Case report Telaprevir in a patient with chronic hepatitis C and cryoglobulinemic glomerulonephritis

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1 Antiviral Therapy 04; 9:57 5 (doi:.85/imp684) Case report Telaprevir in a patient with chronic hepatitis C and cryoglobulinemic glomerulonephritis Stella De Nicola, Alessio Aghemo *, Maria Rosaria Campise, Roberta D Ambrosio, Maria Grazia Rumi, Piergiorgio Messa, Massimo Colombo Centro A.M. e A. Migliavacca, First Division of Gastroenterology, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy Nephrology and Dialysis Division, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy Unità Operativa di Epatologia, Ospedale San Giuseppe, Università degli Studi di Milano, Milan, Italy *Corresponding author Alessio.aghemo@policlinico.mi.it Mixed cryoglobulinemia (MC), the most common extrahepatic manifestation of HCV, may lead to renal involvement ranging from mild urinary abnormalities to nephritic syndrome, eventually evolving to renal failure requiring renal replacement therapy. HCV eradication with pegylated interferon (PEG-IFN) and ribavirin (RBV) is the only curative treatment for MC-related membranoproliferative glomerulonephritis. The addition of directly acting antivirals (DAAs) to PEG-IFN and RBV has significantly improved sustained virological response rates in HCV genotype patients. Safety and efficacy of this regimen in patients with membranoproliferative glomerulonephritis has not been proved yet. Here, we report the case of a woman with HCV--related cryoglobulinemic membranoproliferative glomerulonephritis presenting with severe nephritic syndrome and rapidly progressive renal failure, who received successful treatment with the DAA telaprevir in conjunction with PEG-IFN and RBV. Triple therapy was safe and effective, leading to HCV eradication and complete resolution of acute renal failure. Introduction A significant proportion of patients with chronic HCV infection manifests with at least one extrahepatic involvement during the course of their illness []. The most common extrahepatic manifestation is mixed cryoglobulinemia (MC), which is characterized by the presence of circulating immunocomplexes produced by a B-cell lymphoproliferative disorder []. In most cases MC follows an asymptomatic or paucisymptomatic course, whereas in a minority of patients it can lead to kidney function impairment due to membranoproliferative glomerulonephritis []. Kidney involvement can range from asymptomatic urinary abnormalities, mild proteinuria or hematuria, to nephrotic or nephritic syndrome, and some patients progress to chronic renal insufficiency [4]. It is essential to recognize, diagnose and treat HCV extrahepatic syndromes, even in presence of a mild liver disease. Treatment options for HCV-related glomerulonephritis can be symptomatic, aetiological and pathogenetic, with viral eradication or suppression being universally recognized as the ideal standard-of-care [5]. Although interferon (IFN)-a, pegylated IFN-a (PEG-IFN) and ribavirin (RBV) appear to be safe and effective in patients with MC [6], little is known about the association of first-generation protease inhibitors (telaprevir [TVR] or boceprevir [BOC]) with PEG-IFN and RBV in the more difficult-to-treat HCV- patients. In Phase III studies, triple therapy led to a 5 0% increase in sustained virological response (SVR) rates in HCV--naive patients and a 40 50% increase in SVR rates in HCV- treatment-experienced patients [7 ]. Unfortunately these data, obtained from registration trials, cannot be easily transferred to patients with MCrelated kidney involvement since patients with impaired renal function were excluded. Here, we describe the case of a woman with HCV- chronic hepatitis complicated with cryoglobulinemic glomerulonephritis, who has been successfully and safely treated with a TVR-based regimen. Case A 4-year-old woman has been followed at our centre (Liver Center of the Ospedale Maggiore Policlinico, 04 International Medical Press (print) (online) 57

