Efficacy of oral 20-hydroxyecdysone (BIO101), a MAS receptor activator, in adults with severe COVID-19 (COVA): a randomized, placebo-controlled, phase 2/3 trial.

Background: SARS-CoV-2 binding to ACE2 is potentially associated with severe pneumonia due to COVID-19. The aim of the study was to test whether Mas-receptor activation by 20-hydroxyecdysone (BIO101) could restore the Renin-Angiotensin System equilibrium and limit the frequency of respiratory failure and mortality in adults hospitalized with severe COVID-19. Methods: Double-blind, randomized, placebo-controlled phase 2/3 trial. Randomization: 1:1 oral BIO101 (350 mg BID) or placebo, up to 28 days or until an endpoint was reached. Primary endpoint: mortality or respiratory failure requiring high-flow oxygen, mechanical ventilation, or extra-corporeal membrane oxygenation. Key secondary endpoint: hospital discharge following recovery (ClinicalTrials.gov Number, NCT04472728). Findings: Due to low recruitment the planned sample size of 310 was not reached and 238 patients were randomized between August 26, 2020 and March 8, 2022. In the modified ITT population (233 patients; 126 BIO101 and 107 placebo), respiratory failure or early death by day 28 was 11.4% lower in the BIO101 (13.5%) than in the placebo (24.3%) group, (p = 0.0426). At day 28, proportions of patients discharged following recovery were 80.1%, and 70.9% in the BIO101 and placebo group respectively, (adjusted difference 11.0%, 95% CI [-0.4%, 22.4%], p = 0.0586). Hazard Ratio for time to death over 90 days: 0.554 (95% CI [0.285, 1.077]), a 44.6% mortality reduction in the BIO101 group (not statistically significant). Treatment emergent adverse events of respiratory failure were more frequent in the placebo group. Interpretation: BIO101 significantly reduced the risk of death or respiratory failure supporting its use in adults hospitalized with severe respiratory symptoms due to COVID-19. Funding: Biophytis.

Abatacept, Cenicriviroc, or Infliximab for Treatment of Adults Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial.

Importance: Immune dysregulation contributes to poorer outcomes in COVID-19. Objective: To investigate whether abatacept, cenicriviroc, or infliximab provides benefit when added to standard care for COVID-19 pneumonia. Design, Setting, and Participants: Randomized, double-masked, placebo-controlled clinical trial using a master protocol to investigate immunomodulators added to standard care for treatment of participants hospitalized with COVID-19 pneumonia. The results of 3 substudies are reported from 95 hospitals at 85 clinical research sites in the US and Latin America. Hospitalized patients 18 years or older with confirmed SARS-CoV-2 infection within 14 days and evidence of pulmonary involvement underwent randomization between October 2020 and December 2021. Interventions: Single infusion of abatacept (10 mg/kg; maximum dose, 1000 mg) or infliximab (5 mg/kg) or a 28-day oral course of cenicriviroc (300-mg loading dose followed by 150 mg twice per day). Main Outcomes and Measures: The primary outcome was time to recovery by day 28 evaluated using an 8-point ordinal scale (higher scores indicate better health). Recovery was defined as the first day the participant scored at least 6 on the ordinal scale. Results: Of the 1971 participants randomized across the 3 substudies, the mean (SD) age was 54.8 (14.6) years and 1218 (61.8%) were men. The primary end point of time to recovery from COVID-19 pneumonia was not significantly different for abatacept (recovery rate ratio [RRR], 1.12 [95% CI, 0.98-1.28]; P = .09), cenicriviroc (RRR, 1.01 [95% CI, 0.86-1.18]; P = .94), or infliximab (RRR, 1.12 [95% CI, 0.99-1.28]; P = .08) compared with placebo. All-cause 28-day mortality was 11.0% for abatacept vs 15.1% for placebo (odds ratio [OR], 0.62 [95% CI, 0.41-0.94]), 13.8% for cenicriviroc vs 11.9% for placebo (OR, 1.18 [95% CI 0.72-1.94]), and 10.1% for infliximab vs 14.5% for placebo (OR, 0.59 [95% CI, 0.39-0.90]). Safety outcomes were comparable between active treatment and placebo, including secondary infections, in all 3 substudies. Conclusions and Relevance: Time to recovery from COVID-19 pneumonia among hospitalized participants was not significantly different for abatacept, cenicriviroc, or infliximab vs placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT04593940.

