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

Photonitration of aromatic compounds by tetranitromethane

This thesis describes the photochemical reactions of tetranitromethane with aromatic compounds. These reactions are known to occur by initial formation of a triad consisting of an aromatic radical cation, trinitromethanide ion and nitrogen dioxide and the subsequent reactions which occur involve the recombination of these species of the triad. This thesis is in three major parts. In the first (Chapter 2) the photochemical reactions of tetranitromethane with 1,4,6,7-tetramethylnaphthalene (56), 2,6-dimethylnaphthalene (57) and 1,3-dimethylnaphthalene (58) are described. In all cases the initial recombination step involves the aromatic radical cation and trinitromethanide ion and the reactions of these three naphthalene derivatives further documents the importance of the energy of the delocalized carbon radical formed in the first recombination step. A number of hydroxy/trinitromethyl adducts (84), (98), (102)-(1 04), (114), (115) and nitro/trinitromethyl adducts (75), (94)-(97), (99)-(101), (110)-(113), (122) were isolated as part of this study. In the second part of this thesis (Chapter 3) the analogous reactions of 1,2,3-trimethylbenzene (137), 1,2,4,5-tetramethylbenzene (134), pentamethylbenzene (135) and hexamethylbenzene (136) are described. In the photolysis of 1,2,3-trimethylbenzene ( 137) with tetranitromethane a variety of nitronic esters (159)-(162) are formed in addition to "double" adducts (139), (157), (158) which arise by subsequent addition of nitrogen dioxide to initially formed hydroxy/trinitromethyl adducts (176), (177) and nitro/trinitromethyl adducts (152), (175), and the more usual "single" nitro/trinitromethyl adducts (151)-(156). In the reactions of 1,2,4,5-tetramethylbenzene (134), pentamethylbenzene (135) and hexamethylbenzene (136) evidence was obtained which pointed to increasing instability of initially formed adducts. In particular for pentamethylbenzene (135), nitro/trinitromethyl adducts (244), (245) were formed at -20, -50 and -78° in dichloromethane but rearranged rapidly in solution. For hexamethylbenzene (136) direct evidence of the formation of nitro/trinitromethyl adducts could not be obtained because of the insolubility of the substrate, hexamethylbenzene (136), in the photolysis solvents. However rearrangement products (279)-(282), (287), (288), analogous to those from pentamethylbenzene (135), were obtained from the photolysis of hexamethylbenzene (136) with tetranitromethane. The final part of this thesis (Chapter 4) describes the photolysis of 2,3-dimethylanisole (307) with tetranitromethane. The purpose of this section of the work was to explore the effect of replacing one of the flanking methyl groups in 1,2,3-trimethylbenzene (137) with a methoxy group. In the event "single" hydroxy/trinitromethyl adducts (316), (317) and nitro/trinitromethyl adducts (314), (315) were formed but nitronic esters and "double" adducts, characteristic of the reactions of 1,2,3-trimethylbenzene (137), were notably absent from among the products