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BACKGROUND: Remdesivir improves clinical outcomes in patients hospitalized with moderate-to-severe coronavirus disease 2019 (Covid-19). Whether the use of remdesivir in symptomatic, nonhospitalized patients with Covid-19 who are at high risk for disease progression prevents hospitalization is uncertain. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving nonhospitalized patients with Covid-19 who had symptom onset within the previous 7 days and who had at least one risk factor for disease progression (age ≥60 years, obesity, or certain coexisting medical conditions). Patients were randomly assigned to receive intravenous remdesivir (200 mg on day 1 and 100 mg on days 2 and 3) or placebo. The primary efficacy end point was a composite of Covid-19-related hospitalization or death from any cause by day 28. The primary safety end point was any adverse event. A secondary end point was a composite of a Covid-19-related medically attended visit or death from any cause by day 28. RESULTS: A total of 562 patients who underwent randomization and received at least one dose of remdesivir or placebo were included in the analyses: 279 patients in the remdesivir group and 283 in the placebo group. The mean age was 50 years, 47.9% of the patients were women, and 41.8% were Hispanic or Latinx. The most common coexisting conditions were diabetes mellitus (61.6%), obesity (55.2%), and hypertension (47.7%). Covid-19-related hospitalization or death from any cause occurred in 2 patients (0.7%) in the remdesivir group and in 15 (5.3%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.03 to 0.59; P = 0.008). A total of 4 of 246 patients (1.6%) in the remdesivir group and 21 of 252 (8.3%) in the placebo group had a Covid-19-related medically attended visit by day 28 (hazard ratio, 0.19; 95% CI, 0.07 to 0.56). No patients had died by day 28. Adverse events occurred in 42.3% of the patients in the remdesivir group and in 46.3% of those in the placebo group. CONCLUSIONS: Among nonhospitalized patients who were at high risk for Covid-19 progression, a 3-day course of remdesivir had an acceptable safety profile and resulted in an 87% lower risk of hospitalization or death than placebo. (Funded by Gilead Sciences; PINETREE ClinicalTrials.gov number, NCT04501952; EudraCT number, 2020-003510-12.).
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Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , Monofosfato de Adenosina/efeitos adversos , Monofosfato de Adenosina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina/efeitos adversos , Alanina/uso terapêutico , Antivirais/efeitos adversos , COVID-19/complicações , COVID-19/mortalidade , Comorbidade , Progressão da Doença , Método Duplo-Cego , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , SARS-CoV-2/efeitos dos fármacos , Tempo para o Tratamento , Carga ViralRESUMO
BACKGROUND: Although antivirals remain important for the treatment COVID-19, methods to assess treatment efficacy are lacking. Here, we investigated the impact of remdesivir on viral dynamics and their contribution to understanding antiviral efficacy in the multicenter ACTT-1 clinical trial that randomized patients to remdesivir or placebo. METHODS: Longitudinal specimens collected during hospitalization from a substudy of 642 COVID-19 patients were measured for viral RNA (upper respiratory tract and plasma), viral nucleocapsid antigen (serum), and host immunologic markers. Associations with clinical outcomes and response to therapy were assessed. RESULTS: Higher baseline plasma viral loads were associated with poorer clinical outcomes, and decreases in viral RNA and antigen in blood but not the upper respiratory tract correlated with enhanced benefit from remdesivir. The treatment effect of remdesivir was most pronounced in patients with elevated baseline nucleocapsid antigen levels: the recovery rate ratio was 1.95 (95%CI 1.40-2.71) for levels >245â pg/ml vs 1.04 (95%CI 0.76-1.42) for levels < 245â pg/ml. Remdesivir also accelerated the rate of viral RNA and antigen clearance in blood, and patients whose blood levels decreased were more likely to recover and survive. CONCLUSIONS: Reductions in SARS-CoV-2 RNA and antigen levels in blood correlated with clinical benefit from antiviral therapy.
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Background & objectives: In the current health system, cash incentives are given to accredited social health activists for referring women to public health facilities for specific maternal and child health services, however many reproductive health problems are not included in these services. The objective of this study was to assess the impact of involvement of self-help groups (SHGs) in improving reproductive health seeking behaviour and service utilization by tribal women. Methods: An experimental study was conducted in two tribal blocks of Nasik district (Kalvan and Surgana) in Maharashtra, India, over a period of 18 months. Interventions included training of SHG women and providing incentives to them for conducting health education sessions for reproductive age group women in the community and referring those with the requisite problems, to the health facilities. Pre- and post-intervention focus group discussions and in-depth interviews among SHG women were conducted. Training of service providers on diagnosis and treatment of reproductive morbidities was done, and health service utilization was assessed. Results: Sixty five per cent of the referred women with reproductive morbidities availed services at the public health facilities. A review of records of women seeking services for reproductive health problems showed that there was a significant improvement in the intent for seeking services in the study block as compared to the control block (χ[2]-9.06, P<0.002). Interpretation & conclusions: This study demonstrates the feasibility of utilizing the potential of SHGs for improving reproductive health seeking behaviour of the tribal women. The results suggest that this model could be scaled up to address the neglected reproductive health needs of women without burdening the existing human resources.