Impact of COVID-19 RT-PCR testing of asymptomatic health care workers on absenteeism and hospital transmission during the pandemic.

BACKGROUND: Reducing the transmission of SARS-CoV-2 from asymptomatic and pre-symptomatic patients is critical in controlling the circulation of the virus. METHODS: This study evaluated the prevalence of Reverse transcription polymerase chain reaction (RT-PCR) positivity in serial tests in 429 asymptomatic health care workers (HCW) and its impact on absenteeism. HCW from a COVID-19 reference hospital were tested, screened, and placed on leave. A time-series segmented regression of weekly absenteeism rates was used, and cases of infection among hospitalized patients were analyzed. Viral gene sequencing and phylogenetic analysis were performed on samples from HCW who had a positive result. RESULTS: A significant decrease in absenteeism was detected 3-4 weeks after the intervention at a time of increased transmission within the city. The prevalence of RT-PCR positivity among asymptomatic professionals was 17.3%. Phylogenetic analyses (59 samples) detected nine clusters, two of them strongly suggestive of intrahospital transmission with strains (75% B.1.1.28) circulating in the region during this period. CONCLUSIONS: Testing and placing asymptomatic professionals on leave contributed to control strategy for COVID-19 transmission in the hospital environment, and in reducing positivity and absenteeism, which directly influences the quality of care and exposes professionals to an extra load of stress.

Infliximab for Treatment of Adults Hospitalized with Moderate or Severe Covid-19.

Background: Immune dysregulation contributes to poorer outcomes in severe Covid-19. Immunomodulators targeting various pathways have improved outcomes. We investigated whether infliximab provides benefit over standard of care. Methods: We conducted a master protocol investigating immunomodulators for potential benefit in treatment of participants hospitalized with Covid-19 pneumonia. We report results for infliximab (single dose infusion) versus shared placebo both with standard of care. Primary outcome was time to recovery by day 29 (28 days after randomization). Key secondary endpoints included 14-day clinical status and 28-day mortality. Results: A total of 1033 participants received study drug (517 infliximab, 516 placebo). Mean age was 54.8 years, 60.3% were male, 48.6% Hispanic or Latino, and 14% Black. No statistically significant difference in the primary endpoint was seen with infliximab compared with placebo (recovery rate ratio 1.13, 95% CI 0.99-1.29; p=0.063). Median (IQR) time to recovery was 8 days (7, 9) for infliximab and 9 days (8, 10) for placebo. Participants assigned to infliximab were more likely to have an improved clinical status at day 14 (OR 1.32, 95% CI 1.05-1.66). Twenty-eight-day mortality was 10.1% with infliximab versus 14.5% with placebo, with 41% lower odds of dying in those receiving infliximab (OR 0.59, 95% CI 0.39-0.90). No differences in risk of serious adverse events including secondary infections. Conclusions: Infliximab did not demonstrate statistically significant improvement in time to recovery. It was associated with improved 14-day clinical status and substantial reduction in 28- day mortality compared with standard of care. Trial registration: ClinicalTrials.gov ( NCT04593940 ).

Prognosis of hospitalized children under 2 years of age with co-detection of influenza A and respiratory syncytial virus at the healthcare facility / Prognóstico de crianças hospitalizadas menores de 2 anos com codetecção de influenza A e vírus sincicial respiratório no local de atendimento

Abstract Objectives: the aim of this study is to evaluate the impact of co-detection of Flu A and RSV using rapid immunochromatographic tests at the point of care, in pediatric patients under 2 years of age in a general hospital. Methods: a retrospective cohort study was conducted to analyze clinical outcomes in hospitalized infants with viral respiratory disease with positive results of rapid immunochromatographic test for RSV and/or Flu-A, from 2013 to 2018. A logistic regression model was adjusted to analyze predictors of orotracheal intubation during hospitalization. Results: we analyzed 220 cases: RSV (192), Flu-A (9), co-detection (19). Lethality rate was 1.8% (2 cases), and 88% (194) were under 1 year of age. Mean time of hospitalizations was higher in patients with co-detection. Variables significantly associated with orotracheal intubation were: younger age in months, comorbidities, RSV and Flu-A co-detection, and bacterial pneumonia during hospitalization. Conclusions: RSV and Flu-Aco-detection was associated with the least favorable clinical prognoses in this study. Rapid test diagnosis may provide important information at the point of care, because molecular panels are not widely accessible in general hospitals. Rapid diagnosis allows timely evaluation and treatment.

Resumo Objetivos: avaliar o impacto da codetecção de Influenza A (FluA) e Vírus Sincicial Respiratório (VSR) por meio de testes imunocromatográficos rápidos em tempo real, em pacientes menores de 2 anos em hospital público e universitário. Métodos: estudo de coorte retrospectivo foi conduzido para analisar os desfechos clínicos de crianças hospitalizadas com doença respiratória viral com resultados positivos do teste rápido imunocromatográfico para VSR e/ou FluA, de 2013 a 2018. Um modelo de regressão logística foi ajustado para analisar preditores de intubação orotraqueal durante a internação. Resultados: foram analisados 220 casos: RSV (192), FluA (9) eco-detecção (19). A letalidade foi de 1,8% (2 casos) e 88% (194) casos em menores de 1 ano. O tempo médio de internação foi maior nos pacientes com codetecção. As variáveis significativamente associadas à intubação orotraqueal foram: menor idade em meses, comorbidades, codetecção de VSR e Flu-A e pneumonia bacteriana durante a internação. Conclusões: codetecção VSR e FluA foi associada a prognósticos clínicos desfavoráveis. O teste rápido fornece informações importantes a beira-leito, pois os painéis moleculares não são amplamente acessíveis em hospitais públicos. O diagnóstico rápido permite a avaliação e tratamento oportunos.

Efficacy and safety of glecaprevir/pibrentasvir in treatment-naïve adults with chronic hepatitis C virus genotypes 1-6 in Brazil.

INTRODUCTION AND OBJECTIVES: Glecaprevir/pibrentasvir is a highly effective and well tolerated treatment for hepatitis C infection. Brazilian patients were not included in the original development studies for glecaprevir/pibrentasvir. This study aimed to assess safety and efficacy of glecaprevir/pibrentasvir in treatment-naïve Brazilian adults without cirrhosis or with compensated cirrhosis. PATIENTS AND METHODS: EXPEDITION-3 was a Phase 3, open-label, multicenter study in treatment-naïve Brazilian adults with hepatitis C infection genotype 1-6. Patients without cirrhosis (F2 or F3) or with compensated cirrhosis (F4) received 8 or 12 weeks of glecaprevir/pibrentasvir, respectively. The primary efficacy endpoint was the rate of sustained virologic response at post-treatment Week 12. Secondary endpoints were on-treatment virologic failure and relapse rates. Baseline polymorphisms were assessed in NS3 and NS5A. Adverse events and laboratory abnormalities were monitored. RESULTS: 100 patients were enrolled, 75 received 8 weeks of treatment and 25 received 12 weeks; all patients completed treatment. Overall sustained virologic response at post-treatment Week 12 rate was high (98.0%; 98/100; 95% confidence interval: 93.0-99.4) and remained high regardless of baseline viral or host factors, including demographics, hepatitis C virus RNA levels, polymorphisms in NS3 and/or NS5A, genotype, and relevant comorbidities. 55% of patients reported ≥1 adverse event, the most common being headache (18.0%). Four patients reported serious adverse events; none were considered drug related or led to study drug discontinuation. No hepatic decompensations were observed. CONCLUSIONS: Glecaprevir/pibrentasvir was effective and well tolerated in treatment-naïve Brazilian patients with hepatitis C infection without cirrhosis and with compensated cirrhosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT03219216.

