Real-world safety and effectiveness of tenofovir alafenamide for 144 weeks in Japanese patients with chronic hepatitis B.

Tenofovir alafenamide (TAF), a prodrug of tenofovir, delivers high levels of active drug to hepatocytes and is given in a lower dose than tenofovir disoproxil fumarate (TDF). TAF reduces viral replication in patients with chronic hepatitis B (CHB) similar to TDF and has shown a lower risk of the renal and bone toxicities associated with TDF use. This post-marketing surveillance study examined the safety and effectiveness of TAF in treatment-naïve and -experienced CHB patients who received TAF for 144 weeks at real-world clinical sites in Japan. Safety assessments included the incidence of adverse drug reactions (ADRs), renal and bone events, and changes in selected laboratory parameters. Effectiveness was based on the proportion of patients with HBV DNA levels below the lower limit of quantitation or <29 IU/mL. This analysis included 580 patients; 18.4% of whom were treatment-naïve. The cumulative incidence of ADRs was 0.21 per 100 person-months, and the incidence of serious ADRs was 0.01 (95% CI, 0.00-0.04) per 100 person-months. There were no ADRs of declines in estimated glomerular filtration rates, renal failure or proximal tubulopathy. The most common ADR was hypophosphataemia in seven (1.2%) patients. Two (0.4%) patients each had decreased blood phosphorus, bone mineral density decreased, dizziness and alopecia. Overall, the proportion of virologically suppressed patients increased from 68.8% at baseline to 97.5% at Week 144. These results confirm the real-world safety and effectiveness of TAF in Japanese patients with CHB and are consistent with the findings of other evaluations of the safety and efficacy of TAF in CHB.

Pharmacokinetics and effect on renal function and average daily gain in lambs after castration and tail docking, of firocoxib and meloxicam.

AIMS: To evaluate and compare the pharmacokinetics of IM and oral firocoxib, and IM meloxicam, and detect their effect on renal function and average daily gain (ADG) in lambs undergoing tail docking and castration. METHODS: Seventy-five male Romney lambs, aged 3-6 weeks, were randomised into five treatment groups (n = 15 per group): IM firocoxib (1 mg/kg); oral firocoxib (1 mg/kg); IM meloxicam (1 mg/kg); normal saline (approximately 2 mL, oral); or sham. Following the treatment administration, hot-iron tail docking and rubber ring castration were performed in all groups except the sham group, which did not undergo the procedures, but the animals were handled in the same manner as castrated and tail docked lambs. Blood samples were collected before and 1, 2, 4, 6, 8, 24, 48, 72, 96 and 120 hours after treatment administration, and drug concentrations in plasma were quantified by liquid chromatography and mass spectrometry. Plasma urea and creatinine concentrations were determined at a commercial laboratory. Lamb body weights were recorded before and 2, 4 and 8 weeks after tail docking and castration. The pharmacokinetic analysis was carried out using a non-compartmental approach. Between-group and between-time-point differences were compared using mixed model analyses. RESULTS: There was no evidence for a difference in plasma elimination half-life between firocoxib given IM (LSM 18.6 (SE 1.4) hours), firocoxib given orally (LSM 18.2 (SE 1.4) hours), and meloxicam given IM (LSM 17. 0 (SE 1.4) hours). Firocoxib (IM) had a significantly greater volume of distribution (LSM 3.7 (SE 0.2) L/kg) than IM meloxicam (LSM 0.2 (SE 0.2) L/kg). Lambs in the meloxicam group had higher (p < 0.05) plasma urea and creatinine concentrations than those in the firocoxib, saline and sham groups. Lambs' ADG was decreased (p < 0.01) compared to the other treatment groups in the 0-2 week period following meloxicam administration. CONCLUSIONS AND CLINICAL RELEVANCE: Both formulations of firocoxib had a long plasma elimination half-life and large volume of distribution. There was a transient reduction in ADG in the meloxicam group, possibly due to mild renal toxicity. Comparative studies on dose-response effects of firocoxib and meloxicam in lambs following the procedures are required.Abbreviations: ADG: Average daily gain; Cmax: Maximum concentration; COX: Cyclooxygenase; LOD: Limit of detection; NSAID: Non-steroidal anti-inflammatory drugs; CL: Plasma clearance; T1/2el: Plasma elimination half-life; Tmax: Time to achieve Cmax; Vd: Volume of distribution.

Canagliflozin and Kidney-Related Adverse Events in Type 2 Diabetes and CKD: Findings From the Randomized CREDENCE Trial.

