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1.
Antivir Ther ; 29(2): 13596535241248282, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38725258

RESUMEN

BACKGROUND: Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) fixed-dose combination (FDC) was developed as a once-daily, complete antiretroviral (ARV) regimen therapy to address the need for simplified protease inhibitor-based ARV regimens. This study assessed the swallowability and acceptability for long-term use of scored placebo tablets matching the D/C/F/TAF FDC tablets in children living with HIV-1. METHODS: This study (NCT04006704) was a Phase 1, open-label, randomized, single-dose, 2-period, 2-sequence crossover study in children living with HIV-1, aged ≥6 to <12 years and weighing ≥25 to <40 kg, on a stable ARV regimen for ≥3 months. Participants were asked to swallow whole (size, 21 × 11 × 7 mm) and split matching placebo D/C/F/TAF tablets. Swallowability of the matching placebo D/C/F/TAF tablets (primary endpoint) was assessed by observers. Acceptability of taking matching placebo D/C/F/TAF tablets and current ARVs was evaluated by participants using a 3-point questionnaire. Participants rated the acceptability for long-term daily use of the placebo D/C/F/TAF tablets, and observers assessed how easily caregivers could split a scored tablet by hand, using 3-point questionnaires. RESULTS: Among the 24 participants who enrolled and completed the study, 95.8% (23/24) were able to swallow the whole and split matching placebo D/C/F/TAF tablets after 1 or 2 attempts. Most participants (>70%) rated the acceptability of tablets for long-term daily use as acceptable or good to take. Breaking the tablets was considered easy or OK by 79.2% (19/24) of caregivers. CONCLUSION: Scored D/C/F/TAF FDC tablets are swallowable - with whole favoured over split - and considered at least acceptable for long-term daily intake in children living with HIV-1 aged ≥6 to <12 years. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04006704.


Asunto(s)
Fármacos Anti-VIH , Cobicistat , Darunavir , Combinación de Medicamentos , Emtricitabina , Infecciones por VIH , VIH-1 , Comprimidos , Tenofovir , Humanos , Masculino , Infecciones por VIH/tratamiento farmacológico , Femenino , Cobicistat/administración & dosificación , Cobicistat/uso terapéutico , Niño , Emtricitabina/administración & dosificación , Emtricitabina/uso terapéutico , VIH-1/efectos de los fármacos , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Tenofovir/administración & dosificación , Tenofovir/uso terapéutico , Tenofovir/análogos & derivados , Darunavir/administración & dosificación , Darunavir/uso terapéutico , Alanina/administración & dosificación , Alanina/uso terapéutico , Estudios Cruzados , Deglución , Adenina/análogos & derivados , Adenina/administración & dosificación , Adenina/uso terapéutico
2.
Clin Pharmacol Drug Dev ; 12(11): 1060-1068, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37335552

RESUMEN

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is a fixed-dose combination (FDC) for the treatment of HIV-1 infection in adults and adolescents weighing 40 kg or greater. This Phase 1, randomized, open-label, 2-treatment, 2-sequence, 4-period replicate crossover study (NCT04661397) evaluated the pivotal bioequivalence of a pediatric D/C/F/TAF 675/150/200/10-mg FDC compared with coadministration of the separate commercially available formulations in healthy adults under fed conditions. During each period, participants received either a single oral dose of D/C/F/TAF 675/150/200/10-mg FDC (test) or a single oral dose of darunavir 600 and 75 mg, cobicistat 150 mg, and emtricitabine/tenofovir alafenamide 200/10-mg FDC (reference). Thirty-seven participants were randomly assigned to one of 2 treatment sequence groups: test-reference-reference-test or reference-test-test-reference, with 7 days or more washout between periods. The 90% confidence intervals of the geometric mean ratios for maximum plasma concentration, area under the concentration-time curve from time zero to last measurable concentration, and area under the concentration-time curve extrapolated to infinity for darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fell within conventional bioequivalence limits (80%-125%). No Grade 3/4 adverse events, serious adverse events, or deaths occurred. In conclusion, administration of D/C/F/TAF 675/150/200/10-mg FDC was bioequivalent to coadministration of the separate commercially available formulations.


Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Adulto , Humanos , Fármacos Anti-VIH/administración & dosificación , Cobicistat/administración & dosificación , Estudios Cruzados , Darunavir/administración & dosificación , Emtricitabina/administración & dosificación , Comprimidos , Equivalencia Terapéutica , Infecciones por VIH/tratamiento farmacológico , Combinación de Medicamentos
3.
N Engl J Med ; 385(4): 330-341, 2021 07 22.
Artículo en Inglés | MEDLINE | ID: mdl-34289276

RESUMEN

BACKGROUND: The World Health Organization recommends dolutegravir with two nucleoside reverse-transcriptase inhibitors (NRTIs) for second-line treatment of human immunodeficiency virus type 1 (HIV-1) infection. Evidence is limited for the efficacy of this regimen when NRTIs are predicted to lack activity because of drug resistance, as well as for the recommended switch of an NRTI from tenofovir to zidovudine. METHODS: In a two-by-two factorial, open-label, noninferiority trial, we randomly assigned patients for whom first-line therapy was failing (HIV-1 viral load, ≥1000 copies per milliliter) to receive dolutegravir or ritonavir-boosted darunavir and to receive tenofovir or zidovudine; all patients received lamivudine. The primary outcome was a week 48 viral load of less than 400 copies per milliliter, assessed with the Food and Drug Administration snapshot algorithm (noninferiority margin for the between-group difference in the percentage of patients with the primary outcome, 12 percentage points). RESULTS: We enrolled 464 patients at seven sub-Saharan African sites. A week 48 viral load of less than 400 copies per milliliter was observed in 90.2% of the patients in the dolutegravir group (212 of 235) and in 91.7% of those in the darunavir group (210 of 229) (difference, -1.5 percentage points; 95% confidence interval [CI], -6.7 to 3.7; P = 0.58; indicating noninferiority of dolutegravir, without superiority) and in 92.3% of the patients in the tenofovir group (215 of 233) and in 89.6% of those in the zidovudine group (207 of 231) (difference, 2.7 percentage points; 95% CI, -2.6 to 7.9; P = 0.32; indicating noninferiority of tenofovir, without superiority). In the subgroup of patients with no NRTIs that were predicted to have activity, a viral load of less than 400 copies per milliliter was observed in more than 90% of the patients in the dolutegravir group and the darunavir group. The incidence of adverse events did not differ substantially between the groups in either factorial comparison. CONCLUSIONS: Dolutegravir in combination with NRTIs was effective in treating patients with HIV-1 infection, including those with extensive NRTI resistance in whom no NRTIs were predicted to have activity. Tenofovir was noninferior to zidovudine as second-line therapy. (Funded by Janssen; NADIA ClinicalTrials.gov number, NCT03988452.).


Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Darunavir/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Oxazinas/administración & dosificación , Piperazinas/administración & dosificación , Piridonas/administración & dosificación , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Tenofovir/administración & dosificación , Zidovudina/administración & dosificación , Adolescente , Adulto , Fármacos Anti-VIH/efectos adversos , Niño , Darunavir/efectos adversos , Resistencia a Medicamentos , Quimioterapia Combinada , Femenino , Infecciones por VIH/virología , VIH-1/aislamiento & purificación , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Oxazinas/efectos adversos , Piperazinas/efectos adversos , Piridonas/efectos adversos , Inhibidores de la Transcriptasa Inversa/efectos adversos , Carga Viral , Adulto Joven
4.
AAPS J ; 23(4): 82, 2021 06 07.
Artículo en Inglés | MEDLINE | ID: mdl-34100149

RESUMEN

The single-tablet regimen darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg has undergone phase III studies AMBER (NCT02431247) and EMERALD (NCT02269917) in HIV-infected patients. An existing population pharmacokinetic (PopPK) model for cobicistat-boosted darunavir (DRV) was updated to describe DRV PK in AMBER and EMERALD. For TAF, a PopPK model was developed using richly sampled phase I/II data and updated with sparsely sampled AMBER data. Individual exposure metrics for DRV and TAF in patients receiving D/C/F/TAF were derived (AMBER, n=356; EMERALD, n=750). The DRV PopPK model is a two-compartment model with sequential zero-order, first-order input. TAF PK is described by a one-compartment model with dual parallel input for absorption (slow and fast pathway). DRV covariates were α1-acid-glycoprotein and body weight. TAF covariates were lean body weight and α1-acid-glycoprotein. DRV and TAF PK were unaffected by age, race, or gender. Estimated DRV mean (SD) C0h and AUC24h, respectively, were 1899 (759) ng/mL and 87,909 (20,232) ng*h/mL in AMBER; 1813 (859) ng/mL and 85,972 (22,413) ng*h/mL in EMERALD. Estimated TAF mean (SD) AUC24h was 132 (41) ng*h/mL. These PK parameters were in line with historical data. No apparent relationships of DRV or TAF exposure with efficacy (virologic response) or safety (metabolic, cardiac, liver, gastrointestinal, skin, bone, renal, pancreas, lipid events) parameters were seen. Additionally, our findings demonstrate that in patients with low plasma concentrations, there is no risk of decreased virologic response or virologic rebound. This supports the use of a once-daily, single-tablet regimen of D/C/F/TAF 800/150/200/10 mg for the treatment of HIV-1-infected subjects.


Asunto(s)
Alanina/farmacocinética , Fármacos Anti-VIH/farmacocinética , Cobicistat/farmacocinética , Darunavir/farmacocinética , Emtricitabina/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Tenofovir/análogos & derivados , Adulto , Anciano , Alanina/administración & dosificación , Alanina/efectos adversos , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Variación Biológica Poblacional , Cobicistat/administración & dosificación , Cobicistat/efectos adversos , Darunavir/administración & dosificación , Darunavir/efectos adversos , Combinación de Medicamentos , Emtricitabina/administración & dosificación , Emtricitabina/efectos adversos , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/diagnóstico , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Comprimidos , Tenofovir/administración & dosificación , Tenofovir/efectos adversos , Tenofovir/farmacocinética , Resultado del Tratamiento , Carga Viral/efectos de los fármacos , Adulto Joven
5.
Expert Opin Drug Saf ; 20(11): 1351-1366, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34047238

