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Enpatoran is a selective inhibitor of toll-like receptors 7 and 8 (TLR7/8) that potentially targets pro-inflammatory pathways induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A phase II study conducted in Brazil, the Philippines, and the USA during the early pandemic phase assessed the safety and efficacy of enpatoran in patients hospitalized with COVID-19 pneumonia (NCT04448756). A total of 149 patients, who scored 4 on the World Health Organization's (WHO) 9-point ordinal severity scale, were randomized 1:1:1 and received enpatoran 50 mg (n = 54) or 100 mg (n = 46), or placebo (n = 49) twice daily (b.i.d.) for 14 days plus standard of care. The primary objectives were safety and time to recovery (WHO 9-point scale ≤3). Clinical deterioration (WHO 9-point scale ≥ 5) was a key secondary objective. Treatment-emergent adverse events (TEAEs) were comparable across groups (56.5%-63.0%). Treatment-related TEAEs were numerically higher with enpatoran 50 mg (14.8%) than 100 mg (10.9%) or placebo (8.2%). Serious TEAEs were numerically lower with enpatoran (50 mg 9.3%, 100 mg 2.2%) than placebo (18.4%). The primary efficacy objective was not met; median time to recovery was 3.4-3.9 days across groups, with placebo-treated patients recovering on average faster than anticipated. Clinical deterioration event-free rates up to Day 7 were 90.6%, 95.6%, and 81.6% with enpatoran 50 mg, 100 mg, and placebo, respectively. Enpatoran was well tolerated by patients acutely ill and hospitalized with COVID-19 pneumonia. Positive signals in some secondary end points suggested potential beneficial effects, supporting further evaluation of enpatoran in patients with hyperinflammation due to infection or autoimmunity.
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COVID-19 , Deterioro Clínico , Humanos , SARS-CoV-2 , Inmunosupresores , Pandemias , Resultado del TratamientoRESUMEN
OBJECTIVE: We studied the safety and efficacy of hydroxychloroquine (HCQ) as pre-exposure prophylaxis for COVID-19 in healthcare workers (HCWs), using a meta-analysis of randomised controlled trials (RCTs). DATA SOURCES: PubMed and EMBASE databases were searched to identify randomised trials studying HCQ. STUDY SELECTION: Ten RCTs were identified (n=5079 participants). DATA EXTRACTION AND SYNTHESIS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used in this systematic review and meta-analysis between HCQ and placebo using a Bayesian random-effects model. A pre-hoc statistical analysis plan was written. MAIN OUTCOMES: The primary efficacy outcome was PCR-confirmed SARS-CoV-2 infection and the primary safety outcome was incidence of adverse events. The secondary outcome included clinically suspected SARS-CoV-2 infection. RESULTS: Compared with placebo, HCWs randomised to HCQ had no significant difference in PCR-confirmed SARS-CoV-2 infection (OR 0.92, 95% credible interval (CI): 0.58, 1.37) or clinically suspected SARS-CoV-2 infection (OR 0.78, 95% CI: 0.57, 1.10), but significant difference in adverse events (OR 1.35, 95% CI: 1.03, 1.73). CONCLUSIONS AND RELEVANCE: Our meta-analysis of 10 RCTs investigating the safety and efficacy of HCQ as pre-exposure prophylaxis in HCWs found that compared with placebo, HCQ does not significantly reduce the risk of confirmed or clinically suspected SARS-CoV-2 infection, while HCQ significantly increases adverse events. PROSPERO REGISTRATION NUMBER: CRD42021285093.
