Efficacy and Safety of Remdesivir in People With Impaired Kidney Function Hospitalized for COVID-19 Pneumonia: A Randomized Clinical Trial.

BACKGROUND: Few antiviral therapies have been studied in patients with COVID-19 and kidney impairment. Herein, efficacy, safety, and pharmacokinetics of remdesivir, its metabolites, and sulfobutylether-beta-cyclodextrin excipient were evaluated in hospitalized patients with COVID-19 and severe kidney impairment. METHODS: In REDPINE, a phase 3, randomized, double-blind, placebo-controlled study, participants aged ≥12 years hospitalized for COVID-19 pneumonia with acute kidney injury (AKI), chronic kidney disease (CKD), or kidney failure were randomized 2:1 to receive intravenous remdesivir (200 mg on Day 1; 100 mg daily up to Day 5) or placebo (enrollment: March 2021-March 2022). The primary efficacy endpoint was the composite of all-cause mortality or invasive mechanical ventilation (IMV) through Day 29. Safety was evaluated through Day 60. RESULTS: Although enrollment concluded early, 243 participants were enrolled and treated (remdesivir, n = 163; placebo, n = 80). At baseline, 90 (37.0%) participants had AKI (remdesivir, 60; placebo, 30), 64 (26.3%) had CKD (remdesivir, 44; placebo, 20), and 89 (36.6%) had kidney failure (remdesivir, 59; placebo, 30); 31 (12.8%) were COVID-19 vaccinated. Composite all-cause mortality or IMV through Day 29 was 29.4% and 32.5% in the remdesivir and placebo group, respectively (P = 0.61). Treatment-emergent adverse events were reported in 80.4% versus 77.5% and serious adverse events in 50.3% versus 50.0% of participants who received remdesivir versus placebo, respectively. Pharmacokinetic plasma exposure to remdesivir was not affected by kidney function. CONCLUSIONS: Although underpowered, no significant difference in efficacy was observed between treatment groups. REDPINE demonstrated that remdesivir is safe in those with COVID-19 and severe kidney impairment. (EudraCT number: 2020-005416-22; Clinical Trials.gov number: NCT04745351). TRIAL REGISTRATION: EudraCT number: 2020-005416-22; Clinical Trials.gov number: NCT04745351.

Development and Evaluation of an NTM-IGRA to Guide Pediatric Lymphadenitis Diagnosis.

BACKGROUND: Diagnosis of nontuberculous mycobacteria (NTM) infections remains a challenge. In this study, we describe the evaluation of an immunological NTM-interferon (IFN)-γ release assay (IGRA) that we developed using glycopeptidolipids (GPLs) as NTM-specific antigens. METHODS: We tested the NTM-IGRA in 99 samples from pediatric patients. Seventy-five were patients with lymphadenitis: 25 were NTM confirmed, 45 were of unknown etiology but compatible with mycobacterial infection and 5 had lymphadenitis caused by an etiologic agent other than NTM. The remaining 24 samples were from control individuals without lymphadenitis (latently infected with M. tuberculosis , uninfected controls and active tuberculosis patients). Peripheral blood mononuclear cells were stimulated overnight with GPLs. Detection of IFN-γ producing cells was evaluated by enzyme-linked immunospot assay. RESULTS: NTM culture-confirmed lymphadenitis patient samples had a significantly higher response to GPLs than the patients with lymphadenitis of unknown etiology but compatible with mycobacterial infection ( P < 0.001) and lymphadenitis not caused by NTM ( P < 0.01). We analyzed the response against GPLs in samples from unknown etiology lymphadenitis but compatible with mycobacterial infection cases according to the tuberculin skin test (TST) response, and although not statistically significant, those with a TST ≥5 mm had a higher response to GPLs when compared with the TST <5 mm group. CONCLUSIONS: Stimulation with GPLs yielded promising results in detecting NTM infection in pediatric patients with lymphadenitis. Our results indicate that the test could be useful to guide the diagnosis of pediatric lymphadenitis. This new NTM-IGRA could improve the clinical handling of NTM-infected patients and avoid unnecessary misdiagnosis and treatments.

Etravirina: barrera genética y desarrollo de resistencias / Etravirine: genetic barrier and resistance development

A diferencia de los inhibidores de la transcriptasa inversa no análogos de nucleósidos (ITINAN) de primera generación, para desarrollar resistencia completa a etravirina (ETR) se requiere el acúmulo de varias mutaciones. Muestra una barrera intermedia frente a la aparición de resistencia parcial, y alta para el de resistencia completa. Algunas mutaciones seleccionadas por nevirapina o efavirenz impactan la actividad de ETR, siendo las más frecuentes Y181C, G190A/S, K101E, L100I, Y188L y V90I. El grado de resistencia conferida por cada una es distinto. En la actualidad se dispone de al menos 3 listados de mutaciones que otorgan la puntuación exacta a cada mutación. Estos listados se han validado con el grado de resistencia observado en fenotipos pareados, y con respuesta clínica en los estudios DUET. Los 3 scores muestran un elevado grado de concordancia entre ellos. ETR es, en la actualidad, uno de los antirretrovirales en los que se puede calcular de modo sencillo y con mayor precisión su actividad basándose en datos genotípicos. Las mutaciones seleccionadas tras fracasos a inhibidores de la transcriptasa inversa análogos de nucleósidos, especialmente análogos de la timidina, T69D/N y M184I/V, confieren hipersusceptibilidad frente a ETR (fold change < 0,4) en hasta 1 de cada 3 muestras analizadas. Es crucial la retirada precoz de ITINAN de primera generación en pacientes con fracaso virológico para evitar el acúmulo de mutaciones que puedan comprometer la actividad del fármaco

Unlike first-generation non-nucleoside reverse transcriptase inhibitors (NNRTI), to develop complete resistance to etravirine (ETR), various mutations must be accumulated. This drug shows an intermediate barrier against partial resistance and a high barrier to complete resistance. Some mutations selected by nevirapine or efavirenz affect the activity of ETR, the most frequent being Y181C, G190A/S, K101E, L100I, Y188L and V90I. The grade of resistance conferred by each mutation differs. Currently, there are at least three lists of mutations that confer an exact score to each mutation. These lists have been validated with the grade of resistance observed in paired phenotypes and with clinical response in the DUET studies. The three scores show a high degree of agreement. ETR is currently one of the antiretroviral drugs whose activity can be calculated simply and accurately on the basis of genotypic data. The mutations selected after failure to nucleoside reverse transcriptase inhibitors, thymidine analogue, T69D/N and M184I/V, confer hypersusceptibility to ETR (fold change < 0.4) in up to 1 out of every 3 samples analyzed. The early withdrawal of first-generation NNRTIs in patients with virological failure is essential to avoid the accumulation of mutations that could compromise the activity of this drug

Efectividad de efavirenz versus lopinavir/ritonavir asociado a dos análogos nucleósidos como tratamiento de inicio en pacientes VIH positivos / Effectiveness of efavirenz versus lopinavir / ritonavir associated with two nucleoside analogues as initial therapy for HIV patients

Comparar la efectividad virológica e inmunológica, de dos esquemas, uno basado en efavirenz y el otro en lopinavir/ritonavir, ambos combinados con dos análogos nucleósidos, en pacientes con infección avanzada por VIH, sin tratamiento previo. Estudio observacional de cohorte. Falla virológica definida como carga viral >50 copias/mL en los intervalos 3 a 9, 10 a 16 y 22 a 28 meses después del inicio. Se determinó la variación de CD4+. Se realizó análisis univariado de variables asociadas falla virológica. Se aplicaron Chi², Sum Rank Testy Log Rank Test. 189 pacientes iniciaron tratamiento entre diciembre 2000 y abril 2004, 114 con efavirenz y 45 con lopinavir/ritonavir, combinados con dos análogos nucleósidos. Los grupos fueron comparables en características basales: edad en años (36,5 en efavirenz vs 36,9 en lopinavir/ritonavir, (P=0,78); CD4+ basal (183,3 en efavirenz vs. 143,7 en lopinavir/ritonavir, (P=0,14); carga viral basal (203,696 cop/mL en efavirenz vs 217,772 cop/mL en lopinavir/ritonavir, P=0,77). Para la cohorte completa 87 por ciento obtuvo valores de carga viral indetectable a los 6 meses, 58 por ciento al año y 48 por ciento a los 28 meses. El cambio en el valor de CD4+/mes (+10,5 en efavirenz vs + 9,5 en lopinavir/ritonavir, P=0,77) y el porcentaje de indetectabilidad fueron similares en ambos grupos, tomando en cuenta los pacientes que pudieron seguirse durante el período de observación, cuyo número fue disminuyendo a partir de la muestra inicial. Ambos esquemas fueron comparables en su efectividad en esta cohorte de pacientes en términos de variación de CD4+ y porcentaje de indetectabilidad de carga viral.