RESUMO
BACKGROUND: Carbamazepine (CBZ) is an antiseizure medication known to induce the expression of cytochrome P4503A metabolic enzymes. Here, we describe a man living with HIV who underwent several changes in the daily dose of CBZ, which resulted in different induction effects on darunavir trough concentrations. METHODS: A 59-year-old man with HIV, successfully undergoing maintenance antiretroviral treatment with darunavir/cobicistat once daily (combined with raltegravir), was prescribed CBZ for recurrent trigeminal neuralgia. Over subsequent months, the patient underwent various changes in the doses (from 200 to 800 mg/d) and trough concentrations (from 3.6 to 18.0 mg/L) of CBZ, guided by clinical response to trigeminal neuralgia. RESULTS: A highly significant inverse association was observed between darunavir trough concentration and both CBZ dose or trough concentration (coefficient of determination >0.75, P < 0.0001). Ultimately, the darunavir dose was increased to 600 mg twice daily with ritonavir and dolutegravir to ensure optimal antiretroviral coverage, anticipating potential further uptitration of CBZ doses. CONCLUSIONS: The impact of CBZ on boosted darunavir exposure seemed to be dose- and concentration-dependent. The management of such drug-drug interactions in daily practice was facilitated through therapeutic drug monitoring. This case underscores the importance of a multidisciplinary approach that incorporates both antiretroviral and nonantiretroviral comedications contributing to the optimal management of polypharmacy in individuals living with HIV.
Assuntos
Carbamazepina , Darunavir , Interações Medicamentosas , Infecções por HIV , Humanos , Darunavir/uso terapêutico , Darunavir/farmacocinética , Masculino , Pessoa de Meia-Idade , Carbamazepina/uso terapêutico , Carbamazepina/farmacocinética , Infecções por HIV/tratamento farmacológico , Neuralgia do Trigêmeo/tratamento farmacológico , Ritonavir/uso terapêutico , Ritonavir/administração & dosagem , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/administração & dosagem , Piridonas/farmacocinética , Piridonas/uso terapêutico , Piridonas/sangue , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Piperazinas/uso terapêutico , Piperazinas/farmacocinética , Oxazinas/uso terapêutico , Oxazinas/farmacocinética , Relação Dose-Resposta a Droga , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/administração & dosagem , Monitoramento de Medicamentos/métodosRESUMO
Protease inhibitors (PIs) remain an important component of antiretroviral therapy for the treatment of HIV-1 infection due to their high genetic barrier to resistance development. Nevertheless, the two most commonly prescribed HIV PIs, atazanavir and darunavir, still require co-administration with a pharmacokinetic boosting agent to maintain sufficient drug plasma levels which can lead to undesirable drug-drug interactions. Herein, we describe GS-9770, a novel investigational non-peptidomimetic HIV PI with unboosted once-daily oral dosing potential due to improvements in its metabolic stability and its pharmacokinetic properties in preclinical animal species. This compound demonstrates potent inhibitory activity and high on-target selectivity for recombinant HIV-1 protease versus other aspartic proteases tested. In cell culture, GS-9770 inhibits Gag polyprotein cleavage and shows nanomolar anti-HIV-1 potency in primary human cells permissive to HIV-1 infection and against a broad range of HIV subtypes. GS-9770 demonstrates an improved resistance profile against a panel of patient-derived HIV-1 isolates with resistance to atazanavir and darunavir. In resistance selection experiments, GS-9770 prevented the emergence of breakthrough HIV-1 variants at all fixed drug concentrations tested and required multiple protease substitutions to enable outgrowth of virus exposed to escalating concentrations of GS-9770. This compound also remained fully active against viruses resistant to drugs from other antiviral classes and showed no in vitro antagonism when combined pairwise with drugs from other antiretroviral classes. Collectively, these preclinical data identify GS-9770 as a potent, non-peptidomimetic once-daily oral HIV PI with potential to overcome the persistent requirement for pharmacological boosting with this class of antiretroviral agents.
