FormalPara Key Points

Few patients in low-income populations benefit from third-generation antiseizure medications. In this sociodemographic context, brivaracetam proved to be safe and effective.

Brivaracetam exhibited a sustained response throughout the 12 months of follow-up.

Cost-effectiveness studies should be performed in low-income populations.

1 Introduction

Nearly 70% of people with epilepsy (PWE) can lead a normal life if diagnosed and treated properly [1]. However, most people with this condition living in low-income populations either do not receive treatment or receive it inappropriately [2]. This situation, known as the treatment gap, can affect up to 75% of PWE residing in low-income populations [3]. This leads to a higher risk of mortality, a lower quality of life, an increase in social stigma, and greater workplace discrimination [4]. The treatment gap in epilepsy is multifactorial and is attributed to various factors, encompassing both healthcare system-related issues and the psychosocial conditions of the PWE [5]. Nevertheless, the availability and affordability of antiseizure medications (ASM) are among the primary barriers to accessing treatment, significantly contributing to the treatment gap [6]. It has been demonstrated that the availability and affordability of ASM are limited in low-income populations, and this disparity is even more pronounced in the case of second-generation or third-generation ASM [7]. In line with this, a study found that more than 90% of high-income countries have at least one third-generation medication, in contrast, only 30% of low-income countries have access to these medications [7]. Considering all the aforementioned information, the Intersectoral Global Action Plan on epilepsy has devised a strategy to ensure that, by 2031, at least 80% of PWE have access to appropriate, affordable, and safe ASM, including those of newer generations [8]. Second-generation and third-generation ASM typically exhibit similar efficacy to those of the first generation; however, they offer several advantages in terms of safety, tolerability, and pharmacokinetic properties [9]. This has a positive impact on therapeutic adherence and, consequently, on the prognosis of the disease [10]. Nevertheless, because of availability and affordability issues, very few PWE in low-income populations can benefit from these medications [11]. In this context, the choice of ASM is often determined by costs rather than the clinical conditions and comorbidities of each individual [11].

Brivaracetam is a third-generation ASM that has been approved as adjunctive therapy for the treatment of focal seizures in both children and adults [12]. Its scientific evidence arises from various controlled clinical trials that have confirmed its effectiveness and safety [13,14,15]. Brivaracetam exhibits a selective affinity for the synaptic vesicle protein 2A up to 30 times greater than levetiracetam, and, unlike the latter, it presents a significantly more favorable neuropsychiatric safety profile [16, 17]. Furthermore, it has a linear pharmacokinetics that provides several therapeutic advantages. In this regard, it has a time to peak drug concentration of 1 h, reaches its steady state in less than 24–48 h, and lacks active transport across the blood–brain barrier, resulting in a highly efficient entry into the central nervous system [18]. All of the above makes brivaracetam one of the ASM with the fastest therapeutic onset and without the need for pharmacological titration [19]. In this study, we decided to assess the effectiveness and safety of brivaracetam for the treatment of epilepsy in a low-income population, within a real-world setting. To the best of our knowledge, this is one of the few published studies assessing brivaracetam in a low-income population in Latin America.

2 Methods

2.1 Study Participants

A retrospective cohort study that included PWE treated at a referral center for the management of epilepsy in Bogotá, Colombia (Hospital de Kennedy) was conducted. Hospital de Kennedy is a public hospital in Bogotá that serves as a third-level center for the Kennedy district and its surrounding areas, representing an estimated population of 2 million people. According to government statistics, 15.3% of the population in this area of the city is experiencing monetary poverty, 5.3% face multidimensional poverty and 3.7% of the population is in a state of extreme poverty. In addition to that, PWE living in this area of the city have a high degree of social vulnerability characterized by a low socioeconomic level, as well as high rates of illiteracy and unemployment [20]. Individuals over 18 years of age, with a diagnosis of epilepsy who were prescribed brivaracetam between January 2020 and July 2023, were included. The decision to prescribe the medication was at the discretion of the treating physician.

