RESUMEN
A 59-year-old treatment-naive patient with advanced HIV infection presented with a severe and protracted course of mpox (formerly known as monkeypox) that did not respond to the current mpox treatment options. The patient worsened clinically, and developed new mucocutaneous lesions and necrotic evolution of pre-existing ones, along with multiple bilateral lung nodules and the appearance of a tracheal necrotic lesion. Although severe forms of mpox have been observed in people with severe immune system deficiency, including those with advanced HIV presentation, the immunological mechanisms underlying this observation have not yet been fully explained. To our knowledge, this is the first account of a necrotising mpox in a person living with HIV, with viral shedding for more than 11 months and a comprehensive immunological description. Moreover, we documented the virus' persistence by detecting mpox virus DNA from multiple sites and quantified anti-monkeypox virus IgA, IgM, IgG, and neutralising antibodies in serum samples. The severe HIV-driven immune depression and the presence of other co-infections might skew and impair immune responses, thus contributing to the persistence of monkeypox virus infection. Further investigations of immune responses to monkeypox virus infection in people with severe immunosuppression are required to improve management and prevention.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida , Coinfección , Infecciones por VIH , Mpox , Humanos , Persona de Mediana Edad , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , ADN Viral , Monkeypox virusRESUMEN
BACKGROUND: A rapid ART initiation approach can be beneficial in people with advanced HIV disease, in consideration of their high morbidity and mortality. The aim of our study was to evaluate the feasibility, efficacy and safety of rapid ART start with BIC/FTC/TAF in this setting. METHODS: Pilot, single-centre, single-arm, prospective, phase IV clinical trial conducted in a tertiary Italian hospital. Thirty ART-naïve people presenting with advanced HIV-1 diagnosis (defined as the presence of an AIDS-defining event and/or CD4 cell count <200 µL), were enrolled. Main exclusion criteria were active tuberculosis, cryptococcosis and pregnant/breastfeeding women. BIC/FTC/TAF was started within 7 days from HIV diagnosis. The primary endpoint was clinical or virologic failure (VF). Immunological parameters, safety, feasibility, neurocognitive performances and patient-reported outcomes were assessed as well. RESULTS: Over the study period, 40 (34%) of 116 patients diagnosed with HIV infection at INMI Spallanzani had advanced disease, of whom 30 (26%) were enrolled. The proportion of participants with HIV-RNA <50 cp/mL was 9/30 (30%) at week (w) 4, 19/30 (63%) at w12, 24/30 (80%) at w24, 23/30 (77%) at w36 and 27/30 (90%) at w48. Two unconfirmed VF occurred. No ART discontinuation due to toxicity or VF was observed. No ART modification was performed based on the review of genotype and no mutations for the study drugs were detected. Mean CD4 cells count changed by 133 cells/µL at BL to 309 cells/µL at w 48 and 83% of participants had a CD4 > 200 cells/µL at w 48. Two participants developed IRIS and one was diagnosed with disseminated TB and needed an ART switch. INTERPRETATIONS: Our results support the feasibility, efficacy and safety of BIC/FTC/TAF as a rapid ART strategy in patients with advanced HIV disease.
Asunto(s)
Alanina , Amidas , Fármacos Anti-VIH , Infecciones por VIH , Compuestos Heterocíclicos con 3 Anillos , Piperazinas , Tenofovir/análogos & derivados , Humanos , Femenino , Infecciones por VIH/tratamiento farmacológico , Estudios Prospectivos , Emtricitabina/uso terapéutico , Adenina/uso terapéutico , Piridonas/uso terapéutico , Combinación de Medicamentos , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Fármacos Anti-VIH/uso terapéuticoRESUMEN
OBJECTIVE: To investigate the pharmacokinetics (PK) of tecovirimat in subjects with Mpox. METHODS: This monocentric, prospective, observational study enrolled subjects with Mpox who received standard treatment with oral tecovirimat. Plasma samples for PK assessment were collected at steady state (5-8 days after initiation of antiviral therapy), before and 3, 5, 7 and 12 h after tecovirimat administration. Drug concentrations were determined by validated liquid chromatography coupled with tandem mass spectrometry. PK parameters were calculated using Phoenix 8.1. RESULTS: Overall, 14 male patients hospitalized for severe Mpox with ongoing tecovirimat treatment were enrolled in this study. Six of the 14 patients were living with human immunodeficiency virus (HIV), all of whom were on antiretroviral therapy (ART) and virologically suppressed at the time of hospitalization. Significant differences in tecovirimat PK were observed in subjects without HIV compared with subjects with HIV. In subjects with HIV, the maximum tecovirimat plasma concentration (39%, P≤0.0001), minimum tecovirimat plasma concentration (42%, P=0.0079) and area under the curve from zero to the last measured time-point (40%, P≤0.0001) were significantly lower compared with subjects without HIV, but all concentrations remained above the in-vitro calculated 90% inhibitory concentration. No significant associations were found between demographic/clinical data and tecovirimat PK. All patients recovered completely within 14 (range 6-36) days of treatment initiation. CONCLUSIONS: This study found a significant decrease in plasma exposure of tecovirimat in Mpox patients with HIV on effective ART compared with those without HIV, with no evident impact on clinical outcomes. Although these results need to be confirmed in larger studies, they may provide useful information on the PK of tecovirimat.
Asunto(s)
Infecciones por VIH , Mpox , Humanos , Masculino , Estudios Prospectivos , Infecciones por VIH/tratamiento farmacológico , VIHRESUMEN
BACKGROUND: Remdesivir is the first antiviral drug against SARS-CoV-2 approved for use in COVID-19 patients. OBJECTIVES: To study the pharmacokinetic inter-individual variability of remdesivir and its main metabolite GS-441524 in a real-world setting of COVID-19 inpatients and to identify possible associations with different demographic/biochemical variables. METHODS: Inpatients affected by SARS-CoV-2 infections, undergoing standard-dose remdesivir treatment, were prospectively enrolled. Blood samples were collected on day 4, immediately after (C0) and at 1â h (C1) and 24â h (C24) after infusion. Remdesivir and GS-441524 concentrations were measured using a validated UHPLC-MS/MS method and the AUC0-24 was calculated. At baseline, COVID-19 severity (ICU or no ICU), sex, age, BMI and renal and liver functions were assessed. Transaminases and estimated glomerular filtration rate (e-GFR) were also evaluated during treatment. Linear regression, logistic regression and multiple linear regression tests were used for statistical comparisons of pharmacokinetic parameters and variables. RESULTS: Eighty-five patients were included. The mean (CV%) values of remdesivir were: C0 2091 (99.1%) ng/mL, C1 139.7 (272.4%) ng/mL and AUC0-24 2791 (175.7%) ng·h/mL. The mean (CV%) values of GS-441524 were: C0 90.2 (49.5%) ng/mL, C1 104.9 (46.6%) ng/mL, C24 58.4 (66.9) ng/mL and AUC0-24 1976 (52.6%) ng·h/mL. The multiple regression analysis showed that age (Pâ<â0.05) and e-GFR (Pâ<â0.01) were independent predictors of GS-441524 plasma exposure. CONCLUSIONS: Our results showed a high interpatient variability of remdesivir and GS-441524 likely due to both age and renal function in COVID-19 inpatients. Further research is required to understand whether the pharmacokinetics of remdesivir and its metabolites may influence drug-related efficacy or toxic effect.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , Adenosina/análogos & derivados , Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Antivirales/efectos adversos , Humanos , Pirroles , SARS-CoV-2 , Espectrometría de Masas en Tándem/métodos , Transaminasas , TriazinasRESUMEN
BACKGROUND: Sofosbuvir plus daclatasvir achieves high rates of sustained virologic response (SVR), with no differences according to HIV serostatus. However, only limited information is available on the pharmacokinetic variability of sofosbuvir and daclatasvir in HIV/HCV-coinfected patients. OBJECTIVES: The aim of this study was to identify patient-, treatment-, and disease-related factors that are significantly associated with sofosbuvir and daclatasvir plasma trough concentrations (Ctrough), including liver and renal function, among HIV/HCV-coinfected persons. METHODS: In this observational cohort pilot study, HIV/HCV-coinfected patients undergoing sofosbuvir plus daclatasvir treatment were prospectively enrolled. Biochemical and viro-immunological parameters were assessed at baseline, week 4 (W4), end of treatment (EOT), and after EOT. The FIB-4 score and CKD-EPI equation were used to estimate liver disease and glomerular filtration rate (eGFR), respectively. For sofosbuvir, sofosbuvir metabolite (GS-331007), and daclatasvir, Ctrough was measured at W4 and week 8 (W8), and the mean of the values at those two time points (mean-Ctrough) was calculated. The Mann-Whitney test and Spearman's rank correlation were used to evaluate the correlations between the mean-Ctrough of each direct-acting antiviral (DAA) and the considered variables. RESULTS: Thirty-five patients were included (SVR 94%). An increased GS-331007 mean-Ctrough was significantly correlated with a decreased eGFR at W4 (rho = -0.36; p = 0.037) and EOT (rho = -0.34; p = 0.048). There was a significant correlation between daclatasvir mean-Ctrough and FIB-4 at all time points: baseline (rho = -0.35; p = 0.037), W4 (rho = -0.44; p = 0.008), EOT (rho = -0.40; p = 0.023), and after EOT (rho = -0.39; p = 0.028). CONCLUSIONS: In HIV/HCV-coinfected patients in a real-world setting, exposure to a high GS-331007 Ctrough was associated with a slight decrease in renal function, while advanced hepatic impairment was significantly associated with a lower daclatasvir Ctrough. Though the clinical and therapeutic relevance of these findings may be limited, increasing clinicians' knowledge regarding DAA exposure in difficult-to-treat patients could be relevant in single cases, and further investigations are warranted.
Asunto(s)
Antivirales/farmacocinética , Carbamatos/farmacocinética , Infecciones por VIH , Hepatitis C Crónica , Imidazoles/farmacocinética , Pirrolidinas/farmacocinética , Sofosbuvir/farmacocinética , Valina/análogos & derivados , Antivirales/sangre , Área Bajo la Curva , Carbamatos/sangre , Estudios de Cohortes , Quimioterapia Combinada , Femenino , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Imidazoles/sangre , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estudios Prospectivos , Pirrolidinas/sangre , Sofosbuvir/sangre , Valina/sangre , Valina/farmacocinéticaRESUMEN
To date, vitamin D seems to have a significant role in affecting the prevention and immunomodulation in COVID-19 disease. Nevertheless, it is important to highlight that this pro-hormone has other several activities, such as affecting drug concentrations, since it regulates the expression of cytochrome P450 (CYP) genes. Efavirenz (EFV) pharmacokinetics is influenced by CYPs, but no data are available in the literature concerning the association among vitamin D levels, seasonality (which affects vitamin D concentrations) and EFV plasma levels. For this reason, the aim of this study was to evaluate the effect of 25-hydroxy vitamin D (25(OH)D3) levels on EFV plasma concentrations in different seasons. We quantified 25(OH)D3 by using chemiluminescence immunoassay, whereas EFV plasma concentrations were quantified with the HPLC-PDA method. A total of 316 patients were enrolled in Turin and Rome. Overall, 25(OH)D3levels resulted in being inversely correlated with EFV concentrations. Some patients with EFV levels higher than 4000 ng/mL showed a deficient 25(OH)D3 concentration in Turin and Rome cohorts and together. EFV concentrations were different in patients without vitamin D supplementation, whereas, for vitamin D-administered individuals, no difference in EFV exposure was present. Concerning seasonality, EFV concentrations were associated with 25(OH)D3 deficiency only in winter and in spring, whereas a significant influence was highlighted for 25(OH)D3 stratification for deficient, insufficient and sufficient values in winter, spring and summer. A strong and inverse association between 25(OH)D3and EFV plasma concentrations was suggested. These data suggest that vitamin D is able to affect drug exposure in different seasons; thus, the achievement of the clinical outcome could be improved by also considering this pro-hormone.
Asunto(s)
Alquinos/sangre , Alquinos/uso terapéutico , Benzoxazinas/sangre , Benzoxazinas/uso terapéutico , Ciclopropanos/sangre , Ciclopropanos/uso terapéutico , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Vitamina D/farmacología , Vitaminas/farmacología , Adulto , Estudios de Cohortes , Femenino , Humanos , Italia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Inhibidores de la Transcriptasa Inversa/sangre , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Estaciones del Año , Resultado del Tratamiento , Vitamina D/sangre , Vitaminas/sangreAsunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Alanina/uso terapéutico , Amidas , Fármacos Anti-VIH/uso terapéutico , Emtricitabina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Humanos , Piperazinas , Piridonas/uso terapéutico , Tenofovir/análogos & derivadosAsunto(s)
Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Antivirales/sangre , Antivirales/metabolismo , Tratamiento Farmacológico de COVID-19 , Adenosina Monofosfato/sangre , Adenosina Monofosfato/metabolismo , Adenosina Monofosfato/uso terapéutico , Alanina/sangre , Alanina/metabolismo , Alanina/uso terapéutico , Antivirales/uso terapéutico , Terapia de Reemplazo Renal Continuo , Femenino , Humanos , Persona de Mediana EdadRESUMEN
The immunological mechanisms underlying the clinical presentation of SARS-CoV-2 infection and those influencing the disease outcome remain to be defined. Myeloid-derived suppressor cells (MDSC) have been described to be highly increased during COVID-19, however, their role remains elusive. We performed an in depth analysis of MDSC in 128 SARS-CoV-2 infected patients. Polymorphonuclear (PMN)-MDSC expanded during COVID-19, in particular in patients who required intensive care treatments, and correlated with IL-1ß, IL-6, IL-8, and TNF-α plasma levels. PMN-MDSC inhibited T-cells IFN-γ production upon SARS-CoV-2 peptides stimulation, through TGF-ß- and iNOS-mediated mechanisms, possibly contrasting virus elimination. Accordingly, a multivariate regression analysis found a strong association between PMN-MDSC percentage and fatal outcome of the disease. The PMN-MDSC frequency was higher in non-survivors than survivors at the admission time, followed by a decreasing trend. Interestingly, this trend was associated with IL-6 increase in non-survivors but not in survivors. In conclusion, this study indicates PMN-MDSC as a novel factor in the pathogenesis of SARS-CoV2 infection, and open up to new therapeutic options.
Asunto(s)
Betacoronavirus/inmunología , Infecciones por Coronavirus/patología , Células Supresoras de Origen Mieloide/inmunología , Neumonía Viral/patología , Linfocitos T/inmunología , Anciano , Área Bajo la Curva , Betacoronavirus/aislamiento & purificación , Betacoronavirus/metabolismo , COVID-19 , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/mortalidad , Infecciones por Coronavirus/virología , Femenino , Humanos , Interferón gamma/metabolismo , Interleucina-1beta/sangre , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Células Supresoras de Origen Mieloide/citología , Neutrófilos/citología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Pandemias , Péptidos/inmunología , Péptidos/metabolismo , Neumonía Viral/inmunología , Neumonía Viral/mortalidad , Neumonía Viral/virología , Modelos de Riesgos Proporcionales , Curva ROC , SARS-CoV-2 , Tasa de Supervivencia , Linfocitos T/citología , Linfocitos T/metabolismo , Factor de Crecimiento Transformador beta/sangre , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
BACKGROUND: Remdesivir is a prodrug of the nucleoside analogue GS-441524 and is under evaluation for treatment of SARS-CoV-2-infected patients. OBJECTIVES: To evaluate the pharmacokinetics of remdesivir and GS-441524 in plasma, bronchoalveolar aspirate (BAS) and CSF in two critically ill COVID-19 patients. METHODS: Remdesivir was administered at 200 mg loading dose on the first day followed by 12 days of 100 mg in two critically ill patients. Blood samples were collected immediately after (C0) and at 1 (C1) and 24 h (C24) after intravenous administration on day 3 until day 9. BAS samples were collected on Days 4, 7 and 9 from both patients while one CSF on Day 7 was obtained in one patient. Remdesivir and GS-441524 concentrations were measured in these samples using a validated UHPLC-MS/MS method. RESULTS: We observed higher concentrations of remdesivir at C0 (6- to 7-fold higher than EC50 from in vitro studies) and a notable decay at C1. GS-441524 plasma concentrations reached a peak at C1 and persisted until the next administration. Higher concentrations of GS-441524 were observed in the patient with mild renal dysfunction. Mean BAS/plasma concentration ratios of GS-441524 were 2.3% and 6.4% in Patient 1 and Patient 2, respectively. The CSF concentration found in Patient 2 was 25.7% with respect to plasma. GS-441524 levels in lung and CNS suggest compartmental differences in drug exposure. CONCLUSIONS: We report the first pharmacokinetic evaluation of remdesivir and GS-441524 in recovered COVID-19 patients. Further study of the pharmacokinetic profile of remdesivir, GS-441524 and the intracellular triphosphate form are required.
Asunto(s)
Adenosina Monofosfato/análogos & derivados , Adenosina Trifosfato/análogos & derivados , Alanina/análogos & derivados , Antivirales/farmacocinética , Betacoronavirus , Infecciones por Coronavirus/metabolismo , Enfermedad Crítica/terapia , Neumonía Viral/metabolismo , Adenosina Monofosfato/farmacocinética , Adenosina Monofosfato/uso terapéutico , Adenosina Trifosfato/farmacocinética , Adenosina Trifosfato/uso terapéutico , Anciano , Alanina/farmacocinética , Alanina/uso terapéutico , Antivirales/uso terapéutico , COVID-19 , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/tratamiento farmacológico , Femenino , Humanos , Masculino , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/tratamiento farmacológico , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/fisiología , SARS-CoV-2RESUMEN
OBJECTIVE: Antiretrovirals with long half-lives, such as tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) and efavirenz (EFV), are suitable for reduced frequency dosing, with potential for improved adherence and reduced toxicity and costs. The objective of this study was to investigate the noninferiority of the TDF/FTC/EFV fixed-dose combination on alternate-days versus standard regimen in virologically suppressed patients. DESIGN: A randomized-controlled open-label noninferiority trial enrolling HIV-1-infected patients treated for at least 6 months with TDF/FTC/EFV fixed-dose combination, virologically suppressed (<40 HIV-RNA copies/ml) with EFV plasma concentrations greater than 1000âng/ml, were randomized to maintain TDF/FTC/EFV standard-of-care regimen (SOC, Arm A) or to switch to TDF/FTC/EFV on AlTernAte Days (ATAD, Arm B). METHODS: Primary end-point was the proportion of patients with less than 40 HIV-RNA copies/ml at week 48. RESULTS: One hundred and ninety-seven patients were randomized (98 in the SOC and 99 in the ATAD arm). One hundred and seventy-nine (90.3%) were men, median age 43.2 years, 133 (67.5%) MSM. CD4+ T-cell count at baseline was 706 cells/µl in SOC and 632 cells/µl in ATAD arm. At week 48, 95 (96.9%) patients in SOC and 93 (93.9%) in ATAD had a virological response (-3.0% overall risk difference, 95% CI: -8.86%/2.86%). Median change from baseline at week 48 in CD4+ T-cell count was 29.4 cells/µl (95% CI: 2.5/56.4) in SOC (Pâ=â0.008) and 61.0 cells/µl (95% CI: 32.1/89.9) in ATAD (Pâ<â0.001). Median change of EFV concentration at week 48 from baseline was -6.5âng/ml (95% CI: -103/55) in SOC (Pâ=â0.877) and -1124âng/ml (95% CI: -1375/-928) in ATAD arm (Pâ<â0.001). CONCLUSION: Despite a significant decrease of EFV exposure, TDF/FTC/EFV on ATAD was noninferior to SOC regimen through 48 weeks.
Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Terapia Antirretroviral Altamente Activa/métodos , Benzoxazinas/administración & dosificación , Emtricitabina/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Tenofovir/administración & dosificación , Carga Viral , Adulto , Anciano , Alquinos , Ciclopropanos , Femenino , VIH-1/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , ARN Viral/sangre , Resultado del Tratamiento , Adulto JovenAsunto(s)
Fármacos Anti-VIH/uso terapéutico , Disfunción Cognitiva/complicaciones , Disfunción Cognitiva/epidemiología , Combinación Efavirenz, Emtricitabina y Fumarato de Tenofovir Disoproxil/uso terapéutico , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Adulto , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/sangre , Terapia Antirretroviral Altamente Activa , Combinación Efavirenz, Emtricitabina y Fumarato de Tenofovir Disoproxil/efectos adversos , Combinación Efavirenz, Emtricitabina y Fumarato de Tenofovir Disoproxil/sangre , Femenino , VIH , Infecciones por VIH/psicología , Humanos , Masculino , Cumplimiento de la Medicación , Pruebas de Estado Mental y Demencia , Persona de Mediana Edad , Prevalencia , Factores de RiesgoRESUMEN
Therapeutic drug monitoring may be crucial in selected clinical conditions for the management of HIV infection. In recent years, new antiretrovirals have been introduced and in particular elvitegravir (EVG) is now recommended for first-line and simplification treatment as well as dolutegravir (DTG) and rilpivirine (RPV). The aim of this study was to develop and validate a high-performance liquid chromatography-ultraviolet (HPLC-UV) method for determining EVG and new antiretrovirals DTG and RPV in human plasma. Solid-phase extraction was applied to a 600 µL plasma sample. Chromatographic separation of the three drugs and internal standard was achieved with a gradient of acetonitrile and phosphate buffer on a C18 reverse-phase analytical column with a 20 min analytical run time. EVG and DTG were detected at 265 nm and RPV at 290 nm. Mean intra- and inter-day precisions were < 10%; the mean accuracy was <15%. Extraction recovery ranged between 105 and 82% for the drugs analyzed. Calibration curves were optimized according to the expected ranges of drug concentrations in patients; the coefficient of determination was >0.997 for all drugs. This method allows for monitoring EVG, DTG and RPV in the plasma of HIV-positive patients using HPLC-UV.
RESUMEN
Autism spectrum disorders (ASDs) present a wide range of symptoms characterized by altered sociability, compromised communication and stereotypic/repetitive behaviors. These symptoms are caused by developmental changes, but the mechanisms remain largely unknown. Some lines of evidence suggest an impairment of the cholesterol/isoprenoid metabolism in the brain as a possible cause, but systematic analyses in rodent models of ASDs are lacking. Prenatal exposure to the antiepileptic drug valproate (VPA) is a risk factor for ASDs in humans and generates a well-established model for the disease in rodents. Here, we studied cholesterol/isoprenoid metabolism in different brain areas of infant, adolescent and adult rats prenatally exposed to VPA. VPA-treated rats present autistic-like symptoms, they show changes in cholesterol/isoprenoid homeostasis in some brain areas, a decreased number of oligodendrocytes and impaired myelination in the hippocampus. Together, our data suggest a relation between brain cholesterol/isoprenoid homeostasis and ASDs.
Asunto(s)
Trastorno del Espectro Autista/metabolismo , Encéfalo/metabolismo , Colesterol/metabolismo , Terpenos/metabolismo , Adenilato Quinasa/metabolismo , Animales , Trastorno del Espectro Autista/patología , Encéfalo/crecimiento & desarrollo , Encéfalo/patología , Modelos Animales de Enfermedad , Femenino , Hígado/metabolismo , Masculino , Oligodendroglía/metabolismo , Oligodendroglía/patología , Embarazo , Efectos Tardíos de la Exposición Prenatal , Ratas Wistar , Ácido ValproicoRESUMEN
BACKGROUND: Possible drug-drug interactions (DDIs) between antiretrovirals (ARVs) and direct-acting antiviral agents (DAAs) are of some concern. OBJECTIVES: To investigate ARV plasma trough concentrations (Ctrough) before and during DAAs in patients treated in the real world. METHODS: Single-centre, prospective, observational study including HIV/HCV coinfected persons undergoing DAA treatment. Self-reported adherence was assessed and ARVs Ctrough measured by HPLC-UV. Blood samples were collected before and after 2 months of DAA treatment. RESULTS: One-hundred and thirty-seven patients were included: 21.2% treated with ombitasvir/paritaprevir/ritonavir ± dasabuvir (2D/3D) and 78.8% with sofosbuvir-based regimens. Suboptimal Ctrough before and during DAA was found, respectively, in 3 (10.3%) and 3 (10.3%) cases treated with 2D/3D, and 16 (14.8%) and 11 (10.2%) with sofosbuvir-based regimens, even if self-reported ARV adherence was always ≥93%. In 2D/3D-treated patients, median darunavir Ctrough during DAAs was significantly lower than observed before DAAs [1125 ng/mL (IQR, 810-1616) versus 1903 ng/mL (IQR 1387-3983), respectively] (n = 5; P = 0.009), with a 40.9% decrease. In the same group, no differences in atazanavir or raltegravir concentrations were found. In patients treated with sofosbuvir-based regimens, Ctrough of all ARVs were similar before and during DAAs. CONCLUSIONS: In the real world of HIV/HCV coinfected patients, ARV plasma concentrations during DAAs were generally not different from those found before anti-HCV treatment. Although assessed in a small number of patients, darunavir concentrations during 2D/3D showed a significant reduction when compared with those found before DAAs. ARV plasma concentrations measurement during anti-HCV treatment may give useful information for managing HIV/HCV coinfected persons receiving treatment for both infections.
Asunto(s)
Antirretrovirales , Infecciones por VIH/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , 2-Naftilamina , Anilidas/sangre , Anilidas/farmacocinética , Anilidas/uso terapéutico , Antirretrovirales/sangre , Antirretrovirales/farmacocinética , Antirretrovirales/uso terapéutico , Carbamatos/sangre , Carbamatos/farmacocinética , Carbamatos/uso terapéutico , Coinfección/tratamiento farmacológico , Ciclopropanos , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Humanos , Lactamas Macrocíclicas , Compuestos Macrocíclicos/sangre , Compuestos Macrocíclicos/farmacocinética , Compuestos Macrocíclicos/uso terapéutico , Masculino , Persona de Mediana Edad , Prolina/análogos & derivados , Estudios Prospectivos , Ritonavir/sangre , Ritonavir/farmacocinética , Ritonavir/uso terapéutico , Sofosbuvir/sangre , Sofosbuvir/farmacocinética , Sofosbuvir/uso terapéutico , Sulfonamidas/sangre , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapéutico , Resultado del Tratamiento , Uracilo/análogos & derivados , Uracilo/sangre , Uracilo/farmacocinética , Uracilo/uso terapéutico , ValinaRESUMEN
Direct-acting antiviral agents (DAAs) represent the major advance in hepatitis C virus (HCV) infection treatment leading to extremely high eradication rates in HCV mono- and HIV/HCV co-infected patients. In this scenery, availability of Therapeutic Drug Monitoring (TDM) is of interest to assess plasma concentrations to prevent either therapeutic failure due to suboptimal medication adherence and drug-drug interactions or avoid adverse events. Aim of this study was to develop and validate an Ultra-Performance Liquid Chromatography Mass Spectrometry (UPLC-MS/MS) method for the simultaneous quantification of sofosbuvir, sofosbuvir metabolite (GS-331007), and daclatasvir in human plasma. A simple protein precipitation was applied by adding 200⯵L acetonitrile with internal standard 6,7-Dimethyl- 2,3-di(2-pyridyl) quinoxaline to 100⯵L plasma sample. Drug separation was performed on analytical C-18 Luna Omega column (50â¯mmâ¯×â¯2.1â¯mm I.D.) with particle size of 1.6⯵m. The mobile phase consisting of water containing 0.1% formic acid and acetonitrile at flow 0.4â¯mL/min and a gradient run time of 3.5â¯min. The injection volume was 10⯵L. Anti-HCV drugs were detected in positive electrospray ionization mode. The full scan mass spectral analyses of sofosbuvir, GS-331007, daclatasvir and quinaxoline showed protonated molecule ions and transitions m/z: 530.098â¯ââ¯243.02, 260.93â¯ââ¯112.94, 739.4â¯ââ¯339.27 and 313.03â¯ââ¯77.99 respectively. The linearity of standard curves was excellent (r2â¯>â¯0.99), the absolute recovery of anti-HCV drugs ranged between 95 and 98%, and both imprecision and inaccuracy were <15% according to FDA guidelines. The UPLC-MS/MS method was applied to 16 plasma samples of as many HIV/HCV co-infected patients treated with sofosbuvir and daclatasvir. While sofosbuvir was not detectable in all samples, the median plasma concentrations of daclatasvir and GS-331007 were 223.6⯱â¯319.56â¯ng/mL and 537.11⯱â¯242.09â¯ng/mL, respectively. In conclusion, we describe an UPLC-MS/MS method allowing the simultaneous quantification of sofosbuvir, GS-331007 and daclatasvir in plasma samples. The method was sensitive, specific, robust, and time-saving.