Assuntos
Infecções por HIV , Inibidores da Protease de HIV , HIV-1 , Humanos , Inibidores da Protease de HIV/farmacologia , Inibidores da Protease de HIV/uso terapêutico , Darunavir/farmacologia , Darunavir/uso terapêutico , Sulfato de Atazanavir/farmacologia , Sulfato de Atazanavir/uso terapêutico , Farmacorresistência Viral , HIV-1/genética , Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Protease de HIV/genética , Protease de HIV/metabolismoRESUMO
Background: The primary objective of this study was to estimate the proportion of people living with HIV (PLWH) who switched from a non-protease inhibitor (PI)-based regimen [integrase strand transfer inhibitor (InSTI)-based or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen] to darunavir, cobicistat, emtricitabine, tenofovir alafenamide (D/C/F/TAF). Methods: This was a retrospective study on PLWH treated with a non-PI regimen in January 2017, who switched to D/C/F/TAF or to another antiretroviral therapy (ART) within November 2019. Follow-up was from the start date of D/C/F/TAF until the last available visit or discontinuation for any reason of this regimen. Virological failure (VF) was defined as 2 consecutive HIV-RNA values >50 copies/mL. Characteristics were reported as median (interquartile range) or frequency (%). A univariate Poisson regression model was used to measure the incidence rate of switch to D/C/F/TAF. Changes in laboratory parameters during D/C/F/TAF were assessed by univariate mixed linear models. Results: Overall, 3076 PLWH were included; 83% were male, median age at ART switch was 50 (42-56) years and median time on ART was 5.2 (0.3-13.0) years. PLWH had a median follow-up of 4.76 (3.70-6.38) years; during 17,099 person-years of follow-up (PYFU), 423/3076 (14%) participants discontinued the non-PI-based regimen and 106/423 (25%) switched to D/C/F/TAF, with an overall incidence rate of switch to D/C/F/TAF of 6.2 per 1000-PYFU (95% CI: 5.0-7.4). Among PLWH who switched to D/C/F/TAF, the ongoing regimen was based on NNRTIs in 37 (35%) and on InSTIs in 69 (65%). Main reasons leading to switch to D/C/F/TAF included neuropsychiatric adverse events (37%), VF (26%) and Kaposi sarcoma progression (5%). Conclusion: In the last years, a non-negligible proportion of patients on an NNRTI- or an InSTI-based regimen switched to D/C/F/TAF.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Alanina/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Cobicistat/uso terapêutico , Darunavir/uso terapêutico , Emtricitabina/uso terapêutico , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Estudos Retrospectivos , Inibidores da Transcriptase Reversa , Tenofovir/análogos & derivadosRESUMO
ABSTRACT: High cardiovascular disease risk in people living with HIV is partly attributed to antiretroviral therapy (ART). Lipid response to ART has been extensively studied, yet, little is known how small molecule lipids respond to Integrase inhibitor-based (INSTI-based) compared to Protease inhibitor-based (PI-based) ART regimens.Ancillary study to a phase 3, randomized, open-label trial [AIDS Clinical Trial Group A5257 Study] in treatment-naive HIV-infected patients randomized in a 1:1:1 ratio to receive ritonavir-boosted atazanavir (ATV/r), ritonavir-boosted darunavir (DRV/r) (both PI-based), or raltegravir with Tenofovir Disoproxil Fumarate-TDF plus emtricitabine (RAL, INSTI-based).We examined small molecule lipid response in a subcohort of 75 participants. Lipidomic assays of plasma samples collected pre- and post-ART treatment (48âweeks) were conducted using ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry. The effect of ART regimens was regressed on lipid species response adjusting for the baseline covariates (lipids, age, sex, race, CD4 level, BMI, and smoking). Results were validated in the Centers for AIDS Research Network of Integrated Clinical Systems study (Nâ=â16).Out of 417 annotated lipids, glycerophospholipids (Pâ=â.007) and sphingolipids (Pâ=â.028) had a higher response to ATV/r and DRV/r compared to RAL. The lysophosphatidylcholine (LPCs(16:1),(17:1),(20:3)) and phosphophatidylcholine species (PCs(40:7),(38:4)) had an opposite response to RAL versus ATV/r in the discovery and validation cohort. The INSTI-based regimen had an opposite response of ceramide species ((d38:1), (d42:2)), PCs((35:2), (38:4)), phosphatidylethanolamines (PEs(38:4), (38:6)), and sphingomyelin(SMd38:1) species compared with the PI-based regimens. There were no differences observed between 2 PI-based regimens.We observed differences in response of small molecule lipid species by ART regimens in treatment-naive people living with HIV.
