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6. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype

Author

Toubiana, J., Okada, S., Hiller, J., Oleastro, M., Lagos Gomez, M., Aldave Becerra, J. C., Ouachee-Chardin, M., Fouyssac, F., Girisha, K. M., Etzioni, A., Van Montfrans, J., Camcioglu, Y., Kerns, L. A., Belohradsky, B., Blanche, S., Bousfiha, A., Rodriguez-Gallego, C., Meyts, I., Kisand, K., Reichenbach, J., Renner, E. D., Rosenzweig, S., Grimbacher, B., van de Veerdonk, F. L., Traidl-Hoffmann, C., Picard, C., Marodi, L., Morio, T., Kobayashi, M., Lilic, D., Milner, J. D., Holland, S., Casanova, J. -L., Puel A, Cypowyj S, Thumerelle C, Toulon A, Bustamante J, Tahuil N, SALHI, DALILA, Boiu S, Chopra C, Di Giovanni D, Bezrodnik L, Boutros J, Thomas C, Lacuesta G, Jannier S, Korganow AS, Paillard C, Boutboul, Bué M, Marie-Cardine A, Bayart S, Migaud M, Weiss, Karmochkine M, Garcia-Martinez JM, Stephan JL, Bensaid P, Jeannoel GP, Witte T, Baumann U, Harrer T, Navarrete C, ACOSTA HUGHES, BENJAMIN, Firinu, Pignata C, Picco P, Mendoza D, Lugo Reyes SO, Torres Lozano C, Ortega-Cisneros M, Cortina M, Mesdaghi M, Nabavi M, Español T, Martínez-Saavedra MT, Rezaei N, Zoghi S, Pac M, Barlogis V, Revon-Rivière G, Haimi-Cohen Y, Spiegel R, Miron D, Bouchaib J, Blancas-Galicia L, Toth B, Drexel B, Rohrlich PS, Lesens O, Hoernes M, Drewe E, Abinum M, Sawalle-Belohradsky J, Kindle G, Depner M, Milani L, Nikopensius T, Remm M, Talas UG, Tucker M, Willis M, Leonard S, Meuwissen H, Ferdman RM, CORBO UGULINO, WALLACE, Desai MM, Taur P, Badolato R, Soltesz B, Schnopp C, Jansson AF, Ayvaz D, Shabashova N, Chernyshova L, Bondarenko A, Moshous D, Neven B, Boubidi C, Ailal F, Giardino G, Del Giacco S, Bougnoux ME, Imai K, Okawa T, Mizoguchi Y, Ozaki Y, Takeuchi M, Hayakawa A, Lögering B, Reich K, Buhl T, Eyerich K, Schaller M, Arkwright PD, Gennery AR, Cant AJ, Warris A, Henriet S, Mekki N, Barbouche R, Ben Mustapha I, Bodemer, Polak M, Grimprel E, Burgel PR, Fischer A, Hermine O, Debré M, Kocacyk D, Dhalla F, Patel SY, Moens L, Haerynck F, Dullaers, Hoste L, Sanal O, Kilic SS, Roesler J, Lanternier F, Lortholary O, Fieschi C, Church JA, Roifman C, Yuenyongviwat A, Peterson P, Boisson-Dupuis S, Abel L, Marciano BE, Netea MG., Toubiana, J., Okada, S., Hiller, J., Oleastro, M., Lagos Gomez, M., Aldave Becerra, J. C., Ouachee-Chardin, M., Fouyssac, F., Girisha, K. M., Etzioni, A., Van Montfrans, J., Camcioglu, Y., Kerns, L. A., Belohradsky, B., Blanche, S., Bousfiha, A., Rodriguez-Gallego, C., Meyts, I., Kisand, K., Reichenbach, J., Renner, E. D., Rosenzweig, S., Grimbacher, B., van de Veerdonk, F. L., Traidl-Hoffmann, C., Picard, C., Marodi, L., Morio, T., Kobayashi, M., Lilic, D., Milner, J. D., Holland, S., Casanova, J. -L., Puel, A, Cypowyj, S, Thumerelle, C, Toulon, A, Bustamante, J, Tahuil, N, Salhi, Dalila, Boiu, S, Chopra, C, Di Giovanni, D, Bezrodnik, L, Boutros, J, Thomas, C, Lacuesta, G, Jannier, S, Korganow, A, Paillard, C, Boutboul, Bué, M, Marie-Cardine, A, Bayart, S, Migaud, M, Weiss, Karmochkine, M, Garcia-Martinez, Jm, Stephan, Jl, Bensaid, P, Jeannoel, Gp, Witte, T, Baumann, U, Harrer, T, Navarrete, C, ACOSTA HUGHES, Benjamin, Firinu, Pignata, C, Picco, P, Mendoza, D, Lugo Reyes, So, Torres Lozano, C, Ortega-Cisneros, M, Cortina, M, Mesdaghi, M, Nabavi, M, Español, T, Martínez-Saavedra, Mt, Rezaei, N, Zoghi, S, Pac, M, Barlogis, V, Revon-Rivière, G, Haimi-Cohen, Y, Spiegel, R, Miron, D, Bouchaib, J, Blancas-Galicia, L, Toth, B, Drexel, B, Rohrlich, P, Lesens, O, Hoernes, M, Drewe, E, Abinum, M, Sawalle-Belohradsky, J, Kindle, G, Depner, M, Milani, L, Nikopensius, T, Remm, M, Talas, Ug, Tucker, M, Willis, M, Leonard, S, Meuwissen, H, Ferdman, Rm, CORBO UGULINO, Wallace, Desai, Mm, Taur, P, Badolato, R, Soltesz, B, Schnopp, C, Jansson, Af, Ayvaz, D, Shabashova, N, Chernyshova, L, Bondarenko, A, Moshous, D, Neven, B, Boubidi, C, Ailal, F, Giardino, G, Del Giacco, S, Bougnoux, Me, Imai, K, Okawa, T, Mizoguchi, Y, Ozaki, Y, Takeuchi, M, Hayakawa, A, Lögering, B, Reich, K, Buhl, T, Eyerich, K, Schaller, M, Arkwright, Pd, Gennery, Ar, Cant, Aj, Warris, A, Henriet, S, Mekki, N, Barbouche, R, Ben Mustapha, I, Bodemer, Polak, M, Grimprel, E, Burgel, Pr, Fischer, A, Hermine, O, Debré, M, Kocacyk, D, Dhalla, F, Patel, Sy, Moens, L, Haerynck, F, Dullaers, Hoste, L, Sanal, O, Kilic, S, Roesler, J, Lanternier, F, Lortholary, O, Fieschi, C, Church, Ja, Roifman, C, Yuenyongviwat, A, Peterson, P, Boisson-Dupuis, S, Abel, L, Marciano, Be, and Netea, Mg.

Subjects
Male, 0301 basic medicine, Pediatrics, Clinical Trials and Observations, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], medicine.disease_cause, Biochemistry, Gastroenterology, Cohort Studies, STAT5 Transcription Factor, Medicine, Chronic mucocutaneous candidiasis, Child, Hematology, biology, Progressive multifocal leukoencephalopathy, Candidiasis, Chronic Mucocutaneous, Candidiasis, Orvostudományok, Middle Aged, Phenotype, STAT1 Transcription Factor, Staphylococcus aureus, Child, Preschool, Female, STAT3 Transcription Factor, Adult, Heterozygote, medicine.medical_specialty, Adolescent, Aged, Genetic Predisposition to Disease, Humans, Infant, Young Adult, Genetic Association Studies, Mutation, Immunology, Cell Biology, Chronic Mucocutaneous, Klinikai orvostudományok, Herpesviridae, Mycobacterium tuberculosis, 03 medical and health sciences, Internal medicine, Journal Article, ddc:610, Preschool, Key Points AD STAT1 GOF is the most common genetic cause of inherited CMC and is not restricted to a specific age or ethnic group. STAT1 GOF underlies a variety of infectious and autoimmune features, as well as carcinomas and aneurysms associated with a poor outcome, Type 1 diabetes, Cytopenia, business.industry, medicine.disease, biology.organism_classification, 030104 developmental biology, business
Abstract

