Chronic hepatitis B (CHB) remains incurable due to the immune system's tolerance toward the hepatitis B virus (HBV) surface antigen (HBsAg). This study aimed to achieve a functional cure by breaking HBV tolerance through immunotherapy. CHB patients were treated with either standard nucleotide analog (NA) therapy (Adefovir Dipivoxil, ADV) (Cohort 1) or ADV combined with interferon-alpha (IFN-α) (Cohort 2). Additionally, a third cohort received the THRIL-GM-Vac regimen: three low-dose GM-CSF injections followed by one dose of the HBV vaccine, alongside standard treatment. THRIL-GM-Vac treatment (Cohort 3) achieved a significant 2log10 reduction in HBsAg levels in 21.7% of participants, and 8.7% HBsAg clearance in Cohort 3 compared to 0% and 4.17% in Cohorts 1 and 2, respectively. Furthermore, THRIL-GM-Vac significantly reduced HBV-specific tolerogenic T cells (Tregs), explaining the sustained HBsAg decrease. Upregulation of anti-HBV T cell responses confirmed THRIL-GM-Vac's ability to disrupt HBV tolerance and enhance HBsAg-specific cellular immunity. This suggests its potential effectiveness in treating individuals with moderate to low HBsAg levels. THRIL-GM-Vac treatment in Cohort 3 resulted in 8.7% HBsAg clearance alongside Treg depletion and enhanced anti-viral T cell responses. These findings present a promising strategy to overcome immunotolerance and potentially combat chronic HBV infection.

The nephrotoxicity of adefovir dipivoxil (ADV) can induce Fanconi syndrome, which causes hypophosphatemic osteomalacia. We report a case of a 67-year-old postmenopausal woman who had been receiving long-term adefovir dipivoxil therapy for chronic hepatitis B. She presented with severe bone pain and multiple pseudofractures, and was diagnosed with drug-induced hypophosphatemic osteomalacia. Following discontinuation of adefovir and supplementation with vitamin D and phosphate, her biochemical parameters normalized and bone pain significantly improved, indicating that osteomalacia had been essentially corrected. However, although follow-up bone mineral density (BMD) showed significant improvement compared to pretreatment values, it remained markedly below the reference range for age-matched women. Postmenopausal osteoporosis was therefore suspected, and anti-osteoporotic pharmacotherapy was initiated after correction of osteomalacia. This case suggests that BMD can improve substantially after removal of the causative factor in drug-induced osteomalacia; however, if patients have underlying risk factors for osteoporosis, low BMD may persist even after osteomalacia resolution, necessitating further evaluation and intervention.

Adefovir dipivoxil (ADV), an antiviral agent for chronic hepatitis B virus infection, has been associated with nephrotoxicity, particularly Fanconi syndrome, even at low doses (10 mg/day). Fanconi syndrome is a generalized proximal tubular dysfunction leading to phosphate wasting and hypophosphatemic osteomalacia. Here, the author reports a case of a 58-year-old man with a 2-year history of bone pain involving the left foot, upper back, and left scapula, later extending to the right foot and chest wall, without antecedent trauma. Magnetic resonance imaging revealed insufficiency fractures in both calcanei and healing fractures of the spinous processes from the sixth cervical to the second thoracic vertebrae with callus formation. Whole-body bone scintigraphy demonstrated increased uptake in multiple ribs, the lower sacral region, and the aforementioned areas. Imaging findings, together with elevated serum alkaline phosphatase with increased bone fraction, prompted an extensive malignancy workup, which was negative. The patient had been taking ADV 10 mg daily for 10 years for chronic hepatitis B. Laboratory evaluation showed mild renal dysfunction, hypophosphatemia, hypouricemia, elevated alkaline phosphatase, proteinuria, phosphaturia, and glucosuria without hyperglycemia. He was diagnosed with hypophosphatemic osteomalacia secondary to ADV-induced Fanconi syndrome. After switching from ADV to entecavir and initiating supplementation with calcitriol and phosphate, the patient's symptoms and laboratory abnormalities improved significantly. Careful monitoring of serum phosphate, alkaline phosphatase, and renal function is essential for early recognition and timely intervention in these potentially reversible adverse drug reactions.

