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Volume: 17 Issue: 1 February 2019

FULL TEXT

ARTICLE
Successful Treatment With Direct-Acting Antiviral Agents of Hepatitis C in Patients With End-Stage Renal Disease and Kidney Transplant Recipients

Objectives: The introduction of direct-acting antiviral agents has allowed significant chances for treatment for difficult-to-treat populations. This study aimed to investigate the efficacy, tolerability, and safety of these therapies in both patients with end-stage renal disease and kidney transplant recipients with chronic hepatitis C virus infection.

Materials and Methods: This study was a retrospective analysis with prospective follow-up of patients. The antiviral combination of ombitasvir 25 mg, paritaprevir 75 mg, ritonavir 50 mg, and dasabuvir 50 mg was prescribed to patients with end-stage renal disease or kidney transplant recipients with noncirrhotic or compensated cirrhotic liver disease. The other antiviral combination consisted of sofosbuvir 400 mg and ledipasvir 90 mg, which was recommended to patients with decompensated cirrhosis or those who could not tolerate the first combination regimen. Ribavirin was given to all patients with genotype 1a hepatitis C virus infection. All clinical and laboratory data were recorded at week 4, at end of the treatment, and at 12 weeks after completion of treatment.

Results: In terms of efficacy, sustained virologic response at 12 weeks was achieved in 94% of patients in the end-stage renal disease group and 92% of patients in the kidney transplant group. In terms of tolerability, antiviral treatment was well tolerated in both groups. Cardiac arrest and cerebrovascular accident were seen in the end-stage renal disease group; severe mucositis and glossitis were seen in the kidney transplant group. Hospitalization was needed in 2 patients for treatment of drug interactions with tacrolimus and sirolimus. Renal allograft function worsened in 2 patients, with 1 patient having biopsy-proven antibody-mediated rejection.

Conclusions: We observed great efficacy and safety in both kidney transplant recipients and patients with end-stage renal disease with these agents in treatment of chronic hepatitis C. However, clinicians should remain aware of drug interactions and adverse events in this fragile patient population.


Key words : Immunosuppressive medication, Renal transplant, Sustained virologic response

Introduction

A large observational study on dialysis outcomes and practice patterns conducted between 1996 and 2011 reported that 4735 of 49 762 hemodialysis patients are hepatitis C virus (HCV) positive; however, only about 1% have received antiviral treatment.1 As such, the prevalence of HCV infection in kidney transplant recipients is inevitably common.2 Hepatitis C virus infection can negatively affect patients with end-stage renal disease (ESRD) through increased all-cause mortality attributed not only to liver disease-related death but also to cardiovascular mortality.3 In kidney transplant recipients, HCV infection is an independent risk factor for allograft loss, chronic rejection, transplant glomerulopathy, new-onset diabetes, cardiovascular disease, sepsis, and progressive liver disease.4

Until recently, interferon-based treatment regimens have been used in ESRD patients; however, these have not always been effective or tolerable.5 In addition, kidney transplant recipients could not receive this treatment for HCV infection, except for limited indications, due to the high risk of interferon-induced allograft dysfunction.5,6 The development of direct-acting antiviral agents (DAAs) has dramatically changed the treatment of HCV infection, with successful virus eradication rates and good safety profiles in special populations.7-9

In this study, our aim was to investigate the efficacy, tolerability, and safety of DAA combination therapies in both patients with ESRD and kidney transplant recipients with chronic HCV infection.

Materials and Methods

This study was a retrospective analysis with pros­pective follow-up of ESRD patients requiring hemo­dialysis and kidney transplant recipients who underwent HCV treatment with DAAs post­transplant at the Baskent University Ankara Hospital. Ethics committee approval was received for this retro­spective analysis from the local ethics committee of our institute. All adult patients who met the criteria were enrolled in this study irrespective of their liver fibrosis stage, HCV genotype, or prior HCV treatment history and response. Other inclusion and exclusion criteria were not described. Treatment decisions, including the administration of antiviral medications, were made at the discretion of the gastroenterologist. The choice of DAA com­bination, the treatment duration, and the use of ribavirin were in accordance with the clinical and laboratory characteristics of each patient and in accordance with approval criteria of the national public health insurance system. Patient follow-up was from 12 to 24 weeks depending on treatment duration.