Contains fulltext : 172671.pdf (Publisher’s version ) (Closed access) Since their discovery in patients with autosomal dominant (AD) chronic mucocutaneous candidiasis (CMC) in 2011, heterozygous STAT1 gain-of-function (GOF) mutations have increasingly been identified worldwide. The clinical spectrum associated with them needed to be delineated. We enrolled 274 patients from 167 kindreds originating from 40 countries from 5 continents. Demographic data, clinical features, immunological parameters, treatment, and outcome were recorded. The median age of the 274 patients was 22 years (range, 1-71 years); 98% of them had CMC, with a median age at onset of 1 year (range, 0-24 years). Patients often displayed bacterial (74%) infections, mostly because of Staphylococcus aureus (36%), including the respiratory tract and the skin in 47% and 28% of patients, respectively, and viral (38%) infections, mostly because of Herpesviridae (83%) and affecting the skin in 32% of patients. Invasive fungal infections (10%), mostly caused by Candida spp. (29%), and mycobacterial disease (6%) caused by Mycobacterium tuberculosis, environmental mycobacteria, or Bacille Calmette-Guerin vaccines were less common. Many patients had autoimmune manifestations (37%), including hypothyroidism (22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%). Invasive infections (25%), cerebral aneurysms (6%), and cancers (6%) were the strongest predictors of poor outcome. CMC persisted in 39% of the 202 patients receiving prolonged antifungal treatment. Circulating interleukin-17A-producing T-cell count was low for most (82%) but not all of the patients tested. STAT1 GOF mutations underlie AD CMC, as well as an unexpectedly wide range of other clinical features, including not only a variety of infectious and autoimmune diseases, but also cerebral aneurysms and carcinomas that confer a poor prognosis.

Published
2016
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8. A randomized controlled trial of genotypic HIV drug resistance testing in HIV-1-infected children: the PERA (PENTA 8) trial

Author

Green, H, Gibb, D, Compagnucci, A, Giacomet, V, de Rossi, A, Harper, L, Saïdi, Y, Castelli-Gattinara, G, Pillay, D, Babiker, A, Aboulker, J, Lyall, H, Bacheler, LT, Walker, A, Debré, M, Rosso, R, Burger, D, Della Negra, M, Dunn, D, and Giaquinto, C

Abstract

OBJECTIVE: To evaluate the longer-term utility of genotypic resistance testing in HIV-1-infected children with virological failure. METHODS: Children aged 3 months-18 years switching antiretroviral therapy (ART) with HIV-1 RNA > 2,000 copies/ml were randomized between genotypic testing (Virtual Phenotype) and no testing at baseline and subsequent virological failures. Children were followed to at least 96 weeks. RESULTS: One hundred and seventy eligible children, from 24 clinical centres in six countries, were randomized to resistance testing (n = 87) or no testing (n = 83) between June 2000-July 2003. At baseline, mean HIV-1 RNA and CD4+ T-cell percentage were 4.7 log10 copies/ml and 20%, respectively. Children had taken ART for a mean of 5 years; 24% had received all three classes, 53% nucleoside reverse transcriptase inhibitors (NRTIs)+protease inhibitors (PIs), 9% NRTIs+non-nucleoside reverse transcriptase inhibitors (NNRTIs) and 14% NRTIs only. There was no difference between the arms in the drug classes or the individual PIs/NNRTIs prescribed. However, 49% in the resistance test arm (RT) versus 19% in the no-test arm (NT) continued at least one NRTI from their failing regimen; 56% versus 19% were prescribed didanosine+stavudine as their NRTI backbone. Adjusting for baseline HIV-1 RNA, mean reductions in HIV-1 RNA at 48 weeks were 1.51 log10 copies/ml in the RT arm and 1.23 in the NT arm (P = 0.3); the difference between the arms was smaller at week 96 (RT: 1.50, NT: 1.47; P = 0.9). CONCLUSION: In this first paediatric trial of resistance testing, we observed a substantial difference in NRTI-prescribing behaviour across arms. However statistically significant evidence of a long-term virological or immunological benefit was not observed. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN14367816.

Published
2016

10. Neurocognition and quality of life after reinitiating antiretroviral therapy in children randomized to planned treatment interruption

Author

Ananworanich, J, Melvin, D, Amador, Jt, Childs, T, Medin, G, Boscolo, V, Compagnucci, A, Kanjanavanit, S, Montero, S, Gibb, Dm, PENTA 11 Study Group including Aboulker, J, Babiker, A, Belfrage, E, Bernardi, S, Bologna, R, Burger, D, Butler, K, Castelli Gattinara, G, Castro, H, Clayden, P, Cressey, T, Darbyshire, Jh, Debré, M, de Groot, R, della Negra, M, di Biagio, A, De Rossi, A, Duicelescu, D, Faye, A, Giaquinto, C, Giacomet, V, Grosch Wörner, I, Hainault, M, Klein, N, Lallemant, M, Levy, J, Lyall, H, Marczynska, M, Marques, L, Mardarescu, M, Mellado Peña MJ, Nadal, D, Nastouli, E, Naver, L, Niehues, T, Peckham, C, Pillay, D, Popieska, J, Ramos Amador JT, Rojo Conejo, P, Rosado, L, Rosso, R, Rudin, C, Scherpbier, Hj, Sharland, M, Stevanovic, M, Thorne, C, Tovo, Pier Angelo, Tudor Williams, G, Turkova, A, Valerius, N, Volokha, A, Walker, As, Welch, S, Wintergerst, U, Aboulker, Jp, Burger, Dm, Green, H, Harper, L, Mofenson, L, Moye, J, Saïdi, Y, Cressey, Tr, Jacqz Aigrain, E, Khoo, S, Regazzi, M, Tréluyer, Jm, Ngo Giang Huong, N, Muñoz Fernandez MA, Hill, C, Lepage, P, Pozniak, A, Vella, S, Chêne, G, Vesikari, T, Hadjou, G, Léonardo, S, Riault, Y, Bleier, J, Buck, L, Duong, T, Farrelly, L, Forcat, S, Harrison, L, Horton, J, Johnson, D, Taylor, C, Chalermpantmetagul, S, Peongjakta, R, Khamjakkaew, W, Than in at, K, Chailert, S, Jourdain, G, Le Coeur, S, Floret, D, Costanzo, P, Le Thi TT, Monpoux, F, Mellul, S, Caranta, I, Boudjoudi, N, Firtion, G, Denon, M, Charlemaine, E, Picard, F, Hellier, E, Heuninck, C, Damond, F, Alexandre, G, Tricoire, J, Antras, M, Lachendowier, C, Nicot, F, Krivine, A, Rivaux, D, Notheis, G, Strotmann, G, Schlieben, S, Rampon, O, Zanchetta, M, Ginocchio, F, Viscoli, C, Martino, A, Pontrelli, G, Baldassar, S, Concato, C, Mazza, A, Rossetti, G, Dobosz, S, Oldakowska, A, Popielska, J, Kaflik, M, Stanczak, J, Stanczack, G, Dyda, T, Kruk, M, González Tomé MI, Delgado García, R, Fernandez Gonzalez MT, Mellado Peña, M, Martín Fontelos, P, Garcia Mellado MI, Medina, Af, Ascencion, B, Garcia Bermejo, I, Navarro Gomez DM, Saavedra, J, Prieto, C, Jimenez, Jl, Garcia Torre, A, de José Gómez MI, García Rodriguez MC, Moreno Pérez, D, Núñez Cuadros, E, Asensi Botet, F, Otero Reigada, C, Pérez Tamarit MD, Vilalta, R, Molina Moreno JM, Rainer, T, Schupbach, J, Rutishauser, M, Bunupuradah, T, Butterworth, O, Phasomsap, C, Prasitsuebsai, W, Chuanjaroen, T, Jupimai, T, Ubolyam, S, Phanuphak, P, Puthanakit, T, Pancharoen, C, Mai, C, Namwong, T, Punsakoon, W, Payakachat, S, Chutima, D, Raksasang, M, Foster, C, Hamadache, D, Campbell, S, Newbould, C, Monrose, C, Abdulla, A, Walley, A, Patel, D, Kaye, S, Seery, P, Rankin, A, Wildfire, A, Novelli, V, Shingadia, D, Moshal, K, Flynn, J, Clapson, M, Allen, A, Spencer, L, Rackstraw, C, Ward, B, Parkes, K, Depala, M, Jacobsen, M, Poulsom, H, Barkley, L, Miah, J, Lurie, P, Keane, C, Mcmaster, P, Phipps, M, Orendi, J, Farmer, C, Liebeschuetz, S, Sodeinde, O, Wong, S, Bostock, V, Heath, Y, Scott, S, Gandhi, K, Lewis, P, Daglish, J, Miles, K, Summerhill, L, Subramaniam, B, Weiner, L, Famiglietti, M, Rana, S, Yu, P, Roa, J, Puga, A, Haerry, A., AII - Amsterdam institute for Infection and Immunity, Paediatric Infectious Diseases / Rheumatology / Immunology, and Global Health

