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1. ODYSSEY clinical trial design: a randomised global study to evaluate the efficacy and safety of dolutegravir-based antiretroviral therapy in HIV-positive children, with nested pharmacokinetic sub-studies to evaluate pragmatic WHO-weight-band based dolutegravir dosing

Author

Clare Shakeshaft, Carlo Giaquinto, Tim R. Cressey, Adeodata Kekitiinwa, David M. Burger, Pauline Amuge, Pablo Rojo, Cecilia L. Moore, Osee Behuhuma, Yacine Saϊdi, Linda Barlow-Mosha, James Hakim, Alexandra Compagnucci, Lorna Atwine, Diana M. Gibb, Ebrahim Variava, Hilda Mujuru, Mark F. Cotton, Victor Musiime, Moherndran Archary, Deborah Ford, Cissy Kityo, Thanyawee Puthanakit, Anna Turkova, Avy Violari, Abbas Lugemwa, Medical Research Council Clinical Trials Unit (MRC CTU), University College of London [London] (UCL), University of Zimbabwe (UZ), Baylor College of Medicine Children's Foundation [Kampala, Uganda] (BCMCF), Joint Clinical Research Centre, MUJHU Research Collaboration [Kampala, Uganda] (MUJHURC), Chiang Mai University (CMU), Harvard T.H. Chan School of Public Health, University of Liverpool, Perinatal HIV Research Unit [Johannesburg, South Africa] (PHRU), University of the Witwatersrand [Johannesburg] (WITS), Klerksdorp Tshepong Hospital Complex [Matlosana, South Africa] (KTHC), Family Center for Research with Ubuntu [Cape Town, South Africa] (FCRU), Durban International Clinical Research Site [Durban, South Africa] (DICRS), Essais Thérapeutiques et Maladies Infectieuses, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Chulalongkorn University [Bangkok], Africa Health Research Institute [Hlabisa, South Africa] (AHRI), Hlabisa Hospital [Hlabisa, South Africa] (HH), Radboud University Medical Center [Nijmegen], Università degli Studi di Padova = University of Padua (Unipd), Hospital Universitario 12 de Octubre [Madrid], ODYSSEY Trial Team: Shabinah Ali, Abdel Babiker, Chiara Borg, Anne-Marie Borges Da Silva, Joanna Calvert, Deborah Ford, Joshua Gasa, Diana M Gibb, Nasir Jamil, Sarah Lensen, Emma Little, Fatima Mohamed, Samuel Montero, Cecilia L Moore, Rachel Oguntimehin, Anna Parker, Reena Patel, Tasmin Phillips, Tatiana Sarfati, Karen Scott, Clare Shakeshaft, Moira Spyer, Margaret Thomason, Anna Turkova, Rebecca Turner, Nadine Van Looy, Ellen White, Kaya Widuch, Helen Wilkes, Ben Wynne, Carlo Giaquinto, Tiziana Grossele, Daniel Gomez-Pena, Davide Bilardi, Giulio Vecchia, Alexandra Compagnucci, Yacine Saidi, Yoann Riault, Alexandra Coelho, Laura Picault, Christelle Kouakam, Tim R Cressey, Suwalai Chalermpantmetagul, Dujrudee Chinwong, Gonzague Jourdain, Rukchanok Peongjakta, Pra-Ornsuda Sukrakanchana, Wasna Sirirungsi, Janet Seeley, Sarah Bernays, Magda Conway, Nigel Klein, Eleni Nastouli, Anita De Rossi, Maria Angeles Munoz Fernandez, David Burger, Pauline Bollen, Angela Colbers, Hylke Waalewijn, Cissy M Kityo, Victor Musiime, Elizabeth Kaudha, Annet Nanduudu, Emmanuel Mujyambere, Paul Ocitti Labeja, Charity Nankunda, Juliet Ategeka, Peter Erim, Collin Makanga, Esther Nambi, Abbas Lugemwa, Lorna Atwine, Edridah Keminyeto, Deogratiuos Tukwasibwe, Shafic Makumbi, Emily Ninsiima, Mercy Tukamushaba, Rogers Ankunda, Ian Natuhurira, Miriam Kasozi, Baker Rubinga, Adeodata R Kekitiinwa, Pauline Amuge, Dickson Bbuye, Justine Nalubwama, Winnie Akobye, Muzamil Nsibuka Kisekka, Anthony Kirabira, Gloria Ninsiima, Sylvia Namanda, Gerald Agaba, Immaculate Nagawa, Annet Nalugo, Florence Namuli, Rose Kadhuba, Rachael Namuddu, Lameck Kiyimba, Angella Baita, Eunice Atim, Olivia Kobusingye, Clementine Namajja, Africanus Byaruhanga, Rogers Besigye, Herbert Murungi, Geoffrey Onen, Philippa Musoke, Linda Barlow-Mosha, Grace Ahimbisibwe, Rose Namwanje, Monica Etima, Mark Ssenyonga, Robert Serunjogi, Hajira Kataike, Richard Isabirye, David Balamusani, Monica Nolan, Mark F Cotton, Anita Janese van Rensburg, Marlize Smuts, Catherine Andrea, Sumaya Dadan Sonja Pieterse, Vinesh Jaeven, Candice Makola, George Fourie, Kurt Smith, Els Dobbels, Peter Zuidewind, Hesti Van Huyssteen, Mornay Isaacs, Georgina Nentsa, Thabis Ncgaba, Candice MacDonald, Mandisa Mtshagi, Maria Bester, Wilma Orange, Ronelle Arendze, Mark Mulder, George Fourie, Avy Violari, Nastassja Ramsagar, Afaaf Liberty, Ruth Mathiba, Lindiwe Maseko, Nakata Kekane, Busi Khumlo, Mirriam Khunene, Noshalaza Sbisi, Jackie Brown, Ryphina Madonsela, Nokuthula Mbadaliga, Zaakirah Essack, Reshma Lakha, Aasia Vadee, Derusha Frank, Nazim Akoojee, Maletsatsi Monametsi, Gladness Machache, Yolandie Fourie, Anusha Nanan-Kanjee, Juan Erasmus, Angelous Mamiane, Tseleng Daniel, Fatima Mayat, Nomfundo Maduna, Patsy Baliram, Chaiwat Ngampiyasakul, Pisut Greetanukroh, Wanna Chamjamrat, Praechadaporn Khannak, Pornchai Techakunakorn, Thitiwat Thapwai, Patcharee Puangmalai, Ampai Maneekaew, Pradthana Ounchanum, Yupawan Thaweesombat, Areerat Kongponoi, Jutarat Thewsoongnoen, Suparat Kanjanavanit, Pacharaporn Yingyong, Thida Namwong, Rangwit Junkaew, Ussanee Srirompotong, Patamawadee Sudsaard, Siripun Nuanbuddee, Sookpanee Wimonklang, Sathaporn Na-Rajsima, Suchart Thongpaen, Pattira Runarassamee, Watchara Meethaisong, Arttasid Udomvised, Ebrahim Variava, Modiehi Rakgokong, Dihedile Scheppers, Tumelo Moloantoa, Abdul Hamid Kaka, Tshepiso Masienyane, Akshmi Ori, Kgosimang Mmolawa, Pattamukkil Abraham, Moherndran Archary, Rejoice Mosia, Sajeeda Mawlana, Rosie Mngqibisa, Rashina Nundlal, Elishka Singh, Penelope Madlala, Allemah Naidoo, Sphiwee Cebekhulu, Petronelle Casey, Collin Pillay, Subashinie Sidhoo, Minenhle Chikowore, Lungile Nyantsa, Melisha Nunkoo, Terence Nair, Enbavani Pillay, Sheleika Singh, Sheroma Rajkumar, Osee Behuhuma, Olivier Koole, Kristien Bird, Nomzamo Buthelezi, Mumsy Mthethwa, James Hakim, Hilda Mujuru, Kusum Nathoo, Mutsa Bwakura-Dangarembizi, Ennie Chidziva, Shepherd Mudzingwa, Themelihle Bafana, Colin Warambwa, Godfrey Musoro, Gloria Tinago, Shirley Mutsai, Columbus Moyo, Ruth Nhema, Misheck Nkalo Phiri, Stuart Chitongo, Joshua Choga, Joyline Bhiri, Wilber Ishemunyoro, Makhosonke Ndlovu, Thanyawee Puthanakit, Naruporn Kasipong, Sararut Chanthaburanun, Kesdao Nanthapisal, Thidarat Jupimai, Thornthun Noppakaorattanamanee, Torsak Bunupuradah, Wipaporn Natalie Songtaweesin, Chutima Saisaengjan, Stephan Schultze-Straber, Christoph Konigs, Robin Kobbe, Felicia Mantkowski, Steve Welch, Jacqui Daglish, Laura Thrasyvoulou, Delane Singadia, Sophie Foxall, Judith Acero, Gosia Pasko-Szcech, Jacquie Flynn, Gareth Tudor-Williams, Farhana Abdulla, Srini Bandi, Jin Li, Sean O'Riordan, Dominique Barker, Richard Vowden, Colin Ball Eniola Nsirim, Kathleen McClughlin, India Garcia, Pablo Rojo Conejo, Cristina Epalza, Luis Prieto Tato, Maite Fernandez, Luis Escosa Garcia, Maria José Mellado Peña, Talia Sainz Costa, Claudia Fortuny Guasch, Antoni Noguera Julian, Carolina Estepa, Elena Bruno, Alba Murciano Cabeza, Maria Angeles Muñoz Fernandez, Paula Palau, Laura Marques, Carla Teixeira, Alexandre Fernandes, Rosita Nunes, Helena Nascimento, Andreia Padrao, Joana Tuna, Helena Ramos, Ana Constança Mendes, Helena Pinheiro, Ana Cristina Matos, Flavia Kyomuhendo, Sarah Nakalanzi, Cynthia Mukisa Williams, Ntombenhle Ngcobo, Deborah Pako, Jacky Crisp, Benedictor Dube, Precious Chandiwana, Winnie Gozhora, Ian Weller, Elaine Abrams, Tsitsi Apollo, Polly Clayden, Valériane Leroy, Anton Pozniak, Jane Crawley, Rodolphe Thiébaut, Helen McIlleron, Alasdair Bamford, Hermione Lyall, Andrew Prendergast, Felicity Fitzgerald, Anna Goodman, Malbec, Odile, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11), Radboud University Medical Centre [Nijmegen, The Netherlands], and Universita degli Studi di Padova

