Exploratory analysis of clinical benefit of ipilimumab and nivolumab treatment in patients with metastatic melanoma from a single institution.

PURPOSE: We retrospectively analysed overall survival (OS) and potential predictive biomarkers of OS in patients with metastatic melanoma treated with ipilimumab plus nivolumab in a single institution. METHODS AND PATIENTS: Electronic medical records of patients with advanced melanoma receiving ≥ 1 dose of a combined ipilimumab plus nivolumab regimen between March 3, 2016 and March 7, 2020 in a single institution, were reviewed. OS was analysed using the Kaplan-Meier method. Sub-group analyses were conducted to examine several endpoints according to relevant clinical, molecular and pathological variables using logistic and Cox models. RESULTS: Forty-four cases were reviewed, 38 (86.4%), of whom had cutaneous melanoma, 21 (47.7%) were BRAF mutant, 21 (47.7%) presented high lactate dehydrogenase (LDH) values, 23 (52.3%) had ≥ 3 disease sites, and 10 (22.7%) patients had brain metastases. The median follow-up was 37.7 months, and the median OS was 21.1 months (95% CI 8.2-NR). In the multivariate analysis, the OS was significantly longer in patients with an Eastern Cooperative Oncology Group (ECOG) score of 0, LDH ≤ upper limit of normal, absence of liver metastases and neutrophil-to-lymphocyte ratio (NLR) < 5 (all p ≤ 0.05, log-rank test). These factors allowed the classification of patients into three prognostic risk groups (low/intermediate/high risk) for death. CONCLUSION: Overall survival of real-world patients from our cohort receiving ipilimumab plus nivolumab was lower than in previous studies. The ECOG score, LDH values, the presence of liver metastases and the NLR were independent prognostic factors for survival.

Population pharmacokinetics of daptomycin in critically ill patients.

Daptomycin has shown activity against a wide range of Gram-positive bacteria; however, the approved dosages usually seem insufficient for critically ill patients. The aim of this study was to develop a population pharmacokinetic model for daptomycin in critically ill patients and to estimate the success of the therapy by applying pharmacokinetic/pharmacodynamic (PK/PD) criteria. Sixteen intensive care unit patients were included, four of whom underwent continuous renal replacement therapies (CRRT). Blood and, when necessary, effluent samples were drawn after daptomycin administration at previously defined time points. A population approach using NONMEM 7.3 was performed to analyse data. Monte Carlo simulations were executed to evaluate the suitability of different dosage regimens. The probabilities of achieving the PK/PD target value associated with treatment success (ratio of the area under the plasma concentration-time curve over 24 h divided by the minimum inhibitory concentration (AUC24/MIC ≥ 666)) and to reach daptomycin concentrations linked to toxicity (minimum concentration at steady-state (Cminss) ≥ 24.3 mg/L) were calculated. The pharmacokinetics of daptomycin was best described by a one-compartment model. Elimination was conditioned by the creatinine clearance (Clcr) and also by the extra-corporeal clearance when patients were subjected to continuous renal replacement therapy (CRRT). The PK/PD analysis confirmed that 280- and 420-mg/d dosages would not be enough to achieve high probabilities of target attainment for MIC values ≥ 1 mg/L in patients with Clcr ≥ 60 mL/min or in subjects with lower Clcrs but receiving CRRT. In these patients, higher dosages (560-840 mg/d) should be needed. When treating infections due to MIC values ≥ 4 mg/L, even the highest dose would be insufficient.

Evaluation of antiretroviral-related errors and interventions by the clinical pharmacist in hospitalized HIV-infected patients.

OBJECTIVES: The aim of the study was to identify antiretroviral-related errors in the prescribing of medication to HIV-infected inpatients and to ascertain the degree of acceptance of the pharmacist's interventions. METHODS: An observational, prospective, 1-year study was conducted in a 750-bed tertiary-care teaching hospital by a pharmacist trained in HIV pharmacotherapy. Interactions with antiretrovirals were checked for contraindicated combinations. Inpatient antiretroviral prescriptions were compared with outpatient dispensing records for reconciliation. Renal and hepatic function was monitored to determine the need for dose adjustments. RESULTS: The prescriptions for 247 admissions (189 patients) were reviewed. Sixty antiretroviral-related problems were identified in 41 patients (21.7%). The most common problem was contraindicated combinations (n=20; 33.3%), followed by incorrect dose (n=10; 16.7%), dose omission (n=9; 15%), lack of dosage reduction in patients with renal or hepatic impairment (n=6; 10% and n=1; 1.7%, respectively), omission of an antiretroviral (n=6; 10%), addition of an alternative antiretroviral (n=5; 8.3%) and incorrect schedule according to outpatient treatment (n=3; 5%). Fifteen out of 20 errors were made during admission. A multivariate analysis showed that factors associated with an increased risk of antiretroviral-related problems included renal impairment [odds ratio (OR) 3.95; 95% confidence interval (CI) 1.39-11.23], treatment with atazanavir (OR 3.53; 95% CI 1.61-7.76) and admission to a unit other than an infectious diseases unit (OR 2.50; 95% CI 1.28-4.88). Use of a nonnucleoside reverse transcriptase inhibitor was a protective factor (OR 0.33; 95% CI 0.13-0.81). Ninety-two per cent of the pharmacist's interventions were accepted. CONCLUSION: Antiretroviral-related errors affected more than one-in-five patients. The most common causes of error were contraindicated or not recommended drug-drug combinations and dose-related errors. A clinical pharmacist trained in HIV pharmacotherapy could help to detect errors and reduce the duration of their effect.