Subjects
0301 basic medicine, Male, Pediatrics, medicine.medical_specialty, antiretroviral therapy, children, HIV, neurocognition, neurodevelopment, quality of life, treatment interruption, Immunology and Allergy, Immunology, Infectious Diseases, Adolescent, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Antiretroviral Therapy, HIV Infections, Standard score, 03 medical and health sciences, 0302 clinical medicine, Cognition, Acquired immunodeficiency syndrome (AIDS), Antiretroviral Therapy, Highly Active, Memory span, Medicine, Humans, Highly Active, 030212 general & internal medicine, Child, Wechsler Intelligence Scale for Children, business.industry, Wechsler Adult Intelligence Scale, medicine.disease, 030112 virology, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Treatment Outcome, Anti-Retroviral Agents, Test score, Mann–Whitney U test, Quality of Life, Female, business, Neurocognitive
Abstract

Item does not contain fulltext OBJECTIVE: Understanding the effects of antiretroviral treatment (ART) interruption on neurocognition and quality of life (QoL) are important for managing unplanned interruptions and planned interruptions in HIV cure research. DESIGN: Children previously randomized to continuous (continuous ART, n = 41) vs. planned treatment interruption (PTI, n = 47) in the Pediatric European Network for Treatment of AIDS (PENTA) 11 study were enrolled. At study end, PTI children resumed ART. At 1 and 2 years following study end, children were assessed by the coding, symbol search and digit span subtests of Wechsler Intelligence Scale for Children (6-16 years old) or Wechsler Adult Intelligence Scale (>/=17 years old) and by Pediatrics QoL questionnaires for physical and psychological QoL. Transformed scaled scores for neurocognition and mean standardized scores for QoL were compared between arms by t-test and Mann-Whitney U test, respectively. Scores indicating clinical concern were compared (

Published
2016

11. Inflammatory manifestations in a single-center cohort of patients with chronic granulomatous disease

Author

Alessandra Magnani, Brosselin P, Beauté J, de Vergnes N, Mouy R, Debré M, Suarez F, Hermine O, Lortholary O, Blanche S, Fischer A, and Mahlaoui N

Subjects
interstitial lung disease, inflammation, Chronic granulomatous disease, macrophage, granulomatous, granuloma, primary immunodeficiency, inflammatory bowel diseases
Abstract

BACKGROUND: Chronic granulomatous disease (CGD) is a rare phagocytic disorder that results in not only infections but also potentially severe inflammatory manifestations that can be difficult to diagnose and treat. OBJECTIVE: To describe inflammatory manifestations in a single-center cohort of patients with CGD. METHODS: Medical records of patients treated at Necker-Enfants Malades Hospital (Paris, France) between 1968 and 2009 and registered at the French National Reference Center for Primary Immunodeficiencies (CEREDIH) were retrospectively reviewed. RESULTS: In a study population of 98 patients, a total of 221 inflammatory episodes were recorded in 68 individuals (69.4%). The incidence rate of inflammatory episodes was 0.15 per person-year (0.18 in patients with X-linked [XL] CGD and 0.08 in patients with autosomal-recessive [AR] CGD). The most commonly affected organs were the gastrointestinal tract (in 88.2% of the patients), lungs (26.4%), the urogenital tract (17.6%), and eyes (8.8%). Inflammation at other sites (the skin, central nervous system, and tympanum) and autoimmune manifestations (lupus, arthritis, etc) were recorded in 19.1% and 10.3% of the patients, respectively. Granuloma was found in 50% of the 44 histological analyses reviewed. The risk of inflammatory episodes was 2-fold higher in patients with XL-CGD than in patients with AR-CGD (relative risk, 2.22; 95% CI, 1.43-3.46). CONCLUSIONS: Patients with XL-CGD have a higher risk of developing inflammatory episodes than do patients with AR-CGD. Although the most commonly affected organ is the gastrointestinal tract, other sites can be involved, making the management of patients with CGD a complex, multidisciplinary task.

