Hypophosphatemia in patients with hepatitis B virus infection undergoing long-term adefovir dipivoxil therapy

Original Article

Hypophosphatemia in patients with hepatitis B virusinfection undergoing long-term adefovir dipivoxil therapy

Yuko Shimizu,1 Atsushi Hiraoka,1 Hiroka Yamago,1 Akiko Shiraishi,1 Yusuke Imai,1

Haruka Tatsukawa,1 Tetsuya Tanihira,1 Hideki Miyata,1 Tomoyuki Ninomiya,1

Yoshio Tokumoto,2 Masanori Abe,3 Yoichi Hiasa2 and Kojiro Michitaka1

1Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama City, Departments of2Gastroenterology and Metabology, and 3Community Medicine, Ehime University Graduate School of Medicine,Toon, Japan

Aim: The purpose of this study was to clarify the frequencyof hypophosphatemia and other clinical features in patientswith hepatitis B undergoing long-term therapy with adefovirdipivoxil (ADF).

Methods: Seventeen hepatitis B patients treated with acombination of lamivudine and ADF were analyzed. Theywere divided into two groups: patients who developed hypo-phosphatemia (P < 2.5 mg/dL) (group A) and those who didnot (group B). The frequency of hypophosphatemia and otherclinical features were retrospectively analyzed.

Results: There were six patients (35.3%) in group A. Thetreatment period was 57.3 1 15.6 and 61.8 1 25.7 monthsin groups A and B, respectively. No differences were foundbetween the groups prior to treatment. Among the six

patients in group A, osteomalacia was observed in two, whilea pathological fracture of the scapula was found in one.Decreases in phosphate (96 weeks after starting ADF), esti-mated glomerular filtration rate (eGFR) (48 weeks) and uricacid (24 weeks) levels, and increases in creatinine and alkalinephosphatase were noted in group A.

Conclusion: Hypophosphatemia occurred in 35% of thepatients under the long-term treatment with ADF. Although itwas not possible to predict the decrease in phosphate beforeADF therapy, decreases in uric acid and eGFR may be the earlyevents relating to low phosphatemia.

Key words: adefovir dipivoxil, chronic hepatitis B, Fanconi’ssyndrome, hypophosphatemia, osteomalacia

INTRODUCTION

HEPATITIS B VIRUS (HBV), an incomplete circularDNA virus with approximately 3200 bases,

induces a variety of liver diseases, such as acute hepati-tis, fulminant hepatitis, chronic hepatitis, liver cirrhosisand hepatocellular carcinoma. Approximately 350million people throughout the world are chronicallyinfected with HBV,1,2 with interferon and nucleoside/nucleotide analogs used for treating hepatitis B, ofwhich lamivudine is the first nucleotide analogapproved for hepatitis B patients. This drug has beenreported to be effective for preventing progression from

chronic hepatitis to liver cirrhosis or liver failure,and can prevent the occurrence of hepatocellularcarcinoma.3–6 However, the rate of emergence of resis-tant strains is reported to be high, and breakthroughhepatitis or viral infections occasionally occur.7,8

Adefovir dipivoxil (ADF), known to be effective againstlamivudine-resistant HBV, was approved in 2004 inJapan and is used in combination with lamivudine.9,10 Ithas been reported that the incidence of ADV nephrotox-icity is dose-related, with the standard dose for HIV30 mg daily or higher,11,12 and the majority of patientsreceiving such a dose suffer from renal dysfunction. Onthe other hand, toxicity is not frequent in patients withHBV infection, for whom the approved dose of ADF is10 mg daily.13 Recently, hypophosphatemia and osteo-malacia related to ADF have been reported.14,15 In thepresent study, we analyzed the frequency and clinicalfeatures of hypophosphatemia in patients with hepatitisB undergoing long-term therapy with ADF.

Correspondence: Dr Yuko Shimizu, Gastroenterology Center, EhimePrefectural Central Hospital, 83 Kasugacho, Matsuyama City, Ehime790-0024, Japan. Email: [email protected] 10 March 2013; revision 6 August 2013; accepted 12August 2013.

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Hepatology Research 2014; 44: 1081–1087 doi: 10.1111/hepr.12226

© 2013 The Japan Society of Hepatology 1081

mailto:[email protected]

METHODS

Subjects

AMONG PATIENTS WITH hepatitis B treated witha nucleotide analog at our hospital between

2005 and 2012, 17 patients (13 men, four women,61.3 1 10.0 years old) were treated with lamivudine andADF combination therapy for more than 12 months. Allof these 17 patients were included in this study.

