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.

Atherosclerotic cardiovascular disease risk profile of patients with chronic hepatitis B treated with tenofovir alafenamide or tenofovir disoproxil fumarate for 96 weeks.

BACKGROUND: Patients with chronic hepatitis B (CHB) who switch from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) show changes in lipid profiles. AIM: To evaluate how these changes affect cardiovascular risk. METHODS: This pooled analysis, based on two large prospective studies, evaluated fasting lipid profiles of patients with CHB who were treated with TAF 25 mg/day or TDF 300 mg/day for 96 weeks. Patients who fulfilled the American College of Cardiology criteria (age 40-79 years, high-density lipoprotein [HDL] 20-100 mg/dL, total cholesterol [TC] 130-320 mg/dL and systolic blood pressure 90-200 mmHg) required to assess 10-year atherosclerotic cardiovascular disease (ASCVD) risk with baseline lipid data and at least one post-baseline measurement were included in the ASCVD-risk population. The 10-year ASCVD risk was calculated for patients in this population, and changes from baseline to Week 96 were assessed using intermediate- (≥7.5%) and high-risk (≥20%) cut-offs. RESULTS: Among 1632 patients, 620 (38%) met the criteria for the ASCVD-risk population. At Week 96, fasting levels of all lipids, except TC:HDL ratio, were lower with TDF than TAF. No significant increase was observed in overall ASCVD risk or in any ASCVD-risk categories during the 96-week treatment period compared with baseline. A similar proportion of patients in the TAF and TDF treatment groups (1.3% and 2.3%, respectively; p = 0.34) reported cardiovascular events. CONCLUSION: Despite on-treatment differences in lipid profiles with TAF and TDF, predicted cardiovascular risk and clinical events were similar for both groups after 96 weeks.

Body weight increase and metabolic derangements after tenofovir disoproxil fumarate switch to tenofovir alafenamide in patients with chronic hepatitis B.

BACKGROUND: Lipid-lowering effect was observed during treatment with tenofovir disoproxil fumarate (TDF) for chronic hepatitis B (CHB). However, the metabolic features in patients switching from TDF to tenofovir alafenamide (TAF) remain unclear. AIMS: To compare the impacts of switching from TDF to TAF or from entecavir to TAF on body weight and metabolic features in patients with CHB. METHODS: This was a multi-centre, prospective, observational study in patients with CHB on TDF or entecavir who switched to TAF. Baseline characteristics, lipid profile and sugar profile were determined. This study received IRB approval from each hospital. RESULTS: We enrolled 177 patients on TDF (99) or entecavir (78) and followed them for 48 weeks after the switch to TAF. At baseline, TDF-experienced patients had lower serum triglyceride, total cholesterol, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol than entecavir-experienced patients. The switch from TDF to TAF significantly increased body weight, triglyceride, total cholesterol, HDL, LDL, fasting glucose, glycaemic haemoglobin, insulin and insulin resistance. The switch from entecavir to TAF did not affect these measures. There was no significant difference in atherosclerotic cardiovascular disease risk scores between groups. CONCLUSIONS: The switch from TDF to TAF was associated with weight gain, derangements of lipid profile, and increased insulin resistance in patients with CHB. Long-term effects on these metabolic features need further investigation.

Increased spine bone density in patients with chronic hepatitis B switched to tenofovir alafenamide: A prospective, multinational study.

