Direct-acting Antiviral Agents in Hepatitis C Virus-infected Renal Allograft Recipients: Treatment and Outcome Experience from Single Center

Introduction

Renal transplantation is the treatment of choice for end-stage renal disease (ESRD) patients. Hepatitis C virus (HCV) infection complicates both pre and post-transplantation management of these patients. HCV infection is associated with poor patient and graft survival in renal allograft recipients.[123] However, renal transplantation offers a significant survival advantage to HCV-infected ESRD patients as compared to those who remain on dialysis.[4] The present guidelines suggest that HCV-infected patients should be treated with interferon (IFN)-based therapy with or without direct-acting antiviral agents (DAAs) so as to achieve sustained virological response (SVR) before renal transplantation to minimize chances of post-transplant HCV progression.[56] In ESRD, IFN-based regimens have modest efficacy (SVR 50%–60%) and have poor tolerability resulting into high discontinuation rates (18%–25%).[57] A significant proportion of these patients experience relapse after transplantation.[8] Treatment with conventional or pegylated IFN in postrenal transplant period is associated with high incidence of acute rejection rates (30%–50%), and it is recommended only in life-threatening situations such as fibrosing cholestatic hepatitis.[59] IFN-free regimens consisting combination of DAAs have been highly effective and safe in treating liver transplant recipients having relapse of HCV infection.[101112] However, there is a paucity of data regarding the use of DAAs in renal transplant patients with only few studies in literature.[1314] The aim of present study was to report safety and efficacy of sofosbuvir-based regimens used for the treatment of HCV-infected renal allograft recipients.

Materials and Methods

All HCV-infected renal allograft recipients (n = 68/1254, 5.4%) who underwent renal transplantation at our institute between January 2005 and December 2015 were screened for HCV virus replication. Twenty-eight patients who showed active HCV replication were included in the study. All were counseled for the risk of untreated HCV infection and about the cost, duration, response, and adverse effects of DAA therapy. Two patients with estimated glomerular filtration ratio (eGFR) of <30 ml/min/1.73 m², one patient with hepatic decompensation, and three patients who did not consented for the study were excluded from the study. Thus, 22 patients with replicative HCV virus with an eGFR of ≥30 ml/min/1.73 m² were treated with DAAs. Written informed consent was obtained from all patients before initiation of therapy. The study was approved by the institute's ethics committee.

Results

Pretreatment patient characteristics and baseline laboratory values are shown in Tables 1 and 2, respectively. Majority of the patients had genotype 3 infection (n = 14/22, 64%). Thirteen patients (n = 13/20, 65%) were IFN nonresponder and seven (n = 7/20, 35%) had relapse of HCV replication after transplantation. In two patients, viremia was detected in posttransplant period when evaluated for raised liver enzymes.

Table 1 Clinical characteristics of patients

Table 2 Baseline (week 0) laboratory values of patients

Laboratory parameters during and after therapy are compared with corresponding baseline values in Table 3. At start of therapy, HCV RNA copies were 6505952 ± 6841432 (96425–24175475) logs IU/mL. Twenty patients had undetectable viremia after 4 weeks of therapy (n = 20/22, RVR = 91%). Two patients, both of genotype 1, had persistent viremia at 4 weeks but had significant decline from baseline (from 4345672 to 47207 logs IU/mL and from 24175475 to 23407 logs IU/mL, respectively). All 22 patients had undetectable viremia at end of therapy (ETR = 100%) and during follow-up at 12 and 24 weeks after completion of therapy (both SVR12 and SVR24 = 100%). Changes in the liver enzyme levels are shown in Figure 1. Serum AST, ALT, and GGT levels showed significant decrease during treatment. All the three enzyme levels had normalized by end of therapy and remained similar during the follow-up period.

Table 3 Clinical parameters of patients during and after treatment

Close

Figure 1

Liver enzyme levels before, during, and after therapy. *Significant (P < 0.05) in comparison to corresponding baseline (w0) values

Export to PPT

Compared to baseline, there was a significant fall in hemoglobin levels [Figure 2] at 4 weeks (w4 vs. w0, P = 0.000) and at 12 weeks of therapy (w12 vs. w0, P = 0.037); however, levels became similar at end of treatment (w24 vs. w0, P = 0.112) and on follow-up (w36 vs. w0, P = 0.692 and w48 vs. w0, P = 0.249). Initial ribavirin dose of 600 mg was reduced to 400 mg in five patients and to 200 mg in one patient due to progressive anemia. Four out of these 6 patients had impaired kidney function at baseline (eGFR of 34.2, 37.2, 42.5, and 42.6 ml/min/1.73 m²). Three patients required oral iron and erythropoietin supplementation. One patient with hemoglobin of <7 mg/dl had received one unit of packed red blood cell transfusion. All patients completed therapy with ribavirin. There was no significant change in platelet count during the entire study period.

