Administration Of Adefovir Dipivoxil Research Articles

Adefovir Dipivoxil-induced Osteomalacia: A Rare Case of Misdiagnosis due to Concurrent Thyroid Tumor

Background: Both the administration of adefovir dipivoxil and the elevation of primary parathyroid hormone can result in serum electrolyte abnormalities and the development of metabolic bone disease. Adefovir dipivoxil-induced osteomalacia is a clinical disease that is rarely seen and often leads to misdiagnosis. Case presentation: In this case, the patient developed osteomalacia due to renal tubular toxicity caused by chronic use of adefovir dipivoxil. The drug indirectly affected the secretion of parathyroid hormone (PTH). Coincidentally, the patient also had a tumor below the thyroid, leading to a misdiagnosis. Conclusion: Osteomalacia caused by adefovir dipivoxil is a clinically rare disease, and it is important not to overlook it as it may lead to misdiagnosis. Hence, in cases where laboratory tests reveal abnormal parathyroid hormone levels, it is crucial to inquire about the patient s detailed medication history. This is applicable even in situations where there is evidence suggesting primary hyperparathyroidism.

Effect of Coformer Selection on In Vitro and In Vivo Performance of Adefovir Dipivoxil Cocrystals.

This study aimed to improve the in vitro dissolution, permeability and oral bioavailability of adefovir dipivoxil (ADD) by cocrystal technology and clarify the important role of coformer selection on the cocrystal's properties. ADD was cocrystallized with three small molecules (i.e., paracetamol (PA), saccharin (SAC) and nicotinamide (NIC)), respectively. The obtained ADD-PA cocrystal was characterized by DSC, TGA, PXRD and FTIR. Comparative study on dissolution rates among the three ADD cocrystals were conducted in water and pH 6.8 phosphate buffer. Besides, effects of coformers on intestinal permeability of ADD were evaluated via in vitro Caco-2 cell model and in situ single-pass intestinal perfusion model in rats. Furthermore, in vivo pharmacokinetic study of ADD cocrystals was also compared. Dissolution rates of ADD cocrystals were improved with the order of ADD-SAC cocrystal > ADD-PA cocrystal > ADD-NIC cocrystal. The permeability studies on Caco-2 cell model and single-pass intestinal perfusion model indicated that PA could enhance intestinal absorption of ADD by P-gp inhibition, while SAC and NIC did not. Further in vivo pharmacokinetic study showed that ADD-SAC cocrystal exhibited higher Cmax (1.4-fold) and AUC0-t (1.3-fold) of ADD than administration of ADD alone, and Cmax and AUC0-t of ADD-PA cocrystal were significantly enhanced by 2.1-fold and 2.2-fold, respectively, which was attributed to its higher dissolution and improved intestinal permeability. Coformer selection had an important role on cocrystal's properties, and cocrystallization of ADD with a suitable coformer was an effective approach to enhance both dissolution and bioavailability of ADD.

Follow-Up of Adefovir Dipivoxil Induced Osteomalacia: Clinical Characteristics and Genetic Predictors.

Adefovir dipivoxil (ADV) is widely used for chronic hepatitis B therapy in China. To explore the clinical features and prognosis of ADV-induced osteomalacia and to analyze the association between osteomalacia and genetic variants in 51 drug transporters genes. Clinical and follow-up data of the ADV-treated patients were collected. Target capture sequencing was used to identify genetic variations of 51 drug transporter genes. A total of 193 hepatitis B patients treated with ADV were enrolled, of whom 140 had osteomalacia. The other 53 without osteomalacia were included in the control group. The median duration of ADV treatment before the onset of osteomalacia was 6.5 years (range:1.5–7 years). We found that most patients with osteomalacia had hypophosphatemia, high serum alkaline phosphatase levels, hypouricemia, nondiabetic glycosuria, proteinuria. Stopping ADV administration, supplementing calcitriol and calcium were effective treatments. During 3–6 months of follow-up, the clinical symptoms and biochemical indicators of patients with osteomalacia have been significantly improved. There was no significant difference in duration of adefovir treatment in patients with or without osteomalacia (p = 0.791). Through regression analysis, we found that age was a risk factor for osteomalacia [per 1 year, odds ratio (OR), 1.053; 95% confidence interval (95% CI), 1.020–1.087; p = 0.015]. 1992 single nucleotide variants were found using target capture sequencing. However, the associations of genetic variants of 51 drug transporter genes and the risk of osteomalacia were negligible. Osteomalacia is prone to occur in patients with chronic hepatitis B treated with long-term ADV at a therapeutic dose. After standard treatment, the prognosis is mostly good. We failed to find genetic variants that can predict the risk of ADV-induced osteomalacia.