RATIONALE & OBJECTIVE: Canagliflozin reduced the risk of kidney failure and related outcomes in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) in the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial. This analysis of CREDENCE trial data examines the effect of canagliflozin on the incidence of kidney-related adverse events (AEs). STUDY DESIGN: A randomized, double-blind, placebo-controlled, multicenter international trial. SETTING & PARTICIPANTS: 4,401 trial participants with T2DM, CKD, and urinary albumin-creatinine ratio >300-5,000 mg/g. INTERVENTIONS: Participants were randomly assigned to receive canagliflozin 100 mg/d or placebo. OUTCOMES: Rates of kidney-related AEs were analyzed using an on-treatment approach, overall and by screening estimated glomerular filtration rate (eGFR) strata (30-<45, 45-<60, and 60-<90 mL/min/1.73 m2). RESULTS: Canagliflozin was associated with a reduction in the overall incidence rate of kidney-related AEs (60.2 vs 84.0 per 1,000 patient-years; hazard ratio [HR], 0.71 [95% CI, 0.61-0.82]; P < 0.001), with consistent results for serious kidney-related AEs (HR, 0.72 [95% CI, 0.51-1.00]; P = 0.05) and acute kidney injury (AKI; HR, 0.85 [95% CI, 0.64-1.13]; P = 0.3). The rates of kidney-related AEs were lower with canagliflozin relative to placebo across the 3 eGFR strata (HRs of 0.73, 0.60, and 0.81 for eGFR 30-<45, 45-<60, and 60-<90 mL/min/1.73 m2, respectively; P = 0.3 for interaction), with similar results for AKI (P = 0.9 for interaction). Full recovery of kidney function within 30 days after an AKI event occurred more frequently with canagliflozin versus placebo (53.1% vs 35.4%; odds ratio, 2.2 [95% CI, 1.0-4.7]; P = 0.04). LIMITATIONS: Kidney-related AEs including AKI were investigator-reported and collected without central adjudication. Biomarkers of AKI and structural tubular damage were not measured, and creatinine data after an AKI event were not available for all participants. CONCLUSIONS: Compared with placebo, canagliflozin was associated with a reduced incidence of serious and nonserious kidney-related AEs in patients with T2DM and CKD. These results highlight the safety of canagliflozin with regard to adverse kidney-related AEs. FUNDING: The CREDENCE trial and this analysis were funded by Janssen Research & Development, LLC, and were conducted as a collaboration between the funder, an academic steering committee, and an academic research organization, George Clinical. TRIAL REGISTRATION: The CREDENCE trial was registered at ClinicalTrials.gov with identifier number NCT02065791.

The 48-week safety and therapeutic effects of tenofovir alafenamide in hbv-related acute-on-chronic liver failure: A prospective cohort study.

Tenofovir alafenamide (TAF) has been available in China for a short time, little is known about its safety and efficacy in patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (HBV-ACLF). We conducted this study to further verify the safety and efficacy of TAF in these patients. Eighty-eight eligible subjects were included and divided into three groups: TAF group, TDF group and ETV group. Clinical and laboratory test results were collected and the survival status, virus suppression status and liver and renal function improvement were observed during follow-up. No drug-related adverse events were observed within a 48-week observation period. At week 48, the survival rates of the three groups were 56.5%, 78.3% and 59.5% (p = 0.262). HBV DNA undetectable rates were similar (80.0% vs.75.0% vs.84.6%, respectively, p = 0.863). Liver function improved in all the three groups over time. Compared with the other two groups, patients in the TAF group had a greater decrease in serum creatinine (CR) and an increase in estimated glomerular filtration rate (eGFR), especially at week 12. At week 48, the median changes of CR were -0.7 (IQR -3.0, 13.0) vs. 15.0 (IQR -3.0, 21.0) vs. 5.0 (IQR -9.0, 14.0), respectively (p = 0.334), while the median changes of eGFR were -2.12 (IQR -13.87, 1.44) vs. -10.43 (IQR -20.21, 3.18) vs. -5.31 (IQR -14.72, 5.44) ml/min/1.73 m2 , respectively (p = 0.592). In this real-world clinical study, TAF is as effective as TDF and ETV, and may be more beneficial in protecting renal function in the early stages of antiviral therapy.

Efficacy of different nucleoside analog rescue therapies for entecavir-resistant chronic hepatitis B patients.