The antiviral combination of ombitasvir 25 mg, paritaprevir 75 mg, ritonavir 50 mg, and dasabuvir 50 mg (OBV/PTV/r + DSV) (AbbVie Inc, Chicago, IL, USA) was prescribed to patients with ESRD or kidney transplant recipients with noncirrhotic or compensated cirrhotic liver disease. The other antiviral combination consisted of sofosbuvir 400 mg and ledipasvir 90 mg (Gilead Sciences, Foster City, CA, USA), which was recommended to patients with decompensated cirrhosis or to those who could not tolerate the first combination regimen because of adverse effects or drug interactions. There were no dose adjustments for these DAAs. Ribavirin was given to all patients with genotype 1a HCV infection in accordance with body weight and glomerular filtration rate (GFR). Hence, daily ribavirin doses were as follows: 1000 mg daily for patients < 75 kg, 1200 mg daily for kidney transplant recipients > 75 kg, or 200 mg daily for ESRD patients > 75 kg. Dose reduction or interruption of ribavirin was performed for hematologic adverse events such as severe anemia (hemoglobin level of ≤ 10 g/dL) or when transfusion of packed red blood cells was required. Treatment durations were 12 or 24 weeks based on genotype of HCV and presence of signs of decom­pensated cirrhosis.

Decompensated cirrhosis was defined as the presence of portal hypertension, ascites, varices, spontaneous bacterial peritonitis, hepatic encepha­lopathy, hypoalbuminemia, hyperbilirubinemia, and prolonged prothrombin time. Glomerular filtration rate was calculated using the Modification of Diet in Renal Disease 6 equation formula. A determination of ESRD was given when estimated GFR was lower than 15 mL/min/1.73 m2 or when renal replacement therapy was necessary.10

Demographics, clinical characteristics, comor­bidities and their associated treatment, laboratory tests, concomitant immunosuppressive therapies, adverse events, and virologic data were recorded before treatment, at week 4, at end of treatment, and at 12 weeks after completion of treatment. Complete blood count, serum electrolyte levels, renal function tests, liver function tests, and HCV RNA tests were done at every scheduled clinic appointment. Immunosuppressive levels were only examined for kidney transplant recipients.

Hepatitis C virus RNA was assessed using the quantitative Cobas Amplificator HCV (Roche Molecular Diagnostics, Indianapolis, IN, USA) monitor assay (limit of detection, 15 log IU/mL). Hepatitis C virus genotype and subtype were determined using the Versant HCV Genotype 2.0 test (Siemens Healthcare Diagnostics, Deerfield, IL, USA) line probe assay. Undetectable HCV RNA was defined as virologic response assessed at 4 weeks of treatment and at end of treatment and sustained virologic response at week 12 posttreatment (SVR12). Detectable HCV RNA at any time during treatment was defined as virologic nonresponse.

Adverse events were listed by the physician at every clinic visit and graded based on the World Health Organization toxicity grading scale for determining the severity of adverse events.11

Statistical analyses
Data are presented as either mean and standard deviation or median (ranges). Proportions were compared by chi-square test or Fisher exact test. Quantitative variables were compared by the nonparametric Friedman test. P < .05 was considered to be statistically significant. Statistical analyses were performed using SPSS software (SPSS: An IBM Company, version 19.0, Armonk, NY, USA).

Results

Eighteen patients with ESRD and 12 kidney trans­plant recipients with chronic HCV infection received DAAs from June 2016 to May 2017. Each group was evaluated separately.

In the ESRD group, 12 patients were male, and median age was 55.5 years (range, 40-71 y). All 18 patients had been on hemodialysis for 17.4 ± 4.5 years due to stage 5 chronic kidney disease. The most com­mon cause of ESRD was hypertension (11 patients), which was followed by diabetic nephropathy (4 patients). Seven patients had previous renal transplant and chronic rejection history. The mean estimated GFR was 6 mL/min. The mean baseline hemoglobin level was 10.2 g/dL. Average duration of HCV infection before initiation of DAAs was 15.4 ± 4.4 years. Eleven patients were treatment naive, 4 patients had relapses after interferon treatment, 2 patients were nonres­ponders, and 1 was intolerant to ribavirin because of anemia. None of the patients had decompensated cirrhosis. Thirteen patients had genotype 1b HCV infection; the remaining patients had genotype 1a HCV infection. The baseline mean viral load was 170 000 IU/mL (695 to 2 950 000 IU/mL). Twelve patients received OBV/PTV/r + DSV for 12 weeks, 5 patients received OBV/PTV/r + DSV + ribavirin for 12 weeks, and 1 patient received the sofosbuvir + ledipasvir com­bination for 24 weeks (Table 1).

