Virologic Response to Potent Antiretroviral Therapy and Modeling of HIV Dynamics in Early Pediatric Infection
1Department of Pediatrics, University of Medicine and Dentistry–New Jersey Medical School, Newark, New Jersey; 2Statistical and Data Analysis Center, Harvard School of Public Health, Boston, and 3Department of Pediatrics, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts; 4Children’s Memorial Hospital, Northwestern University, Chicago, Illinois; 5St. Jude Children’s Research Hospital, Memphis, Tennessee
Background.
Human immunodeficiency virus (HIV) infection in infancy features a persistently high viral load and elevated antiretroviral drug clearance rates, which pose significant therapeutic challenges to the clinician. Viral and cellular kinetic analyses performed in HIV‐infected adults have yielded significant insights into the dynamic setting of this viral infection. Similar studies are needed in pediatric populations, in whom differing dynamics might translate into age‐specific treatment approaches.
Methods.Viral and cellular kinetic analyses were performed using a nonlinear mixed‐effects model in a cohort of 48 infants 1–24 months of age enrolled in a trial of ritonavir‐based highly active antiretroviral therapy (HAART).
Results.Infected cell compartment kinetics were comparable with reported adult values, with no age‐specific differences demonstrated—suggesting the ability to suppress viral replication in infants receiving HAART. Comparisons between 2 ritonavir dosing schedules revealed significant improvement in phase 1/2 decay constants in favor of the higher dose. A negative correlation was established between plasma RNA levels and phase 1 decay rates, which has worrisome implications for infant therapeutics given high infant pretreatment plasma virus levels.
Conclusions.Ritonavir‐based HAART regimens in infancy result in HIV decay constants comparable to those reported in adults, without age‐specific variability. Despite higher plasma HIV levels and CD4 lymphocyte counts in infancy, HAART can result in timely, effective control of viral replication.
Received 13 January 2006; accepted 29 January 2006; electronically published 24 May 2007.
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Online publication date: 1-Jun-2009.
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Online publication date: 1-Feb-2009.
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Potential conflicts of interest: E.C. has received grant support from GlaxoSmithKline and Abbott Laboratories, participates on the speakers' bureau for Abbott, and is a shareholder in Abbott. All other authors report no potential conflicts of interest.
Financial support: Public Health Service (grants UO1 AI25883, AI055290, AI38855, and AI41110).
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Present affiliations: Section of Infectious Diseases and International Health, Dartmouth‐Hitchcock Medical Center and Dartmouth Medical School, Lebanon, New Hampshire (P.P.); Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, New York (H.W.).
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Deceased. We dedicate this article to the memory of our long‐standing colleague and team member, John Rodman.
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Study group members are listed after the text.