2.2 Data Collection and Study Variables

Data were collected retrospectively based on the review of medical records. Sociodemographic and clinical variables were obtained from the registry of the initial consultation before the initiation of brivaracetam. These included: age, sex, duration of epilepsy, type of epilepsy, etiology of epilepsy, number of ASM and type of ASM previously received, number of ASM and type of ASM being received at the time brivaracetam was prescribed, non-pharmacological alternative therapies received, indication of initiation of brivaracetam and role of brivaracetam in the antiseizure scheme (replacement for another ASM in polytherapy, conversion to monotherapy or addition to the antiseizure scheme). Baseline ictal frequency was defined as the number of monthly seizures in the month immediately preceding the initiation of brivaracetam. Post-treatment information was obtained from the review of the medical records of the consults closer to months 3, 6, and 12 after the prescription, and the mean time to those consults was calculated. For the effectiveness analysis, data were included only for individuals who demonstrated good adherence to ASM and underwent no modifications to the therapeutic scheme during the follow-up. The primary effectiveness outcome was defined as the mean percentage of seizure reduction, determined by the mean difference between baseline ictal frequency and seizure frequency at 3, 6, and 12 months. Responder rates of more than 50% and seizure freedom were calculated for the same time periods. Measures for seizure reduction were determined based on the frequency of seizures occurring within a month. For the safety analysis, we calculated the retention rate, defined as the percentage of individuals who were still receiving brivaracetam at 3 months regardless of therapeutic response and adverse effects. Adverse effects were assessed in all individuals, regardless of the duration of use, and were defined as symptoms considered by the treating physician or researcher to be directly associated with the use of brivaracetam. A sub-analysis was conducted on individuals for whom brivaracetam was used as a replacement for levetiracetam and on individuals who were converted to brivaracetam monotherapy, evaluating their effectiveness and safety. This study was approved by the institutional ethics committee, with approval number 11 of 2023.

2.3 Statistical Analysis

Descriptive statistics of the variables were performed, the Shapiro–Wilk test was used to test the distribution, and measures of central tendency were chosen according to normality. For the primary outcome, the paired Wilcoxon test was used as the initial ictal frequency distribution was non-normal. A bivariate analysis was performed to determine which baseline clinical variables were associated with a better response to brivaracetam. A bivariate analysis was performed to calculate odds ratios and to assess statistical significance. Variables that reached statistical significance were planned to be included in a logistic regression model; however, as none reached statistical significance, the model was not conducted. A statistically significant result was defined with a p-value ≤ 0.05. All analyses were performed using STATA 17. The study was written according to the STROBE guidelines.

3 Results

3.1 Baseline Characteristics

During the follow-up time, brivaracetam was prescribed to 111 individuals; however, five were excluded because they did not have follow-up consultations with the required information. The analyzed sample consisted of 106 individuals. The median age of the participants was 33 years (interquartile range: 24–44) and 55.7% (n = 59) were women. Most individuals had focal epilepsies of structural and unknown etiology. The mean duration of the disease prior to brivaracetam was 25.4 years (standard deviation [SD]: 13.6). In the initial evaluation before brivaracetam, individuals had a median baseline ictal frequency of four seizures per month (interquartile range: 2–15) and had previously received a mean of 4.4 (SD: 1.8) ASM. The baseline clinical characteristics are summarized in Table 1. The indication for the use of brivaracetam and its role in the therapeutic scheme are described in Table 2.

