Roll-out and effectiveness of HIV pre-exposure prophylaxis in France: An overview.

CONTEXT: Oral HIV pre-exposure prophylaxis (PrEP) has been available and fully reimbursed for people at high risk of sexually acquired HIV infection in France since January 2016. OBJECTIVE: To evaluate the roll-out of PrEP use in France and its real-life effectiveness. The main results of two previously published studies were presented at the second e-congress of the EPI-PHARE scientific interest group on pharmacoepidemiology and public decision support held in June 2022, and are reported in this article. METHODS: Two studies were carried out using the French National Health Data System (SNDS) covering 99% of the French population. A first study aimed to evaluate the roll-out of PrEP use in France from its implementation until June 2021, globally over the entire study period, including an assessment of the impact of the coronavirus disease 2019 (COVID-19) pandemic that started in February 2020 in France. A second study using a nested case-control design was conducted in a cohort of men at high risk of HIV acquisition included between January 2016 and June 2020 to assess the effectiveness of PrEP in the real world. RESULTS: As of 30 June 2021, a total of 42 159 people had initiated PrEP in France. Initiations increased steadily until February 2020, then slowed down sharply from the start of the COVID-19 pandemic and resumed from the first half of 2021. PrEP users were overwhelmingly men (98%), with an average age of 36 years, living in a large urban area (74%), and of whom a minority (7%) were socioeconomically disadvantaged. Throughout the study period, the level of PrEP maintenance from one semester to the next was high (80-90%). However, for 20% of PrEP initiators, no prescription renewals were recorded during the first six months, suggesting a substantial proportion of early treatment discontinuation. A minority (21%) of PrEP renewal prescriptions were made by private practitioners. Among 46 706 men at high risk of HIV infection, 256 patients identified with HIV infection were matched with 1213 controls. PrEP was used by 29% of cases and 49% of controls. Overall, PrEP effectiveness reached 60% (95% confidence interval 46% to 71%), and was increased in people with high PrEP use (93% (84% to 97%)), or after excluding periods of treatment discontinuation (86% (79% to 92%)). PrEP effectiveness was significantly reduced in people under 30 years of age (26% (-21% to 54%)) and in socioeconomically disadvantaged people (-64% (-392% to 45%)), for whom low PrEP uptake rates or high PrEP discontinuation rates were frequently observed. CONCLUSION: PrEP roll-out has been strongly impacted by the COVID-19 pandemic in France. Although it has been substantial among men who have sex with men, additional measures are needed to expand access to PrEP to all other population groups that could benefit from it. Promoting adherence to PrEP (especially among young people and the socioeconomically disadvantaged) will be essential to ensure a higher level of PrEP effectiveness, which has been shown to be lower in real-life settings than in clinical trials.

Roll-out of HIV pre-exposure prophylaxis use in France: A nationwide observational study from 2016 to 2021.

Background: Oral HIV pre-exposure prophylaxis (PrEP) has been available and fully reimbursed for people at high risk of sexually acquired HIV infection in France since January 2016. Its dissemination has been widely promoted to reduce HIV incidence in high-risk populations. This study aimed to assess the roll-out of PrEP use in France from its implementation until mid-2021. Methods: Using the French National Health Data System (SNDS) covering 99% of people residing in France, all PrEP users defined as individuals aged 15 years or older who received at least one dispensing of PrEP between 1 January 2016 and 30 June 2021 were identified. PrEP users number and their socio-demographic and PrEP use characteristics were assessed over time. Findings: As of 30 June 2021, a total of 42 159 individuals had initiated PrEP in France. Monthly PrEP initiations increased steadily up to 1027 in February 2020, and then slowed down sharply from the onset of the COVID-19 epidemic until a recovery in the first half of 2021. PrEP users were overwhelmingly men (97·5%, 41 126/42 159), aged 36 years on average, living in a large metropolitan area (73·8%, 31 096/42 159), and among whom a minority (7·0%, 2966/42 159) were socio-economically disadvantaged. Throughout the study period, 80-90% of users renewed PrEP from one semester to another, suggesting a good level of maintenance among those engaged in treatment. Nevertheless, for 20·1% (7148/35 549) of new PrEP users no prescription renewal was recorded in the first six months after initiation, suggesting a substantial proportion of early treatment discontinuation. Private practitioners accounted for a minority (21·3%, 77 885/366 399) of PrEP renewal prescriptions. Interpretation: PrEP roll-out has been markedly impacted by the COVID-19 pandemic in France. Although PrEP deployment has been substantial among men who have sex with men, further action is needed to expand access to PrEP to all other population groups who could benefit from it and to promote adherence to treatment. Funding: This research was carried out within EPI-PHARE without external funding.

Risk of Myocardial Infarction, Stroke, or Death in New Users of Intravitreal Aflibercept Versus Ranibizumab: A Nationwide Cohort Study.

INTRODUCTION: The risk of thromboembolic events or death in patients treated with intravitreal anti-vascular endothelial growth factor (IVT anti-VEGF) is poorly described on a large scale and by molecule. This study aimed to assess the risk of myocardial infarction (MI), stroke, or death in new users of IVT aflibercept versus ranibizumab in real-world practice. METHODS: A nationwide cohort study using the French National Health Insurance databases covering 99% of the French population was conducted in patients aged 18 years or older who initiated IVT therapy with ranibizumab or aflibercept between 2014 and 2018. Patients were followed for up to 6 years until December 31, 2019. The risks of MI, stroke, and death were compared in new aflibercept versus ranibizumab users using Kaplan-Meier and multivariate Cox proportional hazards models adjusted on sociodemographic characteristics and cardiovascular disease or risk factors. Subgroup analyses were performed according to history of ischemic heart disease or stroke, diabetes, indication for treatment, sex, age, and number of IVT anti-VEGF injections. RESULTS: When compared to new users of ranibizumab (n = 174,794, mean age 76.0 ± 11.9 years, 59.2% female), new users of aflibercept (n = 76,242, mean age 76.6 ± 11.2 years, 59.2% female) did not have an increased risk of MI (n = 1523 incident MI, adjusted hazard ratio [aHR] 1.00; 95% CI 0.89-1.11), stroke (n = 2306 incident strokes, aHR 1.03; 95% CI 0.95-1.13), or death (n = 4135 deaths, aHR 0.98; 95% CI 0.92-1.05). However, a small but non-statistically significant increase in the risk of stroke was observed in new users of aflibercept versus ranibizumab among patients with diabetes (aHR 1.15; 95% CI 0.98-1.35), particularly those with diabetic macular edema (aHR 1.20; 95% CI 1.00-1.44). The remaining subgroup analyses did not change the results. CONCLUSION: Aflibercept and ranibizumab appear to have similar safety profiles with respect to the risk of MI, stroke, or death under real-world conditions of use.

Intravitreal anti-VEGF use in France: a cross-sectional and longitudinal Nationwide observational study.

PURPOSE: To describe the sociodemographic, medical and management characteristics of patients using intravitreal (IVT) anti-vascular endothelial growth factors (VEGF) in France. METHODS: An observational study was conducted in patients treated with IVT ranibizumab or aflibercept, aged 18 years or older using the French National Health Insurance Databases covering 99% of the French population. Patients currently treated in 2018 were included in a cross-sectional approach to describe treatment history over the previous 6 years. Patients newly treated between 2014 and 2018 were included in a longitudinal approach to describe treatment management during up to 6 years of follow-up. Sociodemographic characteristics and medical history were described in both populations. The analyses were performed at the patient level, as no distinction between the eyes could be made. RESULTS: A total of 224 775 current users of IVT anti-VEGF in 2018 (mean age 78.1 ± 11.3 years, 60% female) and 330 969 new users between 2014 and 2018 (mean age 75.9 ± 12.0 years, 59% female) were included. In both populations cardiovascular comorbidities or risk factors were frequent and the main treatment indications were age-related macular degeneration and diabetic macular oedema. Among current users of IVT anti-VEGF in 2018, the mean number of years receiving a treatment was 2.9 ± 2.0 years, with a mean of 13.7 ± 11.8 dispensations. In the longitudinal approach, a 26% increase in IVT anti-VEGF initiation was observed between 2014 and 2018. For new users, the mean number of years receiving a treatment was 1.6 ± 1.6 and 67% had at least three dispensations within the first three months. A treatment interruption was observed for 83% of new users and occurred on average of 6.1 ± 8.1 months after initiation. The mean number of dispensations was 4.8 ± 2.8 in the first year and 2.2 ± 2.9 in the second year. The mean number of eye monitoring examinations was 6.5 ± 4.7 in the first year and 4.6 ± 4.4 in the second year. CONCLUSION: This study described the real-world conditions of IVT anti-VEGF dispensing at the entire French population scale. Less frequent dispensations and surveillance examinations were observed than in monthly schemes applied in registration trials for IVT anti-VEGF. These results may indicate a lack of systematic monitoring associated with fewer injections and/or clinicians' preference for more flexible and personalized injection schemes than those originally recommended.