Published
2014

12. Using CD4 percentage and age to optimize pediatric antiretroviral therapy initiation

Author

Yin, D.E., Warshaw, M.G., Miller, W.C., Castro, H., Fiscus, S.A., Harper, L.M., Harrison, L.J., Klein, N.J., Lewis, J., Melvin, A.J., Tudor Williams, G., Mckinney, R.E., Brouwers, P., Costello, D., Ferguson, E., Fiscus, S., Hodge, J., Hughes, M., Jennings, C., Melvin, A., Mckinney, R., Mofenson, L., Warshaw, M., Smith, M., Spector, S., Stiehm, E., Toye, M., Yogev, R., Babiker, A., Compagnucci, A., De Rossi, A., Giaquinto, C., Darbyshire, J., Debré, M., Gibb, D., Harper, L., Harrison, L., Klein, N., Pillay, D., Saidi, Y., Walker, A., Brody, B., Hill, C., Lepage, P., Modlin, J., Poziak, A., Rein, M., Robb, M., Fleming, T., Vella, S., Kim, K., Bologna, R., Mecikovsky, D., Pineda, N., Sen, L., Mangano, A., Marino, S., Galvez, C., Deluchi, G., Zöhrer, B., Zenz, W., Daghofer, E., Pfurtscheller, K., Pabst, B., Gomez, M., Mcneil, P., Jervis, M., Whyms, I., Kwolfe, D., Scott, S., Mussi Pinhata MM, Issac, M., Cervi, M., Negrini, B., Matsubara, T., de Souza CB, Gabaldi, J., Oliveira, R., Sapia, M., Abreu, T., Evangelista, L., Pala, A., Fernandes, I., Farias, I., Melo M, D.F., Carreira, H., Lira, L., Della Negra, M., Queiroz, W., Lian, Y., Pacola, D., Pinto, J., Ferreira, F., Kakehasi, F., Martins, L., Diniz, A., Lobato, V., Diniz, M., Cleto, S., Costa, S., Romeiro, J., Dollfus, C., Tabone, M., Courcoux, M., Vaudre, G., Dehée, A., Schnuriger, A., Le Gueyades, N., De Bortoli, C., Méchinaud, F., Reliquet, V., Arias, J., Rodallec, A., André, E., Falconi, I., Le Pelletier, A., Monpoux, F., Cottalorda, J., Mellul, S., Lachassinne, E., Galimand, J., Rouzioux, C., Chaix, M., Benabadji, Z., Pourrat, M., Firtion, G., Rivaux, D., Denon, M., Boudjoudi, N., Nganzali, F., Krivine, A., Méritet, J., Delommois, G., Norgeux, C., Guérin, C., Floch, C., Marty, L., Hichou, H., Tournier, V., Faye, A., Le Moal, I., Sellier, M., Dehache, L., Damond, F., Leleu, J., Beniken, D., Alexandre Castor, G., Neubert, J., Niehues, T., Laws, H., Huck, K., Gudowius, S., Siepermann, K., Loeffler, H., Bellert, S., Ortwin, A., Notheis, G., Wintergerst, U., Hoffman, F., Werthmann, A., Seyboldt, S., Schneider, L., Bucholz, B., Feiterna Sperling, C., Peiser, C., Nickel, R., Schmitz, T., Piening, T., Müller, C., Warncke, G., Wigger, M., Neubauer, R., Butler, K., Chong, A., Boulger, T., Menon, A., O'Connell, M., Barrett, L., Rochford, A., Goode, M., Hayes, E., Mcdonagh, S., Walsh, A., Doyle, A., Fanning, J., O'Connor, M., Byrne, M., O'Sullivan, N., Hyland, E., Giacomet, V., Viganò, A., Colombo, I., Trabattoni, D., Berzi, A., Badolato, R., Schumacher, F., Bennato, V., Brusati, M., Sorlini, A., Spinelli, E., Filisetti, M., Bertulli, C., Rampon, O., Zanchetta, M., Mazza, A., Stringari, G., Rossetti, G., Bernardi, S., Martino, A., Castelli Gattinara, G., Palma, P., Pontrelli, G., Tchidjou, H., Furcas, A., Frillici, C., Mazzei, A., Zoccano, A., Concato, C., Duiculescu, D., Oprea, C., Tardei, G., Abaab, F., Mardarescu, M., Draghicenoiu, R., Otelea, D., Alecsandru, L., Matusa, R., Rugina, S., Ilie, M., Netescu, S., Florea, C., Voicu, E., Poalelungi, D., Belmega, C., Vladau, L., Chiriac, A., Ramos Amador JT, Gonzalez Tomé MI, Rojo Conejo, P., Fernandez, M., Delgado Garcia, R., Ferrari, J., Garcia Lopez, M., Mellado Peña MJ, Martin Fontelos, P., Jimenez Nacher, I., Muñoz Fernandez MA, Jimenez, J., García Torre, A., Penin, M., Pineiro Perez, R., Garcia Mellado, I., Finn, A., Lajeunesse, M., Hutchison, E., Usher, J., Ball, L., Dunn, M., Sharland, M., Doerholt, K., Storey, S., Donaghy, S., Chakraborty, R., Wells, C., Buckberry, K., Rice, P., Mcmaster, P., Butler, P., O'Connell C, R., Shenton, J., Haley, H., Orendi, J., Stroobant, J., Navarante, L., Archer, P., Mazhude, C., Scott, D., O'Connell, R., Wong, J., Boddy, G., Shackley, F., Lakshman, R., Hobbs, J., Ball, G., Kudesia, G., Bane, J., Painter, D., Sloper, K., Shah, V., Cheng, A., Aali, A., Ball, C., Hawkins, S., Nayagam, D., Waters, A., Doshi, S., Liebeschuetz, S., Sodiende, B., Shingadia, D., Wong, S., Swan, J., Shah, Z., Collinson, A., Hayes, C., King, J., O'Connor, K., Lyall, H., Fidler, K., Walters, S., Foster, C., Hamadache, D., Newbould, C., Monrose, C., Campbell, S., Yeung, S., Cohen, J., Martinez Allier, N., Melvin, D., Dodge, J., Welch, S., Tatum, G., Gordon, A., Kaye, S., Muir, D., Patel, D., Novelli, V., Moshal, K., Lambert, J., Flynn, J., Farrelly, L., Clapson, M., Spencer, L., Depala, M., Jacobsen, M., Segal, S., Pollard, A., Kelly, D., Yeadon, S., Ohene Kena, B., Peng, Y., Dong, T., Jeffries, K., Snelling, M., Smyth, A., Smith, J., Ward, B., Jungmann, E., Ryan, C., Swaby, K., Buckton, A., Smit, E., Abrams, E., Champion, S., Fernandez, A., Calo, D., Garrovillo, L., Swaminathan, K., Alford, T., Frere, M., Navarra, J., Borkowsky, W., Deygoo, S., Hastings, T., Akleh, S., Ilmet, T., Mohan, K., Bowen, G., Emmanuel, P., Lujan Zimmerman, J., Rodriguez, C., Johnson, S., Marion, A., Graisbery, C., Casey, D., Lewis, G., Guzman Cottrill, J., Croteau, R., Acevedo Flores, M., Gonzalez, M., Angeli, L., Fabregas, L., Valentin, P., Weiner, L., Contello, K., Holz, W., Butler, M., Nachman, S., Kelly, M., Ferraro, D., Rana, S., Reed, C., Yeagley, E., Malheiro, A., Roa, J., Neely, M., Kovacs, A., Homans, J., Rodriguez Lozano, Y., Puga, A., Talero, G., Sellers, R., Lawrence, R., Weinberg, G., Murante, B., Laverty, S., Deveikis, A., Batra, J., Chen, T., Michalik, D., Deville, J., Elkins, K., Marks, S., Jackson Alvarez, J., Palm, J., Fineanganofo, I., Keuth, M., Deveikis, L., Tomosada, W., Van Dyke, R., Alchediak, T., Silio, M., Borne, C., Bradford, S., Eloby Childress, S., Nguyen, K., Rathore, M., Alvarez, A., Mirza, A., Mahmoudi, S., Burke, M., Febo, I., Lugo, L., Santos, R., Church, J., Dunaway, T., Rodier, C., Flynn, P., Patel, N., Discenza, S., Donohoe, M., Luzuriaga, K., Picard, D., Kline, M., Paul, M., Shearer, W., Mcmullen, C., Chadwick, E., Cagwin, E., Kabat, K., Dieudonne, A., Palumbo, P., Johnson, J., Gaur, S., Cerracchio, L., Foca, M., Jurgrau, A., Vasquez Bonilla, S., Silva, G., Gershon, A., Sullivan, J., Bryson, Y., Frenkel, L., Nelson, J., Aboulker, J., Hadjou, G., Léonardo, S., Riault, Y., Saïdi, Y., Buck, L., Forcat, S., Horton, J., Johnson, D., Moore, S., Taylor, C., Collins, D., Buskirk, S., Kamara, P., Nesel, C., Johnson, M., Ferreira, A., Tutko, J., Sprenger, H., Britto, P., Powell, C., Dersimonian, R., Handelsman, E., Ananworanich, J., Belfrage, E., Blanche, S., Bohlin, A., Burger, D., Clayden, P., De Groot, R., Di Biagio, A., Grosch Wörner, I., Hainault, M., Lallemant, M., Levy, J., Marczynska, M., Mellado Pena MJ, Nadal, D., Naver, L., Peckham, C., Popieska, J., Rosado, L., Rosso, R., Rudin, C., Scherpbier, H., Stevanovic, M., Thorne, C., Tovo, P., Valerius, N., Poole, C., Cole, S., and Mcculloh, R.J.

Subjects
CD4-Positive T-Lymphocytes, Male, medicine.medical_treatment, HIV (FISIOLOGIA), lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Human immunodeficiency virus (HIV), HIV Infections, medicine.disease_cause, Treatment failure, Settore BIO/13 - Biologia Applicata, Antiretroviral Therapy, Highly Active, immunologic, Child, HIV, child, reconstitution, treatment failure, Adolescent, Anti-HIV Agents, CD4 Lymphocyte Count, Child, Preschool, Female, Follow-Up Studies, HIV-1, Humans, Infant, Infant, Newborn, Follow up studies, Immunosuppression, medicine.medical_specialty, Settore MED/17 - Malattie Infettive, Antiretroviral Therapy, World health, Article, Internal medicine, medicine, Highly Active, Preschool, Settore MED/04 - Patologia Generale, business.industry, Disease progression, Settore MED/46 - Scienze Tecniche di Medicina di Laboratorio, Newborn, Antiretroviral therapy, Confidence interval, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Immunologic, Reconstitution, Pediatrics, Perinatology and Child Health, Immunology, business
Abstract

BACKGROUND: Quantifying pediatric immunologic recovery by highly active antiretroviral therapy (HAART) initiation at different CD4 percentage (CD4%) and age thresholds may inform decisions about timing of treatment initiation. METHODS: HIV-1-infected, HAART-naive children in Europe and the Americas were followed from 2002 through 2009 in PENPACT-1. Data from 162 vertically infected children, with at least World Health Organization “mild” immunosuppression and CD4% RESULTS: Seventy-two percent of baseline immunosuppressed children recovered to normal within 4 years. Compared with “severe” immunosuppression, more children with “mild” immunosuppression (difference 36%, 95% confidence interval [CI]: 22% to 49%) or “advanced” immunosuppression (difference 20.8%, 95% CI: 5.8% to 35.9%) recovered a normal CD4%. For each 5-year increase in baseline age, the proportion of children achieving a normal CD4% declined by 19% (95% CI: 11% to 27%). Combining baseline CD4% and age effects resulted in >90% recovery when initiating HAART with “mild” immunosuppression at any age or “advanced” immunosuppression at age CONCLUSIONS: Initiating HAART at higher CD4% and younger ages maximizes potential for immunologic recovery. Guidelines should weigh immunologic benefits against long-term risks.

