title: 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.
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.).
authors.affiliation: EA7323, Pharmacology and Drugs Evaluation in Children and Pregnant Women, Université Paris Descartes Sorbonne Paris Cité, Paris, France frantz.foissac@aphp.fr.|Unité de Recherche Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Tarnier, Paris, France.|CIC-0901 INSERM, Cochin-Necker, Paris, France.
authors.forename: Frantz
authors.initials: F
authors.lastname: Foissac
authors.affiliation: Centre for International Health, University of Bergen, Bergen, Norway.|Effective Care Research Unit, University of Fort Hare, East London, South Africa.|School of Public Health, University of the Western Cape, South Africa.
authors.forename: Jörn
authors.initials: J
authors.lastname: Blume
authors.affiliation: EA7323, Pharmacology and Drugs Evaluation in Children and Pregnant Women, Université Paris Descartes Sorbonne Paris Cité, Paris, France.|Unité de Recherche Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Tarnier, Paris, France.|CIC-0901 INSERM, Cochin-Necker, Paris, France.|Service de Pharmacologie Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Université Paris Descartes Sorbonne Paris Cité, Paris, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Tréluyer
authors.affiliation: Centre for International Health, University of Bergen, Bergen, Norway.
authors.forename: Thorkild
authors.initials: T
authors.lastname: Tylleskär
authors.affiliation: University of Zambia, School of Medicine, Department of Pediatrics and Child Health, University Teaching Hospital, Lusaka, Zambia.
authors.forename: Chipepo
authors.initials: C
authors.lastname: Kankasa
authors.affiliation: Centre of International Research for Health, Faculty of Health Sciences, University of Ouagadougou, Ouagadougou, Burkina Faso.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Meda
authors.affiliation: Department of Pediatrics and Child Health, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda.
authors.forename: James K
authors.initials: JK
authors.lastname: Tumwine
authors.affiliation: Effective Care Research Unit, University of Fort Hare, East London, South Africa.|School of Public Health, University of the Western Cape, South Africa.
authors.forename: Mandisa
authors.initials: M
authors.lastname: Singata-Madliki
authors.affiliation: Department of Pediatrics, Frere Hospital and Walter Sisulu University, East London, South Africa.
authors.forename: Kim
authors.initials: K
authors.lastname: Harper
authors.affiliation: EA7323, Pharmacology and Drugs Evaluation in Children and Pregnant Women, Université Paris Descartes Sorbonne Paris Cité, Paris, France.|Service de Pharmacologie Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Université Paris Descartes Sorbonne Paris Cité, Paris, France.
authors.forename: Silvia M
authors.initials: SM
authors.lastname: Illamola
authors.affiliation: EA7323, Pharmacology and Drugs Evaluation in Children and Pregnant Women, Université Paris Descartes Sorbonne Paris Cité, Paris, France.|Unité de Recherche Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Tarnier, Paris, France.|CIC-0901 INSERM, Cochin-Necker, Paris, France.
authors.forename: Naïm
authors.initials: N
authors.lastname: Bouazza
authors.affiliation: CHU Montpellier and INSERM U1058, Montpellier, France.|Université Montpellier, Montpellier, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Nagot
authors.affiliation: CHU Montpellier and INSERM U1058, Montpellier, France.|Université Montpellier, Montpellier, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Van de Perre
authors.affiliation: EA7323, Pharmacology and Drugs Evaluation in Children and Pregnant Women, Université Paris Descartes Sorbonne Paris Cité, Paris, France.|Unité d'Immunologie-Hématologie Pédiatrique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Blanche
authors.affiliation: EA7323, Pharmacology and Drugs Evaluation in Children and Pregnant Women, Université Paris Descartes Sorbonne Paris Cité, Paris, France.|Unité de Recherche Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Tarnier, Paris, France.|CIC-0901 INSERM, Cochin-Necker, Paris, France.|Service de Pharmacologie Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Université Paris Descartes Sorbonne Paris Cité, Paris, France.
authors.forename: Déborah
authors.initials: D
authors.lastname: Hirt
mesh_terms: D019380:Anti-HIV Agents / Q000627:therapeutic use*; D001499:Bayes Theorem; D001942:Breast Feeding / Q000009:adverse effects*; D015658:HIV Infections / Q000517:prevention & control*; D006801:Humans; D007223:Infant; D018445:Infectious Disease Transmission, Vertical / Q000517:prevention & control*; D019259:Lamivudine / Q000627:therapeutic use*; D061466:Lopinavir / Q000627:therapeutic use*; D009035:Mothers; D019438:Ritonavir / Q000627:therapeutic use*
chemical_list: D019380:Anti-HIV Agents; D061466:Lopinavir; D019259:Lamivudine; D019438:Ritonavir
keywords: breastfeeding; pharmacokinetics; preexposure prophylaxis