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COVID-19 , Humanos , COVID-19/prevención & control , Tratamiento Farmacológico de COVID-19 , Personal de Salud , Hidroxicloroquina/efectos adversos , Hidroxicloroquina/farmacología , SARS-CoV-2 , Profilaxis Pre-ExposiciónRESUMEN
BACKGROUND: . Up to 20% of people with HIV (PWH) who undergo virologically suppressed antiretroviral therapy (ART) fail to experience complete immune restoration. We recently reported that plasma anti-CD4 IgG (antiCD4IgG) autoantibodies from immune non-responders specifically deplete CD4 + T cells via antibody-dependent cytotoxicity. However, the mechanism of antiCD4IgG production remains unclear. METHODS: . Blood samples were collected from 16 healthy individuals and 25 PWH on suppressive ART. IgG subclass, plasma lipopolysaccharide (LPS), and antiCD4IgG levels were measured by ELISA. Gene profiles in B cells were analyzed by microarray and quantitative PCR. Furthermore, a patient-derived antiCD4IgG-producing B cell line was generated and stimulated with LPS in vitro. B cell IgG class switch recombination (CSR) was evaluated in response to LPS in splenic B cells from C57/B6 mice in vitro. RESULTS: . Increased plasma anti-CD4 IgGs in PWH were predominantly IgG1 and associated with increased plasma LPS levels as well as B cell expression of TLR2, TLR4, and MyD88 mRNA in vivo. Furthermore, LPS stimulation induced antiCD4IgG production in the antiCD4IgG B cell line in vitro. Finally, LPS promoted CSR in vitro. CONCLUSION: . Our findings suggest that persistent LPS translocation may promote anti-CD4 autoreactive B cell activation and antiCD4IgG production in PWH on ART, which may contribute to gradual CD4 + T cell depletion. This study suggests that reversing a compromised mucosal barrier could improve ART outcomes in PWH who fail to experience complete immune restoration.
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BACKGROUND: Health care workers (HCW) are among the highest risk groups for acquisition of COVID-19 because of occupational exposures. The WHIP COVID-19 Study aimed to evaluate the safety and efficacy of hydroxychloroquine (HCQ) as chemoprophylaxis for SARS-CoV-2 infection in this population. METHODS: HCW, first responders, and other occupationally high-risk participants were enrolled in a randomized, placebo-controlled clinical study of HCQ from April to October 2020. The trial compared daily versus weekly HCQ with placebo and with a prospective cohort on HCQ for autoimmune diseases. Participants were followed for 8 weeks. Serology or a positive polymerase chain reaction test was used to determine laboratory confirmed clinical cases. RESULTS: A total of 624 participants were randomized to placebo (nâ¯=â¯200), weekly HCQ (nâ¯=â¯201), daily HCQ (nâ¯=â¯197). For the primary safety end point, 279 (44.7%) participants experienced adverse event (AE) level II or lower (total AEs nâ¯=â¯589), similar rates in all randomized groups (Pâ¯=â¯.188) with no hospitalizations or interventions required. Only 4 laboratory confirmed COVID-19 cases occurred, with 2 in the placebo arm and one in each HCQ randomized arm. CONCLUSIONS: This randomized placebo-controlled trial was able to demonstrate the safety of HCQ outpatient chemoprophylaxis in high-risk groups against COVID-19. Future studies of chemoprophylaxis for SARS-CoV-2 are needed as the epidemic continues worldwide.
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Tratamiento Farmacológico de COVID-19 , COVID-19 , Socorristas , COVID-19/prevención & control , Personal de Salud , Humanos , Hidroxicloroquina/efectos adversos , Estudios Prospectivos , SARS-CoV-2 , Resultado del TratamientoRESUMEN
Daily adherence to lifelong antiretroviral therapy (ART) is required to achieve long term treatment success. However, patient preferences for ART tablet size have not been well studied. Our study assessed factors associated with the ease of swallowing (EoS) and tolerability of two placebo tablets representing and matching B/F/TAF (BPT) and DTG/ABC/3TC (DPT). Fifty ART-naïve patients were randomized into a two-period cross-over study. Likert scale (1-5) questionnaires were administered to assess patient factors influencing the ease of swallowing, adherence, home medications, medication preferences and perceptions. Comparisons were done using Student t-tests and ordinal regression. Participants were 64% female, 61% white, mean age 43 years, and taking a mean (median) of 4(1) pills/day. BPT was reported to be easier than DPT with ease of swallowability 1.76 vs. 2.42 (p < 0.001) (1 = very easy). DPT tablet was correctly perceived as larger than BPT (p < 0.001); with both tablets perceived as smaller than actual size (p < 0.001). EoS of either tablet was positively associated with the EoS of the largest home tablet medication (p = 0.021, p = 0.03). Patient's perceptions of EoS can affect their medication adherence, especially in HIV, and should be considered in treatment regimens.
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Fármacos Anti-VIH , Infecciones por VIH , Adulto , Fármacos Anti-VIH/uso terapéutico , Estudios Cruzados , Deglución , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Cumplimiento de la Medicación , Comprimidos/uso terapéuticoRESUMEN
CONTEXT: Tocilizumab (TCZ), an interleukin-6 (IL-6) receptor antagonist, has been approved for use in rheumatoid arthritis and cytokine storm syndrome (CSS) associated with chimeric antigen receptor T cells treatment. Although TCZ is currently utilized in the treatment of critically ill coronavirus 2019 (COVID-19) patients, data on survival impact is minimal. OBJECTIVES: To assess the mortality rate of patients presenting with COVID-19 who received TCZ for suspected CSS. METHODS: This retrospective cohort study was conducted at Henry Ford Health System between March 10, 2020 and May 18, 2020. Data collection began in May 2020 and was completed in June 2020. Patients included in the study required hospital admission and had positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction on nasopharyngeal swab. Eligibility criteria to receive TCZ, per hospital protocol, included any of the following: persistent fever, defined as 38.0 °C for at least 6 hours; a diagnosis of the acute respiratory distress syndrome (ARDS); serum ferritin ≥1,000 (ng/mL) or doubling within 24 hours; D-Dimer ≥ 5 (mg/L); serum lactate dehydrogenase ≥500 (IU/L); or interlukin-6 level ≥5 times the upper limit of normal. Dosing was initially determined by weight, then changed to a fixed 400 mg per hospital protocol. A comparator cohort was created from patients with COVID-19 and ARDS who did not receive TCZ. Patient survival was analyzed using the Kaplan-Meier method and compared by log rank test. A multivariable cox regression was applied to evaluate the association between TCZ and mortality. RESULTS: One hundred and thirty patients were evaluated in the study, 54 (41.5%) of whom received TCZ. Patients who received TCZ were younger (mean age, 63.8 vs. 69.4 years; p=0.0083) and had higher body mass indices (mean, 33.9 vs. 30.4; p=0.005). Of the comorbid conditions evaluated, heart disease was more common in the comparator group than the TCZ group (27 patients [35.5%] vs. 10 patients [18.5%]; p=0.034). A Kaplan-Meier survival curve demonstrated no difference in survival between TCZ and comparator patients (log rank p=0.495). In the multivariable Cox regression model for mortality at 30 days, treatment with TCZ was not associated with decreased mortality (hazard ratio, 1.1; 95% confidence interval, 0.53-2.3; p=0.77). Lower mean C-reactive protein (CRP) levels were demonstrated within 48 hours of disposition in the TCZ group (mean TCZ, 4.9 vs. mean comparator, 13.0; p=<0.0001). CONCLUSIONS: In this cohort study, no difference in survival was observed in critically ill patients treated with TCZ.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Anciano , COVID-19/mortalidad , Enfermedad Crítica , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
OBJECTIVE: Subclinical cytomegalovirus (CMV) viremia has been associated with other infections, prolonged hospitalization, and mortality in select immunosuppressed populations. We examined the incidence and outcomes of subclinical CMV viremia in hospitalized patients with systemic autoimmune diseases (AD) [systemic lupus erythematosus (SLE) or anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV)] using a highly sensitive CMV assay. METHODS: Prospectively collected samples were obtained from AD hospitalized patients at study entry with a second sample collected 1 week later or at hospital discharge. Controls included age- and gender- matched inpatients without AD and outpatients with AD. All samples were tested in batch using the Abbott RealTime CMV for investigational use assay (RT assay), with a LLOD (LLOQ) at 21 IU/mL (32 IU/mL). RESULTS: Twenty-three inpatients (10 SLE, 8 AAV, 5 controls), and 31 outpatient controls were recruited. Subclinical CMV viremia was found in 61% (11/18) of inpatient AD subjects, 3% (1/31) of outpatient AD subjects, and in none of the five inpatient controls (p < 0.001). CMV viremia was associated with increased median length of ICU stay (13 vs. 4 days, p = 0.033), hospital stay (17 vs. 9 days, p = 0.014) and increased nosocomial infections (7 vs. 1, p = 0.007). CMV viremia was not associated with overall severity of illness nor with disease-specific activity or damage. CONCLUSION: Over one-half of hospitalized AD patients in our cohort had detectable CMV viremia, which was associated with increased length of hospital stay and nosocomial infections. These data suggest that further study of the immunomodulatory effects of subclinical CMV viremia in AD is warranted.
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Infección Hospitalaria , Infecciones por Citomegalovirus , Lupus Eritematoso Sistémico , Infección Hospitalaria/epidemiología , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/epidemiología , Humanos , Tiempo de Internación , Viremia/epidemiologíaRESUMEN
OBJECTIVE: Examine the effect of a universal facemask policy for healthcare workers (HCW) and incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positivity. METHODS: Daily number of symptomatic HCW tested, SARS-CoV-2 positivity rates, and HCW job-descriptions were collected pre and post Universal HCW facemask policy (March 26, 2020). Multiple change point regression was used to model positive-test-rate data. SARS-CoV-2 testing and positivity rates were compared for pre-intervention, transition, post-intervention, and follow-up periods. RESULTS: Between March 12 and August 10, 2020, 19.2% of HCW were symptomatic for COVID-19 and underwent SARS-CoV-2 testing. A single change point was identified â¼March 28-30 (95% probability). Before the change point, the odds of a tested HCW having a positive result doubled every 4.5 to 7.5âdays. Post-change-point, the odds of a tested HCW having a positive result halved every 10.5 to 13.5âdays. CONCLUSIONS: Universal facemasks were associated with reducing HCW's risk of acquiring COVID-19.
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COVID-19/epidemiología , Personal de Salud/estadística & datos numéricos , Política de Salud/legislación & jurisprudencia , Máscaras , SARS-CoV-2/aislamiento & purificación , COVID-19/diagnóstico , COVID-19/prevención & control , Prueba de COVID-19 , Atención a la Salud , Personal de Salud/clasificación , Humanos , Michigan/epidemiologíaRESUMEN
INTRODUCTION: Hydroxychloroquine has been used for rheumatological diseases for many decades and is considered a safe medication. With the COVID-19 outbreak, there has been an increase in reports associating cardiotoxicity with hydroxychloroquine. It is unclear if the cardiotoxic profile of hydroxychloroquine is previously underreported in the literature or is it a manifestation of COVID-19 and therapeutic interventions. This manuscript evaluates the incidence of cardiotoxicity associated with hydroxychloroquine prior to the onset of COVID-19. METHODS: PubMED, EMBASE, and Cochrane databases were searched for keywords derived from MeSH terms prior to April 9, 2020. Inclusion eligibility was based on appropriate reporting of cardiac conditions and study design. RESULTS: A total of 69 articles were identified (58 case reports, 11 case series). The majority (84%) of patients were female, with a median age of 49.2 (range 16-92) years. 15 of 185 patients with cardiotoxic events were in the setting of acute intentional overdose. In acute overdose, the median ingestion was 17,857 ± 14,873 mg. 2 of 15 patients died after acute intoxication. In patients with long-term hydroxychloroquine use (10.5 ± 8.9 years), new onset systolic heart failure occurred in 54 of 155 patients (35%) with median cumulative ingestion of 1,493,800 ± 995,517 mg. The majority of patients improved with the withdrawal of hydroxychloroquine and standard therapy. CONCLUSION: Millions of hydroxychloroquine doses are prescribed annually. Prior to the COVID-19 pandemic, cardiac complications attributed to hydroxychloroquine were uncommon. Further studies are needed to understand the impact of COVID-19 on the cardiovascular system to understand the presence or absence of potential medication interactions with hydroxychloroquine in this new pathophysiological state.
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Cardiotoxinas/efectos adversos , Cardiopatías , Hidroxicloroquina/efectos adversos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , COVID-19 , Femenino , Cardiopatías/inducido químicamente , Cardiopatías/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Approximately 9 months of the severe acute respiratory syndrome coronavius-2 (SARS-CoV-2 [COVID-19]) spreading across the globe has led to widespread COVID-19 acute hospitalizations and death. The rapidity and highly communicable nature of the SARS-CoV-2 outbreak has hampered the design and execution of definitive randomized, controlled trials of therapy outside of the clinic or hospital. In the absence of clinical trial results, physicians must use what has been learned about the pathophysiology of SARS-CoV-2 infection in determining early outpatient treatment of the illness with the aim of preventing hospitalization or death. This article outlines key pathophysiological principles that relate to the patient with early infection treated at home. Therapeutic approaches based on these principles include 1) reduction of reinoculation, 2) combination antiviral therapy, 3) immunomodulation, 4) antiplatelet/antithrombotic therapy, and 5) administration of oxygen, monitoring, and telemedicine. Future randomized trials testing the principles and agents discussed will undoubtedly refine and clarify their individual roles; however, we emphasize the immediate need for management guidance in the setting of widespread hospital resource consumption, morbidity, and mortality.