The kidney transplant group included 8 men and 4 women, with median age of 51 years (range, 37-67 y). Estimated median time since kidney transplant was 9 years (range, 5-36 y). Seven patients received transplants from living donors, and 6 patients received transplants from deceased donors, with 1 patient having 2 kidney transplants. Average duration of HCV infection before initiation of DAAs was 14.2 ± 5.8 years. The mean estimated GFR was 81.72 mL/min. The mean baseline hemoglobin level was 11.5 g/dL. Five patients (42%) were treatment experienced, and 2 patients (17%) had cirrhosis. Nine patients had genotype 1b HCV infection, and 3 patients had genotype 1a HCV infection. The patients had a mean baseline viral load of 2 280 000 IU/mL (29 300 to 30 900 000 IU/mL). Planned treatment duration was 12 weeks for the 8 patients who received OBV/PTV/r + DSV, the 1 patient who received OBV/PTV/r + DSV + ribavirin, the 1 patient who received sofosbuvir + ledipasvir, and the 1 patient who received sofosbuvir + ledipasvir + ribavirin. Only 1 patient received sofosbuvir + ledipasvir for 24 weeks (Table 2).

Efficacy
In the ESRD group, all patients had undetectable HCV RNA at 4 weeks after initiation of antiviral therapy. Of the 18 patients, 17 patients (94.4%) showed undetectable HCV RNA at the end of treatment, with SVR12 also achieved in these 17 patients (rate of 94.4%). Hepatitis C virus RNA was still negative in 10 patients at 24 weeks after treatment.

In the kidney transplant group, HCV RNA was undetectable in serum at week 4 in 11 patients (92%) and remained undetectable until the end of treatment, with SVR12 also achieved (rate of 92%). Hepatitis C virus RNA was still negative in 7 patients at 24 weeks after treatment.

We observed no differences between patients with or without cirrhosis in terms of SVR12 (100%).

Tolerability and safety
Antiviral treatment was well tolerated in both groups. The most frequent adverse effects were fatigue, nausea, and headache, which did not require any change or discontinuation of medications.

In the ESRD group, 3 patients who received ribavirin had grade 2/3 anemia, resulting in ribavirin dose adjustment or transient cessation and blood product transfusions. One patient with coronary artery disease history died because of ventricular tachycardia and cardiac arrest on day 35 of treatment. Cerebrovascular accident occurred in 1 patient in the ESRD group during treatment, but it was associated with diabetes mellitus and atherosclerosis instead of an adverse drug effect. Although sofosbuvir use is not approved for patients with ESRD, one patient had to be treated with sofosbuvir + ledipasvir because this patient’s medication, amiodarone, was contraindicated with OBV/PTV/r + DSV. This patient was monitored closely, and no adverse effects were observed (Table 3).

In the kidney transplant group, only 1 patient who received ribavirin had grade 2 anemia, resulting in ribavirin dose reduction. One patient discontinued the OBV/PTV/r + DSV therapy on day 65 due to severe mucositis and glossitis (Figure 1). One patient with baseline GFR of 59 mL/min experienced worsening of GFR at the end of treatment with OBV/PTV/r + DSV. The patient required allograft biopsy, and chronic graft rejection was diagnosed. One patient terminated therapy prematurely at his own request on day 5 of treatment. He had severe skin rash and mild deterioration in GFR. No other significant deteriorations of GFR were shown in the other patients (Table 3).

Drug interaction with immunosuppressive agents
All patients were on steroid therapy, 8 patients were taking mycophenolic acid, 6 patients were taking sirolimus, 2 patients were on tacrolimus, and 2 patients were on cyclosporine. Seven patients who received OBV/PTV/r + DSV needed dose rear­rangement of the immunosuppressive agents. Tacrolimus, cyclosporine, and sirolimus doses were reduced gradually in these 7 patients (58%) because of high trough levels of the drugs. Daily doses of mycophenolic acid and steroids were not changed. Hospitalization was needed in 2 patients to perform dose adjustment and to eliminate the adverse effects from high serum levels of tacrolimus and sirolimus, especially in the early treatment period and despite immunosuppressive dose reduction. These 2 patients showed tacrolimus trough levels during therapy of 7 and 8 ng/mL at baseline, 30 and 12 ng/mL at week 4 of therapy, and 5.8 and 4 ng/mL at end of therapy.