Assuntos
Antirretrovirais/efeitos adversos , Lipidômica/métodos , Adulto , Antirretrovirais/uso terapêutico , Sulfato de Atazanavir/efeitos adversos , Sulfato de Atazanavir/uso terapêutico , Distribuição de Qui-Quadrado , Darunavir/efeitos adversos , Darunavir/uso terapêutico , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/fisiopatologia , Humanos , Lipidômica/estatística & dados numéricos , Lipídeos , Masculino , Espectrometria de Massas/métodos , Pessoa de Meia-Idade , Plasma/efeitos dos fármacos , Raltegravir Potássico/efeitos adversos , Raltegravir Potássico/uso terapêutico , Tenofovir/efeitos adversos , Tenofovir/uso terapêuticoRESUMO
Despite aggressive efforts on containment measures for the coronavirus disease 2019 (COVID-19) pandemic around the world, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continuously spreading. Therefore, there is an urgent need for an effective antiviral agent. To date, considerable research has been conducted to develop different approaches to COVID-19 therapy. In addition to early observational studies, which could be limited by study design, small sample size, non-randomized design, or different timings of treatment, an increasing number of randomized controlled trials (RCTs) investigating the clinical efficacy and safety of antiviral agents are being carried out. This study reviews the updated findings of RCTs regarding the clinical efficacy of eight antiviral agents against COVID-19, including remdesivir, lopinavir/ritonavir, favipiravir, sofosbuvir/daclatasvir, sofosbuvir/ledipasvir, baloxavir, umifenovir, darunavir/cobicistat, and their combinations. Treatment with remdesivir could accelerate clinical improvement; however, it lacked additional survival benefits. Moreover, 5-day regimen of remdesivir might show adequate effectiveness in patients with mild to moderate COVID-19. Favipiravir was only marginally effective regarding clinical improvement and virological assessment based on the results of small RCTs. The present evidence suggests that sofosbuvir/daclatasvir may improve survival and clinical outcomes in patients with COVID-19. However, the sample sizes for analysis were relatively small, and all studies were exclusively conducted in Iran. Further larger RCTs in other countries are warranted to support these findings. In contrast, the present findings of limited RCTs did not indicate the use of lopinavir/ritonavir, sofosbuvir/ledipasvir, baloxavir, umifenovir, and darunavir/cobicistat in the treatment of patients hospitalized for COVID-19.
Assuntos
Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Amidas/uso terapêutico , Carbamatos/uso terapêutico , Cobicistat/uso terapêutico , Darunavir/uso terapêutico , Dibenzotiepinas/uso terapêutico , Combinação de Medicamentos , Quimioterapia Combinada , Humanos , Imidazóis/uso terapêutico , Indóis/uso terapêutico , Irã (Geográfico) , Lopinavir/uso terapêutico , Morfolinas/uso terapêutico , Pirazinas/uso terapêutico , Piridonas/uso terapêutico , Pirrolidinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Ritonavir/uso terapêutico , SARS-CoV-2 , Sofosbuvir/uso terapêutico , Resultado do Tratamento , Triazinas/uso terapêutico , Valina/análogos & derivados , Valina/uso terapêuticoRESUMO
This case series describes three patients affected by severe acute respiratory syndrome coronavirus 2, who developed polyradiculoneuritis as a probable neurological complication of coronavirus disease 2019 (COVID-19). A diagnosis of Guillain Barré syndrome was made on the basis of clinical symptoms, cerebrospinal fluid analysis, and electroneurography. In all of them, the therapeutic approach included the administration of intravenous immunoglobulin (0.4 gr/kg for 5 days), which resulted in the improvement of neurological symptoms. Clinical neurophysiology revealed the presence of conduction block, absence of F waves, and in two cases, a significant decrease in amplitude of compound motor action potential cMAP. Due to the potential role of inflammation on symptoms development and prognosis, interleukin-6 (IL-6) and IL-8 levels were measured in serum and cerebrospinal fluid during the acute phase, while only serum was tested after recovery. Both IL-6 and IL-8 were found increased during the acute phase, both in the serum and cerebrospinal fluid, whereas 4 months after admission (at complete recovery), only IL-8 remained elevated in the serum. These results confirm the inflammatory response that might be linked to peripheral nervous system complications and encourage the use of IL-6 and IL-8 as prognostic biomarkers in COVID-19.