Asunto(s)
Antivirales/sangre , Coinfección/tratamiento farmacológico , Infecciones por VIH/tratamiento farmacológico , Hepatitis C/tratamiento farmacológico , Imidazoles/sangre , Sofosbuvir/sangre , Carbamatos , Cromatografía Líquida de Alta Presión/métodos , Humanos , Límite de Detección , Modelos Lineales , Pirrolidinas , Reproducibilidad de los Resultados , Sofosbuvir/análogos & derivados , Sofosbuvir/química , Espectrometría de Masas en Tándem/métodos , Valina/análogos & derivadosRESUMEN
BACKGROUND: Ebola virus, an enveloped virus, is the cause of the largest and most complex Ebola virus disease (EVD) outbreak in West Africa. Blood or body fluids of an infected person may represent a biohazard to laboratory workers. Laboratory tests of virus containing specimens should be conducted in referral centres at biosafety level 4, but based on the severity of clinical symptoms, basic laboratories might be required to execute urgent tests for patients suspected of EVD. The aim of this work was to compare the analytical performances of laboratory tests when Triton X-100, a chemical agent able to inactivate other enveloped viruses, was added to specimens. METHODS: Results of clinical chemistry, coagulation and haematology parameters on samples before and after the addition of 0.1% (final concentration) of Triton X-100 and 1 h of incubation at room temperature were compared. RESULTS: Overall, results showed very good agreement by all statistical analyses. Triton X-100 at 0.1% did not significantly affect the results for the majority of the analytes tested. CONCLUSIONS: Triton X-100 at 0.1% can be used to reduce the biohazard in performing laboratory tests on samples from patients with EVD without affecting clinical decisions.
Asunto(s)
Análisis Químico de la Sangre/métodos , Contención de Riesgos Biológicos/métodos , Fiebre Hemorrágica Ebola/diagnóstico , Fiebre Hemorrágica Ebola/prevención & control , Octoxinol/química , Seguridad , Ebolavirus/aislamiento & purificación , Fiebre Hemorrágica Ebola/sangre , Fiebre Hemorrágica Ebola/transmisión , HumanosRESUMEN
Sildenafil and bosentan are increasingly used for the treatment of pulmonary arterial hypertension (PAH) in HIV-infected patients. However, concerns exist about pharmacokinetic interactions among sildenafil, bosentan and antiretroviral drugs, including protease inhibitors (PI). We describe here the case of an HIV-infected patient with PAH, who was co-administered bosentan 125 mg twice daily and sildenafil 40 mg three times per day, together with a ritonavir-boosted PI-based antiretroviral therapy; plasma levels of bosentan, sildenafil, N-desmethylsildenafil, and PI were measured. The patient had a sildenafil Cthrough and Cmax of 276.94 ng/mL and 1733.19 ng/mL, respectively. The Cthrough and the Cmax of bosentan were 1546.53 ng/mL and 3365.99 ng/mL, respectively. The patient was able to tolerate as high sildenafil blood concentrations as 10 times those usually requested and did not report any significant adverse reaction to sildenafil during the follow-up period. Therapeutic drug monitoring should be considered during sildenafil therapy in patients concomitantly treated with ritonavir-boosted PI.