Adefovir dipivoxil-induced Fanconi syndrome and its predictive factors: A study of 28 cases.

The aim of the present study was to identify monitoring and prevention measures as well as predictive factors for early detection of renal toxicity associated with long-term administration of adefovir dipivoxil in order to avoid progression to Fanconi syndrome. Clinical data of 28 patients with Fanconi syndrome caused by long-term administration of adefovir dipivoxil for the treatment of chronic hepatitis B virus (HBV) infection were collected pre-and post-administration for analysis. Patients presented with fatigue, progressive systemic pain in multiple bones and joints, as well as difficulty in walking and pathological fractures in a number of severe cases. Laboratory examinations revealed hypophosphatemia, elevated serum cystatin C (Cys-C), elevated serum creatinine (SCr), reduced glomerular filtration rate (GFR), positive urinary protein, erythrocytes and glucose, as well as osteoporosis. In consequence, adefovir dipivoxil administration was stopped, and patients received concentrated divitamins, sodium phosphate syrup and calcitriol. Symptoms and abnormalities in laboratory examinations were significantly improved in all patients after 2-6 months. Therefore, serum phosphate, SCr, routine urine parameters, Cys-C and GFR should be monitored regularly in chronic HBV patients treated with adefovir dipivoxil. The following factors were identified as predictive of kidney damage and Fanconi syndrome: Age ≥40 years, living in rural areas, previous renal toxicity, estimated GFR (eGFR) <90 ml/min/1.73 m2, hypertension, diabetes, cirrhosis and duration of adefovir dipivoxil treatment exceeding 24 months. The present results indicate that timely termination of adefovir dipivoxil treatment and replacement with other antiviral agents is critical once renal impairment appears, and that it is necessary to change to other antiviral agents and prolong the interval of administration according to the eGFR level.

Predictors of kidney tubular dysfunction induced by adefovir treatment for chronic hepatitis B.

To investigate the predictors of proximal kidney tubular dysfunction (PKTD) induced by adefovir dipivoxil (ADV) treatment for chronic hepatitis B. Seventy-nine patients (age at the evaluation of PKTD: 56.9±10.7 years) with chronic hepatitis B undergoing long-term oral antiviral nucleos(t)ide analogue treatment were consecutively recruited. PKTD was defined by the presence of at least two of the following five abnormalities: phosphate diabetes, nondiabetic glucosuria, metabolic acidosis, β2-microglobulinuria, or renal hypouricemia. The single-nucleotide polymorphisms (SNPs) in the SLC22A6 gene encoding human organic anion transporter 1 (hOAT1) and ABCC2 encoding multidrug resistance protein 2 (MRP2) were analyzed using the TaqMan Allelic Discrimination Demonstration Kit. Nine (30.0%) of the 30 ADV-treated patients were diagnosed with PKTD, while no patients without ADV developed PKTD (P<0.001). Three patients with ADV were diagnosed with symptomatic osteomalacia. Among the patients who took ADV, those with PKTD were of higher age at initiation, had significantly longer treatment duration, and had a significantly lower body mass index than those without PKTD. The incidence of PKTD dramatically increased after 96 mo from the start of ADV administration. In contrast, the SNPs were not correlated with PKTD. Logistic regression analysis extracted older age at initiation (OR=5.0, 95%CI: 1.1-23.4; P=0.040) and longer treatment duration (OR=3.2, 95%CI: 1.2-8.6; P=0.020) as significant factors associated with PKTD. Our results suggest that the tubular function of the kidney of older patients undergoing long-term ADV treatment should be carefully evaluated.