Mpox, caused by the orthopoxvirus monkeypox virus (MPXV), has garnered worldwide attention during a global outbreak in 2022 and in an ongoing outbreak in Central Africa. Because of drug resistance and toxicity risks with current antiviral treatments, there is still a need for additional antivirals to treat mpox and other orthopoxvirus diseases. We developed in vitro screening assays using recombinant strains of vaccinia virus and MPXV to measure the antiviral potency of compounds, finding that adefovir dipivoxil and tenofovir alafenamide had potent anti-orthopoxvirus activity and low toxicity. These data reinforce interest in repurposing nucleoside analogues as antivirals to treat poxvirus infections and provide a basis for high throughput screening and mechanistic and antiviral resistance studies.

Ensuring the safety of drugs during pregnancy is a critical concern in clinical practice. Animal tests are not always reliable for accurately identifying human teratogens, as evidenced by the infamous thalidomide case. Therefore, there is an urgent need for rapid, dependable, and cost-effective human in vitro assays for potential teratogenic drugs. Here, we utilized human embryoid body (hEB)-based assays, both serum-free and supplemented with pregnant woman serum, along with RNA-sequencing analyses, to demonstrate the effectiveness of hEB transcriptomics as a powerful tool for identifying potential teratogenic drugs, in comparison with other cell systems. Additionally, we subjected our hEB systems to Cmax doses of four nucleoside/nucleotide analogs (adefovir dipivoxil [ADV], entecavir [ETV], lamivudine [LAM], and tenofovir disoproxil fumarate [TDF]), which are used for anti-hepatitis B virus treatment and belong to different pregnancy-related risk categories. Transcriptomics after drug treatments were determined and analyzed for important changes in genes, gene categories, signaling pathways, and cell lineages. TDF and ADV appear to be safer options during the very early stages of embryonic development compared with LAM and ETV. Our findings indicate that EB transcriptomics-based analyses can accurately identify potent teratogens and aid in assessing the potential risk of commonly prescribed drugs during pregnancy.

Long-term use of low-dose adefovir dipivoxil (ADV) has been increasingly associated with Fanconi syndrome; however, cases of Fanconi syndrome combined with peripheral neuropathy remain rare. Here, we report a 67-year-old man who developed progressive limb weakness and sensory abnormalities after approximately 6 years of treatment with 10 mg ADV. He was diagnosed with ADV-associated Fanconi syndrome accompanied by peripheral neuropathy. Following the substitution of ADV with entecavir and 5 months to 6 months of phosphate supplementation, the patient's muscle weakness nearly resolved, and peripheral nerve damage showed significant improvement.

Nucleoside reverse transcriptase inhibitors (NRTIs) and platinum-based chemotherapeutics are widely utilized in cancer treatment. Evidence suggests that drug plasma concentrations are closely linked to both therapeutic efficacy and the risk of adverse effects. Consequently, developing therapeutic drug monitoring (TDM) methods is essential. Here, an effective procedure utilizing QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) techniques for preparing samples and UPLC-MS/MS for simultaneously measuring eight NRTIs and platinum-based drugs in human plasma is described. Chromatographic separation was conducted with an Agilent Eclipse Plus C18 column (4.6 × 100 mm, 3.5 μm) with acetonitrile with 0.1% formic acid as Phase A and 0.1% formic acid in water as Phase B, achieving complete separation within 10 min. The target analytes-lamivudine, telbivudine, emtricitabine, entecavir, tenofovir, nedaplatin, oxaliplatin, and adefovir dipivoxil-exhibited strong linearity within the 10-1000 ng/mL and 1-100 ng/mL ranges, showing correlations (r[2]) ≥ 0.9962. The method demonstrated excellent accuracy (-6.72% to 7.82%) and selectivity (84.53%-110.49%), as well as satisfactory recovery and stability. Overall, this analytical approach can be used to detect the combination of eight NRTIs and platinum-based drugs in human plasma. This method enables plasma drug-level monitoring in real time, with applications for individualized treatment approaches.

