RESUMO
BACKGROUND: Dolutegravir (DTG) plus lamivudine (3TC) has proven highly efficacious as a switching strategy in virologically suppressed people with HIV (PWH). As this strategy was introduced relatively recently, real-world, long-term durability studies are lacking. METHODS: We performed a retrospective review of treatment-experienced patients who started DTG + 3TC in a cohort of PWH. HIV-RNA <50 copies/mL was analysed at 144 weeks in an intention-to-treat (ITT) analysis (missing = failure) and a per-protocol (PP) analysis (patients with missing data or changes for reasons other than virological failure were excluded). RESULTS: The study population comprised 358 PWH (19% women). Median age and time with HIV infection were 51.7 and 13.4 years, respectively. The median number of previous antiretroviral combinations was three. Previous virological failure was reported in 27.1% of patients, and the M184V resistance mutation was detected in 17 patients. At 144 weeks, the percentage of individuals with HIV-RNA <50 copies/mL was 77.4% (277/358) in the ITT analysis and 95.5% (277/290) in the PP analysis. A total of 68 participants were excluded from the PP analysis (data missing, 25, discontinuation due to toxicity, 19; other, 16; death, 8). Two people with virological failure selected resistance-associated mutations (M184V and M184V + R263K). HIV-RNA remained undetectable in 17 patients with a previous history of the M184V mutation. CONCLUSION: Our results confirm the real-world, long-term efficacy, tolerability and high genetic barrier of DTG + 3TC in treatment-experienced PWH. Although scarce, mutations causing resistance to nucleosides and integrase can emerge.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Humanos , Feminino , Masculino , Lamivudina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Oxazinas/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , RNA/uso terapêuticoRESUMO
OBJECTIVES: To assess the effect of protease inhibitor (PI)-based dual therapy on CD4/CD8 ratio during the first year of therapy in antiretroviral therapy (ART)-naïve patients using data from randomized controlled clinical trials. METHODS: We pooled data from the GARDEL and ANDES studies, both randomized controlled clinical trials that recruited ART-naïve people living with HIV and randomly assigned them to receive PI-based dual therapy (DT) or triple therapy (TT) aiming to compare viral efficacy. We compared median CD4/CD8 ratios and the proportion of patients with CD4/CD8 ratio > 1 at 48 weeks after ART initiation in both treatment arms using the Mann-Whitney U-test and the χ2 test. We performed subgroup analysis for patients > 50 years old, with baseline CD4 counts ≤ 200 cells/µL, viral load > 100 000 HIV RNA copies/mL, and ritonavir-boosted lopinavir-based therapy. RESULTS: We analysed data from 571 patients: 292 on DT and 279 on TT. No differences were observed in CD4/CD8 ratio (0.632 vs. 0.617, P = 0.729) or in the proportion of patients with CD4/CD8 ratio > 1 (17.9% vs. 19.3%, P = 0.678) 48 weeks after ART initiation. Subgroup analysis showed no further differences. CONCLUSION: The impact of PI-based DT regimens on the CD4/CD8 ratio during the first year of treatment for ART-naïve patients is similar to that of TT.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Inibidores da Protease de HIV , HIV-1 , Contagem de Linfócito CD4 , Linfócitos T CD8-Positivos , Infecções por HIV/tratamento farmacológico , Humanos , Lamivudina/uso terapêutico , Pessoa de Meia-Idade , Inibidores da Transcriptase Reversa , Ritonavir/farmacologia , Ritonavir/uso terapêutico , Carga ViralRESUMO
BACKGROUND: The European AIDS Clinical Society (EACS) Guidelines cover key aspects of HIV management with major updates every two years. GUIDELINE HIGHLIGHTS: The 2019 Guidelines were extended with a new section focusing on drug-drug interactions and other prescribing issues in people living with HIV (PLWH). The recommendations for treatment-naïve PLWH were updated with four preferred regimens favouring unboosted integrase inhibitors. A two-drug regimen with dolutegravir and lamivudine, and a three-drug regimen including doravirine were also added to the recommended initial regimens. Lower thresholds for hypertension were expanded to all PLWH and for cardiovascular disease prevention, the 10-year predicted risk threshold for consideration of antiretroviral therapy (ART) modification was lowered from 20% to 10%. Frailty and obesity were added as new topics. It was specified to use urine albumin to creatinine ratio to screen for glomerular disease and urine protein to creatinine ratio for tubular diseases, and thresholds were streamlined with the Kidney Disease: Improving Global Outcomes (KDIGO) recommendations. Hepatitis C virus (HCV) treatment recommendations were split into preferred and alternative treatment options. The algorithm for management of recently acquired HCV infection was updated and includes recommendations for early chronic infection management. Treatment of resistant tuberculosis (TB) was streamlined with the World Health Organization (WHO) recommendations, and new tables on immune reconstitution inflammatory syndrome, on when to start ART in the presence of opportunistic infections and on TB drug dosing were included. CONCLUSIONS: The EACS Guidelines underwent major revisions of all sections in 2019. They are available in four different formats including a new interactive web-based version and are translated into Chinese, French, German, Japanese, Portuguese, Russian and Spanish.
