Clinics and Research in Hepatology and Gastroenterology (2015) 39, e67—e69
Available online at
ScienceDirect www.sciencedirect.com
LETTER TO THE EDITOR Renal proximal tubular dysfunction due to tenofovir in a patient with chronic hepatitis B monoinfection Tenofovir (TDF) and entecavir (ETV) are recommended as first-line treatment for hepatitis B (HBV) [1]. In HIV patients, TDF can induce renal proximal tubular acidosis (rPTA). This complication is rarely reported in HBV monoinfected patients during TDF therapy [2—5]. We report a chronic HBV mono-infected patient with rPTA during TDF and summarize previous data. A 55-year-old Caucasian male with (HIV negative) HBeAg negative chronic HBV (HBV DNA level 2.0 × 105 IU/mL) was referred to our hospital. He was previously treated with interferon-alfa for sixteen weeks in 1999 with nonresponse. From 2001 onwards, he received lamivudine which was stopped in 2004 because of non-response with persistent elevated transaminases without HBV DNA level decline (1.9 × 107 IU/mL before and 8.2 × 107 IU/mL at the end). In 2004, lamivudine was switched to adefovir leading to normal transaminases and partial virological response (HBV DNA decline to 9.5 × 103 IU/mL two years after adefovir initiation). In 2007, lamivudine was added to adefovir with complete virological response (HBV DNA < 200 IU/mL) and in 2008 HBeAg-seroconversion. Liver stiffness measurement (Fibroscan® , Echosens, Paris, France) at that time showed F0—F1 fibrosis (6.0 kiloPascal). Since virological suppression after HBe-seroconversion was retained more than one year, lamivudine and adefovir were discontinued in accordance with international guideline [1]. During adefovir, he developed slight but stable renal impairment with creatinine between 100 and 123 mol/L (between 1.13 mg/dL and 1.39 mg/dL, reference value (ref) 64—104 mol/L or 0.72—1.18 mg/dL), which was 83 mol/L (0.94 mg/dL) before adefovir. Unfortunately, in subsequent months, both HBV DNA and ALT levels increased again to 1.1 × 104 IU/mL and 87 U/L (ref 0—45 U/L), respectively. Therefore, it was deemed necessary to resume antiviral therapy. Since resistance to lamivudine was a concern, TDF was considered the treatment of choice. Before TDF, creatinine was 115 mol/L (1.30 mg/dL) with estimated glomerular filtration rate (eGFR) above 60 mL/min/1.73 m2 (ref ≥ 90 mL/min/1.73 m2 ). After 3 months, HBV DNA
http://dx.doi.org/10.1016/j.clinre.2015.01.007 2210-7401/© 2015 Elsevier Masson SAS. All rights reserved.
became undetectable again and ALT normalized. However, he developed persistent hypophosphatemia [serum phosphate level before TDF 0.87 mmol/L (2.69 mg/dL) declining to 0.51 mmol/L (1.70 mg/dL) during treatment (ref 0.80—1.50 mmol/L or 2.48—4.64 mg/dL)] with further increase of creatinine (123 umol/L (1.39 mg/dL), eGFR of 57 mL/min/1.73 m2 ). Additional evaluation revealed hypouricemia (0.18 mmol/L, ref 0.30—0.50 mmol/L), normal bicarbonate (26.2 mmol/L, ref 23.0—29.0 mmol/L) and normal glucose (5.0 mmol/L, ref 3.6—5.6 mmol/L). Urine analysis showed proteinuria (0.51 g/L, ref 0.01—0.14 g/L) and uric acid of 3.0 mmol/L without glucosuria. Twenty hours urinary excretion of phosphate was 39.5 mmol/24 h (ref 12.9—42.0 mmol/24 h), with beta-2-microglobuline 11.7 mg/24 h (ref 0.2 mg/24 h), creatinine 12.0 mmol/24 