Large Vessel Vasculitis as a Possible Mechanism of Vascular Side Effects of Ponatinib: A Case Report.

Arterial occlusive events (AOEs) such as cerebrovascular, cardiovascular and peripheral arterial events are known side effects of ponatinib, assumed due to the rapid development and increase of arteriosclerosis, while the definitive pathomechanisms therefore are still unclear. We present a case of clinically apparent large vessel vasculitis and discuss this phenomenon as a possible mechanism of AOEs beside arteriosclerosis.

Impact of changes in antigen level on CD38/PD-1 co-expression on HIV-specific CD8 T cells in chronic, untreated HIV-1 infection.

Excessive immune activation is a hallmark of chronic uncontrolled HIV infection. During the past years, growing evidence suggests that immune inhibitory signals also play an important role in progressive disease. However, the relationship between positive and negative immune signals on HIV-specific CD8 T cells has not been studied in detail so far in chronic HIV-1 infection. In this study, the expression of markers of positive (CD38) and negative (PD-1) immune signals on virus-specific CD8 T cells in chronic, untreated HIV-1 infection was evaluated using intracellular cytokine staining. Viral escape mutations were assessed by autologous virus sequence analysis and subsequent peptide titration assays. Single-epitope CD8 T-cell responses toward Gag, Pol, and Nef were compared in 12 HIV-1 controllers (viral load <5,000 cp/ml) and 12 HIV-1 progressors (viral load >50,000 cp/ml) and a highly significant increase of CD38/PD-1 co-expression on virus-specific CD8 T cells in progressors was found (P < 0.0001). The level of CD38/PD-1 co-expression was independent of epitope specificity. Longitudinal follow-up revealed a clear drop in CD38/PD-1 co-expression on virus-specific CD8 T cells after the suppression of antigen following either viral escape mutation or the initiation of HAART (P = 0.004). Antigen persistence with a fluctuating viral load revealed stable levels of CD38/PD-1 co-expression whereas significant rises in viral load were accompanied or even preceded by substantial increases in CD38/PD-1 co-expression. The CD38/PD-1 phenotype clearly distinguishes HIV-specific CD8 T-cell responses between controllers and progressors. Whether it plays a causative role in disease progression remains debatable. J. Med. Virol. 82:358-370, 2010. (c) 2010 Wiley-Liss, Inc.

Pharmacokinetics of enfuvirtide in patients treated in typical routine clinical settings.

Therapeutic drug monitoring (TDM) is gaining importance for improving the success of antiretroviral treatment in human immunodeficiency virus-infected patients. However, enfuvirtide (ENF) concentrations are not regularly determined. The objective of this work was to study the pharmacokinetics (PK) of ENF in patients treated in routine clinical settings, to develop a population PK model describing the concentration-time profile, and to establish PK reference values. A liquid chromatography-tandem mass spectrometry method was developed and applied to serum samples submitted for TDM. A two-compartment model with linear absorption and elimination was fitted to 329 concentrations from 131 patients. The PK model was used for simulations resulting in percentile curves for ENF levels for the full dosing interval. The model predicted that a median concentration of 1,968 ng/ml would be reached 12 h after administration of 90 mg of ENF, and 23% and 58% of patients are expected to have concentrations below 1,000 ng/ml and 2,200 ng/ml, respectively. Both values have been proposed as cutoffs for virological efficacy. The median maximum concentration of drug in serum (Cmax) of 3,943 ng/ml, predicted for 3 h after drug administration, is lower than the Cmax reported previously. We found an enormous interpatient variability at every time point, with concentration spectrums covering >1 log and 52% and 123% interindividual variabilities in the typical clearance and volume of distribution, respectively, in contrast to preexisting PK data. In summary, ENF levels are lower and more variable than expected. Many patients may achieve insufficient concentrations. Further covariate analysis in the population PK model might help to identify factors influencing the variability in ENF concentrations.