Assuntos
Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , Fatores Etários , Comorbidade , Interações Medicamentosas , Quimioterapia Combinada , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Lamivudina/uso terapêutico , Oxazinas/uso terapêutico , Piperazinas/uso terapêutico , Piridonas/uso terapêutico , Resultado do Tratamento , Triazóis/uso terapêuticoRESUMO
AIMS: Hepatitis C virus antigen (HCV-Ag) detection requires retesting for samples with grey zone results (GzR), adding cost and time and decreasing reliability. Our aim in this study was to evaluate the frequency and significance of GzR during the use of the automated Architect HCV-Ag assay in routine clinical practice. METHODS AND RESULTS: We studied HCV-Ag levels in 952 serum samples using the ARCHITECT HCV-Ag assay. GzR were detected in 33 samples; 25 were reactive on retesting and 19 were anti-HCV positive. Seventeen of these 19 samples were tested for HCV-RNA and were all reactive (viral loads <104 IU ml-1 ). The remaining six samples were anti-HCV nonreactive and had undetectable HCV-RNA. Eight GzR samples were nonreactive on retesting, seven were anti-HCV nonreactive (three underwent HCV-RNA quantification and were all nonreactive), and one was anti-HCV reactive (HCV-RNA nonreactive). No significant differences were found on comparing HCV-Ag values. CONCLUSIONS: Grey zone results found to be negative on retesting do not need additional technique testing, except in donor screening scenarios, where the use of molecular methods would be advisable. SIGNIFICANCE AND IMPACT OF THE STUDY: The proposed diagnostic algorithm confirms that, eventhough GzR occur, hepatitis C virus antigen is a robust alternative to HCV-RNA detection in the active detection of infections.
Assuntos
Testes Diagnósticos de Rotina/métodos , Hepacivirus/isolamento & purificação , Antígenos da Hepatite C/sangue , Hepatite C/diagnóstico , Algoritmos , Feminino , Hepacivirus/imunologia , Hepatite C/sangue , Anticorpos Anti-Hepatite C/sangue , Humanos , Masculino , RNA Viral/sangue , Reprodutibilidade dos TestesRESUMO
OBJECTIVES: Our aim was to investigate factors associated with baseline blood telomere length in participants enrolled in NEAT 001/ANRS 143, a randomized, open-label trial comparing ritonavir-boosted darunavir (DRV/r) plus raltegravir (RAL) with DRV/r plus tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in antiretroviral therapy (ART)-naïve HIV-positive adults. METHODS: A cross-sectional study of 201 randomly selected participants who had stored samples available was carried out. We measured telomere length (i.e. the relative telomere length, calculated as the telomere to single copy gene ratio) at baseline with monochrome quantitative multiplex polymerase chain reaction (PCR). We used multivariable predictive linear regression to calculate mean differences and 95% confidence intervals (CIs) for the association between baseline telomere length and baseline characteristics. RESULTS: The baseline characteristics of the 201 participants did not differ from those of the 805 participants in the parent trial population: 89% were male, the mean age was 39 years, 83.6% were Caucasian, 93% acquired HIV infection via sexual transmission, the mean estimated time since HIV diagnosis was 2.1 years, the mean HIV-1 RNA load was 4.7 log10 HIV-1 RNA copies/mL, the mean nadir and baseline CD4 counts were 301 and 324 cells/µL, respectively, and the mean CD4:CD8 ratio was 0.4. In the univariate analysis, shorter telomere length was associated with older age (per 10 years) (P < 0.001), HIV-1 RNA ≥ 100 000 copies/mL (P = 0.001), CD4 count < 200 cells/µL (P = 0.037), lower CD4:CD8 ratio (P = 0.018), statin treatment (P = 0.004), and current alcohol consumption (P = 0.035). In the multivariable analysis, older age (P < 0.001) and HIV RNA ≥ 100 000 copies/mL (P = 0.054) were independently associated with shorter telomere length. CONCLUSIONS: Both age and HIV RNA viral load correlated with shorter blood telomere length in untreated persons living with HIV. These results suggest that HIV infection and age have synergistic and independent impacts upon immunosenescence.
