Abstract
Background
The burden of hepatitis C virus (HCV) in India is alarming, with a major share of this virus being witnessed in patients with end-stage renal disease (ESRD). A pan-genotypic combination of sofosbuvir and velpatasvir is found to be safe, effective, and economical in resource-constraint countries such as ours. However, there are scanty data on the efficacy and safety of sofosbuvir and velpatasvir combination in patients with ESRD. Hence, we performed this study to evaluate the safety and efficacy of the combination of sofosbuvir and velpatasvir in patients of chronic hepatitis C (CHC) with ESRD.
Methods
This is an observational study comprising of 40 CHC patients with ESRD on maintenance hemodialysis. All patients were treated with a fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks in case of non-cirrhotic or compensated cirrhosis and 24 weeks in case of decompensated cirrhosis. The efficacy was assessed by sustained virological response defined by negative HCV RNA at 12 weeks (sustained virological response [SVR] 12) post treatment, and safety was assessed by recording any side-effects of all patients.
Results
Out of the 40 patients enrolled in our study, majority were non-cirrhotic (77%), and all were treatment-naive. The mean age was 49.87 ± 12.13 years, and 80% patients were male. The mean baseline HCV RNA was 2.61 ± 7.83 × 106 IU/ml. All the 40 patients (100%) achieved undetectable HCV RNA at the end of treatment; however, 39 patients (97.5%) achieved SVR 12. There was no significant deterioration of estimated glomerular filtration rate (eGFR) after completion of antiviral therapy as compared to the baseline eGFR (13.27 ± 10.32 vs13.54 ± 11.38, P = 0.54). None of the patients reported any serious adverse effects during treatment.
Conclusion
The fixed-dose combination of sofosbuvir and velpatasvir is effective and has showed excellent safety profile in patients of CHC with ESRD.
Keywords: hepatitis C virus, end-stage renal disease, chronic kidney disease, sofosbuvir, velpatasvir
Hepatitis C virus (HCV) infection is a major global public health burden affecting around 71 million people worldwide according to the World Health Organization. The number of deaths due to HCV approximates 4 lakh annually.1 Patients with chronic hepatitis C (CHC) advance to liver cirrhosis and hepatocellular carcinoma (HCC), leading to increased morbidity and mortality in these patients. Moreover, CHC is the foremost indication of liver transplantation in adults.2,3 In India, the prevalence of HCV infection was found to be around 0.5–1.5%.4 Although, the predominant modes of transmission of HCV are blood transfusion and unsafe drug injections, patients with end-stage renal disease (ESRD) undergoing hemodialysis are at high risk of getting infected with HCV.5,6
Co-occurrence of HCV with chronic kidney disease (CKD) not only increases the liver-related complications including liver cirrhosis, decompensated liver disease, and HCC but also enhances the deterioration of renal function as well as increases the cardiovascular complications related to CKD.7,8 HCV infection in post–kidney transplantation increases the risk of new glomerulosclerosis, worsens diabetes mellitus, and sepsis; hence, increasing the risk of post-transplantation mortality.9 Treatment of HCV in patients of CKD is essential to reduce further deterioration of kidney function.
The oral directly acting antivirals have transformed the treatment of HCV infection to a great extent. However, treatment of HCV infection in CKD patients was of major concern as sofosbuvir, a pan-genotypic NS5B inhibitor being the mainstay of therapy in HCV infection was excreted via kidney with significant increase of its inactive GS331007 metabolite.10 The recommended therapies for HCV infection in CKD by the American Association for the Study of Liver Diseases are grazoprevir/elbasvir and glecaprevir/pibrentasvir.11 However, these drugs are not available in India. A fixed-dose combination of sofosbuvir and veplatasvir, combining an NS5B inhibitor with an NS5A inhibitor was found to be safe and efficacious in patients in patients of CKD with HCV infection in few studies; however, the experience with this combination is very much limited. Hence, we conducted this study to determine the efficacy and safety of the fixed-dose combination of sofosbuvir and veplatasvir in patients of CKD with chronic HCV infection undergoing maintenance hemodialysis (MHD).
