RESUMEN
BACKGROUND: This was a substudy of a Phase IV, randomized clinical trial (ClinicalTrials.gov identifier: NCT04295460) aiming to compare the activity of dolutegravir/lamivudine versus dolutegravir plus tenofovir alafenamide/emtricitabine (DTGâ+âTAF/FTC) in the male genital tract. METHODS: Participants were asymptomatic adults without sexually transmitted diseases, treatment-naive people living with HIV (PLWH), with CD4+ T cell counts >200 cells/mm3 and plasma HIV-1-RNA levels >5000 and <500â000 copies/mL, randomized (1:1) to DTGâ+âTAF/FTC or dolutegravir/lamivudine. Blood plasma (BP) and seminal plasma (SP) were collected at baseline and Weeks 4, 8, 12 and 24. HIV-1-RNA was measured in BP and SP using the Cobas 6800 system (Roche Diagnostics) with a lower detection limit of 20 copies/mL. The primary efficacy endpoint was the proportion of subjects with undetectable SP HIV-1-RNA at Week 12 by intention-to-treat analysis. RESULTS: Fifteen participants in the DTGâ+âTAF/FTC and 16 in the dolutegravir/lamivudine arms were analysed, with basal SP viral load of 4.81 (4.30-5.43) and 4.76 (4.09-5.23), Pâ=â0.469, respectively. At Week 12, only one participant in each treatment arm had a detectable SP HIV-1-RNA (DTGâ+âTAF/FTC, 141 copies/mL; dolutegravir/lamivudine, 61 copies/mL). Based on the estimated means, there was no significant difference in the decay of HIV-1-RNA in both BP and SP over time between the two arms of treatment (Fâ=â0.452, Pâ=â0.662, and Fâ=â1.147, Pâ=â0.185, respectively). CONCLUSIONS: After 12 weeks of treatment, there were no differences in the percentage of undetectable SP HIV-1-RNA in naive PLWH who started dolutegravir/lamivudine compared with DTGâ+âTAF/FTC.
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Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Adulto , Humanos , Masculino , Lamivudine/uso terapéutico , VIH-1/genética , Infecciones por VIH/tratamiento farmacológico , Semen , Cinética , Quimioterapia Combinada , Emtricitabina/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Piridonas/uso terapéutico , Oxazinas/uso terapéutico , ARN Viral , Fármacos Anti-VIH/uso terapéuticoRESUMEN
The activation phenotypes and functional changes in monocyte subsets during hepatitis C virus (HCV) elimination in HIV/HCV-coinfected patients were evaluated. Twenty-two HIV/HCV-coinfected patients on suppressive combination antiretroviral treatment (cART) achieving HCV elimination after direct-acting antiviral (DAA) therapy and 10 HIV-monoinfected patients were included. The activation phenotype (10 markers) and polyfunctionality (intracellular interleukin-1α [IL-1α], IL-1ß, IL-6, IL-8, tumor necrosis factor alpha [TNF-α], and IL-10 production) in three monocyte subsets (classical, intermediate, and nonclassical) were evaluated by flow cytometry before and at the end of treatment. Cell-associated HIV DNA levels were assayed by droplet digital PCR. After HCV clearance, there was a significant increase in classical monocyte and decreases in intermediate and nonclassical monocyte levels. The levels of the activation markers CD49d, CD40, and CX3CR1 were decreased after treatment in the monocyte subsets, reaching the levels in HIV-monoinfected patients. After lipopolysaccharide (LPS) stimulation, although polyfunctionality significantly decreased in intermediate and nonclassical monocytes, some combinations, such as the IL-1α- (IL-1α-negative) IL-1ß- IL-6+ (IL-6-producing) IL-8- TNF-α- IL-10- combination, were remarkably increased at the end of treatment compared to the control group. Cell-associated HIV DNA levels correlated with activation markers before but not after treatment. HCV clearance after DAA treatment in patients on cART exerts an anti-inflammatory profile on monocyte subsets, activation phenotypes, and polyfunctionality. However, there is not a complete normalization compared with HIV-monoinfected patients.