Published
2014

13. The immunological and virological consequences of planned treatment interruptions in children with HIV infection

Author

Klein, Nigel, Sefe, Delali, Mosconi, Ilaria, Zanchetta, Marisa, Castro, Hannah, Jacobsen, Marianne, Jones, Hannah, Bernardi, Stefania, Pillay, Deenan, Giaquinto, Carlo, Walker, A. Sarah, Gibb, Diana M., De Rossi, Anita, Paediatric, European Network for Treatment of AIDS 11 Trial Team including Aboulker JP, Ananworanich, J, Babiker, A, Belfrage, E, Bernardi, S, Blanche, S, Bohlin, Ab, Bologna, R, Burger, Dm, Butler, K, Castelli Gattinara, G, Castro, H, Clayden, P, Compagnucci, A, Darbyshire, Jh, Debré, M, Faye, A, de Groot, R, della Negra, M, Duiculescu, D, Giaquinto, C, Gibb, Dm, Grosch Wörner, I, Hainault, M, Harper, L, Klein, N, Lallemant, M, Levy, J, Lyall, H, Marczynska, M, Mardarescu, M, Mellado Peña, Mj, Nadal, D, Niehues, T, Peckham, C, Pillay, D, Ramos Amador, Jt, Rosado, L, Rosso, R, Rudin, C, Saidi, Y, Scherpbier, Hj, Sharland, M, Stevanovic, M, Thorne, C, Tovo, Pier Angelo, Tudor Williams, G, Valerius, N, Walker, As, Welch, S, Wintergerst, U, Aboulker, Jp, Mofenson, L, Moye, J, Saïdi, Y, Cressey, Tr, Jacqz Aigrain, E, Khoo, S, Tréluyer, Jm, De Rossi, A, Ngo Giang Huong, N, Muñoz Fernandez, Ma, Hill, C, Lepage, P, Pozniak, A, Vella, S, Hadjou, G, Léonardo, S, Riault, Y, Buck, L, Farrelly, L, Forcat, S, Harrison, L, Horton, J, Johnson, D, Moore, S, Taylor, C, Chalermpantmetagul, S, Peongjakta, R, Chailert, S, Fregonese, F, Jourdain, G, Butler, D, Carlton, C, Collins, D, Kao, G, Van Buskirk, S, Watson, S, Corradini, S, Floret, D, Le Thi, Tt, Monpoux, F, Cottalorda, J, Lefebvre, Jc, Mellul, S, Boudjoudi, N, Firtion, G, Denon, M, Picard, F, Beniken, D, Damond, F, Alexandre, G, Tricoire, J, Nicot, F, Krivine, A, Rivaux, D, Chaix, Ml, Notheis, G, Strotmann, G, Schlieben, S, Rampon, O, Zanchetta, M, Ginocchio, F, Viscoli, C, Martino, A, Pontrelli, G, Concato, C, Mazza, A, Rossetti, G, Dobosz, S, Oldakowska, A, Popielska, J, Kaflik, M, Stanczak, J, Stanczack, G, Dyda, T, González Tomé, Mi, Delgado García, R, Fernandez Gonzalez, Mt, Martín Fontelos, P, Piñeiro Pérez, R, Penin, M, Garcia Mellado, I, Medina, Af, Ascencion, B, Garcia Bermejo, I, Garcia Vela, Ja, Martin Rubio, I, Gurbindo, D, Navarro Gomez, Ml, Jimenez, Jl, Garcia Torre, A, José Gómez, Mi, García Rodriguez, Mc, Moreno Pérez, D, Núñez Cuadros, E, Asensi Botet, F, Pérez, A, Pérez Tamarit, Md, Gobernado Serrano, M, Gonzales Molina, A, Kalhert, C, Dobrovoljac, M, Berger, C, Nobile, G, Reinhard, S, Schupbach, J, Bunupuradah, T, Puthanakit, T, Pancharoen, C, Butterworth, O, Phasomsap, C, Jupimai, T, Ubolyam, S, Phanuphak, P, Mai, C, Kanjanavanit, S, Namwong, T, Chutima, D, Raksasang, M, Foster, C, Hamadache, D, Campbell, S, Newbould, C, Monrose, C, Patel, D, Kaye, S, Seery, P, Wildfire, A, Novelli, V, Shingadia, D, Moshal, K, Flynn, J, Clapson, M, Allen, A, Spencer, L, Depala, M, Jacobsen, M, Mcmaster, P, Phipps, M, Orendi, J, Farmer, C, Liebeschuetz, S, Sodeinde, O, Wong, S, Heath, Y, Scott, S, Gandhi, K, Lewis, P, Daglish, J, Weiner, L, Famiglietti, M, Rana, S, Yu, P, Roa, J, Puga, A, Haerry, A, and Inma, A.

Subjects
CD31, Genetics and Molecular Biology (all), CD4-Positive T-Lymphocytes, Time Factors, T-CELL RECONSTITUTION, ACTIVE ANTIRETROVIRAL THERAPY, STRUCTURED TREATMENT INTERRUPTION, T-CELL RECONSTITUTION, HIV-1-INFECTED CHILDREN, IMMUNE RECONSTITUTION, THYMIC OUTPUT, 1-INFECTED CHILDREN, Adolescent, Anti-Retroviral Agents, CD8-Positive T-Lymphocytes, Child, Child, Preschool, Drug Administration Schedule, HIV Infections, Humans, Immunophenotyping, Lymphocyte Count, Treatment Outcome, Viral Load, Agricultural and Biological Sciences (all), Biochemistry, Genetics and Molecular Biology (all), Medicine (all), Biochemistry, law.invention, IMMUNE RECONSTITUTION, 0302 clinical medicine, Randomized controlled trial, law, 030212 general & internal medicine, HIV-1-INFECTED CHILDREN, 0303 health sciences, Multidisciplinary, ACTIVE ANTIRETROVIRAL THERAPY, 3. Good health, Medicine, Off Treatment, Poverty-related infectious diseases Infectious diseases and international health [N4i 3], THYMIC OUTPUT, Viral load, Research Article, Science, 1-INFECTED CHILDREN, Auto-immunity, transplantation and immunotherapy [N4i 4], 03 medical and health sciences, Acquired immunodeficiency syndrome (AIDS), medicine, Preschool, 030304 developmental biology, business.industry, medicine.disease, Clinical trial, Immunology, STRUCTURED TREATMENT INTERRUPTION, business, CD8
Abstract

Contains fulltext : 126098.pdf (Publisher’s version ) (Open Access) OBJECTIVES: To evaluate the immunological and viral consequences of planned treatment interruptions (PTI) in children with HIV. DESIGN: This was an immunological and virological sub-study of the Paediatric European Network for Treatment of AIDS (PENTA) 11 trial, which compared CD4-guided PTI of antiretroviral therapy (ART) with continuous therapy (CT) in children. METHODS: HIV-1 RNA and lymphocyte subsets, including CD4 and CD8 cells, were quantified on fresh samples collected during the study; CD45RA, CD45RO and CD31 subpopulations were evaluated in some centres. For 36 (18 PTI, 18 CT) children, immunophenotyping was performed and cell-associated HIV-1 DNA analysed on stored samples to 48 weeks. RESULTS: In the PTI group, CD4 cell count fell rapidly in the first 12 weeks off ART, with decreases in both naive and memory cells. However, the proportion of CD4 cells expressing CD45RA and CD45RO remained constant in both groups. The increase in CD8 cells in the first 12 weeks off ART in the PTI group was predominantly due to increases in RO-expressing cells. PTI was associated with a rapid and sustained increase in CD4 cells expressing Ki67 and HLA-DR, and increased levels of HIV-1 DNA. CONCLUSIONS: PTI in children is associated with rapid changes in CD4 and CD8 cells, likely due to increased cell turnover and immune activation. However, children off treatment may be able to maintain stable levels of naive CD4 cells, at least in proportion to the memory cell pool, which may in part explain the observed excellent CD4 cell recovery with re-introduction of ART.

