Cyclosporine A in hospitalized COVID-19 pneumonia patients to prevent the development of interstitial lung disease: a pilot randomized clinical trial.

Post-COVID-19 interstitial lung disease (ILD) is a new entity that frequently causes pulmonary fibrosis and can become chronic. We performed a single-center parallel-group open-label pilot randomized clinical trial to investigate the efficacy and safety of cyclosporine A (CsA) in the development of ILD in the medium term among patients hospitalized with COVID-19 pneumonia. Patients were randomized 1:1 to receive CsA plus standard of care or standard of care alone. The primary composite outcome was the percentage of patients without ILD 3 months after diagnosis of pneumonia and not requiring invasive mechanical ventilation (IMV) (response without requiring IMV). The key secondary composite outcomes were the percentage of patients who achieve a response requiring IMV or irrespective of the need for IMV, and adverse events. A total of 33 patients received at least one dose of CsA plus standard of care (n = 17) or standard of care alone (n = 16). No differences were found between the groups in the percentage of patients who achieved a response without requiring IMV or a response requiring IMV. A higher percentage of patients achieved a response irrespective of the need for IMV in the CsA plus standard of care group although the RR was almost significant 2.833 (95% CI, 0.908-8.840; p = 0.057). No differences were found between the groups for adverse events. In hospitalized patients with COVID-19 pneumonia, we were unable to demonstrate that CsA achieved a significant effect in preventing the development of ILD. (EU Clinical Trials Register; EudraCT Number: 2020-002123-11; registration date: 08/05/2020).

Seroprevalencia del SARS-CoV-2 en los pacientes con enfermedades inmunomediadas en tratamiento con terapias biológicas y sintéticos dirigidos

Introducción: La seroprevalencia del SARS-CoV-2 en las enfermedades inflamatorias inmunomediadas (IMID) sigue siendo fuente de controversia. Objetivo: Comparar la seroprevalencia de anticuerpos (Ac) anti SARS-CoV-2 en pacientes con IMID en tratamientos con fármacos antirreumáticos modificadores de la enfermedad biológicos (FAMEb) o sintéticos dirigidos (FAMEsd) frente a un grupo de personas sin IMID. Métodos: Estudio de pacientes con IMID y tratamientos con FAMEb y FAMEsd y de individuos sin IMID. Mediante la técnica de inmunoensayo por quimioluminiscencia indirecta, se determinaron las serologías IgG frente al SARS-CoV-2 entre octubre/2020 y mayo/2021. Resultados: Se estudiaron 1.100 sujetos, 550 pacientes con IMID y 550 personas sin IMID. Se observó una seroprevalencia de 16% (88/550) en los pacientes frente a 19,3% (106/550) en el grupo de personas sin IMID, sin significación estadística (OR 0,790 [IC 95% 0,558-1,118]). Comparando los tratamientos con FAMEb o FAMEsd, se observó una tendencia a una menor seroprevalencia con rituximab, en relación con los individuos sin IMID (OR 0,296 [IC 95% 0,0871,007]). Asimismo, se encontró menor seroprevalencia en los pacientes que además de su FAMEb recibían tratamiento con metotrexato, en comparación con el grupo de personas sin IMID (OR 0,432 [IC 95% 0,223-0,835]). Conclusiones: Las IMID en tratamiento con FAMEb o FAMEsd no influyen en la seroprevalencia frente al SARS-CoV-2 de los pacientes. El tratamiento concomitante con metotrexato disminuye de forma significativa la seroprevalencia en estos pacientes.