METHODS
Patients
This is an observational study carried out in the department of hepatology, SCB Medical College and Hospital, Cuttack, including all patients of CKD with CHC treated with a fixed-dose combination of sofusbuvir (400 mg) and veplatasvir (100 mg), between April 2018 and November 2021. The Institutional ethics committee approval was taken for this study (SCB IEC-914-03.08.2021).
Pre-treatment Clinical and Laboratory Evaluation
The patients of CKD planning to start MHD were tested for anti-HCV and liver function test (LFT). Those who were on MHD were tested for anti-HCV every 3 months. Hepatitis C antibody was assessed using the enzyme-linked immunosorbent assay (ELISA) technique. Those patients who were positive for anti HCV investigated for HCV RNA load. HCV RNA was assayed with COBMAN Taqman assay with 15 IU/ml as lower limit of detection. Patients with detectable HCV RNA load were advised baseline hemogram, LFT, renal function test (RFT), Ultrasonography of abdomen and transient elastography. Upper gastrointestinal endoscopy and color Doppler of portal venous system was carried out to look for portal hypertension.
Liver fibrosis was assessed by using transient elastography. The cut-off value for liver fibrosis was >7.1 kPa, and the patients were divided into various grades of fibrosis based on liver stiffness: <7.1 kPa-minimal fibrosis (F0–F1), 7.1–9.4 kPa-moderate fibrosis (F2), 9.5–12.4 kPa-severe fibrosis (F3), and those with values more than 12.5 kPa were cirrhotics (F4).12 All patients were treated with a fixed-dose combination of sofosbuvir (400 mg) plus velpatasvir (100 mg) given daily for 12 weeks or for 24 weeks in cases of decompensated cirrhosis irrespective of genotype and treatment naïve or experienced, hence genotyping of HCV was not done in our study.
Follow-up
Hemogram, LFT, and RFT were done every month till completion of therapy and at 12 weeks after completion of treatment. HCV RNA load was done at the baseline, end of treatment, and 12 weeks post treatment. The undetectable HCV RNA at 12 weeks of completion of treatment was termed as sustained virological response 12 (SVR 12), which corresponds to virological cure. Relapse was defined as detectable HCV RNA in the post-treatment period having achieved SVR 12.13 All patients were followed up for any adverse effects.
Statistical Analysis
Categorical variables were expressed as number (percentage) and continuous variables as mean ± standard deviation for normally distributed data or median if not normally distributed. SPSS 20.0 statistical software (SPSS Inc., Chicago, IL) was used for statistical analysis.
RESULTS
Baseline Characteristics
A total of forty CKD patients on MHD with HCV infection were enrolled in the study. Mean age was 49.87 ± 12.13 years, and males constituted 80% of total study population. The baseline estimated glomerular filtration rate (eGFR) was 11.15 ± 9.95 ml/min per 1.73 m2. Out of the 40 patients, 3 (8%) were decompensated cirrhotic, 6 (15%) were compensated cirrhotic, and the rest 31 (77%) were non-cirrhotic. Mean liver stiffness was 8.77 ± 3.68 kPa, with 17 (43%) patients being F0–F1, 11 (27%) were F2, 7 (17%) were F3, and 5 (13%) were F4. All patients were treatment-naive. Baseline characteristics of CKD patients on MHD with HCV infection are shown in Table 1.
Table 1.