Evaluation of transporter-mediated drug-drug interactions (DDI) with endogenous biomarkers, coupled with physiologically-based pharmacokinetic modeling (PBPK) is envisioned to replace or reduce dedicated DDI clinical trials with clinical probe substrates. The current study developed a PBPK model of adefovir (OAT1 clinical probe) by incorporating experimental measurements of adefovir passive diffusion and OAT1-mediated transport in a mechanistic kidney model for in vitro-in vivo extrapolation of its secretion and renal clearance. The adefovir model was verified with clinical data from nine studies (188 subjects) investigating a range of adefovir intravenous and adefovir-dipivoxil oral doses in White, Japanese, and Chinese populations with healthy renal function. A previously verified probenecid model, incorporating in vivo OAT1/3 inhibitory constant estimated using OAT1/3 endogenous biomarker (4-pyridoxic acid) clinical data, was utilized. The ratio of adefovir maximal plasma concentrations (CmaxR) and area under the curve (AUCR) after mid-to-high single oral doses of probenecid was predicted within the stringent Guest criterion. With the lowest probenecid dose (0.5 g), adefovir AUCR and CmaxR were slightly overpredicted but still within a 1.5-fold error. Application of the adefovir model to patients with severe chronic kidney disease (CKD) accounted for our previously recommended additional 50% decrease in OAT1 activity beyond the decline of glomerular filtration rate. The model successfully predicted 3-fold higher adefovir Cmax and 6-fold higher AUC in patients with severe CKD relative to healthy individuals. This study reinforces the role of PBPK modeling to predict transporter-mediated DDI (coupled with biomarker-informed approach to optimize in vivo inhibitory constant) and the effect of renal impairment on OAT1/3 drugs in lieu of clinical studies.

Many acyclic nucleoside phosphonates such as cidofovir, adefovir dipivoxil, tenofovir disoproxil fumarate, and tenofovir alafenamide have been marketed for the treatment or prophylaxis of infectious diseases. Here, this review highlights potent acyclic nucleoside phosphonates for their potential in the treatment of retrovirus (e.g., human immunodeficiency virus) and DNA virus (e.g., adeno-, papilloma-, herpes- and poxvirus) infections. If properly assessed and/or optimized, some potent acyclic nucleoside phosphonates can be possibly applied in the control of current and emerging infectious diseases.

Objective: To study the curative effect of rehmannia glutinosa leaves total glycoside capsules and the role of mitochondrial autophagy on nucleos(t)ide drug-induced renal injury. Methods: Adefovir dipivoxil (ADV) was used to construct a hepatitis B virus (HBV) transgenic mouse model for renal injury. Renal function was measured in each group at one and two weeks of modeling. Mitochondrial autophagy indicators were measured at two weeks of modeling in renal tissue. Transmission electron microscopy was used to detect mitochondrial autophagy phenomena in renal tissue. The model was established for two weeks. Mouse with renal injury were treated with rehmannia glutinosa leaves total glycoside capsules or isotonic saline for eight weeks by intragastric administration. Renal function was measured. Renal tissue morphology was observed. Mitochondrial autophagy indicators were detected in renal tissue. The protective effect of different concentrations of verbascoside (the main active ingredient of rehmannia glutinosa capsule) was observed on HK-2 cell damage induced by ADV. HK-2 cells were divided into control, ADV, and ADV plus verbascoside groups. The effects of verbascoside at different times and concentrations were observed on the HK-2 mitochondrial autophagy indicators. Fifty patients with chronic hepatitis B were collected who presented with renal injury after treatment with nucleos(t)ide analogs. The random number method was used to divide 29 cases into a control group that received conventional treatment. The treatment group of 21 cases was treated with rehmannia glutinosa leaves total glycoside capsules on the basis of the control group. Serum creatinine (Scr) and urinary protein were detected at eight weeks.The χ(2) test or t-test was used for statistical analysis. Results: Compared with the control group, two weeks of modeling in the ADV group induced renal function injury in HBV mice. The expression of autophagy indicators was higher in the renal tissue of the ADV group than that of the control group. Transmission electron microscopy had revealed mitochondrial autophagy in the renal tissue of the ADV group. Compared with the control group, the renal function of HBV mice treated with rehmannia glutinosa leaves total glycoside capsules improved for two months, and the expressions of autophagy indicators were down-regulated.Verbascoside promoted proliferation in ADV-damaged HK-2 cells, and the expression of autophagy indicators was down-regulated compared with the ADV alone group. In 50 patients with renal function injury, the urinary protein improvement was significantly superior in the treatment group than that in the control group, with eighteen and three cases being effective and ineffective in the treatment group and 12 and 17 cases being effective and ineffective in the control group, with a statistically significant difference (χ(2) = 9.975 0, P = 0.001 6). Serum creatinine was decreased in the treatment group compared with the control group, with 11 and 10 cases being effective and ineffective in the treatment group and 12 and 17 cases being effective and ineffective in the control group, with no statistically significant difference (χ(2) = 0.593 5, P = 0.441 1). Conclusion: Rehmannia glutinosa leaves total glycoside capsule can improve the nucleos(t)ide drug-induced renal function injury in chronic hepatitis B, possibly playing a role via inhibiting PINK1/Parkin-mediated mitochondrial autophagy.