Chronic Hepatitis B with Fanconi’s Syndrome Triggered by Short-term Administration of Adefovir Dipivoxil

The patient was a 45-year-old man who had Down syndrome and hepatitis B virus (HBV) with a high virus load and the presence of hepatitis B e antigen. He had received lamivudine (100mg/day: per os) as nucleoside/ nucleotide analogues (NAs) from April 2005 to December 2012. Although the initial response of HBV DNA was favorable, a high level of viral breakthrough without hepatitis reactivation occurred after 16 -months of lamivudine administration. In December 2012, the therapy with lamivudine was substituted with adefovir dipi‐ voxil (ADV) and entecavir hydrate (ETV) after informed consent was obtained. Serum HBV DNA gradually decreased over 7 -months of this drug substitution; however, there was a gradual increase in the serum alkali‐ phosfatase (ALP) level without increase in the other hepatobiliary enzymes and nephrotoxicity. Since he was suspected as having drug-induced liver damage and nephropathy caused by NAs, ADV and ETV were adminis‐ tered every other day for 3 months, resulting in no improvement. The laboratory data was obtained in December 2013 as follows; peak 3 dominant in the ALP isoenzyme analysis, low levels of serum carcium, phosphorus and urinary acid, excessive urinary excretion of amino acid and increased level of serum creatinine. Thus, we sug‐ gested that he suffered from acquired Fanconi’s syndrome induced by ADV. Administration of ADV was then discontinued after 12 months of drug substitution and only ETV was prescribed. Six months after ADV discon‐ tinuation, some of the indicative markers of renal dysfunction, including Fanconi’s syndrome, were normalized and recovered to the same levels before the combined use of ADV and ETV. The patient had been treated with sodium valproate and carbamazepine for the unstable mental state and epilepsy before the lamivudine adminis‐ tration; however, the negative synergic action among these drugs and NAs was not evaluated sufficiently. Here, we report the earlier onset of Fanconi’s syndrome triggered by ADV, which is usually diagnosed after long-term ADV administration. We suggest that the adequate evaluation of renal function, including proximal tubular damage before administration of ADV and close observation from the early period during treatment with ADV, is required.

Long-term observation of osteomalacia caused by adefovir-induced Fanconi's syndrome.

A 64-year-old man suffering polyarthralgia and bone pain was referred to our hospital. Renal dysfunction, hypophosphatemia and increased levels of bone alkaline phosphatase were found. The patient's serum creatinine level had gradually increased after the initiation of adefovir dipivoxil administration for hepatitis B. In agreement with multifocal uptakes of bone scintigraphy, iliac bone biopsy revealed an abnormal increase in osteoid tissues. Reducing the dose of adefovir and initiating the administration of eldecalcitol were effective for reducing proteinuria and glucosuria, and for ameliorating bone pain with an increase in serum phosphate level. This case first showed a clinical course of hypophosphatemic osteomalacia caused by secondary Fanconi's syndrome for 8 years after adefovir administration. Early diagnosis is important for the reversibility of bone damage and for a better renal prognosis.