MethodsThe patients were divided into two groups; thosewho developed (P < 2.5 mg/dL) (group A) and did notdevelop hypophosphatemia (group B). The frequencyof hypophosphatemia and clinical features (age, sex,duration of treatment, clinical data) were analyzed.Liver function and renal function test results, and HBVmarkers were examined every 1–3 months. The hepatitisB e-antigen (HBeAg) and antibody against HBeAg(anti-HBe) were assayed using a chemiluminescenceimmunoassay. HBV DNA was assayed by transcription-mediated amplification (2005–2007.11) or real-timepolymerase chain reaction (2007.12–2012). Estimatedglomerular filtration rate (eGFR) (mL/min per1.73 m2) was calculated as follows: 194 × (creatinine[Cr] −1.094) × (age −0.287) × (0.739 if female). Abdominalsonography or computed tomography examinations(and other imaging tests, if needed) were done every6–12 months. The administrated dose of ADF was10 mg/day, whereas it was reduced to 10 mg every otherday when eGFR or Cr clearance was decreased between30 to 49 mL/min followed by the criteria written in theinterview form of ADF (Hepsera, GlaxoSmithKline,Tokyo, Japan).

The study was conducted in a retrospective manner.The purpose and details of the study were explainedto the patients, and written informed consent wasobtained from each.

Statistical analysisStatistical analyses were performed using Student’s t-testand Fischer’s exact test using Prism 6 (GraphPad Soft-ware). P < 0.05 was regarded as significant.

RESULTS

SIX PATIENTS (35.3%) showed hypophosphatemiaand were classified as group A. All six patients

showed low phosphate levels, though one showedimprovement after ADF was reduced to a half dose(10 mg/2 days). The other 11 patients were classified as

group B. There were no differences regarding age, sex(male/female) and duration of treatment between thegroups (55.0 1 11.0 vs 58.6 1 8.4 years, 5/1 vs 8/3,57.3 1 15.6 vs 61.8 1 25.7 months, respectively) or forlaboratory data obtained prior to treatment (Table 1).The duration of ADF therapy was more than 2 years inall except for one patient in group B. At the end of theobservation period, laboratory data except for phos-phate were not different between the groups (Table 2).Data at the end of the observation period are shown inTable 2. Besides the level of phosphate, significant dif-ference was found in the rate of bone disease (P = 0.04).Though the differences were not significant, kidneystones or urine crystals was frequently found in group A(4/6 vs 3/11). Kidney stones or urinary crystals withoccult hematuria were found in four patients in group Aand three in group B. None of these patients had urinarystones or crystals before beginning ADF therapy.Mean level of alkaline phosphatase (ALP) was high(690.2 1 725.2 vs 299.2 1 117.9 IU) and that of uricacid was low (4.2 1 2.0 vs 5.6 1 1.6 IU) in group A.

Comparisons of data obtained at the start of ADF withthose from the end of the observation period are shownin Table 3. In group A, a decrease in alanine aminotrans-ferase (ALT) and eGFR, and increases in ALP and Cr werenoted, while no significant differences except for ALTwere seen in group B. Among the six patients in group A,osteomalacia was observed in two and a pathologicalfracture of the scapula was found in one. Profilesfor these three patients are shown in Table 4, in whomthe onset of bone disease was noted at 51, 59 and42 months, respectively, after the start of ADF. Bothpatients with osteomalacia showed prominent hypo-phosphatemia and decreases in bone metal density inX-ray findings, while one had multiple rib fractures andthe other had a fracture of a lower limb. Hypophospha-temia was found before the emergence of these fractures.None of the patients in group B showed bone disease.

Figure 1 shows the inverse correlation between ALPand phosphate at the end of the observation period,while the relationship between uric acid and phosphateis shown in Figure 2. Figure 3 shows the change of phos-phate, uric acid, Cr and eGFR from the start of ADFadministration. Gradual decreases in phosphate andeGFR, and gradual increases in Cr were found in groupA. Although there was no significant difference in uricacid levels between before treatment and the end of theobservation period, a significant decrease was found at24, 48 and 96 weeks. Analysis of the sequential changesin those levels revealed that the first significant decreasein uric acid occurred at 24 weeks, while that of eGFR was

1082 Y. Shimizu et al. Hepatology Research 2014; 44: 1081–1087

© 2013 The Japan Society of Hepatology

at 48 weeks and of phosphate was at 96 weeks in groupA. In group B, significant changes were not found until48 weeks in all of these test items; significant decrease ineGFR and increase in Cr were barely found after 72weeks. Figure 4 shows the changes in these levels in arepresentative subject in group A. Gradual changes wereobserved, with changes in Cr, uric acid and eGFR.