Subjects
0301 basic medicine, Male, Pediatrics, [SDV]Life Sciences [q-bio], HIV Infections, Basket trial, Dolutegravir, Efficacy, HIV, Paediatric, Pharmacokinetic, Randomized control trial, Safety, Adolescent, Body Weight, Child, Child, Preschool, Cohort Studies, Drug Dosage Calculations, Europe, Female, HIV Integrase Inhibitors, HIV-1, Heterocyclic Compounds, 3-Ring, Humans, Oxazines, Piperazines, Pyridones, RNA, Viral, South Africa, Thailand, Treatment Outcome, Uganda, Viral Load, World Health Organization, Zimbabwe, law.invention, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, Heterocyclic Compounds, law, Clinical endpoint, Medicine, Viral, 030212 general & internal medicine, 3. Good health, [SDV] Life Sciences [q-bio], Infectious Diseases, Viral load, Cohort study, Research Article, medicine.medical_specialty, 030106 microbiology, 3-Ring, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, lcsh:RC109-216, Dosing, Preschool, Pregnancy, business.industry, Clinical study design, medicine.disease, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], chemistry, RNA, business
Abstract

Background Dolutegravir (DTG)-based antiretroviral therapy (ART) is highly effective and well-tolerated in adults and is rapidly being adopted globally. We describe the design of the ODYSSEY trial which evaluates the efficacy and safety of DTG-based ART compared with standard-of-care in children and adolescents. The ODYSSEY trial includes nested pharmacokinetic (PK) sub-studies which evaluated pragmatic World Health Organization (WHO) weight-band-based DTG dosing and opened recruitment to children Methods ODYSSEY (Once-daily DTG based ART in Young people vS. Standard thErapY) is an open-label, randomised, non-inferiority, basket trial comparing the efficacy and safety of DTG + 2 nucleos(t) ides (NRTIs) versus standard-of-care (SOC) in HIV-infected children Results Between September 2016 and June 2018, 707 children weighing ≥14 kg were enrolled; including 311 ART-naïve children and 396 children starting second-line. 47% of children were enrolled in Uganda, 21% Zimbabwe, 20% South Africa, 9% Thailand, 4% Europe. 362 (51%) participants were male; median age [range] at enrolment was 12.2 years [2.9–18.0]. 82 (12%) children weighed 14 to Conclusions By employing a basket design, to include ART-naïve and -experienced children, and nested PK sub-studies, the ODYSSEY trial efficiently evaluates multiple scientific questions regarding dosing and effectiveness of DTG-based ART in children. Trial registration NCT, NCT02259127, registered 7th October 2014; EUDRACT, 2014–002632-14, registered 18th June 2014 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002632-14/ES); ISRCTN, ISRCTN91737921, registered 4th October 2014.

Published
2021

2. Long-term clinical, virological and immunological outcomes following planned treatment interruption in HIV-infected children

Author

Nigel Klein, Carlo Giaquinto, Lynda Harper, Tim R. Cressey, Alexandra Compagnucci, Yoann Riault, Annalisa Dalzini, Deborah Ford, Marisa Zanchetta, Yacine Saidi, Riccardo Freguja, A. De Rossi, P. Del Bianco, DM Gibb, and Alasdair Bamford

Subjects
0301 basic medicine, CD4-Positive T-Lymphocytes, medicine.medical_specialty, Adverse outcomes, Human immunodeficiency virus (HIV), HIV Infections, CD8-Positive T-Lymphocytes, medicine.disease_cause, immunology, 03 medical and health sciences, 0302 clinical medicine, Immunophenotyping, children, Pulmonary tuberculosis, Hiv infected, Internal medicine, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Stage (cooking), Child, Randomized Controlled Trials as Topic, Original Research, business.industry, Health Policy, treatment interruption, HIV, Viral Load, 030112 virology, Antiretroviral therapy, CD4 Lymphocyte Count, virology, Infectious Diseases, Treatment Outcome, Treatment interruption, ARV, business
Abstract

OBJECTIVES Planned treatment interruption (PTI) of antiretroviral therapy (ART) in adults is associated with adverse outcomes. The PENTA 11 trial randomized HIV-infected children to continuous ART (CT) vs. CD4-driven PTIs. We report 5 years' follow-up after the end of main trial. METHODS Post-trial, all children resumed ART. Clinical, immunological, virological and treatment data were collected annually. A sub-study investigated more detailed immunophenotype. CT and PTI arms were compared using intention-to-treat. Laboratory parameters were compared using linear regression, adjusting for baseline values; mixed models were used to include all data over time. RESULTS In all, 101 children (51 CT, 50 PTI) contributed a median of 7.6 years, including 5.1 years of post-trial follow-up. Post-trial, there were no deaths, one pulmonary tuberculosis and no other CDC stage B/C events. At 5 years post-trial, 90% of children in the CT vs. 82% in the PTI arm had HIV RNA

Published
2019

3. The EPIICAL project: an emerging global collaboration to investigate immunotherapeutic strategies in HIV-infected children

Author

Eleni Nastouli, Carlo Giaquinto, Paolo Palma, Nadia Mora, Katherine Luzuriaga, William Borkowsky, Caroline Foster, A. De Rossi, Andrew J. Yates, Jintanat Ananworanich, Britta Wahren, Paola Zangari, Nicola Cotugno, Savita Pahwa, Pablo Rojo, Paolo Rossi, María Ángeles Muñoz-Fernández, Stefania Bernardi, Vincent Calvez, Alexandra Compagnucci, Nigel Klein, Emma Concetta Manno, Diana M. Gibb, and Deenan Pillay

Subjects
medicine.medical_specialty, Epidemiology, Immunology, Human immunodeficiency virus (HIV), Reviews, Bioinformatics, medicine.disease_cause, Microbiology, children, Virology, Hiv infected, Medicine, Intensive care medicine, business.industry, Public Health, Environmental and Occupational Health, therapeutic vaccines, HIV, immunotherapies, Early infancy, Antiretroviral therapy, QR1-502, Infectious Diseases, Treatment interruption, Therapeutic vaccine, early treated, Public aspects of medicine, RA1-1270, business
Abstract

Short summary: The EPIICAL (Early-treated Perinatally HIV-infected Individuals: Improving Children's Actual Life with Novel Immunotherapeutic Strategies) project arises from the firm belief that perinatally infected children treated with suppressive antiretroviral therapy (ART) from early infancy represent the optimal population model in which to study novel immunotherapeutic strategies aimed at achieving ART-free remission. This is because HIV-infected infants treated within 2–3 months of life have a much reduced viral reservoir size, and rarely show HIV-specific immunity but preserve normal immune development. The goal of EPIICAL is the establishment of an international collaboration to develop a predictive platform using this model to select promising HIV therapeutic vaccine candidates, leading to prioritisation or deprioritisation of novel immunotherapeutic strategies.To establish this platform, the EPIICAL Consortium aims to: develop predictive models of virological and immunological dynamics associated with response to early ART and to treatment interruption using available data from existing cohorts/studies of early-treated perinatally HIV-infected children; optimise methodologies to better characterise immunological, virological and genomic correlates/profiles associated with viral control; test novel immunotherapeutic strategies using in vivo proof-of-concept (PoC) studies with the aim of inducing virological, immunological and transcriptomic correlates/profiles equivalent to those defined by the predictive model. This approach will strengthen the capacity for discovery, development and initial testing of new therapeutic vaccine strategies through the integrated efforts of leading international scientific groups, with the aim of improving the health of HIV-infected individuals.

Published
2015

4. Hepatic, Renal, Hematologic, and Inflammatory Markers in HIV-Infected Children on Long-term Suppressive Antiretroviral Therapy

Author

Anna Turkova, Pactg, Anrs Study Team, Alexandra Compagnucci, Gareth Tudor-Williams, Yacine Saidi, Linda Harrison, Penpact (Penta ), Meredith G. Warshaw, and Ann J. Melvin

Subjects
0301 basic medicine, Cyclopropanes, Male, Time Factors, Lipopolysaccharide Receptors, HIV Infections, Kidney, Gastroenterology, Lopinavir, chemistry.chemical_compound, 0302 clinical medicine, Interquartile range, Antiretroviral Therapy, Highly Active, 030212 general & internal medicine, Child, biology, virus diseases, General Medicine, Europe, Infectious Diseases, C-Reactive Protein, Cholesterol, Treatment Outcome, Liver, Alkynes, Child, Preschool, Creatinine, Toxicity, Reverse Transcriptase Inhibitors, Female, Drug Monitoring, medicine.drug, medicine.medical_specialty, Efavirenz, Adolescent, Anti-HIV Agents, 030106 microbiology, Electronic Articles, Fibrin Fibrinogen Degradation Products, 03 medical and health sciences, Internal medicine, medicine, Humans, Cystatin C, Inflammation, Ritonavir, business.industry, Interleukin-6, C-reactive protein, Benzoxazines, chemistry, Pediatrics, Perinatology and Child Health, North America, biology.protein, business, Biomarkers
Abstract

Background Data on long-term toxicity of antiretroviral therapy (ART) in HIV-infected children are sparse. PENPACT-1 was an open-label trial in which HIV-infected children were assigned randomly to receive protease inhibitor (PI)- or nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based ART. Methods We examined changes in clinical, immunologic, and inflammatory markers from baseline to year 4 in the subset of children in the PENPACT-1 study who experienced viral suppression between week 24 and year 4 of ART. Liver enzyme, creatinine, and cholesterol levels and hematologic parameters were assessed during the trial. Cystatin C, high-sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), d-dimer, and soluble CD14 (sCD14) were assayed from cryopreserved specimens. Results Ninety-nine children (52 on PI-based and 47 on NNRTI-based ART) met inclusion criteria. The median age at initiation of ART was 6.5 years (interquartile range [IQR], 3.7-13.4 years), and 22% were aged

Published
2017

5. First-line antiretroviral therapy with a protease inhibitor versus non-nucleoside reverse transcriptase inhibitor and switch at higher versus low viral load in HIV-infected children: an open-label, randomised phase 2/3 trial

Author

J. Fanning, M. Keuth, E. Cagwin, E. Lachassinne, S. Campbell, K. Jeffries, J. Tutko, L. Vladau, Raffaele Badolato, Paolo Palma, J. Orendi, I. Colombo, A. Buckton, J. Neubert, Y. Rodriguez Lozano, V. Novelli, E. Belfrage, M. della Negra, N. Boudjoudi, R. Nickel, F. Schumacher, A. Furcas, J. Navarra, C. B. S. de Souza, B. Zöhrer, M. Neely, G. Pontrelli, D. Duiculescu, M. Clapson, K. A. Contello, G. Kudesia, R. Santos, Catherine Dollfus, Raffaella Rosso, G. Lewis, A. Sarah Walker, James Homans, Pier-Angelo Tovo, T. Chen, K. Fidler, V. Reliquet, A. Aali, J. Cottalorda, D. Michalik, Barbra Murante, Marisa Zanchetta, Jaime G. Deville, P. McNeil, Z. Shah, K. O’connor, H. Haley, M. I. Gonzalez Tomé, M. C. Cervi, Rosa Bologna, Abdel Babiker, D. Hamadache, A. Pala, Merlin L. Robb, E. Voicu, Cristina Bertulli, A. Smyth, G. Hadjou, L. Lugo, M. Burke, E. Hayes, Janice Hodge, Marco Tabone, Ram Yogev, A. Jurgrau, Lucia de Araujo Evangelista, K. Nguyen, P. Kamara, N. Le Gueyades, D. Picard, A. Dehée, J. Leleu, D. M. Ferraro, F. Damond, Iraina Fernandes, S. Bradford, K. Swaby, Laura Schneider, Albert Faye, T. Dunaway, Carlo Giaquinto, D. Otelea, C. Jennings, D. Gibb, J. Horton, G. Alexandre-Castor, D. Muir, A. Mazzei, J. Nelson, M. Snelling, M.J. Mellado Peña, S. Welch, C. Belmega, B. V.M. Negrini, L. Garrovillo, S. Walters, C. Müller, Andrew Collinson, Lynda Harper, T. Fleming, C. Concato, Polly Clayden, K. Elkins, A. Schnuriger, I. Farias, Caroline Foster, M. C. Sapia, L. Alecsandru, A. Alvarez, A. Waters, N. O’sullivan, S. Buskirk, Yacine Saidi, R. Pineiro Perez, Elaine J. Abrams, Y. C. Lian, L. Buck, H. Tchidjou, M. Gonzalez, S. Blanche, M. E. Paul, Leonard B. Weiner, K. Moshal, S. Marino, S. Wong, Angela Berzi, D. P. Pacola, A. Rodallec, C. Frillici, C. Rodriguez, Cristiana Oprea, L. Dehache, Anthony C. Gordon, Christine Rouzioux, P. Valentin, Jay A. Levy, Sharon Nachman, Andrea Kovacs, J. Batra, R. Croteau, I. L. Febo, Yvonne J. Bryson, P. Archer, Z. Benabadji, M. Stevanovic, E. Hutchison, G. Boddy, M. Ilie, K. Kabat, C. Monrose, Vania Giacomet, Marianne C. Jacobsen, Antonio Mazza, N. Patel, C. Farmer, A. Krivine, I. Fineanganofo, M. García López, C. Graisbery, CS Peckham, F. Monpoux, William Borkowsky, M. Denon, A. Doyle, T. Schmitz, Ann J. Melvin, Gareth Tudor-Williams, Osvalda Rampon, L. Marty, M. Sellier, M. Fernandez, Marc Foca, C. Hayes, C. Peiser, T. C. Matsubara, A. Finn, P. Martín Fontelos, W. A. Holz, A. Zoccano, Mike Sharland, R. Dersimonian, S. Champion, M. Kline, D. Collins, J.T. Ramos Amador, Angela Di Martino, Hermione Lyall, Christine A. Powell, Stephen A. Spector, J. Swan, S. Eloby-Childress, S. Yeadon, C. McMullen-Jackson, A. L. Chang, Diana M. Gibb, Henriette J. Scherpbier, G. Ball, Hannah Castro, Elena Spinelli, M. Jervis, G. Delommois, S. Scott, I. Garcia Mellado, S. Discenza, P. Lepage, S. Hawkins, F. Méchinaud, Alexandra Compagnucci, T. Ilmet, A. Mangano, H. Carreira, Andrew J. Pollard, G. Silva, L. Cerracchio, R. Sellers, Edward Handelsman, C. Floch, M. Lajeunesse, Stefano Vella, Thalita F. Abreu, N. Martinez-Allier, C. Florea, C. Newbould, I. Grosch-Wörner, M. F. Courcoux, Gert Warncke, I. Whyms, J. C. Gabaldi, T. Piening, F. Hoffman, V. Shah, B. Bucholz, S. Costa, G. Firtion, E. R. Stiehm, J. Palm, S. Deygoo, L. Rosado, V. Tournier, Y. Saïdi, M. Wigger, G. Vaudre, V. Lobato, E. Yeagley, A. B. Bohlin, Delane Shingadia, L. S. Spencer, M. Depala, G. Tardei, S. Akleh, S. Marks, S. Vasquez Bonilla, Stefania Bernardi, D. Costello, S. Segal, S. Gudowius, Saniyyah Mahmoudi, M. Debré, C. Borne, D. Melvin, S. Kaye, S. Johnson, Ellen G. Chadwick, Marie-Laure Chaix, H. Loeffler, G. Stringari, J. L. Jimenez, Arry Dieudonne, G. Notheis, J. Dodge, C. Nesel, D. Mecikovsky, Meredith G. Warshaw, Shunmay Yeung, C. De Bortoli, J. Shenton, R. de Groot, S. Forcat, M. A. Kelly, J. Usher, I. Falconi, M. Rein, D. Nayagam, R. Delgado Garcia, P. McMaster, J. Flynn, S. Rugina, Susan A. Fiscus, S. Liebeschuetz, A. Sorlini, G. Tatum, Magdalena Marczyńska, H. J. Laws, Paul Palumbo, Nigel Klein, E. Daghofer, D. Painter, D. Poalelungi, Anne A. Gershon, L. Martins, N. Pineda, Patricia M. Flynn, J. H. Darbyshire, Michael Hughes, Pim Brouwers, Guido Castelli-Gattinara, M. Byrne, J. Stroobant, G. Talero, C. Reed, D. Patel, F. Nganzali, J. F. Méritet, M. Elizabeth Smith, M. A. Muñoz Fernandez, K. Huck, G. Castelli Gattinara, M. L. Issac, S. Gaur, M. Johnson, K. Mohan, B. Ward, A. Cheng, M. Dunn, M. Frere, T. Alford, K. Doerholt, S. Storey, J. Smith, S. Cleto, A. Ferreira, J. Darbyshire, J. Johnson, A. Marion, P. Butler, K. M. Kim, H. Hichou, D. Casey, L. Farrelly, R. Draghicenoiu, Alessandra Viganò, M. F. Melo, S. Bellert, Jintanat Ananworanich, F. Ferreira, K. Sloper, Deenan Pillay, E. Ferguson, Karina Butler, D. Rivaux, A. D. Fernandez, M. Penin, V. Bennato, M. Filisetti, W. Tomosada, Daria Trabattoni, J. P. Aboulker, A. Diniz, Patricia Emmanuel, C. Rodier, Jorge Pinto, S. McDonagy, M. Goode, K. Swaminathan, H. Sprenger, L. Deveikis, L. Ball, E. André, Susan Laverty, John S. Lambert, F. Abaab, C. Hill, A. Menon, A. García Torre, T. Belger, Christoph Rudin, R. Neubauer, Cornelia Feiterna-Sperling, U. Wintergerst, B. Brody, Silvia Netescu, Ross E. McKinney, Yoann Riault, J. Galimand, G. Deluchi, J. Hobbs, K. Buckberry, C. Mazhude, S. Doshi, Maripat Toye, C. Ball, David M. Burger, A. Werthmann, R. Matusa, J. Wong, Joseph A. Church, M. Pourrat, K. Pfurtscheller, S. Seyboldt, R. Lawrence, M. Butler, D. Scott, T. Niehues, Katherine Luzuriaga, B. Pabst, R. Lakshman, M. Donohoe, A. Ortwin, M. Brusati, M. O’connell, W. Queiroz, M. P. Gomez, J. C. Roa, P. Rojo Conejo, A. De Rossi, C. Norgeux, A. Rochford, Linda Harrison, Tao Dong, W. Zenz, S. Donaghy, S. Mellul, L. M. Lira, Paula Britto, J. Romeiro, C. Taylor, J. Jackson Alvarez, Judith A. Guzman-Cottrill, J. Arias, Lynne M. Mofenson, D. Calo, I. Le Moal, J. Lujan-Zimmerman, T. Alchediak, C. Guérin, Ricardo H. Oliveira, Jonathan Cohen, D. Kwolfe, Ana Puga, L. Navarante, William T. Shearer, L. Angeli, Marc Lallemant, J. Bane, Niels Henrik Valerius, Ayesha Mirza, John F. Modlin, G. Rossetti, David Nadal, M. Acevedo-Flores, F. Shackley, S. Léonardo, E. Smidt, I. Jimenez Nacher, Margarita Silio, Geoffrey A. Weinberg, C. Galvez, F. Kakehasi, L. Fabregas, S. Moore, M. M. Mussi-Pinhata, M. O’connor, M. Diniz, M. Mardarescu, J. King, Sohail Rana, D. Johnson, J. M. Ferrari, Lisa M. Frenkel, T. Hastings, C. Wells, R. B. Van Dyke, G. Bowen, Claire Thorne, L. Sen, E. Hyland, L. Barrett, E Jungmann, Mobeen H. Rathore, D. Beniken, B. Sodiende, C. Ryan, A. Malheiro, Y. Peng, R. O’connell, A. Walsh, John L. Sullivan, A. Deveikis, P. Rice, A. Le Pelletier, and A. Poziak

Subjects
Male, medicine.medical_specialty, Nevirapine, Pediatric AIDS, Adolescent, Anti-HIV Agents, antiretroviral therapy, pediatric HIV/AIDS, antiretroviral therapy, HIV Infections, Article, Nucleoside Reverse Transcriptase Inhibitor, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Antiretroviral Therapy, Highly Active, medicine, Humans, pediatric HIV/AIDS, Protease inhibitor (pharmacology), 030212 general & internal medicine, Child, 0303 health sciences, Intention-to-treat analysis, Reverse-transcriptase inhibitor, 030306 microbiology, business.industry, Infant, South America, Viral Load, Virology, Settore MED/38, 3. Good health, Europe, Infectious Diseases, Nelfinavir, Treatment Outcome, Child, Preschool, North America, Female, Drug Monitoring, business, Viral load, medicine.drug
Abstract

Background Children with HIV will be on antiretroviral therapy (ART) longer than adults, and therefore the durability of first-line ART and timing of switch to second-line are key questions. We assess the long-term outcome of protease inhibitor and non-nucleoside reverse transcriptase inhibitor (NNRTI) first-line ART and viral load switch criteria in children. Methods In a randomised open-label factorial trial, we compared effectiveness of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor versus two NRTIs plus an NNRTI and of switch to second-line ART at a viral load of 1000 copies per mL versus 30,000 copies per mL in previously untreated children infected with HIV from Europe and North and South America. Random assignment was by computer-generated sequentially numbered lists stratified by age, region, and by exposure to perinatal ART. Primary outcome was change in viral load between baseline and 4 years. Analysis was by intention to treat, which we defined as all patients that started treatment. This study is registered with ISRCTN, number ISRCTN73318385. Findings Between Sept 25, 2002, and Sept 7, 2005, 266 children (median age 6.5 years; IQR 2.8-12.9) were randomly assigned treatment regimens: 66 to receive protease inhibitor and switch to second-line at 1000 copies per mL (PI-low), 65 protease inhibitor and switch at 30,000 copies per mL (PI-higher), 68 NNRTI and switch at 1000 copies per mL (NNRTI-low), and 67 NNRTI and switch at 30,000 copies per mL (NNRTI-higher). Median follow-up was 5.0 years (IQR 4.2-6.0) and 188 (71%) children were on first-line ART at trial end. At 4 years, mean reductions in viral load were -3.16 log(10) copies per mL for protease inhibitors versus -3.31 log(10) copies per mL for NNRTIs (difference -0.15 log(10) copies per mL, 95% CI -0.41 to 0.11; p=0.26), and -3.26 log(10) copies per mL for switching at the low versus -3.20 log(10) copies per mL for switching at the higher threshold (difference 0.06 log(10) copies per mL, 95% CI -0.20 to 0.32; p=0.56). Protease inhibitor resistance was uncommon and there was no increase in NRTI resistance in the PI-higher compared with the PI-low group. NNRTI resistance was selected early, and about 10% more children accumulated NRTI mutations in the NNRTI-higher than the NNRTI-low group. Nine children had new CDC stage-C events and 60 had grade 3/4 adverse events; both were balanced across randomised groups. Interpretation Good long-term outcomes were achieved with all treatments strategies. Delayed switching of protease-inhibitor-based ART might be reasonable where future drug options are limited, because the risk of selecting for NRTI and protease-inhibitor resistance is low. Funding Paediatric European Network for Treatment of AIDS (PENTA) and Pediatric AIDS Clinical Trials Group (PACTG/IMPAACT).