h (ref 9.0—18.0 mmol/24 h) and negative glucose screening. The patient had normal serum calcium and vitamin D levels, and had never been exposed to heavy metals, such as cadmium and copper. Dual-energy X-ray absorptiometry (DEXA scan) revealed osteoporosis of the lumbar spine and osteopenia of the hip. Based on these findings, and after exclusion of other causes for renal insufficiency, he was diagnosed with rPTA due to TDF. Entecavir therapy appeared unattractive because of earlier presumed lamivudine resistance. Considering persistent and complete HBV DNA suppression and response to oral sodium phosphate treatment, TDF was continued under intensive monitoring of phosphate and creatinine levels. Currently, electrolytes and phosphate levels are normal, creatinine slightly elevated but stable (between 108 and 117 mol/L, 1.22 and 1.32 mg/dL) and HBV DNA remains undetectable with normal transaminases. TDF is becoming more prominent in the treatment of HBV mono-infected patients. So far, including our case, the association between TDF-related rPTA and HBV monoinfection has been reported in eight patients (summarized in Table 1) [2—5]. Potential risk factors for rPTA are age above 50 years, adefovir pretreatment, simultaneous therapy with renin—angiotensin system inhibitors and preexisting renal insufficiency. In conclusion, rPTA should be considered in patients with chronic HBV monoinfection during TDF treatment when hypophosphatemia develops.
e68
Table 1
Comparison between reported cases of rPTA in HBV mono-infected patients. Case
Gara et al., 2012 [2]
Gracey et al., 2013 [3]
Vigano et al., 2014 [4]
Samarkos et al., 2014 [5] Harkisoen et al., 2014
Age (years), sex
Ethnic origin
HBeAg
Initial HBV DNA (IU/mL)
1
62, M
NM
NM
NM
2
66, M
NM
NM
NM
Fibrosis stage (METAVIR)
Previous HBV therapy
Comedication Years on TDF
Before TDF
NM
None
NM
3.9
Serum creatinine (umol/L) NM
During TDF
Intervention Outcome
Serum phosphate (mmol/L) NM
Serum creatinine (umol/L) NM
Serum phosphate (mmol/L) NM
NM
ADV
NM
3.7
NM
NM
NM
NM
−5
F1
ADV
Telmisartan
7.0
95
1.0
150
0.6
F2
None
None
2.0
94
± 0.9b
135
± 0.7b
3
39, M
Asian
Negative
1.1 × 10
4
54, M
Caucasian
Negative
6.4 × 10−6
c
114
0.69
c
Switch to ETV Switch to ETV Switch to ETV
Favorable
Switch to ETV Switch to ETV
Favorable
Favorable Favorable
5
58, M
Caucasian
Negative
< 12
NM
ADV
None
2.5
79
0.84
Favorable
6
62, M
Caucasian
Negative
1.22 × 10−5
NM
None
3.8
80
0.84c
296
0.55c
Switch to ETV
Favorable
7
87, M
NM
NM
NM
F4
ADV + LAM
Betablocker, ACEinhibitor NM
NM
NM
NM
NM
NM
Stop TDF
Unfavorable
8
55, M
Caucasian
Negative
1.9 × 10−7 a
F0—F1
IFN-a/LAM/ ADV + LAM
None
0.4
115
0.87
123
0.51
Continu TDF, sodium phosphate suppletion
Favorable, stable renal function
NM: not mentioned; IU/mL: international units per milliliter; HBV: hepatitis B virus; ADV: adefovir; LAM: lamivudine; IFN-a: interferon-alfa; TDF: tenofovir; ETV: entecavir. a Conversion copies per milliliter to international units per milliliter. b Estimated from figure in article. c Conversion mg/dL to mmol/L.
Letter to the editor
Letter to the editor
Contribution of authors S. Harkisoen: literature search and selection, writing manuscript; J.E. Arends: literature search, writing manuscript; A.I.M. Hoepelman: writing manuscript; K.J. van Erpecum: patient care and writing manuscript.
