Pharmacokinetics and Safety of Zidovudine, Lamivudine, and Lopinavir/Ritonavir in HIV-infected Children With Severe Acute Malnutrition in Sub-Saharan Africa: IMPAACT Protocol P1092
Year: 2021
Type: article
Abstract: BACKGROUND: Severe acute malnutrition (SAM) may alter the pharmacokinetics (PK), efficacy, and safety of antiretroviral therapy. The phase IV study, IMPAACT P1092, compared PK, safety, and tolerability of zidovudine (ZDV), lamivudine (3TC), and lopinavir/ritonavir (LPV/r) in children with and without SAM. MATERIALS AND METHODS: Children living with HIV 6 to <36 months of age with or without World Health Organization (WHO)-defined SAM received ZDV, 3TC, and LPV/r syrup for 48 weeks according to WHO weight band dosing. Intensive PK sampling was performed at weeks 1, 12, and 24. Plasma drug concentrations were measured using liquid chromatography tandem mass spectrometry. Steady-state mean area under the curve (AUC0-12h) and clearance (CL/F) for each drug were compared. Grade ≥3 adverse events were compared between cohorts. RESULTS: Fifty-two children were enrolled across 5 sites in Africa with 44% (23/52) female, median age 19 months (Q1, Q3: 13, 25). Twenty-five children had SAM with entry median weight-for-height Z-score (WHZ) -3.4 (IQR -4.0, -3.0) and 27 non-SAM had median WHZ -1.0 (IQR -1.8, -0.1). No significant differences in mean AUC0-12h or CL/F were observed (P ≥ 0.09) except for lower 3TC AUC0-12h (GMR, 0.60; 95% CI, 0.4-1.0; P = 0.047) at week 12, higher ZDV AUC0-12h (GMR, 1.52; 1.2-2.0; P = 0.003) at week 24 in the SAM cohort compared with non-SAM cohort. Treatment-related grade ≥3 events did not differ significantly between cohorts (24.0% vs. 25.9%). CONCLUSION: PK and safety findings for ZDV, 3TC, and LPV/r support current WHO weight band dosing of syrup formulations in children with SAM.
Authors: Maxensia Owor, Camlin Tierney, Lauren Ziemba, Renee Browning, John Moye, Bobbie Graham, Christina Reding, Diane Costello, Jennifer Norman, Lubbe Wiesner, Emma Hughes, Meghan E. Whalen, Lynette Purdue, Blandina Theophil Mmbaga, Portia Kamthunzi, Rachel Kawalazira, Kusum Nathoo, Sarah Bradford, Anne Coletti, Francesca. Aweeka, Philippa Musoke
Institutions: MUJHU Research Collaboration, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Frontier Science & Technology Research Foundation, Inc., University of California, Los Angeles, University of Cape Town, University of California, San Francisco, Kilimanjaro Christian Medical Centre, Kilimanjaro Clinical Research Institute, Johns Hopkins University, University of Zimbabwe, Family Health International 360, Makerere University
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Awards: G1220961632, G32641939, SDMC - IMPAACT Leadership Group, International Maternal, Adolescent and Pediatric Therapeutics Clinical Trials Network, The Johns Hopkins University-Blantyre Clinical Trials Unit, University of North Carolina Global HIV Prevention and Treatment Clinical Trials Unit, UCSF-Bay Area Center for AIDS Research, The Johns Hopkins University - Uganda Clinical Trials Unit, IMPAACT Leadership Group
OpenAlex ID: W3122800558