Elevation in Serum Concentration of Bone-Specific Alkaline Phosphatase without Elevation in Serum Creatinine Concentration Secondary to Adefovir Dipivoxil Therapy in Chronic Hepatitis B Virus Infection

Of 168 patients with chronic hepatitis B virus (HBV) infection-related liver disease, 20 patients who had received 100 mg of lamivudine plus 10 mg/day of adefovir dipivoxil (ADV) (ADV group) and 124 patients who had received 0.5 mg/day of entecavir or 100 mg/day of lamivudine (non-ADV group) for >1 year were enrolled. For comparative analyses, 19 well-matched pairs were obtained from the groups by propensity scores. At the time of enrollment, serum creatinine and phosphate concentrations were similar between the ADV and non-ADV groups; however, urinary phosphate (P = 0.0424) and serum bone-specific alkaline phosphatase (BAP) (P = 0.0228) concentrations were significantly higher in the ADV group than in the non-ADV group. Serum BAP was significantly higher at the time of enrollment than before ADV administration in the ADV group (P = 0.0001), although there was no significant change in serum BAP concentration in the non-ADV group. There was a significant positive correlation between the period of ADV therapy and ΔBAP (R 2 = 0.2959, P = 0.0160). Serum BAP concentration increased before increase in serum creatinine concentration and was useful for early detection of adverse events and for developing adequate measures for continuing ADV for chronic HBV infection-related liver disease.

Polymerase mutations rtN238R, rtT240Y and rtN248H of hepatitis B virus decrease susceptibility to adefovir

Long term antiviral therapy with nucleos(t)ide analogs (NAs) may lead to the emergence of drug-resistance viral mutants in chronic hepatitis B virus (HBV) patient. The purpose of this study was to identify adefovir dipivoxil (ADV) resistance mutations of HBV polymerase and determine effective drugs to replace ADV. The reverse transcriptase (RT) coding region was PCR-amplified using HBV DNA extracted from patient blood samples and sequenced. Nineteen substitution mutations were detected. Among them, rtN238R, rtT240Y and rtN248H were often observed in patients receiving ADV administration. These three potential drug resistant sites were introduced into HBV replication-competent plasmids. The in vitro susceptibility of both wild-type (WT) and mutant-type (MT) HBV to NAs was analyzed by Southern blotting and quantitative real-time PCR. The rtN238R, rtT240Y and rtN248H substitutions had no obvious effect on HBV DNA replication or gene expression. The in vitro susceptibility analysis showed that rtN238R, rtT240Y and rtN248H substitutions were responsible for the reduced susceptibility to ADV, and demonstrated a 5.42-, 2.89- and 5.72-fold increase in resistance towards ADV, respectively. However, HBV harbored these mutations retained normal susceptibility to LMV, LdT, ETV and TDF.

Development of osteomalacia in a post-liver transplant patient receiving adefovir dipivoxil

We report the case of a patient treated with living donor-related liver transplantation who suffered from osteomalacia during adefovir dipivoxil (ADV)-containing antiviral therapy for lamivudine-resistant hepatitis B virus infection. The patient had generalized bone pain, with severe hypophosphatemia after 20 mo of ADV therapy. Radiographic studies demonstrated the presence of osteomalacia. The peak plasma ADV level was 38 ng/mL after administration of ADV at 10 mg/d. It was also found that ADV affected the metabolism of tacrolimus, a calcineurin-inhibitor, and caused an increase in the plasma levels of tacrolimus. The disability was reversed with the withdrawal of ADV and with mineral supplementation. ADV can cause an elevation of plasma tacrolimus levels, which may be associated with renal dysfunction. High levels of ADV and tacrolimus can cause nephrotoxicity and osteomalacia. This case highlights the importance of considering a diagnosis of osteomalacia in liver transplantation recipients treated with both ADV and tacrolimus.

Mutations associated with the therapeutic efficacy of adefovir dipivoxil added to lamivudine in patients resistant to lamivudine with type B chronic hepatitis