Assuntos
COVID-19/complicações , Síndrome de Guillain-Barré/complicações , Interleucina-6/líquido cefalorraquidiano , Interleucina-8/líquido cefalorraquidiano , Insuficiência Respiratória/complicações , SARS-CoV-2/patogenicidade , Potenciais de Ação/efeitos dos fármacos , Doença Aguda , Idoso , Antibacterianos/uso terapêutico , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , COVID-19/líquido cefalorraquidiano , COVID-19/virologia , Convalescença , Darunavir/uso terapêutico , Combinação de Medicamentos , Síndrome de Guillain-Barré/líquido cefalorraquidiano , Síndrome de Guillain-Barré/tratamento farmacológico , Síndrome de Guillain-Barré/virologia , Humanos , Hidroxicloroquina/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Interleucina-6/sangue , Interleucina-8/sangue , Lopinavir/uso terapêutico , Masculino , Condução Nervosa/efeitos dos fármacos , Sistema Nervoso Periférico/efeitos dos fármacos , Sistema Nervoso Periférico/patologia , Sistema Nervoso Periférico/virologia , Prognóstico , Insuficiência Respiratória/líquido cefalorraquidiano , Insuficiência Respiratória/tratamento farmacológico , Insuficiência Respiratória/virologia , Ritonavir/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , Tratamento Farmacológico da COVID-19RESUMO
Darunavir: (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl [(2S,3R)-4-{[(4-aminophenyl)sulfonyl] (isobutyl)amino}-3-hydroxy-1-phenyl-2-butanyl]carbamate is a synthetic non-peptide protease inhibitor. On June 2006, it was first approved by the Food and Drug administration (FDA) for treatment of resistant type-1 of the human immunodeficiency virus (HIV). In July 2016, the FDA expanded the approval for use of darunavir in pregnant women with HIV infection. Darunavir prevents the replication of HIV virus by inhibiting the catalytic activity of the HIV-1 protease enzyme, and selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in virus-infected cells, which prevents the formation of mature infectious virus particles. Darunavir is unique among currently available protease inhibitors because it maintains antiretroviral activity against a variety of multidrug-resistant HIV strains. This article discusses, by a critical extensive review of the literature, the description of darunavir in terms of its names, formulae, elemental composition, appearance, and use in the treatment of HIV-infected patients. The article also discusses the methods for preparation of darunavir, its physical-chemical properties, analytical methods for its determination, pharmacological properties, and dosing information.
Assuntos
Darunavir , Infecções por HIV , Inibidores da Protease de HIV , HIV-1 , Darunavir/farmacologia , Darunavir/uso terapêutico , Farmacorresistência Viral , Feminino , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/farmacologia , Inibidores da Protease de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Humanos , Gravidez , Estados UnidosRESUMO
Background/Aims: Switching from a three-drug regimen (3DR: boosted darunavir [bDRV] and two nucleoside reverse transcriptase inhibitors [NRTIs]) to a two-drug regimen (2DR: bDRV and dolutegravir [DTG]) demonstrated non-inferiority with regard to viral suppression in people living with HIV (PLWH) in the DUALIS study. This sub-analysis focuses on changes in metabolic and renal parameters when sparing the NRTI backbone.Methods: DUALIS was a randomized, open-label, multicenter (27) phase 3-trial. Participants were virologically suppressed (HIV-RNA < 50 copies/mL) on 3DR for at least 24 weeks. Subjects were either switched to DTG 50 mg + bDRV 800 mg (with ritonavir 100 mg) (2DR) or continued their regimen consisting of two NRTIs in combination with ritonavir-bDRV (3DR) once daily. Data of metabolic and renal parameters at baseline and week 48 were compared.Results: The LDL-fraction increased by + 13.3 (-3.0 to +31.3) mg/dL on 2DRs and was stable (-14.0 to +18.0 mg/dL) on 3DRs (p < 0.0010).PLWH gained +2.0 (-0.2 to +4.0) kg and +0.2 (-1.9 to +2.1) kg in body weight on 2DRs and 3DRs, respectively 3 (p = 0.0006).The MDRD eGFR decreased by -7,8 (-17.4 to -0.3) mL/min/1.73m2 and 0.4 (-8.8 to +5.7) mL/min/1.73m2 on 2DRs and 3DRs, respectively (p = 0.0002), while serum levels of cystatin C were stable in both arms (2DR: -0.1 to +0.1 mg/L; 3DR: 0.0 to +0.1 mg/L).Conclusions: While being non-inferior in terms of viral suppression, sparing the NRTI backbone showed a non-favorable profile in metabolic or renal parameters over 48 weeks.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Fármacos Anti-HIV/uso terapêutico , Darunavir/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Humanos , Ritonavir/uso terapêuticoRESUMO