Disclosure of interest S.H. the author has not declared any conflicts of interest; J.E.A. Occasional involvements: advisory services: BMS, Janssen, Abbvie MSD and Gilead; I.M.H. Occasional involvements: advisory services: Gilead, Merck, ViiV Healthcare and Janssen, received research grants from a company: Roche, Gilead, Merck and ViiV Healthcare; K.J.v E. Occastional involvements: advisory services: BMS, Abbvie and Gilead, received research grants from a company: Schering Plough and BMS.
References [1] Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology 2009;50:661—2. [2] Gara N, Zhao X, Collins MT, Chong WH, Kleiner DE, Jake Liang T, et al. Renal tubular dysfunction during long-term adefovir or tenofovir therapy in chronic hepatitis B. Aliment Pharmacol Ther 2012;35:1317—25.
e69 [3] Gracey DM, Snelling P, McKenzie P, Strasser SI. Tenofovirassociated Fanconi syndrome in patients with chronic hepatitis B monoinfection. Antivir Ther 2013;18:945—8. [4] Vigano M, Brocchieri A, Spinetti A, Zaltron S, Mangia G, Facchetti F, et al. Tenofovir-induced Fanconi syndrome in chronic hepatitis B monoinfected patients that reverted after tenofovir withdrawal. J Clin Virol 2014;61:600—3. [5] Samarkos M, Theofanis V, Eliadi I, Vlachogiannakos J, Polyzos A. Tenofovir-associated Fanconi syndrome in a patient with chronic hepatitis B. J Gastrointestin Liver Dis 2014;23: 342.
Soeradj Harkisoen a,∗ Joop E. Arends a Andy I.M. Hoepelman a Karel J. van Erpecum b a Department of Internal Medicine and Infectious diseases, University Medical Center Utrecht, Utrecht, The Netherlands b Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands ∗ Corresponding author. Department of Internal Medicine and Infectious diseases, University Medical Center Utrecht, Heidelberglaan 100, PO Box 85500, F02.126, 3508 GA Utrecht, The Netherlands. Tel.: +31 88 75 56 228; fax: +31 30 25 23 741. E-mail address: [email protected] (S. Harkisoen) Available online 3 March 2015
Available online at
ScienceDirect www.sciencedirect.com
LETTER TO THE EDITOR Renal proximal tubular dysfunction due to tenofovir in a patient with chronic hepatitis B monoinfection Tenofovir (TDF) and entecavir (ETV) are recommended as first-line treatment for hepatitis B (HBV) [1]. In HIV patients, TDF can induce renal proximal tubular acidosis (rPTA). This complication is rarely reported in HBV monoinfected patients during TDF therapy [2—5]. We report a chronic HBV mono-infected patient with rPTA during TDF and summarize previous data. A 55-year-old Caucasian male with (HIV negative) HBeAg negative chronic HBV (HBV DNA level 2.0 × 105 IU/mL) was referred to our hospital. He was previously treated with interferon-alfa for sixteen weeks in 1999 with nonresponse. From 2001 onwards, he received lamivudine which was stopped in 2004 because of non-response with persistent elevated transaminases without HBV DNA level decline (1.9 × 107 IU/mL before and 8.2 × 107 IU/mL at the end). In 2004, lamivudine was switched to adefovir leading to normal transaminases and partial virological response (HBV DNA decline to 9.5 × 103 IU/mL two years after adefovir initiation). In 2007, lamivudine was added to adefovir with complete virological response (HBV DNA < 200 IU/mL) and in 2008 HBeAg-seroconversion. Liver stiffness measurement (Fibroscan® , Echosens, Paris, France) at that time showed F0—F1 fibrosis (6.0 kiloPascal). Since virological suppression after HBe-seroconversion was retained more than one year, lamivudine and adefovir were discontinued in accordance with international guideline [1]. During adefovir, he developed slight but stable renal impairment with creatinine between 100 and 123 mol/L (between 1.13 mg/dL and 1.39 mg/dL, reference value (ref) 64—104 mol/L or 0.72—1.18 mg/dL), which was 83 mol/L (0.94 mg/dL) before adefovir. Unfortunately, in subsequent months, both HBV DNA and ALT levels increased again to 1.1 × 104 IU/mL and 87 U/L (ref 0—45 U/L), respectively. Therefore, it was deemed necessary to resume antiviral therapy. Since resistance to lamivudine was a concern, TDF was considered the treatment of choice. Before TDF, creatinine was 115 mol/L (1.30 mg/dL) with estimated glomerular filtration rate (eGFR) above 60 mL/min/1.73 m2 (ref ≥ 90 mL/min/1.73 m2 ). After 3 months, HBV DNA
http://dx.doi.org/10.1016/j.clinre.2015.01.007 2210-7401/© 2015 Elsevier Masson SAS. All rights reserved.