RESUMEN

Introduction: Cumulative use of some first-generation protease inhibitors has been associated with higher rates of dyslipidemia and increased risk of cardiovascular disease. The protease inhibitors most commonly in use are atazanavir and darunavir, which have fewer detrimental lipid effects and greater tolerability. This paper aims to review the evidence of a potential association of these contemporary protease inhibitors with the risk of ischemic CVD and atherosclerotic markers.Areas covered: We searched for publications of randomized trials and observational studies on PubMed from 1 January 2000 onwards, using search terms including: protease inhibitors; darunavir; atazanavir; cardiovascular disease; cardiovascular events; dyslipidemia; mortality; carotid intima media thickness; arterial elasticity; arterial stiffness and drug discontinuation. Ongoing studies registered on clinicaltrials.gov as well as conference abstracts from major HIV conferences from 2015-2020 were also searched.Expert opinion: Atazanavir and darunavir are no longer part of first-line HIV treatment, but continue to be recommended as alternative first line, second- and third-line regimens, as part of two drug regimens, and darunavir is used as salvage therapy. Although these drugs will likely remain in use globally for several years to come, baseline CVD risk should be considered when considering their use, especially as the population with HIV ages.


Asunto(s)
Enfermedades Cardiovasculares/etiología , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/efectos adversos , Animales , Sulfato de Atazanavir/administración & dosificación , Sulfato de Atazanavir/efectos adversos , Aterosclerosis/etiología , Darunavir/administración & dosificación , Darunavir/efectos adversos , Dislipidemias/inducido químicamente , Dislipidemias/complicaciones , Inhibidores de la Proteasa del VIH/administración & dosificación , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto
6.
J Med Virol ; 93(6): 3985-3990, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33300183

RESUMEN

In AMBER and EMERALD, darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg demonstrated high virological response and low virological failure (VF) through week 96. Week 96 resistance analyses are presented. Post-baseline samples for genotyping/phenotyping were analyzed from protocol-defined-VFs with viral load (VL) ≥ 400 copies/ml at failure/later time points. Post-hoc analyses were deep sequencing (AMBER) and HIV-1 proviral DNA sequencing from baseline samples (VL < 50 copies/ml) (EMERALD). Through week 96 across studies, no darunavir, primary protease inhibitor (PI), or tenofovir resistance-associated-mutations (RAMs) occurred in patients continuing (N = 1125) or switching to D/C/F/TAF (N = 715). M184I/V (emtricitabine RAM) was detected in one patient in each arm of AMBER. In EMERALD D/C/F/TAF patients with prior VF and baseline genoarchive data (N = 98), 4% had darunavir RAMs, 36% emtricitabine RAMs, mainly at position 184 (32%), 4% tenofovir RAMs, and 19% ≥3 thymidine-analogue-associated-mutations at screening. The predicted phenotype showed 0% had reduced susceptibility to darunavir, 37% to emtricitabine, and 22% to tenofovir. All achieved VL < 50 copies/ml at week 96/prior discontinuation, with no VF. D/C/F/TAF has a high barrier to resistance; no darunavir, primary PI, or tenofovir RAMs occurred through 96 weeks in AMBER and EMERALD. In EMERALD, baseline archived darunavir, emtricitabine, and tenofovir RAMs in patients with prior VF did not preclude virologic response.


Asunto(s)
Alanina/uso terapéutico , Fármacos Anti-VIH/uso terapéutico , Cobicistat/uso terapéutico , Darunavir/uso terapéutico , Farmacorresistencia Viral Múltiple/genética , Emtricitabina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Tenofovir/análogos & derivados , Alanina/administración & dosificación , Fármacos Anti-VIH/administración & dosificación , Cobicistat/administración & dosificación , Darunavir/administración & dosificación , Combinación de Medicamentos , Emtricitabina/administración & dosificación , VIH-1/genética , Análisis de Secuencia de ADN , Comprimidos , Tenofovir/administración & dosificación , Tenofovir/uso terapéutico , Carga Viral/efectos de los fármacos
7.
J Antimicrob Chemother ; 76(2): 482-486, 2021 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-33221868

RESUMEN

BACKGROUND: Combination therapy with hydroxychloroquine and darunavir/ritonavir or lopinavir/ritonavir has been suggested as an approach to improve the outcome of patients with moderate/severe COVID-19 infection. OBJECTIVES: To examine the safety of combination therapy with hydroxychloroquine and darunavir/ritonavir or lopinavir/ritonavir. METHODS: This was an observational cohort study of patients hospitalized for COVID-19 pneumonia treated with hydroxychloroquine and darunavir/ritonavir or lopinavir/ritonavir. Clinical evaluations, electrocardiograms and the pharmacokinetics of hydroxychloroquine, darunavir and lopinavir were examined according to clinical practice and guidelines. RESULTS: Twenty-one patients received hydroxychloroquine with lopinavir/ritonavir (median age 68 years; 10 males) and 25 received hydroxychloroquine with darunavir/ritonavir (median age 71 years; 15 males). During treatment, eight patients (17.4%) developed ECG abnormalities. Ten patients discontinued treatment, including seven for ECG abnormalities a median of 5 (range 2-6) days after starting treatment. All ECG abnormalities reversed 1-2 days after interrupting treatment. Four patients died within 14 days. ECG abnormalities were significantly associated with age over 70 years, coexisting conditions (such as hypertension, chronic cardiovascular disease and kidney failure) and initial potential drug interactions, but not with the hydroxychloroquine concentration. CONCLUSIONS: Of the patients with COVID-19 who received hydroxychloroquine with lopinavir or darunavir, 17% had ECG abnormalities, mainly related to age or in those with a history of cardiovascular disease.


