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In 2018, a significant neural tube defects (NTD) signal was reported after pre-conceptional exposure to dolutegravir, but was not confirmed in further analysis. Since 2019, dolutegravir-based regimen, an integrase inhibitor (INI), is recommended by WHO as the most-effective first-line therapy in all patients living with HIV. To explore the potential INI-related teratogenic effect, we searched disproportionate signals between exposure to INI-class drugs and congenital anomalies, compared to non-INI drugs, using the international pharmacovigilance database, VigiBase®. We selected all the reports registered in VigiBase® between 01/01/2007 and 30/03/2021 on any antiretroviral drug-related fetal or neonatal adverse drug reactions, declared either in children (<2 years) exposed in utero or in pregnant women (12-50 years). A case/non-case study was conducted to detected signals between congenital anomalies and prenatal exposure to any INI-class drug, compared to non-INI drugs, by estimating adjusted reporting odds ratios (aROR) with 95% confidence intervals (95%CI). We identified 2521 unique reports, among which 664 (26.3%) were related to INI-class use. Overall, 520 congenital anomalies were cited from 327 unique reports, of whom 31.0% were INI-related. Compared to non-INI drugs, no significant disproportionate reporting signal between prenatal exposure to INI-class drugs and congenital anomalies was found (aROR 1.13; 95% CI:0.85-1.51). However, specific significant signals were reported for raltegravir/elvitegravir/dolutegravir drug exposure and urinary malformations (aROR 2.43; 95%CI:1.08-5.43), digestive malformations (aROR 3.09; 95%CI:1.22-7.84), and NTDs (aROR 3.02; 95%CI:1.09-8.37). Although specific congenital anomalies signals associated with raltegravir/elvitegravir/dolutegravir exposure were notified, causal relationship needs to be further investigated in prospective studies.
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Anomalías Inducidas por Medicamentos , Bases de Datos Factuales , Compuestos Heterocíclicos con 3 Anillos , Farmacovigilancia , Piridonas , Humanos , Embarazo , Femenino , Adulto , Adolescente , Anomalías Inducidas por Medicamentos/epidemiología , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Piridonas/efectos adversos , Adulto Joven , Recién Nacido , Niño , Piperazinas/efectos adversos , Persona de Mediana Edad , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/efectos adversos , Inhibidores de Integrasa VIH/uso terapéutico , Oxazinas/efectos adversos , Raltegravir Potásico/efectos adversos , Raltegravir Potásico/uso terapéutico , Preescolar , Sistemas de Registro de Reacción Adversa a Medicamentos/estadística & datos numéricos , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , QuinolonasRESUMEN
Rhegmatogenous retinal detachment (RRD) is a sight-threatening condition with rising global incidence. Identifying factors contributing to seasonal variations in RRD would allow a better understanding of RRD pathophysiology. We therefore performed a retrospective case series study investigating the relationship between RRD occurrence and meteorological factors throughout metropolitan France (the METEO-POC study), particularly the mean temperature over the preceding 10-day period (T-1). Adult patients having undergone RRD surgery and residing in one of the three most populated urban areas of each French region were included (January 2011-December 2018). The study involved 21,166 patients with idiopathic RRD (61.1% males, mean age 59.8-65.1 years). RRD incidence per 100,000 inhabitants increased from 7.79 to 11.81. RRD occurrence was not significantly associated with mean temperature over T-1 in the majority of urban areas (31/36). In a minority of areas (5/36) we observed correlations between RRD incidence and mean temperature over T-1, however these were extremely weak (r = 0.1-0.2; p < 0.05). No associations were found between RRD incidence and secondary outcomes: mean daily temperature over the 10 days prior T-1, minimum/maximum temperatures, rainfall, duration of sunshine, atmospheric pressure, overall radiation, relative humidity, wind speed. Overall, we found no relationships between meteorological parameters and RRD occurrence.
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Desprendimiento de Retina , Humanos , Desprendimiento de Retina/epidemiología , Francia/epidemiología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Incidencia , Estaciones del Año , Conceptos Meteorológicos , Temperatura , AdultoRESUMEN
The Objective of this study was to examine change over time of prevalence of chronic diseases medications (CDM) prescriptions among People living with HIV (PLWH) in Belgium, using Pharmanet database from 2018 to 2021. We identified 13,570, 14,175, 14,588 and 14,813 PLWH in 2018, 2019, 2020 and 2021, respectively. Prescriptions of cardiovascular diseases (CVD) medications (31.7-37.2%) and antidiabetics (7.4-9.0%), increased significantly (p for trend < 0.001 for all), while the prescription of neurological and mental disorders medications (18.0-19.3%) remained stable (p for trend = 0.11) and the prescription of chronic respiratory diseases (CRD) medications decreased from 12.2 to 10.6% (p for trend < 0.001), between 2018 and 2021. It is imperative to ensure that these medications are used appropriately.
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Prescripciones de Medicamentos , Infecciones por VIH , Humanos , Bélgica/epidemiología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Masculino , Femenino , Enfermedad Crónica/tratamiento farmacológico , Persona de Mediana Edad , Adulto , Prescripciones de Medicamentos/estadística & datos numéricos , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/epidemiología , Bases de Datos Factuales , Anciano , PrevalenciaRESUMEN
BACKGROUND: Among the different types of pain related to Parkinson's disease (PD), parkinsonian central pain (PCP) is the most disabling. OBJECTIVES: We investigated the analgesic efficacy of two therapeutic strategies (opioid with oxycodone- prolonged-release (PR) and higher dose of levodopa/benserazide) compared with placebo in patients with PCP. METHODS: OXYDOPA was a randomized, double-blind, double-dummy, placebo-controlled, multicenter parallel-group trial run at 15 centers within the French NS-Park network. PD patients with PCP (≥30 on the Visual Analogue Scale [VAS]) were randomly assigned to receive oxycodone-PR (up to 40 mg/day), levodopa/benserazide (up to 200 mg/day) or matching placebo three times a day (tid) for 8 weeks at a stable dose, in add-on to their current dopaminergic therapy. The primary endpoint was the change in average pain intensity over the previous week rated on VAS from baseline to week-10 based on modified intention-to-treat analyses. RESULTS: Between May 2016 and August 2020, 66 patients were randomized to oxycodone-PR (n = 23), levodopa/benserazide (n = 20) or placebo (n = 23). The mean change in pain intensity was -17 ± 18.5 on oxycodone-PR, -8.3 ± 11.1 on levodopa/benserazide, and -14.3 ± 18.9 in the placebo groups. The absolute difference versus placebo was -1.54 (97.5% confidence interval [CI], -17.0 to 13.90; P = 0.8) on oxycodone-PR and +7.79 (97.5% CI, -4.99 to 20.58; P = 0.2) on levodopa/benserazide. Similar proportions of patients in each group experienced all-cause adverse events. Those leading to study discontinuation were most frequently observed with oxycodone-PR (39%) than levodopa/benserazide (5%) or placebo (15%). CONCLUSIONS: The present trial failed to demonstrate the superiority of oxycodone-PR or a higher dose of levodopa in patients with PCP, while oxycodone-PR was poorly tolerated. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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AIM OF THE STUDY: The French National Health Data System (SNDS) comprises healthcare data that cover 99% of the population (over 67 million individuals) in France. The aim of this study was to present an overview of published pharmacoepidemiological studies using the SNDS in its maturation phase. METHODS: We conducted a systematic literature review of original research articles in the Pubmed and EMBASE databases from January 2012 until August 2018. RESULTS: A total of 316 full-text articles were included, with an annual increase over the study period. Only 16 records were excluded after screening because they did not involve the SNDS but other French healthcare databases. The study design was clearly reported in only 66% of studies of which 57% were retrospective cohorts and 22% cross-sectional studies. The reported study objectives were drug utilization (65%), safety (22%) and effectiveness (9%). Almost all ATC groups were studied but the most frequent ones concerned the nervous system in 149 studies (49%), cardiovascular system drugs in 104 studies (34%) and anti-infectives for systemic use in 50 studies (16%). CONCLUSION: The SNDS is of growing interest for studies on drug use and safety, which could be conducted more in specific populations, including children, pregnant women and the elderly, as these populations are often not included in clinical trials.
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PURPOSE: To evaluate the real-world rates of non-adherence and non-persistence to antiretroviral therapy (ART) among treatment-naïve adult patients with HIV after a 12-month follow-up period in Belgium. METHODS: A retrospective analysis of longitudinal pharmacy claims was conducted using the Pharmanet database from January 1, 2018, to December 31, 2021. Non-adherence was assessed over 12 months and reported as the proportion of days covered below the 80% threshold. Non-persistence was defined as the first 90-day gap in treatment between the two types of ART dispensed. Poisson regression with robust standard error and Cox proportional hazard models were used to assess the factors associated with non-adherence and non-persistence, respectively. RESULTS: Overall, 2999 patients were initiated on ART between 2018 and 2021. After a 12-month follow-up, the proportions of non-adherence and non-persistence were 35.6% and 15.9%, respectively in 2018, and decreased to 18.7% and 6.8%, respectively in 2021. Non-adherence was higher among women, Brussels residents, and those receiving multiple-tablet regimens (MTRs). Similarly, the prevalence of non-persistence was higher among women and MTR recipients. CONCLUSION: Among treatment-naïve adults with HIV in Belgium, non-adherence, and non-persistence to ART showed improvement over the study period but remained at high levels. Disparities were observed by sex and between geographical regions. Prioritizing strategies targeting women in Brussels and facilitating the transition from MTRs to single-tablet regimens should be emphasized optimize adherence to ART in Belgium.