INTRODUCTION: Most of the drugs associations that have been used to treat patients with SARS-CoV-2 infection increase the risk of prolongation of the corrected QT interval (QTc). OBJECTIVE: To evaluate the effects of an association therapy of hydroxychloroquine (HY) plus ritonavir/darunavir (RD) or azithromycin (AZ) on QTc intervals. METHODS: At the beginning of COVID-19 pandemic patients admitted to our hospital were treated with the empiric association of HY/RD; one week later the therapeutic protocol was modified with the combination of HY/AZ. Patients underwent an ECG at baseline, then 3 and 7 days after starting therapy. We prospectively enrolled 113 patients (61 in the HY/RD group-52 in the HY/AZ group). RESULTS: A significant increase in median QTc was reported after seven days of therapy in both groups: from 438 to 452 ms in HY/RD patients; from 433 to 440 ms in HY/AZ patients (p = 0.001 for both). 23 patients (21.2%) had a QTc > 500 ms at 7 days. The risk of developing a QTc > 500 ms was greater in patients with prolonged baseline QTc values (≥ 440 ms for female and ≥ 460 ms for male patients) (OR 7.10 (95% IC 1.88-26.81); p = 0.004) and in patients with an increase in the QTc > 40 ms 3 days after onset of treatment (OR 30.15 (95% IC 6.96-130.55); p = 0.001). One patient per group suffered a malignant ventricular arrhythmia. CONCLUSION: Hydroxychloroquine with both ritonavir/darunavir or azithromycin therapy significantly increased the QTc-interval at 7 days. The risk of developing malignant arrhythmias remained relatively low when these drugs were administered for a limited period of time.
Assuntos
Azitromicina/efeitos adversos , Tratamento Farmacológico da COVID-19 , Darunavir/efeitos adversos , Eletrocardiografia/efeitos dos fármacos , Hidroxicloroquina/uso terapêutico , Síndrome do QT Longo/induzido quimicamente , Ritonavir/efeitos adversos , Idoso , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Azitromicina/uso terapêutico , COVID-19/epidemiologia , Darunavir/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Síndrome do QT Longo/fisiopatologia , Masculino , Pessoa de Meia-Idade , Ritonavir/uso terapêutico , SARS-CoV-2RESUMO
BACKGROUND AND OBJECTIVES: Streptococcus pneumoniae urinary antigen (u-Ag) testing has recently gained attention in the early diagnosis of severe and critical acute respiratory syndrome coronavirus-2/pneumococcal co-infection. The aim of this study is to assess the effectiveness of Streptococcus pneumoniae u-Ag testing in coronavirus disease 2019 (COVID-19) patients, in order to assess whether pneumococcal co-infection is associated with different mortality rate and hospital stay in these patients. MATERIALS AND METHODS: Charts, protocols, mortality, and hospitalization data of a consecutive series of COVID-19 patients admitted to a tertiary hospital in northern Italy during COVID-19 outbreak were retrospectively reviewed. All patients underwent Streptococcus pneumoniae u-Ag testing to detect an underlying pneumococcal co-infection. Covid19+/u-Ag+ and Covid19+/u-Ag- patients were compared in terms of overall survival and length of hospital stay using chi-square test and survival analysis. RESULTS: Out of 575 patients with documented pneumonia, 13% screened positive for the u-Ag test. All u-Ag+ patients underwent treatment with Ceftriaxone and Azithromycin or Levofloxacin. Lopinavir/Ritonavir or Darunavir/Cobicistat were added in 44 patients, and hydroxychloroquine and low-molecular-weight heparin (LMWH) in 47 and 33 patients, respectively. All u-Ag+ patients were hospitalized. Mortality was 15.4% and 25.9% in u-Ag+ and u-Ag- patients, respectively (p = 0.09). Survival analysis showed a better prognosis, albeit not significant, in u-Ag+ patients. Median hospital stay did not differ among groups (10 vs. 9 days, p = 0.71). CONCLUSIONS: The routine use of Streptococcus pneumoniae u-Ag testing helped to better target antibiotic therapy with a final trend of reduction in mortality of u-Ag+ COVID-19 patients having a concomitant pneumococcal infection. Randomized trials on larger cohorts are necessary in order to draw definitive conclusion.