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Comportamentos Relacionados com a Saúde , Saúde Reprodutiva , Criança , Feminino , Humanos , Índia/epidemiologia , Índia/etnologia , Grupos de AutoajudaRESUMO
The urgent response to the COVID-19 pandemic required accelerated evaluation of many approved drugs as potential antiviral agents against the causative pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Using cell-based, biochemical, and modeling approaches, we studied the approved HIV-1 nucleoside/tide reverse transcriptase inhibitors (NRTIs) tenofovir (TFV) and emtricitabine (FTC), as well as prodrugs tenofovir alafenamide (TAF) and tenofovir disoproxilfumarate (TDF) for their antiviral effect against SARS-CoV-2. A comprehensive set of in vitro data indicates that TFV, TAF, TDF, and FTC are inactive against SARS-CoV-2. None of the NRTIs showed antiviral activity in SARS-CoV-2 infected A549-hACE2 cells or in primary normal human lung bronchial epithelial (NHBE) cells at concentrations up to 50 µM TAF, TDF, FTC, or 500 µM TFV. These results are corroborated by the low incorporation efficiency of respective NTP analogs by the SARS-CoV-2 RNA-dependent-RNA polymerase (RdRp), and lack of the RdRp inhibition. Structural modeling further demonstrated poor fitting of these NRTI active metabolites at the SARS-CoV-2 RdRp active site. Our data indicate that the HIV-1 NRTIs are unlikely direct-antivirals against SARS-CoV-2, and clinicians and researchers should exercise caution when exploring ideas of using these and other NRTIs to treat or prevent COVID-19.
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Fármacos Anti-HIV , Tratamento Farmacológico da COVID-19 , Infecções por HIV , HIV-1 , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Emtricitabina/farmacologia , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Humanos , Nucleosídeos/farmacologia , Nucleosídeos/uso terapêutico , Nucleotídeos/farmacologia , Pandemias , RNA Viral , RNA Polimerase Dependente de RNA , SARS-CoV-2 , Tenofovir/farmacologia , Tenofovir/uso terapêuticoRESUMO
BACKGROUND: Remdesivir (RDV) is an intravenous antiviral with activity against SARS-CoV-2 for treatment of hospitalized COVID-19 patients with moderate-to-severe disease. Biomarkers associated with clinical outcomes have been identified for COVID-19, but few evaluated in context of antiviral treatment. Here, we assessed baseline (day 1, prior to first RDV dose) biomarkers and the impact of RDV treatment on longitudinal biomarker readouts. METHODS: Recently, RDV was evaluated in high-risk, non-hospitalized patients with confirmed SARS-CoV-2 infection and was highly effective at preventing disease progression. The randomized, double-blind, placebo-controlled Phase 3 study included 562 participants who received at least 1 dose of study drug, of which 312 consented for longitudinal biomarker assessments at baseline, day 3, and day 14. We assessed sixteen baseline biomarkers and the impact of RDV treatment on longitudinal biomarker readouts. RESULTS: Six well-known, inflammation-associated biomarkers are elevated at baseline in participants meeting the primary endpoint of hospitalization or death by day 28. Moreover, in comparison to placebo, biomarkers in RDV-treated participants show accelerated improvement, including reduction of soluble angiopoietin-2, D-dimer, and neutrophil-to-lymphocyte ratio, as well as an increase in lymphocyte counts. CONCLUSIONS: Overall, the findings in this study suggest that RDV treatment may accelerate the improvement of multiple biomarkers of COVID-19 severity, which are associated with better clinical outcomes during infection. These findings have implications for better understanding the activity of antiviral treatments in COVID-19.
Certain cells and proteins in the blood can act as markers of COVID-19 severity. However, little is known about the impact of antiviral treatments on these markers. Here, we measured protein and cell markers in patient samples before treatment and those taken during the course of COVID-19 in high-risk non-hospitalized patients treated with or without the antiviral remdesivir (RDV). Several markers were improved with RDV treatment, including those associated with normal responses from the immune system and factors involved in blood clotting. These findings further our understanding of the activity of antivirals in COVID-19 and inform future studies to understand how patients with an increased risk of COVID-19 disease progression respond to these treatments.