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Fármacos Anti-VIH , Infecciones por VIH , Cumplimiento de la Medicación , Humanos , Bélgica/epidemiología , Femenino , Masculino , Cumplimiento de la Medicación/estadística & datos numéricos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Adulto , Estudios Retrospectivos , Persona de Mediana Edad , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/administración & dosificación , Bases de Datos Factuales , Adulto Joven , Bases de Datos Farmacéuticas/estadística & datos numéricos , Estudios de Seguimiento , Adolescente , Estudios LongitudinalesRESUMEN
OBJECTIVE: To assess amantadine use and associated factors in the patients with Parkinson's disease (PD). BACKGROUND: Immediate-release amantadine is approved for the treatment of PD and is largely used in clinical practice to treat "levodopa-induced dyskinesia (LIDs). Its use varies according to countries and PD stages. The prospective NS-Park cohort collects features of PD patients followed by 26 French PD Expert Centres. METHODS: Variables used for the analyses included demographics, motor and non-motor PD symptoms and motor complications [motor fluctuations (MFs), LIDs)], antiparkinsonian pharmacological classes and levodopa equivalent daily dose (LEDD). We evaluated: (i) prevalence of amantadine use and compared clinical features of amantadine users vs. non-users (cross-sectional analysis); (ii) factors associated with amantadine initiation (longitudinal analysis); (iii) amantadine effect on LIDs, MFs, apathy, impulse control disorders and freezing of gait (Fog) (longitudinal analysis). RESULTS: Amantadine use prevalence was 12.6% (1,585/12,542, median dose = 200 mg). Amantadine users were significantly younger, with longer and more severe PD symptoms, greater LEDD and more frequent use of device-aided/surgical treatment. Factors independently associated with amantadine initiation were younger age, longer PD duration, more frequent LIDs, MFs and FoG, higher LEDD and better cognitive function. 9 of the 658 patients on amantadine had stopped it at the following visit, after 12-18 months (1.3%). New users of amantadine presented a higher improvement in LIDs and MF compared to amantadine never users. CONCLUSIONS: About 12% of PD patients within the French NS-Park cohort used amantadine, mostly those with younger age and more severe PD. Amantadine initiation was associated with a subsequent reduction in LIDs and MFs.
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Amantadina , Antiparkinsonianos , Enfermedad de Parkinson , Amantadina/uso terapéutico , Amantadina/efectos adversos , Humanos , Masculino , Femenino , Francia/epidemiología , Anciano , Antiparkinsonianos/efectos adversos , Antiparkinsonianos/uso terapéutico , Antiparkinsonianos/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/epidemiología , Persona de Mediana Edad , Estudios Prospectivos , Discinesia Inducida por Medicamentos/epidemiología , Discinesia Inducida por Medicamentos/etiología , Estudios Transversales , Levodopa/efectos adversos , Levodopa/administración & dosificación , Estudios Longitudinales , Estudios de CohortesRESUMEN
BACKGROUND: Use of psychostimulants and relative drugs has increased worldwide in treatment of attention-deficit hyperactivity disorder (ADHD) in adolescents and adults. Recent studies suggest a potential association between use of psychostimulants and psychotic symptoms. The risk may not be the same between different psychostimulants. OBJECTIVE: To assess whether amphetamine or atomoxetine use is associated with a higher risk of reporting symptoms of psychosis than methylphenidate use in adolescents and adults, particularly in patients with ADHD. METHODS: Using VigiBase, the WHO's pharmacovigilance database, disproportionality of psychotic symptoms reporting was assessed among adverse drug reactions related to methylphenidate, atomoxetine and amphetamines, from January 2004 to December 2018, in patients aged 13-25 years. The association between psychotic symptoms and psychostimulants was estimated through the calculation of reporting OR (ROR). FINDINGS: Among 13 863 reports with at least one drug of interest, we found 221 cases of psychosis with methylphenidate use, 115 with atomoxetine use and 169 with a prescription of an amphetamine drug. Compared with methylphenidate use, amphetamine use was associated with an increased risk of reporting psychotic symptoms (ROR 1.61 (95% CI 1.26 to 2.06)]. When we restricted the analysis to ADHD indication, we found a close estimate (ROR 1.94 (95% CI 1.43 to 2.64)). No association was found for atomoxetine. CONCLUSION: Our study suggests that amphetamine use is associated with a higher reporting of psychotic symptoms, compared with methylphenidate use. CLINICAL IMPLICATIONS: The prescription of psychostimulants should consider this potential adverse effect when assessing the benefit-risk balance.
