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A Phase II/III Trial of Lopinavir/Ritonavir Dosed According to the WHO Pediatric Weight Band Dosing Guidelines

Pinto, Jorge A. MD, DSc*; Capparelli, Edmund V. PharmD†‡; Warshaw, Meredith MSS, MA§; Zimmer, Bonnie MS; Cressey, Tim R. PhD§‖**; Spector, Stephen A. MD†‡; Qin, Min PhD§; Smith, Betsy MD††; Siberry, George K. MD‡‡; Mirochnick, Mark MD§§for the IMPAACT P1083 Team

The Pediatric Infectious Disease Journal: February 2018 - Volume 37 - Issue 2 - p e29–e35
doi: 10.1097/INF.0000000000001817
HIV Reports

Background: The World Health Organization (WHO) recommends weight band dosing of antiretrovirals for children. Data are limited describing drug exposure/safety of lopinavir/ritonavir using WHO weight band dosing.

Methods: International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1083 was a phase II/III trial assessing the pharmacokinetics (PK) and short-term safety, tolerance and efficacy of lopinavir/ritonavir in human immunodeficiency virus–infected children 3–25 kg dosed according to WHO weight bands, with liquid solution or meltrex extrusion tablets. The main PK target was an area under the curve (AUC0–24) of 80–320 μg·h/mL.

Results: Of 97 enrolled participants, median age 2.5 years, 89 (91.8%) completed the protocol. Median LPV dose was 303 mg/m2. The geometric mean (90% confidence limits) LPV PK AUC0–24 was 196 (177–217) μg·h/mL and C min was 2.47 (1.52–4.02) μg/mL. AUC0–24 was within the target range for 79% of participants. The median (Q1, Q3) difference between individual observed PK parameters and those expected if Food and Drug Administration dosing guidelines were followed was 30.7 (7.9, 54.3) for AUC0–24 and 0.56 (0, 1.27) for C min. Ten (10%) participants had grade 3 or 4 events deemed related to study treatment, mostly asymptomatic laboratory abnormalities. Three participants died of unrelated study treatment causes. At week 24, 57 of 79 (72%) participants reached viral suppression and the median increase in CD4% (n = 83) was 6.0 (P < 0.0001).

Conclusions: WHO weight band dosing guidelines in children achieved adequate LPV plasma exposure but was higher than that expected with Food and Drug Administration dosing guidelines. Despite the higher LPV exposure, the treatment was well tolerated and the 24-week efficacy data were favorable.

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From the *Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; University of California, San Diego, California; Rady Children’s Hospital San Diego, San Diego, California; §Harvard TH Chan School of Public Health, Boston, Massachusetts; Frontier Science & Technology Research Foundation, Buffalo, New York; Program for HIV Prevention and Treatment (PHPT/IRD UMI174), Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand; **Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom; ††National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland; ‡‡Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland; and §§Boston University School of Medicine, Boston, Massachusetts.

Accepted for publication September 16, 2017.

Presented in part at the Conference on Retrovirus and Opportunistic Infections (CROI); February 2013; Boston, MA.

Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under Award Numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC) and UM1AI106716 (IMPAACT LC), with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

The authors have no conflicts of interest to disclose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (

Address for correspondence: Jorge A. Pinto, MD, DSc, Department of Pediatrics, Faculdade de Medicina, Universidade Federal de Minas Gerais, Av. Alfredo Balena 190, Room # 161, Belo Horizonte, MG 30130-100, Brazil. E-mail:

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