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Coinfección , Infecciones por VIH , Hepatitis C Crónica , Hepatitis C , Antivirales/uso terapéutico , Coinfección/tratamiento farmacológico , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Hepacivirus , Hepatitis C/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , Humanos , MonocitosRESUMEN
OBJECTIVES: To analyse whether integrase inhibitor (InSTI)-based regimens achieve better immunological recovery than NNRTI- or boosted PI (bPI)-based regimens as initial ART. METHODS: In a retrospective analysis, we selected patients who initiated ART with two NRTIs plus an InSTI, an NNRTI or a bPI and maintained both the same 'third drug' and an HIV-RNA <50 copies/mL in ≥95% of determinations once undetectable viral load had been achieved. We compared CD4+ count, %CD4+ and CD4+/CD8+ ratio recovery over 2 years. Data were analysed using mixed-effects regression models for repeated measures. RESULTS: Of the 836 patients included, 208, 481 and 147 initiated with InSTI, NNRTI and bPI, respectively. For CD4+, %CD4+ and CD4+/CD8+ two main slopes were identified: from month 0 to month 6, with the highest increments; and from month 6 to month 24, with smaller increases every semester. Although the patients on InSTI achieved undetectable viral load faster, for CD4+ and %CD4+ there were no differences in the slopes of change according to the third drug either for the first phase (P=0.137 and P=0.393, respectively) or from month 6 onwards (P=0.834 and P=0.159, respectively). The increase in CD4+/CD8+ was slightly higher for bPI compared with InSTI (difference of 0.0119, 95% CI 0.0020-0.0205; P=0.018), but clinically negligible. From month 6 onwards, no differences were found between treatment groups (P=0.176). CONCLUSIONS: Immune restoration measured as CD4+ count, %CD4+ and CD4+/CD8+ increases was independent of the third antiretroviral drug class used when given with two NRTIs.
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Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Inhibidores de Integrasa VIH/uso terapéutico , Inhibidores de la Proteasa del VIH/uso terapéutico , Reconstitución Inmune , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Adulto , Recuento de Linfocito CD4 , Relación CD4-CD8 , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Carga Viral/efectos de los fármacosRESUMEN
BACKGROUND: S. pneumoniae is the leading cause of community-acquired pneumonia in the solid organ transplant recipient (SOTR); nevertheless, the prevalence of colonization and of the colonizing/infecting serotypes has not been studied in this population. In this context, the aim of the present study was to describe the rate, characteristics, and clinical impact of S. pneumoniae nasopharyngeal carriage. METHODS: A prospective observational cohort of Solid Organ Transplant recipients (SOTR) was held at the University Hospital Virgen del Rocío, Seville, Spain with the aim to evaluate the S. pneumoniae colonization and the serotype prevalence in SOTR. Two different pharyngeal swabs samples from 500 patients were included in two different seasonal periods winter and spring/summer. Optochin and bile solubility tests were performed for the isolation of thew strains. Antimicrobial susceptibility studies (MICs, mg/l) of levofloxacin, trimethoprim-sulfamethoxazole, penicillin, amoxicillin, cefotaxime, ceftriaxone, erythromycin, azithromycin and vancomycin for each isolate were determined by E-test strips. Capsular typing was done by sequential multiplex PCR reactions. A multivariate logistic regression analysis of factors potentially associated with pneumococcal nasopharyngeal carriage and disease was performed. RESULTS: Twenty-six (5.6%) and fifteen (3.2%) patients were colonized in winter and spring/summer periods, respectively. Colonized SOT recipients compared to non-colonized patients were more frequently men (79.5% vs. 63.1%, P < 0.05) and cohabitated regularly with children (59% vs. 32.2%, P < 0.001). The most prevalent serotype in both studied periods was 35B. Forty-five percent of total isolates were included in the pneumococcal vaccine PPV23. Trimethoprim-sulfamethoxazole and macrolides were the less active antibiotics. Three patients had non-bacteremic pneumococcal pneumonia, and two of them died. CONCLUSIONS: Pneumococcal colonization in SOTR is low with the most colonizing serotypes not included in the pneumococcal vaccines.
