key: cord-0978436-m0vmvwyz authors: Moreno-Pérez, Oscar; Merino, Esperanza; Ramos, Jose Manuel; Rodríguez, Juan Carlos; Diaz, Carmina; Mas, Patricio; Reus, Sergio; Sánchez-Martínez, Rosario; Boix, Vicente; Chico-Sánchez, Pablo; Sánchez-Payá, José; Portilla, Joaquín title: El ácido valproico podría ayudar en la lucha contra el COVID-19: un estudio de casos y controles date: 2022-02-14 journal: Neurologia DOI: 10.1016/j.nrl.2022.01.007 sha: 9fee1160cacb553edecca472e8b2aed9ea4acc31 doc_id: 978436 cord_uid: m0vmvwyz Objetivo: Existe evidencia preliminar sobre el efecto antiviral del ácido valproico (VPA). Nuestro objetivo fue investigar la incidencia y la gravedad de la infección por SARS-CoV-2 en usuarios de VPA en comparación con la población general. Material y métodos: Estudio de casos – controles anidado en una cohorte, realizado entre el 1 de marzo y el 17 de diciembre de 2020. De forma retrospectiva, identificamos en nuestro departamento de salud a las personas con infección confirmada por SARS-CoV-2 usuarias de VPA (definido como caso). Comprobamos el régimen de VPA (todo el tiempo (TT) (292 días) o al menos el 20% del período de estudio (no-TT) (≥58 días) y si los niveles de VPA estaban en rango terapéutico (RT) (50-100 mcg / mL) en los últimos 24 meses. Calculamos la incidencia acumulada de infección por SARS-CoV-2 e ingreso en los casos, comparándola con la población general no expuesta a VPA (controles). Resultados: Durante el período de estudio se detectaron 6183 PCR + entre 281 035 habitantes, de estos, 746 fueron hospitalizados. 691 pacientes estaban en VPA no-TT y 628 (90,1%) TT. La indicación para el uso de VPA fue la epilepsia en el 54,9%. La incidencia de PCR + fue 1,736% (OR 0,785 (IC 95% 0,443-1,390) y 1,910% (OR 0,865 (IC 95% 0,488-1,533), en pacientes con VPA no-TT y VPA TT, respectivamente, frente a 2,201% en personas sin indicación de VPA. Los pacientes con VPA en RT tenían un riesgo menor de PCR + (OR 0,233 (IC del 95%: 0,057-0,951) no-TT; OR 0,218 (IC del 95%: 0,053-0,890) TT). La incidencia de ingreso hospitalario fue menor en pacientes con VPA (OR 0,543 (IC del 95%: 0,076 a 3,871). Conclusión: Los pacientes con VPA dentro del rango terapéutico tuvieron una reducción de la incidencia de infección por SARS-Cov-2 superior al 75%. Existe una tendencia a la baja en el riesgo de admisión por COVID-19 por SARS-CoV-2 en pacientes en terapia con VPA. Estos hallazgos justifican una mayor investigación. Objective: There is early evidence about Valproic acid (VPA) antiviral effect. Our aim was to investigate the incidence and severity of SARS-CoV-2 infection in VPA users as compared with the general population. Material and Methods: A case-control study nested within a cohort, carried out between March 1 and December 17, 2020. Retrospectively, we identified confirmed SARS-CoV-2 infection patients exposed to VPA in our health department (defined as case). We ascertained VPA regimen (all the time (AT)(292 days) or at least 20% of the study period (notAT)(≥58 days) and if VPA levels were in therapeutic range (ATR) (50-100 mcg/mL) in the last 24 months. We calculated the cumulative incidence of SARS-CoV-2 infection and hospital admission in the cases, comparing it with the general unexposed VPA population (controls). Results: During the study period, 6183 PCR+ were detected among 281035 inhabitants, of these, 746 were hospitalized. 691 patients were on VPA notAT and 628 (90.1%) AT. The indication for VPA use was epilepsy in 54.9%. The incidence of PCR+ was 1.736 % (OR 0.785 (95%CI 0.443-1.390) and 1.910 % (OR 0.865 (95%CI 0.488-1.533), on VPA notAT and VPA AT patients, respectively vs. 2.201% in people without VPA regimen. Those patients with VPA ATR had a lower risk of PCR + (OR 0.233 (95%CI 0.057-0.951) notAT; OR 0.218 (95%CI 0.053-0.890) AT). Hospital admission incidence was lower in patient on VPA (OR was 0.543 (95% CI 0.076 to 3.871). Conclusion: Patients with VPA within the therapeutic range had a reduction of SARS-Cov-2 infection incidence greater than 75%. There is a downward trend in the risk of COVID-19 admission by SARS-CoV-2 in patients on VPA therapy. These findings warrant further investigation. Objetivo: Existe evidencia preliminar sobre el efecto antiviral del ácido valproico (VPA). Nuestro objetivo fue investigar la incidencia y la gravedad de la infección por SARS-CoV-2 en usuarios de VPA en comparación con la población general. Material y métodos: Estudio de casos -controles anidado en una cohorte, realizado entre el 1 de marzo y el 17 de diciembre de 2020. De forma retrospectiva, identificamos en nuestro departamento de salud a las personas con infección confirmada por SARS-CoV-2 usuarias de VPA (definido como caso). Comprobamos el régimen de VPA (todo el tiempo (TT) (292 días) o al menos el 20% del período de estudio (no-TT) (≥58 días) y si los niveles de VPA estaban en rango terapéutico (RT) (50-100 mcg / mL) en los últimos 24 meses. Calculamos la incidencia acumulada J o u r n a l P r e -p r o o f 6 de infección por SARS-CoV-2 e ingreso en los casos, comparándola con la población general no expuesta a VPA (controles). Resultados: Durante el período de estudio se detectaron 6183 PCR + entre 281 035 habitantes, de estos, 746 fueron hospitalizados. 