Published
2013

14. FRI0509 Chromosome 22Q11.2 Deletion Syndrome (Digeorge Syndrome) and Autoimmunity: A French Retrospective Pediatric Study of 15 Cases

Author

Freychet, C., primary, Debré, M., additional, Bader Meunier, B., additional, Lemelle, I., additional, Pagnier, A., additional, Taque, S., additional, Munzer, M., additional, Jeziorski, E., additional, Hatchuel, Y., additional, Launay, D., additional, Quartier, P., additional, Mahlaoui, N., additional, and Stephan, J.L., additional

Published
2015
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15. Pharmacokinetic study of once-daily versus twice-daily abacavir and lamivudine in HIV type-1-infected children aged 3-< 36 months

Author

Paediatric European Network for Treatment of AIDS including Jacqz Aigrain, E, Harrison, L, Zhao, W, Compagnucci, A, Castro, H, Farrelly, L, Saidi, Y, Hamadache, D, Welch, S, Wintergerst, U, Forcat, S, Hadjou, G, Firtion, G, Snowden, W, Giaquinto, C, Gibb, D, Burger, D, Aboulker, Jp, Brothers, C, Gibb, Dm, Jacqz Aigrain, E, Snowdon, W, Lyall, H, Pharo, C, Le Provost, M, Saïdi, Y, Adkison, K, Song, I, Thoofer, N, Yeo, J, Clayden, P, Cressey, Tr, Khoo, S, Tréluyer, Jm, Babiker, A, Bohlin, Ab, Butler, K, Castelli Gattinara, G, Darbyshire, J, Debré, M, Faye, A, de Groot, R, della Negra, M, Duicelescu, D, Grosch Wörner, I, Kind, C, Lallemant, M, Levy, J, Marczynska, M, Peña, Mj, Nadal, D, Niehues, T, Peckham, C, Amador, Jt, Rosado, L, Rudin, C, Scherpbier, H, Sharland, M, Stevanovic, M, Tovo, Pier Angelo, Tudor Williams, G, Valerius, N, Walker, As, and Wintergerst, U.

Subjects
Infectious diseases and international health [NCEBP 13], Human immunodeficiency virus (HIV), HIV Infections, Pharmacology, medicine.disease_cause, 030226 pharmacology & pharmacy, Gastroenterology, 0302 clinical medicine, Abacavir, Pharmacology (medical), 030212 general & internal medicine, Viral, Child, Preschool, Drug Administration Schedule, Drug Therapy, Combination, HIV-1, Humans, Infant, RNA, Viral, Treatment Outcome, Anti-HIV Agents, Dideoxynucleosides, Lamivudine, Reverse Transcriptase Inhibitors, Infectious Diseases, Medicine (all), Child, 3. Good health, Combination, Viral load, medicine.drug, medicine.medical_specialty, Bioequivalence, Article, Invasive mycoses and compromised host [N4i 2], 03 medical and health sciences, Pharmacokinetics, Drug Therapy, Internal medicine, medicine, Dosing, Preschool, business.industry, Poverty-related infectious diseases [N4i 3], Confidence interval, RNA, business
Abstract

Background Once-daily dosing of abacavir and lamivudine has been approved for adults, but paediatric data are insufficient. We conducted a pharmacokinetic study of once-daily and twice-daily abacavir and lamivudine in children aged 3–Methods Children with stable HIV type-1 (HIV-1) RNA levels after 12 weeks treatment with twice-daily abacavir (8 mg/kg) with or without lamivudine (4 mg/kg) underwent plasma pharmacokinetic sampling. Children then switched to once-daily abacavir (16 mg/kg) with or without lamivudine (8 mg/kg), and sampling was repeated 4 weeks later. The area under the plasma concentration– time curve over 24 h (AUC0–24) and the maximum concentration (Cmax) were compared using geometric mean ratios (GMRs); 90% confidence intervals (CIs) within the range of 0.80–1.25 were considered bioequivalent. Results A total of 18 children (4, 6 and 8 in the 3–0–24, once-daily versus twice-daily, was 1.07 (90% CI 0.92–1.23) for abacavir and 0.91 (90% CI 0.79–1.06) for lamivudine. Cmax almost doubled on once-daily versus twice-daily dosing: abacavir and lamivudine GMRs were 2.04 (90% CI 1.73–2.42) and 1.78 (90% CI 1.52–2.09), respectively. At baseline, 12, 24 and 48 weeks, 89%, 94%, 100% and 89% of children had HIV-1 RNAConclusions Bioequivalence was demonstrated on AUC0–24 between twice-daily and once-daily abacavir; very similar AUC0–24 values were seen for twice-daily and once-daily lamivudine. Given that viral load suppression rates were maintained, these data suggest that once-daily abacavir and lamivudine might be an option for children aged 3–

Published
2010

16. Plasma drug concentrations and virologic evaluations after stopping treatment with nonnucleoside reverse-transcriptase inhibitors in HIV type 1-infected children

Author

Cressey, Tr, Green, H, Khoo, S, Treluyer, Jm, Compagnucci, A, Saidi, Y, Lallemant, M, Gibb, Dm, Burger, Dm, Collaborators: Aboulker JP, Paediatric European Network for Treatment of AIDS II Study G. r. o. u. p., Babiker, A, Blanche, S, Bohlin, Ab, Butler, K, Castelli Gattinara, G, Clayden, P, Darbyshire, Jh, Debré, M, de Groot, R, della Negra, M, Duicelescu, D, Giaquinto, C, Grosch Wörner, I, Kind, C, Levy, J, Lyall, H, Marczynska, M, Mellado Peña MJ, Nadal, D, Niehues, T, Peckham, C, Ramos Amador JT, Rosado, L, Rudin, C, Scherpbier, Hj, Sharland, M, Stevanovic, M, Tovo, Pier Angelo, Tudor Williams, G, Valerius, N, Walker, As, Wintergerst, U, Aboulker, Jp, Harper, L, Klein, N, Mofenson, L, Moye, J, Saïdi, Y, Jacqz Aigrain, E, Tréluyer, Jm, Clerici, M, De Rossi, A, Ngo Giang Huong, N, Muñoz Fernandez MA, Pillay, D, Hill, C, Lepage, P, Pozniak, A, Vella, S, Eliette, V, Hadjou, G, Léonardo, S, Pitrou, C, Riault, Y, Buck, L, Farrelly, L, Johnson, D, Taylor, C, Chalermpantmetagul, S, Peongjakta, R, Chailert, S, Fregonese, F, Jourdain, G, Butler, D, Carlton, C, Collins, D, Kao, G, Van Buskirk, S, Watson, S, Corradini, S, Floret, D, Laplace, J, Monpoux, F, Cottalorda, J, Lefebvre, Jc, Mellul, S, Boudjoudi, N, Firtion, G, Faye, A, Beniken, D, Damond, F, Tricoire, J, Krivine, A, Chaix, Ml, Notheis, G, Strotmann, G, Schlieben, S, Rampon, O, Zanchetta, M, Rosso, R, Repeto, E, Vitale, F, Martino, A, Bernardi, S, Mazza, A, Rossetti, G, Dobosz, S, Oldakowska, A, Popielska, J, Kaflik, M, Stanczak, J, Stanczac, T, González Tomé MI, Delgado García, R, José Mellado Peña, M, Martín Fontelos, P, Piñeiro Pérez, R, Alimenti, A, Penin, M, Gurbindo, D, Navarro Gomez ML, Jimenez, Jl, Prieto, C, de José Gómez MI, García Rodriguez MC, Moreno Pérez, D, Núñéz Cuadros, E, Asensi Botet, F, Pérez, A, Pérez Tamarit MD, Kalhert, C, Schupbach, J, Bunupuradah, T, Ananworanich, J, Phanuphak, P, Intasan, J, Ubolyam, S, Kanjanavanit, S, Namwong, T, Foster, C, Hamadache, D, Campbell, S, Hanley, C, Walsh, C, Kaye, S, Seery, P, Novelli, V, Shingadia, D, Flynn, J, Clapson, M, Jacobsen, M, Mcmaster, P, Hawkes, E, Liebeschuetz, S, Sodeinde, O, Wong, S, Walsh, S, Heath, Y, Weiner, L, Famiglietti, M, Rana, S, Yu, P, Roa, J, Puga, A, Haerry, A, Regazzi, M, Villani, S, Gibbons, S, Jullien, V, Rey, E, Treluye, Jm, Rodríguez Nóvoa, S, Tawon, Y., University of Zurich, and Green, H

Subjects
Cyclopropanes, Male, Time Factors, Infectious diseases and international health [NCEBP 13], HIV Infections, Drug resistance, Pharmacology, THERAPY, PROPHYLAXIS, 2726 Microbiology (medical), chemistry.chemical_compound, Plasma, immune system diseases, Medicine, Child, Reverse-transcriptase inhibitor, RESISTANCE, THERAPY, EXPOSURE, PHARMACOGENETICS, PROPHYLAXIS, virus diseases, Drug holiday, Viral Load, Infectious Diseases, Alkynes, Child, Preschool, Reverse Transcriptase Inhibitors, Female, Viral load, medicine.drug, Microbiology (medical), medicine.medical_specialty, Efavirenz, Nevirapine, Adolescent, CD4-CD8 Ratio, 610 Medicine & health, Article, Invasive mycoses and compromised host [N4i 2], Internal medicine, Drug Resistance, Viral, Humans, Protease inhibitor (pharmacology), EXPOSURE, PHARMACOGENETICS, business.industry, Poverty-related infectious diseases [N4i 3], 2725 Infectious Diseases, Benzoxazines, CD4 Lymphocyte Count, Regimen, chemistry, Withholding Treatment, 10036 Medical Clinic, Mutation, HIV-1, Microbial pathogenesis and host defense [UMCN 4.1], business, RESISTANCE
Abstract