Background: The seroprevalence of SARS-CoV-2 in immunemediated inflammatory diseases (IMID) remains controversial. Aim: To compare the seroprevalence of antibodies (Ab) to SARS-CoV-2 in patients with IMID receiving treatment with biological diseasemodifying antirheumatic drugs (bDMARD) or targeted synthetic (tsDMARD) versus a group of people without IMID. Methods: Study of patients with IMID and treatments with bDMARD and tsDMARD and individuals without IMID. IgG serology against SARS-CoV-2 was measured using the two-step sandwich immunoassay technique by indirect chemiluminescence between October 2020 and May 2021. Results: A total of 1100 subjects were studied, 550 patients with IMID and 550 persons without IMID. A seroprevalence of 16% (88/550) was observed in patients versus 19.3% (106/550) in the group of people without IMID, without statistical significance (OR 0.790 [95% CI 0.558-1.118]). Comparing the treatments with bD- MARD or tsDMARD, there was a tendency to lower seroprevalence with rituximab, in relation to individuals without IMID (OR 0.296 [95% CI 0.087-1.007]). In addition, lower seroprevalence was found in patients who received methotrexate treatment in addition to their bDMARD, compared to the group of individuals without IMID (OR 0.432 [95% CI 0.223-0.835]). Conclusions: IMIDs in treatment with bDMARDs or tsDMARDs do not influence the seroprevalence against SARS-CoV-2 in patients. Concomitant treatment with methotrexate significantly decreased seroprevalence in these patients.

The Real-World Study of Immunogenicity and Safety of the Adjuvant Recombinant Vaccine against Varicella Zoster Virus in Patients with Immune-Mediated Inflammatory Diseases Treated with Janus Kinase Inhibitors.

Background. The risk of herpes zoster reactivation is increased in immunocompromised patients, especially in those with immune-mediated inflammatory diseases (IMIDs) on Janus kinase inhibitor (JAKi) treatment. The recombinant subunit herpes zoster vaccine (RZV) is a non-live vaccine, recently approved for this subgroup of patients, which shows high rates of vaccine effectiveness, with few adverse effects reported in clinical trials. Purpose. The aim of this real-world study was to determine the immunogenicity and safety of RZV in IMID patients on JAKi treatment. Methods. The increase in the concentration of anti-gE antibody for varicella zoster virus post-vaccination, compared to the pre-vaccination concentration, was analyzed to test the humoral immune response. Adverse effects after the first and second vaccine doses were registered. Results. In total, 49 patients were analyzed, and a fourfold increase in antibody concentration was achieved in almost 40% of subjects, with only one serious local adverse effect. Discussion. The resulting immunogenicity was lower than that observed in clinical trials, probably due to the presence of immune disease and immunosuppressive treatment, and to the fact that this was a real-world study. No differences in response according to age, previous virus zoster reactivation, or concomitant treatments were found. Conclusions. RZV was well tolerated and reached the immune response objective in 40% of patients. These results reinforce the importance of including RZV vaccination for immunosuppressed patients. Real-world studies regarding vaccine effectiveness are still needed in order to gain a full understanding of the response to RZV in this group of patients.

Analysis of the costs associated with the follow-up of HIV patients discontinuing antiretroviral treatment due to lack of effectiveness or unacceptable toxicity in Spain.

OBJECTIVE: To assess the use of resources and the costs associated with  following up patients infected with the human immunodeficiency virus after  discontinuation of an antiretroviral treatment and initiation of a new one due to  a lack of effectiveness or unacceptable toxicity, as compared to the costs  involved in the routine follow-up of patients on antiretroviral treatment, from  the Spanish National Health System perspective. Method: The use of resources (clinical tests, medical visits, and hospital pharmacy visits) associated with following three profiles of patients  infected with the human immunodeficiency virus (stable ones, those  discontinuing an existing antiretroviral treatment and being switched to a new  one due to a lack of effectiveness, and those discontinuing an existing antiretroviral treatment and being switched to a new one due to  unacceptable toxicity) was identified, based on clinical practice guidelines and  the findings of a multidisciplinary expert panel (n = 5). The experts agreed on  the main adverse events leading to discontinuation, classifying them into  gastrointestinal, renal, osseous, musculoskeletal, dermatological, hepatic, lipid  profile-related, neuropsychiatric and sexual alterations. Unit costs were  identified from official healthcare costs databases. The cost  (€, 2020) of  following up each patient profile was estimated, excluding the cost of the  antiretroviral treatment itself, with a time horizon of two years. RESULTS: The per-patient cost of following up stable patients over two years  was estimated at €4,148 (tests: €2,293; visits: €1,855). Patient follow-up after  discontinuation of an existing antiretroviral treatment and initiation of a  different one due to a lack of effectiveness was estimated at €5,434 (tests:  €2,777; visits: €2,657). The cost of follow-up after discontinuation of an  existing regimen and initiation of a new one due to unacceptable toxicity varied  according to the adverse event prompting the switch, ranging from  €4,690 for lipid profile dysregulation, to €5,304, for musculoskeletal  alterations. In this patient profile, the cost of tests ranged from €2,403 to  €3,017, and that of visits from €2,287 to €2,842. CONCLUSIONS: The cost associated with following up of patients infected with  the human immunodeficiency virus after discontinuation of an existing  antiretroviral regimen and initiation of a new one is higher than that of routine  follow-up, without taking the cost of drugs into account. The treatment  discontinuation rate is a relevant factor when selecting the most appropriate  therapy for each patient.

