Hypophosphataemia During Long-term Adefovir Dipivoxil Therapy In Patients With Hepatitis B Virus Infection

BackgroundAdefovir dipivoxil(ADV)is an oral prodrug of adefovir,which was metabolized intracellularly to adefovir diphosphate,a competitive inhibitor of HBV DNA polymerase that results in termination of the growing DNA chain.ADV is eliminated by the kidneys via glomerular filtration and active tubular secretion.The accumulation of ADV in renal proximal tubules appears to be related to ADV-related nephrotoxicity.Nephrotoxicity is defined by an increase>0.5 mg/dL from baseline in serum creatinine or a serum increase phosphorus value of<15 mg/L on two consecutive occasions.However,a few cases of hypophosphatemia and osteomalacia caused by long-term use of ADV have been reported recently.ObjectiveThis study was designed to assess the cumulative incidence of hypophophatemia caused by long-term treatment with ADV and explore the risk factors.MethodsPatients who were treated with ADV or ADV plus lamivudine(LAM)for more than 1 year were recruited retrospectively from the Second Hospital of Shandong University in China between June 2005 and June 2016.All patients were evaluated every 3～12months after the initiation of ADV treatment.Besides clinical assessment,biochemical analysis and virological markers were examined at each visit.Serum phosphate level,alkaline phosphatase(ALP),serum creatinine(Scr)and estimated glomerular filtration rate(eGFR)were assessed.The eGFR was calculated by the CKD-EPI(SCr-CysC)equation.The cumulative incidence of hypophophatemia and potential risks were analyzed.Results1.This study comprised 243 patients,including 183 male and 60 female patients and 171 CHB and 72 liver cirrhosis(LC)patients.The median age of the patients was 42 years(14～68)and the total duration of ADV was 66 months(12～120).One hundred and seventy-five patients were received ADV and 68 patients were treated with ADV plus LAM.2.Twenty-four patients showed hypophosphatemia during the therapy,the earliest one occurred at the 15 months after treatment and most(70.8%)was happened between 5 and 8 years.The cumulative rates of hypophosphatemia increased steadily during the treatment and reached as high as 25.3%at the 10 years.The 2-,3-,4-,、5-,6-,7-,8-,9-.10-year cumulative incidence of hypophosphatemia was 0.9,1.4,2.5,5.1,8.2,14.1,18,20.4 and 25.3%,respectively.The cumulative incidence of hypophosphatemia at 2-10 years was 0.6,0.6,0.6,3.2,6.2,11.2,14.2,14.2,and 19.9%for the patients with CHB and that was 1.5,3.3,7.9,10.4,13.7,23.9,32.3,49.3 and 49.3%for the patients with LC(Log-Rank.χ2=6.685,P=0.010).3.Clinical features and laboratory data were campared between the hypophosphatemia and none-hypophosphatemia.The results of univariate analysis showed that diagnosis with LC,administration with ADV plus LAM,decrease of eGFR,increase of ALP,Scr and cystatin C(CysC)were associated with decrease in serum phosphate(P<0.05).4.Multivariate analysis explored that LC(HR=2.662,P=0.010)and administration with ADV plus LAM(HR=2.886,P=0.020)were significant predictive risks for hypophosphatemia.5.A correlation analysis was done on serum phosphorus levels and eGFR levels and our data showed that γ =0.141,P=0.003。The age at the end of the observation was divided into two groups,Log-Rank test showed that x2=8.942,P=0.003,indicating that the occurrence of hypophosphatemia for the patients who older than 60 years old was higher than that for the patients who younger than 60 years old.Conclusions1.This study has shown that hypophosphatemia can be acquired for the long-term use of ADV patients with chronic HBV infection,and the cumulative incidence increased with the prolongation of ADV.The earliest one occurred at the 15 months after treatment and most 70.8%(17/24)was happened between 5 and 8 years.For early diagnosis,we suggest that patients who take ADV should be checked with regular laboratory monitoring,including tests of serum ALP,creatinine,CysC,phosphorus and evaluation of eGFR.2.Univariate analysis showed that diagnosis with LC,administration with ADV plus with LAM,increase of ALP,Scr,CysC and decrease of eGFR were significantly between the hypophosphatemia and none-hypophosphatemia.3.Multivariate analysis explored that LC and administration with ADV plus LAM were significant predictive risks for hypophosphatemia.More attention should be paid for those patients。Log-Rank test results indicated that the occurrence of hypophosphatemia for the patients who older than 60 years old was higher than that for the patients who younger than 60 years old。Age may also be a contributing factor to the occurrence of the hypophosphatemia.4.Although there is a correlation between eGFR and serum phosphorus(γ=0.141,P=0.003),both the tests of serum creatinine,CysC,evaluation of eGFR and the serum phosphorus should be monitored regularly.