Daily low dose intravesical cidofovir for the treatment of BK virus associated hemorrhagic cystitis after allogeneic stem cell transplantation.

INTRODUCTION: BK virus associated hemorrhagic cystitis(BKV-AHC) is a serious complication observed after allogeneic stem cell transplantation and the current therapeutic options are scarce with substantial renal side effects. Although the guidelines recommend intravenous cidofovir application with caution to nephrotoxicity, there are few studies which investigated intravesical administration and reported similar therapeutic results with less renal side effects. METHODS: We administered low dose, daily and consecutive (75 mg/day, for 5 days) intravesical cidofovir to 25 patients with BKV-AHC that developed after (ASCT). RESULTS: The response rate in our cohort was 92% and relapse was not encountered in 84% of the patient population during one year of follow-up. The median BK urine viral load significantly decreased from 260,000,000 IU/mL to 53,000,000 IU/mL after a week of treatment (p = 0.0001). Rise in serum creatinine was observed in 5 patients during treatment and post-treatment nephrotoxicity was seen in only 1 patient. CONCLUSIONS: Daily low dose intravesical cidofovir might be an effective treatment option for BKV-AHC after ASCT with favorable less systemic side effects.

Cidofovir-induced anterior uveitis in an allogeneic stem cell transplant recipient.

Anterior uveitis is a reported complication of intravenous cidofovir, almost exclusively described in human immunodeficiency virus (HIV) infected patients treated for cytomegalovirus retinitis. In this study, we report the case of an allogeneic stem cell transplant recipient with significant visual impairment and hypotony following administration of high-dose intravenous cidofovir for hemorrhagic cystitis due to BK virus.

Selatogrel: A Novel Subcutaneous P2Y12 Inhibitor.

ABSTRACT: The use of a P2Y12 inhibitor as a component of dual antiplatelet therapy in patients with an acute coronary syndrome (ACS) is well established. However, the P2Y12 inhibitors currently available have pharmacokinetic limitations due to delayed absorption, lack of enteral access for administration with oral formulations, need for intravenous access with cangrelor, or need for metabolization to be ideal in the critical 3-hour window during an ACS. Selatogrel is a novel, potent, reversible, and selective 2-phenylprimdine-4-carboxamide administered subcutaneously under development. Results from preclinical, phase 1, and phase 2 trials have confirmed that the agent provides sustained and reversible P2Y12 platelet inhibition with an acceptable safety profile. The most commonly reported adverse effects include minor bleeding and dyspnea. Phase 3 trials are being designed to understand the critical role this agent can play in upstream management of patients with ACS including a more defined understanding of the adverse effect profile, how to transition from this agent to an oral agent, who will be administering, and does this agent allow for a safe and quick transition to coronary artery bypass graft surgery if needed. Should it obtain approval, selatogrel has the potential to provide a unique and advantageous mechanism for P2Y12 inhibition.

Safety and efficacy of intravenously administered cidofovir in adult haematopoietic cell transplant recipients: a retrospective multicentre cohort study.