OBJETIVO: Estimar el uso de recursos y costes asociados al seguimiento de  pacientes con infección por el virus de la inmunodeficiencia humana tras  discontinuación del tratamiento antirretroviral actual debido a falta de  efectividad o toxicidad inaceptable y cambio a un nuevo tratamiento antirretroviral, comparado con el seguimiento habitual de los  pacientes con tratamiento antirretroviral, desde la perspectiva del Sistema  Nacional de Salud español.Método: Se identificó el uso de recursos (pruebas clínicas, visitas médicas,  visitas a la farmacia hospitalaria) asociado al seguimiento de pacientes con  infección por el virus de la inmunodeficiencia humana en tres perfiles de  pacientes (estable, discontinuación y cambio por falta de efectividad,  discontinuación y cambio por toxicidad inaceptable), a partir de las guías de  práctica clínica y un panel de expertos multidisciplinar (n = 5). Los expertos  consensuaron los principales eventos adversos que conducían a la  discontinuación, agrupándolos en: alteraciones gastrointestinales, renales,  óseas, musculoesqueléticas, dermatológicas, hepáticas y del perfil lipídico,  trastornos neuropsiquiátricos y sexuales. Los costes unitarios se identificaron a  partir de bases de datos oficiales  assode costes sanitarios y de la literatura.  Se estimó el coste (€, 2020) del seguimiento en cada perfil de paciente, sin  incluir el coste derivado del tratamiento antirretroviral, en un horizonte  temporal de dos años. RESULTADOS: El coste por paciente a dos años se estimó en 4.148 € (pruebas:  2.293 €; visitas: 1.855 €) para el seguimiento del paciente estable. El  seguimiento del paciente tras discontinuación por falta de efectividad y cambio  de tratamiento antirretroviral se estimó en 5.434 € (pruebas: 2.777 €; visitas:  2.657 €). El coste del seguimiento tras la discontinuación por toxicidad  inaceptable y cambio de tratamiento antirretroviral varió en función del evento  adverso que motivó el cambio, oscilando entre 4.690 € para las alteraciones  del perfil lipídico, y 5.304 € para las alteraciones musculoesqueléticas. En este  perfil de pacientes, las pruebas variaron entre 2.403 € y 3.017 € y las visitas  entre 2.287 € y 2.842 €. CONCLUSIONES: El coste asociado al seguimiento del paciente con infección por  el virus de la inmunodeficiencia humana tras discontinuación y cambio a un  nuevo tratamiento antirretroviral es mayor comparado con el seguimiento  habitual, sin tener en cuenta el coste farmacológico. La tasa de discontinuación  del tratamiento antirretroviral es un factor relevante a la hora  de seleccionar la terapia más adecuada para cada paciente.