691 pacientes estaban en VPA no-TT y 628 (90,1%) TT. La indicación para el uso de VPA fue la epilepsia en el 54,9%. La incidencia de PCR + fue 1,736% (OR 0,785 (IC 95% 0,443-1,390) y 1,910% (OR 0,865 (IC 95% 0,488-1,533), en pacientes con VPA no-TT y VPA TT, respectivamente, frente a 2,201% en personas sin indicación de VPA. Los pacientes con VPA en RT tenían un riesgo menor de PCR + (OR 0,233 (IC del 95%: 0,057-0,951) no-TT; OR 0,218 (IC del 95%: 0,053-0,890) TT). La incidencia de ingreso hospitalario fue menor en pacientes con VPA (OR 0,543 (IC del 95%: 0,076 a 3,871). Conclusión: Los pacientes con VPA dentro del rango terapéutico tuvieron una reducción de la incidencia de infección por SARS-Cov-2 superior al 75%. Existe una tendencia a la baja en el riesgo de admisión por COVID-19 por SARS-CoV-2 en pacientes en terapia con VPA. Estos hallazgos justifican una mayor investigación. Objective: There is early evidence about Valproic acid (VPA) antiviral effect. Our aim was to investigate the incidence and severity of SARS-CoV-2 infection in VPA users as compared with the general population. Material and Methods: A case-control study nested within a cohort, carried out between March 1 and December 17, 2020. Retrospectively, we identified confirmed SARS-CoV-2 infection patients exposed to VPA in our health department (defined as case). We ascertained VPA regimen (all the time (AT)(292 days) or at least 20% of the study period (notAT)(≥58 days) and if 7 VPA levels were in therapeutic range (ATR) (50-100 mcg/mL) in the last 24 months. We calculated the cumulative incidence of SARS-CoV-2 infection and hospital admission in the cases, comparing it with the general unexposed VPA population (controls). Hospital admission incidence was lower in patient on VPA (OR was 0.543 (95% CI 0.076 to 3.871). Conclusion: Patients with VPA within the therapeutic range had a reduction of SARS-Cov-2 infection incidence greater than 75%. There is a downward trend in the risk of COVID-19 admission by SARS-CoV-2 in patients on VPA therapy. These findings warrant further investigation. As the SARS-CoV-2 epidemic continues to expand, drug repurposing research is marked by failures (hydroxychloroquine, azithromycin, ivermectin, convalescent plasma), weak outcomes (remdesivir, baricitinib, tocilizumab), and small victories (dexamethasone) 1 . Epilepsy is a common neurological condition with a worldwide prevalence of around 1% 2,3 . The association between epilepsy and COVID-19 outcomes remains unclear. Recently, a systematic review and meta-analysis suggested that patients with epilepsy are at risk of having poor COVID- VPA along with its amidic derivatives (valpromide and valnoctamide) has been shown as a potential broad-spectrum antiviral, since it inhibited in vitro infection by enveloped viruses from various viral families 8, 9 . Several studies have reported their antiviral activity against herpesviruses, cytomegalovirus, West Nile virus RNA, and the reactivation of Epstein-Barr virus 9 . VPA and its amidic derivatives valpromide (VPD) and valnoctamide (VCD) acts at different molecular levels of the viral cycle, and may be part of the solution to the growing problem of viral resistance against traditional antivirals, that prominently affects the herpesvirus family. Singh et al. 10 have recently shown that VPA could also have an antiviral effect against SARS-CoV-2, as it reduces the amount of angiotensin-converting enzyme 2 (ACE-2) in endothelial cells, the main cellular receptor that this coronavirus uses to enter the cell. This new knowledge about "mechanism of action" of VPA provides a novel potential therapeutic drug target for prevention and treatment of COVID-19. The absence of published clinical data warrants immediate further investigation, while we await evidence from clinical trials. Our aim was to investigate whether SARS-CoV2 infection was less common or less severe among VPA users. We performed a case-control study nested within a cohort in the General Hospital of Alicante health department, a tertiary hospital in the southeast of Spain. Between March 1 and December 17, all patients with suspected SARS-CoV-2 infection in the Health area (281035 inhabitants) were included through RT-PCR determination. In those with diagnosis, it was verified if they were exposed to Valproic, defined as cases, and those who had not been exposed The incidence of PCR -confirmed diagnoses of COVID-19 was 1. The incidence of COVID-19 hospital admission was 0.144% (1/691) in patients under VPA at least 20% of the evaluated period, and 0.265% (745/280344) in Alicante population without VPA; estimated OR was 0.543 (95% CI 0.076 to 3.871) (p = 0.536) (see figure 1 ). In those patients under VPA regimen all the evaluated period, the incidence of COVID-19 hospital admission was 0.159% (1/628) and the estimated OR 0.598 (95% CI 0.084 to 4.262)(p = 0.604). The only VPA admitted patient was a middle age male with infantile cerebral