Journal of Clinical Virology 61 (2014) 600–603
Contents lists available at ScienceDirect
Journal of Clinical Virology journal homepage: www.elsevier.com/locate/jcv
Case report
Tenofovir-induced Fanconi syndrome in chronic hepatitis B monoinfected patients that reverted after tenofovir withdrawal Mauro Viganò b , Alessandra Brocchieri c , Angiola Spinetti d , Serena Zaltron d , Giampaolo Mangia a , Floriana Facchetti a , Alessandro Fugazza c , Francesco Castelli d , Massimo Colombo a , Pietro Lampertico a,∗ a “A. M. and A. Migliavacca” Center for Liver Disease, I Gastroenterology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy b Liver Unit, Ospedale San Giuseppe, Università degli Studi di Milano, Milan, Italy c Medicine Unit, Ospedale Maggiore di Lodi, Lodi, Italy d University Division of Infectious and Tropical Diseases, University of Brescia and Brescia Spedali Civili General Hospital, Brescia, Italy
a r t i c l e
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Article history: Received 11 June 2014 Received in revised form 12 September 2014 Accepted 25 September 2014 Keywords: Adverse drug reaction Fanconi syndrome Tenofovir Hepatitis B virus Entecavir
a b s t r a c t Tenofovir disoproxil fumarate (TDF) is a nucleotide reverse transcriptase inhibitor widely used to treat patients with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infection. Despite the excellent safety records of this regimen, a few cases of acute renal failure and Fanconi syndrome have been reported among HIV patients exposed to TDF. In the HBV monoinfection scenario, only two cases of TDF-associated Fanconi syndrome have been reported thus far. Here, we describe two additional patients with chronic hepatitis B (CHB) who developed a TDF-induced Fanconi syndrome that reverted after TDF withdrawal and had viral replication fully suppressed upon switching to entecavir (ETV). Though the overall risk of TDF associated severe renal toxicity in HBV patients appears to be negligible, both glomerular and tubular function should be monitored in patients exposed to TDF, especially when other renal risk factors or a history of previous exposure to adefovir dipivoxil (ADV) are present. © 2014 Elsevier B.V. All rights reserved.
1. Why these cases are important The clinical efficacy and safety of TDF have been demonstrated in registration and field practice studies in both nucleos(t)ides (NUC)naïve and lamivudine (LMV)-resistant HBV patients [1,2]. However, the safety profile of TDF has been challenged in HIV-seropositive patients by reports of treatment-related Fanconi syndrome, a severe condition resulting from proximal renal tubular toxicity, which leads to impaired re-absorption of amino acids, uric acid, bicarbonate, glucose and phosphate associated to increased urinary excretion of these solutes [3,4]. In HBV monoinfected patients, TDFinduced Fanconi syndrome has only been described in two patients
Abbreviations: TDF, tenofovir disoproxil fumarate; HIV, human immunodeficiency virus; HBV, hepatitis B virus; CHB, chronic hepatitis B; ETV, entecavir; NUCs, nucleos(t)ides; LMV, lamivudine; ADV, adefovir dipivoxil; HCV, hepatitis C virus; ALT, alanine aminotransferase; eGFR, estimated glomerular filtration; TmPO4 , maximal tubular re-absorption of phosphate. ∗ Corresponding author at: I Gastroenterology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Via F. Sforza 35, 20122 Milan, Italy. Tel.: +39 0255035432; fax: +39 0250320410. E-mail address: [email protected] (P. Lampertico). http://dx.doi.org/10.1016/j.jcv.2014.09.016 1386-6532/© 2014 Elsevier B.V. All rights reserved.
[5]. Here, we report two additional HBV patients with TDF-induced Fanconi in whom renal function fully recovered following TDF withdrawal and had viral replication fully suppressed upon switching to ETV.
2. Cases description 2.1. First case (A) A 58-year-old Italian male clerk with HBeAg-negative CHB and LMV-resistance, without any co-morbidity, started TDF 245 mg/day in 2009 after 24 months ADV 10 mg/day monotherapy. At the time of switch, serum creatinine was 0.90 mg/dL (79.2 mol/L), eGFR by MDRD was 89 mL/min/1.73 m2 and phosphate was 2.6 mg/dL with a normal dipstick urine analysis. Nine months later a slight increase in serum creatinine with normoglycemic glycosuria and proteinuria at urine dipstick analysis was noticed (Table 1a and Fig. 1a). Since eGFR remained unchanged during the following months, the patient continued with TDF full dose until August 2011 (30 months after starting TDF) when the clinical picture suddenly worsened. Glomerular function further deteriorated [creatinine
M. Viganò et al. / Journal of Clinical Virology 61 (2014) 600–603
601
Table 1a Time course of biochemical, virological and urinary parameters during TDF and ETV in an ADV-experienced CHB patient developing a Fanconi syndrome (case A).