Discussion

In this study, we evaluated the efficacy and safety of new-generation antiviral therapies for chronic HCV infection in patients with ESRD and in kidney transplant recipients on different immunosup­pressive medications. Our study was based on real-life data with prospective follow-up and retrospective assessment. It was clear that DAAs had high cure rates in these patients. We observed that DAAs are safe and have tolerable adverse effects. However, we encountered difficulty regarding management of interactions between DAAs and immunosuppressive medications. The most serious adverse effects were severe mucositis and glossitis, which required stopping of the medication. Renal allograft function worsened in 2 patients, with 1 patient having biopsy-proven antibody-mediated rejection and the other discontinuing therapy prematurely by his own decision. Expected anemia related to ribavirin use was resolved with dose reduction of ribavirin and blood transfusion.

Interferon-based therapy for HCV has been often contraindicated in the setting of kidney transplant because of increased risk of acute rejection.12,13 In addition, patients with ESRD have poor tolerance and outcomes with interferon-based regimens.12,13 After a 20-year interferon-based treatment modality, the introduction of DAAs has revolutionized HCV infection treatment, especially in these special populations.12,13 At our center, we have also observed great efficacy and safety in both kidney transplant recipients and patients with ESRD since the new-generation DAAs have become available.

In our ESRD group, the combination of OBV/PTV/r + DSV with or without ribavirin in 17 patients and the combination of sofosbuvir + ledipasvir in 1 patient were successful, with SVR12 rate of 94.4%. Moreover, HCV RNA was still negative in 10 patients at week 24 after treatment. Pockros and associates also showed that OBV/PTV/r + DSV provided success, with SVR12 rate of 90% in 20 patients with stage 4 or 5 chronic kidney disease.14

Because sofosbuvir is eliminated by the renal pathway, the risk of drug accumulation in patients with stage 4 or 5 chronic kidney disease should be of concern.15 However, the use of sofosbuvir-based therapies in patients with baseline renal function impairment (estimated GFR < 45 mL/min) is associated with a higher virologic response and lower risk of worsening renal function and adverse events.15 Li and associates16 published a meta-analysis of 11 studies involving the reports of Roth and colleagues, Saxena and colleagues, and Toyoda and colleagues in which the Newcastle-Ottawa scale score was 9. This meta-analysis comprised 264 patients, who were assessed and compared regarding efficacy of sofosbuvir-based therapies and non-sofosbuvir-based therapies. Comparisons showed SVR12 rates of 89.4% and 94.7%, respectively.16 It was concluded that there were no significant differences in efficacy between these 2 therapeutic regimens in patients with ESRD.16 The most common adverse effect was anemia, with 12.1% having severe adverse effects.16 Cardiac disorders were found in 6 patients, and 1 patient died because of cardiac arrest.16 Four patients had vascular disorders.16

In 98 patients with stages 1 to 3 chronic kidney disease on sofosbuvir-based therapy, Sise and associates reported that the overall SVR12 rate was 81% and adverse events were common (81%), but serious adverse events (17%) and treatment dis­continuations (8%) were not common.17 Our data support these findings, showing that the 17 patients on OBV/PTV/r + DSV with or without ribavirin and the 1 patient on sofosbuvir + ledipasvir, all of whom were on hemodialysis with estimated GFR < 30 mL/min, had safe and successful treatment. No patient required therapy discontinuation due to antiviral therapy-related adverse events. However, 3 of our patients had also anemia, 1 patient died due to cardiac arrhythmia and cardiac arrest, and 1 patient had a type of cerebrovascular accident. Although we did not associate these reactions to the treatment directly, except anemia, more data are needed to distinguish the adverse events from probable clinical complications because of preexisting conditions (diabetes mellitus, atherosclerosis, and so forth). Although there appears to be a risk of ribavirin-related anemia, ribavirin has not been removed from our treatment protocols, with no reduction in antiviral activity in this group with removal. Moreover, stable hemoglobin levels can be maintained by dose reduction or temporary cessation of ribavirin.