BACKGROUND: Data on patients switched to tenofovir alafenamide (TAF) from nucleos(t)ide analogues (NUCs) other than tenofovir disoproxil fumarate are limited. AIMS: To assess the treatment and renal/bone safety outcomes following the switch to TAF. METHODS: We prospectively enrolled adult patients with chronic hepatitis B (CHB) who switched from any NUC to TAF at 14 centres in Japan, Korea, Taiwan and the U.S. Study outcomes were viral suppression (VR; HBV DNA < 20 IU/mL), biochemical response (BR; alanine aminotransferase normalisation), and changes in estimated glomerular filtration rate (eGFR) and T-scores (L-spine) by bone absorptiometry by 24 months after switch to TAF. RESULTS: We enrolled 270 eligible patients. Mean age was 58.1; 58.2% were male; 12.2% had cirrhosis and 73.3% previously received entecavir monotherapy. VR rate increased significantly from 95.2% to 98.8% by 24 months after the switch to TAF (p = 0.014). Between the switch and 24 months later, the mean spine T-score improved significantly from -1.43 ± 1.36 to -1.17 ± 1.38 (p < 0.0001), while there was no significant change in mean eGFR (88.4 ± 16.9-89.5 ± 16.3 mL/min/1.73 m2 , p = 0.13). On multivariable analysis adjusted for age, sex, baseline spine T-score and prior TDF or adefovir dipivoxil use, male sex was significantly associated with lower risk of worsening spine T-score (odds ratio: 0.29, p = 0.020), while age was significantly associated with a higher risk of worsening chronic kidney disease stage (OR: 1.07, p = 0.019). CONCLUSIONS: At 24 months after the switch to TAF, VR rates and spine bone density improved significantly while renal function remained stable.

The Effects of Safinamide in Chinese and Non-Chinese Patients with Parkinson's Disease.

INTRODUCTION: Ethnicity differences are an important determinant in the clinical manifestation of Parkinson's disease (PD), but they are not yet widely recognized, particularly regarding the response to dopaminergic medications. The aim of this paper is to analyze the efficacy and safety of safinamide in Chinese patients with PD in the pivotal studies SETTLE and XINDI compared to the non-Chinese population of the SETTLE trial. METHODS: SETTLE (NCT00627640) and XINDI (NCT03881371) were phase III, randomized, double-blind, placebo-controlled, multicenter trials. Patients received safinamide or placebo as add-on to levodopa. The primary efficacy endpoint was the change in the mean total daily OFF time. Secondary efficacy endpoints included total daily ON time, ON time with no/non-troublesome dyskinesia, Unified Parkinson's Disease Rating Scale, and Parkinson's Disease Questionnaire-39 items. Safety was evaluated through the frequency of adverse events. Data from 440 non-Chinese and 109 Chinese patients in the SETTLE study, and 305 Chinese patients in the XINDI trial were considered for this post hoc analysis. RESULTS: Significant positive results were seen in favor of safinamide in all populations for the primary and secondary endpoints, with no differences in terms of magnitude. No "treatment by ethnicity" interaction was detected for any parameters, confirming the homogeneity of treatment effects between different populations. The safety and tolerability of safinamide in Chinese patients were similar to those in the other ethnic groups, without unexpected adverse reactions. CONCLUSIONS: Safinamide was shown to improve PD symptoms and quality of life in different ethnic populations, without any treatment by race interaction. Further studies are warranted to investigate potential differences in a real-life situation. TRIAL REGISTRATION NUMBER: SETTLE (NCT00627640) and XINDI (NCT03881371).

Real-world use of Safinamide in motor fluctuating Parkinson's disease patients in Italy.

INTRODUCTION: Safinamide is a recent antiparkinsonian drug that modulates both dopaminergic and glutamatergic systems with positive effects on motor and nonmotor symptoms of Parkinson's disease (PD). Here, we aimed to describe the efficacy and safety of safinamide in the Italian PD patients in real-life conditions. METHODS: We performed a sub-analysis of the Italian cohort of the SYNAPSES study, a multi-country, multi-center, retrospective-prospective cohort observational study, designed to investigate the use of safinamide in routine clinical practice. Patients received for the first time a treatment with safinamide and were followed up for 12 months. The analysis was conducted on the overall population and in subgroups of interest: i) patients > 75 years, ii) patients with relevant comorbidities and iii) patients affected by psychiatric symptoms. RESULTS: Italy enrolled 616/1610 patients in 52 centers, accounting for 38% of the entire SYNAPSES cohort. Of the patients enrolled, 86.0% were evaluable at 12 months, with 23.3% being > 75 years, 42.4% with psychiatric conditions and 67.7% with relevant comorbidities. Safinamide was effective on motor symptoms and fluctuations as measured through the Unified PD rating scale III and IV scores, and on the total score, without safety issues in none of the subgroups considered. CONCLUSION: The SYNAPSES data related to Italian patients confirms the good safety profile of safinamide even in special groups of patients. Motor fluctuations and motor impairment improved at the follow-up suggesting the significant role of safinamide in managing motor symptoms in PD patients.