became undetectable again and ALT normalized. However, he developed persistent hypophosphatemia [serum phosphate level before TDF 0.87 mmol/L (2.69 mg/dL) declining to 0.51 mmol/L (1.70 mg/dL) during treatment (ref 0.80—1.50 mmol/L or 2.48—4.64 mg/dL)] with further increase of creatinine (123 umol/L (1.39 mg/dL), eGFR of 57 mL/min/1.73 m2 ). Additional evaluation revealed hypouricemia (0.18 mmol/L, ref 0.30—0.50 mmol/L), normal bicarbonate (26.2 mmol/L, ref 23.0—29.0 mmol/L) and normal glucose (5.0 mmol/L, ref 3.6—5.6 mmol/L). Urine analysis showed proteinuria (0.51 g/L, ref 0.01—0.14 g/L) and uric acid of 3.0 mmol/L without glucosuria. Twenty hours urinary excretion of phosphate was 39.5 mmol/24 h (ref 12.9—42.0 mmol/24 h), with beta-2-microglobuline 11.7 mg/24 h (ref 0.2 mg/24 h), creatinine 12.0 mmol/24 h (ref 9.0—18.0 mmol/24 h) and negative glucose screening. The patient had normal serum calcium and vitamin D levels, and had never been exposed to heavy metals, such as cadmium and copper. Dual-energy X-ray absorptiometry (DEXA scan) revealed osteoporosis of the lumbar spine and osteopenia of the hip. Based on these findings, and after exclusion of other causes for renal insufficiency, he was diagnosed with rPTA due to TDF. Entecavir therapy appeared unattractive because of earlier presumed lamivudine resistance. Considering persistent and complete HBV DNA suppression and response to oral sodium phosphate treatment, TDF was continued under intensive monitoring of phosphate and creatinine levels. Currently, electrolytes and phosphate levels are normal, creatinine slightly elevated but stable (between 108 and 117 mol/L, 1.22 and 1.32 mg/dL) and HBV DNA remains undetectable with normal transaminases. TDF is becoming more prominent in the treatment of HBV mono-infected patients. So far, including our case, the association between TDF-related rPTA and HBV monoinfection has been reported in eight patients (summarized in Table 1) [2—5]. Potential risk factors for rPTA are age above 50 years, adefovir pretreatment, simultaneous therapy with renin—angiotensin system inhibitors and preexisting renal insufficiency. In conclusion, rPTA should be considered in patients with chronic HBV monoinfection during TDF treatment when hypophosphatemia develops.
