This PDF is for personal use only. To obtain commercial reprints, Tenofovir-associated Fanconi Syndrome in patients with chronic hepatitis B monoinfection David M Gracey, Paul Snelling, Paul McKenzie, Simone I Strasser Antiviral Therapy 2013; 10.3851/IMP2649 Submission date 15th April 2013 Acceptance date 8th May 2013 Publication date 10th July 2013 This provisional PDF matches the article and figures as they appeared upon acceptance. Copyedited and fully formatted PDF and full text (HTML) versions will be made available soon. For information about publishing your article in Antiviral Therapy go to http://www.intmedpress.com/index.cfm?pid=12 2013 International Medical Press ISSN 1359-6535
Case report Publication: Antiviral Therapy; Type: Case report Tenofovir-associated Fanconi Syndrome in patients with chronic hepatitis B monoinfection David M Gracey 1,2 *, Paul Snelling 1, Paul McKenzie 2,3, Simone I Strasser 2,4 1 Renal Unit, Royal Prince Alfred Hospital, Sydney, Australia 2 Central Clinical School, Faculty of Medicine, University of Sydney, Sydney, Australia 3 Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia 4 AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia *Corresponding author e-mail: david.gracey@sswahs.nsw.gov.au Abstract Tenofovir disoproxil fumarate (TDF) is increasingly used in patients with chronic hepatitis B (CHB) infection. Although associated with renal toxicity in HIV-infected patients, renal dysfunction has been reported rarely in the monoinfected CHB population. To date, TDF-associated Fanconi Syndrome has not been reported. Here we present two cases of TDF-associated Fanconi Syndrome with rapid resolution after its cessation. We then discuss risk factors for TDF nephrotoxicity and its implications for screening for renal disease in those patients with CHB monoinfection on TDF, and the use of TDF in at risk populations. Accepted 8 May 2013, published online 10 July 2013 Introduction This PDF is for personal use only. To obtain commercial reprints, Tenofovir disoproxil fumarate (TDF) is a highly effective antiviral nucleotide analogue reverse transcriptase inhibitor (NRTI), which is active against both human immunodeficiency virus (HIV) and hepatitis B virus (HBV) [1]. Tenofovir was approved by the United States Food and Drug Administration for the treatment of HIV in 2001 and for chronic hepatitis B (CHB) monoinfection in 2008 and is recommended in international guidelines as a first line agent for treatment-naïve CHB patients, as well as in those patients with treatment emergent drug resistance [2 5] TDF is also effective in treating CHB in patients co-infected with HIV and in HBV-positive solid organ transplant recipients [6,7]. Amongst the HIV-infected patient population treated with TDF, nephrotoxicity has been reported, although is uncommon, with 1-2% of patients affected [8]. Renal dysfunction has also been seen in CHB patients co-infected with HIV [6]. The most prominent renal toxicity is proximal renal tubular dysfunction and, in some cases, the Fanconi Syndrome. The Fanconi Syndrome is characterized by a global dysfunction of the proximal renal tubule, leading to an excess urinary
Publication: Antiviral Therapy; Type: Case report excretion of solutes handled by the proximal tubule, such as phosphate, glucose and bicarbonate. It manifests clinically with acidosis, electrolyte imbalances and osteomalacia [9]. If severe, these features may be life-threatening. To date, renal toxicity has been reported rarely in ongoing registration studies of TDF in CHB moninfection [10]. However, up to 15% of monoinfected CHB patients treated with adefovir (ADF) or TDF or both developed proximal renal tubular dysfunction, defined by the de novo appearance of at least three clinical features of the Fanconi Syndrome, in one small study [11]. Dose-dependant nephrotoxicity of TDF has also been demonstrated in animal studies [12]. The Fanconi Syndrome has not been reported in HBV monoinfected patients. Here we report two cases of the Fanconi Syndrome in patients undergoing treatment with TDF for CHB monoinfection. We then discuss the implications of these cases for the screening and management of monoinfected CHB patients on TDF, focusing on groups at risk of