Browsing by Author "Chadwick EG"

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Establishing Dosing Recommendations for Efavirenz in HIV/TB-Coinfected Children Younger Than 3 Years.
(2019-Aug-01) Bwakura Dangarembizi M; Samson P; Capparelli EV; Moore CB; Jean-Philippe P; Spector SA; Chakhtoura N; Benns A; Zimmer B; Purdue L; Jackson C; Wallis C; Libous JL; Chadwick EG; Department of Paediatrics and Child Health, University of Zimbabwe College of Health Sciences, Harare, Zimbabwe.; Rady Children's Hospital, San Diego, CA.; IMPAACT Operations Center, FHI360, Durham, NC.; BARC-SA and Lancet Laboratories, Johannesburg, South Africa.; National Institutes of Allergy and Infectious Diseases, Bethesda, MD.; Division of Infectious Diseases, Department of Pediatrics, University of California, San Diego, La Jolla, CA.; Harvard T.H. Chan School of Public Health, Center for Biostatistics in AIDS Research, Boston, MA.; Eunice Kennedy Shriver National Institute for Child Health and Human Development, National Institutes of Health, Bethesda, MD.; Department of Pediatrics, Texas Children's Hospital Baylor College of Medicine, Houston, TX.; Northwestern University's Feinberg School of Medicine, Chicago, IL.; Frontier Science and Technology Research Foundation, Amherst, NY.; Centre for Infectious Disease Research in Zambia, Lusaka, Zambia.; University of Alabama at Birmingham, Birmingham, AL.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)
BACKGROUND: CYP2B6 516 genotype-directed dosing improves efavirenz (EFV) exposures in HIV-infected children younger than 36 months, but such data are lacking in those with tuberculosis (TB) coinfection. METHODS: Phase I, 24-week safety and pharmacokinetic (PK) study of EFV in HIV-infected children aged 3 to <36 months, with or without TB. CYP2B6 516 genotype classified children into extensive metabolizers (516 TT/GT) and poor metabolizers [(PMs), 516 TT]. EFV doses were 25%-33% higher in children with HIV/TB coinfection targeting EFV area under the curve (AUC) 35-180 μg × h/mL, with individual dose adjustment as necessary. Safety and virologic evaluations were performed every 4-8 weeks. RESULTS: Fourteen children from 2 African countries and India with HIV/TB enrolled, with 11 aged 3 to <24 months and 3 aged 24-36 months, 12 extensive metabolizers and 2 PMs. Median (Q1, Q3) EFV AUC was 92.87 (40.95, 160.81) μg × h/mL in 8/9 evaluable children aged 3 to <24 months and 319.05 (172.56, 360.48) μg × h/mL in children aged 24-36 months. AUC targets were met in 6/8 and 2/5 of the younger and older age groups, respectively. EFV clearance was reduced in PM's and older children. Pharmacokinetic modeling predicted adequate EFV concentrations if children younger than 24 months received TB-uninfected dosing. All 9 completing 24 weeks achieved viral suppression. Five/14 discontinued treatment early: 1 neutropenia, 3 nonadherence, and 1 with excessive EFV AUC. CONCLUSIONS: Genotype-directed dosing safely achieved therapeutic EFV concentrations and virologic suppression in HIV/TB-coinfected children younger than 24 months, but further study is needed to confirm appropriate dosing in those aged 24-36 months. This approach is most important for young children and currently a critical unmet need in TB-endemic countries.
Impact of CYP2B6 genotype, tuberculosis therapy, and formulation on efavirenz pharmacokinetics in infants and children under 40 months of age.
(2022-Mar-15) Nikanjam M; Tran L; Chadwick EG; Bwakura-Dangarembizi M; Bolton Moore C; Samson P; Spector SA; Chakhtoura N; Jean-Philippe P; Frenkel L; Zimmer B; Benns A; Libous J; Capparelli EV; Maternal and Pediatric Infectious Disease Branch (MPIDB), Eunice Kennedy Shriver National Institute for Child Health and Human Development, National Institutes of Health.; Department of Paediatrics and Child Health, University of Zimbabwe College of Health Sciences, Harare, Zimbabwe.; Frontier Science and Technology Research Foundation, Amherst, New York.; Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina.; Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, California.; Department of Pediatrics, University of Washington, Seattle, Washington.; Department of Pediatrics, Northwestern University's Feinberg School of Medicine, Chicago, Illinois, USA.; Statistical and Data Management Center (SDMC) Harvard T.H. Chan School of Public Health, Center for Biostatistics in AIDS Research/Frontier Science Foundation, Boston, Massachusetts.; Division of AIDS, National Institutes of Allergy and Infectious Diseases, Bethesda, Maryland, USA.; Centre for Infectious Disease Research in Zambia, Lusaka, Zambia.; Centre for Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama.; IMPAACT Operations Center, FHI360, Durham, North Carolina, USA.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)
OBJECTIVE: Dosing efavirenz (EFV) in children less than 3 years of age is challenging due to large variability in drug levels. This study evaluated differences in pharmacokinetics with tuberculosis (TB) therapy, formulation, age, and CYP2B6 genotype. DESIGN: Pharmacokinetic data from three IMPAACT/PACTG studies (P382, P1021, and P1070) for children initiating therapy less than 40 months of age were evaluated. METHODS: Pharmacokinetic data were combined in a population pharmacokinetic model. Exposure from the 2-week pharmacokinetic visit was compared with changes in viral RNA between the Week 0 and Week 4 visits. RESULTS: The model included 103 participants (19 on TB therapy). CYP2B6 516 genotype information was available for 82 participants (TT: 15, GT: 28, GG: 39). Median age at the first pharmacokinetic visit was 17.0 months (range: 2.0-39.0 months). Liquid formulation led to a 42% decrease in bioavailability compared with opened capsules. TB therapy (isoniazid and rifampin) led to a 29% decreased clearance, however Monte Carlo simulations demonstrated the majority of participants on TB therapy receiving standard EFV dosing to be in the target area under the curve range. Clearance was 5.3-fold higher for GG than TT genotype and 3.3-fold higher for GT than TT genotype. Age did not have a significant effect on clearance in the final model. Initial viral RNA decay was lower for patients in the lowest quartile of exposures (area under the curves) than for higher quartiles (P = 0.013). CONCLUSION: EFV dosing should account for CYP2B6 516 genotype and formulation, but does not require adjustment for concurrent TB therapy.
The epidemiology of adolescents living with perinatally acquired HIV: A cross-region global cohort analysis.
(2018-Mar) Slogrove AL; Schomaker M; Davies MA; Williams P; Balkan S; Ben-Farhat J; Calles N; Chokephaibulkit K; Duff C; Eboua TF; Kekitiinwa-Rukyalekere A; Maxwell N; Pinto J; Seage G; Teasdale CA; Wanless S; Warszawski J; Wools-Kaloustian K; Yotebieng M; Timmerman V; Collins IJ; Goodall R; Smith C; Patel K; Paul M; Gibb D; Vreeman R; Abrams EJ; Hazra R; Van Dyke R; Bekker LG; Mofenson L; Vicari M; Essajee S; Penazzato M; Anabwani G; Q Mohapi E; N Kazembe P; Hlatshwayo M; Lumumba M; Goetghebuer T; Thorne C; Galli L; van Rossum A; Giaquinto C; Marczynska M; Marques L; Prata F; Ene L; Okhonskaia L; Rojo P; Fortuny C; Naver L; Rudin C; Le Coeur S; Volokha A; Rouzier V; Succi R; Sohn A; Kariminia A; Edmonds A; Lelo P; Ayaya S; Ongwen P; Jefferys LF; Phiri S; Mubiana-Mbewe M; Sawry S; Renner L; Sylla M; Abzug MJ; Levin M; Oleske J; Chernoff M; Traite S; Purswani M; Chadwick EG; Judd A; Leroy V; Bronx-Lebanon Hospital Center (Icahn School of