ESPE Abstracts (2016) 86 RFC1.8

Adrenal Dysfunction in HIV-Exposed Uninfected Infants Receiving Ritonavir-Boosted Lopinavir, an HIV Protease Inhibitor, for the Prevention of Breastfeeding HIV Transmission. An ANRS 12174 Substudy

Michel Polaka,b, Stefan Wudyc,d, Nicolas Medae,f, Michaela Hartmannc,d, Chipepo Kankasag,h, James Tumwinen,o, Kathleen Labordea,b, Justus Hofmeyri, Roselyne Vallol,m, Nicolas Nagotl,m, Thorkild Tylleskärj,k, Philippe Van de Perrel,m & Stéphane Blanchea,b

aHôpital Universitaire Necker Enfants Malades, Paris, France; bUniversité Paris Descartes, Paris, France; cCenter of Child and Adolescent Medicine, Giessen, Germany; dJustus Liebig University, Giessen, Germany; eCenter of International Research for Health, Ouagadougou, Burkina Faso; fUniversity of Ouagadougou, Ouagadougou, Burkina Faso; gUniversity Teaching Hospital, Lusaka, Zambia; hUniversity of Zambia, School of medicine, Lusaka, Zambia; iCecilia Makiwane Hospital, East London Hospital Complex, East London, South Africa; jCenter for International Health, Bergen, Norway; kUniversity of Bergen, Bergen, Norway; lINSERM U1058, Montpellier, France; mUniversité Montpellier, Montpellier, France; nSchool of Medicine, College of Health Sciences, Kampala, Uganda; oMakerere University, Kampala, Uganda

Background: We recently demonstrated that both ritonavir-boosted lopinavir (LPV/r) and lamivudine (3TC, a nucleoside analogue) given to breastfed infants can reduce the risk of post natal HIV transmission (ANRS 12174 trial; Nagot, Lancet 2016). In another setting we previously showed the occurrence of adrenal dysfunction in newborn perinatally exposed to LPV/r leading to acute adrenal insufficiency in premature babies (Simon, JAMA 2011).

Objective and hypotheses: Within the ANRS 12174 trial, the administration, randomly assigned, of LPV/r as a monotherapy prophylaxis up to one year in exposed uninfected infants, as compared to 3TC, offered a unique opportunity to study the potential adrenal impact of LPV/r in infants.

Method: According to protocol and ethical authorizations, frozen serum samples collected at Week 6 (W6) and Week 26 (W26) from infants enrolled in Burkina Faso were blindly analyzed using steroid profiling by GC-MS.

Results: 96 infants (LPV/r: 49, 3TC: 47) samples were analyzed. A marked increase of dehydroepiandrosterone (DHEA) was observed in LPV/r exposed infants as compared to 3TC (median (IQR)): 3.0 (1.6–4.8) vs 1.4 (0.5–3.5) at W6 and 0.4 (0.0–0.8) vs 0.1 (0.0–0.3) ng/ml at W26 respectively, both P<0.001). In infants with high DHEA level at W6 (> 5 ng/ml (n=11)), other adrenal hormones were also significantly increased as compared with 38 with DHEA<5).

Conclusion: In comparison with lamivudine, LPV/r exposure during the first year of life is associated with a significant, early adrenal dysfunction sustained during exposure. This effect may result from the interactions between LPV/r and the immature infant’s adrenal and/or an increased ACTH like effect. Further analyses on samples collected after LPV/r discontinuation are pending. There was no difference in severe adverse events incidence between the two treatment groups in the entire cohort (n=1236), but subtle impact on growth and genital development are actively monitored.