Assuntos
Antirretrovirais/uso terapêutico , Infecções por HIV , Telômero , Adulto , Idoso , Estudos Transversais , Darunavir/uso terapêutico , Emtricitabina/uso terapêutico , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , RNA Viral/análise , Raltegravir Potássico/uso terapêutico , Ritonavir/uso terapêutico , Tenofovir/uso terapêuticoRESUMO
Background: BRCA1 and BRCA2 (BRCA1/2)-deficient tumors display impaired homologous recombination repair (HRR) and enhanced sensitivity to DNA damaging agents or to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). Their efficacy in germline BRCA1/2 (gBRCA1/2)-mutated metastatic breast cancers has been recently confirmed in clinical trials. Numerous mechanisms of PARPi resistance have been described, whose clinical relevance in gBRCA-mutated breast cancer is unknown. This highlights the need to identify functional biomarkers to better predict PARPi sensitivity. Patients and methods: We investigated the in vivo mechanisms of PARPi resistance in gBRCA1 patient-derived tumor xenografts (PDXs) exhibiting differential response to PARPi. Analysis included exome sequencing and immunostaining of DNA damage response proteins to functionally evaluate HRR. Findings were validated in a retrospective sample set from gBRCA1/2-cancer patients treated with PARPi. Results: RAD51 nuclear foci, a surrogate marker of HRR functionality, were the only common feature in PDX and patient samples with primary or acquired PARPi resistance. Consistently, low RAD51 was associated with objective response to PARPi. Evaluation of the RAD51 biomarker in untreated tumors was feasible due to endogenous DNA damage. In PARPi-resistant gBRCA1 PDXs, genetic analysis found no in-frame secondary mutations, but BRCA1 hypomorphic proteins in 60% of the models, TP53BP1-loss in 20% and RAD51-amplification in one sample, none mutually exclusive. Conversely, one of three PARPi-resistant gBRCA2 tumors displayed BRCA2 restoration by exome sequencing. In PDXs, PARPi resistance could be reverted upon combination of a PARPi with an ataxia-telangiectasia mutated (ATM) inhibitor. Conclusion: Detection of RAD51 foci in gBRCA tumors correlates with PARPi resistance regardless of the underlying mechanism restoring HRR function. This is a promising biomarker to be used in the clinic to better select patients for PARPi therapy. Our study also supports the clinical development of PARPi combinations such as those with ATM inhibitors.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Rad51 Recombinase/genética , Animais , Proteína BRCA1/genética , Proteína BRCA2/genética , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Mutação em Linhagem Germinativa , Humanos , Camundongos , Camundongos Nus , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Reparo de DNA por Recombinação/efeitos dos fármacos , Reparo de DNA por Recombinação/genética , Estudos Retrospectivos , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Background: Dual therapy (DT) with a ritonavir-boosted PI (PI/r) plus lamivudine has proven non-inferior (12% margin) to triple therapy (TT) with PI/r plus two nucleos(t)ide reverse transcriptase inhibitors [N(t)RTIs] in four clinical trials. It remains unclear whether DT is non-inferior based on the US FDA endpoint (virological failure with a margin of 4%) or in specific subgroups. Methods: We performed a systematic search (January 1990 to March 2017) of randomized controlled trials that compared switching of maintenance ART from TT to DT. The principal investigators were contacted and agreed to share study databases. The primary endpoint was non-inferiority of DT to TT based on the current FDA endpoint (4% non-inferiority margin for virological failure at week 48). We also analysed whether efficacy was modified by gender, active HCV infection and type of PI. Effect estimates and 95% CIs were calculated using generalized estimating equation-based models. Results: We found 881 references that yielded eight articles corresponding to four clinical trials (1051 patients). At week 48, 4% of patients on DT versus 3.04% on TT had experienced virological failure (difference 0.9%; 95% CI -1.2% to 3.1%), and 84.7% of patients on DT versus 83.2% on TT had <50 copies of HIV RNA/mL (FDA snapshot algorithm) (difference 1.4%; 95% CI -2.8% to 5.8%). Gender, active HCV infection and type of PI had no effect on differences in treatment efficacy between DT and TT. Conclusions: DT was non-inferior to TT using both current and past FDA endpoints. The efficacy of DT was not influenced by gender, active HCV infection status, or type of PI.
Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , Lamivudina/uso terapêutico , Ritonavir/uso terapêutico , Carga Viral/efeitos dos fármacos , Interpretação Estatística de Dados , HIV-1/efeitos dos fármacos , Humanos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: The European AIDS Clinical Society (EACS) Guidelines have since 2005 provided multidisciplinary recommendations for the care of HIV-positive persons in geographically diverse areas. GUIDELINE HIGHLIGHTS: Major revisions have been made in all sections of the 2017 Guidelines: antiretroviral treatment (ART), comorbidities, coinfections and opportunistic diseases. Newly added are also a summary of the main changes made, and direct video links to the EACS online course on HIV Management. Recommendations on the clinical situations in which tenofovir alafenamide may be considered over tenofovir disoproxil fumarate are provided, and recommendations on which antiretrovirals can be used safely during pregnancy have been revised. Renal and bone toxicity and hepatitis C virus (HCV) treatment have been added as potential reasons for ART switches in fully virologically suppressed individuals, and dolutegravir/rilpivirine has been included as a treatment option. In contrast, dolutegravir monotherapy is not recommended. New recommendations on non-alcoholic fatty liver disease, chronic lung disease, solid organ transplantation, and prescribing in elderly are included, and human papilloma virus (HPV) vaccination recommendations have been expanded. All drug-drug interaction tables have been updated and new tables are included. Treatment options for direct-acting antivirals (DAAs) have been updated and include the latest combinations of sofosbuvir/velpatasvir/voxilaprevir and glecaprevir/pibrentasvir. Recommendations on management of DAA failure and acute HCV infection have been expanded. For treatment of tuberculosis (TB), it is underlined that intermittent treatment is contraindicated, and for resistant TB new data suggest that using a three-drug combination may be as effective as a five-drug regimen, and may reduce treatment duration from 18-24 to 6-10 months. CONCLUSIONS: Version 9.0 of the EACS Guidelines provides a holistic approach to HIV care and is translated into the six most commonly spoken languages.