nephrotoxicity and current guidelines. Cases This PDF is for personal use only. To obtain commercial reprints, A 39-year-old male of South East Asian descent with CHB was referred to the renal service because of progressive renal impairment. He was a participant in a phase 3 clinical trial evaluating the safety and efficacy of TDF in patients with HBeAg negative CHB (GS-US-174-0102), and was randomized to the comparison arm of ADF 10mg daily for 48 weeks before switching to open-label treatment with TDF 300mg daily for up to 7 years. At study entry, his HBV DNA level was 110,000 IU/ml and liver biopsy revealed mildly active chronic hepatitis (Metavir score A1 F1). In addition to CHB, he also had hypertension, controlled with telmisartan, but had no other co-morbidities and no known history of renal disease. Before commencing TDF the serum creatinine was 95 mol/l and the egfr 81 ml/min/1.73m 2. At the time of switching to TDF 48 weeks later the serum creatinine was 96 mol/l, egfr 80 ml/min/1.73m 2. After commencing TDF, there was a slow increase in his serum creatinine level to a peak of 150 mol/l; egfr 46 ml/min/1.73m 2 (Fig 1a). Hepatitis B virus DNA fell from 45,000 IU/mL at the time of commencing TDF, and was undetectable within 15 months of TDF treatment. At his initial renal review 48 months after commencing TDF, the serum creatinine was 127 mol/l and egfr 59 ml/min/1.73m 2. At that time he was receiving marketed TDF having completed the clinical trial, and having elected not to participate in a follow-on study. He never reached a level of creatinine or creatinine clearance to stop or reduce treatment while enrolled in the clinical trial. At full renal evaluation he had low-grade proteinuria (0.6 g/24 hours) but no microhematuria. He had a persistently low serum uric acid level (0.21 mmol/l) and glycosuria. A renal biopsy was undertaken while he was still taking TDF, and demonstrated evidence of proximal tubular injury (Fig 2a) with abundant granular cytoplasm and reactive nuclear enlargement (Fig 2b). Electron microscopy
Publication: Antiviral Therapy; Type: Case report confirmed abundant giant mitochondria (Fig 2c), as reported in HIV-infected patients with TDFassociated Fanconi Syndrome [8]. The patient was subsequently switched to entecavir 0.5mg daily with a slow, sustained improvement in his renal function (see figure 1) and a normalization of his serum uric acid, as well as a disappearance of his proteinuria. At his last review over 24 months since ceasing TDF, the serum creatinine had not returned to the normal range (117 mol/l; egfr 64 ml/min/1.73m 2 ), meaning a loss of 16 ml/min/1.73m 2 of egfr since he had been treated with TDF. He had no features of proximal renal tubular dysfunction. The second patient was referred for renal assessment in February 2012 because of renal dysfunction (fig 1b). He was a 54-year-old man of Mediterranean heritage; he had been on TDF 300mg daily for HBeAg-negative CHB for 24 months. His initial HBV DNA level was 6,400,000 IU/mL and was undetectable by 12 months of TDF treatment. A liver biopsy performed in 2010 demonstrated mild active hepatitis, but no fibrosis (Metavir score A1 F2). He was overweight with a history of dyslipidemia, borderline hypertension not on medical therapy, and had mild obstructive sleep apnea. In the 2 years prior to commencing TDF his serum creatinine was intermittently elevated, but was normal (94 mol/l) on the day TDF was commenced and the egfr was 77 ml/min/1.73m 2. At that time he did not have proteinuria or haematuria. On initial review by the renal physician the serum creatinine was 135 mol/l and egfr 51ml/min/1.73m 2. He had aminoaciduria, glycosuria, low-grade proteinuria (0.2 g/24 hours), hypophosphataemia (0.68 mmol/l) and hypouricaemia (0.08 mmol/l). He had an elevated 24-hour phosphate excretion. This presentation was consistent with TDF-associated Fanconi Syndrome, and he was subsequently switched to entecavir 0.5mg daily. Given the distinct clinical features, a renal biopsy was not undertaken and a trial of TDF cessation was undertaken. Three months after ceasing TDF and switching to entecavir, the serum creatinine had fallen to 106 mol/l and the egfr was 67 ml/min/1.73m 2. His proteinuria and