Asunto(s)
Antivirales/efectos adversos , Tratamiento Farmacológico de COVID-19 , Darunavir/efectos adversos , Hidroxicloroquina/efectos adversos , Lopinavir/efectos adversos , Antivirales/administración & dosificación , Antivirales/sangre , Antivirales/uso terapéutico , COVID-19/epidemiología , Estudios de Cohortes , Darunavir/administración & dosificación , Darunavir/sangre , Darunavir/uso terapéutico , Quimioterapia Combinada , Electrocardiografía , Francia , Humanos , Hidroxicloroquina/administración & dosificación , Hidroxicloroquina/sangre , Hidroxicloroquina/uso terapéutico , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/epidemiología , Lopinavir/administración & dosificación , Lopinavir/sangre , Lopinavir/uso terapéutico , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Resultado del Tratamiento
8.
Yonsei Med J ; 61(9): 826-830, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32882767

RESUMEN

We retrospectively reviewed patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections who were admitted to an intensive care unit in Daegu, South Korea. The outcomes of patients who did (cases) or did not (controls) receive darunavir-cobicistat (800-150 mg) therapy were compared. Fourteen patients received darunavir-cobicistat treatment, and 96 received other antiviral therapy (controls). Overall, the darunavir-cobicistat group comprised patients with milder illness, and the crude mortality rate of all patients in the darunavir-cobicistat group was lower than that in the controls [odds ratio (OR) 0.20, 95% confidence interval (CI) 0.04-0.89, p=0.035]. After 1:2 propensity-score matching, there were 14 patients in the darunavir-cobicistat group, and 28 patients in the controls. In propensity score-matched analysis, the darunavir-cobicistat group had lower mortality than the controls (OR 0.07, 95% CI 0.01-0.52, p=0.009). In conclusion, darunavir-cobicistat therapy was found to be associated with a significant survival benefit in critically ill patients with SARS-CoV-2 infection.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Cobicistat/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Darunavir/uso terapéutico , Inhibidores de la Proteasa del VIH/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Adulto , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Betacoronavirus , COVID-19 , Estudios de Casos y Controles , Cobicistat/administración & dosificación , Cobicistat/efectos adversos , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/mortalidad , Enfermedad Crítica , Darunavir/administración & dosificación , Darunavir/efectos adversos , Femenino , Inhibidores de la Proteasa del VIH/administración & dosificación , Inhibidores de la Proteasa del VIH/efectos adversos , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/mortalidad , República de Corea/epidemiología , Estudios Retrospectivos , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Resultado del Tratamiento
9.
Eur Rev Med Pharmacol Sci ; 24(15): 8219-8225, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32767353

RESUMEN

OBJECTIVE: At the end of 2019, the Novel Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), spread rapidly from China to the whole world. Circadian rhythms can play crucial role in the complex interplay between viruses and organisms, and temporized schedules (chronotherapy) have been positively tested in several medical diseases. We aimed to compare the possible effects of a morning vs. evening antiviral administration in COVID patients. PATIENTS AND METHODS: We retrospectively evaluated all patients admitted to COVID internal medicine units with confirmed SARS-CoV-2 infection, and treated with darunavir-ritonavir (single daily dose, for seven days). Age, sex, length of stay (LOS), pharmacological treatment, and timing of antiviral administration (morning or evening), were recorded. Outcome indicators were death or LOS, and laboratory parameters, e.g., variations in C-reactive protein (CRP) levels, ratio of arterial oxygen partial pressure (PaO2, mmHg) to fractional inspired oxygen (FiO2) (PaO2/FiO2), and leucocyte count. RESULTS: The total sample consisted of 151 patients, 33 (21.8%) of whom were selected for antiviral treatment. The mean age was 61.8±18.3 years, 17 (51.5%) were male, and the mean LOS was 13.4±8.6 days. Nine patients (27.3%) had their antiviral administration in the morning, and 24 (72.7%) had antiviral administration in the evening. No fatalities occurred. Despite the extremely limited sample size, morning group subjects showed a significant difference in CRP variation, compared to that in evening group subjects (-65.82±33.26 vs. 83.32±304.89, respectively, p<0.032). No significant differences were found for other parameters. CONCLUSIONS: This report is the first study evaluating temporized morning vs. evening antiviral administration in SARS-CoV-2 patients. The morning regimen was associated with a significant reduction in CRP values. Further confirmations with larger and multicenter samples of patients could reveal novel potentially useful insights.