Switching Tenofovir Disoproxil Fumarate (TDF) to Tenofovir Alafenamide Fumarate (TAF) in Hepatitis B/HIV Co-Infection: A Feasibility Study.

PURPOSE: Tenofovir alafenamide (TAF) delivers the active metabolite more efficiently to target cells compared with tenofovir disoproxil fumarate (TDF). Recent studies suggest that TAF is efficacious in treatment naïve individuals who are co-infected with HBV/HIV and may have superior effects on HBV e antigen (HBeAg) seroconversion in this setting. The primary objective of this study was to explore the feasibility of switching from TDF to TAF in HBV/HIV co-infection. METHODS: In this single-arm, multicenter, open-label study, we recruited patients (n = 20) who were on stable TDF-based antiviral therapy for at least 12 months. All participants had undetectable HIV RNA and HBV DNA levels at the time of screening and were converted to a TAF-based treatment regimen (TAF + emtricitabine + third agent) for 48 weeks. FINDINGS: Twenty-seven individuals were invited to take part in the screening process; 3 met the exclusion criteria and a further 4 withdrew consent prior to enrolment. The remaining participants were predominantly male (70%), non-cirrhotic (95%) and of Afro-Caribbean ethnicity (60%). All were co-infected with HIV-1 and established on long-term antiretroviral treatment prior to enrolment (median 6.5 years). No adverse events related to the study drug were observed, and most patients (89.5%) maintained undetectable HIV RNA and HBV DNA throughout the follow-up period. IMPLICATIONS: Switching from TDF to TAF in HBV/HIV co-infection was safe, well tolerated and maintained virological suppression in most patients. Additional studies are needed to confirm these findings in larger cohorts and explore other endpoints.

Bictegravir/Emtricitabine/Tenofovir Alafenamide Treatment: Efficacy and Tolerability in Clinical Practice.

Objective: Analysis of bictegravir/emtricitabine/tenofovir alafenamide (BFTAF) efficacy and safety in virologically suppressed people living with HIV (PLWH) in clinical practice. Patients and methods: The retrospective cohort study, which included adult treatment-experienced and virologically suppressed PLWH, switched to BFTAF from June 2019 to June 2021. Efficacy and safety were evaluated as virological failure (VF=2 consecutive HIV-RNA>50 copies/mL or a single HIV-RNA>400 copies/mL) and treatment failure (TF=VF or discontinuation for any reason) until data freezing (August 2022). Results: Of the 1040 PLWH included, 67.8% switched from elvitegravir/cobicistat/FTAF. VF occurred in 4.2% (n=44), with incidence rate of 1.63 per 1000 person-months of follow-up (PMFU) and probability at 24-30 months of 3.8%-4.0%, respectively. Out of the 44 VF, in 75% virological re-suppression was achieved while maintaining BFTAF. Discontinuation occurred in 15% after a median time of 13.5 months of follow-up, with an incidence rate of 5.67 per 1000 PMFU, and a probability at 24-30 months of 11.9%-15.3%, respectively. Main discontinuation reasons were simplification (51.3%) and toxicity (21.8%, involving CNS in half of cases). TF occurred in 18.6% with an incidence rate of 7.01 per 1000 PMFU after a median time of 13.6 observation months; probability at 24-30 months was 14.8%-18.4%, respectively. Conclusion: BFTAF has proven effective and well tolerated in clinical practice.