hypophosphataemia had also completely resolved. At his last review, over 18 months since ceasing TDF the serum creatinine was 108; egfr 66 ml/min/1.73m 2, meaning a loss of 10ml/min/1.73m 2 of egfr since he had been treated with TDF. He had no features of proximal renal tubular dysfunction. Discussion This PDF is for personal use only. To obtain commercial reprints, This is the first report of tenofovir-associated Fanconi Syndrome in HBV monoinfection. This report highlights that not only patients with HIV or HIV-HBV coinfection, but also patients with HBVmonoinfection are at risk for this potentially severe complication of TDF therapy. However, data to date suggest that nephrotoxicity is less evident in HBV monoinfection [13]. As well, the estimated reduction in glomerular filtration rate was less in the HBV monoinfected population when compared to the HIV monoinfected population in one study [14]. In the European cohort study of tenofovir in HBV monoinfection, the proportion of patients with an egfr <50ml/min remained stable throughout the study [15].
Publication: Antiviral Therapy; Type: Case report Risk factors for the development of TDF-associated nephrotoxicity have been identified in HIVinfected patients, although not all patients have identifiable risk factors. Risk factors include increased age, pre-existing renal impairment, concomitant use of nephrotoxic medications, co-morbidities such as diabetes and hypertension, and use of some protease inhibitors [5]. In the patients reported here, the first patient had prior treatment with ADF, an antiviral agent recognized for nephrotoxicity [16], which may have predisposed him to developing TDF- associated renal damage. He was also known to have hypertension and borderline renal impairment. The second patient also had pre-existing mild renal impairment, possibly related to long-standing mild hypertension. In treatment-naïve patients with CHB who have evidence of pre-existing renal impairment, TDF may not be an ideal choice of antiviral agent and perhaps entecavir should be recommended. In treatment-experienced patients, it may still be the best choice of agent as, to date; no TDF-associated antiviral drug resistance has been reported. Patients undergoing long-term treatment with TDF should be monitored in order to detect renal dysfunction. The HIV Medicine Society of the Infectious Diseases Society of America has recommended that patients who are receiving TDF be screened at least every 6 months for egfr, serum phosphate, proteinuria and glycosuria [17]. Three monthly testing in the initial year of therapy has also been suggested [8]. The European Society for the Study of the Liver (EASL) recommends monitoring with serum creatinine (estimated creatinine clearance) and serum phosphate levels in all patients with CHB undergoing treatment with adefovir or tenofovir. They recommend monitoring every 3 months in the first year and 6 monthly thereafter, with more intense monitoring in those with high renal risk or development of renal dysfunction [4]. Practice guidelines form the American Association for the Study of the Liver (AASLD) [3] and the Asia Pacific Association for the Study of the Liver (APASL) [18] are less specific. Nephrotoxicity may develop in patients without obvious risk factors for TDF-associated pathology and may be seen at variable times after the commencement of therapy; hence, it is important that all patients placed on a TDF-containing antiviral regimen be carefully monitored [8]. If significant abnormalities are detected, and there is an effective alternative agent, TDF treatment should be stopped. Apart from adjustment of dosage according to creatinine level, there are no current recommendations for patients with multi-drug resistance who require tenofovir because of lack of availability of a suitable alternative agent. Disclosure statement SIS is a clinical investigator and member of hepatitis B scientific advisory boards for Gilead Sciences and Bristol-Myer Squibb. References This PDF is for personal use only. To obtain commercial reprints, 1. Gallant JE, DeJesus E, Arribas JR, et al. Tenofovir DF, emtricitabine, and efavirenz vs zidovudine, lamivudine and efavirenz for HIV. N Engl J Med 2006; 354:251 260.