e68
Table 1
Comparison between reported cases of rPTA in HBV mono-infected patients. Case
Gara et al., 2012 [2]
Gracey et al., 2013 [3]
Vigano et al., 2014 [4]
Samarkos et al., 2014 [5] Harkisoen et al., 2014
Age (years), sex
Ethnic origin
HBeAg
Initial HBV DNA (IU/mL)
1
62, M
NM
NM
NM
2
66, M
NM
NM
NM
Fibrosis stage (METAVIR)
Previous HBV therapy
Comedication Years on TDF
Before TDF
NM
None
NM
3.9
Serum creatinine (umol/L) NM
During TDF
Intervention Outcome
Serum phosphate (mmol/L) NM
Serum creatinine (umol/L) NM
Serum phosphate (mmol/L) NM
NM
ADV
NM
3.7
NM
NM
NM
NM
−5
F1
ADV
Telmisartan
7.0
95
1.0
150
0.6
F2
None
None
2.0
94
± 0.9b
135
± 0.7b
3
39, M
Asian
Negative
1.1 × 10
4
54, M
Caucasian
Negative
6.4 × 10−6
c
114
0.69
c
Switch to ETV Switch to ETV Switch to ETV
Favorable
Switch to ETV Switch to ETV
Favorable
Favorable Favorable
5
58, M
Caucasian
Negative
< 12
NM
ADV
None
2.5
79
0.84
Favorable
6
62, M
Caucasian
Negative
1.22 × 10−5
NM
None
3.8
80
0.84c
296
0.55c
Switch to ETV
Favorable
7
87, M
NM
NM
NM
F4
ADV + LAM
Betablocker, ACEinhibitor NM
NM
NM
NM
NM
NM
Stop TDF
Unfavorable
8
55, M
Caucasian
Negative
1.9 × 10−7 a
F0—F1
IFN-a/LAM/ ADV + LAM
None
0.4
115
0.87
123
0.51
Continu TDF, sodium phosphate suppletion
Favorable, stable renal function
NM: not mentioned; IU/mL: international units per milliliter; HBV: hepatitis B virus; ADV: adefovir; LAM: lamivudine; IFN-a: interferon-alfa; TDF: tenofovir; ETV: entecavir. a Conversion copies per milliliter to international units per milliliter. b Estimated from figure in article. c Conversion mg/dL to mmol/L.
Letter to the editor
Letter to the editor
Contribution of authors S. Harkisoen: literature search and selection, writing manuscript; J.E. Arends: literature search, writing manuscript; A.I.M. Hoepelman: writing manuscript; K.J. van Erpecum: patient care and writing manuscript.
Disclosure of interest S.H. the author has not declared any conflicts of interest; J.E.A. Occasional involvements: advisory services: BMS, Janssen, Abbvie MSD and Gilead; I.M.H. Occasional involvements: advisory services: Gilead, Merck, ViiV Healthcare and Janssen, received research grants from a company: Roche, Gilead, Merck and ViiV Healthcare; K.J.v E. Occastional involvements: advisory services: BMS, Abbvie and Gilead, received research grants from a company: Schering Plough and BMS.
References [1] Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology 2009;50:661—2. [2] Gara N, Zhao X, Collins MT, Chong WH, Kleiner DE, Jake Liang T, et al. Renal tubular dysfunction during long-term adefovir or tenofovir therapy in chronic hepatitis B. Aliment Pharmacol Ther 2012;35:1317—25.
e69 [3] Gracey DM, Snelling P, McKenzie P, Strasser SI. Tenofovirassociated Fanconi syndrome in patients with chronic hepatitis B monoinfection. Antivir Ther 2013;18:945—8. [4] Vigano M, Brocchieri A, Spinetti A, Zaltron S, Mangia G, Facchetti F, et al. Tenofovir-induced Fanconi syndrome in chronic hepatitis B monoinfected patients that reverted after tenofovir withdrawal. J Clin Virol 2014;61:600—3. [5] Samarkos M, Theofanis V, Eliadi I, Vlachogiannakos J, Polyzos A. Tenofovir-associated Fanconi syndrome in a patient with chronic hepatitis B. J Gastrointestin Liver Dis 2014;23: 342.
Soeradj Harkisoen a,∗ Joop E. Arends a Andy I.M. Hoepelman a Karel J. van Erpecum b a Department of Internal Medicine and Infectious diseases, University Medical Center Utrecht, Utrecht, The Netherlands b Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands ∗ Corresponding author. Department of Internal Medicine and Infectious diseases, University Medical Center Utrecht, Heidelberglaan 100, PO Box 85500, F02.126, 3508 GA Utrecht, The Netherlands. Tel.: +31 88 75 56 228; fax: +31 30 25 23 741. E-mail address: [email protected] (S. Harkisoen) Available online 3 March 2015