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Estimulantes del Sistema Nervioso Central , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Metilfenidato , Trastornos Psicóticos , Adulto , Humanos , Adolescente , Anfetamina/efectos adversos , Metilfenidato/efectos adversos , Clorhidrato de Atomoxetina/efectos adversos , Estimulantes del Sistema Nervioso Central/efectos adversosRESUMEN
INTRODUCTION: Previous studies have identified an interaction between protein kinase inhibitors (PKIs) and proton pump inhibitors (PPIs) in patients with lung cancer. This type of interaction may reduce the efficacy of PKIs. However, the effect of PKI-PPI interaction on patient mortality remains controversial. This study set out to determine the impact of PKI-PPI interaction on overall survival for lung cancer patients. MATERIALS AND METHODS: This study was conducted using data from the French National Health Care Database from January 1, 2011 to December 31, 2021. We identified patients with: (i) an age equal to or greater than 18 years; (ii) lung cancer; and (iii) at least one reimbursement for one of the following drugs: erlotinib, gefitinib, afatinib and osimertinib. Patients were followed-up between the first date of PKI reimbursement and either December 31, 2021 or if they died, the date on which death occurred. The cumulative exposure to PPI duration during PKI treatment was calculated as the ratio between the number of concomitant exposure days to PKI and PPI and the number of exposure days to PKI. A survival analysis using a Cox proportional hazards model was then performed to assess the risk of death following exposure to a PKI-PPI interaction. RESULTS: 34,048 patients received at least one reimbursement for PKIs of interest in our study: 26,133 (76.8 %) were exposed to erlotinib; 3,142 (9.2 %) to gefitinib; 1,417 (4.2 %) to afatinib; and 3,356 (9.9 %) to osimertinib. Patients with concomitant exposure to PKI-PPI interaction during 20 % or more of the PKI treatment period demonstrated an increased risk of death (HR, 1.60 [95 % CI, 1.57-1.64]) compared to other patients. When this cut-off varied from 10 % to 80 %, the estimated HR ranged from 1.46 [95 % CI, 1.43-1.50] to 2.19 [95 % CI, 2.12-2.25]. DISCUSSION/CONCLUSION: In our study, an elevated risk of death was observed in patients exposed to PKI-PPI interaction. Finally, we were able to identify a dose-dependent effect for this interaction. This deleterious effect of osimertinib and PPI was revealed for the first time in real life conditions.
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Neoplasias Pulmonares , Inhibidores de Proteínas Quinasas , Inhibidores de la Bomba de Protones , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Inhibidores de la Bomba de Protones/uso terapéutico , Inhibidores de la Bomba de Protones/efectos adversos , Inhibidores de la Bomba de Protones/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/efectos adversos , Masculino , Femenino , Anciano , Persona de Mediana Edad , Estudios de Cohortes , Afatinib/uso terapéutico , Afatinib/farmacología , Compuestos de Anilina/uso terapéutico , Compuestos de Anilina/farmacología , Compuestos de Anilina/efectos adversos , Acrilamidas/uso terapéutico , Acrilamidas/farmacología , Anciano de 80 o más Años , Interacciones Farmacológicas , Francia/epidemiología , Adulto , Gefitinib/uso terapéutico , Gefitinib/farmacología , Estudios RetrospectivosRESUMEN
Background: In addition to the clinical burden, asthma is responsible for a high economic burden. However, little is known about the economic burden of asthma prior to death. Objective: We performed an economic analysis to describe the costs during 12 and 24 months prior to asthma death between 2013 and 2017 in France. Methods: An observational cohort study was established using the French national health insurance database. Direct medical and non-medical costs, as well as costs related to absence from the workplace, were included in the analysis. Results: In total, 3,829 patients were included in the final analysis. Over 24 and 12 months prior to death, total medical costs per patient were 27,542 [26,545-28,641] and 16,815 [16,164-17,545], respectively. Total medical costs clearly increased over 24 months prior to death. Over 12 months prior to death, costs increased significantly according to age categories, with mean total costs of 8,592, 15,038, and 17,845, respectively, for the categories <18 years old, 18-75 years old, and 75+ years old (p < 0.0001). Over 12 months prior to death, costs were statistically higher in patients with a dispensation of six or more SABA canisters compared to those with a dispensation of five or less canisters (p < 0.0001). In multivariate analysis, comorbidities, hospital as location of death, and dispensation of 12 or more canisters of SABA per year are independent factors of the highest costs. Conclusion: To conclude, the economic burden of asthma death is high and increases with time, age, and SABA dispensation.
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Asma , Estrés Financiero , Humanos , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Bases de Datos Factuales , Francia/epidemiología , HospitalesRESUMEN
BACKGROUND: Considering data from the literature in favor of active educational intervention to teach pharmacovigilance, we describe an innovative model of distance learning clinical reasoning sessions (CRS) of pharmacovigilance with 3rd year medical French students. METHODS: The three main objectives were to identify the elements necessary for the diagnosis of an adverse drug reaction, report an adverse drug reaction and perform drug causality assessment. The training was organized in 3 stages. First, students practiced clinical reasoning (CRS) by conducting fictive pharmacovigilance telehealth consultations. Second, students wrote a medical letter summarizing the telehealth consultation and analyzing the drug causality assessment. This letter was sent to the teacher for a graded evaluation. In the third stage was a debriefing course with all the students. RESULTS: Of the 293 third-year medical students enrolled in this course, 274 participated in the distance learning CRS. The evaluation received feedback from 195 students, with an average score of 8.85 out of 10. The qualitative evaluation had only positive feedback. The students appreciated the different format of the teaching, with the possibility to be active. CONCLUSION: Through distance CRS of pharmacovigilance, medical students' competences to identify and report adverse drug reactions were tested. The students experienced the pharmacovigilance skills necessary to detect adverse drug reactions in a manner directly relevant to patient care. The overall evaluation of the students is in favor of this type of method.