Table 1 Sociodemographic and clinical characteristics at baseline
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Table 2 Indications and role of brivaracetam. Indications for initiating brivaracetam and its role within the ASM scheme. Description of the last recorded dose of brivaracetam in milligrams
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3.2 Effectiveness

The effectiveness analysis was performed using information from the follow-up consults at 3, 6 and 12 months, including only those individuals who received the medication continuously and in whom no changes were made in the ASM scheme. A statistically significant difference was observed in the mean number of monthly pre-brivaracetam and post-brivaracetam seizures at 3, 6, and 12 months (Fig. 1). The mean percentage reduction in seizures was 55.3%, 66.9%, and 63.8% at 3, 6, and 12 months, respectively. The percentage of individuals who achieved a ≥ 50% reduction in seizures at 3, 6, and 12 months was 60%, 63.8%, and 65.9%, respectively. The percentage of individuals who achieved seizure freedom at 3, 6, and 12 months was 28%, 31%, and 41.5%, respectively. A sub-analysis was conducted in individuals for whom brivaracetam was used as a replacement for levetiracetam (n = 36). Of these individuals, 38.9% (n = 14) discontinued levetiracetam because of adverse effects, while 61.1% (n = 22) discontinued it because of a lack of seizure control. At 3 months of follow-up, the mean percentage of seizure reduction, the percentage of individuals with a ≥ 50% reduction, and the percentage of seizure freedom were 40.4%, 62.5%, and 29.2%, respectively (p = 0.015). Another sub-analysis was conducted on individuals who were converted to brivaracetam monotherapy (n = 8). In this group, the mean monthly seizure frequency decreased from 3.5 (SD: 24.1) at baseline to 2.25 (SD: 8.74) at the 3-month follow-up (p = 0.058), indicating a mean percentage reduction in seizures of 35.7%. A bivariate analysis was conducted to examine the statistical significance of the therapeutic response to brivaracetam in relation to all clinical variables included in this study. However, no significant association was observed, and consequently, a multivariate regression model could not be conducted.

Fig. 1
figure 1

Change in mean monthly seizure frequency at 3, 6, and 12 months after initiation of brivaracetam. The analysis was conducted only in patients who received the medication continuously and in whom no changes were made to the antiseizure medication scheme. The mean percentage reduction in monthly seizures was 55.3%, 66.9%, and 63.8% at 3, 6, and 12 months, respectively. * The p-value was calculated using the paired Wilcoxon test owing to the non-normal distribution of the baseline ictal frequency

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3.3 Safety

Safety analysis was performed in all individuals who received brivaracetam. The retention rate at 3 months was 89% (n = 95). The discontinuation of brivaracetam was because of adverse effects in seven individuals, a lack of seizure control in two individuals, and logistic difficulties with medication delivery in two individuals. During the follow-up period, 18.7% (n = 20) of the individuals experienced adverse effects, with the most common being neuropsychiatric symptoms, dizziness, and somnolence (Table 3). No serious adverse effects were reported. A sub-analysis was conducted on individuals who were switched from levetiracetam to brivaracetam (n = 36), revealing that only 2.7% (n = 1) experienced a new adverse effect.

Table 3 Adverse effects attributed to brivaracetam. Some patients experienced more than one adverse effect
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4 Discussion