Published
2011
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6. Population analysis of the pregnancy-related modifications in lopinavir pharmacokinetics and their possible consequences for dose adjustment

Author

Jean-Marc Tréluyer, Stéphanie Chhun, Gérard Pons, Elie Azria, Marion Bouillon-Pichault, Odile Launay, Emmanuelle Pannier, Anne Krivine, Vincent Jullien, Olivier Taulera, Ghislaine Firtion, Laurent Finkielsztejn, and Alexandra Compagnucci

Subjects
Microbiology (medical), medicine.medical_specialty, Anti-HIV Agents, Metabolic Clearance Rate, Population, Urology, HIV Infections, Pyrimidinones, Pharmacology, Biology, Lopinavir, Plasma, Pharmacokinetics, Pregnancy, medicine, Humans, Tissue Distribution, Pharmacology (medical), Trough Concentration, education, Chromatography, High Pressure Liquid, Volume of distribution, education.field_of_study, medicine.diagnostic_test, Gestational age, medicine.disease, Infectious Diseases, Therapeutic drug monitoring, Female, Monte Carlo Method, medicine.drug
Abstract

Objectives To investigate the possible necessity of an increase in lopinavir dose during pregnancy in order to achieve the concentrations previously defined as predictive of virological efficacy. Patients and methods Lopinavir pharmacokinetics were investigated by a population approach performed on 145 HIV-infected women, including 74 pregnant women. The final model was used to determine the probability of achievement of the target trough concentrations by Monte Carlo simulations. Results The typical population estimates (inter-individual variability %) of apparent clearance (CL/F) and volume of distribution were 4.38 L/h (24%) and 58.4 L (59%), respectively. Pregnancy associated with a gestational age >15 weeks and delivery were found to increase lopinavir CL/F by 39% and 58%, respectively. With the standard 400 mg twice-a-day regimen, the probability of reaching the 1 mg/L target trough concentration for protease inhibitor (PI)-naive patients was 99% and 96% for non-pregnant and pregnant women, respectively. An important decrease in the probability of achieving the 5.7 mg/L target trough concentration for salvage therapy was observed for non-pregnant women (55%), this decrease being even greater for pregnant women (21%). Raising the lopinavir dose to 600 mg twice daily increased these probabilities to 87% and 53% for non-pregnant and pregnant women, respectively. Conclusions Modification of the lopinavir dose is unlikely to be required for PI-naive pregnant women; however, in pregnant women who have previously received a PI, therapeutic drug monitoring and/or empirical increasing of the dose should be considered.

Published
2009

7. Pregnancy outcomes in women with HIV type-1 receiving a lopinavir/ritonavir-containing regimen

Author

Jean Patrick Le Meaux, Dominique Cabrol, Olivier Taulera, Thomas Schmitz, Odile Launay, Constance Moutafoff, Emmanuelle Pannier, Anne Krivine, Alexandra Compagnucci, Vassilis Tsatsaris, Ghislaine Firtion, Laurent Finkielsztejn, and Elie Azria

Subjects
Adult, medicine.medical_specialty, Lopinavir/ritonavir, HIV Infections, Pyrimidinones, Lopinavir, Cohort Studies, Obstetric Labor, Premature, Acquired immunodeficiency syndrome (AIDS), Pregnancy, Internal medicine, medicine, Humans, Pharmacology (medical), Pregnancy Complications, Infectious, Sida, Adverse effect, Pharmacology, Ritonavir, biology, business.industry, Pregnancy Outcome, HIV Protease Inhibitors, medicine.disease, biology.organism_classification, Regimen, Infectious Diseases, Immunology, HIV-1, Drug Therapy, Combination, Female, France, business, medicine.drug
Abstract

Background The pregnancy-related adverse effects of antiretroviral therapy (ART) have yielded discordant results, which could be explained in part by the heterogeneity of ART protocols. The objective of our study was to explore whether lopinavir/ritonavir (LPV/r) exposure during pregnancy is associated with adverse outcomes. Methods Data on 100 consecutive HIV type-1 (HIV-1)-infected women receiving LPV/r during pregnancy and who delivered after 15 weeks gestational age (GA) between January 2003 and June 2007 in a single centre were analysed. For each HIV-1-infected woman, two uninfected women matched by age, parity and geographical origin were selected among patients delivering during the same period. Preterm delivery (PTD), vasculoplacental complications, gestational glucose intolerance and post-partum complication rates were compared between cases and controls. Factors associated with PTD and post-partum complications were assessed in HIV-1-infected women by a logistic regression model. Results Rates of vasculoplacental complication and gestational glucose intolerance were not higher among HIV-1-infected women than in controls. PTD was higher in HIV-1-infected women (21%) than in controls (10%; PConclusions In this population of HIV-1-infected pregnant women receiving LPV/r, the risk of PTD was higher than in HIV-1-uninfected controls. As PTD risk was not associated with early exposure to LPV/r, these data support current guidelines to initiate ART earlier in pregnancy.