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Nasofaringe/microbiología , Trasplante de Órganos/efectos adversos , Infecciones Neumocócicas/epidemiología , Streptococcus pneumoniae/aislamiento & purificación , Adulto , Antibacterianos , Niño , Femenino , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Infecciones Neumocócicas/microbiología , Vacunas Neumococicas , Prevalencia , Estudios Prospectivos , Serogrupo , España/epidemiología , Streptococcus pneumoniae/efectos de los fármacos , Streptococcus pneumoniae/patogenicidad , Receptores de Trasplantes/estadística & datos numéricosRESUMEN
BACKGROUND: Colistin is recommended in the empirical treatment of ventilator-associated pneumonia (VAP) with a high prevalence of carbapenem-resistant gram-negative bacilli (CR-GNB). However, the efficacy and safety of colistin are not well defined. METHODS: A multicenter prospective randomized trial conducted in 32 European centers compared the efficacy and safety of colistin (4.5 million unit loading dose followed by a maintenance dose of 3 million units every 8 h) versus meropenem (2 g every 8 h), both in combination with levofloxacin (500 mg every 12 h) for 7-14 days in patients with late VAP. Between May 2012 and October 2015, 232 patients were randomly assigned to the 2 treatment groups. The primary endpoint was mortality at 28 days after randomization in the microbiologically modified intention-to-treat (mMITT) population. Secondary outcomes included clinical and microbiological cure, renal function at the end of the treatment, and serious adverse events. The study was interrupted after the interim analysis due to excessive nephrotoxicity in the colistin group; therefore, the sample size was not achieved. RESULTS: A total of 157 (67.7%) patients were included in the mMITT population, 36 of whom (22.9%) had VAP caused by CR-GNB. In the mMITT population, no significant difference in mortality between the colistin group (19/82, 23.2%) and the meropenem group (19/75, 25.3%) was observed, with a risk difference of - 2.16 (- 15.59 to 11.26, p = 0.377); the noninferiority of colistin was not demonstrated due to early termination and limited number of patients infected by carbapenem-resistant pathogens. Colistin plus levofloxacin increased the incidence of renal failure (40/120, 33.3%, versus 21/112, 18.8%; p = 0.012) and renal replacement therapy (11/120, 9.1%, versus 2/112, 1.8%; p = 0.015). CONCLUSIONS: This study did not demonstrate the noninferiority of colistin compared with meropenem, both combined with levofloxacin, in terms of efficacy in the empirical treatment of late VAP but demonstrated the greater nephrotoxicity of colistin. These findings do not support the empirical use of colistin for the treatment of late VAP due to early termination. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01292031. Registered 9 February 2011.
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Colistina/normas , Meropenem/normas , Neumonía Asociada al Ventilador/tratamiento farmacológico , Anciano , Antibacterianos/efectos adversos , Antibacterianos/normas , Antibacterianos/uso terapéutico , Colistina/efectos adversos , Colistina/uso terapéutico , Estudios de Equivalencia como Asunto , Femenino , Humanos , Masculino , Meropenem/efectos adversos , Meropenem/uso terapéutico , Persona de Mediana Edad , Estudios Prospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Influenza vaccine effectiveness is not optimal in solid organ transplant recipients (SOTR). We hypothesized that a booster dose might increase it. METHODS: TRANSGRIPE 1-2 is a phase 3, randomized, controlled, multicenter, open-label clinical trial. Patients were randomly assigned (1:1 stratified by study site, type of organ, and time since transplantation) to receive 1 dose (control group) or 2 doses (booster group) of the influenza vaccine 5 weeks apart. RESULTS: A total of 499 SOTR were enrolled. Although seroconversion at 10 weeks did not meet significance in the modified intention-to-treat population, seroconversion rates were significantly higher in the booster arm for the per-protocol population (53.8% vs 37.6% for influenza A(H1N1)pdm; 48.1% vs 32.3% for influenza A(H3N2); and 90.7% vs 75% for influenza B; P < .05). Furthermore, seroprotection at 10 weeks was higher in the booster group: 54% vs 43.2% for A(H1N1)pdm; 56.9% vs 45.5% for A(H3N2); and 83.4% vs 71.8% for influenza B (P < .05). The number needed to treat to seroprotect 1 patient was <10. The clinical efficacy (99.2% vs 98.8%) and serious adverse events (6.4% vs 7.5%) were similar for both groups. CONCLUSIONS: In SOTR, a booster strategy 5 weeks after standard influenza vaccination is safe and effective and induces an increased antibody response compared with standard influenza vaccination consisting of a single dose. CLINICAL TRIALS REGISTRATION: EudraCT (2011-003243-21).
