Perceptions de la pratique des essais cliniques sur le VIH/sida par les médecins prescripteurs des antirétroviraux agréés de Kinshasa (RD Congo)

in Bulletin de la Société de Pathologie Exotique (2012)

Le but de cette étude, réalisée entre novembre 2005 et janvier 2006 auprès des prescripteurs d’antirétroviraux (ARV), était de cerner leurs perceptions sur les enjeux contextuels liés à la pratique des ... [more ▼]

Le but de cette étude, réalisée entre novembre 2005 et janvier 2006 auprès des prescripteurs d’antirétroviraux (ARV), était de cerner leurs perceptions sur les enjeux contextuels liés à la pratique des essais sur le VIH/sida à Kinshasa. Pour effectuer le repérage de ces enjeux, un ques- tionnaire a été élaboré et finalisé à la suite de la phase explo- ratoire de notre enquête afin d’apprécier les points de vue des médecins agréés par le Programme national de lutte contre le sida du Congo (PNLS) et qui jouent le premier rôle dans le contexte de leur pratique professionnelle. Sur 50 médecins sollicités pour participer à notre enquête, 35 ont retourné le questionnaire, dix n’étaient pas disponibles au moment de l’enquête et cinq n’ont pas retourné le questionnaire à l’adresse et dans le délai que nous avions indiqués. Les résul- tats obtenus témoignent de la nécessité de renforcer les capa- cités des acteurs locaux. Un des objectifs visés par la conduite locale de ces essais étant le transfert des connais- sances, il est nécessaire, au vu des résultats, d’affirmer le rôle pédagogique du comité d’éthique local. Cela devra permettre de relever le défi de la contextualisation et de réduire les tensions susceptibles de compromettre le bon déroulement des essais cliniques. [less ▲]

Deleterious Mutations in LRBA Are Associated with a Syndrome of Immune Deficiency and Autoimmunity

in American Journal of Human Genetics (2012), 90

Most autosomal genetic causes of childhood-onset hypogammaglobulinemia are currently not well understood. Most affected individ- uals are simplex cases, but both autosomal-dominant and autosomal-recessive ... [more ▼]

Most autosomal genetic causes of childhood-onset hypogammaglobulinemia are currently not well understood. Most affected individ- uals are simplex cases, but both autosomal-dominant and autosomal-recessive inheritance have been described. We performed genetic linkage analysis in consanguineous families affected by hypogammaglobulinemia. Four consanguineous families with childhood-onset humoral immune deficiency and features of autoimmunity shared genotype evidence for a linkage interval on chromosome 4q. Sequencing of positional candidate genes revealed that in each family, affected individuals had a distinct homozygous mutation in LRBA (lipopolysaccharide responsive beige-like anchor protein). All LRBA mutations segregated with the disease because homozygous individuals showed hypogammaglobulinemia and autoimmunity, whereas heterozygous individuals were healthy. These mutations were absent in healthy controls. Individuals with homozygous LRBA mutations had no LRBA, had disturbed B cell development, defec- tive in vitro B cell activation, plasmablast formation, and immunoglobulin secretion, and had low proliferative responses. We conclude that mutations in LRBA cause an immune deficiency characterized by defects in B cell activation and autophagy and by susceptibility to apoptosis, all of which are associated with a clinical phenotype of hypogammaglobulinemia and autoimmunity. [less ▲]

A national cohort of HIV-infected patients in Belgium: design and main characteristics.

in Acta Clinica Belgica (2012), 67(5), 333-7

In Belgium, individual laboratory and treatment data of all HIV-infected patients seen in the 9 AIDS Reference Centres and 7 AIDS Reference Laboratories are collected prospectively since 2006. We present ... [more ▼]

In Belgium, individual laboratory and treatment data of all HIV-infected patients seen in the 9 AIDS Reference Centres and 7 AIDS Reference Laboratories are collected prospectively since 2006. We present here an analysis of patients recorded in the cohort database between 1st of January 2006 and 31st of December 2008. During that period, 11982 patients were under medical follow-up in Belgium. Sixty-one percent of the patients were male and the median age was 39.8 at the time of first recorded viral load. Among the patients whose nationality or probable mode of transmission was recorded, nearly half (48.0%) were Belgian and 38.3% originated from Sub-Saharan Africa; heterosexual contacts were reported in the majority of cases (56.0%) followed by homosexual contacts (35.3%). A total of 145 deaths were reported. Around three quarters of the patients were on ART. The median CD4 cell count rose from 470 cells/mm3 in 2006 to 501 cells/mm3 in 2008. This cohort enabled us to obtain comprehensive information on the numbers and characteristics of HIV-infected patients currently being followed up in Belgium, and on trends in antiretroviral therapy and biological results. This will serve for planning purposes, evaluation of access to care and as a source of information for further studies. [less ▲]

