Lopinavir-Ritonavir Impairs Adrenal Function in Infants-Reference-Cited by-同舟云学术

Lopinavir-Ritonavir Impairs Adrenal Function in Infants

Published:2019-10-21 Issue:4 Volume:71 Page:1030-1039
ISSN:1058-4838
Container-title:Clinical Infectious Diseases
language:en
Short-container-title:

Author:

Kariyawasam Dulanjalee¹²³,Peries Marianne⁴,Foissac Frantz⁵⁶,Eymard-Duvernay Sabrina⁴,Tylleskär Thorkild⁷,Singata-Madliki Mandisa⁸,Kankasa Chipepo⁹,Meda Nicolas¹⁰,Tumwine James¹¹,Mwiya Mwiya⁹,Engebretsen Ingunn⁷,Flück Christa E¹²,Hartmann Michaela F¹³,Wudy Stefan A¹³,Hirt Deborah⁵⁶,Treluyer Jean Marc⁵⁶,Molès Jean-Pierre⁴,Blanche Stéphane¹⁴,Van De Perre Philippe⁵¹⁵,Polak Michel¹²³,Nagot Nicolas⁴¹⁵,Nagot N,Vallo R,Marechal V,Neveu D,Peries M,Van de Perre P,Kankasa C,Mwiya M,Siuluta C,Rutagwera D,Tumwine J K,Kwagala M,Ndeezi G,Meda N,Traore H,Some E,Neboua D,Hofmeyr G J,Sunday A,Singata M,Hofmeyr G J,Sunday A,Jackson D,Engebretsen I M S,Sommerfelt H,Tylleskar T,Lombard C,Blanche S,Sommerfelt H,Rekacewicz C,

Affiliation:

1. Pediatric Endocrinology, Gynecology, and Diabetology Unit, Hopital Universitaire Necker-Enfants Malades, Assistance Publique-Hopitaux de Paris (AP-HP), Paris, France

2. INSERM U1016, Faculte de Medecine, Universite Paris Descartes, Sorbonne Paris Cite, Paris, France

3. IMAGINE Institute, Paris, France

4. Pathogenesis and Control of Chronic Infections, INSERM U1058, Universite de Montpellier, Etablissement Francais du Sang, Montpellier, France

5. Service de Pharmacologie Clinique, Hopital Cochin, AP-HP, Groupe Hospitalier Paris Centre, France

6. Universite Paris Descartes, EA7323, Sorbonne Paris Cite, France

7. Centre for International Health, University of Bergen, Bergen, Norway

8. Effective Care Research Unit, University of Fort Hare, Cecilia Makiwane Hospital, East London, South Africa

9. University of Zambia, School of Medicine, Department of Pediatrics and Child Health, University Teaching Hospital, Lusaka, Zambia

10. Center 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. Pediatric Endocrinology, Diabetology, and Metabolism, Department of Pediatrics and Department of BioMedical Research, University Hospital Inselspital Bern, University of Bern, Bern, Switzerland

13. Steroid Research and Mass Spectrometry Unit, Division of Pediatric Endocrinology and Diabetology, Center of Child and Adolescent Medicine, Justus-Liebig-University, Giessen, Germany

14. Pediatric Immunology-Hematology and Rheumatology Unit, Hopital Universitaire Necker-Enfants Malades, AP-HP, Paris, France

15. Centre Hospitalo-Universitaire (CHU) de Montpellier, Montpellier, France

Abstract

Abstract Background Perinatal treatment with lopinavir boosted by ritonavir (LPV/r) is associated with steroidogenic abnormalities. Long-term effects in infants have not been studied. Methods Adrenal-hormone profiles were compared at weeks 6 and 26 between human immunodeficiency virus (HIV)-1–exposed but uninfected infants randomly assigned at 7 days of life to prophylaxis with LPV/r or lamivudine (3TC) to prevent transmission during breastfeeding. LPV/r in vitro effect on steroidogenesis was assessed in H295R cells. Results At week 6, 159 frozen plasma samples from Burkina Faso and South Africa were assessed (LPV/r group: n = 92; 3TC group: n = 67) and at week 26, 95 samples from Burkina Faso (LPV/r group: n = 47; 3TC group: n = 48). At week 6, LPV/r-treated infants had a higher median dehydroepiandrosterone (DHEA) level than infants from the 3TC arm: 3.91 versus 1.48 ng/mL (P < .001). Higher DHEA levels (>5 ng/mL) at week 6 were associated with higher 17-OH-pregnenolone (7.78 vs 3.71 ng/mL, P = .0004) and lower testosterone (0.05 vs 1.34 ng/mL, P = .009) levels in LPV/r-exposed children. There was a significant correlation between the DHEA and LPV/r AUC levels (ρ = 0.40, P = .019) and Ctrough (ρ = 0.40, P = .017). At week 26, DHEA levels remained higher in the LPV/r arm: 0.45 versus 0.13 ng/mL (P = .002). Lopinavir, but not ritonavir, inhibited CYP17A1 and CYP21A2 activity in H295R cells. Conclusions Lopinavir was associated with dose-dependent adrenal dysfunction in infants. The impact of long-term exposure and potential clinical consequences require evaluation. Clinical Trials Registration NCT00640263

Funder

French National Institute of Health and Medical Research–National Agency for Research on AIDS and Viral Hepatitis

Research Council of Norway

Publisher

Oxford University Press (OUP)

Subject

Infectious Diseases,Microbiology (medical)

Link

http://academic.oup.com/cid/advance-article-pdf/doi/10.1093/cid/ciz888/30665886/ciz888.pdf

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