2 S De Nicola et al. Milan, Italy) since 007 for chronic HCV-b infection, acquired through a blood transfusion in 987 for surgical reasons. At the time of presentation, blood tests showed transaminase values the upper limit of normal, high viral load (,49,08 IU/ml) and preserved liver function tests. Transient elastography and abdominal ultrasound showed no signs of advanced disease. Antiviral treatment was deferred for personal reasons with the patient maintaining regular follow-up visits every 6 months. In May 009, the patient suddenly developed nephritic syndrome and rapidly progressive renal failure requiring hospitalization. A kidney biopsy was performed and showed a diffuse and active membranoproliferative glomerulonephritis with a large amount of endocapillary thrombi and small vessel occlusion due to heavy myointimal proliferation. At that time antiviral therapy with PEG-IFN and RBV was contraindicated due to heart failure, thus the patient was treated with multiple dialytic sessions, plasmapheresis and immunosuppressive therapy with methylprednisolone and mycophenolate mofetil. This was associated with progressive improvement and renal function returned to normal values on April 0. Initial immunosuppressive regimen was slowly tapered and it was decided to treat the patient with PEG-IFN-aa 80 mg/ week and ribavirin 800 mg/day for 48 weeks under strict hepatological and nephrological follow-up visits. Transaminase values quickly normalized and HCV RNA values decreased > logs compared with baseline after weeks of treatment, eventually becoming undetectable at week 0. During treatment we observed a progressive reduction of proteinuria (from 0.6 g/day to 0. g/day) and persistently normal renal function (plasma creatinine mg/dl and glomerular filtration rate 9 ml/min). Treatment was stopped at week 48 but a virological relapse was observed 4 weeks after therapy completion (Figure ). Complete blood and urine examinations performed after occurrence of relapse showed mild progressive increase in proteinuria suggesting a kidney flare. On December 0 the patient was hospitalized with acute renal failure due to recurrent nephritic syndrome. Treatment with six sessions of plasmapheresis and concomitant immunosuppressive therapy Figure. Biochemical and virological parameters during first treatment course and 6 months follow-up PEG-IFN 80 µg/weeks + RBV 800 mg/day HCV RNA Proteinuria 6 Stop treatment.5 HCV RNA, log copies/ml Proteinuria amount, g/day Limit of detection Baseline f.up f.up 6 f.up Creatinine, mg/dl Haemoglobin, g/dl F.up, follow-up; PEG-IFN, pegylated interferon-α; RBV, ribavirin International Medical Press

3 Telaprevir in HCV and cryoglobulinemic glomerulonephritis with methylprednisolone and mycophenolate mofetil was started. During admission, proteinuria partially remitted and after months, kidney function returned to normal values. Proteinuria was still present but below g/day. Given the deterioration of kidney function associated with HCV relapse and the on-treatment response to the previous course of PEG-IFN/RBV therapy, we decided to re-treat the patient with anti-hcv therapy after mycophenolate mofetil withdrawal and methylprednisolone tapered to a maintenance dose of 5 mg/day. At that time both TVR and BOC were European Medicines Agency (EMA) approved but still not reimbursable in Italy. Of note, in non-cirrhotic HCV patients who relapsed to a previous course of PEG-IFN and RBV, the SVR rates in Phase III studies with TVR were 8% compared with %, with the former standardof-care PEG-IFN/RBV therapy [8,]. For this reason TVR was obtained through Janssen s compassionate use programme. In May 0 the patient started PEG-IFN-aa 80 mg/week, RBV 800 mg/day (8 mg/kg/day) and TVR 750 mg every 8 h. The choice to underdose RBV was motivated by the development of severe anaemia during the first course of PEG-IFN/RBV therapy, which required blood transfusions and epoetin-a support. Serum HCV RNA, measured by Abbott Real Time PCR (< lower limit of detection), became undetectable at week of therapy and remained undetectable until TVR completion (week ). The patient achieved an extended rapid virological response, defined as HCV RNA negativity from week 4 to week of treatment, which allowed us to stop treatment after 4 weeks []. During treatment, serum creatinine remained normal, proteinuria disappeared and no significant increase in estimated glomerular filtration rate measured with the CKD-EPI formula was noted (baseline: 8 ml/ min; week : 80 ml/min; week 4: 79 ml/min; Figure ). Treatment was generally well-tolerated, the only side effect being a grade anaemia managed with epoetin-a 0,000 UI/week and oral iron supplementation. The patient achieved an SVR as serum HCV RNA remained negative 4 weeks following Figure. Biochemical and virological parameters during second treatment course and 6 months follow-up PEG-IFN + RBV TVR 750 mg/8 h HCV RNA Proteinuria 6 Stop treatment.5 HCV RNA. log copies/ml Proteinuria amount, g/day Baseline f.up f.up 6 f.up Creatinine, mg/dl Haemoglobin, g/dl 9 8 F.up, follow-up; PEG-IFN, pegylated interferon-α; RBV, ribavirin; TVR, telaprevir. Antiviral Therapy