Medicine at Mount Sinai), Bronx, New York, United States of America.; National Institute of Child Health and Human Development (NICHD), US National Institutes of Health, Rockville, Maryland, United States of America.; Institute of Child Health, University College London, London, United Kingdom.; UNICEF, New York, New York, United States of America.; Inserm (French Institute of Health and Medical Research), CESP UMR Villejuif, France.; School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil.; University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado, United States of America.; ICAP at Columbia University Mailman School of Public Health, New York, New York, United States of America.; Harvard T. H. Chan School of Public Health, Boston, Massachusetts, United States of America.; CHU Gabriel Touré, Bamako, Mali.; Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC, United States of America.; Feinberg School of Medicine, Northwestern University, Evanston, Illinois, United States of America.; University Children's Hospital, Basel, Switzerland.; MRC Clinical Trials Unit at University College London, London, United Kingdom.; Centro Hospitalar do Porto, Porto, Portugal.; Republican Hospital of Infectious Diseases, St Petersburg, Russian Federation.; Rutgers New Jersey Medical School, Newark, New Jersey, United States of America.; Tulane University, New Orleans, Louisiana, United States of America.; Medical University of Warsaw, Hospital of Infectious Diseases in Warsaw, Warsaw, Poland.; Karolinska University Hospital, Stockholm, Sweden.; Yopougon University Hospital, University Félix Houphouët-Boigny, Abidjan, Côte d'Ivoire.; Baylor International Pediatric AIDS Initiative, Kampala, Uganda.; Epicentre, Médecins Sans Frontières, Paris, France.; Indiana University School of Medicine, Indianapolis, Indiana, United States of America.; Center for Infectious Diseases Epidemiology and Research, University of Cape Town, Cape Town, South Africa.; College of Public Health, Ohio State University, Columbus, Ohio, United States of America.; Department of Health Sciences, University of Florence, Florence, Italy.; Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.; Lighthouse Trust Clinic, Lilongwe, Malawi.; World Health Organization, Geneva, Switzerland.; Inserm (French Institute of Health and Medical Research), UMR 1027 Université Toulouse 3, Toulouse, France.; Wits Reproductive Health and HIV Institute, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.; Shupyk National Medical Academy of Postgraduate Education, Kiev, Ukraine.; TREAT Asia/amfAR, Bangkok, Thailand.; Baylor International Pediatric AIDS Initiative, Mbeya, Tanzania.; Hospital Doce de Octubre, Madrid, Spain.; Hospital de Santa Maria/CHLN, Lisbon, Portugal.; Baylor International Pediatric AIDS Initiative, Lilongwe, Malawi.; Baylor International Pediatric AIDS Initiative, Texas Children's Hospital-USA, Houston, Texas, United States of America.; Baylor International Pediatric AIDS Initiative, Mbabane, Swaziland.; Universidade Federal de São Paulo, São Paulo, Brazil.; Pediatric Hospital Kalembe Lembe, Lingwala, Kinshasa, Democratic Republic of Congo.; Family AIDS Care and Education Services, Kenya Medical Research Institute, Kisumu, Kenya.; Academic Model Providing Access to Healthcare (AMPATH), Eldoret, Kenya.; International AIDS Society, Geneva, Switzerland.; Baylor International Pediatric AIDS Initiative, Maseru, Lesotho.; PENTA Foundation, Padova, Italy.; Center for Infectious Disease Research in Zambia, Lusaka, Zambia.; Hospital St Pierre Cohort, Bruxelles, Belgium.; Erasmus MC University Medical Center Rotterdam-Sophia Children's Hospital, Rotterdam, the Netherlands.; Institut National d'Etudes Démograhiques (Ined), F-75020 Paris, France.; Institut de Recherche pour le Développement (IRD) 174/PHPT, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand.; Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain.; SolidarMed Lesotho, Mozambique and Zimbabwe, Lucerne, Switzerland.; Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.; Harriet Shezi Children's Clinic, Chris Hani Baragwanath Hospital, Johannesburg, South Africa.; Desmond Tutu HIV Centre, University of Cape Town, Cape Town, South Africa.; GHESKIO Center, Port-au-Prince, Haiti.; Kirby Institute, UNSW, Sydney, Australia.; Victor Babes Hospital, Bucharest, Romania.; Baylor International Pediatric AIDS Initiative, Gaborone, Botswana.; University of Ghana School of Medicine and Dentistry, Accra, Ghana.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)