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Inmunidad , Inmunomodulación , Vacunas contra la Influenza/inmunología , Gripe Humana/prevención & control , Receptores de Trasplantes , Vacunas de Productos Inactivados/inmunología , Anticuerpos Antivirales/inmunología , Comorbilidad , Femenino , Humanos , Subtipo H1N1 del Virus de la Influenza A/inmunología , Subtipo H3N2 del Virus de la Influenza A/inmunología , Virus de la Influenza B/inmunología , Vacunas contra la Influenza/administración & dosificación , Vacunas contra la Influenza/efectos adversos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Trasplante de Órganos , Vacunación , Vacunas de Productos Inactivados/administración & dosificación , Vacunas de Productos Inactivados/efectos adversosRESUMEN
Real-life data on doravirine (DOR) in different drug combinations are limited. We evaluated the effectiveness of DOR plus two nucleos(t)ide reverse transcriptase inhibitors (NRTI), mainly abacavir/lamivudine, and dual therapies in people with HIV (PWH), mostly virologically suppressed. Ambispective observational study that enrolled adults PWH who initiated a DOR-based regimen from September 2020 to February 2022 at a referral center in Spain. Participants were grouped as follows: A, received DOR plus two NRTI; B, dual therapy (DT) with DOR plus dolutegravir (DTG) or darunavir/cobicistat (DRVc); C, DOR plus ≥two antiretroviral drugs. The primary endpoints were treatment effectiveness at week 48 by intention-to-treat (ITT) and per-protocol analysis (OT). A cohort of 187 participants, 91% virologically suppressed, were analyzed after a median follow-up of 112 weeks (80-136). Group A received DOR plus abacavir/lamivudine (ABV/3TC) (n = 109) or tenofovir/emtricitabine (TFV/3TC) (n = 45). At week 48, the effectiveness of DOR plus ABV/3TC by ITT was 90.8% (CI95, 88.0-93.6), better than with TFV/FTC [73.3% (66.7-79.9); P = 0.003]. Only one virologic failure was observed. Mild adverse effects were the cause of treatment discontinuation in 7.8%, followed by switching to a single-tablet regimen. In group B, the effectiveness by ITT was 92.9% (CI95, 88.0-97.8) at week 48. No adverse effects or virologic failure were registered in this group. DOR plus two NRTI or DT have long-term effectiveness and safety as a switching option for PWH, mostly virologically suppressed. The DOR plus ABV/3TC combination has shown even better effectiveness than TFV/FTC.IMPORTANCEDOR-based regimens have shown long-term effectiveness and safety in PWH, mostly virologically suppressed. The combination of DOR plus ABV/3TC has shown even better safety and effectiveness than TFV/FTC. DOR plus two NRTI offers cost benefits compared to other regimens.
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Fármacos Anti-VIH , Infecciones por VIH , Lamivudine , Piridonas , Triazoles , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Femenino , Piridonas/efectos adversos , Masculino , Adulto , Persona de Mediana Edad , Lamivudine/uso terapéutico , Lamivudine/efectos adversos , Lamivudine/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/administración & dosificación , Triazoles/uso terapéutico , Triazoles/efectos adversos , Triazoles/administración & dosificación , Didesoxinucleósidos/uso terapéutico , Didesoxinucleósidos/efectos adversos , Didesoxinucleósidos/administración & dosificación , Combinación de Medicamentos , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Oxazinas/uso terapéutico , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Inhibidores de la Transcriptasa Inversa/efectos adversos , España , Resultado del Tratamiento , Cobicistat/uso terapéutico , Cobicistat/efectos adversos , Cobicistat/administración & dosificación , Darunavir/uso terapéutico , Darunavir/efectos adversos , Piperazinas/efectos adversos , Carga Viral/efectos de los fármacos , VIH-1/efectos de los fármacos , VIH-1/genética , Ciclopropanos , Didesoxiadenosina/análogos & derivadosRESUMEN
Objective: To compare the long-term effects on immune parameters, inflammation, and HIV-1 reservoir after switching to a two-drug (2DR) versus maintaining an integrase inhibitor (InSTI)-based three-drug regimen (3DR). Methods: Cross-sectional study in which HIV-1 treatment-naïve people started and maintained an InSTI-based 3DR or, at different times, switched to 2DR (dolutegravir or darunavir/cobicistat + lamivudine). CD4+ and CD8+ T-cell activation and exhaustion, plasma concentrations of hs-CRP, D-dimer, P-selectin, IL-1ß, IL-6, TNF-α, IFN-γ, IP-10, sTNFR-I/II, MIP-1α/ß, I-FABP, LBP, sCD14, sCD163, MCP-1, and cellular-associated HIV-1-DNA and -RNA were quantified by flow cytometry, different immunoassays, and droplet digital PCR, respectively. The U de Mann-Whitney test evaluated differences between 3DR and 2DR. Immune recovery was evaluated using a general linear model for repeated measures adjusted for different co-variables. Results: Fifty participants per group were included. The median time on 3DR was 82 months for the 3DR group and 30 months for the 2DR group, after which it switched to 2DR for a median of 57 months. We did not find differences between both groups in any of the parameters analyzed. Specifically, some values in 3DR and 2DR were hs-CRP, 0.92 mg/L (0.45-2.23) vs. 1.23 (0.61-2.38); D-dimer, 190.0 µg/L (150.0-370.0) vs. 190.0 (150.0-397.5); IL-6, 2.8 pg/mL (1.3-5.3) vs. 3.2 (2.1-4.7); sCD14, 4.5 ng/mL (3.3-6.2) vs. 5.0 (3.6-6.1), respectively, all p ≥ 0.399. Conclusion: In the long term, switching to 2DR does not negatively affect immunologic parameters, inflammatory markers, or HIV-1 reservoir. Clinical trial registration: identifier NCT04076423.