Análisis de los costes asociados al seguimiento de pacientes con VIH que discontinúan el tratamiento antirretroviral por falta de eficacia o toxicidad inaceptable en España / Analysis of the costs associated with the follow-up of HIV patients discontinuing antiretroviral treatment due to lack of effectiveness or unacceptable toxicity in Spain

Objetivo: Estimar el uso de recursos y costes asociados al seguimientode pacientes con infección por el virus de la inmunodeficiencia humanatras discontinuación del tratamiento antirretroviral actual debido a faltade efectividad o toxicidad inaceptable y cambio a un nuevo tratamientoantirretroviral, comparado con el seguimiento habitual de los pacientescon tratamiento antirretroviral, desde la perspectiva del Sistema Nacionalde Salud español.Método: Se identificó el uso de recursos (pruebas clínicas, visitasmédicas, visitas a la farmacia hospitalaria) asociado al seguimiento depacientes con infección por el virus de la inmunodeficiencia humana entres perfiles de pacientes (estable, discontinuación y cambio por faltade efectividad, discontinuación y cambio por toxicidad inaceptable), apartir de las guías de práctica clínica y un panel de expertos multidisciplinar (n = 5). Los expertos consensuaron los principales eventos adversos que conducían a la discontinuación, agrupándolos en: alteracionesgastrointestinales, renales, óseas, musculoesqueléticas, dermatológicas,hepáticas y del perfil lipídico, trastornos neuropsiquiátricos y sexuales.Los costes unitarios se identificaron a partir de bases de datos oficiales de costes sanitarios y de la literatura. Se estimó el coste (€, 2020) delseguimiento en cada perfil de paciente, sin incluir el coste derivado deltratamiento antirretroviral, en un horizonte temporal de dos años.Resultados: El coste por paciente a dos años se estimó en 4.148 €(pruebas: 2.293 €; visitas: 1.855 €) para el seguimiento del pacienteestable. (AU)

Objective: To assess the use of resources and the costs associatedwith following up patients infected with the human immunodeficiency virusafter discontinuation of an antiretroviral treatment and initiation of a newone due to a lack of effectiveness or unacceptable toxicity, as comparedto the costs involved in the routine follow-up of patients on antiretroviraltreatment, from the Spanish National Health System perspective.Method: The use of resources (clinical tests, medical visits, and hospitalpharmacy visits) associated with following three profiles of patients infected with the human immunodeficiency virus (stable ones, those discontinuing an existing antiretroviral treatment and being switched to a newone due to a lack of effectiveness, and those discontinuing an existingantiretroviral treatment and being switched to a new one due to unacceptable toxicity) was identified, based on clinical practice guidelinesand the findings of a multidisciplinary expert panel (n = 5). The expertsagreed on the main adverse events leading to discontinuation, classifyingthem into gastrointestinal, renal, osseous, musculoskeletal, dermatological,hepatic, lipid profile-related, neuropsychiatric and sexual alterations. Unitcosts were identified from official healthcare costs databases. The cost (€, 2020) of following up each patient profile was estimated, excludingthe cost of the antiretroviral treatment itself, with a time horizon of twoyears.Results: The per-patient cost of following up stable patients over twoyears was estimated at €4,148 (tests: €2,293; visits: €1,855). Patientfollow-up after discontinuation of an existing antiretroviral treatment andinitiation of a different one due to a lack of effectiveness was estimatedat €5,434 (tests: €2,777; visits: €2,657). (AU)

Use of Generic Antiretroviral Drugs and Single-Tablet Regimen De-Simplification for the Treatment of HIV Infection in Spain.

The present study sought to describe the use of generic drugs and single-tablet regimen (STR) de-simplification for the treatment of human immunodeficiency virus (HIV) infection among 41 hospitals from the cohort of the Spanish HIV/AIDS Research Network (CoRIS). In June 2018, we collected information on when generic antiretroviral drugs (ARVs) were introduced in the different hospitals, how the decisions to use them were made, and how the information was provided to the patients. Most of the nine available generic ARVs in Spain by June 2018 had been introduced in at least 85% of the participating hospitals, except for zidovudine (AZT)/lamivudine (3TC) and AZT. The time difference between the effective marketing date of each generic ARV and its first dispensing date in the hospitals was much shorter for the more recently approved generic ARV since the year 2017. However, only up to 20% of the hospitals de-simplified efavirenz (EFV)/tenofovir disoproxil (TDF)/emtricitabine (FTC), dolutegravir (DTG)/abacavir (ABC)/3TC, and rilpivirine (RPV)/TDF/FTC (to generic EFV+TDF/FTC, DTG+generic ABC/3TC, and RPV+generic TDF/FTC, respectively), whereas the generic STR EFV/TDF/FTC was introduced in 87.8% of the centers. The median times between the date of effective marketing of generic TDF/FTC and the date of de-simplification of EFV/TDF/FTC and RPV/TDF/FTC were 723 [interquartile range (IQR): 369-1,119] and 234 (IQR: 142-264) days, respectively; this time was 155 (IQR: 28-287) days for de-simplification of DTG/ABC/3TC. In conclusion, despite the widespread use of generic ARVs, STRs de-simplification was only undertaken in <20% of the hospitals. There was wide variability in the timing of the introduction of each generic ARV after they were available in the market.