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BACKGROUND: Depression is a highly incident condition and some drugs have been described as inducing or worsening depression. However, literature on this topic is rare and possibly outdated. METHODS: We performed disproportionality analyses using VigiBase®, the largest pharmacovigilance database worldwide to identify drugs associated with depression. Then we excluded drugs already known as depressogenic according to American Summary of Product Characteristics (SPC). We then reviewed drug mechanism of action, scientific literature and European SPC for each drug identified to assess a level of plausibility. We measured Reporting Odds Ratio (ROR) statistically significant and superior to 1, suggesting a significant association between a drug and the reporting of depressive symptoms. RESULTS: Out of the 5237 drugs extracted on VigiBase®, we have retained 89 new drugs associated with depression. More than half of drugs of interest are from nervous system. Opicapone (ROR: 20.66 95 %CI: 15.62-27.33), and gadoversetamide (ROR 18.62, 95 %CI 9.63-35.95) were the drugs with the highest ROR. Among the 89 drugs, 38 were considered already described such as suvorexant or ivacaftor, 20 likely associated such as anti-migraines drugs or new antipsychotic drugs and 31 potentially associated. LIMITATIONS: Pharmacovigilance studies have many inherent limitations, such as under-reporting bias, notoriety effect and protopathic bias. These results are not intended to establish a causal link, only a statistical association. CONCLUSION: We found a strong statistical signal and pharmacological plausibility for 58 new depressogenic drugs. This update list of suspected drugs may prove useful for doctors faced with potential cases of drug-induced depression or to stay aware in case. Other studies are needed to confirm the list.
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Antipsicóticos , Farmacovigilancia , Humanos , Depresión/inducido químicamente , Depresión/epidemiología , Bases de Datos Factuales , Organización Mundial de la SaludRESUMEN
Objective: To assess the quality of reporting of adverse events in clinical trials of covid-19 drugs based on the CONSORT (Consolidated Standards of Reporting Trials) harms extension and according to clinical trial design, and to examine reporting of serious adverse events in drug trials published on PubMed versus clinical trial summaries on ClinicalTrials.gov. Design: Systematic review. Data sources: PubMed and ClinicalTrials.gov registries were searched from 1 December 2019 to 17 February 2022. Eligibility criteria for selecting studies: Randomised clinical trials evaluating the efficacy and safety of drugs used to treat covid-19 disease in participants of all ages with suspected, probable, or confirmed SARS-CoV-2 infection were included. Clinical trials were screened on title, abstract, and text by two authors independently. Only articles published in French and English were selected. The Cochrane risk of bias tool for randomised trials (RoB 2) was used to assess risk of bias. Results: The search strategy identified 1962 randomised clinical trials assessing the efficacy and safety of drugs used to treat covid-19, published in the PubMed database; 1906 articles were excluded after screening and 56 clinical trials were included in the review. Among the 56 clinical trials, no study had a high score for quality of reporting of adverse events, 60.7% had a moderate score, 33.9% had a low score, and 5.4% had a very low score. All clinical trials with a very low score for quality of reporting of adverse events were randomised open label trials. For reporting of serious adverse events, journal articles published on PubMed under-reported 51% of serious adverse events compared with clinical trial summaries published on ClinicalTrials.gov. Conclusions: In one in three published clinical trials on covid-19 drugs, the quality of reporting of adverse events was low or very low. Differences were found in the number of serious adverse events reported in journal articles versus clinical trial summaries. During the covid-19 pandemic, risk assessment of drugs in clinical trials of covid-19 drugs did not comply with good practice recommendations for publication of results. Systematic review registration: European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) EUPAS45959.
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BACKGROUND: The association between dental problems and sublingual/buccal buprenorphine is unclear. We conducted an analysis of dental adverse drug reactions reported with sublingual/buccal buprenorphine in VigiBase®, the pharmacovigilance database of the World Health Organization. RESEARCH DESIGN AND METHODS: We performed disproportionality analyses to compare the reporting rates of dental problems with sublingual/buccal buprenorphine, compared to other buprenorphine formulations and methadone. Significant signals were considered if the lower boundary of the 95% confidence interval of the Reporting Odds Ratio (ROR) was > 1; cases were ≥ 3 and p-value <0.05. We conducted sensitivity analyses by calculating the ROR according to the reporter's qualification and the reporting continent (United States of America and Europe). RESULTS: We included 30,769 reports with all buprenorphine forms. We found 20 cases of dental problems with sublingual/buccal buprenorphine. Sublingual/buccal buprenorphine was associated with an overreporting of dental problems compared to other buprenorphine formulations (ROR = 15.10; 95% CI [7.50-30.39]; p < 0.005) and compared to methadone (ROR = 6.02; 95% CI [3.21-11.30]; p < 0.005). Overreporting of dental problems was consistent in sensitivity analyses, except in Europe compared with other buprenorphine formulations and with methadone. CONCLUSIONS: Sublingual/buccal buprenorphine might increase the risk of reporting dental problems. However, these results do not modify the benefits of sublingual/buccal buprenorphine in the treatment of opioid use disorders.