OBJECTIVES: To evaluate the safety and efficacy of cidofovir for the treatment of double-stranded DNA (dsDNA) viral infections following allogeneic haematopoietic cell transplant (HCT). METHODS: This was a retrospective multicentre cohort study including adult HCT recipients who received ≥1 dose of IV-administered cidofovir for any dsDNA viral infection from 2006 to 2019. The objectives were to describe the rate of and risk factors for nephrotoxicity and virological response by the end of treatment (EOT). RESULTS: We included 165 patients from nine centres. Cidofovir was administered at 5 mg/kg/week (N = 115; 69.7%), 1 mg/kg/week (18; 10.9%), 3 mg/kg/week (12; 7.3%) or 1 mg/kg three times/week (11; 6.7%). Cidofovir was administered for adenovirus, cytomegalovirus (CMV) and BK virus infection in 75 (45.5%), 64 (38.8%) and 51 (30.9%) patients, respectively. Among 158 patients with renal function data at baseline and EOT, 40 (25.3%) developed nephrotoxicity. In multivariable analyses, age (OR 1.04; P = 0.05), weight (OR 1.05; P = 0.01), CMV infection (OR 3.6; P = 0.02), liposomal amphotericin B (OR 8.06; P = 0.05) and IV voriconazole/posaconazole (OR 13.0; P = 0.003) were predictors of nephrotoxicity. Creatinine concentration was significantly higher at EOT (1.16 ±â€Š0.95 mg/dL) compared with baseline (0.91 ±â€Š0.39 mg/dL; P < 0.001), but improved by 2 weeks (0.91 ±â€Š0.84 mg/dL; P = 0.007) and 4 weeks (0.96 ±â€Š0.89 mg/dL; P = 0.03) post-EOT. Median viral load significantly declined for patients with adenovirus DNAaemia by EOT (P < 0.0001) and for patients with CMV DNAaemia by EOT + 4 weeks (P = 0.003), but not for patients with BK virus DNAaemia. CONCLUSIONS: One in four HCT recipients treated with IV cidofovir developed largely reversible nephrotoxicity. Careful selection of patients and close follow-up of renal function may minimize toxicity.

Insights from In Vitro and Clinical Data to Guide Transition from the Novel P2Y12 Antagonist Selatogrel to Clopidogrel, Prasugrel, and Ticagrelor.

Reduced pharmacodynamic (PD) effects of irreversible oral P2Y12 receptor antagonists have been reported when administered during cangrelor infusion. Therefore, the PD interaction liability of the novel P2Y12 receptor antagonist selatogrel with irreversible (i.e., clopidogrel, prasugrel) and reversible (i.e., ticagrelor) oral P2Y12 receptor antagonists was investigated in vitro and in healthy subjects. In vitro, selatogrel reduced the effects of clopidogrel and prasugrel in a concentration-dependent manner, while additive effects were observed for the combination of selatogrel and ticagrelor. Accordingly, a single-center, randomized, double-blind, two-way crossover study was conducted consisting of six groups. In each group (N = 12), an open-label loading dose of 300 or 600 mg clopidogrel, 60 mg prasugrel, or 180 mg ticagrelor was administered 30 minutes (i.e., at t max of selatogrel) or 12 hours after a single subcutaneous dose of 16 mg selatogrel or placebo. Inhibition of platelet aggregation (IPA) was assessed at various time points up to 48 hours. Reduced IPA was determined when clopidogrel or prasugrel was administered 30 minutes after selatogrel (∼40 and 70% lower IPA, respectively, at 24 hours postdosing). However, when administering prasugrel 12 hours after selatogrel, IPA was not impacted (>90% IPA) and in the case of clopidogrel reduced effects were partially mitigated. Similar IPA was determined for ticagrelor when administered 30 minutes after selatogrel or placebo. In conclusion, reduced IPA was observed for clopidogrel and prasugrel when administered after selatogrel, which can be mitigated by applying an appropriate time interval. No PD interaction with ticagrelor was observed.

Osteomalacia and renal failure due to Fanconi syndrome caused by long-term low-dose Adefovir Dipivoxil: a case report.

