Time to Switch to Second-line Antiretroviral Therapy in Children With Human Immunodeficiency Virus in Europe and Thailand.

Background: Data on durability of first-line antiretroviral therapy (ART) in children with human immunodeficiency virus (HIV) are limited. We assessed time to switch to second-line therapy in 16 European countries and Thailand. Methods: Children aged <18 years initiating combination ART (≥2 nucleoside reverse transcriptase inhibitors [NRTIs] plus nonnucleoside reverse transcriptase inhibitor [NNRTI] or boosted protease inhibitor [PI]) were included. Switch to second-line was defined as (i) change across drug class (PI to NNRTI or vice versa) or within PI class plus change of ≥1 NRTI; (ii) change from single to dual PI; or (iii) addition of a new drug class. Cumulative incidence of switch was calculated with death and loss to follow-up as competing risks. Results: Of 3668 children included, median age at ART initiation was 6.1 (interquartile range (IQR), 1.7-10.5) years. Initial regimens were 32% PI based, 34% nevirapine (NVP) based, and 33% efavirenz based. Median duration of follow-up was 5.4 (IQR, 2.9-8.3) years. Cumulative incidence of switch at 5 years was 21% (95% confidence interval, 20%-23%), with significant regional variations. Median time to switch was 30 (IQR, 16-58) months; two-thirds of switches were related to treatment failure. In multivariable analysis, older age, severe immunosuppression and higher viral load (VL) at ART start, and NVP-based initial regimens were associated with increased risk of switch. Conclusions: One in 5 children switched to a second-line regimen by 5 years of ART, with two-thirds failure related. Advanced HIV, older age, and NVP-based regimens were associated with increased risk of switch

Investigations of multivalent ligand-receptor interactions in microfluidic devices

Due to the character of the original source materials and the nature of batch digitization, quality control issues may be present in this document. Please report any quality issues you encounter to [email protected], referencing the URI of the item.Includes bibliographical references (leaves 42-45).Issued also on microfiche from Lange Micrographics.The objective of the studies presented herein was to obtain thermodynamic data on surface confined multivalent ligand - receptor interactions. Novel microfluidic strategies in conjunction with total internal reflection fluorescence microscopy (TIRFM) were designed in order to achieve this. Concanavalin A bound to α-manno-sylated lipids on supported phospholipid bilayers was chosen as a model bivalent system. The acquired binding parameters on bilayers containing various ligand densities were examined by modifying available thermodynamic models. In the case of bivalent systems, two individual dissociation constants could be extracted from the experimental data. The values of these parameters demonstrated significant binding enhancement due to the presence of a fluid membrane interface

Backbone dynamics of SDF-1α determined by NMR: Interpretation in the presence of monomer–dimer equilibrium

SDF-1α is a member of the chemokine family implicated in various reactions in the immune system. The interaction of SDF-1α with its receptor, CXCR4, is responsible for metastasis of a variety of cancers. SDF-1α is also known to play a role in HIV-1 pathogenesis. The structures of SDF-1α determined by NMR spectroscopy have been shown to be monomeric while X-ray structures are dimeric. Biochemical data and in vivo studies suggest that dimerization is likely to be important for the function of chemokines. We report here the dynamics of SDF-1α determined through measurement of main chain 15N NMR relaxation data. The data were obtained at several concentrations of SDF-1α and used to determine a dimerization constant of ∼5 mM for a monomer–dimer equilibrium. The dimerization constant was subsequently used to extrapolate values for the relaxation data corresponding to monomeric SDF-1α. The experimental relaxation data and the extrapolated data for monomeric SDF-1α were analyzed using the model free approach. The model free analysis indicated that SDF-1α is rigid on the nano- to picosecond timescale with flexible termini. Several residues involved in the dimer interface display slow micro- to millisecond timescale motions attributable to chemical exchange such as monomer–dimer equilibrium. NMR relaxation measurements are shown to be applicable for studying oligomerization processes such as the dimerization of SDF-1α