Pharmacokinetics, safety, and tolerability of inhaled remdesivir in healthy participants.

Intravenous remdesivir (RDV) is US Food and Drug Administration-approved for hospitalized and nonhospitalized individuals with coronavirus disease 2019. RDV undergoes intracellular metabolic activation to form the active triphosphate, GS-443902, and other metabolites. Alternative administration routes, including localized pulmonary delivery, can lower systemic exposure and maximize exposure at the site of action. This study evaluated the pharmacokinetics (PK) and safety of inhaled RDV in healthy adults. This phase Ia, randomized, placebo-controlled study evaluated inhaled RDV in healthy participants randomized 4:1 to receive RDV or placebo as single doses (4 cohorts) or multiple once-daily doses (3 cohorts). Doses in cohorts 1-6 were administered as an aerosolized solution for inhalation through a sealed facemask; doses in cohort 7 were administered as an aerosolized solution for inhalation through a mouthpiece. Safety was assessed throughout the study. Seventy-two participants were enrolled (inhaled RDV, n = 58 and placebo, n = 14). Following single RDV doses, RDV, GS-704277, and GS-441524 plasma PK parameters indicated dose-proportional increases in area under the concentration-time curve (AUC) extrapolated to infinite time, AUC from time zero to last quantifiable concentration, and maximum observed concentration. Analyte plasma concentrations after multiple RDV doses were consistent with those for single-dose RDV. Analyte plasma exposures were lower when RDV was administered with a mouthpiece versus a sealed facemask. The most common adverse events included nausea, dizziness, and cough. Single- and multiple-dose inhaled RDV exhibited linear and dose-proportional plasma PK. Administration of RDV via inhalation was generally safe and well-tolerated.

Tenofovir disoproxil fumarate versus tenofovir alafenamide on risk of osteoporotic fracture in patients with chronic hepatitis B: A nationwide claims study in South Korea.

BACKGROUND: As tenofovir disoproxil fumarate (TDF) requires long-term use, a reduction in bone density should be considered a possibility when treating patients with chronic hepatitis B (CHB) with aging and systemic diseases. Patients treated with tenofovir alafenamide (TAF) have improved bone mineral density loss compared to patients treated with TDF. Although improvements in bone density caused by TAF have been reported, studies on the actual reduction of fractures are insufficient. AIM: To evaluate the impact of TAF on the risk of osteoporotic fractures in comparison with that of TDF. METHODS: Using the national claims data of the Health Insurance Review and Assessment Service, we conducted a retrospective cohort study of 32,582 patients with CHB who had been initially treated with TDF or TAF between November 2017 and December 2020. The numbers of patients treated with TDF and TAF were 20,877 and 11,705, respectively. The annual fracture rate per 100 patients in each group was calculated, and the Cox proportional hazard ratio (HR) was analysed after applying inverse probability treatment weights (IPTW) for both groups. RESULTS: Among 32,582 patients, the average age was 47.8 ± 11.2 years, 64.5% were men, and the follow-up period was 24.4 ± 11.6 months. The incidence of osteoporotic fractures was 0.78 and 0.49 per 100 person-years in the TDF and TAF groups, respectively. After application of IPTW, the HR was 0.68 (95% confidence interval 0.55-0.85, p = 0.001). CONCLUSION: TAF-treated patients with CHB had a significantly lower risk of osteoporotic fracture than TDF-treated patients.

Effectiveness and Safety of Remdesivir in Treating Hospitalised Patients with COVID-19: A Propensity Score Analysis of Real-Life Data from a Monocentric Observational Study in Times of Health Emergency.