BACKGROUND: Progressive bone pain and fracture and abnormal positron emission tomography combined with a computed tomography are main reasons for the oncologists suspecting bone tumor. During the patient's medical treatment, the oncologists' unfamiliarity with adverse reactions to anti-HBV drugs were main reason for the long-term exposure to the drug and the adverse reaction (ADR) experienced by the patient. CASE PRESENTATION: A 63-year-old Chinese man had a 27-month history of progressive generalized bone pain combined with spontaneous fractures. Positron emission tomography combined with a computed tomography, revealed an abnormal increase in ribose metabolism and low positron serum inorganic phosphorus concentration (0.7; 0.78-1.65 mmol/L). Serum creatinine level was 252 µmol/L (53-97) µmol/L, and glomerular filtration rate was 22.79 mL/min/1.73 m2. The patient was referred to a multidisciplinary clinic to clarify the diagnosis of myeloma or bone tumor for further treatment in 2017. His medical history revealed that he had a 30-year history of chronic hepatitis B infection. He had received lamivudine at a daily dose of 100 mg for 19 years (1990 to 2009), which had been changed to adefovir (10 mg/day) owing to lamivudine resistance in 2009. Based on the changes in the patient's laboratory markers and the results of emission computed tomography and other radiographic findings, adefovir-induced hypophosphatemic osteomalacia due to acquired renal Fanconi syndrome was suspected by the clinical pharmacist. Considerable clinical improvement was observed after adefovir discontinuation and the administration of entecavir (1.0 mg, every other day). CONCLUSION: Fanconi syndrome with osteomalacia can develop in patients with chronic hepatitis B infection being treated with adefovir at a conventional low dosage of 10 mg/day. This case highlights the importance of ADR as a differential diagnosis and the need of pharmacists with drug safety expertise expert in the patient management.

Retrospective analysis of the clinical characteristics of adefovir dipivoxil-induced Fanconi's syndrome in the Chinese population.

WHAT IS KNOWN AND OBJECTIVE: To explore the clinical characteristics of adefovir dipivoxil-induced Fanconi's syndrome in the Chinese population and provide a reference for rational drug use in the clinic. METHODS: By searching the CNKI, Wanfang, Chinese VIP, PubMed/MEDLINE, Web of Knowledge, Ovid, Elsevier and SpringerLink databases during 1 January 2008 to 31 December 2019, 78 studies of ADV-induced Fanconi's syndrome involving a total of 110 patients were collected and analysed retrospectively. RESULTS AND DISCUSSION: Prolonged usage of adefovir dipivoxil at low doses to treat hepatitis B might cause Fanconi's syndrome as the first symptom, especially for use over 12 months.The main clinical manifestation was bone pain accompanied by hypophosphataemia, elevated alkaline phosphatase (ALP), urine glycosuria and urine protein. X-rays and bone mineral density (BMD) examinations were mainly used to characterized osteoporosis. The patients had pain relief within 1 week to 1 month, and the biochemical indicators returned to normal within from 2 to 4 months. WHAT IS NEW AND CONCLUSION: Sufficient attention is required before and during exposure to long-term ADV therapy. The clinical picture, laboratory and radiograph alterations are important clues for ADV-induced Fanconi's syndrome.

Brincidofovir: understanding its unique profile and potential role against adenovirus and other viral infections.

Brincidofovir (BCV) is a lipid conjugate of cidofovir with good oral bioavailability, enabling optimal intracellular levels of the active drug. Lower rates of nephrotoxicity and myelotoxicity make it a favorable alternative. Despite a greater safety profile among pediatric hematopoietic cell transplant recipients, the oral formulation has been associated with increased gastrointestinal toxicity in adult hematopoietic cell transplant recipients. Oral BCV continues to be developed as a countermeasure against smallpox, while a potentially safer intravenous preparation has been out licensed to another company. BCV has demonstrated great in vitro potency against double-stranded DNA viruses, especially adenovirus. Because of its importance for immunocompromised patients, this review aims to evaluate BCV's clinical and safety profile to support its continued development.

In Vitro and In Vivo Renoprotective Effects of Telbivudine in Chronic Hepatitis B Patients Receiving Nucleotide Analogue.