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Buprenorfina , Trastornos Relacionados con Opioides , Humanos , Estados Unidos , Buprenorfina/efectos adversos , Farmacovigilancia , Metadona/efectos adversos , Trastornos Relacionados con Opioides/epidemiología , Trastornos Relacionados con Opioides/rehabilitación , Administración SublingualRESUMEN
BACKGROUND: About 1.3 million pregnant women lived with HIV and were eligible to receive antiretroviral therapy (ART) worldwide in 2021. The World Health Organization recommends protease inhibitors (PI)-based regimen as second or third-line during pregnancy. With remaining pregnant women exposed to PIs, there is still an interest to assess whether this treatment affects perinatal outcomes. Adverse perinatal outcomes after prenatal exposure to PI-based ART remain conflicting: some studies report an increased risk of preterm birth (PTB) and low-birth-weight (LBW), while others do not find these results. We assessed adverse perinatal outcomes associated with prenatal exposure to PI-based compared with non-nucleoside reverse transcriptase (NNRTI)-based ART. METHODS: We performed a systematic review searching PubMed, Reprotox, Clinical Trial Registry (clinicaltrials.gov) and abstracts of HIV conferences between 01/01/2002 and 29/10/2021. We used Oxford and Newcastle-Ottawa scales to assess the methodological quality. Studied perinatal outcomes were spontaneous abortion, stillbirth, congenital abnormalities, PTB (< 37 weeks of gestation), very preterm birth (VPTB, < 32 weeks of gestation), LBW (< 2500 grs), very low-birth-weight (VLBW, < 1500 g), small for gestational age (SGA) and very small for gestational age (VSGA). The association between prenatal exposure to PI-based compared to NNRTI-based ART was measured for each adverse perinatal outcome using random-effect meta-analysis to estimate pooled relative risks (RR) and their corresponding 95% confidence intervals (CI). Pre-specified analyses were stratified according to country income and study quality assessment, and summarized when homogeneous. RESULTS: Out of the 49,171 citations identified, our systematic review included 32 published studies, assessing 45,427 pregnant women. There was no significant association between prenatal exposure to PIs compared to NNRTIs for VPTB, LBW, SGA, stillbirth, and congenital abnormalities. However, it was inconclusive for PTB, and PI-based ART is significantly associated with an increased risk of VSGA (sRR 1.41 [1.08-1.84]; I2 = 0%) compared to NNRTIs. CONCLUSIONS: We did not report any significant association between prenatal exposure to PIs vs NNRTIs-based regimens for most of the adverse perinatal outcomes, except for VSGA significantly increased (+ 41%). The evaluation of antiretroviral exposure on pregnancy outcomes remains crucial to fully assess the benefice-risk balance, when prescribing ART in women of reproductive potential with HIV. PROSPERO NUMBER: CRD42022306896.
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Antirretrovirales , Infecciones por VIH , Complicaciones del Embarazo , Efectos Tardíos de la Exposición Prenatal , Femenino , Humanos , Recién Nacido , Embarazo , Antirretrovirales/efectos adversos , Antirretrovirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Péptido Hidrolasas/efectos adversos , Péptido Hidrolasas/uso terapéutico , Resultado del Embarazo , Nacimiento Prematuro/inducido químicamente , Nacimiento Prematuro/epidemiología , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Inhibidores de la Transcriptasa Inversa/efectos adversos , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Mortinato/epidemiología , Recién Nacido de Bajo Peso , Aborto Espontáneo/inducido químicamente , Aborto Espontáneo/epidemiología , Anomalías Congénitas/epidemiología , Anomalías Congénitas/etiología , Complicaciones del Embarazo/inducido químicamente , Complicaciones del Embarazo/epidemiologíaRESUMEN
RATIONALE: While meta-analyses of clinical trials found that lurasidone and partial dopamine agonists (brexpiprazole and aripiprazole) were the antipsychotics less likely to cause QTc prolongation, and sertindole, amisulpride, and ziprasidone were the most frequently associated with this adverse drug reaction; no real-world studies have investigated this risk between the different antipsychotics. OBJECTIVES AND METHODS: Using data recorded from 1967 to 2019 in VigiBase®, the World Health Organization's Global Individual Case Safety Reports database, we performed disproportionality analysis to investigate the risk of reporting QT prolongation between 20 antipsychotics. RESULTS: Sertindole had the highest risk of reporting QT prolongation, followed by ziprasidone and amisulpride. Lurasidone was associated with the lowest risk. First-generation antipsychotics were associated with a greater QT prolongation reporting risk (ROR, 1.21; 95%CI, 1.10-1.33) than second-generation antipsychotics. A positive correlation was found between the risk of reporting QT prolongation and affinity for hERG channel (R2 = 0.14, slope = Pearson coefficient = 0.41, p value = 0.1945). CONCLUSIONS: This large study in a real-world setting suggests that sertindole and ziprasidone were the antipsychotics drugs associated with the highest risk of QT prolongation reporting. Our results suggest that lurasidone is less associated with QT interval prolongation reports. Our study also suggests that antipsychotics with the higher hERG affinity are more associated with to QT prolongations reports.
