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Pharmacology

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

Frantz Foissac, Jörn Blume, Jean-Marc Tréluyer, Thorkild Tylleskär, Chipepo Kankasa, Nicolas Meda, James K. Tumwine, Mandisa Singata-Madliki, Kim Harper, Silvia M. Illamola, Naïm Bouazza, Nicolas Nagot, Philippe Van de Perre, Stéphane Blanche, Déborah Hirt
Frantz Foissac
aEA7323, Pharmacology and Drugs Evaluation in Children and Pregnant Women, Université Paris Descartes Sorbonne Paris Cité, Paris, France
bUnité de Recherche Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Tarnier, Paris, France
cCIC-0901 INSERM, Cochin-Necker, Paris, France
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Jörn Blume
dCentre for International Health, University of Bergen, Bergen, Norway
eEffective Care Research Unit, University of Fort Hare, East London, South Africa
fSchool of Public Health, University of the Western Cape, South Africa
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Jean-Marc Tréluyer
aEA7323, Pharmacology and Drugs Evaluation in Children and Pregnant Women, Université Paris Descartes Sorbonne Paris Cité, Paris, France
bUnité de Recherche Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Tarnier, Paris, France
cCIC-0901 INSERM, Cochin-Necker, Paris, France
gService de Pharmacologie Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Université Paris Descartes Sorbonne Paris Cité, Paris, France
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Thorkild Tylleskär
dCentre for International Health, University of Bergen, Bergen, Norway
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Chipepo Kankasa
hUniversity of Zambia, School of Medicine, Department of Pediatrics and Child Health, University Teaching Hospital, Lusaka, Zambia
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Nicolas Meda
iCentre of International Research for Health, Faculty of Health Sciences, University of Ouagadougou, Ouagadougou, Burkina Faso
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James K. Tumwine
jDepartment of Pediatrics and Child Health, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda
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Mandisa Singata-Madliki
eEffective Care Research Unit, University of Fort Hare, East London, South Africa
fSchool of Public Health, University of the Western Cape, South Africa
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Kim Harper
kDepartment of Pediatrics, Frere Hospital and Walter Sisulu University, East London, South Africa
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Silvia M. Illamola
aEA7323, Pharmacology and Drugs Evaluation in Children and Pregnant Women, Université Paris Descartes Sorbonne Paris Cité, Paris, France
gService de Pharmacologie Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Université Paris Descartes Sorbonne Paris Cité, Paris, France
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Naïm Bouazza
aEA7323, Pharmacology and Drugs Evaluation in Children and Pregnant Women, Université Paris Descartes Sorbonne Paris Cité, Paris, France
bUnité de Recherche Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Tarnier, Paris, France
cCIC-0901 INSERM, Cochin-Necker, Paris, France
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Nicolas Nagot
lCHU Montpellier and INSERM U1058, Montpellier, France
mUniversité Montpellier, Montpellier, France
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Philippe Van de Perre
lCHU Montpellier and INSERM U1058, Montpellier, France
mUniversité Montpellier, Montpellier, France
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Stéphane Blanche
aEA7323, Pharmacology and Drugs Evaluation in Children and Pregnant Women, Université Paris Descartes Sorbonne Paris Cité, Paris, France
nUnité d'Immunologie-Hématologie Pédiatrique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France
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Déborah Hirt
aEA7323, Pharmacology and Drugs Evaluation in Children and Pregnant Women, Université Paris Descartes Sorbonne Paris Cité, Paris, France
bUnité de Recherche Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Tarnier, Paris, France
cCIC-0901 INSERM, Cochin-Necker, Paris, France
gService de Pharmacologie Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Université Paris Descartes Sorbonne Paris Cité, Paris, France
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DOI: 10.1128/AAC.01869-16
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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.)

FOOTNOTES

    • Received 26 August 2016.
    • Returned for modification 1 October 2016.
    • Accepted 18 November 2016.
    • Accepted manuscript posted online 28 November 2016.
  • Supplemental material for this article may be found at https://doi.org/10.1128/AAC.01869-16 .

  • Copyright © 2017 American Society for Microbiology.

All Rights Reserved .

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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
Frantz Foissac, Jörn Blume, Jean-Marc Tréluyer, Thorkild Tylleskär, Chipepo Kankasa, Nicolas Meda, James K. Tumwine, Mandisa Singata-Madliki, Kim Harper, Silvia M. Illamola, Naïm Bouazza, Nicolas Nagot, Philippe Van de Perre, Stéphane Blanche, Déborah Hirt for the ANRS 12174 Trial Group
Antimicrobial Agents and Chemotherapy Jan 2017, 61 (2) e01869-16; DOI: 10.1128/AAC.01869-16

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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
Frantz Foissac, Jörn Blume, Jean-Marc Tréluyer, Thorkild Tylleskär, Chipepo Kankasa, Nicolas Meda, James K. Tumwine, Mandisa Singata-Madliki, Kim Harper, Silvia M. Illamola, Naïm Bouazza, Nicolas Nagot, Philippe Van de Perre, Stéphane Blanche, Déborah Hirt for the ANRS 12174 Trial Group
Antimicrobial Agents and Chemotherapy Jan 2017, 61 (2) e01869-16; DOI: 10.1128/AAC.01869-16
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KEYWORDS

Anti-HIV Agents
Breast Feeding
HIV infections
Infectious Disease Transmission, Vertical
Lamivudine
lopinavir
ritonavir
breastfeeding
pharmacokinetics
preexposure prophylaxis

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