Brief Report: Patients' Experiences and Opinions After Desimplification of Their Single-Tablet Regimens for the Treatment of HIV Infection: A Survey in a Multicentre Cohort.

OBJECTIVES: The aims of this study were to describe patients' experiences after single-tablet regimen (STR) desimplification and its impact on self-reported treatment adherence and quality of life. METHODS: We performed a survey among all patients from the multicenter cohort of the Spanish HIV/AIDS Network who had desimplified the STRs dolutegravir/abacavir/lamivudine (DGT/ABC/3TC) or rilpivirine/tenofovir disoproxil fumarate/emtricitabine to their separate components (DTG + generic ABC/3TC or RPV + generic TDF/FTC) between December 2016 and November 2018. RESULTS: Among 216 patients who fulfilled inclusion criteria, 138 (63.9%) completed the questionnaire. Most of the patients (78.3%) knew what generic drugs are, only 8.7% believed that treatment with 2 pills is less effective than treatment with an STR, and 67.4% agreed that it is reasonable to take 2 pills instead of 1 for HIV treatment to decrease costs for the health care system. After desimplification, 13.0% of the patients stated they had more secondary effects, 8.0% had forgotten one or more doses more frequently than before, and 10.9% had sometimes forgotten to take 1 pill, but not the other. A proportion of 30.4% reported not being happy to take more pills a day, and 10.1% experienced a worse quality of life after the treatment desimplification. CONCLUSIONS: After STR desimplification, most of the patients had a fair knowledge about generic antiretrovirals, and they agreed to desimplify their STR to decrease costs. Although almost a third of the respondents were not happy to take 2 pills a day, only a minority reported worse adherence or quality of life.

Incidence of COVID-19 in 902 Patients With Immunomediated Inflammatory Diseases Treated With Biologics and Targeted Synthetic Disease-Modifying Antirheumatic Drugs-Findings From the BIOCOVID Study.

OBJECTIVES: The aim of this study was to examine the incidence of coronavirus disease 2019 (COVID-19) among patients with immunomediated inflammatory diseases (IMIDs) treated with biologic or targeted synthetic disease-modifying antirheumatic drugs (bDMARDs and tsDMARDs) and to evaluate the influence of either IMIDs or related therapies on the incidence and evolution of COVID-19. METHODS: This observational, cross-sectional study was conducted from January 31, 2020, to May 15, 2020. Data of 902 patients were obtained from clinical records in hospitals, primary care units, and community pharmacies. Inclusion criteria were adults with IMIDs treated with bDMARDs or tsDMARDs who started therapy 3 months prior to study commencement. Patients with poor adherence to treatments were excluded. COVID-19 was classified as "definitive" (severe acute respiratory syndrome coronavirus 2 polymerase chain reaction [PCR]-positive), "possible" (characteristic symptoms and negative PCR), and "suspected" (characteristic symptoms but PCR not performed). RESULTS: COVID-19 was diagnosed in 70 patients (11 definitive, 19 possible, and 40 suspected). The cumulative incidence of definitive COVID-19 was 1.2%. When considering all cases, the incidence was 7.8%. Patients on biosimilars tumor necrosis factor blockers were more likely to have a diagnosis of COVID-19 (odds ratio, 2.308; p < 0.001). Patients on anti-B-cell therapies had a lower incidence of infections (p = 0.046). Low rates of hospitalization (14.3%), pneumonia (14.3%), death (2.9%), or thrombosis (2.9%) were observed, and 94.3% of patients recovered. CONCLUSIONS: The cumulative incidence of confirmed cases of COVID-19 was similar to the general population, with generally low hospitalization, intensive care management, and mortality rates. COVID-19 incidence was less frequent in patients with more severe immunosuppression.

