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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
LETTER TO THE EDITOR  
Year : 2019  |  Volume : 30  |  Issue : 5  |  Page : 1184-1186
Severe hepatotoxicity of ritonavir, ombitasvir, paritaprevir, and dasabuvir in a kidney transplant recipient


Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, University Hospital Center Zagreb and School of Medicine, University of Zagreb, Zagreb, Croatia

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Date of Submission04-Dec-2018
Date of Acceptance06-Dec-2018
Date of Web Publication4-Nov-2019
 

How to cite this article:
Bukal N, Furic-Cunko V, Juric I, Katalinic L, Dedo A, Basic-Jukic N. Severe hepatotoxicity of ritonavir, ombitasvir, paritaprevir, and dasabuvir in a kidney transplant recipient. Saudi J Kidney Dis Transpl 2019;30:1184-6

How to cite this URL:
Bukal N, Furic-Cunko V, Juric I, Katalinic L, Dedo A, Basic-Jukic N. Severe hepatotoxicity of ritonavir, ombitasvir, paritaprevir, and dasabuvir in a kidney transplant recipient. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2019 Nov 23];30:1184-6. Available from: http://www.sjkdt.org/text.asp?2019/30/5/1184/270279


To the Editor,

Hepatitis C virus (HCV) is considered a risk factor for progression of chronic kidney disease, posttransplantation glomerular disease, rejection, and poor kidney graft survival. It is an important cause of morbidity and mortality in kidney transplant recipients and is assodated with new-onset diabetes and posttransplant lymphoproliferative disorder.[1] However, HCV-infected patients have a lower mortality following transplantation compared with mortality on dialysis and HCV infection in the potential recipient is not a contraindication for transplantation. Most HCV-infected transplant recipients are infected prior to transplant, while on dialysis. The transmission of HCV through kidney transplantation is rare due to screening of donors.[2] All transplant candidates should be screened for HCV infection including those who were previously successfully treated for HCV infection, with advances in HCV antiviral therapy. HCV infection can be successfully cured in the majority of patients, either before or after the transplant.[3] Regimen selection for the treatment of chronic HCV infection after transplantation depends on genotype, extent of underlying liver disease, and antiviral treatment history, as well as potential drug interactions and availability and costs of comparable regimens.[4],[5] Ombitasvirparitaprevir-ritonavir with or without dasabuvir is most susceptible to drug interactions with immunosuppressant drugs, mainly due to the influence of ritonavir on multiple enzymes. The interactions between calcineurin inhibitors and ritonavir can be difficult to control, and blood levels of calcineurin inhibitors can be reduced for up to three months after direct-acting antiviral (DAA) therapy. If this antiviral therapy is used with cyclosporine, the dose of cyclosporine should be reduced to one-fifth of the current dose with frequent measurement of cyclosporine levels and subsequent dose modifications. Upon discontinuation of antiviral therapy, the previous cyclosporine dose should be resumed based on therapeutic drug monitoring.[5],[6] Furthermore, 1% of individuals experienced serum alanine transaminase (ALT) levels greater than 5 times the upper limit of normal after starting treatment. It is typically asymptomatic, generally occurred during the first four weeks of treatment (mean time 20 days, range 8–57 days), and most, resolved with ongoing therapy.[7]

Informed consent was obtained from the patient before presenting the report.