AIM: Renal toxicity of adefovir disoproxil (ADV) and tenofovir disoproxil fumarate (TDF) is a significant concern in chronic hepatitis B (CHB) patients. Early observational clinical data suggested that telbivudine (LdT) might have renoprotective effects. METHODS: In this prospective study, consecutive CHB patients on combined lamivudine (LAM) + ADV/TDF were switched to LdT + ADV/TDF at recruitment and were followed up for 24 months. Estimated glomerular filtration rate (eGFR) was calculated with the modification of diet in renal disease equation. The effects of LdT on cell viability and expression of kidney injury or apoptotic biomarkers were investigated in cultured renal tubular epithelial cell line HK-2. RESULTS: Thirty-one patients (median age 55 years, 90.3% male) were recruited (54.8% TDF: 45.2% ADV). Serum HBV DNA was undetectable at all time points. Median eGFR was 70.2 (IQR 62.6-77.9) and 81.5 (IQR 63.6-99.1) mL/min/1.73 m2 at baseline and 24 months, respectively (p < 0.001). Downstaging of chronic kidney disease was observed in eight (25.8%) patients and was more common in ADV-treated compared to TDF-treated patients (7/8 vs. 1/17, p = 0.011; OR 16, 95% CI 1.643-155.766, p = 0.017). In vitro data showed that adding LdT to ADV or TDF was associated with improved cell viability and lower expression of injury and apoptotic biomarkers compared with ADV or TDF alone. Treatment was prematurely discontinued in four(12.9%) patients due to myalgia. CONCLUSIONS: Clinical and in vitro data suggest that LdT has renoprotective effects in patients on long-term ADV/TDF treatment. LdT may be considered as an adjuvant therapy in this special group of patients with renal impairment (NCT03778567).

Low-dose adefovir dipivoxil-induced hypophosphatemia osteomalacia in five chronic hepatitis B virus-infected patients. Is low-dose adefovir dipivoxil-induced nephrotoxicity completely reversible?

Adefovir dipivoxil (ADV) is one of the most important nucleostide analogues currently in use for the treatment of chronic hepatitis B virus (HBV) infection. Low-dose ADV-induced nephrotoxicity in most cases was reported to be reversible after the discontinuation of ADV or by decreasing the dose of ADV. In our study, we have 5 documented cases of low-dose ADV-induced hypophosphatemia osteomalacia with or without Fanconi syndrome which were diagnosed in our hospital between 2010 and 2017. Three patients were observed to have a full recovery after the discontinuation of ADV. Two patients had persistently elevated urine ß2-microglobulin levels and out of these two patients, one patient had persistent hypophosphatemia after the cessation of ADV. These cases illustrated that the use of low-dose ADV increased the risk of nephrotoxicity, and in some patients, low-dose ADV-induced nephrotoxicity was not completely reversible. Patients of East Asian origin, especially those with a low body mass index, were prone to a relatively higher risk of developing low-dose ADV-induced nephrotoxicity; therefore, it was worth paying attention to the side effects caused by low-dose ADV.

Brca1 is involved in tolerance to adefovir dipivoxil­induced DNA damage.

Nucleos(t)ide analogues (NAs) are currently the most important anti­viral treatment option for patients with chronic hepatitis B (CHB). Adefovir dipivoxil (ADV), a diester pro­drug of adefovir, has been widely used for the clinical therapy of hepatitis B virus infection. It has been previously reported that adefovir induced chromosomal aberrations (CAs) in the in vitro human peripheral blood lymphocyte assay, while the genotoxic mechanism remains elusive. To evaluate the possible mechanisms, the genotoxic effects of ADV on the TK6 and DT40 cell lines, as well as DNA repair­deficient variants of DT40 cells, were assessed in the present study. A karyotype assay revealed ADV­induced CAs, particularly chromosomal breaks, in wild­type DT40 and TK6 cells. A γ­H2AX foci formation assay confirmed the presence of DNA damage following treatment with ADV. Furthermore, Brca1­/­ DT40 cells exhibited an increased sensitivity to ADV, while the knockdown of various other DNA damage­associated genes did not markedly affect the sensitivity. These comprehensive genetic studies identified the genotoxic capacity of ADV and suggested that Brca1 may be involved in the tolerance of ADV­induced DNA damage. These results may contribute to the development of novel drugs against CHB with higher therapeutic efficacy and less genotoxicity.