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Biomarcadores , Infecciones por VIH , Inhibidores de Integrasa VIH , VIH-1 , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Infecciones por VIH/sangre , Masculino , VIH-1/efectos de los fármacos , VIH-1/inmunología , Femenino , Biomarcadores/sangre , Adulto , Estudios Transversales , Inhibidores de Integrasa VIH/uso terapéutico , Persona de Mediana Edad , Carga Viral , Inflamación/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD4-Positivos/inmunología , Oxazinas/uso terapéuticoRESUMEN
We evaluated the safety and viral rebound, after analytical treatment interruption (ATI), of vedolizumab and ART in recent HIV-1 infection. We used this model to analyze the impact of α4ß7 on the HIV-1 reservoir size. Participants started ART with monthly Vedolizumab infusions and ATI was performed at week 24. Biopsies were obtained from ileum and caecum at baseline and week 24. Vedolizumab levels, HIV-1 reservoir, flow cytometry and cell-sorting and antibody competition experiments were assayed. Vedolizumab was safe and well-tolerated. No participant achieved undetectable viremia off ART 24 weeks after ATI. Only a modest effect on the time to achieve >1000 HIV-RNA copies/mL and the proportion of participants off ART was observed, being higher compared to historical controls. Just before ATI, α4ß7 expression was associated with HIV-1 DNA and RNA in peripheral blood and with PD1 and TIGIT levels. Importantly, a complete blocking of α4ß7 was observed on peripheral CD4+ T-cells but not in gut (ileum and caecum), where α4ß7 blockade and vedolizumab levels were inversely associated with HIV-1 DNA. Our findings support α4ß7 as an important determinant in HIV-1 reservoir size, suggesting the complete α4ß7 blockade in tissue as a promising tool for HIV-cure combination strategies.
RESUMEN
BACKGROUNDPersistent controllers (PCs) maintain antiretroviral-free HIV-1 control indefinitely over time, while transient controllers (TCs) eventually lose virological control. It is essential to characterize the quality of the HIV reservoir in terms of these phenotypes in order to identify the factors that lead to HIV progression and to open new avenues toward an HIV cure.METHODSThe characterization of HIV-1 reservoir from peripheral blood mononuclear cells was performed using next-generation sequencing techniques, such as full-length individual and matched integration site proviral sequencing (FLIP-Seq; MIP-Seq).RESULTSPCs and TCs, before losing virological control, presented significantly lower total, intact, and defective proviruses compared with those of participants on antiretroviral therapy (ART). No differences were found in total and defective proviruses between PCs and TCs. However, intact provirus levels were lower in PCs compared with TCs; indeed the intact/defective HIV-DNA ratio was significantly higher in TCs. Clonally expanded intact proviruses were found only in PCs and located in centromeric satellite DNA or zinc-finger genes, both associated with heterochromatin features. In contrast, sampled intact proviruses were located in permissive genic euchromatic positions in TCs.CONCLUSIONSThese results suggest the need for, and can give guidance to, the design of future research to identify a distinct proviral landscape that may be associated with the persistent control of HIV-1 without ART.FUNDINGInstituto de Salud Carlos III (FI17/00186, FI19/00083, MV20/00057, PI18/01532, PI19/01127 and PI22/01796), Gilead Fellowships (GLD22/00147). NIH grants AI155171, AI116228, AI078799, HL134539, DA047034, MH134823, amfAR ARCHE and the Bill and Melinda Gates Foundation.