Asunto(s)
Antivirales/administración & dosificación , Infecciones por Coronavirus/tratamiento farmacológico , Darunavir/administración & dosificación , Cronoterapia de Medicamentos , Mortalidad Hospitalaria , Tiempo de Internación/estadística & datos numéricos , Neumonía Viral/tratamiento farmacológico , Ritonavir/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Betacoronavirus , Análisis de los Gases de la Sangre , Proteína C-Reactiva , COVID-19 , Infecciones por Coronavirus/metabolismo , Quimioterapia Combinada , Humanos , Italia , Recuento de Leucocitos , Persona de Mediana Edad , Oxígeno/metabolismo , Pandemias , Presión Parcial , Neumonía Viral/metabolismo , Estudios Retrospectivos , SARS-CoV-2 , Tratamiento Farmacológico de COVID-19
10.
J Gastrointestin Liver Dis ; 29(3): 470, 2020 09 09.
Artículo en Inglés | MEDLINE | ID: mdl-32830825
11.
J Popul Ther Clin Pharmacol ; 27(S Pt 1): e26-e30, 2020 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-32650356

RESUMEN

At the end of December 2019, the Health Commission of the city of Wuhan, China, alerted the World Health Organization (WHO) to a pneumonia cluster in the city. The cause was identified as being a new virus, later named SARS-CoV-2. We can distinguish three clinical phases of the disease with a distinct pathogenesis, manifestations and prognosis. Here, we describe the case of a 45-year-old male, successfully treated for Coronavirus disease (COVID-19). The patient was feeling sick in early April 2020; he had a fever and pharyngodynia. When he came to our COVID hospital, his breathing was normal. The nasopharyngeal swab specimen turned out positive. High-resolution computed tomography (HRCT) showed mild interstitial pneumonia. The patient was admitted to our department and treated with hydroxychloroquine, ritonavir, darunavir, azithromycin and enoxaparin. On day seven of the disease, the patient's respiratory condition got worse as he was developing acute respiratory distress syndrome (ARDS). He was given tocilizumab and corticosteroids and was immediately treated with non-invasive mechanical ventilation (NIMV). His condition improved, and in the ensuing days, the treatment gradually switched to a high-flow nasal cannula (HFNC); after 18 days, the patient's clinical condition was good.The successful results we have been able to obtain are closely associated with avoidance of invasive ventilation that may lead to intensive care unit (ICU)-related superinfections. In our opinion, it is fundamental to understand that COVID-19 is a systemic disease that is a consequence of an overwhelming inflammatory response, which can cause severe medical conditions, even in young patients.


Asunto(s)
Infecciones por Coronavirus/terapia , Neumonía Viral/terapia , Corticoesteroides/administración & dosificación , Corticoesteroides/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Azitromicina/administración & dosificación , Azitromicina/uso terapéutico , COVID-19 , China , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/patología , Darunavir/administración & dosificación , Darunavir/uso terapéutico , Progresión de la Enfermedad , Enoxaparina/administración & dosificación , Enoxaparina/uso terapéutico , Humanos , Hidroxicloroquina/administración & dosificación , Hidroxicloroquina/uso terapéutico , Masculino , Persona de Mediana Edad , Ventilación no Invasiva , Pandemias , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/patología , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/etiología , Síndrome de Dificultad Respiratoria/terapia , Ritonavir/administración & dosificación , Ritonavir/uso terapéutico
13.
Infection ; 48(5): 779-782, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32418190

RESUMEN

At present, there is no definitive antiviral treatment for coronavirus disease 2019 (COVID-19). We describe our early experience with remdesivir in four critically ill COVID-19 patients. Patients received a 200 mg loading dose, followed by 100 mg daily intravenously for up to 10 days. All patients had been previously treated with other antivirals before remdesivir initiation. One patient experienced a torsade de pointes requiring cardiac resuscitation and one died due to multiple organ failure. Three patients showed biochemical signs of liver injury. Lymphocyte count increased in all patients soon after remdesivir initiation. Nasal swab SARS-CoV-2 RNA became negative in three of four patients after 3 days of therapy. We observed an in vivo virological effect of remdesivir in four critically ill, COVID-19 patients, coupled with a significant burden of adverse events. Although limited by the low number of subjects studied, our preliminary experience may be relevant for clinicians treating COVID-19.


Asunto(s)
Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Antivirales/administración & dosificación , Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , ARN Viral/sangre , Adenosina Monofosfato/administración & dosificación , Adenosina Monofosfato/efectos adversos , Alanina/administración & dosificación , Alanina/efectos adversos , Antivirales/efectos adversos , Betacoronavirus/inmunología , COVID-19 , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/fisiopatología , Enfermedad Hepática Inducida por Sustancias y Drogas/virología , Convalecencia , Infecciones por Coronavirus/virología , Enfermedad Crítica , Darunavir/administración & dosificación , Darunavir/efectos adversos , Esquema de Medicación , Combinación de Medicamentos , Resultado Fatal , Humanos , Hidroxicloroquina/administración & dosificación , Hidroxicloroquina/efectos adversos , Lopinavir/administración & dosificación , Lopinavir/efectos adversos , Insuficiencia Multiorgánica/inducido químicamente , Insuficiencia Multiorgánica/diagnóstico , Insuficiencia Multiorgánica/fisiopatología , Insuficiencia Multiorgánica/virología , Pandemias , Neumonía Viral/virología , Ritonavir/administración & dosificación , Ritonavir/efectos adversos , SARS-CoV-2 , Torsades de Pointes/inducido químicamente , Torsades de Pointes/diagnóstico , Torsades de Pointes/fisiopatología , Torsades de Pointes/virología
14.
Drug Dev Ind Pharm ; 46(5): 732-743, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32290722

