The New Political History

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66569/2/10.1177_000276427702100204.pd

Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings

Background:Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world.Methods and Findings:1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure.An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72-1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54-0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39-0.64 for women; HR 0.79, CI 0.62-1.00 for men; p = 0.01). Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12-2.04; p = 0.007).Conclusion: EFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are advantageous for use of this regimen for initial treatment of HIV-1 infection in resource-limited countries. ATV+DDI+FTC had inferior efficacy and is not recommended as an initial antiretroviral regimen.Trial Registration:http://www.ClinicalTrials.gov NCT00084136

Quantification et systématisation 3D du débit sanguin cérébral à partir des images tomoscintigraphiques d'un traceur de perfusion à l'équilibre (HMPAO-TC99m,ECD-TC99m)

La méthode d'analyse graphique de Patlak est une technique non invasive de quantification du débit sanguin cérébral global (DSC). Elle repose sur une modélisation bi-compartimentale qui tient compte des caractéristiques physico-chimiques des traceurs employés (ECD-TC99m, HMPAO-TC99m). Le temps de transit du traceur, à travers la membrane hémato encéphalique, est déterminé par analyse graphique des courbes activité-temps. La correction de ce paramètre permet le calcul de l'indice de perfusion cérébrale préalable au calcul du DSC global. Des mesures du DSC global effectuées sur des cas cliniques montrent une forte corrélation entre les valeurs du DSC mesurées en intra- et inter-observateurs. En revanche, l'analyse des résultats expérimentaux relatifs à la quantification du DSC régional par tracé de régions d'intérêt (ROIs) sur des coupes TEMP de perfusion, met en évidence les limites de cette technique, en particulier pour les mesures inter observateurs et dans les cas pathologiques. Les paramètres engendrant cette variabilité sont : le choix des coupes planaires représentant la structure neuro-anatomique à étudier, l'épaisseur de ces coupes, ainsi que la taille des ROIs tracées. Il découle de ces tests expérimentaux qu'une approche volumique par recalage automatique d'un atlas cérébral représentant les structures à analyser constituerait la solution à ce problème. Ceci a fait l'objet de la deuxième partie de notre travail qui a consisté à caractériser automatiquement la variation du DSC dans des ROIs définies par recalage des images TEMP de perfusion et un modèle conceptuel de la systématisation vasculaire cérébrale conçu au sein de notre laboratoire. Cette approche de systématisation et de quantification automatique de la perfusion cérébrale a été testée sur une vingtaine de patients. Les résultats qui en ont découlé montrent l'efficacité de la technique et son utilité potentielle en routine clinique.In routine clinical studies it is certainly helpful to use non-invasive and simple techniques, to evaluate quantitatively the mean cerebral blood flow (CBF). Patlak graphical analysis approach, using intravenous radionuclide angiography with 99mTC-ECD or 99m TC-HMPAO, is a method witch does not require the determination of a specific compartment model, and based, only, on the evaluation of the unidirectional influx constant of the tracer across the blood brain barrier. The brain perfusion index, required to estimate the mean CBF, is calculated by standardisation of this influx rates value. The intra and inter observer variability studies indicates high reproducibility of this technique. However, after applying Lassen's correction algorithm to quantify SPECT images, the evaluation of regional CBF (rCBF) with conventional ROIs setting showed significant variability especially in inter-observer and for the pathological cases. This variability is due to many parameters like ROIs sizes, images selection and/or thickness, etc. To perform more precise results and less variability of cerebral perfusion quantification we have developed an original approach by constructing a 3D atlas of the systematisation of the brain vascularisation. This template is deformed to match rCBF SPECT volume. This process allows automatic characterisation of rCBF variation into vascular cerebral territories. In order to validate this technique, we examined the rCBF values of 26 patients with various cerebrovascular diseases. The results obtained from this experimentation showed that this technique is suitable for automatic quantification and systematisation of CBF in clinical routine.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF