Lopinavir-Ritonavir Impairs Adrenal Function in Infants

• Published in: Clinical infectious diseases Vol. 71; no. 4; pp. 1030 - 1039
• Main Authors: Kariyawasam, Dulanjalee, Peries, Marianne, Foissac, Frantz, Eymard-Duvernay, Sabrina, Tylleskär, Thorkild, Singata-Madliki, Mandisa, Kankasa, Chipepo, Meda, Nicolas, Tumwine, James, Mwiya, Mwiya, Engebretsen, Ingunn, Flück, Christa E, Hartmann, Michaela F, Wudy, Stefan A, Hirt, Deborah, Treluyer, Jean Marc, Molès, Jean-Pierre, Blanche, Stéphane, Van De Perre, Philippe, Polak, Michel, Nagot, Nicolas
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 14.08.2020; Oxford University Press (OUP)
• Subjects: Anti-HIV Agents - adverse effects; Burkina Faso; Child; Female; HIV Infections - drug therapy; Humans; Infant; Life Sciences; Lopinavir - therapeutic use; Pregnancy; Ritonavir - adverse effects; South Africa; Steroid 21-Hydroxylase; South Africa; Burkina Faso; adrenal function impairment; CYP21 and CYP17 inhibition; HIV infant prophylaxis; lopinavir
• ISSN: 1058-4838; 1537-6591
• 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 Giving lopinavir to infants during their first year of life induces early, asymptomatic adrenal disruption compatible with the combined inhibition of CYP 21 and CYP 17 enzymes. The impact of prolonged treatment on the adrenal glands may require further attention.