Denosumab improves clinical manifestations of hypophosphatemic osteomalacia by adefovir-induced Fanconi syndrome: a case report.

BACKGROUND: Adefovir dipivoxil is a nucleotide analogue that is approved for treatment of chronic hepatitis B. Adefovir dipivoxil is associated with proximal tubular dysfunction, resulting in Fanconi syndrome, which can cause secondary hypophosphatemic osteomalacia. We describe a case of a patient with hypophosphatemic osteomalacia secondary to Fanconi syndrome induced by adefovir dipivoxil concomitantly with osteoporosis in whom clinical symptoms were improved by adding denosumab (a human monoclonal antibody targeting the receptor activator of nuclear factor-κB ligand) to preceding administration of vitamin D3. CASE PRESENTATION: A 60-year-old Japanese man had been receiving low-dose adefovir dipivoxil (10 mg/day) to treat chronic hepatitis B for approximately 5 years. He presented to an orthopedic surgeon with severe pain of the right hip and no trauma history, and fracture of the neck of the right femur was identified. In addition, 99mTc-hydroxymethylene diphosphate scintigraphy revealed significantly abnormal uptake in the bilateral ribs, hips, and knees, and he was therefore referred to our university hospital for evaluation of multiple pathological fractures. We diagnosed hypophosphatemic osteomalacia due to Fanconi syndrome induced by adefovir dipivoxil therapy. Although we reduced the patient's adefovir dipivoxil dose and added calcitriol (active vitamin D3), he did not respond and continued to complain of bone pain. Several bone resorption markers and bone-specific alkaline phosphatase were also persistently elevated. Therefore, we added denosumab to vitamin D3 supplementation for treatment of excessive bone resorption. Two months after initiation of denosumab, his hip and knee pain was relieved, along with a decrease in serum alkaline phosphatase and some bone resorption markers. CONCLUSIONS: Although denosumab is not generally an appropriate treatment for acquired Fanconi syndrome, it may be useful for patients who have hypophosphatemic osteomalacia due to adefovir dipivoxil-induced Fanconi syndrome associated with excessive bone resorption. However, clinicians should keep in mind that if denosumab is administered to patients with hypophosphatemic osteomalacia accompanied by excessive bone resorption, adequate vitamin D and/or phosphate supplementation should be done before administration of denosumab.

[Adefovir Dipivoxil-induced Fanconi's Syndrome and Osteomalacia Following Multiple Bone Fractures in a Patient with Chronic Hepatitis B].

We herein present the case of a 66-year-old Japanese man with Fanconi's syndrome. He had been receiving adefovir dipivoxil (ADV) for the treatment of entecavir (ETV)-resistant chronic hepatitis B (CHB) for four years in his 8-year treatment of hepatocellular carcinoma (HCC), but was referred to our hospital after increased levels of bone pain in his ribs, knees, and ankles. Renal dysfunction, hypophosphatemia, and increased levels of bone alkaline phosphatase were found by a hematology test after admission for treatment of HCC. Radiography and 99m Tc-labeled hydroxymethylene diphosphonate (HMDP) scintigraphy revealed multiple insufficiency fractures in the ribs, knees, ankles, and heels. After switching from ADV to tenofovir disoproxil fumarate (TDF) and treatment with calcitriol and sodium dihydrogenphosphate, the patient's serum phosphate levels slightly increased and renal dysfunction did not improve, but after six months his clinical symptoms disappeared. To detect and prevent adverse effects from ADV, physicians and pharmacists should carefully monitor renal function and serum phosphate levels in patients with hepatitis B virus (HBV) treated for a long time with ADV.

Toxic myopathy with multiple deletions in mitochondrial DNA associated with long-term use of oral anti-viral drugs for hepatitis B: A case study.