Contains fulltext : 71467.pdf (Publisher’s version ) (Open Access) BACKGROUND: The optimum strategy for stopping treatment with drugs that have different half-lives in a combination regimen to minimize the risk of selecting drug-resistant viruses remains unknown. We evaluated drug concentrations in plasma, human immunodeficiency virus (HIV) load, and development of drug resistance after a planned treatment interruption of a nonnucleoside reverse-transcriptase inhibitor (NNRTI)-containing regimen in HIV type 1-infected children. METHODS: Children with viral loads or =30% (for children aged 2-6 years) or CD4 cell percentages > or =25% and CD4 cell counts > or =500 cells/microL (for children aged 7-15 years) were randomized to either a planned treatment interruption or to continuous therapy. In the planned treatment interruption arm, either (1) treatment with nevirapine or efavirenz was stopped, and treatment with the remaining drugs was continued for 7-14 days, or (2) nevirapine or efavirenz were replaced by a protease inhibitor, and all drugs were stopped after 7-14 days. Sampling for determination of plasma drug concentrations, measurement of viral load, and drug resistance testing was scheduled at day 0, day 7 (drug concentrations only), day 14, and day 28 after interruption of treatment with an NNRTI. RESULTS: Treatment with an NNRTI was interrupted for 35 children (20 were receiving nevirapine, and 15 were receiving efavirenz). Median time from NNRTI cessation to stopping all drugs was 9 days (range, 6-15 days) for nevirapine and 14 days (range, 6-18 days) for efavirenz. At 7 days, 1 (5%) of 19 and 4 (50%) of 8 children had detectable nevirapine and efavirenz concentrations, respectively; efavirenz remained detectable in 3 (25%) of 12 children at 14 days. At 14 days, viral load was > or =50 copies/mL in 6 of 16 children interrupting treatment with nevirapine (range, 52-7000 copies/mL) and in 2 of 12 children interrupting treatment with efavirenz (range, 120-1600 copies/mL). No new NNRTI mutations were observed. CONCLUSIONS: In children with virological suppression who experienced interruption of treatment with an NNRTI, staggered or replacement stopping strategies for a median of 9 days for nevirapine and 14 days for efavirenz were not associated with the selection of NNRTI resistance mutations.

Published
2008
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17. A randomized controlled trial of genotypic HIV drug resistance testing in HIV-1-infected children: the PERA (PENTA 8) trial

Author

Green, H, Gibb, DM, Compagnucci, A, Giacomet, V, de Rossi, A, Harper, L, Saïdi, Y, Castelli-Gattinara, G, Pillay, D, Babiker, AG, Aboulker, JP, Lyall, H, Bacheler, LT, Walker, AS, Debré, M, Rosso, R, Burger, DM, Della Negra, M, Dunn, DT, and Giaquinto, C

Subjects
virus diseases
Abstract

OBJECTIVE: To evaluate the longer-term utility of genotypic resistance testing in HIV-1-infected children with virological failure. METHODS: Children aged 3 months-18 years switching antiretroviral therapy (ART) with HIV-1 RNA > 2,000 copies/ml were randomized between genotypic testing (Virtual Phenotype) and no testing at baseline and subsequent virological failures. Children were followed to at least 96 weeks. RESULTS: One hundred and seventy eligible children, from 24 clinical centres in six countries, were randomized to resistance testing (n = 87) or no testing (n = 83) between June 2000-July 2003. At baseline, mean HIV-1 RNA and CD4+ T-cell percentage were 4.7 log10 copies/ml and 20%, respectively. Children had taken ART for a mean of 5 years; 24% had received all three classes, 53% nucleoside reverse transcriptase inhibitors (NRTIs)+protease inhibitors (PIs), 9% NRTIs+non-nucleoside reverse transcriptase inhibitors (NNRTIs) and 14% NRTIs only. There was no difference between the arms in the drug classes or the individual PIs/NNRTIs prescribed. However, 49% in the resistance test arm (RT) versus 19% in the no-test arm (NT) continued at least one NRTI from their failing regimen; 56% versus 19% were prescribed didanosine+stavudine as their NRTI backbone. Adjusting for baseline HIV-1 RNA, mean reductions in HIV-1 RNA at 48 weeks were 1.51 log10 copies/ml in the RT arm and 1.23 in the NT arm (P = 0.3); the difference between the arms was smaller at week 96 (RT: 1.50, NT: 1.47; P = 0.9). CONCLUSION: In this first paediatric trial of resistance testing, we observed a substantial difference in NRTI-prescribing behaviour across arms. However statistically significant evidence of a long-term virological or immunological benefit was not observed. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN14367816.

Published
2006

19. Granulomatous inflammation in cartilage-hair hypoplasia: risks and benefits of anti-TNF alpha monoclonal antibodies

Author

Moshous, D, primary, Meyts, I, additional, Fraitag, S, additional, Janssen, C, additional, Debré, M, additional, Suarez, F, additional, Toelen, J, additional, De Boeck, K, additional, Roskams, T, additional, Deschildre, A, additional, Picard, C, additional, Bodemer, C, additional, Wouters, C, additional, and Fischer, A, additional

Published
2011
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21. High adenosine deaminase level among healthy probands of Diamond Blackfan anemia (DBA) cosegregates with the DBA gene region on chromosome 19q13. The DBA Working Group of Société d'Immunologie Pédiatrique (SHIP)

Author

Willig, T.N., Pérignon, J.L., Gustavsson, P., Gane, P., Draptchinskaya, N., Testard, H., Girot, R., Debré, M., Stéphan, J.L., Chenel, C., Cartron, J.P., Dahl, Niklas, Tchernia, G., Willig, T.N., Pérignon, J.L., Gustavsson, P., Gane, P., Draptchinskaya, N., Testard, H., Girot, R., Debré, M., Stéphan, J.L., Chenel, C., Cartron, J.P., Dahl, Niklas, and Tchernia, G.

Abstract

Phenotypic characterization of Diamond Blackfan Anemia (DBA) patients and their relatives was performed in 54 families. Complete blood count, fetal hemoglobin level, erythrocyte i antigen expression, and erythrocyte adenosine deaminase (eADA) activities were quantitated in patients and relatives. eADA was elevated in 28 of 34 transfusion-independent DBA patients, whereas persistence of erythrocyte i antigen was noticed in only 10 of 20 DBA patients. High eADA activities were also found in 14 of 149 healthy family members, allowing us to identify an isolated high eADA phenotype in these families. In contrast, increase in erythrocyte i antigen expression, elevated fetal hemoglobin levels, and macrocytosis were much less frequently noted in nonaffected members of the DBA families studied. Importantly, isolated high eADA phenotype was found to be significantly associated with genetic markers on chromosome 19 that segregate with the DBA phenotype. Isolated high eADA phenotype thus seems to reflect a silent phenotype of DBA in affected families. These findings suggest that elevated eADA activity in unaffected individuals needs to be taken into account during genetic assessment of DBA families and could be used for accurate assessment of mode of inheritance.