BACKGROUND: Entecavir (ETV) is recommended as a first-line anti-HBV treatment. However, many chronic hepatitis B patients initiate anti-HBV treatment such as lamivudine and telbivudine with low genetic barriers in China, which leads to compensatory mutations and increases the rate of ETV resistance. The management of ETV resistance in China is an essential clinical issue. METHODS: Patients from 2011 to 2017 with nucleos(t)ide analog resistance were screened and 72 patients with ETV resistance were included. These patients received different rescue therapies including an ETV and adefovir (ADV) combination therapy group (n = 25), a tenofovir (TDF) monotherapy group (n = 27), and an ETV and TDF combination therapy group (n = 20). Virologic, biochemical, and serologic responses were compared among the three groups. RESULTS: The rate of ETV resistance among all HBV-resistant variants increased from 6.04% in 2011 to 15.02% in 2017. TDF monotherapy and TDF combination groups showed similar rates of negative HBV DNA at 48 weeks (74.07% vs 70.00%, P > 0.05), while the ETV and ADV group showed the worst virologic response (28.00%). Also, TDF monotherapy and TDF combination therapy showed similar decline of HBV DNA at weeks 12, 24, and 48. There was no significant difference in the rates of HBeAg clearance, ALT normalization, and abnormal renal function among the three groups. CONCLUSIONS: TDF monotherapy showed a comparable virologic response to TDF and ETV combination therapy and a better virologic response than ETV and ADV combination therapy. Thus, TDF monotherapy is the preferred rescue therapy for ETV resistance.

Treatment Response to SGLT2 Inhibitors: From Clinical Characteristics to Genetic Variations.

SGLT2 (sodium-glucose cotransporter 2) inhibitors are a new class of antihyperglycaemic drugs that act on the proximal tubules of the kidney. They have shown efficacy in the management of diabetes mellitus type 2 and their cardiovascular and renal safety have been extensively investigated and confirmed in clinical trials. However, inter-individual differences in response to treatment with SGLT2 inhibitors may present in everyday clinical practice, and good predictors of glycemic response and the risk for adverse events in an individual patient are lacking. As genetic variability of SGLT2 may influence the treatment response, pharmacogenetic information could support the choice of the most beneficial treatment strategy in an individual patient. This review focuses on the clinical and genetic factors that may influence the treatment response to SGLT2 inhibitors in type 2 diabetes patients with comorbid conditions.

Comparison of the Efficacy and Renal Safety of Bisphosphonate Between Low-Dose/High-Frequency and High-Dose/Low-Frequency Regimens in a Late-Stage Chronic Kidney Disease Rat Model.

The efficacy and renal safety of low-dose/high-frequency (LDHF) dosing and high-dose/low-frequency (HDLF) dosing of bisphosphonates (BPs) are comparable in patients with normal kidney function but might be different in patients with late-stage chronic kidney disease (CKD). This study aimed to compare the efficacy and renal safety of two different dosage regimens of a BP, alendronate (ALN), in stage 4 CKD using a rat model. Male, 10-week-old Sprague-Dawley rats were subjected to either 5/6 nephrectomy or sham surgery. The animals received subcutaneous administration of vehicle (daily) or ALN in LDHF dosage regimen (LDHF-ALN: 0.05 mg/kg/day) or HDLF dosage regimen (HDLF-ALN: 0.70 mg/kg/2 weeks). Medications commenced at 20 weeks of age and continued for 10 weeks. Micro-computed tomography, histological analysis, infrared spectroscopic imaging, and serum and urine assays were performed to examine the efficacy and renal safety of the ALN regimens. Both LDHF-ALN and HDLF-ALN increased bone mass, improved micro-structure, and enhanced mechanical properties, without causing further renal impairment in CKD rats. Histologically, however, HDLF-ALN more efficiently suppressed bone turnover, leading to more mineralized trabecular bone, than LDHF-ALN in CKD rats, whereas such differences between LDHF-ALN and HDLF-ALN were not observed in sham rats. Both LDHF-ALN and HDLF-ALN showed therapeutic effects on high bone turnover osteoporosis in CKD stage 4 rats without causing further renal impairment. However, as HDLF-ALN more efficiently suppressed bone turnover than LDHF-ALN in late-stage CKD, HDLF-ALN might be more appropriate than LDHF-ALN for fracture prevention in high bone turnover osteoporosis patients with late-stage CKD.

Efficacy and safety of once-monthly risedronate in osteoporosis subjects with mild-to-moderate chronic kidney disease: a post hoc subgroup analysis of a phase III trial in Japan.