In a real-world setting, within a low-income population, brivaracetam has shown to be effective and safe for the treatment of drug-resistant epilepsies. To the best of our knowledge, this is one of the few published studies assessing brivaracetam in a low-income population in Latin America, demonstrating that PWE living in this context can significantly benefit from the use of third-generation ASM. The included individuals had long-standing epilepsy with a mean disease duration of 25.4 years. They were highly refractory to medical treatment as they had previously used a mean of 4.4 ASM and had a median baseline ictal frequency of four seizures per month. In this drug-resistant context, brivaracetam showed a positive therapeutic response that was maintained throughout the 12 months of follow-up. In fact, the percentage of individuals who achieved a ≥ 50% reduction in seizures at 3, 6, and 12 months was 60%, 63.8%, and 65.9% respectively. These results are consistent with those observed in other studies conducted in populations with similar sociodemographic conditions [21, 22]. Our effectiveness results are superior to those observed in real-world studies conducted in populations with high economic resources. For instance, a recent real-world study conducted by Villanueva et al., which assessed the effectiveness and tolerability of brivaracetam in individuals from Australia, Europe, and the USA, found that at 3, 6, and 12 months, a therapeutic response (≥ 50% seizure reduction) was achieved by 32.1%, 36.7%, and 36.9% of individuals, respectively [23]. Another real-world study from the UK reported a ≥ 50% responder rate of 30.8% [24]. In this regard, several clinical scenarios have been described in which brivaracetam appears to be particularly useful and could potentially explain our higher effectiveness results. For instance, the concomitant use of sodium channel blockers has been identified as a predictor of a favorable outcome [25]. In fact, this combination has been associated with better effectiveness, improved tolerance, higher rates of therapeutic response, lower rates of adverse effects, and a reduced likelihood of treatment withdrawal because of adverse events [25, 26]. In highly active focal epilepsies, a study demonstrated that brivaracetam was more effective in individuals experiencing fewer than five seizures per month compared with those experiencing more than 20 seizures per month (45.8% vs 22.6%, p < 0.001) [27]. In the same study, brivaracetam achieved a sustained seizure response in 51.2% of participants who had previously tried fewer than five ASM, compared with 26.5% when six or more ASM had been attempted (p < 0.001) [27]. In line with this, another study demonstrated that brivaracetam was more effective when used as early adjunctive therapy (after one to two ASM), achieving a sustained therapeutic response in 60.3% compared with 34.3% when used as late adjunctive therapy (p < 0.001) [28]. In older adults (aged over 65 years) with focal epilepsies and in individuals with post-stroke epilepsy, brivaracetam has also been shown to be particularly useful [29, 30]. We could not establish a clinical profile associated with a better response to brivaracetam; however, in our cohort, 87.7% of individuals were receiving a concomitant sodium channel blocker, had a median baseline ictal frequency of four seizures per month and had previously used a mean of 4.4 ASM. Taking into account all the information mentioned above, these findings from our population could potentially explain our higher effectiveness results.

Individuals from our cohort achieved a sustained response throughout the 12 months of follow-up. The sustained response rate has emerged as a more stringent measure of effectiveness that provides reliable information about the response to treatment [26, 31]. For brivaracetam, some prospective and retrospective studies have assessed this measure, suggesting that it has an early and sustained action [26, 31]. Our results support the idea that brivaracetam provides an advantage in this aspect. This is desirable as there is evidence that a loss of antiseizure effectiveness develops during prolonged treatment with most ASM [32]. Another important result from our cohort is that previous exposure to levetiracetam does not affect the effectiveness or safety of brivaracetam. In the 36 individuals for whom brivaracetam was used as a replacement for levetiracetam, the mean percentage of seizure reduction, the percentage of ≥ 50% seizure reduction and the percentage of seizure freedom were 40.4%, 62.5%, and 29.2%, respectively. Additionally, only one individual in this sub-population experienced adverse events after the prescription of brivaracetam. These observations suggest that the previous use of levetiracetam does not preclude the use of brivaracetam. In this regard, Hirsch et al. found that PWE previously treated with levetiracetam achieved a 21.7% of seizure freedom when switched to brivaracetam [33]. Another study conducted by Snoeren et al. found that among the non-responders to levetiracetam treatment, 46.2% had a positive response to brivaracetam treatment, and the incidence of neuropsychiatric adverse events was significantly lower (55.1% vs 22.4%, p < 0.05) [34]. This is consistent with evidence suggesting that, despite belonging to the same pharmacological class (brivaracetam and levetiracetam), there exist significant differences in the pharmacokinetics as well as in the mechanism of action, which could positively impact the therapeutic response and safety profile [35]. As mentioned before, brivaracetam exhibits a selective affinity for the synaptic vesicle protein 2A up to 30 times greater than levetiracetam, and, unlike the latter, it presents a significantly more favorable neuropsychiatric safety profile [16, 17]. Furthermore, it has a linear pharmacokinetics that provides several therapeutic advantages. In this regard, it has a time to peak drug concentration of 1 h, reaches its steady state in less than 24–48 h, and lacks active transport across the blood–brain barrier, resulting in a highly efficient entry into the central nervous system [18]. All the above makes brivaracetam one of the ASM with the fastest therapeutic onset and without the need for pharmacological titration [19].