Close

Figure 2

Hemoglobin levels before, during, and after therapy. *Significant (P < 0.05) in comparison to corresponding baseline (w0) values

Export to PPT

As compared to baseline values, there was no significant changes in eGFR [Figure 3] during or after completion of therapy. There was no significant change in spot urinary protein-to-creatinine ratios from baseline values to end of therapy and last follow-up. There was no episode of acute rejection or any graft loss during the study period.

Close

Figure 3

Estimated glomerular filtration rate levels before, during, and after therapy. *Significant (P < 0.05) in comparison to corresponding baseline (w0) values

Export to PPT

All patients were on triple immunosuppression including a CNI (tacrolimus, n = 20 or cyclosporine, n = 2). There was a significant decrease in tacrolimus trough level [Figure 4] during treatment, at the end of treatment, and during the follow-up period. Compared to baseline, tacrolimus dose was higher during treatment, at the end of therapy, but was similar at end of follow-up. Twelve patients required tacrolimus dose adjustment during DAA therapy (increased, n = 10/12, 83% and decreased, n = 2/12, 17%) and 8 patients required dose adjustment during follow-up (increased, n = 5/8, 62% and decreased, n = 3/8, 38%). There was no alteration in cyclosporine level or dose. Doses of mycophenolate and prednisolone were not changed during the study.

Close

Figure 4

Tacrolimus trough levels and tacrolimus doses before, during, and after therapy. *Significant (P < 0.05) comparisons with corresponding baseline (w0) values

Export to PPT

Eight patients had new-onset diabetes after transplantation (NODAT); six patients were on insulin therapy and one patient was on oral hypoglycemic agent. There was neither a significant change in fasting glucose levels nor requirement of total insulin dose during or after treatment.

Discussion

In the present study, we observed RVR and SVR with the therapy without any breakthrough HCV replication during the study period. Treatment was associated with rapid decline in both hepatocellular and biliary duct injury as evidenced by rapid normalization serum levels of AST, ALT, and GGT during initial 4 to 12 weeks. Our results were similar to those recently published studies with the use of DDAs in renal allograft recipients with RVR of 70%–88%, ETR of 100%, and SVR12 of 100%.[1314] Similar to them, we have also observed that tolerance to the therapy was excellent without significant adverse effects that can be attributed to sofosbuvir, daclatasvir, or ledipasvir. The fall in hemoglobin level (mean decrease of 0.8 mg/dl) in ribavirin-based therapy was expected; however, it was well tolerated. Ribavirin exerts concentration-dependent toxicity through oxidative membrane damage leading to extravascular hemolysis and fall in hemoglobin.[19] Ribavirin dose was reduced because of progressive anemia in three patients; other patients were managed with iron and erythropoietin supplementation. Only one of the patients required blood transfusion. Of note, all the three patients who developed anemia after ribavirin had preexisting allograft dysfunction (i.e., eGFR of 30–44 ml/min/1.73 m²). However, no patient discontinued ribavirin before completion of therapy. Incremental dosing protocol with a weight-based maximum dose of ribavirin and use of erythropoietin can minimize this problem.[20] There was no significant change in renal function or degree of proteinuria during the study. No episode of acute rejection or graft loss occurred.

Although HCV-infected renal transplant recipients had poorer patient and graft survival rates than non-infected ones, still renal transplantation offers significant survival advantage as compared to those who remain on dialysis, thus is considered as the treatment of choice.[34] As compared to non-infected renal allograft recipients, these patients carry increased risk of NODAT, secondary infections, and acute liver failure.[12] Excess mortality is due to higher incidence of cardiovascular disease, sepsis, chronic liver disease, and malignancy.[3] Lower allograft survival has been attributed to higher rate of rejections, transplant glomerulopathy, and de novo post-transplant glomerular disease.[21] The treatment of HCV infection has been associated with decrease in the incidence of these complications.[22] However, IFN-based therapy is relatively contraindicated in renal allograft recipients because of high incidence of acute rejections.[59] The accumulating data on safety and efficacy of DDAs will boost confidence of using these agents in the treatment of HCV infection in post-transplant period.[23]

A trend of decrease in tacrolimus trough levels was observed during therapy and increase in dose of tacrolimus was required to maintain the recommended drug level for that period. Similar observations have been reported from previous studies.[1214] Patients with chronic liver disease usually require lesser dose of CNIs to maintain similar trough levels as compared to those without.[24] The mechanism of increased calcineurin level in HCV-infected patients and its decline after clearance of viremia is currently unknown and may be related to alteration of hepatic metabolism of the drug and improvement in hepatic function.[2425] Hence, frequent drug-level monitoring and careful dose adjustment are required during and after therapy to prevent acute rejection due to lower drug levels. However, we have not studied the changes in the area under curve of the tacrolimus with the therapy in these patients.

Conclusion

Sofosbuvir-based therapy is highly effective and well tolerated without any adverse impact on renal function in HCV-infected renal allograft recipients. Although initial results are promising, the long-term outcomes including breakthrough HCV replication and effect on progression of chronic liver disease are yet to be seen.