4 S De Nicola et al. treatment completion; no urinary abnormality has been detected so far (Figure ). Discussion To the best of our knowledge this is the first report of safe and effective TVR-based treatment of a patient with cryoglobulinemic membranoproliferative glomerulonephritis caused by HCV- infection. TVR and BOC are major breakthroughs for the treatment of patients with chronic HCV- infection. Most of the current knowledge on these regimens derives from Phase II and III studies and their relative sub-analysis, and only few real-life data experiences, which includes also patients with extrahepatic comorbidities, have been reported in detail [7,]. Thus, several groups of difficult-totreat, or difficult-to-cure patients, are still understudied, including patients with cirrhosis and patients with HCV-related glomerulonephritis excluded from these trials. Since no safety or efficacy data of TVR/BOC therapy in patients with clinically relevant MC syndrome have been reported, the Italian national health agency has excluded reimbursement for DAAs in patients with severe MC syndrome: a decision driven more from caution than from evidence. In theory efficacy and safety of TVR/BOC should not differ in patients with renal disease, with the exemption of anaemia, which can worsen in patients with kidney involvement. RBV clearance is reduced in patients with renal failure [,4], leading to increased blood concentrations of the drug and more severe on-treatment anaemia. In the presence of creatinine clearance below 50 ml/min, RBV adjusted dosage is recommended. Anaemia is often a severe complication of triple therapy, especially in patients with cirrhosis [5]. MCrelated anaemia should not be caused by TVR as the drug is mainly (>80%) excreted in faeces, leaving <% to renal excretion. Supporting TVR safety in patients with kidney disease, Dumortier and coworkers [6] described four HCV- haemodialysed patients awaiting kidney transplantation, who received TVR in France. Following a PEG-IFN/RBV lead-in phase, patients started weeks of therapy, which was safe and well-tolerated, with none of them discontinuing for side effects. In three patients, however, severe anaemia developed, requiring an increase in erythropoietin dose. Differently from the French study, we preferred to start a first-line therapy with immunosuppressive drugs, introducing anti-hcv therapy only when kidney function reverted to normal. Our choice was motivated by several reasons: to avoid severe anaemia as a result of RBV overdosing and to a concern regarding the risk of interactions between TVR and the immunosuppressive drugs the patient was receiving. Drug interactions are a prominent issue as TVR is both a potent inhibitor and a metabolite of CYPA4 [7]. Our patient was treated with oral prednisone, whose serum concentrations are increased significantly when TVR is coadministered, and mycophenolate mofetil, which should not be influenced by TVR but is known to worsen the severity of anaemia when used in combination with RBV. For this reason, before starting anti-hcv therapy, both drugs were tapered and mycophenolate mofetil discontinued when kidney function was normal. This strategy was rewarding both in antiviral efficacy as well as in safety as it allowed us to spare the patient from most side effects. In contrast to the findings reported in a recent study, we did not observe any signs of renal impairment during TVR administration [8]. One possible explanation is that our patient lacked any of the baseline factors (advanced age, arterial hypertension, diabetes mellitus and increased serum creatinine levels) that Mauss and colleagues [8] identified as predictors of kidney impairment during TVR/BOC therapy. TVR and BOC should therefore be considered as a valid treatment option in patients with MC severe kidney involvement, such as membranoproliferative glomerulonephritis, providing that an immunosuppressive drug regimen precedes the DAA-based regimen. The aim is to improve and possibly restore kidney function as well as to avoid concomitant administration of drugs with potentially dangerous interactions. Disclosure statement MC received grant and research support from Merck, Roche, BMS and Gilead Sciences. He is on the advisory committees of Merck, Roche, Novartis, Bayer, BMS, Gilead Sciences, Tibotec, Vertex and Achillion. He has received honoraria for speaking and teaching from Tibotec, Roche, Novartis, Bayer, BMS, Gilead Sciences and Vertex. AA has received grant and research support from Roche and Gilead Sciences. He has received honoraria for speaking and teaching from Roche, Janssen and Merck. He has received travel support from BMS, GlaxoSmithKline, Bayer, Janssen, Roche and Merck. MGR has received honoraria for speaking and teaching from Roche and BMS. She is on the advisory committee for Janssen and has received travel support from Roche. All other authors declare no competing interests. References. Cacoub P, Renou C, Rosenthal E, et al. Extrahepatic manifestations associated with hepatitis C virus infection. A prospective multicenter study of patients. Medicine 000; 79: Johnson RJ, Gretch DR, Yamabe H, Hart J, Bacchi CE. Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. N Engl J Med 99; 8: International Medical Press

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