Serum phosphate (mg/dL) Serum creatinine (mg/dL) eGFRc (mL/min) Proteinuriad (mg/dL) Glycosuriad (mg/dL) Serum bicarbonate (mmol/L) Serum calcium (mg/dL) Serum sodium (mEq/L) Serum potassium (mEq/L) ALT (IU/L) HBV DNA (IU/mL)
TDF starta
TDF (9th mo◦ )
TDF (30th mo)
2.6
2.6
2.0
2.1
0.9
1.04
1.30
1.32
89 neg neg na
75 50 200 na
56 70 300 na
55 50 500 19.3
9.5 145 5.1
9.4 143 4.7
na 143 4.6
28
Contents lists available at ScienceDirect
Journal of Clinical Virology journal homepage: www.elsevier.com/locate/jcv
Case report
Tenofovir-induced Fanconi syndrome in chronic hepatitis B monoinfected patients that reverted after tenofovir withdrawal Mauro Viganò b , Alessandra Brocchieri c , Angiola Spinetti d , Serena Zaltron d , Giampaolo Mangia a , Floriana Facchetti a , Alessandro Fugazza c , Francesco Castelli d , Massimo Colombo a , Pietro Lampertico a,∗ a “A. M. and A. Migliavacca” Center for Liver Disease, I Gastroenterology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy b Liver Unit, Ospedale San Giuseppe, Università degli Studi di Milano, Milan, Italy c Medicine Unit, Ospedale Maggiore di Lodi, Lodi, Italy d University Division of Infectious and Tropical Diseases, University of Brescia and Brescia Spedali Civili General Hospital, Brescia, Italy
a r t i c l e
i n f o
Article history: Received 11 June 2014 Received in revised form 12 September 2014 Accepted 25 September 2014 Keywords: Adverse drug reaction Fanconi syndrome Tenofovir Hepatitis B virus Entecavir
a b s t r a c t Tenofovir disoproxil fumarate (TDF) is a nucleotide reverse transcriptase inhibitor widely used to treat patients with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infection. Despite the excellent safety records of this regimen, a few cases of acute renal failure and Fanconi syndrome have been reported among HIV patients exposed to TDF. In the HBV monoinfection scenario, only two cases of TDF-associated Fanconi syndrome have been reported thus far. Here, we describe two additional patients with chronic hepatitis B (CHB) who developed a TDF-induced Fanconi syndrome that reverted after TDF withdrawal and had viral replication fully suppressed upon switching to entecavir (ETV). Though the overall risk of TDF associated severe renal toxicity in HBV patients appears to be negligible, both glomerular and tubular function should be monitored in patients exposed to TDF, especially when other renal risk factors or a history of previous exposure to adefovir dipivoxil (ADV) are present. © 2014 Elsevier B.V. All rights reserved.
1. Why these cases are important The clinical efficacy and safety of TDF have been demonstrated in registration and field practice studies in both nucleos(t)ides (NUC)naïve and lamivudine (LMV)-resistant HBV patients [1,2]. However, the safety profile of TDF has been challenged in HIV-seropositive patients by reports of treatment-related Fanconi syndrome, a severe condition resulting from proximal renal tubular toxicity, which leads to impaired re-absorption of amino acids, uric acid, bicarbonate, glucose and phosphate associated to increased urinary excretion of these solutes [3,4]. In HBV monoinfected patients, TDFinduced Fanconi syndrome has only been described in two patients
Abbreviations: TDF, tenofovir disoproxil fumarate; HIV, human immunodeficiency virus; HBV, hepatitis B virus; CHB, chronic hepatitis B; ETV, entecavir; NUCs, nucleos(t)ides; LMV, lamivudine; ADV, adefovir dipivoxil; HCV, hepatitis C virus; ALT, alanine aminotransferase; eGFR, estimated glomerular filtration; TmPO4 , maximal tubular re-absorption of phosphate. ∗ Corresponding author at: I Gastroenterology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Via F. Sforza 35, 20122 Milan, Italy. Tel.: +39 0255035432; fax: +39 0250320410. E-mail address: [email protected] (P. Lampertico). http://dx.doi.org/10.1016/j.jcv.2014.09.016 1386-6532/© 2014 Elsevier B.V. All rights reserved.
[5]. Here, we report two additional HBV patients with TDF-induced Fanconi in whom renal function fully recovered following TDF withdrawal and had viral replication fully suppressed upon switching to ETV.
2. Cases description 2.1. First case (A) A 58-year-old Italian male clerk with HBeAg-negative CHB and LMV-resistance, without any co-morbidity, started TDF 245 mg/day in 2009 after 24 months ADV 10 mg/day monotherapy. At the time of switch, serum creatinine was 0.90 mg/dL (79.2 mol/L), eGFR by MDRD was 89 mL/min/1.73 m2 and phosphate was 2.6 mg/dL with a normal dipstick urine analysis. Nine months later a slight increase in serum creatinine with normoglycemic glycosuria and proteinuria at urine dipstick analysis was noticed (Table 1a and Fig. 1a). Since eGFR remained unchanged during the following months, the patient continued with TDF full dose until August 2011 (30 months after starting TDF) when the clinical picture suddenly worsened. Glomerular function further deteriorated [creatinine
M. Viganò et al. / Journal of Clinical Virology 61 (2014) 600–603
601
Table 1a Time course of biochemical, virological and urinary parameters during TDF and ETV in an ADV-experienced CHB patient developing a Fanconi syndrome (case A).
Serum phosphate (mg/dL) Serum creatinine (mg/dL) eGFRc (mL/min) Proteinuriad (mg/dL) Glycosuriad (mg/dL) Serum bicarbonate (mmol/L) Serum calcium (mg/dL) Serum sodium (mEq/L) Serum potassium (mEq/L) ALT (IU/L) HBV DNA (IU/mL)
TDF starta
TDF (9th mo◦ )
TDF (30th mo)
2.6
2.6
2.0
2.1
0.9
1.04
1.30
1.32
89 neg neg na
75 50 200 na
56 70 300 na
55 50 500 19.3
9.5 145 5.1
9.4 143 4.7
na 143 4.6
28