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Infecciones por VIH , VIH-1 , Humanos , VIH-1/genética , Leucocitos Mononucleares , Provirus/genética , Infecciones por VIH/tratamiento farmacológico , Antirretrovirales/uso terapéuticoRESUMEN
BACKGROUND: Plasmacytoid dendritic cells (pDCs) sense viral and bacterial products through Toll-like receptor (TLR)-7 and -9 and translate this sensing into Interferon-α (IFN-α) production and T-cell activation. The understanding of the mechanisms involved in pDCs stimulation may contribute to HIV-cure immunotherapeutic strategies. The objective of the present study was to characterize the immunomodulatory effects of TLR agonist stimulations in several HIV-1 disease progression phenotypes and in non HIV-1 infected donors. METHODS: pDCs, CD4 and CD8 T-cells were isolated from 450 ml of whole blood from non HIV-1 infected donors, immune responders (IR), immune non responders (INR), viremic (VIR) and elite controller (EC) participants. pDCs were stimulated overnight with AT-2, CpG-A, CpG-C and GS-9620 or no stimuli. After that, pDCs were co-cultured with autologous CD4 or CD8 T-cells and with/without HIV-1 (Gag peptide pool) or SEB (Staphylococcal Enterotoxin B). Cytokine array, gene expression and deep immunophenotyping were assayed. FINDINGS: pDCs showed an increase of activation markers levels, interferon related genes, HIV-1 restriction factors and cytokines levels after TLR stimulation in the different HIV-disease progression phenotypes. This pDC activation was prominent with CpG-C and GS-9620 and induced an increase of HIV-specific T-cell response even in VIR and INR comparable with EC. This HIV-1 specific T-cell response was associated with the upregulation of HIV-1 restriction factors and IFN-α production by pDC. INTERPRETATION: These results shed light on the mechanisms associated with TLR-specific pDCs stimulation associated with the induction of a T-cell mediated antiviral response which is essential for HIV-1 eradication strategies. FUNDING: This work was supported by Gilead fellowship program, the Instituto de Salud Carlos III (Fondo Europeo de Desarrollo Regional, FEDER, "a way to make Europe") and the Red Temática de Investigación Cooperativa en SIDA and by the Spanish National Research Council (CSIC).
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Células Dendríticas , Receptor Toll-Like 9 , Receptor Toll-Like 9/metabolismo , Citocinas/metabolismo , Adyuvantes Inmunológicos , FenotipoRESUMEN
OBJECTIVE: Successful clinical trials are subject to recruitment. Recently, the REJUVENATE trial, a prospective phase 2a open-label, single-arm interventional clinical trial conducted within the Innovative Medicines Initiative-supported Combatting Bacterial Resistance in Europe-Carbapenem Resistance project, was published, with 85% of the recruitment performed in Spain. We analysed the recruitment success in this trial by establishing a model of recruitment practice. METHODS: A descriptive qualitative study was performed from May 2016 to October 2017 at 10 participating Spanish centres. Data were extracted from: (1) feasibility questionnaires to assess the centre's potential for patient enrolment; (2) delegation of responsibility records; (3) pre-screening records including an anonymised list of potentially eligible and (4) screening and enrolment records. A descriptive analysis of the features was performed by the participating centre. Pearson's and Spearman's correlation coefficients were calculated to determine factors of recruitment success. RESULTS: The highest recruitment rate was observed in Hospitals 3 and 6 (58.8 and 47.0 patients per month, respectively). All the study teams were multidisciplinary with a median of 15 members (range: 7-22). Only Hospitals 3, 5 and 6 had dedicated nursing staff appointed exclusively to this study. Moreover, in those three hospitals and in Hospital 9, the study coordinator performed exclusive functions as a research planner, and did not assume these functions for the other hospitals. The univariate analysis showed a significant association between recruitment success and months of recruitment (p=0.024), number of staff (p<0.001), higher number of pharmacists (p=0.005), infectious disease specialists (p<0.001), the presence of microbiologist in the research team (p=0.018) and specifically dedicated nursing staff (p=0.036). CONCLUSIONS: The existence of broad multidisciplinary teams with staff dedicated exclusively to the study as well as the implementation of a well-designed local patient assessment strategy were the essential optimisation factors for recruitment success in Spain. TRIAL REGISTRATION NUMBER: NCT02655419; EudraCT 2015-002726-39; analysis of pre-screened patients.