This PDF is for personal use only. To obtain commercial reprints, Publication: Antiviral Therapy; Type: Case report 2. Yuen M, Lai C. Treatment of chronic hepatits B: Evolution over two decades. J Gastroenterol Hepatol 2011; 26 Suppl. 1:138 143. 3. Lok AS, McMahon BJ. Chronic hepatitis B: Update 2009. Hepatology 2009; 50:661 662. 4. European Association For The Study Of The Liver. Clinical Practice Guidelines: management of chronic hepatitis B. J Hepatol 2009; 50:227 242. 5. Liaw YF, Leung N, Kao JH, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int. 2008; 2:263 283. 6. Ratcliffe L, Beadsworth M, Pennell A, et al. Managing hepatitis B/HIV co-infected: adding entecavir to truvada (tenofovir disoproxil/emtricitabine) experienced patients. AIDS 2011; 25:1051 1056. 7. Daude M, Rostaing L, Saune K, et al. Tenofovir therapy in hepatitis B virus-positive solid-organ transplant recipients. Transplantation 2011; 91:916 920. 8. Hall AM, Hendry BM, Nitsch D, et al. Tenofovir-associated kidney toxicity in HIV-infected patients: a review of the evidence. Am J Kidney Dis 2011; 57:773 780. 9. Fanconi G. Der Fruhenfantile nephrotisch-glykosurische zergwuchs mit hyperphostamischer rachitis. Jahrb. Kinderheilkd. 1936; 147:299 338. 10. Fontana R. Side effects of long-term oral antiviral therapy for Hepatits B. Hepatology 2009; S185 S195. 11. Gara N, Zhao X, Collins MT, et al. Renal tubular dysfunction during long-term adefovir or tenofovir therapy in chronic hepatitis B. Aliment Pharmacol Ther 2012; 35:1317 1325. 12. Van Rompay KKA, Durand-Gasselin L, Brignolo LL, et al. Chronic administration of tenofovir to rhesus macaques from infancy through adulthood and pregnancy: summary of pharmacokinetics and biological and virological effects. Antimicrob Agents Chemother 2008; 52:3144 3160. 13. Pol S, Lampertico P. First-line treatment of chronic hepatitis B with entecavir or tenofovir in real life settings: from clinical trials to clinical practice. Viral Hep 2012; 19:377 386. 14. Mauss S, Berger F, Filmann N, et al. Effect of HBV polymerase inhibitors on renal function in patients with chronic hepatitis B. J Hepatol 2011; 55:1235 1240. 15. Lampertico P, Soffredini R, Vigano M et al. 2 year effectiveness and safety of tenofovir in 302 NUCnaïve patients with chronic hepatits B: a multicentre European study in clinical practice. Hepatology. 2011;54(Suppl 1): Abstract 1433. 16. Izzedine H, Hulot JS, Launay-Vacher V, et al. renal safety of adefovir dipivoxil in patients with chronic hepatitis B: two doubleblind, randomized, placebo controlled studies. Kidney Int 2004; 66:1153 1158. 17. Gupta SK, Eustace JA, Winton JA, et al. Guidelines for the management of chronic kidney disease in HIV-infected patients: recommendations of the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis 2005; 40:1559. 18. Liaw YF, Leung N, Kao JH, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int. 2008; 2:263 283. Figure 1: Serum creatinine ( mol/l) and serum phosphate (mmol/l) before and after cessation of Tenofovir in case 1 (Fig 1a) and case 2 (Fig1b). Figure 2: Renal biopsy findings in case 1. Haematoxylin and eosin x10 (fig 2a) Haematoxylin and eosin x40 (fig 2b) and electron microscopy (fig 2c). The light microscopic findings were of prominent proximal tubular abnormalities with large eosinophillic inclusions on high power. The electron microscopy demonstrated abnormal giant mitochondria, as reported in in HIV-infected patients with tenofovirinduced nephrotoxicity [8].
This PDF is for personal use only. To obtain commercial reprints,
This PDF is for personal use only. To obtain commercial reprints,