BACKGROUND AND OBJECTIVES: Remdesivir is an antiviral agent, which was shown to be safe and effective in treating early COVID-19, but its favourable impact in hospitalised patients with non-critical disease is still under investigation. The present study aimed to assess the effectiveness and safety of remdesivir as a treatment for hospitalised patients with COVID-19 by a propensity score analysis of observational data. METHODS: In this monocentric retrospective cohort study, the effectiveness and safety of a 5-day course of remdesivir (200 mg intravenously at Day 1, then 100 mg from Days 2-5) in association with the standard of care were assessed in comparison with the standard of care only. The primary endpoint was the proportion of recovery on Day 14. RESULTS: Of 3662 eligible inpatients who tested positive for the severe acute respiratory syndrome coronavirus 2 genome by nasopharyngeal swab at admission, 861 (24%) non-critical patients were included in a propensity score analysis and 281 (33%) were exposed to remdesivir. In total, 242/281 (86.1%) and 435/580 (75.0%) patients recovered in exposed and non-exposed, respectively, with a relative improvement of 11.1% (95% CI + 5.8 to 16.5%; unadjusted odds ratio: 2.07, 95% CI 1.40-3.05, p = 0.0001; after adjustment by propensity score weighting, odds ratio: 1.92, 95% CI 1.30-2.83, p = 0.001). In treated patients, 1 (0.03%) anaphylactic reaction and 1 (0.03%) acute reaction during drug injection were reported, and 24 (8.5%) patients stopped the treatment due to adverse reactions. No significant differences were found with respect to the secondary efficacy endpoints (in-hospital all-cause death, need for intensive care treatments, clinical improvement score at Day 28) and safety endpoints (any and serious adverse reactions). CONCLUSION: A 5-day course of remdesivir in association with the standard of care effectively promoted recovery from COVID-19 among non-critical in-hospital patients and had an acceptable safety profile.

Broadening access to tenofovir alafenamide for the treatment and prevention of HIV-1 infection.

INTRODUCTION: Tenofovir alafenamide (TAF), a prodrug of tenofovir, achieves higher intracellular concentrations of tenofovir-diphosphate and 90% lower plasma concentrations of tenofovir compared to tenofovir disoproxil fumarate (TDF). TAF is associated with improved renal and bone safety outcomes. AREAS COVERED: We review the efficacy and safety of TAF-containing regimens in adults and pediatrics. We highlight safety data during pregnancy, drug interactions during co-administration with tuberculosis treatment, and critical knowledge gaps to be addressed for the successful implementation of TAF in low- and middle-income countries. We performed a search on MEDLINE PubMed and conference websites for relevant articles published from January 2010 to March 2023. EXPERT OPINION: Current evidence demonstrates that TAF has similar efficacy and tolerability, superior bone and renal safety, and higher rates of dyslipidemia and weight gain, compared with TDF. However, there are several knowledge gaps, in specific sub-populations, that require action. Emerging data suggests that TAF is safe during pregnancy, although fuller safety data to support TAF use in pregnancy is needed. Similarly, there is a lack of evidence that TAF can be used in combination with rifamycin-based tuberculosis treatment in PWH and TB. Further studies are needed to fill knowledge gaps and support the wider rollout of TAF.

Association of Remdesivir use with bradycardia: A systematic review and meta-analysis.

Remdesivir has been used for coronavirus disease 2019 (COVID-19) pneumonia with oxygen requirements that do not require mechanical intubation, and several studies showed a reduction in disease duration. However, there is a concern about bradycardia as its side effect. We aimed to investigate the association between Remdesivir and bradycardia by integrating findings from prior studies. We queried PubMed and EMBASE in February 2023 and performed a meta-analysis of studies investigating bradycardia in patients who did or did not receive Remdesivir. The outcome of interest was the rate of bradycardia and in-hospital mortality. We identified eight studies involving 8993 patients, of which seven studies investigated bradycardia. Six studies were observational, one was a case-control, and one was a randomized trial. Incidence of bradycardia was 400/3480 patients (22.3%, 95% confidence interval, CI: [6.5-54.4], I2 = 99%) in the Remdesivir group and 294/5005 (9.8%, 95% CI: [2.8-29], I2 = 98.61) in the non-Remdesivir group. The odds ratio of bradycardia was 2.11 (95% CI: [1.65-2.71], I2 = 22%, p < 0.001) for the Remdesivir group. There was no difference in mortality between the two groups. Patients who received Remdesivir for COVID-19 were more likely to develop bradycardia. The effect of confounding factors should be considered to further clarify the possible association.

