HIV-1-infected patients from the French National Observatory experiencing virological failure while receiving enfuvirtide

Objectives We studied gp41 mutations associated with failing enfuvirtide salvage therapy. Methods This multicentre study involved patients with HIV-1 plasma viral load (pVL) > 5000 copies/mL after at least 3 months of uninterrupted enfuvirtide therapy and with plasma samples available at inclusion (T0), at initial enfuvirtide failure (T1) and at last follow-up visit during continued failing enfuvirtide therapy (T2). The HR-1 and HR-2 domains of the gp41 gene were sequenced at T0, T1 and T2. Results Ninety-nine patients were enrolled. At baseline, the median pVL and CD4 cell count were 5.1 log copies/mL and 72 cells/mm3, respectively. Based on the ANRS Resistance Group algorithm, the proportion of patients harbouring viruses with enfuvirtide resistance mutations increased significantly between T0 and T1. In the HR-1 domain, the V38A/M, Q40H, N42T, N43D and L45M mutations wereselected (P < 0.02). In the HR-2 domain, no mutations were significantly selected during the follow-up. None of the mutations was associated with a CD4 cell count increment. Conclusions Mutations selected during failing enfuvirtide salvage therapy are mainly located in the HR-1 domain of the gp41 gene, between codons 38 and 45. No mutations were associated with an increase in the CD4 cell coun

The association of N-palmitoylethanolamine with the FAAH inhibitor URB597 impairs melanoma growth through a supra-additive action

<p>Abstract</p> <p>Background</p> <p>The incidence of melanoma is considerably increasing worldwide. Frequent failing of classical treatments led to development of novel therapeutic strategies aiming at managing advanced forms of this skin cancer. Additionally, the implication of the endocannabinoid system in malignancy is actively investigated.</p> <p>Methods</p> <p>We investigated the cytotoxicity of endocannabinoids and their hydrolysis inhibitors on the murine B16 melanoma cell line using a MTT test. Enzyme and receptor expression was measured by RT-PCR and enzymatic degradation of endocannabinoids using radiolabeled substrates. Cell death was assessed by Annexin-V/Propidium iodine staining. Tumors were induced in C57BL/6 mice by s.c. flank injection of B16 melanoma cells. Mice were injected i.p. for six days with vehicle or treatment, and tumor size was measured each day and weighted at the end of the treatment. Haematoxylin-Eosin staining and TUNEL assay were performed to quantify necrosis and apoptosis in the tumor and endocannabinoid levels were quantified by HPLC-MS. Tube formation assay and CD31 immunostaining were used to evaluate the antiangiogenic effects of the treatments.</p> <p>Results</p> <p>The <it>N</it>-arachidonoylethanolamine (anandamide, AEA), 2-arachidonoylglycerol and <it>N</it>- palmitoylethanolamine (PEA) reduced viability of B16 cells. The association of PEA with the fatty acid amide hydrolase (FAAH) inhibitor URB597 considerably reduced cell viability consequently to an inhibition of PEA hydrolysis and an increase of PEA levels. The increase of cell death observed with this combination of molecules was confirmed in vivo where only co-treatment with both PEA and URB597 led to decreased melanoma progression. The antiproliferative action of the treatment was associated with an elevation of PEA levels and larger necrotic regions in the tumor.</p> <p>Conclusions</p> <p>This study suggests the interest of targeting the endocannabinoid system in the management of skin cancer and underlines the advantage of associating endocannabinoids with enzymatic hydrolysis inhibitors. This may contribute to the improvement of long-term palliation or cure of melanoma.</p

Modelling human choices: MADeM and decision‑making

Research supported by FAPESP 2015/50122-0 and DFG-GRTK 1740/2. RP and AR are also part of the Research, Innovation and Dissemination Center for Neuromathematics FAPESP grant (2013/07699-0). RP is supported by a FAPESP scholarship (2013/25667-8). ACR is partially supported by a CNPq fellowship (grant 306251/2014-0)

Non-AIDS defining cancers in the D:A:D Study-time trends and predictors of survival : a cohort study

