F3	5 (16.1%)
F4	3 (9.6%)
Cirrhosis	3 (9.6%)
Compensated	2 (6.4%)
Decompensated	1 (3.2%)
Esophageal varices and portal hypertension	1 (3.2%)
Patients underwent renal transplantation	14 (45.2%)
Post-treatment	12 (38.7%)
During treatment (cadaveric transplantation)	2 (6.4%)

The cause of ESRD was unknown in the majority (74.2%, N = 23), diabetic nephropathy in 19.3% (N = 6), and IgA nephropathy in 6.4% (N = 2). All patients had received a blood transfusion with mean transfusion of 3.8 ± 2.2 units of packed cell volume. Six (19.1%) patients had hepatitis B co-infection and were treated with entecavir therapy in modified doses.

Further, 21 (67.7%) patients had genotype 1 , while the rest had genotype 3 (N = 10, 32.2%). The median RNA viral load (10log) was 10⁶ (IQR: 10⁵-10⁷) copies/ml. Eight (25.8%) patients had significant fibrosis on TE. Three (9.6%) patients had cirrhosis, of which one had decompensated cirrhosis with portal hypertension and esophageal varices.

After starting treatment, 19 (61.3%) patients had a negative viral load at 4th week, while all patients achieved a virologic response at the end of treatment. Also, 30 (96.8%) patients achieved SVR12. One patient relapsed who went on to develop decompensated cirrhosis on follow-up and was restarted on sofosbuvir + velpatasvir + Ribavirin (modified renal dose). He achieved a negative viral PCR report after eight weeks of treatment and is still on treatment.

No patient developed major adverse effect requiring admission, discontinuation of treatment, or died during therapy. Three (9.7%) patients had dyspepsia and one (3.2%) patient had headache. Two (6.4%) patients had a drop in hemoglobin >2 gm./dl, one of which required blood transfusion, while other required increase in the doses of erythropoietin (Table 2).

Table 2.

Outcomes of Patients on Maintenance Hemodialysis Treated With Sofosbuvir–Velpatasvir Fixed-Drug Combination.

Outcome
Early treatment discontinuation	None
Negative viral load at 4 weeks	19 (61.3%)
End-treatment response	31 (100%)
SVR12 weeks	30 (96.8%)
Relapse	1 (3.2%)
Therapy safety
Anemia
> 2 gm/dl decrease in hemoglobin	2 (6.4%)
Blood transfusion	1 (3.2%)
Increase in the dose of erythropoietin	1 (3.2%)
Erythropoietin requirement during treatment IU/week (mean ± SD)	10,387.1 ± 1,085.6
Hemoglobin during treatment (gm./dl) (mean ± SD)	8.9 ± 1.4
Headache	1 (3.2%)
Dyspepsia	3 (9.7%)
Treatment interruption due to adverse effects	None
Hospitalization due to adverse effects	None
Death	None

Twelve (38.7%) patients underwent live renal transplantation after achieving SVR12, while two (6.4%) patients underwent deceased donor renal transplant while on therapy. All 14 patients are on standard dose triple immunosuppression. Five patients received injection basiliximab as induction for transplant. None of the patients had relapsed till writing of this article after transplantation (minimum follow-up three months).

Discussion

In our knowledge, this is the first reported experience of fixed-dose combination therapy of sofosbuvir–velpatasvir in ESRD patients on renal replacement therapies in India.

A major concern with this novel pan-genotypic regimen in CKD (GFR < 30 ml/min/1.73 m2) is the accumulation of sofosbuvir metabolite GS-331007 in ESRD patients, as glomerular filtration and secretion is the major route of elimination (80%), with only 15% extra-renal elimination.¹⁵ This metabolite causes anemia and rapid deterioration of the glomerular filtration rate in CKD. On the other hand, velpatasvir is majorly excreted in feces (94%), and only 0.4% of the dose is excreted via kidney.¹⁵ Various combinations of DAAs with sofosbuvir have been reported safe and efficacious in recent studies in dialysis-dependent patients.^16,17Agarwal et al¹⁶ have shown good efficacy (90% SVR) and safety of full-dose (400((((( mg) sofosbuvir-based DAAs (daclatasvir, ribavirin) in maintenance hemodialysis patients in India. In our study, we achieved a 96.77% SVR rate with one (3.2%) relapse who responded to the addition of ribavirin to fixed-drug combination. Furthermore, none of the 14 patients who underwent kidney transplantation with standard immunosuppressive regimen relapsed. In our analysis, this fixed-drug combination showed excellent efficacy both in dialysis-dependent and post-transplant patients.

No treatment strategy can be considered efficacious and comparable without a good safety profile. In this study, no major adverse effects were noted resulting in drug withdrawal, hospital admission, or death. The most commonly noted side effect was dyspepsia (9.6%), followed by anemia (6.45%). One patient who required blood transfusion was on ribavirin and with decompensated cirrhosis, so anemia cannot be solely attributed to the drug only. This safety profile in our study is comparable to other studies.^10,11,16

Our study showed comparable results to recently published multi-centric phase 2 open label study in terms of efficacy and safety of this drug combination in ESRD patients.¹⁸ This study by Borgia et al included diverse races with a mean age of 60 years, 22% patients were treatment-experienced and 29% patients had cirrhosis. As compared to this study, our study group was younger (age:39.8 ± 10.8 years), all patients were treatment-naïve; and only 3(9.6%) patients had cirrhosis. Most patients had HCV genotype 1. Our study showed similar efficacy (achieved SVR12 96.8% versus 95%). The most common side effects in this study were headache (17%) and fatigue (14%), and no major adverse event was attributed to the study treatment.

However, the limited number of the patients, few patients with cirrhosis, and the study design limit the generalizability of our findings. Further prospective, placebo-controlled trials are needed for confirmation of the results.

In developing countries like ours where disease burden of HCV is high with financial constraints, limited genotype analysis centers, and unavailability of AASLD-approved drugs, this pan-genotypic fixed-drug combination of sofosbuvir–velpatasvir can become a fascinating option for treating patients on renal replacement therapies. However, further prospective studies and randomized controlled trials are needed for confirmation of the result.

Conflicts of interest

The authors have none to declare.

Appendix A. Supplementary data

The following is the supplementary data to this article: