Ritonavir-based highly active antiretroviral therapy in human immunodeficiency virus type 1-infected infants younger than 24 months of age.
BACKGROUND
Few data are available regarding clinical outcomes or dosing requirements for the protease inhibitor ritonavir in human immunodeficiency virus (HIV)-infected children younger than under 24 months of age.


METHODS
This prospective, multicenter phase I/II open label treatment trial used ritonavir, zidovudine and lamivudine to treat protease inhibitor-naive, HIV-infected infants between the ages of 4 weeks and 24 months. Two sequential dosing cohorts were treated with 350 or 450 mg/m(2) ritonavir every 12 hours; this report includes results of pharmacokinetics, safety, tolerability and efficacy through 104 weeks of follow-up of all subjects.


RESULTS
Fifty HIV-infected children were treated. By week 16, 36 had achieved HIV-1 RNA <400 copies/mL (72% intent-to-treat, 84% as-treated analysis); by week 104, 18 maintained durable viral suppression (36% intent-to-treat, 46% as-treated). Poor medication adherence by caregiver report contributed to virologic failure. Few subjects experienced treatment-limiting toxicity: emesis or ritonavir refusal in 6 (12%); and severe but reversible anemia or elevated serum hepatic transaminases in 1 (4%) each. Apparent oral clearance was higher and the median predose concentrations were substantially lower than those found in adults. Median z scores for weight and height for age/gender were below normal at baseline but improved by week 104.


CONCLUSIONS
A combination regimen of ritonavir, zidovudine and lamivudine was generally safe and produced sustained viral suppression in more than one-third of infants who initiated therapy before 2 years of age. Improved palatability of liquid preparations of protease inhibitors, supporting infrastructure and behavioral approaches to improve medication adherence with antiretrovirals will likely be necessary to further improve efficacy.
Chadwick
Ellen Gould
EG
Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. egchadwick@childrensmemorial.org
Rodman
John H
JH
Britto
Paula
P
Powell
Christine
C
Palumbo
Paul
P
Luzuriaga
Katherine
K
Hughes
Michael
M
Abrams
Elaine J
EJ
Flynn
Patricia M
PM
Borkowsky
William
W
Yogev
Ram
R
D000367:Age Factors; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects / Q000379:methods*; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D015658:HIV Infections / Q000151:congenital* / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D019259:Lamivudine / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D020714:Maximum Tolerated Dose; D011446:Prospective Studies; D018570:Risk Assessment; D019438:Ritonavir / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D012720:Severity of Illness Index; D016037:Single-Blind Method; D015996:Survival Rate; D016896:Treatment Outcome; D015215:Zidovudine / Q000008:administration & dosage / Q000493:pharmacokinetics
D019259:Lamivudine; D015215:Zidovudine; D019438:Ritonavir