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Aztreonam , Compuestos de Azabiciclo , Humanos , Estudios Prospectivos , España , Encuestas y CuestionariosRESUMEN
Introduction: The use of systemic corticosteroids in severely ill patients with coronavirus disease 2019 (COVID-19) is controversial. We aimed to evaluate the efficacy and safety of corticosteroid pulses in patients with COVID-19 pneumonia. Methods: A quasi-experimental study, before and after, was performed in a tertiary referral hospital, including admitted patients showing COVID-19-associated pneumonia. The standard treatment protocol included targeted COVID-19 antiviral therapy from 23rd March 2020, and additionally pulses of methylprednisolone from 30th March 2020. The primary outcome was a composite endpoint combining oro-tracheal intubation (OTI) and death within 7 days. Results: A total of 24 patients were included. Standard of care (SOC) (before intervention) was prescribed in 14 patients, while 10 received SOC plus pulses of methylprednisolone (after intervention). The median age of patients was 64.5 years and 83.3% of the patients were men. The primary composite endpoint occurred in 13 patients (92.9%) who received SOC vs. 2 patients (20%) that received pulses of methylprednisolone (odds ratio, 0.02; 95% confidence interval, 0.001 to 0.25; p = 0.019). Length of hospitalization in survivors was shorter in the corticosteroids group (median, 14.5 [8.5-21.8] days vs. 29 [23-31] days, p = 0.003). There were no differences in the development of infections between both groups. There were 3 deaths, none of them in the corticosteroids group. Conclusions: In patients with severe pneumonia due to COVID-19, the administration of methylprednisolone pulses was associated with a lower rate of OTI and/or death and a shorter hospitalization episode.
Introducción: El uso de corticosteroides sistémicos en pacientes gravemente enfermos por enfermedad coronavírica de 2019 (covid-19) es controvertido. Nuestro objetivo fue evaluar la eficacia y la seguridad de los pulsos de corticoesteroides en los pacientes con neumonía por covid-19. Métodos: Se realizó un ensayo cuasiexperimental, tipo antes y después, en un hospital terciario de referencia que incluyó a pacientes ingresados por neumonía asociada a covid-19. El protocolo de tratamiento estándar incluía un tratamiento antiviral dirigido contra el virus de la covid-19 desde el 23 de marzo de 2020 y añadió pulsos de metilprednisolona desde el 30 de marzo de 2020. El resultado primario fue un criterio combinado compuesto por la intubación orotraqueal y el fallecimiento durante los siguientes siete días. Resultados: Se incluyó un total de 24 pacientes. El protocolo de tratamiento (antes de la intervención) se prescribió en 14 pacientes, mientras que 10 recibieron el protocolo de tratamiento además de los pulsos de metilprednisolona (después de la intervención). La edad media de los pacientes fue de 64,5 años y el 83,3% de los pacientes eran hombres. El resultado combinado primario tuvo lugar en 13 pacientes (92,9%) que recibieron el protocolo de tratamiento frente a 2 pacientes (20%) que recibieron los pulsos de metilprednisolona (odds ratio = 0,02; intervalo de confianza del 95% = 0,001-0,25; p = 0,019). La duración de la hospitalización en los supervivientes fue más corta en el grupo que recibió corticoesteroides (media = 14,5 [8,5-21,8] días frente a 29 [23-31] días, p = 0,003). No hubo diferencias en el desarrollo de infecciones entre ambos grupos. Hubo tres fallecimientos, ninguno de ellos en el grupo que recibió corticoesteroides. Conclusiones: En los pacientes con neumonía grave por covid-19, la administración de pulsos de metilprednisolona se asoció a unas tasas menores de intubación orotraqueal y/o muerte y a episodios de hospitalización más cortos.
RESUMEN
Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection induces an exacerbated inflammation driven by innate immunity components. Dendritic cells (DCs) play a key role in the defense against viral infections, for instance plasmacytoid DCs (pDCs), have the capacity to produce vast amounts of interferon-alpha (IFN-α). In COVID-19 there is a deficit in DC numbers and IFN-α production, which has been associated with disease severity. In this work, we described that in addition to the DC deficiency, several DC activation and homing markers were altered in acute COVID-19 patients, which were associated with multiple inflammatory markers. Remarkably, previously hospitalized and nonhospitalized patients remained with decreased numbers of CD1c+ myeloid DCs and pDCs seven months after SARS-CoV-2 infection. Moreover, the expression of DC markers such as CD86 and CD4 were only restored in previously nonhospitalized patients, while no restoration of integrin ß7 and indoleamine 2,3-dyoxigenase (IDO) levels were observed. These findings contribute to a better understanding of the immunological sequelae of COVID-19.