Baseline Characteristics of CKD Patients With HCV Infection on Maintenance Hemodialysis.
| Characteristics | N = 40 |
|---|---|
| Age in years (mean ± SD) | 49.87 ± 12.13 |
| Gender | |
| Male | 32 (80%) |
| Female | 8 (20%) |
| Hg, gm/dl | 8.85 ± 1.79 |
| Total platelet count, lacs/cmm | 1.91 ± 5.47 |
| ALT, IU/L | 45.47 ± 21.22 |
| AST, IU/L | 55.90 ± 33.60 |
| Albumin, mg/dl | 3.67 ± 0.56 |
| Creatinine, mg/dl | 9.31 ± 4.97 |
| eGFR at baseline, mL/min per 1.73 m2 | 11.15 ± 9.95 |
| Duration of dialysis, months (mean ± SD) | 21.28 ± 11. |
| Baseline HCV RNA (106/ml) | 2.61 ± 7.83 |
| Stage of liver disease | |
| Chronic hepatitis C | 31 (77%) |
| Compensated cirrhosis | 6 (15%) |
| Decompensated cirrhosis | 3 (8%) |
| Liver stiffness | 8.77 ± 3.68 |
| F0–F1 | 17 (43%) |
| F2 | 11 (27%) |
| F3 | 7 (17%) |
| F4 | 5 (13%) |
Abbreviations: ALT = Alanine Transaminase; CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; HCV = hepatitis C virus; SD = standard deviation.
Outcome
The mean baseline HCV RNA was 2.61 ± 7.83 × 106 IU/ml. Outcomes of CKD patients on MHD, treated with sofosbuvir and velpatasvir is shown in Table 2. All the 40 patients (100%) achieved undetectable HCV RNA at the end of treatment. SVR12, undetectable HCV RNA 12 week post treatment, was achieved in 39 patients (97.5%). One patient who did not achieve SVR was having decompensated cirrhosis, although treatment naïve. The comparison of eGFR at the baseline and at 12 weeks of completion of therapy is depicted in Figure 1. There was no significant deterioration of eGFR after completion of antiviral therapy as compared to the baseline eGFR (13.27 ± 10.32 vs13.54 ± 11.38,P = 0.54). Out of the 40 patients, 3 patients had undergone renal transplantation. One patient died after 28 days of renal transplantation, and other two patients are doing well after 2 years of renal transplantation with no recurrence of HCV infection.
Table 2.
Outcomes and Safety of CKD Patients on MHD, Treated With Sofusbuvir and Veplatavir.
| Outcome | N = 40 |
|---|---|
| Negative viral load at week 4 | 28 (70%) |
| End of treatment response | 40 (100%) |
| SVR at 12 weeks post treatment | 39 (97.5%) |
| Safety | |
| Nausea | 5 (12.5%) |
| Headache | 4 (10%) |
| Fatigue | 4 (10%) |
| Light-headedness | 3 (7.5%) |
| Interruption of treatment due to adverse effects | None |
Abbreviations: CKD = chronic kidney disease; MHD = maintenance hemodialysis; SVR = sustained virological response.
Figure 1.
The comparison of eGFR at the baseline and at 12 weeks of completion of therapy.
Abbreviation: eGFR = estimated glomerular filtration rate.
Safety
Table 2 reveals safety of CKD patients on MHD, treated with sofosbuvir and velpatasvir. The most common adverse effects encountered in this study were light headedness in 6 (15%) patients, followed by nausea 5 (12.5%), fatigue 4 (10%), and headache (10%). The hemoglobin before antiviral treatment was 8.85 ± 1.79 gm/dl and at SVR12, was 8.65 ± 1.45 gm/dl; this was not statistically significant (P > 0.05). None of the patients interrupted treatment due to any adverse effects. There was no deterioration in liver or kidney disease during treatment and on ollow-up.