Extended treatment with pegylated interferon alfa/ribavirin in patients with genotype 2/3 chronic hepatitis C who do not achieve a rapid virological response: final analysis of the randomised N-CORE trial.

BACKGROUND AND AIMS: The combination of pegylated interferon alfa/ribavirin will likely remain the treatment of choice for HCV genotype 2/3 patients in financially constrained countries for the foreseeable future. Patients with poor on-treatment response may benefit from treatment extension. This study examined the effect of 48 versus 24 weeks of peginterferon alfa-2a/ribavirin on the sustained virological response (SVR) in patients with HCV genotype 2/3 who did not achieve rapid virological response (RVR). METHODS: N-CORE was a multicentre, randomised, phase III study. HCV genotype 2/3 patients receiving peginterferon alfa-2a/ribavirin without a rapid but with an early virological response were randomised at week 24 to stop treatment (Arm A) or continue to 48 weeks (Arm B). The primary efficacy endpoint was SVR. RESULTS: Two hundred thirty-five patients were enrolled. End of treatment response was similar in both treatment arms. SVR24 rates were not significantly greater in the extended treatment arm compared with the standard 24-week treatment in either the intention-to-treat or the per-protocol populations (61 vs. 52 %, p = 0.1934 and 63 vs. 52 %, p = 0.1461, respectively). Serious adverse events occurred more frequently in patients receiving extended treatment duration (12 %) versus 24-week therapy (4 %). CONCLUSIONS: It is unclear whether the extension of peginterferon alfa-2a/ribavirin treatment may benefit HCV genotype 2/3 patients who do not achieve RVR. The study was stopped early because recruitment was slower than anticipated, and this may have limited the statistical impact of these findings.

Re-treatment of previous non-responders and relapsers to interferon plus ribavirin with peginterferon alfa-2a (40KD), ribavirin ± amantadine in patients with chronic hepatitis C: randomized multicentre clinical trial.

INTRODUCTION: A large number of patients with chronic hepatitis C have not been cured with interferon-based therapy. Therefore, we evaluated the efficacy of amantadine combined with the standard of care(pegylated interferon plus ribavirin) in patients who had not responded to or had relapsed after ≥ 24 weeks of treatment with conventional interferon plus ribavirin. MATERIAL AND METHODS: Patients stratified by previous response (i.e., non-response or relapse) were randomized to 48 weeks of open-label treatment with peginterferon alfa-2a (40KD) 180 µg/week plus ribavirin 1,000/1,200 mg/day plus amantadine 200 mg/day (triple therapy), or the standard of care (peginterferon alfa-2a [40KD] plus ribavirin). RESULTS: The primary outcome was sustained virological response (SVR), defined as undetectable hepatitis C virus RNA in serum (< 50 IU/mL) at end of follow-up (week 72). Among patients with a previous non-response, 12/53 (22.6%; 95% confidence interval [CI] 12.3-36.2%) randomized to triple therapy achieved an SVR compared with 16/52 (30.8%; 95% CI 18.7-45.1%) randomized to the standard of care. Among patients with a previous relapse 22/39 (56.4%; 95% CI 39.6-72.2%) randomized to triple therapy achieved an SVR compared with 23/38 (60.5%; 95% CI 43.4-76.0%) randomized to the standard of care. Undetectable HCV RNA (< 50 IU/mL) at week 12 had a high positive predictive value for SVR. A substantial proportion of non-responders and relapsers to conventional interferon plus ribavirin achieve an SVR when re-treated with peginterferon alfa-2a (40KD) plus ribavirin. CONCLUSION: Amantadine does not enhance SVR rates in previously treated patients with chronic hepatitis C and cannot be recommended in this setting.

Primary antiretroviral drug resistance among HIV type 1-infected individuals in Brazil.