Published
2008

8. Highly active antiretroviral therapy started in infants under 3 months of age

Author

M Debre, Carlo Giaquinto, Diana M. Gibb, Marie-Laure Chaix, Albert Faye, Aboulker Jp, Lynda Harper, Alexandra Compagnucci, Yacine Saidi, AS Walker, A Babiker, and JH Darbyshire

Subjects
Male, medicine.medical_specialty, Immunology, HIV Infections, Drug resistance, Antiretroviral Therapy, Highly Active, Internal medicine, Drug Resistance, Viral, Humans, Immunology and Allergy, Medicine, Prospective Studies, Adverse effect, Prospective cohort study, Didanosine, Nelfinavir, business.industry, Stavudine, Infant, Newborn, Infant, Viral Load, CD4 Lymphocyte Count, Surgery, Treatment Outcome, Infectious Diseases, Tolerability, HIV-1, RNA, Viral, Female, business, Viral load, Follow-Up Studies, medicine.drug
Abstract

OBJECTIVE: To assess the feasibility and impact of highly active antiretroviral therapy (HAART) started in vertically HIV-1-infected infants less than 3 months of age. DESIGN: A multicentre, phase I/II, non-randomized, open-label study (PENTA 7). METHODS: Adverse events, plasma HIV-1 RNA, CD4 cell counts, CD4 cell percentage (CD4%) and clinical progression were recorded at baseline and prospectively to 72 weeks in order to assess the toxicity, tolerability and efficacy of a combination of stavudine, didanosine and nelfinavir. Selection of genotypic resistance was also investigated. RESULTS: Twenty infants, of whom only three had Centers for Disease Control and Prevention stage B, initiated HAART at median age 2.5 months (range, 0.9-4.7) with median HIV-1 RNA concentration 5.5 log10 copies/ml (range, 3.2-6.8) and CD4% 33% (range, 11-66). Median follow-up was 96 weeks (range, 60-144). At week 72, 11 infants were still taking the original treatment. Few adverse events were reported related to treatment, all minor and causing treatment interruption in only three infants. No AIDS-defining events occurred; one child died of non-HIV-related causes (prematurity). All but two had CD4% > 25% at 72 weeks; however, 14 infants had virological failure and six acquired resistance mutations. CONCLUSIONS: Early treatment with stavudine, didanosine and nelfinavir was well tolerated and associated with good clinical and immunological outcomes at week 72. However, a high rate of virological failure with emergence of genotypic resistance is of great concern. More palatable drug combinations for infants and closer drug monitoring are required.

Published
2004

9. Early antiretroviral therapy in children perinatally infected with HIV: a unique opportunity to implement immunotherapeutic approaches to prolong viral remission

Author

Carlo Giaquinto, Britta Wahren, Paolo Palma, Jintanat Ananworanich, Nigel Klein, Deenan Pillay, Caroline Foster, María Ángeles Muñoz-Fernández, Stefania Bernardi, Anita De Rossi, William Borkowsky, Eleni Nastouli, Alexandra Compagnucci, Savita Pahwa, Pablo Rojo, Paola Zangari, Paolo Rossi, Katherine Luzuriaga, Vincent Calvez, and DM Gibb

Subjects
Viral rebound, medicine.medical_specialty, Adolescent, Population, Human immunodeficiency virus (HIV), Placebo-controlled study, HIV Infections, medicine.disease_cause, Immune system, Early Medical Intervention, Medicine, Humans, education, Intensive care medicine, Child, Settore MED/38 - Pediatria Generale e Specialistica, education.field_of_study, business.industry, Transmission (medicine), Incidence (epidemiology), Infant, Newborn, Infant, Viral Vaccines, Antiretroviral therapy, Infectious Disease Transmission, Vertical, Infectious Diseases, Anti-Retroviral Agents, Child, Preschool, Immunology, Immunotherapy, business
Abstract

Summary From the use of antiretroviral therapy to prevent mother-to-child transmission to the possibility of HIV cure hinted at by the Mississippi baby experience, paediatric HIV infection has been pivotal to our understanding of HIV pathogenesis and management. Daily medication and indefinite antiretroviral therapy is recommended for children infected with HIV. Maintenance of life-long adherence is difficult and the incidence of triple-class virological failure after initiation of antiretroviral therapy increases with time. This challenge shows the urgent need to define novel strategies to provide long-term viral suppression that will allow safe interruption of antiretroviral therapy without viral rebound and any associated complications. HIV-infected babies treated within a few days of birth have a unique combination of a very small pool of integrated viruses, a very high proportion of relatively HIV resistant naive T cells, and an unparalleled capacity to regenerate an immune repertoire. These features make this group the optimum model population to investigate the potential efficacy of immune-based therapies. If successful, these investigations could change the way we manage HIV infection.

Published
2014

10. O222 Treatment interruption in children with chronic HIV-infection: the results of the paediatric European network for treatment of AIDS (PENTA) 11 trial

Author

F Monpoux, C Taylor, S Kanjavanit, Carlo Giaquinto, Nicole Ngo-Giang-Huong, Hannah Green, Uwe Wintergerst, Lynne M. Mofenson, Marc Lallemant, David Nadal, Alexandra Compagnucci, Yacine Saidi, Magdalena Marczyńska, Mig Tomé, Hermione Lyall, Diana M. Gibb, and J Moye

Subjects
Pediatrics, medicine.medical_specialty, business.industry, Public health, Public Health, Environmental and Occupational Health, Human immunodeficiency virus (HIV), medicine.disease, medicine.disease_cause, Infectious Diseases, Acquired immunodeficiency syndrome (AIDS), Treatment interruption, Immunology, medicine, Presentation (obstetrics), business
Abstract

ss Open Acce Oral presentation O222 Treatment interruption in children with chronic HIV-infection: the results of the paediatric European network for treatment of AIDS (PENTA) 11 trial DM Gibb*1, A Compagnucci2, H Green3, M Lallemant4, Y Saidi2, N NgoGiang-Huong4, C Taylor3, L Mofenson5, F Monpoux6, MIG Tome7, M Marczynska8, D Nadal9, U Wintergerst10, S Kanjavanit11, H Lyall12, C Giaquinto13 and J Moye4

Published
2008

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