Treatment of Immunocompromised, Critically Ill Patients with Influenza A H1N1 Infection with a Combination of Oseltamivir, Amantadine, and Zanamivir.

Immunocompromised patients are at increased risk of complications of influenza virus infection. We report on two critically ill patients on immunosuppressive medication with influenza pneumonia. In both patients, oseltamivir monotherapy did not result in clearance of the virus after 18 and five days, respectively. After adding zanamivir and amantadine to the treatment, PCRs on pharyngeal and/or plasma specimens turned negative in both patients after four and three days, respectively. We suggest, that in critically ill patients with influenza A H1N1 infection, treatment efficacy should be monitored closely and treatment with a combination of antiviral drugs should be considered.

Improving the management of warfarin in aged-care facilities utilising innovative technology: a proof-of-concept study.

OBJECTIVE: In aged-care facilities (ACFs) monitoring of warfarin can be logistically challenging and International Normalised Ratio (INR control) is often suboptimal. We aimed to determine whether an integrated information and communications technology system and the use of point-of-care (POC) monitors by nursing staff could improve the INR control of aged-care facility residents who take warfarin. METHODS: Nursing staff identified residents who were prescribed warfarin in participating ACFs. A computer program (MedePOC) was developed to store and transmit INR results from the ACFs to general practitioners (GPs) for dosage adjustment. Nursing staff received training in the use of the CoaguChek XS point-of-care INR monitor and the MedePOC software. Following a run-in phase, eligible patients were monitored weekly for up to 12 weeks. The primary outcome was the change in the time in therapeutic range (TTR) in the intervention phase compared to the TTR in the 12 months preceding the study. All GPs, nursing staff and patients were surveyed for their experiences and opinions of the project. KEY FINDINGS: Twenty-four patients and 19 GPs completed the trial across six ACFs. The mean TTR for all patients improved non-significantly from 58.9 to 60.6% (P=0.79) and the proportion of INR tests in range improved non-significantly from 57.1 to 64.1% (P=0.21). The mean TTR improved in 14 patients (58%) and in these patients the mean absolute improvement in TTR was 23.1%. A post hoc analysis of the INR data using modified therapeutic INR ranges to reflect the dosage adjustment practices of GPs suggested that the intervention did lead to improved INR control. The MedePOC program and POC monitoring was well received by nursing staff. CONCLUSIONS: Weekly POC INR monitoring conducted in ACFs and electronic communication of the results and warfarin doses resulted in non-significant improvements in INR control in a small cohort of elderly residents. Further research involving modification to the communication strategy and a longer follow-up period is warranted to investigate whether this strategy can improve INR control and clinical outcomes in this vulnerable population.

Therapeutic drug monitoring of antiretroviral drugs at home using dried blood spots: a proof-of-concept study.

BACKGROUND: In HIV-infected patients, therapeutic drug monitoring (TDM) of antiretroviral drugs is recommended in special populations and in specific situations to optimize therapy. Currently, TDM is performed via measurement of drug plasma concentrations; however, dried blood spots (DBS) may offer a patient friendly and cost-effective alternative. Therefore, this proof-of-concept study assessed the feasibility of TDM of antiretroviral drugs using DBS with sampling at home. METHODS: Included patients were instructed to sample three DBS just before drug intake at three consecutive days at home and one DBS sample together with their routine venous sampling. All samples were analysed using liquid chromatography coupled to tandem mass spectrometry. Feasibility was investigated with a questionnaire and via determination of the calculated plasma trough concentrations. RESULTS: In total, 50 patients (48 male, mean age 50 years [range 29-69]) have been included, of whom most were virologically and immunologically well-controlled. In total, 200 DBS were collected, of which 87.5% were suitable for analysis. The questionnaire showed that most patients (68%) successfully obtained their first DBS and 51% preferred DBS over plasma sampling. Plasma trough concentrations could adequately be determined from DBS. CONCLUSIONS: This proof-of-concept study confirms the feasibility of TDM of antiretroviral drugs using DBS with sampling at home, thereby opening the possibility to obtain trough concentrations at home in populations where venous sampling is difficult.

Use of dried blood spots for the determination of plasma concentrations of nevirapine and efavirenz.