A small number of individuals in our cohort were converted to brivaracetam monotherapy. Although this group was small, it proved to be interesting, as some drug regulatory agencies currently allow the extrapolation of monotherapy data from adjunctive therapy studies [36]. In this group, the mean monthly seizure frequency decreased from 3.5 (SD: 24.1) at baseline to 2.25 (SD: 8.74) at the 3-month follow-up (p = 0.058), indicating a mean percentage reduction in seizures of 35.7%. These findings are consistent with those recently published by Lattanzi et al., who found that at 12 months of follow-up, 58.1% of individuals were seizure free, with a retention rate of 83.9% [36]. These results suggest that in a real-life setting, brivaracetam may be useful in the treatment of focal epilepsy, not only as adjunctive therapy but also as conversion to monotherapy.

In terms of safety, the retention rate in our study was 89%, and the primary reason for withdrawal was adverse effects, consistent with findings from some of the largest real-world cohorts [23,24,25]. In our cohort, neuropsychiatric adverse effects were the most frequently reported, affecting 8.5% of the individuals. Among these, irritability was the most commonly described adverse effect. Nevertheless, brivaracetam appears to be a safe ASM in this regard, with a low incidence of neuropsychiatric adverse effects reported in 5.9–9.3% across the most representative real-world studies [23,24,25].

Our study reinforces the idea that third-generation ASM are both safe and effective for treating epilepsy in individuals residing in low-income regions of the world. Unfortunately, owing to availability and affordability issues, many individuals from these populations are unable to access the advantages offered by these newer ASM. In line with this, a recent survey revealed a significant disparity in the availability of at least one second-generation or third-generation ASM across country income classifications. More than 90% of high-income countries reported availability, whereas only 30% of low-income countries did. Additionally, certain newer ASM, including rufinamide, perampanel, and cannabinoids, were inaccessible in almost all low-income countries [7]. The most prevalent barrier to accessing newer ASM is cost. However, in the case of brivaracetam, several studies have demonstrated its cost effectiveness, resulting in potential savings for the health system in individuals with drug-resistant epilepsy, with a fixed and predictable annual cost [37,38,39]. These studies should be replicated within the context of low-income populations to assist physicians in these countries in choosing an ASM based on the clinical factors of each individual, rather than solely considering cost and affordability. Customized regulation of prices for ASM, expanding the coverage of individual assistance programs, enhancing governmental support, and updating the World Health Organization essential medication list, which has remained largely unchanged for the last decades, are strategies that can enhance the affordability of newer ASM across low-income regions of the world [7, 11].

The limitations to this study are proper to its retrospective nature. We acknowledge the potential for missing information and the absence of a control group; however, it is important to note that the effectiveness analysis was exclusively conducted in individuals who maintained a consistent ASM scheme during the follow-up period. Therefore, it is assumable that the described effectiveness data are directly related to brivaracetam. A selection bias might be present as PWE were collected from the database of a single hospital. Additionally, there was variability in the time to each consult; however this limitation was assessed by calculating the mean time to the follow-up consults. We were able to demonstrate that the timing of the consultations closely aligned with the desired schedule. Our results belong to a very selective population of active and severe epilepsy in a specific socioeconomic context. For these reasons, the data cannot be extrapolated to the entire population. Nevertheless, this is a real-world study from a low-income population that better reflects the effectiveness and safety of brivaracetam.

5 Conclusions

In a real-world setting, brivaracetam has been shown to be safe and effective for the treatment of epilepsy in individuals from a low-income population. Brivaracetam exhibited a high response rate, a substantial retention rate, and a favorable neuropsychiatric safety profile, making it a suitable alternative in this socioeconomic scenario. Our results highlight that PWE living in this context can significantly benefit from the use of third-generation ASM; however, cost-effectiveness studies should be performed in these populations. The sustained response over time is also a desirable feature that requires confirmation in studies with a different methodology.