No evidence of rapid reversibility of tenofovir alafenamide and/or integrase strand transfer inhibitor-associated weight gain.

OBJECTIVE: We aimed to determine the reversibility of at least 7% weight gain within 12 months following tenofovir alafenamide (TAF) and/or integrase strand transfer inhibitor (INSTI) discontinuation in people with HIV (PWH) from the Dutch ATHENA cohort. DESIGN AND METHODS: PWH with at least 7% weight gain within 24 months after first switch to TAF and/or INSTI whilst being virally suppressed were selected, excluding those with comorbidities/co-medication known to be associated with weight gain. PWH who discontinued only TAF, only INSTI or TAF+INSTI, with available follow-up weight, were included. Mean weight change in the 24 months prior to and 12 months after discontinuation was modelled using mixed-effects linear regression. Factors associated with yearly weight change were assessed using linear regression. RESULTS: In 115 PWH, discontinuing only TAF ( n  = 39), only INSTI ( n  = 53) or TAF+INSTI ( n  = 23), the adjusted mean modelled weight change in the 24 months prior to discontinuation was +4.50 kg [95% confidence interval (CI) 3.04-6.10], +4.80 kg (95% CI 2.43-7.03) and +4.13 kg (95% CI 1.50-7.13), respectively, and -1.89 kg (95% CI -3.40 to -0.37), -1.93 kg (95% CI -3.92 to +0.07) and -2.55 kg (95% CI -5.80 to +0.02) in the 12 months postdiscontinuation. A greater number of years since HIV diagnosis was associated with greater reversibility of weight gain. No associations were found between weight change postdiscontinuation and changes in NRTI backbone or anchor agent at moment of discontinuation. CONCLUSION: There was no evidence of rapid reversibility of at least 7% TAF-associated and/or INSTI-associated weight gain after discontinuation of these agents. Studies of larger and more diverse populations of PWH are required to more fully understand the degree to which weight gain is reversible when discontinuing TAF and/or INSTI.

Real world data of a German Parkinson's disease population: effectiveness and safety of safinamide in routine clinical practice.

BACKGROUND: Parkinson's Disease (PD) is a common progressive neurodegenerative disorder that leads to an imbalance of various neurotransmitters and affects cognitive, motor and non-motor function. Safinamide inhibits monoamine oxidase B in a highly selective and reversible manner and beyond that has anti-glutamatergic properties, with positive effects on motor and non-motor symptoms. The aim of the study was to obtain data about the effectiveness and tolerability of safinamide under routine clinical practice conditions in unselected patients with Parkinson's disease (PD). METHODS: A post-hoc analysis of the German cohort of the European SYNAPSES study (a non-interventional cohort study). Patients were treated with safinamide as an add-on to levodopa and followed-up for 12 months. Analyses were done in the total cohort and in clinically relevant subgroups (patients older than 75 years; with relevant comorbidities; with psychiatric conditions). RESULTS: 181 PD patients were eligible for analysis. Motor symptoms included bradykinesia (76.8%), rigidity (77.3%), tremor (58.6%), and postural instability (27.1%). Non-motor symptoms were reported in 161 patients (89.0%), mainly psychiatric symptoms (43.1%), sleep disorders (35.9%), fatigue (30.9%), and pain (27.6%). 28.7% of patients were aged 75 years or older, 84.5% had relevant comorbidities, and 38.1% had psychiatric conditions. During treatment, the rate of motor complications decreased from 100.0% to 71.1%. UPDRS scores improved under safinamide, with a clinically important effect in 50% in the total score and 45% in the motor score. The positive effect on motor complications occurred already at the 4-month visit and was maintained over 12 months. At least one adverse event (AE)/adverse drug reaction (ADR) was reported by 62.4%/25.4% of patients, AEs were generally mild or moderate, and completely resolved. Only 5 (1.5%) AEs had a definite relationship to safinamide. CONCLUSIONS: The benefit-risk profile of safinamide was favourable and consistent with the total cohort of the SYNAPSES study. In the subgroups, findings were congruent with the total population, which allows the clinical utilisation of safinamide also in more vulnerable patient groups.