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Atención Ambulatoria , COVID-19/terapia , SARS-CoV-2 , Anticoagulantes/uso terapéutico , COVID-19/fisiopatología , Humanos , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/uso terapéutico , Oxígeno/uso terapéuticoRESUMEN
The surge of coronavirus disease 2019 (COVID-19) hospitalizations at our 877-bed quaternary care hospital in Detroit led to an emergent demand for Infectious Diseases (ID) consultations. The traditional 1-on-1 consultation model was untenable. Therefore, we rapidly restructured our ID division to provide effective consultative services. We implemented a novel unit-based group rounds model that focused on delivering key updates to teams and providing unit-wide consultations simultaneously to all team members. Effectiveness of the program was studied using Likert-scale survey data. The survey captured data from the first month of the Detroit COVID-19 pandemic. During this period there were approximately 950 patients hospitalized for treatment of COVID-19. The survey of trainees and faculty reported an overall 95% positive response to delivery of information, new knowledge acquisition, and provider confidence in the care of COVID-19 patients. This showed that the unit-based consult model is a sustainable effort to provide care during epidemics.
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COVID-19 , Enfermedades Transmisibles , Humanos , Pandemias , Derivación y Consulta , SARS-CoV-2RESUMEN
BACKGROUND: COVID-19 disease has spread globally and was declared a pandemic on March 11, 2020, by the World Health Organization. On March 10, the State of Michigan confirmed its first 2 cases of COVID-19, and the number of confirmed cases has reached 47,182 as of May 11, 2020, with 4555 deaths. SETTING: Currently, little is known if patients living with HIV (PLWH) are at a higher risk of severe COVID-19 or if their antiretrovirals are protective. This study presents epidemiologic and clinical features of COVID-19 infected PLWH in Detroit, Michigan. METHODS: This is a case series that included 14 PLWH with laboratory-confirmed COVID-19 infection who were evaluated at Henry Ford Hospital in Detroit, Michigan, between March 20, 2020, and April 30, 2020. RESULTS: Fourteen PLWH were diagnosed with COVID-19. Twelve patients were men and 2 were women; 13 patients were virally suppressed. Eight patients were hospitalized, and 6 patients were told to self-quarantine at home after their diagnoses. Three patients who were admitted expired during their hospital stay. No patient required bilevel positive airway pressure or nebulizer use in the emergency department, and none developed acute respiratory distress syndrome, pulmonary embolism, deep venous thrombosis, or a cytokine storm while on therapy for COVID-19. CONCLUSION: Although the clinical spectrum of COVID-19 among PLWH cannot be fully ascertained by this report, it adds to the data that suggest that HIV-positive patients with SARS-CoV-2 infection are not at a greater risk of severe disease or death as compared to HIV-negative patients.
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Infecciones por Coronavirus/complicaciones , Infecciones por VIH/complicaciones , Neumonía Viral/complicaciones , Negro o Afroamericano , COVID-19 , Comorbilidad , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/etnología , Femenino , Infecciones por VIH/epidemiología , Infecciones por VIH/etnología , Hispánicos o Latinos , Humanos , Masculino , Pandemias , Neumonía Viral/epidemiología , Neumonía Viral/etnologíaRESUMEN
SIGNIFICANCE: The United States is in an acceleration phase of the COVID-19 pandemic. Currently there is no known effective therapy or vaccine for treatment of SARS-CoV-2, highlighting urgency around identifying effective therapies. OBJECTIVE: The purpose of this study was to evaluate the role of hydroxychloroquine therapy alone and in combination with azithromycin in hospitalized patients positive for COVID-19. DESIGN: Multi-center retrospective observational study. SETTING: The Henry Ford Health System (HFHS) in Southeast Michigan: large six hospital integrated health system; the largest of hospitals is an 802-bed quaternary academic teaching hospital in urban Detroit, Michigan. PARTICIPANTS: Consecutive patients hospitalized with a COVID-related admission in the health system from March 10, 2020 to May 2, 2020 were included. Only the first admission was included for patients with multiple admissions. All patients evaluated were 18 years of age and older and were treated as inpatients for at least 48h unless expired within 24h. EXPOSURE: Receipt of hydroxychloroquine alone, hydroxychloroquine in combination with azithromycin, azithromycin alone, or neither. MAIN OUTCOME: The primary outcome was in-hospital mortality. RESULTS: Of 2,541 patients, with a median total hospitalization time of 6 days (IQR: 4-10 days), median age was 64 years (IQR:53-76 years), 51% male, 56% African American, with median time to follow-up of 28.5 days (IQR:3-53). Overall in-hospital mortality was 18.1% (95% CI:16.6%-19.7%); by treatment: hydroxychloroquine+azithromycin, 157/783 (20.1% [95% CI: 17.3%-23.0%]), hydroxychloroquine alone, 162/1202 (13.5% [95% CI: 11.6%-15.5%]), azithromycin alone, 33/147 (22.4% [95% CI: 16.0%-30.1%]), and neither drug, 108/409 (26.4% [95% CI: 22.2%-31.0%]). Primary cause of mortality was respiratory failure (88%); no patient had documented torsades de pointes. From Cox regression modeling, predictors of mortality were age>65 years (HR:2.6 [95% CI:1.9-3.3]), white race (HR:1.7 [95% CI:1.4-2.1]), CKD (HR:1.7 [95%CI:1.4-2.1]), reduced O2 saturation level on admission (HR:1.5 [95%CI:1.1-2.1]), and ventilator use during admission (HR: 2.2 [95%CI:1.4-3.3]). Hydroxychloroquine provided a 66% hazard ratio reduction, and hydroxychloroquine+azithromycin 71% compared to neither treatment (p<0.001). CONCLUSIONS AND RELEVANCE: In this multi-hospital assessment, when controlling for COVID-19 risk factors, treatment with hydroxychloroquine alone and in combination with azithromycin was associated with reduction in COVID-19 associated mortality. Prospective trials are needed to examine this impact.
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Azitromicina/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Mortalidad Hospitalaria , Hidroxicloroquina/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Anciano , Betacoronavirus , COVID-19 , Infecciones por Coronavirus/mortalidad , Quimioterapia Combinada , Femenino , Hospitalización , Humanos , Pacientes Internos , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/mortalidad , Estudios Retrospectivos , Factores de Riesgo , SARS-CoV-2 , Tratamiento Farmacológico de COVID-19RESUMEN
The SARS-CoV-2 virus spreading across the world has led to surges of COVID-19 illness, hospitalizations, and death. The complex and multifaceted pathophysiology of life-threatening COVID-19 illness including viral mediated organ damage, cytokine storm, and thrombosis warrants early interventions to address all components of the devastating illness. In countries where therapeutic nihilism is prevalent, patients endure escalating symptoms and without early treatment can succumb to delayed in-hospital care and death. Prompt early initiation of sequenced multidrug therapy (SMDT) is a widely and currently available solution to stem the tide of hospitalizations and death. A multipronged therapeutic approach includes 1) adjuvant nutraceuticals, 2) combination intracellular anti-infective therapy, 3) inhaled/oral corticosteroids, 4) antiplatelet agents/anticoagulants, 5) supportive care including supplemental oxygen, monitoring, and telemedicine. Randomized trials of individual, novel oral therapies have not delivered tools for physicians to combat the pandemic in practice. No single therapeutic option thus far has been entirely effective and therefore a combination is required at this time. An urgent immediate pivot from single drug to SMDT regimens should be employed as a critical strategy to deal with the large numbers of acute COVID-19 patients with the aim of reducing the intensity and duration of symptoms and avoiding hospitalization and death.
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Tratamiento Farmacológico de COVID-19 , Leprostáticos/uso terapéutico , Pandemias , SARS-CoV-2 , Telemedicina/métodos , COVID-19/epidemiología , Quimioterapia Combinada , HumanosRESUMEN
Peri/post-operative antibiotic prophylaxis (POABP) has become standard practice for preventing surgical site infections (SSI) in head and neck cancer patients undergoing microvascular reconstruction, but few data exist on optimal POABP regimens. Current surgical prophylaxis guideline recommendations fail to account for the complexity of microvascular reconstruction relative to other head and neck procedures, specifically regarding wound classification and antibiotic duration. Selection of POABP spectrum is also controversial, and must balance the choice between too narrow, risking subsequent infection, or too broad, and possible unwanted effects (e.g. antibiotic resistance, Clostridium difficile-associated diarrhea). POABP regimens should retain activity against bacteria expected to colonize the upper respiratory/salivary tracts, which include Gram-positive organisms and facultative anaerobes. However, Gram-negative bacilli also contribute to SSI in this setting. POABP doses should be optimized in order to achieve therapeutic tissue concentrations at the surgical site. Antibiotics targeted towards methicillin-resistant Staphylococcus aureus or Pseudomonas aeruginosa are not warranted for all patients. Prolonged POABP durations have shown no differences in SSI when compared to short POABP durations, but prolonged durations provide unnecessarily antibiotic exposure and risk for adverse effects. Given the lack of standardization behind antibiotic POABP in this setting and the potential for poor patient outcomes, this practice necessitates an additional focus of surgeons and antimicrobial stewardship programs. The purpose of this review is to provide an overview of POABP evidence and discuss pertinent clinical implications of appropriate use.
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Profilaxis Antibiótica , Infecciones Bacterianas/prevención & control , Neoplasias de Cabeza y Cuello/cirugía , Infecciones Bacterianas/complicaciones , Neoplasias de Cabeza y Cuello/complicaciones , Neoplasias de Cabeza y Cuello/microbiología , Humanos , Microbiota , Infección de la Herida Quirúrgica/tratamiento farmacológico , Infección de la Herida Quirúrgica/microbiologíaRESUMEN
Vaccines hold promise both for the prevention of infections and as potential immunologic therapy for patients with autoimmune disease (AD). These patients are at high risk for both common and opportunistic infections, but this risk can be significantly reduced and even obviated with the use of recommended available vaccines. Unfortunately, patients with ADs are not routinely offered or provided indicated vaccinations and have higher rates of complications from vaccine-preventable illnesses than patients without ADs. In addition, vaccine therapy is currently under study for the treatment of autoimmune disorders, with early studies demonstrating immunomodulatory effects that may counter undesired immune activation and alleviate disease activity.
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Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Transmisibles/etiología , Inmunoterapia/métodos , Vacunación/métodos , Enfermedades Autoinmunes/complicaciones , Enfermedades Transmisibles/tratamiento farmacológico , Humanos , Huésped Inmunocomprometido , Vacunación/efectos adversosRESUMEN
BACKGROUND: Combination antiretroviral therapy (ART) suppresses HIV-1 replication, but does not restore CD4 T-cell counts in all individuals. To investigate the effects of maraviroc on HIV-1 persistence and the relations between virologic and immunologic parameters in individuals with incomplete CD4 T-cell recovery, we performed a prospective, open-label pilot trial in which maraviroc was added to a suppressive ART regimen for 24 weeks. DESIGN: A5256 was a single-arm trial in which individuals on suppressive ART with incomplete CD4 T-cell recovery added maraviroc for 24 weeks. METHODS: We quantified low-level, residual viremia in plasma and total HIV-1 DNA and 2-long terminal repeat (2-LTR) circles in peripheral blood mononuclear cells before and after maraviroc intensification. We also evaluated markers of CD4 and CD8 T-cell immune activation (%CD38HLA-DR) and apoptosis (%caspase3/Bcl-2). RESULTS: No effect of maraviroc was found on the probability of detectable plasma viremia (≥1âcopy/ml; nâ=â31, exact McNemar Pâ=â1.0) or detectable 2-LTR circles (nâ=â28, Pâ=â0.25) or on total HIV-1 DNA (nâ=â28, 90% confidence interval -0.1, +0.3 log10âcopies/10 CD4 T-cells). Premaraviroc HIV-1 DNA levels were inversely related to premaraviroc %CD38HLA-DR CD4 T-cells (Spearmanâ=â-0.52, Pâ=â0.004), and lower premaraviroc HIV-1 DNA levels were associated with larger decreases in %CD38HLA-DR CD4 T-cells during maraviroc intensification (Spearmanâ=â0.44, Pâ=â0.018). CONCLUSION: In individuals on suppressive ART with incomplete CD4 T-cell recovery, maraviroc intensification did not affect measures of HIV-1 persistence but did decrease persistent CD4 T-cell immune activation especially in individuals with low preintensification levels of HIV-1 DNA.
