Lopinavir-Ritonavir Impairs Adrenal Function in Infants

Dulanjalee Kariyawasam; Marianne Peries; Frantz Foissac; Sabrina Eymard-Duvernay; Thorkild Tylleskär; Mandisa Singata-Madliki; Chipepo Kankasa; Nicolas Meda; James Tumwine; Mwiya Mwiya; Ingunn Engebretsen; Christa E Flück; Michaela F Hartmann; Stefan A Wudy; Deborah Hirt; Jean Marc Treluyer; Jean-Pierre Molès; Stéphane Blanche; Philippe Van De Perre; Michel Polak; Nicolas Nagot; ANRS 12174 Trial Group

doi:10.1093/cid/ciz888

Lopinavir-Ritonavir Impairs Adrenal Function in Infants

Clin Infect Dis. 2020 Aug 14;71(4):1030-1039. doi: 10.1093/cid/ciz888.

Authors

Dulanjalee Kariyawasam^{1

2

3}, Marianne Peries⁴, Frantz Foissac^{5

6}, Sabrina Eymard-Duvernay⁴, Thorkild Tylleskär⁷, Mandisa Singata-Madliki⁸, Chipepo Kankasa⁹, Nicolas Meda¹⁰, James Tumwine¹¹, Mwiya Mwiya⁹, Ingunn Engebretsen⁷, Christa E Flück¹², Michaela F Hartmann¹³, Stefan A Wudy¹³, Deborah Hirt^{5

6}, Jean Marc Treluyer^{5

6}, Jean-Pierre Molès⁴, Stéphane Blanche¹⁴, Philippe Van De Perre^{5

15}, Michel Polak^{1

2

3}, Nicolas Nagot^{4

15}; ANRS 12174 Trial Group

Collaborators

ANRS 12174 Trial Group:
N Nagot, R Vallo, V Marechal, D Neveu, M Peries, P Van de Perre, C Kankasa, M Mwiya, C Siuluta, D Rutagwera, J K Tumwine, M Kwagala, G Ndeezi, N Meda, H Traore, E Some, D Neboua, G J Hofmeyr, A Sunday, M Singata, G J Hofmeyr, A Sunday, D Jackson, I M S Engebretsen, H Sommerfelt, T Tylleskar, C Lombard, S Blanche, H Sommerfelt, C Rekacewicz

Affiliations

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.

PMID: 31633158
DOI: 10.1093/cid/ciz888

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.

Keywords: CYP21 and CYP17 inhibition; HIV infant prophylaxis; adrenal function impairment; lopinavir.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-HIV Agents* / adverse effects
Burkina Faso
Child
Female
HIV Infections* / drug therapy
Humans
Infant
Lopinavir / therapeutic use
Pregnancy
Ritonavir / adverse effects
South Africa
Steroid 21-Hydroxylase

Substances

Anti-HIV Agents
Lopinavir
CYP21A2 protein, human
Steroid 21-Hydroxylase
Ritonavir

Associated data

ClinicalTrials.gov/NCT00640263