Pharmacogenetics of tenofovir renal toxicity in HIV-positive Southern Africans.

OBJECTIVE: Renal toxicity is more common with tenofovir disoproxil fumarate (TDF) than with tenofovir alafenamide fumarate (TAF). We investigated whether polymorphisms in genes relevant to tenofovir disposition affect renal toxicity among HIV-positive Southern Africans. METHODS: Genetic sub-study of adults randomized to initiate TAF or TDF together with dolutegravir and emtricitabine was conducted. Outcomes were changes from week 4 to 48 in the estimated glomerular filtration rate (eGFR) and from baseline to week 48 in urine retinol-binding protein and urine ß2-microglobulin adjusted for urinary creatinine (uRBP/Cr and uB2M/Cr). Primary analyses prioritized 14 polymorphisms previously reported to be associated with tenofovir disposition or renal outcomes, and all polymorphisms in 14 selected genes. We also explored genome-wide associations. RESULTS: 336 participants were enrolled. Among 14 polymorphisms of primary interest, the lowest P values for change in eGFR, uRBP/Cr, and uB2M/Cr were ABCC4 rs899494 ( P  = 0.022), ABCC10 rs2125739 ( P  = 0.07), and ABCC4 rs1059751 ( P  = 0.0088); and in genes of interest, the lowest P values were ABCC4 rs4148481 ( P  = 0.0013), rs691857 ( P  = 0.00039), and PKD2 rs72659631 ( P  = 0.0011). However, none of these polymorphisms withstood correction for multiple testing. Genome-wide, the lowest P values were COL27A1 rs1687402 ( P  = 3.4 × 10 -9 ), CDH4 rs66494466 ( P  = 5.6 × 10 -8 ), and ITGA4 rs3770126 ( P  = 6.1 × 10 -7 ). CONCLUSION: Two ABCC4 polymorphisms, rs899494 and rs1059751, were nominally associated with change in eGFR and uB2M/Cr, respectively, albeit in the opposite direction of previous reports. COL27A1 polymorphism was genome-wide significantly associated with change in eGFR.

Short-course remdesivir for healthcare-associated COVID-19: Case series from a non-acute care hospital.

Healthcare-associated COVID-19 among vulnerable patients leads to disproportionate morbidity and mortality. Early pharmacologic intervention may reduce negative sequelae and improve survival in such settings. This study aimed to describe outcome of patients with healthcare-associated COVID-19 who received early short-course remdesivir therapy. We reviewed the characteristics and outcome of hospitalized patients who developed COVID-19 during an outbreak that involved two wards at a non-acute care hospital in Japan and received short-course remdesivir. Forty-nine patients were diagnosed with COVID-19, 34 on a comprehensive inpatient rehabilitation ward and 15 on a combined palliative care and internal medicine ward. Forty-seven were symptomatic and 46 of them received remdesivir. The median age was 75, and the median Charlson comorbidity index was 6 among those who received it. Forty-one patients had received one or two doses of mRNA vaccines, while none had received a third dose. Most patients received 3 days of remdesivir. Of the patients followed up to 14 and 28 days from onset, 41/44 (95.3%) and 35/41(85.4%) were alive, respectively. Six deaths occurred by 28 days in the palliative care/internal medicine ward and two of them were possibly related to COVID-19. Among those who survived, the performance status was unchanged between the time of onset and at 28 days.