Oral nucleoside analogs (NAs) reduce hepatitis B virus (HBV) replication by inhibiting HBV DNA polymerase. However, NAs can also affect human mitochondrial DNA (mtDNA) polymerase, which can lead to mtDNA depletion (quantitative abnormality). Indeed, several mitochondrial myopathy cases have been reported in which a reduced mtDNA copy number was induced by oral NAs for hepatitis B. Herein, we report a case of toxic myopathy with multiple mtDNA deletions (qualitative abnormality) associated with long-term use of NAs for hepatitis B. A 68-year-old woman, who underwent long-term treatment with lamivudine and adefovir for chronic hepatitis B, developed proximal muscle weakness in the four extremities. Neurological examination showed mild proximal muscle weakness and atrophy in the four extremities. Upon admission to our hospital, her blood lactate/pyruvate ratio during an aerobic exercise test was elevated. Myogenic patterns were observed in lower limb muscles on electromyographic examination. Muscle magnetic resonance imaging revealed diffuse atrophy of proximal muscles in the four extremities with no signal changes. A biopsy from the biceps brachii muscle showed an abnormally large variation in fiber size, scattered muscle fibers with decreased cytochrome c oxidase activity, and ragged-red fibers. Analysis of mtDNA from skeletal muscle revealed no decrease in copy number but increased incidence of multiple deletions, including a deletion of 4977 base pairs (known as the common deletion) reflecting oxidative stress-induced mtDNA damage. This case study indicates that long-term oral antiviral therapy for hepatitis B can induce chronic oxidative damage to mtDNA resulting in qualitative mtDNA abnormalities and toxic myopathy.

Clinical Pharmacology of the Reversible and Potent P2Y12 Receptor Antagonist ACT-246475 After Single Subcutaneous Administration in Healthy Male Subjects.

ACT-246475 is a selective and reversible P2Y12 receptor antagonist inducing inhibition of platelet aggregation (IPA). A randomized, double-blind, placebo-controlled, parallel-design study was performed to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of escalating single subcutaneous doses of ACT-246475 (1, 2, 4, 8, 16, or 32 mg) in healthy male subjects (N = 8 per dose, 3:1 active:placebo ratio). Pharmacodynamic effects were assessed based on maximum platelet aggregation and P2Y12 reaction units using light transmission aggregometry and VerifyNow® assays, respectively. ACT-246475 was safe and well tolerated up to 32 mg based on adverse event data and absence of clinically relevant changes in hematology, biochemistry, vital signs, and electrocardiogram variables. Median time to reach maximum plasma concentration was 0.5-0.75 hours, and geometric mean terminal half-life ranged from 1.3 to 9.2 hours across the tested dose range. Exposure to ACT-246475 was dose proportional across all dose groups. The maximal %IPA was reached within 30 minutes after subcutaneous administration of ACT-246475. A dose-dependent duration and extent of effect were observed based on area under the effect curve and maximum effect data. Similar results were observed for maximum platelet aggregation and P2Y12 reaction units. The %IPA was ≥85% at doses ≥2 mg. This level of %IPA was extended to at least 12 hours in the 32-mg dose group. The safety and pharmacokinetic/pharmacokinetic profile with quick onset and adequate duration of IPA support further investigation in patients with coronary artery disease.

Hypophosphatemic Osteomalacia Associated with Adefovir-induced Fanconi Syndrome Initially Diagnosed as Diabetic Kidney Disease and Vitamin D Deficiency.

A 68-year-old man with type 2 diabetes mellitus and chronic hepatitis B infection was referred to the nephrology department before planned surgery for hepatocellular carcinoma. He had been receiving low-dose adefovir dipivoxil (ADV) for 11 years. Laboratory findings revealed impaired re-absorption in the proximal renal tubules. He had been diagnosed with diabetic kidney disease and osteomalacia due to vitamin D deficiency; thus, ADV was not discontinued until he was referred to us. In this case, concomitant diabetes mellitus and vitamin D deficiency might have prevented the early diagnosis of ADV-induced Fanconi syndrome.