DISCUSSION

LEVEL OF PHOSPHATE is affected by many factorssuch as endocrine factors, complicated diseases and

environmental factors. Thyroid hormone and growthhormones as well as parathyroid hormone (PTH) areknown to relate with the level of phosphate. Intestinaldiseases including malabsorption syndrome may causelow phosphatemia due to disturbance of absorptionor exceed secretion of phosphate from the intestine.Several medicines such as sorafenib may also cause lowphosphatemia. In the present study, level of PTH or

other hormones was not assayed in all cases, but nopatients in the present study showed symptoms of theabove diseases, and none of them had taken other medi-cines inducing low phosphatemia. Therefore, low phos-phatemia in the present study was supposed to becaused by administration of ADF.

In the present study, hypophosphatemia occurred in35.3% of patients treated with ADF, which was higherthan that in a previous report (6.5%).16 This differencemay be due to the different periods of ADF therapy, asthat was approximately 60 months in the present studyand 48 weeks in the other report. Therefore, the risk ofhypophosphatemia during long-term therapy may behigher than previously thought.

The mechanism of hypophosphatemia developmentin patients being treated with ADF has been reported tobe related to toxicity of the drug in proximal convolutedtubules of the kidneys. Injury to those tubules causes adisturbance of reabsorption as well as increased excre-tion of amino acids, sugar, uric acid, bicarbonate and

Table 1 Data obtained at beginning of ADF treatment

Group A Group B P

Age Years 60.2 1 13.0 61.9 1 8.6 0.54Sex Male : female 5:1 8:3 0.91Body mass index 21.3 1 3.0 22.2 1 3.4 0.53Diagnosis CH : LC : after transplantation 2:3:1 9:2:0 0.51Decreased ADF dose + : − 0:6 3:8 0.51genotype C : A (not determined) 3:1 (2) 7:0 (4) 0.36HBeAg/Anti-HBe +/− : −/+ : other 3:2:1 4:3:4 0.94HBV-DNA Log copy/mL 6.5 1 1.4 7.2 1 2.1 0.24Diabetes Mellitus + : − 3:3 4:7 0.64Hypertension + : − 3:3 3:8 0.60Albumin mg/dL 3.9 1 0.7 3.7 1 0.7 0.54Total bilirubin mg/dL 3.6 1 6.2 1.1 1 0.7 0.59AST IU 146.0 1 202.2 134.7 1 120.0 0.53ALT IU 198.5 1 287.6 168.5 1 204.4 0.54White blood cells /μL 5178 1 2631 4607 1 1335 0.59Hemoglobin g/dL 13.8 1 1.1 13.6 1 2.1 0.56Platelets ×104/μL 13.4 1 5.3 14.8 1 6.1 0.58ALP IU 285.2 1 61.9 330.3 1 167.2 0.59Uric acid mg/dL 5.2 1 1.5 5.3 1 1.7 0.55BUN mg/dL 13.4 1 4.3 17.3 1 6.7 0.40Cr mg/dL 0.6 1 0.2 0.9 1 0.3 0.07eGFR mL/min per 1.73 m2 99.6 1 24.9 67.7 1 24.8 0.05Calcium mg/dL 9.2 1 0.9 9.0 1 0.7 0.61Phosphate mg/dL 3.2 1 0.9 3.4 1 0.5 0.53

ALP, alkaline phosphatase; ALT, alanine aminotransferase; anti-HBe, hepatitis B virus e-antibody; AST, aspartate aminotransferase; BUN,blood urea nitrogen; CH, chronic hepatitis; Cr, creatinine; eGFR, estimated glomerular filtration rate; HBeAg, hepatitis B virus e-antigen;LC, liver cirrhosis; N.S., not significant.

Hepatology Research 2014; 44: 1081–1087 Hypophosphatemia by adefovir dipivoxil 1083


phosphate in urine, resulting in renal tubular acidosis,low uric academia and hypophosphatemia. These con-ditions are designated as Fanconi’s syndrome and thatdue to ADF has been reported.17,18 Prolongation of theseconditions results in osteomalacia and pathologicalfractures, while electrolyte abnormalities and osteope-nia cause such symptoms as muscle weakness, fatigue,

bone pain and pseudofractures.19–21 As a result, osteo-malacia develops and patient quality of life is reduced.