Antidepressants and Hepatotoxicity: A Cohort Study among 5 Million Individuals Registered in the French National Health Insurance Database.

BACKGROUND: Hepatotoxicity may be a concern when prescribing antidepressants. Nevertheless, this risk remains poorly understood for serotonin and noradrenaline reuptake inhibitors (SNRIs: venlafaxine, milnacipran, duloxetine) and 'other antidepressants' (mianserin, mirtazapine, tianeptine and agomelatine), particularly in comparison with selective serotonin reuptake inhibitors (SSRIs: fluoxetine, citalopram, paroxetine, sertraline, fluvoxamine, escitalopram), which are by far the most commonly prescribed antidepressants. OBJECTIVE: We quantified the risk of serious liver injury associated with new use of SNRIs and 'other antidepressants' compared with SSRIs in real-life practice. METHODS: Based on the French national health insurance database, this cohort study included 4,966,825 individuals aged 25 years and older with a first reimbursement of SSRIs, SNRIs or 'other antidepressants' between January 2010 and June 2015. We compared the risk of serious liver injury within the 6 months following antidepressant initiation according to antidepressant class, with SSRIs as the reference, using an inverse probability-of-treatment-weighted Cox proportional hazard model adjusted for demographic characteristics and risk factors of liver injury. RESULTS: We identified 382 serious liver injuries overall (none for milnacipran initiators). Age and gender standardized incidence rates per 100,000 person-years were 19.2 for SSRIs, 22.2 for venlafaxine, 12.6 for duloxetine, 21.5 for mianserin, 32.8 for mirtazapine, 31.6 for tianeptine and 24.6 for agomelatine initiators. Initiation of antidepressants of interest versus SSRIs was not associated with an increased risk of serious liver injury [adjusted hazard ratios (95% confidence interval): venlafaxine 1.17 (0.83-1.64), duloxetine 0.54 (0.28-1.02), mianserin 0.90 (0.58-1.41), mirtazapine 1.17 (0.67-2.02), tianeptine 1.35 (0.82-2.23) and agomelatine 1.07 (0.51-2.23)]. This finding was confirmed by the results of an additional study using a case-time-control design. CONCLUSION: These results do not provide evidence of an increased risk of serious liver injury following initiation of SNRIs or 'other antidepressants' compared with SSRIs in real-life practice. This could reflect an inherent lack of difference in risk between the drug classes, or the fact that individuals with higher susceptibility to drug-induced liver injury are not prescribed drugs considered to be more hepatotoxic.

Is there really a link between benzodiazepine use and the risk of dementia?

INTRODUCTION: Several studies have highlighted an increased risk of dementia in benzodiazepine users. As dementia incidence and benzodiazepine use are both high, particularly in the elderly, even a moderate increase in this risk would induce a tremendous number of cases and have a major public health impact. AREAS COVERED: The aim of this article was to systematically review published observational studies having assessed the relation between benzodiazepine use and dementia, to assess and rank their quality and to provide a balanced opinion about the plausibility of a causal relationship. EXPERT OPINION: Out of the ten studies retrieved, nine reported an increased risk of dementia in benzodiazepine users. The risk increased with cumulative dose and treatment duration and when long-acting molecules were used. Even if the causal nature of this association remains unproved, the reviewed material provides arguments for evoking a causal link. Further research would be necessary to elucidate the mechanism of this effect, if any, to evaluate the risk of exposure in younger population and the influence of risk factors such as depression. In any case, the body of evidence seems sufficient for avoiding prescriptions or renewals that are not fully justified and indiscriminate long-term use.