Assuntos
Antirretrovirais/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Adulto , Antirretrovirais/efeitos adversos , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Coinfecção/tratamento farmacológico , Interações Medicamentosas , Europa (Continente) , Feminino , Humanos , Masculino , Guias de Prática Clínica como Assunto , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Sociedades CientíficasRESUMO
OBJECTIVES: PROTEA is a randomized controlled trial to assess the efficacy and safety of darunavir/ritonavir (DRV/r) monotherapy as an alternative to triple therapy. METHODS: Patients fully suppressed on first-line antiretrovirals (viral load < 50 HIV-1 RNA copies/mL) were switched to DRV/r 800/100 mg once daily, either as monotherapy (n = 137) or with two nucleoside reverse transcriptase inhibitors (NRTIs) (n = 136). Treatment failure was HIV-1 RNA level ≥ 50 copies/mL at week 96 or discontinuation of study treatment [Food and Drug Administration (FDA) snapshot algorithm]. RESULTS: Patients were mainly male and white, with mean age 44 years. In the primary efficacy analysis, the percentage of patients with HIV-1 RNA < 50 copies/mL by week 96 [intent to treat (ITT)] was lower in the DRV/r monotherapy arm (103 of 137 patients; 75%) than in the triple therapy arm (116 of 136 patients; 85%) [difference -10.1%; 95% confidence interval (CI) -19.5, -0.7%]. In the switch-included analysis, monotherapy was noninferior to triple therapy. In a post hoc analysis, for patients with nadir CD4 count ≥ 200 cells/µL, rates of HIV-1 RNA suppression were 82 of 96 patients (85%) in the DRV/r monotherapy arm and 88 of 106 patients (83%) in the triple therapy arm. No treatment-emergent primary protease inhibitor mutations were detected in either arm. The frequency of adverse events was similar in the two arms; however, one patient in the monotherapy arm was hospitalized with HIV encephalitis and elevated cerebrospinal fluid HIV-1 RNA. CONCLUSIONS: In this study, in patients with HIV-1 RNA < 50 copies/mL at baseline, switching to DRV/r monotherapy showed lower efficacy vs. triple therapy at week 96 in the primary ITT switch-equals-failure analysis, particularly in patients with CD4 counts < 200 cells/µL.
Assuntos
Fármacos Anti-HIV/efeitos adversos , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Darunavir/efeitos adversos , Inibidores da Transcriptase Reversa/efeitos adversos , Ritonavir/efeitos adversos , Adulto , Fármacos Anti-HIV/administração & dosagem , Terapia Antirretroviral de Alta Atividade/métodos , Darunavir/administração & dosagem , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Transcriptase Reversa/administração & dosagem , Ritonavir/administração & dosagem , Resultado do Tratamento , Carga ViralRESUMO
We aimed to explore the brain imaging correlates of vocal emotion processing in a group of HIV+ individuals and to compare the vocal emotion processing of HIV+ individuals with a group of healthy adults. We conducted multiple linear regressions to determine the cerebral correlates of a newly designed vocal emotion processing test in a sub-group of HIV+ individuals who completed the cerebral magnetic resonance scan (n = 36). Separately, we test whether the association between our test scores and each cerebral measure persisted regardless of the presence of neurocognitive impairment. We also calculated differences in average test scores between the total HIV+ group (n = 100) and a healthy adult group (n = 46). We found a positive association between the test scores and several brain area volumes: right frontal, temporal and parietal lobes, bilateral thalamus, and left hippocampus. We found a negative association between inflammatory markers in frontal white matter and the test scores. After controlling by neurocognitive impairment, several brain area volumes remained positively associated to the prosody test scores. Moreover, the whole HIV+ sample had significantly poorer test scores than healthy adults, but only in the subset of HIV+ individuals with neurocognitive impairment. For the first time, our results suggest that cerebral dysfunctions in particular brain areas involved in the processing of emotional auditory stimuli may occur in HIV+ individuals. These results highlight the need for broad characterization of the neuropsychological consequence of HIV brain damages.