A 52-year-old man with an end-stage renal disease caused by membranoproliferative glomerulonephritis received his allograft from a deceased donor in February 2008. He was hospitalized in May 2018 for titration of the dose of cyclosporine due to approved therapy for chronic HCV infection with ritonavir, ombitasvir, paritaprevir, and dasabuvir. He had started with hemodialysis in 1990. During the year 1999, he was infected with HCV, genotype 3a, received interferon-alpha (INF-a) during the next year and achieved sustained virologie response until the year 2002, when he got re-infected with HCV-genotype 1b that was not treated. After the transplantation in February 2008, serum creatinine values were between 180 and 200 μmol/L until October 2016 when he was hospitalized because of atrial fibrillation. Coronary angiography revealed subtotal stenosis of the left anterior descending artery and 50% stenosis of the obtuse marginal branch. He was treated with non-vitamin K oral anticoagulant (rivaroxaban), and amiodarone, which was introduced in 2016. In January 2017, he was readmitted to the hospital for the evaluation of allograft dysfunction. Biopsy showed chronic active humoral rejection with positive donor-specific antibodies. He received boluses of corticosteroids and intravenous immunoglobulins. Gradually, the serum creatinine decreased to basic values. Considering that the HCV infection was detected early and untreated, genotype was 1b with mildly elevated values of aminotransferases, the hepatologist suggested DAA-based INF-free treatment for 12 weeks (8 weeks may be considered in previously untreated genotype lb-infected patients with minimal-to-moderate fibrosis). Fibroscan showed stiffness of 7.1 kPa and IQR (EXPAND) of 2.6 kPa. HCV RNA was 9.62 ×106 IU. Before starting with DAA therapy, amiodarone was discontinued in consultation with the cardiologist (it is contra-indicated because of high dependence on CYP3A for clearance and, an elevated plasma level of this medication is associated with serious events).[6] Ten days after starting antiviral therapy, elevated serum levels of cyclosporine of 133–200 μg/L were noted (despite the reduction in dose to one-fifth of the initial dose) with hepatic impairment and dominant ALT elevation [ALT raised from 351–513–756 to 942 U/L, aspartate amino-transferase (AST) from 194–273–393 to 486 U/L, gamma glutamate transpeptidase and bilirubin were within the previous range and alkaline phosphatase was 103–100–106–129 U/L], Initially, in collaboration with the hepatologist, it was thought that it was a toxic lesion caused by elevated cyclosporine and hence, the dose was further decreased. However, despite normal levels of cyclosporine, AST and ALT levels were still increasing. A toxic reaction to antiviral therapy was suspected, and after 22 days, DAAs were stopped which resulted in return of aminotransferases to almost normal values. Subsequent values of HCV RNA were negative, which further supports a toxic effect of antiviral medications. He was discharged from the hospital with serum creatinine of 280 μmol/L, which on the last visit had decreased to 180 μmol/L; HCV RNA remained negative.

HCV infection increases morbidity and mortality after renal transplantation. The decision of when and how to treat HCV-infected kidney transplant candidates and recipients should be tailored on an individual basis, in close collaboration with specialists in transplant and HCV management.[4] We describe a case of a kidney transplant recipient with HCV infection and newly verified hepatic lesion after starting antiviral treatment, which was a result of drug-to-drug interactions and toxicity due to the high number of co-medications and the burden on liver metabolism of the majority of antivirals.

In conclusion, given the importance of interaction between immunosuppressive and antiviral therapy, we suggest that renal transplant recipients with HCV infection should be closely monitored by both hepatologists and nephrologists with a frequent determination of cyclosporine trough levels and serum creatinine measurements.

Conflict of interest: None declared.



 
   References Top

1.
Lee JJ, Lin MY, Chang JS, et al. Hepatitis C virus infection increases risk of developing end-stage renal disease using competing risk analysis. PLoS One 2014;9:e100790.  Back to cited text no. 1
    
2.
Baid-Agrawal s, Pascual M, Moradpour D, Somasundaram R, Muche M. Hepatitis C virus infection and kidney transplantation in 2014: What’s new? Am J Transplant 2014:14:2206-20.  Back to cited text no. 2
    
3.
Kidney Disease: Improving Global Outcomes. KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of Hepatitis C in chronic kidney disease. Guideline 4: Management of HCV-infected patients before and after kidney transplantation. Kidney Int 2008;73:S53-68.  Back to cited text no. 3
    
4.
Recommendations for Testing, Managing and Treating Hepatitis c. Joint panel from the American Association of the Study of Liver Diseases and the Infectious Disease Society of America. Available from: http://www.hcvguidelines.com. [Last accessed on 2018 Nov 25].  Back to cited text no. 4
    
5.
Sawiński D, Kaur N, Ajeti A, et al. Successful treatment of hepatitis C in renal transplant recipients with direct-acting antiviral agents. Am J Transplant 2016 ; 16:1588-95.  Back to cited text no. 5
    
6.
Available from: https://www.medicines.org.uk/emc/product/3644/smpc# UNDESIRABLE_EFF ECTS. [Last accessed on 23 November 2018].  Back to cited text no. 6
    
7.
Fernández I, Muñoz-Gómez R, Pascasio JM, et al. Efficacy and tolerability of interferon-free antiviral therapy in kidney transplant recipients with chronic hepatitis Cz. J Hepatol 2017:66: 718-23.  Back to cited text no. 7
    

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Correspondence Address:
Nikolina Basic-Jukic
Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, University Hospital Center Zagreb and School of Medicine, University of Zagreb, Zagreb
Croatia
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DOI: 10.4103/1319-2442.270279

PMID: 31696862

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