Effectiveness and tolerability of dolutegravir and abacavir/lamivudine administered as two separate pills compared to their equivalent single-tablet regimen in a multicentre cohort in Spain.

INTRODUCTION: We aimed to assess the effectiveness and tolerability of dolutegravir (DTG), abacavir (ABC) and lamivudine (3TC) administered as branded STR (DTG/ABC/3TC) or as two separate pills (DTG and either branded ABC/3TC [DTG+(ABC/3TC)b] or generic ABC/3TC [DTG+(ABC/3TC)g]). METHODS: We included individuals from the multicentre cohort of the Spanish HIV/AIDS Research Network (CoRIS) who received DTG/ABC/3TC, DTG+(ABC/3TC)b or DTG+(ABC/3TC)g during 2015 to 2018. We used multivariable logistic regression to compare the proportion of antiretroviral-naïve individuals who achieved viral suppression (VS) (viral load ≤50 copies/mL) at 24 weeks of initiating with DTG+(ABC/3TC)b or DTG+(ABC/3TC)g versus DTG/ABC/3TC. We also calculated the proportion of virologically suppressed individuals who maintained VS at 24 weeks after switching from DTG/ABC/3TC to DTG+(ABC/3TC)g. RESULTS: During the study period, 829, 68 and 47 treatment-naïve individuals started treatment with DTG/ABC/3TC, DTG+(ABC/3TC)b or DTG+(ABC/3TC)g respectively. The proportions of individuals who changed their regimens due to side effects during the first 24 weeks were 3.7%, 4.4% and 6.4% respectively (p = 0.646). We did not find significant differences in VS at 24 weeks among individuals starting with DTG+(ABC/3TC)b or DTG+(ABC/3TC)g compared to those initiating with DTG/ABC/3TC. Among 177 virologically suppressed individuals who switched from DTG/ABC/3TC to DTG+(ABC/3TC)g, 170 (96.0%) maintained VS at 24 weeks. CONCLUSIONS: In naïve individuals, the effectiveness and tolerability at 24 weeks of DTG plus ABC/3TC administered as two separate pills, either as branded or generic ABC/3TC, was similar to the STR DTG/ABC/3TC. Switching the STR DTG/ABC/3TC to its separate components DTG+(ABC/3TC)g in virologically suppressed individuals did not seem to impair its effectiveness.

Physicians' opinions on generic antiretroviral drugs and single-tablet regimen de-simplification for the treatment of HIV infection: a multicentre survey in Spain.

OBJECTIVES: To assess the attitudes and opinions about generic antiretroviral drugs (ARVs) and single-tablet regimen (STR) de-simplification among physicians prescribing HIV treatment in the cohort of the Spanish HIV/AIDS Research Network (CoRIS). METHODS: An online questionnaire with 27 structured questions was sent to all physicians (n=199) who prescribed ARVs among the 45 centres participating in the cohort. RESULTS: A total of 169 (84.9%) physicians answered the questionnaire. Only 4.1% of the physicians would never prescribe generic ARVs, but 53.3% would not prescribe them if the number of pills per day increased and 89.3% would not prescribe them if the number of doses per day increased. However, 84.0% of the physicians agreed to prescribe generic ARVs if doing so would decrease costs for the public healthcare system. The percentages of physicians stating that generic ARVs (compared with branded ones) would be associated with worse adherence, more adverse effects or more probability of virological failure, provided that the number of pills and doses per day would not change, were low: 0.6%, 7.7% and 3.6%, respectively. However, these percentages were much higher if the generic ARV entailed breaking an STR: 63.9%, 18.9% and 42.0%, respectively. Most physicians stated that they needed more information about the effectiveness and safety of generic ARVs and the price difference compared with their branded equivalents. CONCLUSIONS: Although most physicians were confident about prescribing generic ARVs, the majority had strong concerns about de-simplifying STR, and they also needed more information about generic drugs.