Assuntos
Sintomas Afetivos/fisiopatologia , Percepção Auditiva , Disfunção Cognitiva/fisiopatologia , Infecções por HIV/fisiopatologia , Adulto , Sintomas Afetivos/complicações , Sintomas Afetivos/diagnóstico por imagem , Sintomas Afetivos/virologia , Mapeamento Encefálico , Estudos de Casos e Controles , Disfunção Cognitiva/complicações , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/virologia , Feminino , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/patologia , Lobo Frontal/virologia , Infecções por HIV/complicações , Infecções por HIV/diagnóstico por imagem , Infecções por HIV/virologia , Hipocampo/diagnóstico por imagem , Hipocampo/patologia , Hipocampo/virologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Lobo Parietal/diagnóstico por imagem , Lobo Parietal/patologia , Lobo Parietal/virologia , Fala , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/patologia , Lobo Temporal/virologia , Tálamo/diagnóstico por imagem , Tálamo/patologia , Tálamo/virologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Substância Branca/virologiaRESUMO
OBJECTIVES: The aim of this analysis was to review the evidence and update a meta-analysis evaluating the efficacy and safety results from randomized controlled trials of ritonavir-boosted protease inhibitor (PI/r) monotherapy. METHODS: A PubMed/EMBASE search was conducted to find randomized trials of PI/r monotherapy vs. triple therapy in patients with HIV-1 RNA suppression at baseline (<50 HIV-1 RNA copies/mL). Rates of virological suppression were analysed using switch-equals-failure and intensification-included endpoints [intent-to-treat (ITT)]. The rate of treatment-emergent resistance mutations, neurocognitive function endpoints, and cerebrospinal fluid (CSF) HIV-1 RNA were also analysed by treatment arm. RESULTS: There were 2303 patients from 13 different randomized clinical trials of darunavir/r monotherapy (n = 784: MONET, MONOI, Monarch and PROTEA), lopinavir/r monotherapy (n = 829: OK pilot, OK-04, KalMo, KALESOLO, KRETA, MOST and DREAM), atazanavir/r monotherapy (n = 103: MODAT), or all three (n = 587: PIVOT). HIV-1 RNA plasma suppression was lower in the PI/r monotherapy arm compared with the triple therapy arm in the switch-equals-failure analysis [difference -8.3%; 95% confidence interval (CI) -11.9 to -4.8%], but not when intensification was included (difference 0.5%; 95% CI -2.5 to 3.6%). Rates of resistance mutations were similar between arms, as was overall neurocognitive function. CONCLUSIONS: PI/r monotherapy showed a higher risk of plasma HIV-1 RNA elevations. However, there was no increased risk of treatment-emergent drug resistance, neurocognitive endpoints did not differ, and HIV-1 RNA suppression rates after intensification were similar between PI/r monotherapy and triple therapy.
Assuntos
Sulfato de Atazanavir/uso terapêutico , Darunavir/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , Lopinavir/uso terapêutico , Ritonavir/uso terapêutico , Líquido Cefalorraquidiano/virologia , Esquema de Medicação , Quimioterapia Combinada , Infecções por HIV/sangue , HIV-1/genética , Humanos , RNA Viral/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
The aim of this study was the evaluation of the influence of the susceptibility patterns of Escherichia coli and Klebsiella pneumoniae isolates, specifically the presence of extended-spectrum ß-lactamases and the geographical area (Europe and USA), on the meropenem dosing requirements in critically ill patients with different degrees of renal function by estimation of the probability of pharmacokinetic/pharmacodynamic (PK/PD) target attainment. Additionally, estimation of the PK/PD breakpoints according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) approach was also an objective. Six dosing regimens were evaluated: 0.5 g, 1 g and 2 g every 8 h given as 0.5-h or 3-h infusions. Pharmacokinetic data were obtained from the literature, and susceptibility data to meropenem for E. coli and K. pneumoniae were collected from the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) surveillance study. For the same dose level, the 3-h infusion provided a probability of target attainment (PTA) ≥90 % for minimum inhibitory concentration (MIC) values up to two-fold dilution higher than those obtained with the 0.5-h infusion. For E. coli, the cumulative fraction of response (CFR) was 100 % in most cases, and neither the dose nor the infusion length nor the geographical area significantly affected the probability to reach the target. With regards to K. pneumoniae, the CFR increased when increasing the dose and decreasing the creatinine clearance (CLCR). The CFR for Spanish and USA strains was higher than that calculated for European strains. Meropenem PK/PD breakpoints are dependent on the dose, infusion length and CLCR, ranging from 2 to 32 mg/L. Based on our results, meropenem administered as a extended infusion is the best option to treat infections due to E. coli and K. pneumoniae.
Assuntos
Antibacterianos/administração & dosagem , Estado Terminal/terapia , Infecções por Enterobacteriaceae/tratamento farmacológico , Infecções por Enterobacteriaceae/microbiologia , Enterobacteriaceae/efeitos dos fármacos , Tienamicinas/administração & dosagem , Algoritmos , Antibacterianos/farmacocinética , Farmacorresistência Bacteriana , Enterobacteriaceae/genética , Europa (Continente) , Feminino , Geografia , Humanos , Testes de Função Renal , Masculino , Meropeném , Testes de Sensibilidade Microbiana , Método de Monte Carlo , Fatores de Risco , Tienamicinas/farmacocinética , Estados Unidos , beta-Lactamases/biossíntese , beta-Lactamases/genéticaRESUMO
Disposable masks, formed mainly from polymers, often incorporate various chemical additives to enhance their performance. These additives, which include plasticizers, may be released during mask usage, presenting a novel source of human exposure to these compounds. In this study, the presence of 16 organophosphate esters (OPEs), 11 phthalates, and four alternative plasticizers, in four various types of face masks, were studied, as well as their release during simulated mask use (artificial laboratory conditions). Total plasticizer concentrations exhibited minimal variation across different mask types, with mean values of 7.27 µg/face mask for surgical, 8.61 µg/face mask for reusable, 11.0 µg/face mask for KN-95, and 13.9 µg/face mask for FFP2 masks. To explore plasticizer release behavior, inhalation experiments were conducted under different conditions. The findings revealed a significant temperature-dependent enhancement in plasticizer release from masks, subsequently increasing human inhalation exposure. The inhalation experiments showed variation in the release percentages, ranging from 0.1 to 95 %, depending on the specific compound and mask type. Notably, OPEs exhibited a mean release percentage of 1.0 %, similar to phthalates, which showed a 1.2 % release. Although alternative plasticizers were less frequently released, they still presented a notable percentage of release of 4.1 %. Daily intake estimations via inhalation ranged from 0.01 to 9.04 ng/kg body weight (bw)/day for these additives. Using these estimations, carcinogenic and non-carcinogenic risks associated with this exposure to these compounds were evaluated. All calculated values for the specific compounds studied in this paper remained below the established threshold limits. However, they do represent an additional exposure pathway that, when considered alongside other more predominant routes such as indoor/outdoor inhalation, dermal absorption, and dietary intake, makes the total exposure worthy of consideration.
RESUMO
BACKGROUND: Discontinuation of thymidine nucleoside reverse transcriptase inhibitors (tNRTIs) is the only proven strategy for improving lipoatrophy. It is unclear whether switching to NRTI-sparing or to non-thymidine NRTI-containing therapy has differential effects on body fat recovery. METHODS: This was a 96 week, open-label, randomized study in suppressed patients with moderate/severe lipoatrophy and no prior virological failure while receiving a protease inhibitor and who had their triple NRTI regimen (zidovudine/lamivudine/abacavir) switched to lopinavir/ritonavir plus abacavir/lamivudine for a 1 month run-in period and then randomized to lopinavir/ritonavir plus abacavir/lamivudine versus lopinavir/ritonavir monotherapy. The KRETA trial is registered with ClinicalTrials.gov (number NCT00865007). RESULTS: Of 95 patients included, 88 were randomized to lopinavir/ritonavir plus abacavir/lamivudine (nâ=â44) or lopinavir/ritonavir monotherapy (nâ=â44). Median (IQR) baseline limb fat was 2.5 (1.6-3.7) kg in the lopinavir/ritonavir plus abacavir/lamivudine group and 2.5 (2.0-5.4) kg in the lopinavir/ritonavir monotherapy group. Six patients in the triple therapy group and 13 in the monotherapy group had discontinued study drugs by week 96. Although there were limb fat gains in each group at weeks 48/96 (+324/+358 g in lopinavir/ritonavir plus abacavir/lamivudine, Pâ=â0.09/0.07, versus +215/+416 g in the lopinavir/ritonavir monotherapy group, Pâ=â0.28/0.16), differences between groups were not significant [difference +109 g (95% CI -442, +660)/-57 g (95% CI -740, +625)]. CONCLUSIONS: In lipoatrophic patients treated with zidovudine/lamivudine/abacavir, switching to lopinavir/ritonavir monotherapy had no additional benefit in limb fat recovery relative to switching to lopinavir/ritonavir with abacavir/lamivudine. These data suggest that non-thymidine nucleosides such as abacavir/lamivudine are not an obstacle to limb fat recovery.
Assuntos
Tecido Adiposo/patologia , Terapia Antirretroviral de Alta Atividade/métodos , Didesoxinucleosídeos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , Lamivudina/uso terapêutico , Lipodistrofia/complicações , Lopinavir/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Ritonavir/uso terapêutico , Absorciometria de Fóton , Adulto , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Atrofia , Composição Corporal/fisiologia , Química Farmacêutica , Didesoxinucleosídeos/efeitos adversos , Feminino , Infecções por HIV/virologia , Inibidores da Protease de HIV/efeitos adversos , Humanos , Análise de Intenção de Tratamento , Lamivudina/efeitos adversos , Lipídeos/sangue , Lopinavir/efeitos adversos , Masculino , Pessoa de Meia-Idade , Inibidores da Transcriptase Reversa/efeitos adversos , Ritonavir/efeitos adversos , Falha de TratamentoRESUMO
INTRODUCTION: Cardiac myxoma is an important but uncommon cause of stroke in younger patients. Few published case series analyse the frequency and clinical presentation of neurological complications in patients with myxoma. OBJECTIVE: To list all neurological complications from cardiac myxoma recorded in our hospital in the past 28 years. PATIENTS AND METHODS: We retrospectively reviewed the neurological manifestations of cardiac myxoma in patients treated in our hospital between December 1983 and March 2012. RESULTS: Of the 36 patients with cardiac myxoma, 8 (22%) presented neurological manifestations. Half were women and mean age of patients was 52.4 ± 11.6 years. Sudden-onset hemiparesis was the most frequent neurological symptom (63%). Established ischaemic stroke was the most common clinical manifestation (75%), followed by transient ischemic attack. The most commonly affected territory corresponded to the middle cerebral artery. Myxoma was diagnosed by echocardiography in all cases. Mean myxoma size was 4.1cm and most of the tumours (63%) had a polypoid surface. All tumours were successfully removed by surgery. There were no in-hospital deaths. CONCLUSIONS: Cardiac myxomas frequently present with neurological symptoms, especially ischaemic events (established stroke or transient ischaemic attack), in younger patients with no cardiovascular risk factors. The anterior circulation is more frequently affected, especially the middle cerebral artery. Echocardiography can facilitate prompt diagnosis and early treatment of the lesion.
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Neoplasias Cardíacas/complicações , Mixoma/complicações , Doenças do Sistema Nervoso/etiologia , Adulto , Isquemia Encefálica/etiologia , Eletrocardiografia , Feminino , Seguimentos , Neoplasias Cardíacas/patologia , Humanos , Infarto da Artéria Cerebral Média/etiologia , Masculino , Pessoa de Meia-Idade , Mixoma/patologia , Doenças do Sistema Nervoso/patologia , Neuroimagem , Paresia/etiologia , Estudos Retrospectivos , Acidente Vascular Cerebral/etiologia , Resultado do TratamentoRESUMO
Clinical Pathways are care plans that are applied to clinical processes with a predictable course, with the intention of protocolizing these processes and reducing the variability in their management. Our objective was to develop a clinical pathway for 131I metabolic therapy in its application to differentiated thyroid cancer. A work team was organized consisting of doctors (Endocrinology and Nuclear Medicine), nursing staff (Hospitalization Unit and Nuclear Medicine), Radiophysics and the Clinical Management and Continuity of Care Support Service. For the design of the clinical pathway, several team meetings were held, in which the literature reviews were pooled and the design and development of the clinical pathway was undertaken in accordance with current clinical guidelines. This team achieved consensus on the development of the care plan, establishing its key points and drafting the different documents that make up the Clinical Pathway: Timeframe-based schedule, Clinical Pathway Variation Record Document, Patient Information Documents, Patient Satisfaction Survey, Pictogram Brochure, Quality Assessment Indicators. Finally, the clinical pathway was presented to all the clinical departments involved and to the Medical Director of the Hospital and is now being implemented in clinical practice.
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Procedimentos Clínicos , Neoplasias da Glândula Tireoide , Humanos , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/radioterapiaRESUMO
BACKGROUND: In the MONotherapy in Europe with Tmc114 (MONET) trial, darunavir/ritonavir (DRV/r) monotherapy showed noninferior efficacy vs. two nucleoside reverse transcriptase inhibitors (NRTIs) plus DRV/r at the primary 48-week analysis. The trial was continued to week 144 to assess the durability of the results. METHODS: A total of 256 patients with viral load < 50 HIV-1 RNA copies/mL on current highly active antiretroviral therapy (HAART) for at least 6 months switched to DRV/r 800/100 mg once daily, either as monotherapy (n=127) or with two NRTIs (n=129). Treatment failure was defined as two consecutive HIV RNA levels above 50 copies/mL [time to loss of virological response (TLOVR)] by week 144, or discontinuation of study drugs. RESULTS: Eighty-one per cent of patients were male and 91% were Caucasian, and they had a median baseline CD4 count of 575 cells/uL. More patients in the DRV/r monotherapy arm had hepatitis C virus coinfection at baseline than in the control arm (18% vs. 12%, respectively). By week 144, the percentage of patients with HIV RNA < 50 copies/mL [intent to treat (ITT), TLOVR, switch=failure method] was 69% vs. 75% in the DRV/r monotherapy and triple therapy arms [difference= -5.9%; 95% confidence interval (CI) -16.9%, +5.1%]; by a strict ITT analysis (switches not considered failures), the percentage of patients with HIV RNA < 50 copies/mL was 84% vs. 83.5%, respectively (difference= +0.5%; 95% CI -8.7%, +9.7%). Twenty-one and 13 patients had two consecutive HIV RNA results above 50 copies/mL in the DRV/r monotherapy arm and triple therapy arm, respectively, of whom 18 of 21 (86%) and 10 of 13 (77%) had HIV RNA < 50 copies/mL at week 144. CONCLUSIONS: In this study, for patients with HIV RNA < 50 copies/mL at baseline, switching to DRV/r monotherapy showed noninferior efficacy to DRV/r plus two NRTIs in a strict ITT (switches not considered failures) analysis, but not in a TLOVR switch equals failure analysis.