Infection with drug-resistant human immunodeficiency virus type 1 (HIV-1) has been documented in all countries that have surveyed for it and may result in an unfavorable response to therapy. The prevalence and characteristics of individuals with transmitted resistance to antiretroviral drugs have been scarcely described in Brazil. We performed antiretroviral resistance testing prior to initiation of therapy in 400 subjects enrolled from 20 centers in 13 Brazilian cities between March and September 2007. Genotyping was conducted using PCR-amplified HIV pol products by automated sequencing, and genotype interpretation was done according to the IAS-USA consensus. Of 400 eligible participants, 387 (95.8%) were successfully tested. Seven percent of antiretroviral-naive patients carried viruses with one or more major mutation associated with drug resistance. The prevalence of these mutations was 1.0% for protease inhibitors, 4.4% for nonnucleoside reverse transcriptase inhibitors, and 1.3% for nucleoside reverse transcriptase inhibitors. The frequency of multidrug resistance among the resistant strains was 13.6%. Among subjects infected with drug-resistant virus, the majority were infected with subtype B viruses (91%). Subjects from the city of São Paulo had higher transmitted resistance mutations compared to the rest of the country. Reporting a partner taking antiretroviral medications was associated with a higher chance of harboring HIV variants with major drug resistance mutations [odds ratio = 2.57 (95% confidence interval, 1.07-6.16); p = 0.014]. Resistance testing in drug-naive individuals identified 7% of subjects with mutations associated with reduced susceptibility to antiretroviral drugs. Continued surveillance of drug-resistant HIV-1 in Brazil is warranted when guidelines for HIV prophylaxis and treatment are updated. Resistance testing among drug-naive patients prior to treatment initiation should be considered, mainly directed at subjects whose partners are already on antiretroviral therapy.

The implementation of a surgical antibiotic prophylaxis program: the pivotal contribution of the hospital pharmacy.

BACKGROUND: Although surgical site infection rates have decreased with the prophylactic use of antibiotics, the inappropriateness of surgical antibiotic prophylaxis is still a worldwide problem. Various strategies have been used to address this problem. This study describes the implementation of a perioperative antibiotic prophylaxis protocol that emphasizes the contribution of the pharmacist. METHODS: A descriptive study design was used to evaluate the impact of the protocol on the appropriateness of prophylaxis in a private university hospital. The surgical antibiotic prophylaxis of all surgeries was evaluated for 1 month before and 1 month after the implementation of the protocol. RESULTS: The appropriateness of the indication for prophylaxis rose from 56.4% to 100% and that of the postoperative maintenance prophylactic antibiotics rose from 21.9% to 95.7%. The cost of the perioperative antibiotic prophylaxis per surgery decreased 40.5%. CONCLUSION: The implementation of a cost-effective perioperative antibiotic prophylaxis protocol was the result of a multidisciplinary effort. The hospital pharmacist participated in education activities as part of the discussion groups on the perioperative antibiotic prophylaxis protocol that involved all participants and in managerial actions that optimized the process of ordering, dispensing, administering, and documenting the perioperative antibiotic prophylaxis.

Infecçäo pelo vírus da Hepatite C entre parturientes: soroprevalência, análise dos fatores de risco, infecctividade e transmissäo vertical / Hepatitis C virus infection in parturients: seroprevalence, analysis of risk factors, infectivity and vertical transmission

O estudo realizado no Hospital Universitário da Pontifícia Universidade Católica de Campinas entre janeiro de 1994 e julho de 1998 constou de duas partes: a primeira, sobre a soroprevalência do VHC entre parturientes, os fatores de risco envolvidos e o potencial de infectividade entre as mulheres com anti-VHC-EIA positivo,e a segunda, sobre a transmissäo vertical do VHC. Na investigaçäo da prevalência dessa infecçäo, participaram 6995 mulheres que tiveram o sangue coletado na sal de parto e que responderam a uma entrevista padräo, realizada durante a internaçäo, objetivando a pesquisa de antecedentes epidemiológicos relativos a microosganismos veiculados pelas vias sanguíneas e (ou) sexual. Utilizaram-se análises de associaçäo e modelos de regressäo múltipla na relaçäo da positividade do RIBA e da presença do RNA-VHC com as variáveis epidemiológicas.