[Gentetics, environment and determinants of autoimmune diseases].

in Revue Médicale de Liège (2012), 67

We initiate this review article by a brief description of a few monogenic autoimmune diseases such as the APECED and the IPEX syndrome because they allow understand the fundamental mechanisms of self ... [more ▼]

We initiate this review article by a brief description of a few monogenic autoimmune diseases such as the APECED and the IPEX syndrome because they allow understand the fundamental mechanisms of self tolerance. Next we describe with more details the complex autoimmune diseases and discuss the recent data regarding the associated genetic and environmental factors and their modes of interaction. The conclusion of the article deals with the practical implications of this inherent complexity for the researcher and the clinician. [less ▲]

Vitamine D et maladies infectieuses

Conference (2011, November 24)

Mice with Disrupted Type I Protein Kinase A Anchoring in T Cells Resist Retrovirus-Induced Immunodeficiency

in Journal of Immunology (2011), 186(9), 5119-30

Type I protein kinase A (PKA) is targeted to the TCR-proximal signaling machinery by the A-kinase anchoring protein ezrin and negatively regulates T cell immune function through activation of the C ... [more ▼]

Type I protein kinase A (PKA) is targeted to the TCR-proximal signaling machinery by the A-kinase anchoring protein ezrin and negatively regulates T cell immune function through activation of the C-terminal Src kinase. RI anchoring disruptor (RIAD) is a high-affinity competitor peptide that specifically displaces type I PKA from A-kinase anchoring proteins. In this study, we disrupted type I PKA anchoring in peripheral T cells by expressing a soluble ezrin fragment with RIAD inserted in place of the endogenous A-kinase binding domain under the lck distal promoter in mice. Peripheral T cells from mice expressing the RIAD fusion protein (RIAD-transgenic mice) displayed augmented basal and TCR-activated signaling, enhanced T cell responsiveness assessed as IL-2 secretion, and reduced sensitivity to PGE2- and cAMP-mediated inhibition of T cell function. Hyperactivation of the cAMP–type I PKA pathway is involved in the T cell dysfunction of HIV infection, as well as murine AIDS, a disease model induced by infection of C57BL/6 mice with LP-BM5, a mixture of attenuated murine leukemia viruses. LP-BM5–infected RIADtransgenic mice resist progression of murine AIDS and have improved viral control. This underscores the cAMP–type I PKA pathway in T cells as a putative target for therapeutic intervention in immunodeficiency diseases. [less ▲]

Comparison of phenotypic and genotypic tropism determination in triple-class-experienced HIV patients eligible for maraviroc treatment.

in Journal of Antimicrobial Chemotherapy (2011), 66(2), 265-72

BACKGROUND: Determination of HIV-1 tropism is a pre-requisite to the use of CCR5 antagonists. This study evaluated the potential of population genotypic tropism tests (GTTs) in clinical practice, and the ... [more ▼]

BACKGROUND: Determination of HIV-1 tropism is a pre-requisite to the use of CCR5 antagonists. This study evaluated the potential of population genotypic tropism tests (GTTs) in clinical practice, and the correlation with phenotypic tropism tests (PTTs) in patients accessing routine HIV care. METHODS: Forty-nine consecutive plasma samples for which an original Trofile(TM) assay was performed were obtained from triple-class-experienced patients in need of a therapy change. Viral tropism was defined as the consensus of three or more tropism calls obtained from the combination of two independent population PTT assays (Trofile Biosciences, San Francisco, CA, USA, and Virco, Beerse, Belgium), population GTTs and GTTs based on ultra-deep sequencing. If no consensus was reached, a clonal PTT was performed in order to finalize the tropism call. This two-step approach allowed the definition of a reference tropism call. RESULTS: According to the reference tropism result, 35/49 samples were CCR5 tropic (R5) (patients eligible for maraviroc treatment) and 14/49 were assigned as non-R5 tropic. The non-R5 samples [patients not eligible for maraviroc treatment according to the FDA/European Medicines Agency (EMEA) label] group included both the CXCR4 (X4) samples and the dual and mixed CCR5/CXCR4 (R5/X4) samples. Compared with Trofile(TM) population PTTs, population GTTs showed a higher sensitivity (97%) and a higher negative predictive value (91%), but almost equal specificity and an equal positive predictive value. CONCLUSIONS: In line with recent reports from clinical trial data, our data support the use of population genotypic tropism testing as a tool for tropism determination before the start of maraviroc. [less ▲]

