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Pneumocystis jirovecii pneumonia is the main cause of severe respiratory failure in patients with advanced HIV disease who do not receive P. jirovecii prophylaxis. Other aetiological agents may contribute to the respiratory failure in these patients, which is highlighted by the case described below: A patient with advanced HIV disease was treated for a dual-infection with pandemic influenza A (H1N1) and P. jirovecii. Initially, his condition improved, but deteriorated after the emergence of oseltamivir-resistant influenza virus. This is the first documented case of emergence of drug-resistant influenza virus in a patient infected with HIV with a pandemic influenza A (H1N1) and P. jirovecii double infection., (Copyright © 2013 Wiley Periodicals, Inc.)

A new and reliable mass spectrometric method using an isotope dilution method in combination with matrix-assisted laser desorption/ionization-triple quadrupole tandem mass spectrometry (ID-MALDI-QqQ-MS/MS) has been developed and validated for the determination of concentrations of the antiretroviral drug tenofovir (TNV) in plasma from HIV-infected adults. The advantage of this new method is that (1) the method is ultrafast and (2) can be applied for high-throughput measurement of TNV in plasma. The method is based on a simple plasma deproteinization step in combination with the use of [adenine-(13) C(5) ]-TNV as the internal standard. TNV and [adenine-(13) C(5) ]-TNV were monitored by multiple reaction monitoring using the transition m/z 288.0 → 176.2 and m/z 293.2 → 181.2 for TNV and [adenine-(13) C(5) ]-TNV, respectively. The method was validated according to the most recent FDA guidelines for the development and validation of (new) bio-analytical assays. Validated method parameters were: linearity, accuracy, precision and stability of the method. The lowest limit of quantification was 0.10 µmol/l, whereas the limit of detection determined at a signal-to-noise ratio (S/N = 3:1) in pooled drug free human control plasma was 0.04 µmol/l. The validated method was successfully applied and tested for its clinical feasibility by the analysis of plasma samples from selected HIV-infected adults receiving the prodrug tenofovir disoproxil fumarate. Observed plasma TNV concentrations ranged between 0.11 and 0.76 µmol/l and measured plasma TNV concentrations were within the therapeutically relevant concentration range., (Copyright © 2011 John Wiley & Sons, Ltd.)

Kaletra (Abott Laboratories) is a co-formulated medication used in the treatment of HIV-1-infected children, and it contains the two antiretroviral protease inhibitor drugs lopinavir and ritonavir. We validated two new ultrafast and high-throughput mass spectrometric assays to be used for therapeutic drug monitoring of lopinavir and ritonavir concentrations in whole blood and in plasma from HIV-1-infected children. Whole blood was blotted onto dried blood spot (DBS) collecting cards, and plasma was collected simultaneously. DBS collecting cards were extracted by an acetonitrile/water mixture while plasma samples were deproteinized with acetone. Drug concentrations were determined by matrix-assisted laser desorption/ionization-triple quadrupole tandem mass spectrometry (MALDI-QqQ-MS/MS). The application of DBS made it possible to measure lopinavir and ritonavir in whole blood in therapeutically relevant concentrations. The MALDI-QqQ-MS/MS plasma assay was successfully cross-validated with a commonly used high-performance liquid chromatography (HPLC)-ultraviolet (UV) assay for the therapeutic drug monitoring (TDM) of HIV-1-infected patients, and it showed comparable performance characteristics. Observed DBS concentrations showed as well, a good correlation between plasma concentrations obtained by MALDI-QqQ-MS/MS and those obtained by the HPLC-UV assay. Application of DBS for TDM proved to be a good alternative to the normally used plasma screening. Moreover, collection of DBS requires small amounts of whole blood which can be easily performed especially in (very) young children where collection of large whole blood amounts is often not possible. DBS is perfectly suited for TDM of HIV-1-infected children; but nevertheless, DBS can also easily be applied for TDM of patients in areas with limited or no laboratory facilities.

The initiation of antiretroviral therapy has resulted in an impressive reduction in the rate of disease progression in AIDS and HIV-1-related deaths in children; however, there are still several major challenges to be faced in order to improve therapy. A major topic that needs to be dealt with is the establishment of the optimal dosage of antiretroviral therapy for children. This review presents the currently available peer-reviewed data on the pharmacokinetics of nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs) and fusion inhibitors (FIs) in children. In addition, the data are discussed in relation to the currently available European and US guidelines and the US FDA-approved drug labels. High intra- and interpatient variability in pharmacokinetics are often observed for all antiretroviral drugs. The number of children included in the pharmacokinetic studies is often small and children are often divided into divergent groups using different dosage levels and/or drug formulations. For a substantial number of antiretroviral drugs, dosage recommendations, especially for young children, are still absent in the European and US guidelines. The recommended drug dosages in the guidelines are often different from that in the officially approved drug product label. In addition, the recommended drug dosages may deviate between the European and US guidelines. Thus, while practioners aim to meet the recommendations in the official guidelines, patients may receive highly divergent dosages of medication. The high intra- and interpatient variability in pharmacokinetics of antiretroviral drugs in children hampers the application of fixed dosages of antiretroviral drugs. For PIs and NNRTIs, plasma drug levels correlate with viral suppression and drug toxicity. NRTIs are prodrugs that are intracellularly converted to their active triphosphate form and, therefore, plasma NRTI levels correlate poorly with viral suppression. Therapeutic drug monitoring of PIs and NNRTIs should be considered to optimise HIV therapy in children.