Abacavir, zidovudine, or stavudine as paediatric tablets for African HIV-infected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial

BACKGROUND: WHO 2013 guidelines recommend universal treatment for HIV-infected children younger than 5 years. No paediatric trials have compared nucleoside reverse-transcriptase inhibitors (NRTIs) in first-line antiretroviral therapy (ART) in Africa, where most HIV-infected children live. We aimed to compare stavudine, zidovudine, or abacavir as dual or triple fixed-dose-combination paediatric tablets with lamivudine and nevirapine or efavirenz. METHODS: In this open-label, parallel-group, randomised trial (CHAPAS-3), we enrolled children from one centre in Zambia and three in Uganda who were previously untreated (ART naive) or on stavudine for more than 2 years with viral load less than 50 copies per mL (ART experienced). Computer-generated randomisation tables were incorporated securely within the database. The primary endpoint was grade 2-4 clinical or grade 3/4 laboratory adverse events. Analysis was intention to treat. This trial is registered with the ISRCTN Registry number, 69078957. FINDINGS: Between Nov 8, 2010, and Dec 28, 2011, 480 children were randomised: 156 to stavudine, 159 to zidovudine, and 165 to abacavir. After two were excluded due to randomisation error, 156 children were analysed in the stavudine group, 158 in the zidovudine group, and 164 in the abacavir group, and followed for median 2·3 years (5% lost to follow-up). 365 (76%) were ART naive (median age 2·6 years vs 6·2 years in ART experienced). 917 grade 2-4 clinical or grade 3/4 laboratory adverse events (835 clinical [634 grade 2]; 40 laboratory) occurred in 104 (67%) children on stavudine, 103 (65%) on zidovudine, and 105 (64%), on abacavir (p=0·63; zidovudine vs stavudine: hazard ratio [HR] 0·99 [95% CI 0·75-1·29]; abacavir vs stavudine: HR 0·88 [0·67-1·15]). At 48 weeks, 98 (85%), 81 (80%) and 95 (81%) ART-naive children in the stavudine, zidovudine, and abacavir groups, respectively, had viral load less than 400 copies per mL (p=0·58); most ART-experienced children maintained suppression (p=1·00). INTERPRETATION: All NRTIs had low toxicity and good clinical, immunological, and virological responses. Clinical and subclinical lipodystrophy was not noted in those younger than 5 years and anaemia was no more frequent with zidovudine than with the other drugs. Absence of hypersensitivity reactions, superior resistance profile and once-daily dosing favours abacavir for African children, supporting WHO 2013 guidelines. FUNDING: European Developing Countries Clinical Trials Partnership

Path Planning for a Space-Based Manipulator System Based on Quantum Genetic Algorithm

In this study, by considering a space-based, n-joint manipulator system as research object, a kinematic and a dynamic model are constructed and the system&#39;s nonholonomic property is discussed. In light of the nonholonomic property unique to space-based systems, a path planning method is introduced to ensure that when an end-effector moves to the desired position, a floating base achieves the expected pose. The trajectories of the joints are first parameterized using sinusoidal polynomial functions, and cost functions are defined by the pose deviation of the base and the positional error of the end-effector. At this stage, the path planning problem is converted into a target optimization problem, where the target is a function of the joints. We then adopt a quantum genetic algorithm (QGA) to solve this objective optimization problem to attain the optimized trajectories of the joints and then execute nonholonomic path planning. To test the proposed method, we carried out a simulation on a six-degree-of-freedom (DOF) space-based manipulator system (SBMS). The results showed that, compared to traditional genetic optimization algorithms, the QGA converges more rapidly and has a more accurate output.</p