In the kidney transplant group, OBV/PTV/r + DSV with or without ribavirin in 8 patients and sofosbuvir + ledipasvir with or without ribavirin in 3 patients were successful combinations, showing SVR12 of 92%. Moreover, HCV RNA was still negative in 7 patients at 24 weeks after completion of treatment. Gentil and associates reported that, in 9 kidney transplant recipients who were treated with OBV/PTV/r + DSV, 5 patients finished treatment; however, the other 4 patients stopped therapy early because of neurotoxicity, hepatotoxicity and gastro­intestinal events.18 This multicenter study from Spain showed that antiviral therapy with sofosbuvir in 108 other kidney transplant patients resulted in virologic response in 97.8% of patients.18 In a study of 443 posttransplant patients evaluated by Saxena and associates, 52 of 55 patients had noticeable SVR12 (94.5%) when treated with sofosbuvir-containing regimens (n = 46) or when treated with OBV/PTV/r + DSV therapy (n = 9).19 Kamar and associates showed a 100% SVR12 rate in 25 kidney transplant recipients who were treated with sofosbuvir-based therapies.20 In a multicenter phase 2 clinical trial, Colombo and associates observed SVR12 of 99% in 114 kidney transplant recipients treated with sofosbuvir + ledipasvir.21

The kidney transplant recipients in our study showed some adverse reactions and adverse antiviral interactions with immunosuppressive medications. One patient experienced chronic graft rejection, and another patient had severe mucositis and glossitis. Ribavirin-containing regimens caused grade 2 anemia in 2 patients. Seven kidney transplant reci­pients required rearrangement of immunosup­pressive therapy. In 103 kidney transplant recipients who received DAAs and predominantly sofosbuvir-based therapy, Fernandez and associates reported that 55% of patients required dose adjustments in their immunosuppressive drugs.22 It is especially important to note that drug interactions were more prominent with the use of OBV/PTV/r + DSV in our study, similar to previously reported.23 Trough concentrations of tacrolimus, cyclosporine, and sirolimus were strictly monitored during the treatment. We performed proper dose regulation of immunosuppressant drugs according to the recommendations supplied by the manufacturers. It is noteworthy that only 2 patients had allograft dysfunction under controlled immunosuppressive dose. However, we were not able to elucidate which factors were related to renal dysfunction beyond antiviral therapy or immunosuppressants in the patients. Bhamidimarri and associates reported that, in 15 kidney transplant recipients treated with sofosbuvir + ledipasvir with or without ribavirin, renal function frequently worsened, with 3 patients (20%) having biopsy-proven antibody-mediated rejection and 10 patients (67%) requiring tacrolimus dose adjustments.24 In contrast, Saxena and colleagues found that impaired renal function was exceptional and mainly related to supratherapeutic tacrolimus levels.19

Despite the promising results regarding the use of DAAs, our study had several limitations. First, our sample size was not sufficient to allow a precise verdict. Second, the treatment regimens were mainly determined in accordance with national health insurance rules regarding economic restrictions on reimbursement of DAAs in our country. This explained why the sofosbuvir + ledipasvir combination was less often used compared with other reports. Finally, we did not evaluate fibrosis stage in all patients, with only some patients having liver biopsy. In addition, liver ultrasonography was not yet available in our clinic.

In conclusion, our results overall strongly supported that antiviral treatment of HCV infection with DAAs is highly efficacious and well-tolerated in patients with ESRD and in kidney transplant recipients. The addition of ribavirin to the treatment protocols requires further confirmation in a larger series. Because this patient population has a fragile background due to comorbidities and the necessity of close follow-up and dose adjustments of immuno­suppressive agents, clinicians who are involved in their care should remain aware of drug interactions and adverse events.


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Volume : 17
Issue : 1
Pages : 52 - 58
DOI : 10.6002/ect.2018.0095


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From the 1Department of Gastroenterology, the 2Department of Nephrology, and the 3Department of Transplant Surgery, Baskent University Faculty of Medicine, Ankara, Turkey
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Diğdem Özer Etik, Cevher Sok. No: 7/12 Kurtulus, Ankara 06511, Turkey
Phone: +90 5332402368
E-mail: digdemozer@hotmail.com