palsy with mild COVID-19 and a favorable outcome. We have information about VPA therapeutic range in 442 (63.9%) of the patients included in the study. Patients with VPA within the therapeutic range had a lower risk of COVID-19 diagnosis (PCR -confirmed SARS-CoV-2) during the study period, in the global cohort -patients under VPA at least 20% of the evaluated period (OR 0.233 (95% CI 0.057-0.951), p= 0.042) and in the subpopulation on AVP regimen during the whole study period (OR 0.218 (95% CI 0.053-0.890), p = 0.034). No patient with VPA within therapeutic range was admitted to the hospital. The results of this epidemiological study on a large population, show half the risk of COVID-19 admission in patients on VPA therapy. This downward trend in risk is consistent across age and sex, although was not statistically significant. Globally, there is no clear reduction in the risk of PCR confirmed diagnoses of COVID-19 in patients with VPA use; however, in those patients with AVP within the therapeutic range the risk reduction of SARS-Cov-2 infection is greater than 75%. This antithrombotic potential, along with its proven antiplatelet effects 18 , would have potential benefits in coagulopathy a hallmark of severe COVID-19 17 . These in vitro data would support our working hypothesis and data, so that, patients on VPA therapy could present a lower rate of infection by SARS-CoV-2, and in those who become infected, less viral replication, which was related to less severe disease and COVID-19 admission 19 . Epilepsy is a neurological comorbidity that needs special attention in the outbreak of COVID-19 4 . The effect of the pandemic in patients with epilepsy is controversial. Several reports have shown that most patients with epilepsy experience worsened seizures during this pandemic, which may lead to higher morbidity and mortality rates 20,21 . Lallana et al. 22 have reported an increase in depression rates after the first wave, that along with drug-resistant epilepsy and a reduction in family income were independent risk factors for an increased seizure frequency. Nonetheless, other studies have shown that seizure frequency and severity remained unchanged in most patients during the COVID-19 pandemic and the lockdown 23, 24 . Regarding the longitudinal effects of the COVID-19 pandemic, Gonzalez-Martinez et al. 24 found lower QoL, particularly related to daily activities, and higher somnolence. Regarding epilepsy and COVID-19 severity, a systematic review and meta-analysis of 13 studies with 67,131 patients with COVID-19 suggested that patients with epilepsy are at risk of having poor COVID-19 outcomes, specifically in terms of disease severity (OR, 1.69; 95%CI: 1.11-2.59) and mortality rate (OR, 1.71; 95%CI: 1.14-2.56) 4 . The results also showed that the association between epilepsy and increased risk of developing severe COVID-19 is influenced by sex and neurodegenerative disease. Considering this evidence together, the use of VPA in patients with epilepsy as an antiepileptic and potential antiviral drug seems an extremely interesting strategy, with potential benefits in reducing SARS-CoV-2 infection and its unfavorable clinical evolution towards serious forms that require hospital admission. Some important limitations need to be addressed. First, this is a one-center retrospective and observational analysis. The risk of residual confounding cannot be ruled out in this type of study. The lack of information about associated comorbidities, changes in lifestyle -social isolation of patients with epilepsy during the pandemic, a record of adherence to VPA, the absence of VPA levels in a third of the sample and finally, and the therapeutic approach on an outpatient basis after the diagnosis of COVID-19 (for example dexamethasone), limits our findings. Sample size limitations, with only one patient admitted in people under VPA, prevents the evaluation of the effect of VPA on clinical outcomes in hospitalized patients. This new knowledge about "antiviral mechanism of action" of VPA and its potential benefits in COVID-19, along with our reported real-world evidence, provide a novel potential therapeutic drug target for prevention of COVID-19. These findings warrant further investigation in VPA preexposure epidemiological studies and prospective, adequately-powered, randomized trials. Valproic acid effects on COVID-19 are currently being evaluated in clinical studies (e.g. Clinicaltrials.gov NCT04513314). Nevertheless we will have to wait for stronger evidence before prescribing VPA to COVID-19 patients with pre-existing pathologies, however, VPA appear to be a candidate for further repurposing to patients with generalized epilepsy, bipolar disorders, or even migraine at risk of COVID-19. None of the authors has any conflict of interest to disclose. Funding: no external funding was received. The information of this article have not been presented in any meeting(s). We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. 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The data are not publicly available due to privacy or ethical restrictions.