Limited data are available on the safety and efficacy of anti-resorptive agents, particularly once-monthly bisphosphonates, for use in osteoporotic patients with chronic kidney disease (CKD). We conducted a post hoc analysis of data from a 12-month, randomized, double-blind, phase III study to evaluate the safety and efficacy of once-monthly risedronate (RIS-OM) 75 mg tablets in Japanese osteoporosis patients with mild-to-moderate CKD. Patients who received RIS-OM 75 mg were stratified by baseline estimated glomerular filtration rate (eGFR; ≥ 90, ≥ 60 to < 90, or ≥ 30 to < 60 mL/min/1.73 m2). Safety endpoints were incidence of adverse events (AEs) and percent change from baseline in eGFR, serum creatinine, calcium, and phosphorus. Efficacy endpoints were percent change from baseline in lumbar spine bone mineral density (BMD) and bone turnover markers (BTMs). In 420 patients included (age 67.7 ± 6.7 years, women 98.8%), the incidence of all AEs, gastrointestinal disorders, acute phase reaction, non-vertebral fractures, and renal and urinary disorders was not significantly different among subgroups. Interaction between subgroups and time was significant for eGFR (p = 0.010) and serum creatinine (p = 0.001) but considered to be regression to the mean and clinically insignificant. BMD significantly increased while BTMs significantly decreased from baseline with a similar degree of change among the subgroups. In conclusion, RIS-OM 75 mg showed consistent safety and efficacy in suppressing bone turnover and increasing BMD in Japanese primary osteoporosis patients with mild-to-moderate CKD. These results should, however, be interpreted with caution because the number of patients with moderate CKD was limited.

96 weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection.

BACKGROUND & AIMS: Tenofovir alafenamide (TAF) is a new prodrug of tenofovir developed to treat patients with chronic hepatitis B virus (HBV) infection at a lower dose than tenofovir disoproxil fumarate (TDF) through more efficient delivery of tenofovir to hepatocytes. In 48-week results from two ongoing, double-blind, randomized phase III trials, TAF was non-inferior to TDF in efficacy with improved renal and bone safety. We report 96-week outcomes for both trials. METHODS: In two international trials, patients with chronic HBV infection were randomized 2:1 to receive 25 mg TAF or 300 mg TDF in a double-blinded fashion. One study enrolled HBeAg-positive patients and the other HBeAg-negative patients. We assessed efficacy in each study, and safety in the pooled population. RESULTS: At week 96, the differences in the rates of viral suppression were similar in HBeAg-positive patients receiving TAF and TDF (73% vs. 75%, respectively, adjusted difference -2.2% (95% CI -8.3 to 3.9%; p = 0.47), and in HBeAg-negative patients receiving TAF and TDF (90% vs. 91%, respectively, adjusted difference -0.6% (95% CI -7.0 to 5.8%; p = 0.84). In both studies the proportions of patients with alanine aminotransferase above the upper limit of normal at baseline, who had normal alanine aminotransferase at week 96 of treatment, were significantly higher in patients receiving TAF than in those receiving TDF. In the pooled safety population, patients receiving TAF had significantly smaller decreases in bone mineral density than those receiving TDF in the hip (mean % change -0.33% vs. -2.51%; p <0.001) and lumbar spine (mean % change -0.75% vs. -2.57%; p <0.001), as well as a significantly smaller median change in estimated glomerular filtration rate by Cockcroft-Gault method (-1.2 vs. -4.8 mg/dl; p <0.001). CONCLUSION: In patients with HBV infection, TAF remained as effective as TDF, with continued improved renal and bone safety, two years after the initiation of treatment. Clinicaltrials.gov number: NCT01940471 and NCT01940341. LAY SUMMARY: At week 96 of two ongoing studies comparing the efficacy and safety of tenofovir alafenamide (TAF) to tenofovir disoproxil fumarate (TDF) for the treatment of chronic hepatitis B patients, TAF continues to be as effective as TDF with continued improved renal and bone safety. Registration: Clinicaltrials.gov number: NCT01940471 and NCT01940341.

Tenofovir alafenamide as a rescue therapy in a patient with HBV-cirrhosis with a history of Fanconi syndrome and multidrug resistance.