BACKGROUND: Globally, the population of adolescents living with perinatally acquired HIV (APHs) continues to expand. In this study, we pooled data from observational pediatric HIV cohorts and cohort networks, allowing comparisons of adolescents with perinatally acquired HIV in "real-life" settings across multiple regions. We describe the geographic and temporal characteristics and mortality outcomes of APHs across multiple regions, including South America and the Caribbean, North America, Europe, sub-Saharan Africa, and South and Southeast Asia. METHODS AND FINDINGS: Through the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER), individual retrospective longitudinal data from 12 cohort networks were pooled. All children infected with HIV who entered care before age 10 years, were not known to have horizontally acquired HIV, and were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017. Our primary analysis describes patient and treatment characteristics of APHs at key time points, including first HIV-associated clinic visit, antiretroviral therapy (ART) start, age 10 years, and last visit, and compares these characteristics by geographic region, country income group (CIG), and birth period. Our secondary analysis describes mortality, transfer out, and lost to follow-up (LTFU) as outcomes at age 15 years, using competing risk analysis. Among the 38,187 APHs included, 51% were female, 79% were from sub-Saharan Africa and 65% lived in low-income countries. APHs from 51 countries were included (Europe: 14 countries and 3,054 APHs; North America: 1 country and 1,032 APHs; South America and the Caribbean: 4 countries and 903 APHs; South and Southeast Asia: 7 countries and 2,902 APHs; sub-Saharan Africa, 25 countries and 30,296 APHs). Observation started as early as 1982 in Europe and 1996 in sub-Saharan Africa, and continued until at least 2014 in all regions. The median (interquartile range [IQR]) duration of adolescent follow-up was 3.1 (1.5-5.2) years for the total cohort and 6.4 (3.6-8.0) years in Europe, 3.7 (2.0-5.4) years in North America, 2.5 (1.2-4.4) years in South and Southeast Asia, 5.0 (2.7-7.5) years in South America and the Caribbean, and 2.1 (0.9-3.8) years in sub-Saharan Africa. Median (IQR) age at first visit differed substantially by region, ranging from 0.7 (0.3-2.1) years in North America to 7.1 (5.3-8.6) years in sub-Saharan Africa. The median age at ART start varied from 0.9 (0.4-2.6) years in North America to 7.9 (6.0-9.3) years in sub-Saharan Africa. The cumulative incidence estimates (95% confidence interval [CI]) at age 15 years for mortality, transfers out, and LTFU for all APHs were 2.6% (2.4%-2.8%), 15.6% (15.1%-16.0%), and 11.3% (10.9%-11.8%), respectively. Mortality was lowest in Europe (0.8% [0.5%-1.1%]) and highest in South America and the Caribbean (4.4% [3.1%-6.1%]). However, LTFU was lowest in South America and the Caribbean (4.8% [3.4%-6.7%]) and highest in sub-Saharan Africa (13.2% [12.6%-13.7%]). Study limitations include the high LTFU rate in sub-Saharan Africa, which could have affected the comparison of mortality across regions; inclusion of data only for APHs receiving ART from some countries; and unavailability of data from high-burden countries such as Nigeria. CONCLUSION: To our knowledge, our study represents the largest multiregional epidemiological analysis of APHs. Despite probable under-ascertained mortality, mortality in APHs remains substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe. Collaborations such as CIPHER enable us to monitor current global temporal trends in outcomes over time to inform appropriate policy responses.