Adefovir dipivoxil toxicity appears to be related toorganic anion transporter (hOAT1)-mediated cellularaccumulation and transport of fluorescein methotrexatewith multidrug resistance-associated protein2 (Mrp2).In vitro studies have demonstrated that overexpression

Table 2 Data obtained at end of observation period

Group A Group B P

ADF administrated time Months 57.3 1 15.6 61.8 1 25.7 0.49Total amount of administrated ADF mg 15800.0 1 5914.4 16213.6 1 8812.9 0.57Decreased dose of ADF + : − 1:5 1:10 0.75HBeAg/anti-HBe +/− : −/+ : other 0:3:3 4:3:4 0.61HBV DNA 32.1 : <2.1 : undetected 0:3:3 3:3:5 0.73Bone disease + : − 3:3 0:11 0.04Kidney stones or urine crystals + : − 4:2 3:8 0.16Albumin mg/dL 4.3 1 0.8 4.2 1 0.7 0.43Total bilirubin mg/dL 1.5 1 1.8 0.8 1 0.5 0.52AST IU 32.7 1 28.3 27.2 1 15.0 0.54ALT IU 21.0 1 14.3 20.8 1 12.6 0.57White blood cells /μL 5225 1 1372 4305 1 1236 0.21Hemoglobin g/dL 14.2 1 1.8 13.8 1 2.1 0.57Platelets ×104/μL 14.4 1 5.2 15.3 1 5.5 0.55ALP IU 690.2 1 725.2 299.2 1 117.9 0.15Uric acid mg/dL 4.2 1 2.0 5.6 1 1.6 0.17BUN mg/dL 14.5 1 3.4 19.1 1 6.0 0.11Cr mg/dL 0.9 1 0.3 1.0 1 0.2 0.29eGFR mL/min per 1.73 m2 67.3 1 21.8 57.6 1 19.0 0.21Calcium mg/dL 9.2 1 0.9 9.4 1 0.6 0.57Phosphate mg/dL 2.1 1 0.7 3.2 1 0.3 0.007

ADF, adefovir dipivoxil; ALP, alkaline phosphatase; ALT, alanine aminotransferase; anti-HBe, hepatitis B virus e-antibody; AST, aspartateaminotransferase; BUN, blood urea nitrogen; Cr, creatinine; eGFR, estimated glomerular filtration rate; HBeAg, hepatitis B viruse-antigen.

Table 3 Comparison of data obtained at beginning of ADF treatment and end of observation period

Group A P Group B P

Beginning End of observation Beginning End of observation

ALT IU 198.5 1 287.6 21.0 1 14.3 0.03 168.5 1 204.4 20.8 1 12.6 0.004ALP IU 285.2 1 61.9 690.2 1 725.2 0.03 330.3 1 167.2 299.2 1 117.9 0.55Uric acid mg/dL 5.2 1 1.5 4.2 1 2.0 0.57 5.3 1 1.7 5.6 1 1.6 0.53BUN mg/dL 13.4 1 4.3 14.5 1 3.4 0.70 17.3 1 6.7 19.1 1 6.0 0.32Cr mg/dL 0.6 1 0.2 0.9 1 0.3 0.04 0.9 1 0.3 1.0 1 0.2 0.39eGFR mL/min per 1.73 m2 99.6 1 24.9 67.3 1 21.8 0.05 67.7 1 24.8 57.6 1 19.0 0.49Calcium mg/dL 9.2 1 0.9 9.2 1 0.9 0.90 9.0 1 0.7 9.4 1 0.6 0.35Phosphate mg/dL 3.2 1 0.9 2.0 1 0.6 0.02 3.4 1 0.5 3.2 1 0.3 0.67

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Cr, creatinine;eGFR, estimated glomerular filtration rate.



of hOAT1 in Chinese hamster ovary cells exposed toADF and cidofovir resulted in increases in intracellularconcentrations of both drugs.22–25

In the present study, the clinical features and labora-tory data for groups A and B prior to ADF therapy weresimilar, and it was not possible to predict the emergenceof hypophosphatemia in individual patients beforebeginning treatment. However, decreases in uric acidand eGFR, and an increase in Cr was found in patientswith low phosphatemia. In addition, reverse correlationwas found between ALP and phosphate. Elevation ofALP was supposed to be originated from bone due tosecondary elevation of PTH followed by low phospha-temia. On the other hand, phosphate and uric acid

showed positive correlation. These two substances arereabsorbed from the proximal tubule of the kidney.Although the transporters of phosphate and uric acid inthe proximal tubule are different, decrease of the bothsubstances was supposed to be due to the damage ofthe proximal tubule by ADF. It should be noted thatdecrease in serum phosphate was significant at 96 weeksafter beginning ADF, whereas significant decreases inuric acid and eGFR, and an increase in Cr occurred at 24,48 and 72 weeks, respectively. These data indicated thatdecreases in uric acid and eGFR preceded the decrease ofphosphate. It might be suspected that the screening forthose parameters may be useful to predict hypophos-phatemia or following bone complications. However,

Table 4 Patients with bone disease

Patient 1 Patient 2 Patient 3

Age 51 70 36Sex Male Female MaleDiagnosis of liver disease Liver cirrhosis Chronic hepatitis Liver cirrhosisStart of lamivudine Aug-2004 Feb 2006 Jan 2005Dose of lamivudine 100 mg daily 100 mg daily 100 mg dailyStart of adefovir May 2005 Dec 2006 Sep 2006Dose of adefovir 10 mg daily 10 mg daily 10 mg dailyHypophosphatemia May 2007 Dec 2008 Mar 2008Kidney stones or urine crystals

with occult hematuriaOct 2008 (41 months later) Oct 2008 (22 months later) Jan 2010 (40 months later)

Calcium phosphate andcalcium oxalate with occulthematuria

Calcium oxalate with occulthematuria

Renal stones

Bone disease Aug 2009 (51 months later) Nov 2011 (59 months later) Mar 2010 (42 months later)Osteomalacia Osteomalacia Scapula fracture

4

mg/

dlP

hosp

hate

3

2

r = –0.53p = 0.04

1

00 500 1000 1500

ALP

2000 2500IU/L

Figure 1 Relationship between alkaline phosphatase (ALP)and phosphate (data obtained at end of observation period).

4

mg/

dlP

hosp

hate

3

2

r = 0.63p = 0.031

00 2 4 6

Uric acid

8mg/dl

Figure 2 Relationship between uric acid and phosphate (dataobtained at end of observation period).



the present data is not enough to conclude that decreaseof uric acid and eGFR is an earlier event. It is needed toconfirm whether it is right or not by analyzing largenumber of subjects or by another validation study. Ingroup B in the present study, decrease of eGFR wasfound but decrease of phosphate was not found. Itshould be noted that some patients in group B showedelevated Cr or decreased eGFR. Careful follow-up exami-nations are needed for such patients to check foremergence of hypophosphatemia in the near future. Inaddition, kidney stones or urinary crystals with occulthematuria were noted in a considerable number of ourpatients, which was considered to be caused by increasesin various substances in urine caused by a disturbance ofreabsorption in the proximal tubules. Screening of urinein patients treated with ADF may be also important.

(a) %150

100

Pho

spha

te

50

00 24 48 72

Week Week

96

∗

120

(b) %200

150

100

Uric

aci

d

50

00 24 48 72 96

∗∗∗

120

(c) %200

150

100

Cre

atin

ine

50

00 24 48 72

Week Week

96

∗∗∗ ∗ ∗ ∗ ∗

∗ ∗∗ ∗

120

(d) %150

100

eGF

R

50

00 24 48 72 96 120

Figure 3 Changes in parameters in relation to period of adefovir dipivoxil (ADF) treatment. (a) Phosphate. (b) Uric acid. (c)Creatinine. (d) Estimated glomerular filtration rate (eGFR). *P < 0.05 as compared with beginning of treatment. , group A;

, group B.

60%0 24 48

Week72 96 120

80%

100%

66.2 59.8 53.0 48.6 46.1Creatinine (mg/dl) 0.99 1.09 1.19 1.29 1.34 1.34

46.1eGFR (ml/min/1.73 m2)3.2 3 2.9 2.7 2.6 2.2Phosphate (mg/dl)4.2 6.5 5.8 5.7 5.5 5.0Uric acid (mg/dl)

120%

140%

Figure 4 Changes in phosphate, creatinine, estimated glo-merular filtration rate (eGFR) and uric acid in group A.Percentages obtained at the beginning of treatment were con-sidered to be 100% and changes in those values are shown.

, creatinine; , eGFR; , phosphate; , uric acid.



In conclusion, hypophosphatemia occurred in 35%of the patients under long-term treatment with ADF.Although it was not possible to predict the decrease inphosphate before ADF therapy, decreases in uric acidand eGFR may be the early events relating to lowphosphatemia. Additional studies are needed to clarifywhether these phenomena precede low phosphatemia.

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Hypophosphatemia in patients with hepatitis B virus infection undergoing long-term adefovir dipivoxil therapy