Asunto(s)
COVID-19/inmunología , Células Dendríticas/inmunología , SARS-CoV-2/inmunología , Células Cultivadas , Femenino , Humanos , Inmunidad Innata/inmunología , Inflamación/inmunología , Interferón-alfa/inmunología , Leucocitos Mononucleares/inmunología , Masculino , Índice de Severidad de la EnfermedadRESUMEN
: Human CD300a is known to promote the infection by dengue and other enveloped viruses and is overexpressed on CD4 T cells from HIV-1-infected patients. We found that infected CD4+RA- T cells from untreated HIV-1-infected patients were mostly CD300a+. Furthermore, CD300a expressing CD4+RA- T cells from healthy donors were significantly more infected by HIV-1 in vitro than CD300a- cells. CD300a might represent a biomarker of susceptibility to HIV-1 infection on memory CD4 T lymphocytes.
Asunto(s)
Antígenos CD/metabolismo , Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/diagnóstico , VIH-1 , Receptores Inmunológicos/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Infecciones por VIH/inmunología , Humanos , Memoria Inmunológica , Receptores Inmunológicos/genética , Receptores Inmunológicos/inmunologíaRESUMEN
Hemagglutination-inhibitory antibodies are usually highly strain specific with little effect on infection with drifted or shifted strains. The significance of broadly cross-reactive non-HAI anti-influenza antibodies against conserved domains of virus glycoproteins, such as the hemagglutinin (HA) stalk, is of great interest. We characterize a cohort of 40 H1N1pmd09 influenza-infected patients and identify lower respiratory symptoms (LRSs) as a predictor for development of pneumonia. A binomial logistic regression of log10 pre-existing antibody values shows that the probability of LRS occurrence decreased with increased anti-HA full-length and stalk antibody ELISA titers. However, a multilevel logistic regression model adjusted by other potential serocorrelates demonstrates that only antibodies directed against the stalk of HA correlate with protection from lower respiratory infection, limiting disease progression. Our predictive model indicates that a threshold of protective immunity based on broadly cross-reactive HA stalk antibodies could be feasible.
Asunto(s)
Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Hemaglutininas/inmunología , Gripe Humana/inmunología , Síntomas del Sistema Urinario Inferior/inmunología , Adulto , Anciano , Animales , Línea Celular , Protección Cruzada/inmunología , Reacciones Cruzadas/inmunología , Perros , Femenino , Pruebas de Inhibición de Hemaglutinación/métodos , Humanos , Subtipo H1N1 del Virus de la Influenza A/inmunología , Síntomas del Sistema Urinario Inferior/virología , Células de Riñón Canino Madin Darby , Masculino , Persona de Mediana Edad , Pruebas de Neutralización/métodos , Adulto JovenRESUMEN
Primary immunodeficiencies (PIDs) are rare, undiagnosed and potentially fatal diseases. Clinical manifestations of PID can be fatal or leave sequelae that worsen the quality of life of patients. Traditionally, the treatment of PIDs has been largely supportive, with the exception of bone marrow transplantation and, more recently, gene therapy. The discovering of new affected pathways, the development of new molecules and biologics, and the increasing understanding of the molecular basis of these disorders have created opportunities in PIDs therapy. This document aims to review current knowledge and to provide recommendations about the diagnosis and clinical management of adults and children with PIDs based on the available scientific evidence taking in to account current practice and future challenges. A systematic review was conducted, and evidence levels based on the available literature are given for each recommendation where available.
Asunto(s)
Síndromes de Inmunodeficiencia , Enfermedades de Inmunodeficiencia Primaria , Adulto , Trasplante de Médula Ósea , Niño , Consenso , Humanos , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/terapia , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Calidad de VidaRESUMEN
Primary immunodeficiencies (PIDs) are rare, undiagnosed and potentially fatal diseases. Clinical manifestations of PID can be fatal or leave sequelae that worsen the quality of life of patients. Traditionally, the treatment of PIDs has been largely supportive, with the exception of bone marrow transplantation and, more recently, gene therapy. The discovering of new affected pathways, the development of new molecules and biologics, and the increasing understanding of the molecular basis of these disorders have created opportunities in PIDs therapy. This document aims to review current knowledge and to provide recommendations about the diagnosis and clinical management of adults and children with PIDs based on the available scientific evidence taking in to account current practice and future challenges. A systematic review was conducted, and evidence levels based on the available literature are given for each recommendation where available.