RESUMEN

The aim of this study is to develop Darunavir (DRV) proliposome powder for oral delivery. Darunavir-loaded oral proliposome powder (OPP) was prepared by a solvent evaporation technique with varying independent variables at three different levels. Based on different levels, proliposome powder formulation was optimized by using Box-Behnken design. The formulations were analyzed for its size distribution, entrapment efficiency, and surface morphology. Optimized proliposome batch A was evaluated for physical parameter, morphological parameters, entrapment efficiency, followed by in vitro, ex vivo, and in vivo studies. Oral proliposome powder showed good micromeritic properties with angle of repose was less than 30°, Carr's index and Hausner's ratio were also less than 21 and 1.25, respectively. The mean size of the vesicles was in the range of 180-290 nm. The assay and entrapment efficiency of pro-liposome powder formulations were 79.00 ± 0.2 and 93.46 ± 0.2%, respectively. In vitro release of DRV proliposome powder was 78.17 ± 0.1% after 24 h which shows good release from the vesicle of proliposome. Ex vivo permeation study shows 58.11% enhancement which shows good permeation. The optimize batch A of proliposome powder indicated 50% enhancement in the relative bioavailability as compared to the DRV suspension. The results showed that proliposome powder containing DRV can efficiently deliver in to the blood stream. This drug delivery system has been designed as a novel platform for potential oral delivery of drugs having poor water solubility and high first-pass metabolism.


Asunto(s)
Darunavir/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Diseño de Fármacos , Desarrollo de Medicamentos/métodos , Inhibidores de la Proteasa del VIH/administración & dosificación , Administración Oral , Animales , Darunavir/síntesis química , Darunavir/metabolismo , Liberación de Fármacos/efectos de los fármacos , Liberación de Fármacos/fisiología , Inhibidores de la Proteasa del VIH/síntesis química , Inhibidores de la Proteasa del VIH/metabolismo , Intestino Delgado/efectos de los fármacos , Intestino Delgado/metabolismo , Liposomas , Masculino , Técnicas de Cultivo de Órganos , Tamaño de la Partícula , Polvos , Ratas , Ratas Sprague-Dawley , Difracción de Rayos X/métodos
16.
Patient ; 13(3): 375-387, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32266663

RESUMEN

OBJECTIVE: This prospective, multicenter, non-interventional cohort study enrolling human immunodeficiency virus (HIV)-1-infected, virally suppressed adult outpatients in Italy aimed to describe results obtained from patient-reported outcome questionnaires regarding treatment satisfaction and symptom perceptions in HIV-1-positive patients who switched to cobicistat-boosted darunavir antiretroviral regimens, coming from ritonavir-boosted protease inhibitors. METHODS: Patients entered this study between June 2016 and February 2017, once their treating physician had considered them eligible for cobicistat-boosted darunavir-based treatment as per clinical practice. Patients' satisfaction regarding regimen and current symptom burdens were assessed using two previously validated, patient-reported outcome questionnaires: HIV Treatment Satisfaction Questionnaire (HIV-TSQ) and HIV Symptoms Distress Module (HIV-SDM). These questionnaires were administered at prespecified time-points: enrollment (Visit 1), 4-8 weeks later (Visit 2), and 48 ± 6 weeks after study enrollment (Visit 4). Data of patient-reported outcome total scores for both questionnaires are presented as median with 25th-75th percentiles. Questionnaires scores were analyzed overall and stratified by gender when applicable. A p value of less than 0.05 was considered statistically significant. A sensitivity analysis was conducted to evaluate the role of lost to follow-up, using the "last observation carried forward" method. RESULTS: A total of 348 patients were enrolled in this study; 296 patients (208 male and 88 female) provided both evaluable HIV-TSQ and HIV-SDM at enrollment and at 4-8 weeks, while 250 patients (174 male and 76 female) provided questionnaire data at enrollment and at 48 ± 6 weeks. The total scores of HIV-TSQ showed improvements in patient satisfaction in the overall population both at Visit 2 and Visit 4 (p < 0.001, sign test) and also when stratified by gender throughout the study period. In addition, the overall burden of symptoms, as shown by the HIV-SDM scores, decreased. CONCLUSIONS: Switching to a cobicistat-boosted darunavir-based therapy led to overall increased patient satisfaction and reduced symptom burden when compared with previous regimens. The use of patient-reported outcomes in clinical daily practice could provide a useful tool towards achieving guideline goals to achieve "fourth 90", having 90% of virally suppressed patients with a good health-related quality of life.


Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Cobicistat/administración & dosificación , Darunavir/administración & dosificación , Quimioterapia Combinada , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/administración & dosificación , Medición de Resultados Informados por el Paciente , Adulto , Estudios de Cohortes , Femenino , Humanos , Italia , Masculino , Persona de Mediana Edad , Satisfacción del Paciente , Estudios Prospectivos , Encuestas y Cuestionarios
17.
HIV Res Clin Pract ; 21(1): 34-43, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-32129161

RESUMEN

Antiretroviral therapies have been tested with the goal of maintaining virological suppression with a particular attention in limiting drug-related toxicity. With this aim we designed the DUAL study: a randomized, open-label, multicenter, 96 weeks-long pilot exploratory study in virologically suppressed HIV-1+ patients with the aim of evaluating the immunovirological success and the impact on non-HIV related morbidity of switching to a dual therapy with darunavir-ritonavir (DRV/r) and rilpivirine (RPV). We recruited patients who received a PI/r-containing HAART for ≥6 months, HIV-RNA < 50 cp/mL for ≥3 months, eGFR > 60 mL/min/1,73m2, without DRV or RPV RAMs. We randomized patients in arm A: RPV + DRV/r QD or arm B: ongoing triple therapy. The primary endpoint has been defined as the percentage of patients with HIV-RNA < 50 cp/mL at week 48 (ITT). VACS index, Framingham CVD risk (FRS) and urinary RBP (uRBP) were calculated. We used Chi-square or Fisher statistics for categorical variables and Mann-Whitney U for continuous ones. Forty-one patients were enrolled (22 in arm A, 14 in arm B, plus 5 screening failures): 30 patients reached 96 weeks: 100% had HIV-RNA < 50 cp/mL in arm A versus 91.7% in arm B. Similar changes were observed in median CD4/mL between baseline and week 96 (+59 versus - 31, p: n.s.). Thirty-one in arm A and 23 in arm B adverse events took place, whereas only 1 was serious (arm A: turbinate hypertrophy, unrelated to HAART). Among the 6 discontinuations (3 in A, 3 in B), only 1 was related to adverse event (arm A: G3 depression, insomnia, weakness). VACS index, median FRS and median uRBP values did not vary from baseline to week 96. At 96-weeks all patients switched to a QD 2-drug regimen based on DRV/r + RPV maintained HIV-RNA suppression, but a single patient who showed a virological failure at week 4. CD4 counts increased overtime without significant differences between the two arms. The novel dual regimen was well tolerated with the same amount of discontinuation as the control arm. VACS index, FRS and uRBP did not differ between arms at week 96.


Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Darunavir/administración & dosificación , Quimioterapia Combinada , Infecciones por VIH/tratamiento farmacológico , Rilpivirina/administración & dosificación , Ritonavir/administración & dosificación , Viremia/tratamiento farmacológico , Adulto , Esquema de Medicación , Femenino , Infecciones por VIH/mortalidad , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/genética , VIH-1/fisiología , Humanos , Italia , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Carga Viral/efectos de los fármacos , Viremia/mortalidad , Viremia/virología
18.
Mol Pharm ; 17(3): 852-864, 2020 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-32017579

RESUMEN

Clinical trials have demonstrated partial protection against HIV-1 infection by vaginal microbicide formulations based on antiretroviral (ARV) drugs. Improved formulations that will maintain sustained drug concentrations at viral target sites in the cervicovaginal mucosa are needed. We have previously demonstrated that treatment of cervicovaginal cell lines with ARV drugs can alter gene expression of drug transporters, suggesting that the mucosal disposition of ARV drugs delivered vaginally can be modulated by drug transporters. This study aimed to investigate in vivo modulation of drug transporter expression in a nonhuman primate model by tenofovir and darunavir released from film formulations. Cervicovaginal tissues were collected from drug-naïve macaques and from macaques vaginally treated with film formulations of tenofovir or darunavir. Drug release in vaginal fluid as well as drug absorption in cervicovaginal tissues and lymph nodes were verified by mass spectrometry. The effects of exposure to drugs on the expression of transporters relevant to ARV drugs were evaluated by quantitative PCR. We showed expression in cervicovaginal tissue of drug-naïve macaques of transporters important for distribution of ARV drugs, albeit at lower levels compared to human tissue for key transporters including P-glycoprotein. Concentrations of tenofovir and darunavir well above the EC50 values determined in vitro were detected in vaginal fluid and vaginal tissues of macaques treated with drug-dissolving films over 24 h and were also comparable to those shown previously to modulate drug transporter expression. Accordingly, Multidrug Resistance associated Protein 2 (MRP2) in cervicovaginal tissue was upregulated by both tenofovir and darunavir. The two drugs also differentially induced and/or inhibited expression of key uptake transporters for reverse transcriptase inhibitors and protease inhibitors. The lower expression of key transporters in macaques may result in increased retention of ARV drugs at the simian cervicovaginal mucosa compared to the human mucosa and has implications for translation of preclinical data. Modulation of drug transporter expression by tenofovir and darunavir points to the potential benefit of MRP2 inhibition to increase ARV drug penetration through the cervicovaginal epithelium.