Tenofovir disoproxil fumarate (TDF) is a recommended first-line therapy for both naïve and experienced patients with chronic hepatitis B (CHB), although reduced estimated glomerular filtration rate (eGFR), hypophosphatemia, hyperphosphaturia and Fanconi syndrome have been reported in some patients. Entecavir (ETV) could be considered as a rescue therapy for TDF-treated patients developing renal dysfunction, though patients with prior history of treatment with lamivudine (LAM) can develop ETV resistance strains, which can lead to potentially severe hepatitis flares. Tenofovir alafenamide (TAF), a new prodrug of tenofovir, has recently been developed to improve the renal and bone safety profile compared to TDF, while maintaining the same virologic efficacy. The recently published 48-week phase III TAF registration studies confirmed the superior safety profile. Here we describe a case of a 75-year-old woman with HBV mono-infection and compensated cirrhosis who developed ETV resistant strains and grade 3 chronic kidney disease after many years of LAM and adefovir (ADV) treatment and a TDF-induced Fanconi syndrome. The administration of 25mg/day of TAF, granted as part of a compassionate use program, rapidly suppressed viral replication to undetectable levels without worsening renal function or side effects.

Comparison of three diuretic treatment strategies for patients with acute decompensated heart failure.

BACKGROUND: There are few prospective data available for establishing a standard diuretic administration regimen for patients with acute decompensated heart failure (ADHF). We aimed to assess the safety and efficacy of three regimens of furosemide administration in patients with ADHF with regard to diuresis, renal functions, and in-hospital outcomes. METHODS: A total of 43 patients who presented with ADHF were randomized into three groups: (a) continuous infusion (cIV) of 160 mg furosemide for 16 h/day (n = 15); (b) bolus injections (bI) of 80 mg furosemide twice a day (n = 14); (c) and administration of 160 mg furosemide plus hypertonic saline solution (HSS) as an infusion for 30 min once a day (n = 14). All regimens were continued for 48 h. Study endpoints were negative fluid balance assessed by loss of body weight, change in the serum creatinine (baseline to 48 h and baseline to compensated state), and length of hospitalization. RESULTS: There was no significant difference in the mean change in serum creatinine level at the end of 48 h between groups (p = 0.08). There was also no significant difference among groups regarding loss of body weight (p = 0.66). A significantly shorter hospitalization was observed in patients treated with HSS compared with the other groups (cIV group 6.6 ± 3.4 days vs. bI group 7.9 ± 4.1 days vs. HSS group 3.7 ± 1.3 days; p < 0.01). CONCLUSION: All three furosemide regimens have similar renal safety and efficacy measures. However, administration of furosemide plus HSS may be the preferred diuretic strategy because of its shorter hospital stay.

Renal safety of tenofovir alafenamide-based antiretroviral therapy in people with HIV: A mini-review.

Antiretroviral therapy (ART) has significantly enhanced the outlook for people with HIV(PWH), yet certain ART medications can adversely affect the renal function of these patients. Of particular concern is the nephrotoxicity associated with tenofovir disoproxil fumarate (TDF). Compared to TDF, tenofovir alafenamide (TAF), another prodrug of tenofovir (TFV), results in lower TFV plasma levels, thereby alleviating the TFV-associated mitochondrial toxicity on proximal renal tubular cells. Currently, numerous clinical trials and real-world studies have demonstrated the favorable renal safety profile of ART regimens incorporating TAF for PWH. This paper seeks to consolidate the available evidence regarding the renal safety of TAF-based regimens in PWH, encompassing both the general PWH and those with renal impairment or predisposing factors, in order to offer recommendations and insights for TAF clinical application.

Five-year Treatment with Tenofovir Alafenamide Achieves High Rates of Viral Suppression, Alanine Aminotransferase Normalization, and Favorable Bone and Renal Safety in Chinese Chronic Hepatitis B Patients.

Background and Aims: After 3-years (144 week) of double-blind treatment in Chinese chronic hepatitis B patients in two ongoing phase 3 studies, tenofovir alafenamide (TAF) showed similar efficacy to tenofovir disoproxil fumarate (TDF), with improved renal and bone safety. In this study, we aimed to report the 5-year results from 2 years into the open-label TAF treatment phase. Methods: All participants completing the 144-week double-blind treatment were eligible to receive open-label TAF 25 mg once daily up to week 384. Serial analysis of viral suppression (hepatitis B virus DNA <29 IU/mL), alanine aminotransferase normalization, serological responses, and safety outcomes at year 5 (week 240) was performed. Results: The open-label phase included 93% (311/334) of the enrolled participants, which included 212 who switched from double-blind TAF to open-label TAF (TAF-TAF) and 99 who switched from double-blind TDF to open-label TAF (TDF-TAF). Baseline characteristics were comparable. Week 240 viral suppression rates were similar between groups [93.4% vs. 93.9%; difference: -1.5%, (95% CI: -6.4 to -3.5), p=0.857]. Alanine aminotransferase normalization and serological response rates were higher in the TAF-TAF group than in the TDF-TAF group. The frequencies of adverse events and laboratory abnormalities were low and similar between groups. Both groups had similar small numerical declines from baseline in estimated glomerular filtration rate at year 5 (week 240, -2.85 mL/min vs. -3.29 mL/min, p=0.910). The greater declines in renal and bone parameters in the TDF-TAF group through week 144 improved after switching to TAF. Conclusions: The 5-year TAF treatment efficacy was high and similar to that of 3-year TDF followed by 2-year TAF in Chinese chronic hepatitis B patients. Favorable effects on bone and renal parameters were sustained with TAF treatment alone and were observed following the switch from TDF to TAF.

Real-world data for the renal safety of abemaciclib combined with bisphosphonate in HR+/HER2- advanced breast cancer.

OBJECTIVE: Our study evaluated the renal safety of abemaciclib plus endocrine therapy (ET) with bisphosphonate as a treatment option for hormone receptor positive, human epidermal growth factor receptor 2 (HER-2) negative (HR+/HER2-) advanced breast cancer (ABC), especially with bone metastasis. METHODS: Data were collected from HR+/HER2- ABC patients who received abemaciclib with ET between March 2021 and May 2022 in a single medical center in China. We performed an analysis of the change in serum creatine (Cr) and creatine clearance (CrCl), time to first abnormal Cr value, and Common Terminology Criteria for Adverse Events grade of increased creatinine. RESULTS: A total of 210 patients were included in the final analysis, with a median age of 56 years and a median weight of 65 kg. Any grade laboratory-assessing increased Cr occurred in 87.1% of patients, while CrCl rarely went down to 30 ml/min. Associations between start dose with grade of increased Cr and menopausal status with alert value, which is defined as creatinine clearance <30 ml/min, were indicated. CONCLUSION: This study shows that abemaciclib combined with bisphosphonate would be safe for renal function in HR+/HER2- ABC patients with bone metastases.

Bictegravir/emtricitabine/tenofovir alafenamide as initial treatment for HIV-1: five-year follow-up from two randomized trials.

Background: Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) is a single-tablet regimen recommended for HIV-1 treatment. The safety and efficacy of B/F/TAF as initial therapy was established in two Phase 3 studies: 1489 (vs dolutegravir [DTG]/abacavir/lamivudine) and 1490 (vs DTG + F/TAF). After 144 weeks of randomized follow-up, an open-label extension evaluated B/F/TAF to 240 weeks. Methods: Of 634 participants randomized to B/F/TAF, 519 completed the double-blinded treatment, and 506/634 (80%) chose the 96-week open-label B/F/TAF extension, which was completed by 444/506 (88%) participants. Efficacy was based on the secondary outcome of the proportion of participants with HIV-1 RNA <50 copies/mL at Week 240 by missing = excluded and missing = failure methods. All 634 participants who were randomized to B/F/TAF and received at least one dose of B/F/TAF were included in efficacy and safety analyses. (Study 1489: ClinicalTrials.govNCT02607930; EudraCT 2015-004024-54. Study 1490: ClinicalTrials.govNCT02607956; EudraCT 2015-003988-10). Findings: Of those with available virologic data, 98.6% (95% CI [97.0%-99.5%], 426/432) maintained HIV-1 RNA <50 copies/mL at Week 240 (missing = excluded); when missing virologic data were considered as failure, 67.2% (95% CI [63.4%-70.8%], 426/634) maintained HIV-1 RNA <50 copies/mL. Mean (SD) change in CD4+ count from baseline was +338 (236.2) cells/µL. No treatment-emergent resistance to B/F/TAF was detected. Adverse events led to drug discontinuation in 1.6% (n = 10/634) of participants (n = 5 with events considered drug-related). No discontinuations were due to renal adverse events. Median (IQR) total cholesterol increased 21 (1,42) mg/dL from baseline; the change in total cholesterol:HDL was 0.1 (-0.5,0.6). Median (IQR) weight change from baseline was +6.1 kg (2.0, 11.7) at Week 240. In Study 1489, hip and spine bone mineral density mean percent changes from baseline were ≤0.6%. Interpretation: Through 5 years of follow-up, B/F/TAF maintained high rates of virologic suppression with no treatment-emergent resistance and rare drug discontinuations due to adverse events. These results demonstrate the durability and safety of B/F/TAF in people with HIV. Funding: Gilead Sciences.