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Antipsicóticos , Síndrome de QT Prolongado , Humanos , Antipsicóticos/efectos adversos , Amisulprida , Clorhidrato de Lurasidona/efectos adversos , Farmacovigilancia , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/epidemiologíaRESUMEN
PURPOSE: Fosfomycin trometamol has been recommended as first-line bactericidal antibiotic for urinary tract infections in pregnant women since 2015 in France. However, studies assessing fosfomycin safety in pregnancy are sparse. This study aimed to assess the risk of major Congenital Anomaly (CA) after fosfomycin exposure during the first trimester of pregnancy. METHODS: We performed a comparative study in EFEMERIS, the French database including expecting mothers covered by the French Health Insurance System of Haute-Garonne from July 1st, 2004 to December 31th, 2018. EFEMERIS contains prescribed and dispensed reimbursed medications during pregnancy and pregnancy outcomes. Logistic regressions have been conducted to compare three groups: (1) pregnancies exposed at least once to fosfomycin; (2) pregnancies exposed at least once to nitrofurantoin; and (3) pregnancies exposed neither to fosfomycin nor to nitrofurantoin, another antibiotic prescribed for urinary infections, before and during pregnancy. RESULTS: A total of 2724 (2.0%) pregnant women received at least one fosfomycin prescription during the first trimester, 650 (0.5%) received nitrofurantoin during the first trimester, and 133,502 (97.5%) pregnant women were not exposed to fosfomycin nor to nitrofurantoin. First trimester pregnancy exposure to fosfomycin was not associated with an increased risk of major CA, compared to first trimester exposure to nitrofurantoin (2.0% versus 2.5%; ORa = 0.80 [0.44-1.47]), or to pregnancies unexposed to fosfomycin and nitrofurantoin (2.0% versus 2.1%; ORa = 0.97 [0.73-1.30]). CONCLUSION: This is the first large comparative study assessing fosfomycin safety in pregnancy. It does not exhibit an increased risk of major CA after fosfomycin exposure during the first trimester of pregnancy.
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Fosfomicina , Infecciones Urinarias , Embarazo , Femenino , Humanos , Primer Trimestre del Embarazo , Fosfomicina/efectos adversos , Nitrofurantoína/efectos adversos , Resultado del Embarazo , Antibacterianos/efectos adversos , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/epidemiologíaRESUMEN
Population-based data on the epidemiology of progressive multifocal leukoencephalopathy, its predisposing conditions and mortality rate are lacking, although such data are crucial to raise awareness among clinicians and to lay foundations for future therapeutic trials in immunomodulating therapies. In our study, patients were identified by interrogating the French national healthcare reimbursement database from 1 January 2008 to 31 December 2017, using progressive multifocal leukoencephalopathy International Classification of Diseases code and a patient's selection algorithm. Overall incidence rate, 1-year all-cause mortality rate and survival patterns were calculated, and factors associated with death were identified using a multivariate Cox proportional hazards regression model. Our cohort is the largest to date, comprising 584 patients with incident progressive multifocal leukoencephalopathy. The overall incidence in France from 2010 to 2017 was stable during the study period at 0.11 per 100 000 person-years, 95% confidence interval [0.10-0.12]. Predisposing diseases were HIV infection (43.7%), followed by haematological malignancies (21.9%), chronic inflammatory diseases (20.2%), solid organ transplantation (4.3%), solid neoplasm (4.1%) and primary immune deficiency (1.5%). The 1-year mortality rate was 38.2%, with a 95% confidence interval (34.2-42.2). In multivariate analysis, factors independently associated with death were older age [adjusted hazard ratio 0.33 (0.20-0.53) for patients aged 20 to 40 compared with patients aged over 60], male gender [adjusted hazard ratio 0.73 (0.54-0.99) for females compared with males] and predisposing immunosuppressive disease, with the highest risk for solid neoplasms [adjusted hazard ratio 4.34 (2.25-8.37)], followed by haematological malignancies [adjusted hazard ratio 3.13 (1.85-5.30)] and HIV infection [adjusted hazard ratio 1.83 (1.12-3.00)], compared with chronic inflammatory diseases. Immune reconstitution inflammatory syndrome was notified in 7.0% of patients. In conclusion, incidence of progressive multifocal leukoencephalopathy is stable in France, and HIV infection remains the main predisposing disease. This large-size cohort uncovers a higher risk of mortality for male patients compared to females, and the worst prognosis for patients with solid neoplasm, while prognosis in patients with haematological malignancies appeared less dismal than in previous studies.