Benzodiazepine use and risk of Alzheimer's disease: case-control study.

OBJECTIVES: To investigate the relation between the risk of Alzheimer's disease and exposure to benzodiazepines started at least five years before, considering both the dose-response relation and prodromes (anxiety, depression, insomnia) possibly linked with treatment. DESIGN: Case-control study. SETTING: The Quebec health insurance program database (RAMQ). PARTICIPANTS: 1796 people with a first diagnosis of Alzheimer's disease and followed up for at least six years before were matched with 7184 controls on sex, age group, and duration of follow-up. Both groups were randomly sampled from older people (age >66) living in the community in 2000-09. MAIN OUTCOME MEASURE: The association between Alzheimer's disease and benzodiazepine use started at least five years before diagnosis was assessed by using multivariable conditional logistic regression. Ever exposure to benzodiazepines was first considered and then categorised according to the cumulative dose expressed as prescribed daily doses (1-90, 91-180, >180) and the drug elimination half life. RESULTS: Benzodiazepine ever use was associated with an increased risk of Alzheimer's disease (adjusted odds ratio 1.51, 95% confidence interval 1.36 to 1.69; further adjustment on anxiety, depression, and insomnia did not markedly alter this result: 1.43, 1.28 to 1.60). No association was found for a cumulative dose <91 prescribed daily doses. The strength of association increased with exposure density (1.32 (1.01 to 1.74) for 91-180 prescribed daily doses and 1.84 (1.62 to 2.08) for >180 prescribed daily doses) and with the drug half life (1.43 (1.27 to 1.61) for short acting drugs and 1.70 (1.46 to 1.98) for long acting ones). CONCLUSION: Benzodiazepine use is associated with an increased risk of Alzheimer's disease. The stronger association observed for long term exposures reinforces the suspicion of a possible direct association, even if benzodiazepine use might also be an early marker of a condition associated with an increased risk of dementia. Unwarranted long term use of these drugs should be considered as a public health concern.

Benzodiazepine use and risk of dementia: prospective population based study.

OBJECTIVE: To evaluate the association between use of benzodiazepines and incident dementia. DESIGN: Prospective, population based study. SETTING: PAQUID study, France. PARTICIPANTS: 1063 men and women (mean age 78.2 years) who were free of dementia and did not start taking benzodiazepines until at least the third year of follow-up. MAIN OUTCOME MEASURES: Incident dementia, confirmed by a neurologist. RESULTS: During a 15 year follow-up, 253 incident cases of dementia were confirmed. New use of benzodiazepines was associated with an increased risk of dementia (multivariable adjusted hazard ratio 1.60, 95% confidence interval 1.08 to 2.38). Sensitivity analysis considering the existence of depressive symptoms showed a similar association (hazard ratio 1.62, 1.08 to 2.43). A secondary analysis pooled cohorts of participants who started benzodiazepines during follow-up and evaluated the association with incident dementia. The pooled hazard ratio across the five cohorts of new benzodiazepine users was 1.46 (1.10 to 1.94). Results of a complementary nested case-control study showed that ever use of benzodiazepines was associated with an approximately 50% increase in the risk of dementia (adjusted odds ratio 1.55, 1.24 to 1.95) compared with never users. The results were similar in past users (odds ratio 1.56, 1.23 to 1.98) and recent users (1.48, 0.83 to 2.63) but reached significance only for past users. CONCLUSIONS: In this prospective population based study, new use of benzodiazepines was associated with increased risk of dementia. The result was robust in pooled analyses across cohorts of new users of benzodiazepines throughout the study and in a complementary case-control study. Considering the extent to which benzodiazepines are prescribed and the number of potential adverse effects of this drug class in the general population, indiscriminate widespread use should be cautioned against.