Городские вести. 2012. № 078

Objective: Immune activation is associated with morbidity/mortality in HIV-infection despite antiretroviral therapy (ART). We investigated whether microbial translocation drives immune activation in HIV-infected Ugandan children. Methods: Nineteen markers of immune activation/inflammation were measured over 96 weeks in HIV-infected Ugandan children in CHAPAS-3 (ISRCTN69078957) and HIV-uninfected age-matched controls. Microbial translocation was assessed using molecular techniques including next-generation sequencing. Results: Of 249 children included, 120 were HIV-infected ART-naïve and 22 ART-experienced (median (IQR) age 2.8(1.7-4.0) and 6.5(5.9-9.2) years; median baseline CD4% 20(14-24) and 35(31-39)). 107 were HIV-uninfected controls. Median (IQR) CD4% increase was 17(12-22) at week-96 in ART-naïve children, and viral load was<100 copies/mL in 76%/91% ART-naïve/experienced. Immune activation decreased with ART. Children could be divided by immune activation markers into clusters: cluster-1 (majority HIV-uninfected); cluster-2 (mixed HIV-uninfected/ART-naïve/ART-experienced); and cluster-3 (majority ART-naïve). Immune activation was low in cluster-1, decreased in cluster-3, and persisted in cluster-2. Blood microbial DNA levels were negative/very low across groups, with no difference between clusters except Enterobacteriaceae (higher in cluster-1,p<0.0001). Conclusion: Immune activation decreased with ART, with marker-clustering indicating different activation patterns by HIV/ART status. Levels of bacterial DNA in blood were low regardless of HIV/ART/immune activation status. Microbial translocation did not drive immune activation in this setting

Abacavir, zidovudine, or stavudine as paediatric tablets for African HIV-infected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial.

WHO 2013 guidelines recommend universal treatment for HIV-infected children younger than 5 years. No paediatric trials have compared nucleoside reverse-transcriptase inhibitors (NRTIs) in first-line antiretroviral therapy (ART) in Africa, where most HIV-infected children live. We aimed to compare stavudine, zidovudine, or abacavir as dual or triple fixed-dose-combination paediatric tablets with lamivudine and nevirapine or efavirenz.In this open-label, parallel-group, randomised trial (CHAPAS-3), we enrolled children from one centre in Zambia and three in Uganda who were previously untreated (ART naive) or on stavudine for more than 2 years with viral load less than 50 copies per mL (ART experienced). Computer-generated randomisation tables were incorporated securely within the database. The primary endpoint was grade 2-4 clinical or grade 3/4 laboratory adverse events. Analysis was intention to treat. This trial is registered with the ISRCTN Registry number, 69078957.Between Nov 8, 2010, and Dec 28, 2011, 480 children were randomised: 156 to stavudine, 159 to zidovudine, and 165 to abacavir. After two were excluded due to randomisation error, 156 children were analysed in the stavudine group, 158 in the zidovudine group, and 164 in the abacavir group, and followed for median 2·3 years (5% lost to follow-up). 365 (76%) were ART naive (median age 2·6 years vs 6·2 years in ART experienced). 917 grade 2-4 clinical or grade 3/4 laboratory adverse events (835 clinical [634 grade 2]; 40 laboratory) occurred in 104 (67%) children on stavudine, 103 (65%) on zidovudine, and 105 (64%), on abacavir (p=0·63; zidovudine vs stavudine: hazard ratio [HR] 0·99 [95% CI 0·75-1·29]; abacavir vs stavudine: HR 0·88 [0·67-1·15]). At 48 weeks, 98 (85%), 81 (80%) and 95 (81%) ART-naive children in the stavudine, zidovudine, and abacavir groups, respectively, had viral load less than 400 copies per mL (p=0·58); most ART-experienced children maintained suppression (p=1·00).All NRTIs had low toxicity and good clinical, immunological, and virological responses. Clinical and subclinical lipodystrophy was not noted in those younger than 5 years and anaemia was no more frequent with zidovudine than with the other drugs. Absence of hypersensitivity reactions, superior resistance profile and once-daily dosing favours abacavir for African children, supporting WHO 2013 guidelines.European Developing Countries Clinical Trials Partnership