Published
1998

23. Relationship between Changes in Thymic Emigrants and Cell-Associated HIV-1 Dna in HIV-1-Infected Children Initiating Antiretroviral Therapy

Author

De Rossi, Anita, Walker, A Sarah, Forni, Davide De, Klein, Nigel, Gibb, Diana M, Aboulker, J-P, Babiker, A, Compagnucci, A, Darbyshire, J, Debré, M, Gersten, M, Giaquinto, C, Gibb, DM, Jones, A, Aboulker, J-P, Babiker, A, Blanche, S, Bohlin, A-B, Butler, K, Castelli-Gattinara, G, Clayden, P, Darbyshire, J, Debré, M, de Groot, R, Faye, A, Giaquinto, C, Gibb, DM, Griscelli, C, Grosch-Wörner, I, Levy, J, Lyall, H, Mellado Pena, M, Nadal, D, Peckham, C, Ramos Amador, JT, Rosado, L, Rudin, C, Scherpbier, H, Sharland, M, Tovo, PA, Valerius, N, Wintergerst, U, Boucher, C, Clerici, M, de Rossi, A, Klein, N, Loveday, C, Muñoz-Fernandez, M, Pillay, D, Rouzioux, C, Babiker, A, Darbyshire, J, Gibb, DM, Harper, L, Johnson, D, Kelleher, P, McGee, L, Poland, A, Walker, AS, Aboulker, J-P, Carrière, I, Compagnucci, A, Debré, M, Eliette, V, Leonardo, S, Moulinier, C, Saidi, Y, Galli, L, Foot, A, Kershaw, H, Caul, O, Tarnow-Mordi, W, Petrie, J, McIntyre, P, Appleyard, K, Gibb, DM, Novelli, V, Klein, N, McGee, L, Ewen, S, Johnson, M, Gibb, DM, Cooper, E, Fisher, T, Barrie, R, Norman, J, King, D, and Larsson-Sciard, E-L

Abstract

Objectives and methods To investigate the relationship between cell-associated HIV-1 dynamics and recent thymic T-cell emigrants, HIV-1 DNA and T-cell receptor rearrangement excision circles (TREC, a marker of recent thymic emigrants) were measured in peripheral blood mononuclear cells in 181 samples from 33 HIV-1-infected children followed for 96 weeks after antiretroviral therapy (ART) initiation.Results At baseline, HIV-1 DNA was higher in children with higher TREC (P=0.02) and was not related to age, CD4 or HIV-1 RNA in multivariate analyses (P>0.3). Overall, TREC increased and HIV-1 DNA decreased significantly after ART initiation, with faster HIV-1 DNA declines in children with higher baseline TREC (P=0.009). The greatest decreases in HIV-1 DNA occurred in children with the smallest increases in TREC levels during ART (P=0.002). However, this inverse relationship between changes in HIV-1 DNA and TREC tended to vary according to the phase of HIV-1 RNA decline (P=0.13); for the same increase in TREC, HIV-1 DNA decline was much smaller during persistent or transient viraemia compared with stable HIV-1 RNA suppression.Conclusions Overall, these findings indicate that TREC levels predict HIV-1 DNA response to ART and suggest that immune repopulation by thymic emigrants adversely affects HIV-1 DNA decline in the absence of persistent viral suppression, possibly by providing a cellular source for viral infection and replication.

Published
2005
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32. Treatment of children with HIV infection

Author

Gibb, D.M., primary, Darbyshire, J.H., additional, Debré, M., additional, Giaquinto, C., additional, Aboulker, J.P., additional, Martinez, M., additional, and Tudor-Williams, G., additional

Published
1995
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35. Infusion of Fc gamma fragments for treatment of children with acute immune thrombocytopenic purpura.

Author

Debré, M, Bonnet, M C, Fridman, W H, Carosella, E, Philippe, N, Reinert, P, Vilmer, E, Kaplan, C, Teillaud, J L, and Griscelli, C

Abstract

Treatment of acute immune thrombocytopenic purpura (ITP) with intravenous immunoglobulin (IVIG) induces partial or complete responses, shown by transient or persistent increases in platelet count. The clinical benefit could be due to blockade of the Fc gamma receptor (Fc gamma R); platelets sensitised by IgG could not be cleared by cells of the reticuloendothelial system if Fc gamma R on these cells was blocked with IVIG. To find out whether this putative mechanism is correct, we treated twelve children who had acute ITP with intravenous infusions of Fc gamma fragments. Eleven children showed rapid increases in platelet counts to above the critical value of 50 x 10(9)/L, thereby avoiding major haemorrhagic risk. The response was stable in six patients and transient in five. No adverse reactions were observed. In responders who had detectable platelet-associated IgG before treatment (> 1500 IgG per platelet), platelet IgG fell substantially with treatment. Serum soluble CD16 (sCD16 or sFc gamma RIII) concentrations, measured in five children, showed transient or stable increases that correlated with the rise in platelet count. No sCD16 was detected in the Fc gamma preparation used. We conclude that the infusion of Fc gamma fragments is an efficient treatment of acute ITP in children. The efficacy of Fc gamma fragments strengthens the hypothesis that Fc gamma R blockade is the main mechanism of action of IVIG in ITP, although other immunoregulatory mechanisms triggered by the presence of increased sCD16 concentrations in serum could be involved in the clinical benefit observed. [ABSTRACT FROM AUTHOR]

Published
1993
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38. Impact of age, leukocyte count and day 21-bone marrow response to chemotherapy on the long-term outcome of children with philadelphia chromosome-positive acute lymphoblastic leukemia in the pre-imatinib era: results of the FRALLE 93 study

Author

Debre Marianne, Lejars Odile, Stephan Jean-Louis, Piguet Christophe, Schmitt Claudine, Demeocq Francois, Le Gall Edouard, Vannier Jean-Pierre, Perel Yves, Auclerc Marie-Francoise, Gandemer Virginie, Jonveaux Philippe, Cayuela Jean-Michel, Chevret Sylvie, Leverger Guy, and Baruchel Andre

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background We explored the heterogeneity of philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1-ALL) in a study of the effect of early features on prognosis in children. Here we report the long-term results of the FRALLE 93 study conducted in the era before the use of tyrosine kinase inhibitors. Methods Between 1993 and 1999, 36 children with Ph1-ALL were enrolled into the FRALLE 93 protocol. After conventional four-drug induction, children were stratified by availability of an HLA-matched sibling. Results Complete remission (CR) was observed in 26 children (72%), of which 13 underwent allogeneic bone marrow transplantation (BMT). Thirty-one children were good responders to prednisone, defined on day 8, and 21 were good responders to chemotherapy, defined by day-21 bone marrow (M1). Overall five-year disease-free survival (DFS) was 42 ± 9.7%. Based on multivariate analysis, two groups showed marked differences in five-year outcome: children with age3 and day-21 M1 marrow had a more favorable prognosis (14 pts: 100% CR, event free survival [EFS]: 57%, overall survival [OS]: 79%), than the high-risk group (22 patients: 55% CR, EFS: 18%, OS: 27%) (p < 0.005). We also observed a non statistically significant difference (p = 0.14) in outcome between these groups for transplanted patients (5-year DFS: 83 ± 14% and 33 ± 15%, respectively). Conclusion Age, leukocyte count and early response to treatment defined by the D21 bone marrow response provide an accurate model for outcome prediction. The combination of available tools such as minimal residual disease assessment with determination of these simple factors could be useful for refining indications for BMT in the current era of tyrosine-kinase inhibitor-based therapy.

Published
2009
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42. Severe cutaneous papillomavirus disease after haemopoietic stem-cell transplantation in patients with severe combined immune deficiency caused by common gammac cytokine receptor subunit or JAK-3 deficiency.

Author

Laffort C, Le Deist F, Favre M, Caillat-Zucman S, Radford-Weiss I, Debré M, Fraitag S, Blanche S, Cavazzana-Calvo M, de Saint Basile G, de Villartay JP, Giliani S, Orth G, Casanova JL, Bodemer C, Fischer A, Laffort, Caroline, Le Deist, Françoise, Favre, Michel, and Caillat-Zucman, Sophie

Abstract

Haemopoietic stem-cell transplantation is a life-saving treatment for severe combined immune deficiency. However, there has been little long-term follow-up of this treatment. There is evidence for the persistance of partial immunodeficiency associated with significant infections, including severe human papillomavirus (HPV) disease. We did a retrospective analysis of severe HPV disease in a group of 41 patients with severe combined immune deficiency from one centre who were alive 10 years or longer after haemopoietic stem-cell transplantation. Nine of the 41 patients had extensive chronic HPV disease limited to the skin, with a median onset at 8 years after transplantation. Four had lesions typical of epidermodysplasia verruciformis, a rare genodermatosis. Transplant characteristics, immune status, and chimerism of these nine patients did not differ significantly from those of the other patients. The nine patients with HPV disease had severe combined immune deficiency associated with either common gammac receptor cytokine subunit or Janus kinase-3 (JAK-3) deficiency. By contrast, patients with other forms of severe combined immune deficiency did not have any signs of HPV disease. That genetic causes are the only predisposing factor to be identified for severe combined immune deficiency, suggests that natural-killer cells or gammac/JAK-3-dependent signalling in keratinocytes could have a role in anti-HPV immunity. [ABSTRACT FROM AUTHOR]

Published
2004
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