Assuntos
Antibacterianos/uso terapêutico , Antivirais/uso terapêutico , Coinfecção/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Mortalidade Hospitalar , Pneumonia Pneumocócica/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/uso terapêutico , Antígenos de Bactérias/urina , Azitromicina/uso terapêutico , Betacoronavirus , COVID-19 , Ceftriaxona/uso terapêutico , Cobicistat/uso terapêutico , Coinfecção/urina , Infecções por Coronavirus/complicações , Estudos Transversais , Darunavir/uso terapêutico , Combinação de Medicamentos , Feminino , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Tempo de Internação/estatística & dados numéricos , Levofloxacino/uso terapêutico , Lopinavir/uso terapêutico , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Pandemias , Pneumonia Pneumocócica/complicações , Pneumonia Pneumocócica/diagnóstico , Pneumonia Pneumocócica/urina , Pneumonia Viral/complicações , Estudos Retrospectivos , Ritonavir/uso terapêutico , SARS-CoV-2 , Streptococcus pneumoniae/imunologia , Tratamento Farmacológico da COVID-19RESUMO
To date the severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2), known as COVID-19, is for clinicians the most difficult global therapeutic problem. In this landscape, the management of patients with chronic kidney disease, acute kidney injury or patients undergoing immunosuppressant therapies for kidney transplant or glomerular diseases, represent a clinical challenge for nephrologists, especially in patients with severe acute lung involvement. Therefore in this setting, due to the lack of anti-COVID treatment schedules, tailored management is mandatory to reduce the side effects, as consequence of impaired renal function and drugs interactions. We report the main treatment actually used against SARS-CoV-2, underlining its possible use in the nephropatic patients and the central role of nephrologists to improve the clinical outcome.
Assuntos
Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Corticosteroides/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Amidas/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , COVID-19 , Cobicistat/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Darunavir/uso terapêutico , Combinação de Medicamentos , Humanos , Rim/efeitos dos fármacos , Rim/lesões , Rim/fisiopatologia , Lopinavir/uso terapêutico , Pandemias , Pneumonia Viral/tratamento farmacológico , Pirazinas/uso terapêutico , Insuficiência Renal Crônica/complicações , Terapia de Substituição Renal/métodos , Ritonavir/uso terapêuticoRESUMO
CASE REPORT: A 64-year-old woman presented to our emergency department during the outbreak of the covid-19 emergency in Italy with syncope, anosmia, mild dyspnoea and atypical chest and dorsal pain. A chest CT scan showed an acute type B aortic dissection (ATBAD) and bilateral lung involvement with ground-glass opacity, compatible with interstitial pneumonia. Nasopharyngeal swabs resulted positive for SARS-CoV-2. For the persistence of chest pain, despite the analgesic therapy, we decided to treat her with a TEVAR. Patient's chest and back pain resolved during the first few days after the procedure. No surgical or respiratory complications occurred and the patient was discharged 14 days after surgery. DISCUSSION: By performing the operation under local anesthesia, it was possible to limit both the staff inside the operatory room and droplet/aerosol release. Since we had to perform the operation in a hemodynamics room, thanks to the limited extension of the endoprosthesis and the good caliber of the right vertebral artery we were able to reduce the risk of spinal cord ischemia despite the lack of a revascularization of the left subclavian artery. CONCLUSIONS: A minimally invasive total endovascular approach allows, through local anesthesia and percutaneous access, to avoid surgical cut down and orotracheal intubation. This, combined with a defined management protocol for infected patients, seems to be a reasonable way to perform endovascular aortic procedures in urgent setting, even in a SARSCoV- 2 positive patient. KEY WORDS: COVID-19, Dissection, TEVAR.