Systematic review and model-based analysis to identify whether renal safety risks of URAT1 inhibitors are fully determined by uric acid-lowering efficacies.

OBJECTIVE: Renal safety risk is currently an important factor that hinders the development of uric acid transporter 1 (URAT1) inhibitors. This study aimed to compare the renal safety and uric acid-lowering efficacy of different URAT1 inhibitors and clarify the association between them. METHODS: A systematic review of published randomized controlled trials on URAT1 inhibitors was conducted to investigate the incidence of renal safety events. A model-based analysis was performed to predict the uric acid-lowering efficacy of representative URAT1 inhibitors. RESULTS: The overall renal safety event incidences of lesinurad, verinurad, dotinurad, SHR4640, and benzbromarone in patients with hyperuricemia were 11.2 % (142/1264), 12.0 % (34/284), 0.5 % (2/421), 2.3 % (5/213), and 1.3 % (5/393), respectively. A semi-mechanistic pharmacokinetic/pharmacodynamic model was used to establish the dose-exposure-effect relationship of lesinurad, verinurad, dotinurad, and SHR4640 with or without the combination of xanthine oxidase inhibitors (XOIs). The efficacy ranking of the intermediate dose of URAT1 inhibitors with once-daily dosing was 2 mg dotinurad > 10 mg verinurad > 5 mg SHR4640 > 400 mg lesinurad. The combination of 80 mg febuxostat and 600 mg allopurinol reduced the 24-h cumulative renal uric acid excretion by 48.4 % and 48.3 %, respectively. CONCLUSION: Uric acid-lowering efficacy is not an independent factor for the renal safety risk of different URAT1 inhibitors, and structural differences could be responsible for the difference. The adverse renal effects of URAT1 inhibitors are dose-dependent, and the combination with high doses of XOIs can significantly reduce the renal safety risk by reducing uric acid excretion by the kidneys.

Tenofovir amibufenamide vs tenofovir alafenamide for treating chronic hepatitis B: A real-world study.

BACKGROUND: The efficacy and safety profile of tenofovir amibufenamide (TMF) in chronic hepatitis B (CHB) patients is not well-established. AIM: To compare the efficacy and safety of TMF and tenofovir alafenamide (TAF) over a 48-wk period in patients with CHB. METHODS: A total of 215 subjects meeting the inclusion criteria were enrolled and divided into two groups: TMF group (n = 106) and the TAF group (n = 109). The study included a comparison of virological response (VR): Undetectable hepatitis B virus DNA levels, alanine transaminase (ALT) normalization rates, renal function parameters, and blood lipid profiles. RESULTS: At 24 and 48 wk, VR rates for the TMF group were 53.57% and 78.57%, respectively, compared with 48.31% and 78.65% for the TAF group (P > 0.05). The VR rates were also similar in both groups among patients with low-level viremia, both hepatitis B e antigen (HBeAg)-positive and HBeAg-negative subgroups. The TMF cohort showed ALT normalization and renal safety profiles similar to the TAF group. There was a notable increase in total cholesterol levels in the TAF group (P = 0.045), which was not observed in the TMF group (P > 0.05). In patients with liver cirrhosis, both groups exhibited comparable VR and ALT normalization rates and renal safety profiles. However, the fibrosis 4 score at 48 wk showed a significant reduction in the TAF group as compared to the TMF group within the liver cirrhosis subgroup. CONCLUSION: Our study found TMF is as effective as TAF in treating CHB and has a comparable safety profile. However, TAF may be associated with worsening lipid profiles.

Cardiovascular and renal outcomes of GLP-1 receptor agonists vs. DPP-4 inhibitors and basal insulin in type 2 diabetes mellitus: A systematic review and meta-analysis.