Asunto(s)
Antirretrovirales/uso terapéutico , Terapia Antirretroviral Altamente Activa/métodos , Linfocitos T CD4-Positivos/inmunología , Ciclohexanos/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/aislamiento & purificación , Triazoles/uso terapéutico , Carga Viral , Recuento de Linfocito CD4 , Linfocitos T CD8-positivos/inmunología , Femenino , Infecciones por VIH/inmunología , Infecciones por VIH/patología , Infecciones por VIH/virología , Humanos , Masculino , Maraviroc , Persona de Mediana Edad , Estudios Prospectivos , Resultado del TratamientoRESUMEN
Discrepancies between HIV-1 RNA results assayed by different FDA-approved platforms have been reported. Plasma samples collected from 332 randomly selected clinical trial participants during the second year of antiretroviral treatment were assayed with three FDA-approved platforms: UltraSensitive Roche Amplicor Monitor, v1.5 (Monitor), the Abbott RealTime HIV-1 test on the m2000 system (Abbott), and the Roche TaqMan HIV-1 test, v2.0 (TaqMan). Samples from 61 additional participants with confirmed HIV-1 RNA levels of >50 copies/ml during trial follow-up were also included. Endpoints were HIV-1 RNA quantification of ≤50 copies/ml versus >50 copies/ml at an individual-sample level (primary) and determination of confirmed virologic failure (VF) from longitudinal samples. A total of 389 participants had results obtained from all assays on at least one sample (median = 6). Proportions of results of >50 copies/ml were 19% (Monitor), 22% (TaqMan), and 25% (Abbott). Despite indication of strong agreement (Cohen's kappa, 0.76 to 0.82), Abbott was more likely to detect HIV-1 RNA levels of >50 copies/ml than Monitor (matched-pair odds ratio [mOR] = 4.2; modified Obuchowski P < 0.001) and TaqMan (mOR = 2.1; P < 0.001); TaqMan was more likely than Monitor (mOR = 2.6; P < 0.001). Despite strong agreement in classifying VF across assay comparisons (kappa, 0.75 to 0.92), at a 50-copies/ml threshold, differences in the probability of VF classification (in the same direction as primary) were apparent (all McNemar's P < 0.007). At a 200-copies/ml VF threshold, no differences between assays were apparent (all P > 0.13). Despite strong agreement among assays, significant differences were observed with respect to detecting HIV-1 RNA levels of >50 copies/ml and identifying VF at the 50-copies/ml threshold. This has important implications for the definition of VF in clinical trials and clinical practice.
Asunto(s)
Infecciones por VIH/virología , VIH-1/aislamiento & purificación , Plasma/virología , ARN Viral/sangre , Carga Viral/métodos , Adolescente , Adulto , Anciano , Antirretrovirales/uso terapéutico , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Sensibilidad y Especificidad , Insuficiencia del Tratamiento , Adulto JovenRESUMEN
OBJECTIVES: Simplified maintenance therapy with ritonavir-boosted atazanavir (ATV/r) provides an alternative treatment option for HIV-1 infection that spares nucleoside analogs (NRTI) for future use and decreased toxicity. We hypothesized that the level of immune activation (IA) and recovery of lymphocyte populations could influence virologic outcomes after regimen simplification. METHODS: Thirty-four participants with virologic suppression ≥ 48 weeks on antiretroviral therapy (2 NRTI plus protease inhibitor) were switched to ATV/r alone in the context of the ACTG 5201 clinical trial. Flow cytometric analyses were performed on PBMC isolated from 25 patients with available samples, of which 24 had lymphocyte recovery sufficient for this study. Assessments included enumeration of T-cells (CD4/CD8), natural killer (NK) (CD3+CD56+CD16+) cells and cell-associated markers (HLA-DR, CD's 38/69/94/95/158/279). RESULTS: Eight of the 24 patients had at least one plasma HIV-1 RNA level (VL) >50 copies/mL during the study. NK cell levels below the group median of 7.1% at study entry were associated with development of VL >50 copies/mL following simplification by regression and survival analyses (p = 0.043 and 0.023), with an odds ratio of 10.3 (95% CI: 1.92-55.3). Simplification was associated with transient increases in naïve and CD25+ CD4+ T-cells, and had no impact on IA levels. CONCLUSIONS: Lower NK cell levels prior to regimen simplification were predictive of virologic rebound after discontinuation of nucleoside analogs. Regimen simplification did not have a sustained impact on markers of IA or T lymphocyte populations in 48 weeks of clinical monitoring. TRIAL REGISTRATION: ClinicalTrials.gov NCT00084019.