Des interactions complexes entre les origines du VIH et sa pandemie, les activites coloniales en Afrique et la medecine coloniale Belge au Congo

in Revue Médicale de Liège (2011), 66(9), 478-84

In this review article on the origin of HIV, we start from a historical fact which involved physicians from Liege working in Belgian Congo: the vaccination against polio of hundreds of thousands of ... [more ▼]

In this review article on the origin of HIV, we start from a historical fact which involved physicians from Liege working in Belgian Congo: the vaccination against polio of hundreds of thousands of Congolese between 1957 and 1960. We explain the genesis of an alternative hypothesis postulating that this campaign was at the origin of HIV pandemy. We show that the hypothesis is unfounded in view of genetic and epidemiological evidence on the one hand and after thorough examination of the activity reports of the Laboratoire Medical de Stanleyville on the other. In the second part of the article, we analyse the importance of other factors which might have contributed to the emergence of the pandemy. Some of these are clearly iatrogenic such as the prophylactic injections of pentamidine against trypanosomiasis, others are of demographic and sociological nature. All of them have a direct link with colonisation. [less ▲]

Vaccinations in patients with immune-mediated inflammatory diseases.

in Rheumatology (2010), 49(10), 1815-27

Patients with immune-mediated inflammatory diseases (IMID) such as RA, IBD or psoriasis, are at increased risk of infection, partially because of the disease itself, but mostly because of treatment with ... [more ▼]

Patients with immune-mediated inflammatory diseases (IMID) such as RA, IBD or psoriasis, are at increased risk of infection, partially because of the disease itself, but mostly because of treatment with immunomodulatory or immunosuppressive drugs. In spite of their elevated risk for vaccine-preventable disease, vaccination coverage in IMID patients is surprisingly low. This review summarizes current literature data on vaccine safety and efficacy in IMID patients treated with immunosuppressive or immunomodulatory drugs and formulates best-practice recommendations on vaccination in this population. Especially in the current era of biological therapies, including TNF-blocking agents, special consideration should be given to vaccination strategies in IMID patients. Clinical evidence indicates that immunization of IMID patients does not increase clinical or laboratory parameters of disease activity. Live vaccines are contraindicated in immunocompromized individuals, but non-live vaccines can safely be given. Although the reduced quality of the immune response in patients under immunotherapy may have a negative impact on vaccination efficacy in this population, adequate humoral response to vaccination in IMID patients has been demonstrated for hepatitis B, influenza and pneumococcal vaccination. Vaccination status is best checked and updated before the start of immunomodulatory therapy: live vaccines are not contraindicated at that time and inactivated vaccines elicit an optimal immune response in immunocompetent individuals. [less ▲]

Long-term efficacy and safety of Raltegravir combined with optimized background therapy in treatment-experienced patients with drug-resistant HIV infection: week 96 results of the BENCHMRK 1 and 2 phase iii trials.

in Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America (2010), 50(4), 605-12

BENCHMRK-1 and -2 are ongoing double-blind phase III studies of raltegravir in patients experiencing failure of antiretroviral therapy with triple-class drug-resistant human immunodeficiency virus ... [more ▼]

BENCHMRK-1 and -2 are ongoing double-blind phase III studies of raltegravir in patients experiencing failure of antiretroviral therapy with triple-class drug-resistant human immunodeficiency virus infection. At week 96 (combined data), raltegravir (400 mg twice daily) plus optimized background therapy was generally well tolerated, with superior and durable antiretroviral and immunological efficacy, compared with optimized background therapy alone. [less ▲]