Assuntos
Aneurisma da Aorta Torácica/cirurgia , Dissecção Aórtica/cirurgia , Betacoronavirus/isolamento & purificação , Implante de Prótese Vascular/métodos , Infecções por Coronavirus/prevenção & controle , Procedimentos Endovasculares/métodos , Controle de Infecções/métodos , Transmissão de Doença Infecciosa do Paciente para o Profissional/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Anestesia Local , Dissecção Aórtica/complicações , Antibioticoprofilaxia , Anticoagulantes/uso terapêutico , Antivirais/uso terapêutico , Aneurisma da Aorta Torácica/complicações , COVID-19 , Contraindicações de Procedimentos , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/transmissão , Darunavir/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Quimioterapia Combinada , Enoxaparina/uso terapêutico , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Complicações Intraoperatórias/prevenção & controle , Intubação Intratraqueal/efeitos adversos , Pessoa de Meia-Idade , Nasofaringe/virologia , Salas Cirúrgicas , Isolamento de Pacientes , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/transmissão , Ritonavir/uso terapêutico , SARS-CoV-2 , Isquemia do Cordão Espinal/prevenção & controle , Artéria Vertebral/cirurgiaRESUMO
BACKGROUND: Darunavir is an anti-HIV protease inhibitor repurposed for SARS-CoV-2 treatment. OBJECTIVE: The aim of this study was to assess the population pharmacokinetics of darunavir in SARS-CoV-2 patients compared with HIV patients. METHODS: Two separate models were created by means of a nonlinear mixed-effect approach. The influence of clinical covariates on each basic model was tested and the association of significant covariates with darunavir parameters was assessed at multivariate regression and classification and regression tree (CART) analyses. Monte Carlo simulation assessed the influence of covariates on the darunavir concentration versus time profile. RESULTS: A one-compartment model well-described darunavir concentrations in both groups. In SARS-CoV-2 patients (n = 30), interleukin (IL)-6 and body surface area were covariates associated with darunavir oral clearance (CL/F) and volume of distribution (Vd), respectively; no covariates were identified in HIV patients (n = 25). Darunavir CL/F was significantly lower in SARS-CoV-2 patients compared with HIV patients (4.1 vs. 10.3 L/h; p < 0.001). CART analysis found that an IL-6 level of 18 pg/mL may split the SARS-CoV-2 population in patients with low versus high darunavir CL/F (mean ± standard deviation 3.47 ± 1.90 vs. 8.03 ± 3.24 L/h; proportion of reduction in error = 0.46). Median (interquartile range) darunavir CL/F was significantly lower in SARS-CoV-2 patients with IL-6 levels ≥ 18 pg/mL than in SARS-CoV-2 patients with IL-6 levels < 18 pg/mL or HIV patients (2.78 [2.16-4.47] vs. 7.24 [5.88-10.38] vs. 9.75 [8.45-13.79] L/h, respectively; p < 0.0001). Increasing IL-6 levels affected darunavir concentration versus time simulated profiles. We hypothesized that increases in IL-6 levels associated with severe SARS-CoV-2 disease may downregulate the cytochrome P450 (CYP) 3A4-mediated metabolism of darunavir. CONCLUSIONS: This is a proof-of-concept of SARS-CoV-2 disease-drug interactions, and may support the need for optimal dose selection of sensitive CYP3A4 substrates in severe SARS-CoV-2 patients.
Assuntos
Infecções por Coronavirus/tratamento farmacológico , Darunavir/farmacocinética , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/farmacocinética , Interleucina-6/sangue , Pneumonia Viral/tratamento farmacológico , Adulto , Fatores Etários , Idoso , Betacoronavirus , Pesos e Medidas Corporais , COVID-19 , Comorbidade , Citocromo P-450 CYP3A , Darunavir/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Inibidores da Protease de HIV/uso terapêutico , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Modelos Biológicos , Método de Monte Carlo , Pandemias , Estudos Retrospectivos , SARS-CoV-2 , Fatores SexuaisRESUMO
OBJECTIVES: The aim of this study was to evaluate penetration of antiretrovirals into compartments and efficacy of a dual, NRTI-sparing regimen in acute HIV infection (AHI). DESIGN: Single-arm, open-label pilot study of participants with AHI initiating ritonavir-boosted darunavir 800âmg once daily and etravirine 400âmg once daily or 200âmg twice daily within 30 days of AHI diagnosis. METHODS: Efficacy was defined as HIV RNA less than 200âcopies/ml by week 24. Optional sub-studies included pharmacokinetics analysis from genital fluids (weeks 0-4, 12, 48), cerebrospinal fluid (CSF) (weeks 2-4, 24 and 48) and endoscopic biopsies (weeks 4-12 and 36-48). Neuropsychological performance was assessed at weeks 0, 24 and 48. RESULTS: Fifteen AHI participants were enrolled. Twelve (80%) participants achieved HIV RNA less than 200âcopies/ml by week 24. Among 12 participants retained through week 48, nine (75%) remained suppressed to less than 50âcopies/ml. The median time from ART initiation to suppression less than 200 and less than 50âcopies/ml was 59 and 86 days, respectively. The penetration ratios for etravirine and darunavir in gut associated lymphoid tissue were 19.2 and 3.05, respectively. Most AHI participants achieving viral suppression experienced neurocognitive improvement. Of the three participants without overall improvement in neurocognitive functioning as measured by impairment ratings (more than two tests below 1 SD), two had virologic failure. CONCLUSION: NRTI-sparing ART started during AHI resulted in rapid viral suppression similar to NRTI-based regimens. More novel and compact two-drug treatments for AHI should be considered. Early institution of ART during AHI appears to improve overall neurocognitive function and may reduce the risk of subsequent neurocognitive impairment. CLINICALTRIALS.GOV:: NCT00855413.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Darunavir/farmacocinética , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Ritonavir/farmacocinética , Adulto , Contagem de Linfócito CD4 , Darunavir/uso terapêutico , Farmacorresistência Viral , Quimioterapia Combinada , Feminino , HIV/genética , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Ritonavir/uso terapêutico , Resultado do Tratamento , Carga Viral/efeitos dos fármacosRESUMO
O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referentes ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 16 artigos e 4 protocolos.
Assuntos
Humanos , Pneumonia Viral/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Ozônio/uso terapêutico , Avaliação da Tecnologia Biomédica , Imunoglobulinas/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Vacina BCG/uso terapêutico , Estudos Transversais , Estudos de Coortes , Corticosteroides/uso terapêutico , Ritonavir/uso terapêutico , Combinação de Medicamentos , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Células-Tronco Mesenquimais , Lopinavir/uso terapêutico , Darunavir/uso terapêutico , Hidroxicloroquina/uso terapêuticoRESUMO
O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referentes ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 14 artigos e 13 protocolos.
Assuntos
Humanos , Pneumonia Viral/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Ribavirina/uso terapêutico , Avaliação da Tecnologia Biomédica , Dexametasona/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Vancomicina/uso terapêutico , Ganciclovir/uso terapêutico , Estudos de Coortes , Corticosteroides/uso terapêutico , Azitromicina/uso terapêutico , Ritonavir/uso terapêutico , Oseltamivir/uso terapêutico , Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Lopinavir/uso terapêutico , Linezolida/uso terapêutico , Darunavir/uso terapêutico , Cobicistat/uso terapêutico , Interferon beta-1a/uso terapêutico , Adalimumab/uso terapêutico , Abatacepte/uso terapêutico , Etanercepte/uso terapêutico , Cefepima/uso terapêutico , Meropeném/uso terapêutico , Hidroxicloroquina/uso terapêuticoRESUMO
O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referentes ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 21 artigos e 8 protocolos.
Assuntos
Pneumonia Viral/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , Esteroides/uso terapêutico , Avaliação da Tecnologia Biomédica , Vacina BCG/uso terapêutico , Heparina/uso terapêutico , Almitrina/uso terapêutico , Estudos de Coortes , Corticosteroides/uso terapêutico , Enoxaparina/uso terapêutico , Azitromicina/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Darunavir/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Ipilimumab/uso terapêutico , Fondaparinux/uso terapêutico , Nivolumabe/uso terapêutico , Antagonistas dos Receptores Histamínicos/uso terapêutico , Hidroxicloroquina/uso terapêutico , Anticoagulantes/uso terapêuticoRESUMO
O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referentes ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 21 artigos e 15 protocolos.
Assuntos
Humanos , Pneumonia Viral/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Avaliação da Tecnologia Biomédica , Imunoglobulinas/uso terapêutico , Metilprednisolona/uso terapêutico , Vacinas/uso terapêutico , Heparina/uso terapêutico , Estudos de Coortes , Azitromicina/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Ritonavir/uso terapêutico , Combinação de Medicamentos , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Células-Tronco Mesenquimais , Darunavir/uso terapêutico , Adalimumab/uso terapêutico , Rituximab/uso terapêutico , Infliximab/uso terapêutico , Clopidogrel/uso terapêutico , Ticagrelor/uso terapêutico , Hidroxicloroquina/uso terapêutico , Anticoagulantes/uso terapêuticoRESUMO
O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referentes ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 14 artigos e 6 protocolos.