OBJECTIVES: Plasma concentrations are frequently used for therapeutic drug monitoring of antiretroviral drugs. Dried blood spot sampling offers a patient-friendly and easy alternative to plasma sampling. However, dried blood spot concentrations are not necessarily equal to plasma concentrations and therefore the objective of this work was to establish the relationship between nevirapine and efavirenz dried blood spot and plasma concentrations to facilitate clinical implementation of dried blood spot sampling. METHODS: Paired dried blood spot and plasma samples were obtained from 40 HIV-infected patients on nevirapine and 40 on efavirenz treatment. All samples were analysed using validated HPLC-tandem mass spectrometry methods for the two matrices. Theoretical plasma concentrations were calculated from dried blood spot concentrations using the formula [dried blood spot concentration/(1 - haematocrit)] × fraction bound to plasma proteins = plasma concentration. Linear regression and Bland-Altman analysis were used to compare the two methods. RESULTS: Dried blood spot and plasma concentrations of nevirapine and efavirenz correlated well (r(2) = 0.867 and 0.972, respectively), although efavirenz dried blood spot concentrations were 39.8% (SD 7.1%) lower than plasma concentrations. Theoretical plasma concentrations (using patient-specific haematocrit) of nevirapine and efavirenz were similar to measured plasma concentrations, with a mean difference between the two methods of 0.29 mg/L (SD 1.35 mg/L) and 0.08 mg/L (SD 0.31 mg/L), respectively. CONCLUSIONS: Dried blood spot concentrations of nevirapine and efavirenz were equal to plasma concentrations after correction for haematocrit and compound-specific plasma protein binding and can therefore be used in clinical practice.

Treatment of HIV infection with the CCR5 antagonist maraviroc.

IMPORTANCE OF THE FIELD: The emergence of resistance in treatment-experienced HIV patients often limits therapeutic success of the currently available antiretroviral drugs. New drug classes are thus required. Maraviroc is the first chemokine receptor 5 antagonist approved for use in treatment experienced HIV patients with a R5-tropic virus. AREAS COVERED IN THIS REVIEW: For this review, data from pharmacokinetic, Phase II and III clinical trials were reviewed. WHAT THE READER WILL GAIN: The objectives of this review were to discuss the pharmacokinetics and clinical efficacy and safety of maraviroc in treatment-experienced and -naive HIV patients with R5-tropic virus. Additionally, tropism testing was discussed. TAKE HOME MESSAGE: Maraviroc is effective in previously treated patients with R5-tropic virus only. Also, maraviroc will be an attractive option for HIV-1-infected treatment-naive patients with R5-tropic viruses only, once genotypic assays have been validated.

Simultaneous quantification of emtricitabine and tenofovir nucleotides in peripheral blood mononuclear cells using weak anion-exchange liquid chromatography coupled with tandem mass spectrometry.

Emtricitabine (FTC) and tenofovir (TFV) are widely used antiviral agents that require intracellular phosphorylation to become active. This article describes the development and validation of an assay for the simultaneous quantification of FTC mono-, di- and triphosphate (FTC-MP, -DP and -TP), TFV and TFV mono- and diphosphate (TFV-MP and -DP) in peripheral blood mononuclear cells. Reference compounds and internal standards were obtained by thermal degradation of FTC-TP, TFV-DP, stable isotope-labeled TFV-DP and stable isotope-labeled cytosine triphosphate. Cells were lysed in methanol:water (70:30, v/v) and the extracted nucleotides were analyzed using weak anion-exchange chromatography coupled with tandem mass spectrometry. Calibration ranges in PBMC lysate from 0.727 to 36.4, 1.33 to 66.4 and 1.29 to 64.6 nM for FTC-MP, FTC-DP and FTC-TP and from 1.51 to 75.6, 1.54 to 77.2 and 2.54 to 127 nM for TFV, TFV-MP and TFV-DP, respectively, were validated. Accuracies were within -10.3 and 16.7% deviation at the lower limit of quantification at which the coefficients of variation were less than 18.2%. At the other tested levels accuracies were within -14.3 and 9.81% deviation and the coefficients of variation lower than 14.7%. The stability of the compounds was assessed under various analytically relevant conditions. The method was successfully applied to clinical samples.