BACKGROUND:Non-AIDS defining cancers (NADC) are an important cause of morbidity and mortality in HIV-positive individuals. Using data from a large international cohort of HIV-positive individuals, we described the incidence of NADC from 2004-2010, and described subsequent mortality and predictors of these.METHODS:Individuals were followed from 1st January 2004/enrolment in study, until the earliest of a new NADC, 1st February 2010, death or six months after the patient's last visit. Incidence rates were estimated for each year of follow-up, overall and stratified by gender, age and mode of HIV acquisition. Cumulative risk of mortality following NADC diagnosis was summarised using Kaplan-Meier methods, with follow-up for these analyses from the date of NADC diagnosis until the patient's death, 1st February 2010 or 6 months after the patient's last visit. Factors associated with mortality following NADC diagnosis were identified using multivariable Cox proportional hazards regression.RESULTS:Over 176,775 person-years (PY), 880 (2.1%) patients developed a new NADC (incidence: 4.98/1000PY [95% confidence interval 4.65, 5.31]). Over a third of these patients (327, 37.2%) had died by 1st February 2010. Time trends for lung cancer, anal cancer and Hodgkin's lymphoma were broadly consistent. Kaplan-Meier cumulative mortality estimates at 1, 3 and 5 years after NADC diagnosis were 28.2% [95% CI 25.1-31.2], 42.0% [38.2-45.8] and 47.3% [42.4-52.2], respectively. Significant predictors of poorer survival after diagnosis of NADC were lung cancer (compared to other cancer types), male gender, non-white ethnicity, and smoking status. Later year of diagnosis and higher CD4 count at NADC diagnosis were associated with improved survival. The incidence of NADC remained stable over the period 2004-2010 in this large observational cohort.CONCLUSIONS:The prognosis after diagnosis of NADC, in particular lung cancer and disseminated cancer, is poor but has improved somewhat over time. Modifiable risk factors, such as smoking and low CD4 counts, were associated with mortality following a diagnosis of NADC

Analyse clonale de l'ADN VIH-1 pendant une interruption de traitement chez des patients en multi-échec thérapeutique

Les interruptions de traitement (IT) chez des patients infectés par le VIH en multi-échec thérapeutique s accompagnent souvent d une resensibilisation de la population virale plasmatique résistante. Une analyse clonale a été effectuée pour déterminer l importance de l archivage de variants résistants VIH-1 et ses conséquences sur l échec virologique après la reprise du traitement. Un fragment du gène pol a été cloné et séquencé à partir de cellules mononuclées du sang circulant à la fin de l IT. Les séquences des différents clones ont été comparées pour quatre patients aux séquences plasmatiques globales avant et après l IT, ainsi qu au moment de l échec. Chez deux patients en échec post-IT, des variants minoritaires archivés ont été détectés dans l ADN proviral. Ces variants résistants sont phylogénétiquement liés au virus présent avant l IT et au moment de l échec, suggérant la réexpansion de VIH résistants à partir de quasi espèces archivées.TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Etude de la variabilité génétique du VIH-1 en Côte d'Ivoire et relation avec la résistance aux antiviraux

Le VIH-1 est caractérisé par une grande variabilité génétique. Dans les pays en développement où circulent la majorité des sous-types non B, la résistance naturelle aux antirétroviraux (ARV) due à la diversité génétique ou la résistance primaire liée à la transmission de virus résistants sont peu documentées. Nous avonscaractérisé la diversité génétique de variants VIH retrouvés dans une population de patients naifs de traitement antirétroviral à Abidjan, Côte d'Ivoire. Dans cette population virale appartenant majoritairement au recombinant CRF02_AG, nous avons montré que la prévalence des mutations de résistance augmentait régulièrement entre 1997 et 2004. Nous avons également caractérisé le génome entier de certains virus et décrit des recombinants secondaires impliquant dans leur structure génomique le CRF09_cpx et d'autres recombinants déjà décrits. L'ensemble de ces données constitue une base pour la poursuite d'un suivi longitudinal de la résistance et de la diversité génétique du VIH-1 en Côte d'Ivoire.One of the major characteristics of HIV is its high genetic diversity. In developing countries where HIV-1 non-B subtypes are predominant, few data concerning HIV-1 natural or primary resistance to antiretroviral drug are available. We characterized the genetic diversity of HIV-1 variants infecting drug-naive patients from Abidjan, Côte d'Ivoire. Most HIV-1 viruses were recombinant CRF02_AG. In this population, we showed an increasing frequency of key resistance mutations from 1997 to 2004. Moreover, a number of HIV-1 genomes were entirely sequenced. We characterized second-generation HIV-1 recombinants with genomic structure involving CRF09_cpx and other previously described recombinants. A continued monitoring of HIV-1 resistance and genetic diversity is necessary in Côte d'Ivoire.BORDEAUX2-BU Santé (330632101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Spinal cord stimulation for complex regional pain syndrome type 1 with dystonia: a case report and discussion of the literature.

Complex Regional Pain Syndrome type 1 (CRPS-1) is a debilitating chronic pain disorder, the physiopathology of which can lead to dystonia associated with changes in the autonomic, central and peripheral nervous system. An interdisciplinary approach (pharmacological, interventional and psychological therapies in conjunction with a rehabilitation pathway) is central to progress towards pain reduction and restoration of function