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Observational studies have identified the potential prognostic value for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) viral load and anti-SARS-CoV-2 antibodies in coronavirus disease 2019 (COVID-19). However, viral load in nasopharyngeal (NP) swabs produced inconsistent results in prognostic analyses, and the prognostic value of viral load or antibodies has not been confirmed in large clinical trials. COVACTA and REMDACTA were double-blind, randomized, controlled trials with a combined enrollment of 1078 patients hospitalized with COVID-19 treated with tocilizumab or placebo in COVACTA or tocilizumab plus remdesivir or placebo plus remdesivir in REMDACTA. We assessed the potential prognostic value of NP and serum SARS-CoV-2 viral load and serum anti-SARS-CoV-2 antibodies at baseline as biomarkers for clinical outcomes in patients enrolled in these trials. In adjusted Cox proportional hazard models, serum viral load was a more reliable predictor of clinical outcomes than NP viral load; high serum viral load was associated with higher risk for death and mechanical ventilation/death and lower likelihood of hospital discharge (high vs. negative viral load hazard ratios [95% confidence interval {CI}] were 2.87 [1.57-5.25], 3.86 [2.23-6.68], and 0.23 [0.14-0.36], respectively, in COVACTA and 8.11 [2.95-22.26], 10.29 [4.5-23.55], and 0.21 [0.15-0.29], respectively, in REMDACTA) and high serum viral load correlated with levels of inflammatory cytokines and lung damage biomarkers. High anti-SARS-CoV-2 spike protein antibody (ACOV2S) levels were associated with higher likelihood of hospital discharge (high vs. below the limit of quantification hazard ratios [95% CI] were 2.55 [1.59-4.08] for COVACTA and 1.54 [1.13-2.09] for REMDACTA). These results support the role of baseline SARS-CoV-2 serum viral load and ACOV2S antibody titers in predicting clinical outcomes for patients hospitalized with COVID-19.
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COVID-19 , Humanos , SARS-CoV-2 , Prognóstico , Carga Viral , Pulmão , Anticorpos AntiviraisRESUMO
Intravenous remdesivir (RDV) is US Food and Drug Administration-approved for hospitalized and nonhospitalized individuals with coronavirus disease 2019. RDV undergoes intracellular metabolic activation to form the active triphosphate, GS-443902, and other metabolites. Alternative administration routes, including localized pulmonary delivery, can lower systemic exposure and maximize exposure at the site of action. This study evaluated the pharmacokinetics (PK) and safety of inhaled RDV in healthy adults. This phase Ia, randomized, placebo-controlled study evaluated inhaled RDV in healthy participants randomized 4:1 to receive RDV or placebo as single doses (4 cohorts) or multiple once-daily doses (3 cohorts). Doses in cohorts 1-6 were administered as an aerosolized solution for inhalation through a sealed facemask; doses in cohort 7 were administered as an aerosolized solution for inhalation through a mouthpiece. Safety was assessed throughout the study. Seventy-two participants were enrolled (inhaled RDV, n = 58 and placebo, n = 14). Following single RDV doses, RDV, GS-704277, and GS-441524 plasma PK parameters indicated dose-proportional increases in area under the concentration-time curve (AUC) extrapolated to infinite time, AUC from time zero to last quantifiable concentration, and maximum observed concentration. Analyte plasma concentrations after multiple RDV doses were consistent with those for single-dose RDV. Analyte plasma exposures were lower when RDV was administered with a mouthpiece versus a sealed facemask. The most common adverse events included nausea, dizziness, and cough. Single- and multiple-dose inhaled RDV exhibited linear and dose-proportional plasma PK. Administration of RDV via inhalation was generally safe and well-tolerated.
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Alanina , Adulto , Humanos , Voluntários Saudáveis , Monofosfato de Adenosina/efeitos adversos , Alanina/efeitos adversos , Método Duplo-Cego , Relação Dose-Resposta a DrogaRESUMO
INTRODUCTION: In the PINETREE study, early remdesivir treatment reduced risk of coronavirus disease 2019 (COVID-19)-related hospitalizations or all-cause death versus placebo by 87% by day 28 in high-risk, non-hospitalized patients. Here we report results of assessment of heterogeneity of treatment effect (HTE) of early outpatient remdesivir, focusing on time from symptom onset and number of baseline risk factors (RFs). METHODS: PINETREE was a double-blind, placebo-controlled trial of non-hospitalized patients with COVID-19 who were randomized within 7 days of symptom onset and had ≥ 1 RF for disease progression (age ≥ 60 years, obesity [body mass index ≥ 30], or certain coexisting medical conditions). Patients received remdesivir intravenously (200 mg on day 1 and 100 mg on days 2 and 3) or placebo. RESULTS: In this subgroup analysis, HTE of remdesivir by time from symptom onset at treatment initiation and number of baseline RFs was not detected. Treatment with remdesivir reduced COVID-19-related hospitalizations independent of stratification by time from symptom onset to randomization. Of patients enrolled ≤ 5 days from symptom onset, 1/201 (0.5%) receiving remdesivir and 9/194 (4.6%) receiving placebo were hospitalized (hazard ratio [HR] 0.10; 95% confidence interval [CI] 0.01-0.82). Of those enrolled at > 5 days from symptom onset, 1/78 (1.3%) receiving remdesivir and 6/89 (6.7%) receiving placebo were hospitalized (HR 0.19; 95% CI 0.02-1.61). Remdesivir was also effective in reducing COVID-19-related hospitalizations when stratified by number of baseline RFs for severe disease. Of patients with ≤ 2 RFs, 0/159 (0.0%) receiving remdesivir and 4/164 (2.4%) receiving placebo were hospitalized; of those with ≥ 3 RFs, 2/120 (1.7%) receiving remdesivir and 11/119 (9.2%) receiving placebo were hospitalized (HR 0.16; 95% CI 0.04-0.73). CONCLUSIONS: In the outpatient setting, benefit of remdesivir initiated within 7 days of symptoms appeared to be consistent across patients with RFs. Therefore, it may be reasonable to broadly treat patients with remdesivir regardless of comorbidities. TRIAL REGISTRATION: ClinicalTrials.gov number NCT04501952.
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OBJECTIVE: Type 1 diabetes (T1DM) is associated with other autoimmune diseases (AIDs), which may have serious health consequences. The epidemiology of AIDs in T1DM is not well defined in adults with T1DM. In this cross-sectional cohort study, we sought to characterize the incident ages and prevalence of AIDs in adults with T1DM across a wide age spectrum. RESEARCH DESIGN AND METHODS: A total of 1,212 adults seen at the Washington University Diabetes Center from 2011 to 2018 provided informed consent for the collection of their age, sex, race, and disease onset data. We performed paired association analyses based on age at onset of T1DM. Multivariate logistic regression was used to evaluate the independent effects of sex, race, T1DM age of onset, and T1DM duration on the prevalence of an additional AID. RESULTS: Mean ± SD age of T1DM onset was 21.2 ± 14.4 years. AID incidence and prevalence increased with age. Female sex strongly predicted AID risk. The most prevalent T1DM-associated AIDs were thyroid disease, collagen vascular diseases, and pernicious anemia. T1DM age of onset and T1DM duration predicted AID risk. Patients with late-onset T1DM after 30 years of age had higher risks of developing additional AIDs compared with patients with younger T1DM onset. CONCLUSIONS: The prevalence of AIDs in patients with T1DM increases with age and female sex. Later onset of T1DM is an independent and significant risk factor for developing additional AIDs. Individuals who are diagnosed with T1DM at older ages, particularly women, should be monitored for other autoimmune conditions.
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Doenças Autoimunes/epidemiologia , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/etiologia , Criança , Pré-Escolar , Estudos de Coortes , Estudos Transversais , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Etnicidade , Feminino , Seguimentos , Humanos , Incidência , Lactente , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: A subgroup of patients with adrenal cortisol hypersecretion fails to meet the biochemical criteria for Cushing's syndrome. Appropriate therapy for this entity, subclinical Cushing's syndrome (subclinical CS), is unclear. We examined outcomes for patients who underwent unilateral adrenalectomy for subclinical CS. METHODS: Between 2003 and 2006, all patients who underwent adrenalectomy for cortisol hypersecretion caused by an adrenal mass were examined. We analyzed biochemical, metabolic, and clinical outcomes. RESULTS: Overall, 24 patients underwent adrenalectomy for adrenal cortisol hypersecretion, of which 9 were found to have subclinical CS. Median serum cortisol was 2.0 microg/dL (range, 1.1-6.1) after 1-mg overnight dexamethasone suppression testing. Suspicious clinical findings on preoperative examination included skin bruising, unexplained weight gain, proximal muscle weakness, abnormal fat pads, skin thinning, fatigue, and facial plethora. During a median follow-up period of 5 months (range, 1-30 months), all 8 patients with easy bruising noted resolution postoperatively. Fatigue improved in 4 of 5 patients, muscle weakness in 6 of 8 patients, and weight in 7 of 9 patients, with a median body mass index change of -2.0 kg/m(2) (range, -7.1 to +0.5 kg/m(2)). CONCLUSION: Adrenalectomy improves clinical and metabolic parameters for many patients with subclinical CS.