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Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , RNA Viral/efeitos dos fármacos , Inibidores da Transcriptase Reversa/uso terapêutico , Ritonavir/uso terapêutico , Sulfonamidas/uso terapêutico , Síndrome da Imunodeficiência Adquirida/imunologia , Adulto , Idoso , Contagem de Linfócito CD4 , Darunavir , Esquema de Medicação , Feminino , Inibidores da Protease de HIV/administração & dosagem , Humanos , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , RNA Viral/imunologia , Inibidores da Transcriptase Reversa/administração & dosagem , Ritonavir/administração & dosagem , Sulfonamidas/administração & dosagem , Inquéritos e Questionários , Resultado do Tratamento , Carga ViralRESUMO
We described clinical characteristics and outcome of 160 patients over 65 years (01 September to 31 August 2021) who had a first positive SARS-CoV-2 PCR- test more than 14 days after full vaccination and were hospitalized with COVID-19. Median age of included patients was 84 years, 61.2% were over 80 years; 50.6% were male and most (82.5%) has at least one comorbidity. Up to 84% received specific treatment against COVID-19, including 76.9% low-flow oxygen therapy. We found that overall mortality was 25.6% and 30.6% in those older than 80 years. A higher mortality was significantly associated with older age and treatment with tocilizumab. Our data showed that although COVID-19 vaccines continue protecting elderly patients against hospitalization and death and might improve the prognosis after hospitalization in patients with breakthrough infections, mortality in this population -especially in those older than 80 years- remains very high.
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COVID-19 , Idoso , Idoso de 80 Anos ou mais , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Comorbidade , Feminino , Hospitalização , Humanos , Masculino , SARS-CoV-2RESUMO
Background: Nonalcoholic fatty liver disease (NAFLD) is a major nonacquired immune deficiency syndrome-defining condition for persons with human immunodeficiency virus (PWH). We aimed to validate noninvasive tests for the diagnosis of NAFLD in PWH. Methods: This is a cross-sectional study of PWH on stable antiretroviral therapy with persistently elevated transaminases and no known liver disease. The area under the receiver operating characteristic curve (AUROC) was calculated to compare the diagnostic accuracy of liver biopsy with abdominal ultrasound, transient elastography (TE) (including controlled attenuation parameter [CAP]), and noninvasive markers of steatosis (triglyceride and glucose index [TyG], hepatic steatosis index [HSI], fatty liver index [FLI]) and fibrosis ([FIB]-4, aminotransferase-to-platelet ratio index [APRI], NAFLD fibrosis score). We developed a diagnostic algorithm with serial combinations of markers. Results: Of 146 patients with increased transaminase levels, 69 underwent liver biopsy (90% steatosis, 61% steatohepatitis, and 4% F ≥3). The AUROC for steatosis was as follows: ultrasound, 0.90 (0.75-1); CAP, 0.94 (0.88-1); FLI, 0.81 (0.58-1); HSI, 0.74 (0.62-0.87); and TyG, 0.75 (0.49-1). For liver fibrosis ≥F3, the AUROC for TE, APRI, FIB-4, and NAFLD fibrosis score was 0.92 (0.82-1), 0.96 (0.90-1), 0.97 (0.93-1), and 0.85 (0.68-1). Optimal diagnostic performance for liver steatosis was for 2 noninvasive combined models of tests with TyG and FLI/HSI as the first tests and ultrasound or CAP as the second tests: AUROC = 0.99 (0.97-1, P < .001) and 0.92 (0.77-1, P < .001). Conclusions: Ultrasound and CAP performed best in diagnosing liver steatosis, and FLI, TyG, and HSI performed well. We propose an easy-to-implement algorithm with TyG or FLI as the first test and ultrasound or CAP as the second test to accurately diagnose or exclude NAFLD.
RESUMO
HIV infection is now almost 40 years old. In this time, along with the catastrophe and tragedy that it has entailed, it has also represented the capacity of modern society to take on a challenge of this magnitude and to transform an almost uniformly lethal disease into a chronic illness, compatible with a practically normal personal and relationship life. This anniversary seemed an ideal moment to pause and reflect on the future of HIV infection, the challenges that remain to be addressed and the prospects for the immediate future. This reflection has to go beyond merely technical approaches, by specialized professionals, to also address social and ethical aspects. For this reason, the Health Sciences Foundation convened a group of experts in different aspects of this disease to discuss a series of questions that seemed pertinent to all those present. Each question was presented by one of the participants and discussed by the group. The document we offer is the result of this reflection.