OBJECTIVE: To compare the cardiovascular and renal outcomes of GLP-1 RA versus DPP4i and basal insulin in the management of T2DM. METHODS: Data from 22 studies involving over 200,000 participants were pooled using the inverse variance method and random-effects meta-analysis. The review was reported in accordance with PRISMA. RESULTS: Compared with DPP4i, treatment with GLP-1 RA was associated with a greater benefit on composite cardiovascular outcomes (HR:0.77, 95% CI:0.69-0.87), myocardial infarction (HR:0.82, 95% CI:0.69-0.97), stroke (HR:0.83, 95% CI: 0.74-0.93), cardiovascular mortality (HR:0.76, 95% CI:0.68-0.85) and all-cause mortality (HR:0.65, 95% CI:0.48-0.90). There was no difference in effect on heart failure (HR:0.97, 95% CI:0.82-1.15). Compared with basal insulin, GLP-1 RA was associated with better effects on composite cardiovascular outcomes (HR:0.62, 95% CI:0.48-0.79), heart failure (HR:0.57, 95% CI:0.35-0.92), myocardial infarction (HR:0.70, 95% CI:0.58-0.85), stroke (HR:0.50, 95% CI:0.40-0.63) and all-cause mortality (HR:0.31, 95% CI:0.20-0.48). Evidence from a small number of studies suggests that GLP-1 RA had better effects on composite and individual renal outcomes, such as eGFR, compared with either DPP4i and basal insulin. CONCLUSION: Available evidence suggests that treating T2DM with GLP-1 RA can yield better benefits on composite and specific cardiorenal outcomes than with DPP4i and basal insulin. PROSPERO REGISTRATION NUMBER: CRD42022335504.

Effects of zoledronic acid and ibandronic acid on renal functions and calcium, phosphorus and alkaline phosphatase levels in breast cancer patients with bone metastases: a retrospective analysis.

AIM OF THE STUDY: Bone is a common site of metastasis in patients with breast cancer. Skeletal complications associated with bone metastasis are commonly treated with bisphosphonates. However, there are a number of side-effects associated with these, such as renal failure, hypocalcemia and osteonecrosis of the jaw. We aimed to determine the effects of ibandronic and zoledronic acid on serum creatinine (SCr), calcium (Ca), phosphorus (P), alkaline phosphatase (ALP) and estimated glomerular filtration rates (eGFR). The objective was to determine the safety of these bisphosphonates, especially zoledronic acid. MATERIAL AND METHODS: Forty-one patients diagnosed with breast cancer (all with bone metastasis) were enrolled. We retrospectively evaluated bisphosphonate type, duration of treatment, infusion time and the parameters SCr, Ca, P, ALP and eGFR. RESULTS: Nineteen patients were included in the zoledronic acid group and 22 in the ibandronic acid group. Mean age in the ibandronic acid group was 53.27 ±11.01, and 53.26 ±9.98 in the zoledronic acid group. Median duration of administration in the ibandronic acid group was 11 (7-37) months, and 10 (7-57) months in the zoledronic acid group. SCr levels did not change significantly during the study period. Pre- and post-treatment Ca levels were also unchanged, but serum ALP levels in the ibandronic acid group and P levels in the zoledronic acid decreased after the final administration; eGFR was unchanged by the end of the study. CONCLUSIONS: Zoledronic and ibandronic acid are safe modalities in the treatment of skeletal events in breast cancer patients with bone metastasis.

Febuxostat Therapy for Patients with Gout and Stage 2-4 CKD: a Retrospective Study.

INTRODUCTION: The aim of this study is to explore the efficacy and renal safety of febuxostat in gout and stage 2-4 chronic kidney disease (CKD) and factors that correlated with target serum urate (SU). METHODS: A single-center retrospective study including male patients with gout and CKD was conducted. SU, the rate of SU < 360 µmol/L (RAT), and renal safety were analyzed in subjects who received febuxostat over 44 weeks. Factors that correlated with target SU were also explored. RESULTS: Between January 2017 and March 2021, 102 patients (stage 2 CKD: n = 27; stage 3 CKD: n = 70; stage 4 CKD: n = 5) were enrolled. The SU level reduced significantly over 44 weeks (600.76 ± 95.42 versus 405.52 ± 111.93 µmol/L; P < 0.05), and RAT increased to 39.20%. The overall estimated glomerular filtration rate (eGFR) level improved over 44 weeks (52.05 ± 11.68 versus 55.46 ± 14.49 mL/min/1.73 cm2, P < 0.05). An obvious improvement of eGFR was observed in stage 3 CKD, in patients with ≤ 1 risk factor (hypertension, diabetic mellitus, hyperlipidemia, or usage of non-steroidal anti-inflammatory drugs), and in patients with terminal SU < 360 µmol/L (P < 0.05). Logistic regression analysis indicated that baseline SU level and body weight were correlated with RAT. Further analysis revealed that patients with SU < 600 µmol/L and body weight ≤ 70 kg reached higher RAT (56.7%). CONCLUSIONS: Febuxostat demonstrated efficacy and renal safety in patients with gout and CKD in clinical practice. Achieving the target SU could obviously improve renal function. Baseline SU level and body weight could affect the achievement of target SU.