Factors influencing the therapeutic efficacy of adefovir dipivoxil added to continuing lamivudine have not been elucidated in lamivudine-resistant patients with type B chronic hepatitis. The viral mutations influencing the efficacy of treatment with adefovir dipivoxil were investigated by sequencing analysis of the whole virus genome. Thirty patients resistant to lamivudine receiving adefovir dipivoxil therapy added to lamivudine were studied. From serum samples obtained before the administration of adefovir dipivoxil, full-length viral DNA sequences were determined by PCR-direct sequencing. Susceptibility of the virus to adefovir was examined further using in vitro transfection analysis. By screening the whole viral genome, the presence of two mutations, a T-to-C/G/A mutation at nt1753 (V1753) and an A-to-C mutation at nt2189 (C2189), correlated with the higher incidence of sustained viral DNA clearance during therapy (P < 0.005 and P < 0.05). In multivariate analysis, the V1753 (P = 0.001) and the C2189 (P = 0.007) mutations, and elevated transaminase (P = 0.011) and low viral load (P = 0.008) at the baseline were selected as significant independent factors associated with improved antiviral efficacy. In vitro transfection analysis showed no differences in susceptibility to adefovir among wild-type virus and C1753 and C2189 mutant viruses, suggesting that the virus possessing these mutations may be eradicated more efficiently than the wild-type virus by treatment regardless of a direct antiviral effect of adefovir.

Efficacy of adefovir dipivoxil in the treatment of lamivudine‐resistant hepatitis B virus genotype C infection

Adefovir dipivoxil (ADV) is a nucleotide analogue that is known to be effective for lamivudine-resistant hepatitis B virus (HBV) mutants as well as wild-type HBV. The aim of this study is to assess the efficacy of ADV against lamivudine-resistant genotype C HBV mutants. Thirty-five patients with breakthrough hepatitis due to lamivudine-resistant HBV received ADV 10 mg daily with discontinuation of lamivudine. Quantitative HBV DNA, HBeAg, liver function test including alanine aminotransferase (ALT) was checked every 4-12 weeks to evaluate the efficacy of ADV. ADV was administered for a median of 48 weeks (range: 24-120 weeks). The rate of serum HBV DNA loss was 68.6%, 80.0%, 84.0%, and 88.2% at weeks 12, 24, 36, and 48, respectively. The rate of serum HBeAg seroconversion was 8.3% and 14.3% at weeks 24 and 48, respectively. The rate of serum ALT normalization at week 48 was 70.6%. Within 32 weeks after stopping ADV therapy, serum HBV DNA levels increased to a median of 378.9 pg/ml in 88.9% of patients, who were treated for a median of 40 weeks. Moreover, in some patients, the ALT level increased to more than five times the upper limit of normal. Administration of ADV is an effective option for the treatment of patients with lamivudine-resistant genotype C HBV infection.

Adefovir rapidly suppresses hepatitis B in HBeAg‐negative patients developing genotypic resistance to lamivudine†

Progression of hepatitis B in patients with lamivudine-resistant strains is slowed down by adefovir dipivoxil (ADV). Whether the time point of ADV administration (genotypic vs. phenotypic resistance) influences the outcome of therapy is unknown. We compared the outcome of ADV therapy in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B patients with genotypic and phenotypic resistance to lamivudine. Ten milligrams of ADV was administered daily for 2 years to 46 HBeAg-negative patients at the time of phenotypic resistance (group A, >6 log(10) copies/mL of hepatitis B virus [HBV] DNA and high alanine aminotransferase [ALT] levels) and 28 patients at the time of genotypic resistance (group B, 3-6 log(10) copies/mL of HBV-DNA and normal ALT). HBV DNA was assessed every 2 months using Versant 3.0 assay, and lamivudine resistance was confirmed via INNO-LiPA assay in all patients. By month 3, HBV DNA tested negative in all patients from group B compared with only 20 (46%) in group A (P < .0001). The 2-year rates of virological response were 100% in the former patients and 78% in the latter ones (P < .0001). ALT levels remained persistently normal in all group B patients, whereas in group A patients they normalized at rates of 50% at month 6 (P < .0001), 72% at month 12 (P < .01), and 93% at month 24. None of the patients developed ADV resistance or ADV-related side effects. In conclusion, to optimize antiviral treatment in HBeAg-negative patients selecting resistant strains to lamivudine, ADV should be added to lamivudine as soon as genotypic resistance is detected.