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Infecciones por VIH , Neoplasias Hematológicas , Leucoencefalopatía Multifocal Progresiva , Neoplasias , Femenino , Humanos , Masculino , Persona de Mediana Edad , Anciano , Leucoencefalopatía Multifocal Progresiva/epidemiología , Infecciones por VIH/epidemiología , Infecciones por VIH/complicaciones , Neoplasias Hematológicas/complicaciones , Francia/epidemiologíaRESUMEN
OBJECTIVE: Our aim was to assess the real-world effectiveness of immune checkpoint inhibitors for treatment of patients with progressive multifocal leukoencephalopathy (PML). METHODS: We conducted a multicenter survey compiling retrospective data from 79 PML patients, including 38 published cases and 41 unpublished cases, who received immune checkpoint inhibitors as add-on to standard of care. One-year follow-up data were analyzed to determine clinical outcomes and safety profile. Logistic regression was used to identify variables associated with 1-year survival. RESULTS: Predisposing conditions included hematological malignancy (n = 38, 48.1%), primary immunodeficiency (n = 14, 17.7%), human immunodeficiency virus/acquired immunodeficiency syndrome (n = 12, 15.2%), inflammatory disease (n = 8, 10.1%), neoplasm (n = 5, 6.3%), and transplantation (n = 2, 2.5%). Pembrolizumab was most commonly used (n = 53, 67.1%). One-year survival was 51.9% (41/79). PML-immune reconstitution inflammatory syndrome (IRIS) was reported in 15 of 79 patients (19%). Pretreatment expression of programmed cell death-1 on circulating T cells did not differ between survivors and nonsurvivors. Development of contrast enhancement on follow-up magnetic resonance imaging at least once during follow-up (OR = 3.16, 95% confidence interval = 1.20-8.72, p = 0.02) was associated with 1-year survival. Cerebrospinal fluid JC polyomavirus DNA load decreased significantly by 1-month follow-up in survivors compared to nonsurvivors (p < 0.0001). Thirty-two adverse events occurred among 24 of 79 patients (30.4%), and led to treatment discontinuation in 7 of 24 patients (29.1%). INTERPRETATION: In this noncontrolled retrospective study of patients with PML who were treated with immune checkpoint inhibitors, mortality remains high. Development of inflammatory features or overt PML-IRIS was commonly observed. This study highlights that use of immune checkpoint inhibitors should be strictly personalized toward characteristics of the individual PML patient. ANN NEUROL 2023;93:257-270.
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Síndrome Inflamatorio de Reconstitución Inmune , Virus JC , Leucoencefalopatía Multifocal Progresiva , Humanos , Leucoencefalopatía Multifocal Progresiva/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Estudios Retrospectivos , Síndrome Inflamatorio de Reconstitución Inmune/tratamiento farmacológicoRESUMEN
Background A target mismatch profile can identify good clinical response to recanalization after acute ischemic stroke, but does not consider region specificities. Purpose To test whether location-weighted infarction core and mismatch, determined from diffusion and perfusion MRI performed in patients with acute stroke, could improve prediction of good clinical response to mechanical thrombectomy compared with a target mismatch profile. Materials and Methods In this secondary analysis, two prospectively collected independent stroke data sets (2012-2015 and 2017-2019) were analyzed. From the brain before stroke (BBS) study data (data set 1), an eloquent map was computed through voxel-wise associations between the infarction core (based on diffusion MRI on days 1-3 following stroke) and National Institutes of Health Stroke Scale (NIHSS) score. The French acute multimodal imaging to select patients for mechanical thrombectomy (FRAME) data (data set 2) consisted of large vessel occlusion-related acute ischemic stroke successfully recanalized. From acute MRI studies (performed on arrival, prior to thrombectomy) in data set 2, target mismatch and eloquent (vs noneloquent) infarction core and mismatch were computed from the intersection of diffusion- and perfusion-detected lesions with the coregistered eloquent map. Associations of these imaging metrics with early neurologic improvement were tested in multivariable regression models, and areas under the receiver operating characteristic curve (AUCs) were compared. Results Data sets 1 and 2 included 321 (median age, 69 years [IQR, 58-80 years]; 207 men) and 173 (median age, 74 years [IQR, 65-82 years]; 90 women) patients, respectively. Eloquent mismatch was positively and independently associated with good clinical response (odds ratio [OR], 1.14; 95% CI: 1.02, 1.27; P = .02) and eloquent infarction core was negatively associated with good response (OR, 0.85; 95% CI: 0.77, 0.95; P = .004), while noneloquent mismatch was not associated with good response (OR, 1.03; 95% CI: 0.98, 1.07; P = .20). Moreover, adding eloquent metrics improved the prediction accuracy (AUC, 0.73; 95% CI: 0.65, 0.81) compared with clinical variables alone (AUC, 0.65; 95% CI: 0.56, 0.73; P = .01) or a target mismatch profile (AUC, 0.67; 95% CI: 0.59, 0.76; P = .03). Conclusion Location-weighted infarction core and mismatch on diffusion and perfusion MRI scans improved the identification of patients with acute stroke who would benefit from mechanical thrombectomy compared with the volume-based target mismatch profile. Clinical trial registration no. NCT03045146 © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Nael in this issue.