Análisis de la duración y los motivos de cambio de la primera combinación de tratamiento antirretroviral / Analysis of the duration of and reasons for changing the first combination of antiretroviral therapy

Objetivo Conocer la duración y los motivos de cambio de las distintas combinaciones de fármacos utilizadas como inicio del tratamiento antirretroviral en pacientes naive. Métodos Estudio observacional y retrospectivo en el que se incluyeron todos los pacientes con infección por VIH que iniciaron tratamiento antirretroviral en un hospital universitario de referencia de alta tecnología durante el periodo comprendido entre el 1 de enero de 2003 y el 31 de diciembre de 2005. El seguimiento se realizó hasta el 31 de diciembre de 2008. Para estimar la probabilidad acumulada de interrupción del tratamiento se utilizó el método de Kaplan-Meier. Resultados Se incluyeron un total de 441 pacientes. La mediana de duración del primer tratamiento fue de 384 (intervalo intercuartil 84–1.290) días. Los regímenes basados en inhibidores de la transcriptasa inversa no análogos de nucleósidos y aquellos que incluían como análogos de nucleósidos abacavir o tenofovir en combinación con lamivudina o emtricitabina presentaron una duración significativamente mayor que el resto. Los principales motivos de finalización fueron las reacciones adversas aunque en un porcentaje menor que el obtenido en estudios anteriores. No se hallaron asociaciones entre el resto de características de los pacientes o del tratamiento y el riesgo de interrupción. Discusión Aunque la duración del primer tratamiento antirretroviral sigue siendo corta, actualmente se producen menos cambios por reacciones adversas y por pérdidas de seguimiento. Los motivos podrían ser una mejor tolerancia y una menor complejidad. No obstante, son necesarios más estudios para determinar el beneficio de un régimen frente a otro y poder generalizar estos resultados (AU)

Objective To determine the duration of and reasons behind changing the various combinations of drugs used for the initiation of antiretroviral treatment in naïve patients. Methods A retrospective observational study that included all patients with HIV infection who started antiretroviral therapy in a high-tech university reference hospital during the period from 1 January 2003 and 31 December 2005. Patients were followed until 31 December 2008. To estimate the cumulative probability of discontinuation the Kaplan-Meier method was used. Results A total of 441 patients were included. The average duration of the first treatment was 384 (interquartile interval 84–1290) days. The regimen based on non-nucleoside reverse transcriptase inhibitors and those that included as nucleosides abacavir or tenofovir in combination with lamivudine or emtricitabine showed a significantly longer duration than the rest. The main reasons for termination were the side effects, although in a lesser percentage than that obtained in previous studies. No associations were found between the rest of the characteristics of the patients or of the treatment and the risk of termination. Discussion Although the duration of the first antiretroviral treatment remains short, currently fewer changes are made due to side effects and due to loss to follow-up. The reasons may be better tolerance and less complexity. However, more studies are needed to determine the benefits of one regimen or another, and to be able to generalise the results (AU)

[Analysis of the duration of and reasons for changing the first combination of antiretroviral therapy]. / Análisis de la duración y los motivos de cambio de la primera combinación de tratamiento antirretroviral.

OBJECTIVE: To determine the duration of and reasons behind changing the various combinations of drugs used for the initiation of antiretroviral treatment in naïve patients. METHODS: A retrospective observational study that included all patients with HIV infection who started antiretroviral therapy in a high-tech university reference hospital during the period from 1 January 2003 and 31 December 2005. Patients were followed until 31 December 2008. To estimate the cumulative probability of discontinuation the Kaplan-Meier method was used. RESULTS: A total of 441 patients were included. The average duration of the first treatment was 384 (interquartile interval 84-1290) days. The regimen based on non-nucleoside reverse transcriptase inhibitors and those that included as nucleosides abacavir or tenofovir in combination with lamivudine or emtricitabine showed a significantly longer duration than the rest. The main reasons for termination were the side effects, although in a lesser percentage than that obtained in previous studies. No associations were found between the rest of the characteristics of the patients or of the treatment and the risk of termination. DISCUSSION: Although the duration of the first antiretroviral treatment remains short, currently fewer changes are made due to side effects and due to loss to follow-up. The reasons may be better tolerance and less complexity. However, more studies are needed to determine the benefits of one regimen or another, and to be able to generalise the results.