Asunto(s)
Darunavir/farmacocinética , Composición de Medicamentos/métodos , Infecciones por VIH/prevención & control , Inhibidores de la Proteasa del VIH/farmacocinética , VIH-1 , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Tenofovir/farmacocinética , Regulación hacia Arriba/efectos de los fármacos , Vagina/metabolismo , Administración Intravaginal , Animales , Transporte Biológico/efectos de los fármacos , Línea Celular Tumoral , Darunavir/administración & dosificación , Modelos Animales de Enfermedad , Femenino , Infecciones por VIH/virología , Inhibidores de la Proteasa del VIH/administración & dosificación , Humanos , Macaca fascicularis , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Tenofovir/administración & dosificación , Distribución Tisular
19.
J Acquir Immune Defic Syndr ; 83(4): 373-380, 2020 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-31923087

RESUMEN

BACKGROUND: This study aims to evaluate the pharmacokinetics of an increased dose of darunavir (800 mg twice daily) with 100 mg ritonavir during pregnancy and postpartum. METHODS: Darunavir (DRV) and ritonavir (RTV; r) intensive pharmacokinetic evaluations were performed at steady state during the second and third trimesters of pregnancy (DRV/r 800/100 mg bid) and 2-3 weeks postpartum (DRV/r 600/100 mg twice daily). Plasma concentrations of darunavir and ritonavir were measured using high-performance liquid chromatography. Target darunavir area under the concentration time curve (AUC) was >70% (43.6 µg × h/mL) of median AUC (62.3 µg × h/mL) in nonpregnant adults on twice daily darunavir-ritonavir 600/100 mg. RESULTS: Twenty-four women were included in the analysis. Darunavir AUC0-12 was lower with the increased dose during the second {[geometric mean ratio (GMR) of 0.62 (IQR 0.44-0.88); P = 0.055]} and third trimesters [GMR 0.64 (IQR 0.55-0.73); P = <0.001] compared with postpartum. Darunavir apparent clearance was higher during the second [GMR 1.77 (IQR 1.24-2.51); P = 0.039] and third trimesters [GMR 2.01 (IQR 1.17-2.35); P = <0.001] compared with postpartum. Similarly, ritonavir AUC0-12 was lower during the third trimester [GMR 0.65 (IQR 0.52-0.82); P = 0.007] compared with postpartum, whereas its apparent clearance was higher during the third trimester [GMR 1.53 (IQR 1.22-1.92); P = 0.008] compared with postpartum. No major drug-related safety concerns were noted. CONCLUSIONS: Increasing darunavir dose to 800 mg BID failed to significantly increase darunavir exposure compared with 600 mg BID. Other strategies, such as increasing the ritonavir dose should be investigated.


Asunto(s)
Darunavir/farmacocinética , Darunavir/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Adulto , Darunavir/administración & dosificación , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Femenino , VIH/efectos de los fármacos , Infecciones por VIH/sangre , Humanos , Embarazo , Complicaciones Infecciosas del Embarazo/sangre , Ritonavir/administración & dosificación , Ritonavir/farmacocinética , Ritonavir/uso terapéutico , Estadística como Asunto , Adulto Joven
20.
AIDS Res Hum Retroviruses ; 36(1): 48-57, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31516033

RESUMEN

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is being investigated in two Phase III trials, AMBER (NCT02431247; treatment-naive adults) and EMERALD (NCT02269917; treatment-experienced, virologically suppressed adults). Week 48 AMBER and EMERALD resistance analyses are presented. Postbaseline samples for genotyping/phenotyping were analyzed from protocol-defined virologic failures (PDVFs) with viral load (VL) ≥400 copies/mL at failure/later time points. Post hoc analyses were deep sequencing in AMBER, and HIV-1 proviral DNA from baseline samples (VL <50 copies/mL) in EMERALD. Through week 48 across both studies, no darunavir, primary PI, or tenofovir resistance-associated mutations (RAMs) were observed in HIV-1 viruses of 1,125 participants receiving D/C/F/TAF or 629 receiving boosted darunavir plus emtricitabine/tenofovir-disoproxil-fumarate. In AMBER, the nucleos(t)ide analog reverse transcriptase inhibitor (N(t)RTI) RAM M184I/V was identified in HIV-1 of one participant during D/C/F/TAF treatment. M184V was detected pretreatment as a minority variant (9%). In EMERALD, in participants with prior VF and genoarchive data (N = 140; 98 D/C/F/TAF and 42 control), 4% had viruses with darunavir RAMs, 38% with emtricitabine RAMs, mainly at position 184 (41% not fully susceptible to emtricitabine), 4% with tenofovir RAMs, and 21% ≥ 3 thymidine analog-associated mutations (24% not fully susceptible to tenofovir) detected at screening. All achieved VL <50 copies/mL at week 48 or prior discontinuation. D/C/F/TAF has a high genetic barrier to resistance; no darunavir, primary PI, or tenofovir RAMs were observed through 48 weeks in AMBER and EMERALD. Only one postbaseline M184I/V RAM was observed in HIV-1 of an AMBER participant. In EMERALD, baseline archived RAMs to darunavir, emtricitabine, and tenofovir in participants with prior VF did not preclude virologic response.


Asunto(s)
Adenina/análogos & derivados , Cobicistat/administración & dosificación , Darunavir/administración & dosificación , Farmacorresistencia Viral , Emtricitabina/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Adenina/administración & dosificación , Adulto , Alanina , Fármacos Anti-VIH/administración & dosificación , Esquema de Medicación , Combinación de Medicamentos , Infecciones por VIH/epidemiología , VIH-1/efectos de los fármacos , Humanos , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Comprimidos/administración & dosificación , Tenofovir/análogos & derivados , Carga Viral/efectos de los fármacos
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