Discussion
The patients of ESRD infected with HCV are considered to be special population as they pose a great risk of transmission to those who are undergoing renal replacement therapy.14 Non sofosbuvir-based therapy such as elbasvir–grazoprevir and glecaprevir–pibrentasvir are recommended for HCV infection in patients with ESRD.15,16 However, these regimens are not available in most parts of world and elbasvir–grazoprevir is not pan-genotypic. Hence, the sofosbuvir and velpatasvir therapy appears to be the ultimate first-line therapy for ESRD patients infected with HCV. However, metabolism of sofosbuvir in the liver results in generation of intermediate metabolite GS-331007. Both sofosbuvir and GS-331007 are excreted mainly by the kidney, and concentration of both these products is significantly higher in patients with eGFR < 30 ml/min/m2. Nevertheless, sofosbuvir-containing regimens were found to be safe in HCV patients with severe renal impairment even in patients with eGFR < 30 ml/min/1.73 m2.15,17
In our study, we found that HCV patients with ESRD who are undergoing hemodialysis had an SVR rate of 97.5 %, with fixed-dose combination of sofosbuvir and velpatasvir treatment for 12 weeks. One patient did not achieve SVR and was a patient of decompensated cirrhosis although treatment-naive. The sofosbuvir and velpatasvir treatment for 12 weeks was safe, effective, and well-tolerated without any serious side-effects or treatment-related discontinuation of drugs. Our result is at par with various trials, which showed that sofosbuvir and velpatasvir treatment for 12 weeks in patients with ESRD infected with HCV resulted in higher SVR rates irrespective of genotype or cirrhosis status.18,19,20 Another multicentric study by Borgia et al. conducted in 22 cities of various countries had found an SVR rate of 95% among HCV-infected patients with ESRD treated with fixed-dose combination of sofosbuvir and velpatasvir, and there were no treatment-related side-effects.21
The deterioration of renal function is always a concern in patients of ESRD with HCV infection treated with sofosbuvir based regimens. Various studies have found that treatment of HCV infection with sofosbuvir-based regimen is not associated with change in eGFR and progression of CKD to ESRD.22,23 In our study, we also revealed that there was no worsening of renal function in patients of CKD with HCV infection treated with the combination of sofosbuvir and velpatasvir. The most common side effects noted in our study was nausea in 12.5%, followed by headache and fatigue in 10% patients. None of our study population experienced serious adverse events accredited to treatment with sofosbuvir and velpatasvir. One study from India has reported headache as the most common symptom in 17 % of patients, followed by fatigue in 14% of patients.24
Our study has various limitations. The low sample size is the major limitation of our study. As the ELISA method was used to detect HCV positivity, the possibility of false negativity of anti-HCV test in CKD patients could be one of the limitations of our study. The genotype of HCV patients was not assessed in our study as it is not available in our center. As our study is an observational study, the follow-up data of patients achieving SVR 12 are not available to diagnose relapse/reinfection post SVR. Alpha-fetoprotein was not documented in initial evaluation and follow-up. Despite of these limitations, our study presents real-world data in Indian settings, showing effectiveness and safety of the combination of sofosbuvir and velpatasvir in HCV-infected CKD patients.
In conclusion, pan-genotypic fixed-dose combination of sofosbuvir and velpatasvir can be an excellent option for treatment of HCV-infected CKD patients who are on MHD. In resource-constraint country such as ours, with unavailability of several pan-genotypic drugs, our study supports use of sofosbuvir and veplatasvir combination in HCV patients with severe renal impairment with extremely good efficacy and safety profile.
Credit authorship contribution statement
Conceptualization: Manas Kumar Behera, PrabirMajji, Sanatan Behera, Manoj Pani, Arupam Mohapatra, Umesh Chandra Patra, Susant Kumar Jena. Formal analysis: Manas Kumar Behera, Prabir Majji, Arupam Mohapatra. Methodology: Manas Kumar Behera, Prabir Majji, Susant Kumar Jena. Resources: Manoj Pani, Arupam Mohapatra. Supervision: Umesh Chandra Patra, Susant Kumar Jena. Writing—original draft: Manas Kumar Behera, Prabir Majji, Sanatan Behera, Susant Kumar Jena. Writing, review & editing: Manas Kumar Behera, Prabir Majji, Sanatan Behera, Manoj Pani, Arupam Mohapatra, Umesh Chandra Patra, Susant Kumar Jena.
Conflicts of interest
All authors have none to declare.
Acknowledgment
None.
Funding
None.
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