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Antimicrob Agents Chemother. 2017 Jan 24;61(2). pii: e01869-16. doi: 10.1128/AAC.01869-16. Print 2017 Feb.

Are Prophylactic and Therapeutic Target Concentrations Different?: the Case of Lopinavir-Ritonavir or Lamivudine Administered to Infants for Prevention of Mother-to-Child HIV-1 Transmission during Breastfeeding.

Author information

1
EA7323, Pharmacology and Drugs Evaluation in Children and Pregnant Women, Université Paris Descartes Sorbonne Paris Cité, Paris, France frantz.foissac@aphp.fr.
2
Unité de Recherche Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Tarnier, Paris, France.
3
CIC-0901 INSERM, Cochin-Necker, Paris, France.
4
Centre for International Health, University of Bergen, Bergen, Norway.
5
Effective Care Research Unit, University of Fort Hare, East London, South Africa.
6
School of Public Health, University of the Western Cape, South Africa.
7
EA7323, Pharmacology and Drugs Evaluation in Children and Pregnant Women, Université Paris Descartes Sorbonne Paris Cité, Paris, France.
8
Service de Pharmacologie Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Université Paris Descartes Sorbonne Paris Cité, Paris, France.
9
University of Zambia, School of Medicine, Department of Pediatrics and Child Health, University Teaching Hospital, Lusaka, Zambia.
10
Centre of International Research for Health, Faculty of Health Sciences, University of Ouagadougou, Ouagadougou, Burkina Faso.
11
Department of Pediatrics and Child Health, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda.
12
Department of Pediatrics, Frere Hospital and Walter Sisulu University, East London, South Africa.
13
CHU Montpellier and INSERM U1058, Montpellier, France.
14
Université Montpellier, Montpellier, France.
15
Unité d'Immunologie-Hématologie Pédiatrique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France.

Abstract

The ANRS 12174 trial assessed the efficacy and tolerance of lopinavir (LPV)-ritonavir (LPV/r) prophylaxis versus those of lamivudine (3TC) prophylaxis administered to breastfed infants whose HIV-infected mothers were not on antiretroviral therapy. In this substudy, we assessed LPV/r and 3TC pharmacokinetics to evaluate the percentage of infants with therapeutic plasma concentrations and to discuss these data in the context of a prophylactic treatment. Infants from the South African trial site underwent blood sampling for pharmacokinetic study at weeks 6, 26, and 38 of life. We applied a Bayesian approach to derive the 3TC and LPV pharmacokinetic parameters on the basis of previously published pharmacokinetic models for HIV-infected children. We analyzed 114 LPV and 180 3TC plasma concentrations from 69 infants and 92 infants, respectively. A total of 30 LPV and 20 3TC observations were considered missing doses and discarded from the Bayesian analysis. The overall population analysis showed that 30 to 40% of the infants did not reach therapeutic targets, regardless of treatment group. The median LPV trough concentrations at weeks 6, 26, and 38 were 2.8 mg/liter (interquartile range [IQR], 1.7 to 4.4 mg/liter), 5.6 mg/liter (IQR, 3.2 to 7.7 mg/liter), and 3.4 mg/liter (IQR, 2.3 to 7.3 mg/liter), respectively. The median 3TC area under the curve from 0 to 12 h after the last drug intake were 5.6 mg · h/liter (IQR, 4.1 to 7.8 mg · h/liter), 5.9 mg · h/liter (IQR, 5.1 to 7.5 mg · h/liter), and 7.3 mg · h/liter (IQR, 4.9 to 8.5 mg · h/liter) at weeks 6, 26, and 38, respectively. Use of the therapeutic doses recommended by the WHO would have resulted in a higher proportion of infants achieving the targets. However, no HIV-1 infection was reported among these infants. These results suggest that the prophylactic targets for both 3TC and LPV may be lower than the therapeutic ones. For treatment, the WHO dosing guidelines should be suitable to maintain values above the therapeutic pharmacokinetic targets in most infants. (This study has been registered at ClinicalTrials.gov under identifier NCT00640263.).

KEYWORDS:

breastfeeding; pharmacokinetics; preexposure prophylaxis

PMID:
27895016
PMCID:
PMC5278704
DOI:
10.1128/AAC.01869-16
[Indexed for MEDLINE]
Free PMC Article

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