Adrenal Enzyme Impairment in Neonates and Adolescents Treated with Ritonavir and Protease Inhibitors for HIV Exposure or Infection

Abstract

Background: Human deficiency virus (HIV) protease inhibitors (PIs) are widely used drugs whose effects are pharmacologically enhanced by ritonavir, a potent cytochrome P450 inhibitor. We reported previously that prophylactic postnatal ritonavir-PI therapy in HIV-exposed neonates was associated with increases in plasma 17-hydroxyprogesterone (17-OHP) and dehydroepiandrosterone sulfate (DHEA-S). Aims: To further investigate adrenal function in neonates and adolescents given ritonavir-PI. Methods: Adrenal function was assessed prospectively in 3 HIV-exposed neonates given short-term prophylactic treatment and 3 HIV-infected adolescents given long-term treatment. Plasma cortisol, 17-OHP, 17-OH-pregnenolone, DHEA-S, and androstenedione were measured before and after ACTH administration. Results: None of the patients had clinical signs of adrenal dysfunction. The only neonate exposed to ritonavir-PI in utero had up to 3-fold increases in plasma 17-OHP. Increases in 17-OH-pregnenolone of up to 3.1-fold were noted in 4 of the 6 patients, and all 6 patients had elevations in DHEA-S (up to 20.4-fold increase) and/or DHEA (up to 4.7-fold) and/or androstenedione (up to 5.2-fold). All these parameters improved after treatment completion. Conclusion: Neonates and adolescents given ritonavir-PI exhibit a similar adrenal dysfunction profile consistent with an impact on multiple adrenal enzymes. These abnormalities require evaluation, given the potentially long exposure times.

Inhibition of CYP3A7 DHEA-S Oxidation by Lopinavir and Ritonavir: An Alternative Mechanism for Adrenal Impairment in HIV Antiretroviral-Treated Neonates

“…Thus, here we are proposing an alternative mechanism for the adrenal hormonal imbalance observed in neonates treated with ritonavir-boosted lopinavir entailing the inhibition of CYP3A7 by ritonavir (and to a lesser extent lopinavir) that would hinder DHEA-S (and DHEA) metabolism and cause accumulation of the androgen hormone(s) and their precursors. This alternative mechanism is in agreement with the study by Kariyawasam et al in 2014 where neonates receiving the ritonavir-boosted lopinavir had normal cortisol levels before and after ACTH stimulation (conflicting with CYP21A2 involvement), whereas 17-OHP, DHEA, and DHEA-S plasma levels were elevated . An interesting case report was published regarding a 10-day-old full-term neonate who, after receiving an ARV combinatorial treatment of two NRTIs and the NNRTI nevirapine, presented severe symptoms of lethargy and respiratory distress .…”

“…The use of ritonavir-boosted lopinavir as a prophylactic ARV treatment for pregnant women and neonates has been assessed in several clinical settings, uncovering adrenal hormonal imbalance and leading, in some cases, to transient adrenal dysfunction, in particular, for preterm and previously in utero exposed infants. ,, Abnormal plasma levels of 17-OHP, DHEA, and DHEA-S have been measured in neonates receiving the protease inhibitor combination with mean increases of about 3-, 5-, and 20-fold the normal values, respectively. , The ritonavir-boosted lopinavir regimen has been well characterized in adults, with both drugs acting as substrates and inhibitors of the CYP3A enzymes. ,,,, However, understanding the effect of this ARV regimen on the metabolism of the endogenous androstane steroid hormone DHEA-S by the hepatic CYP3A7, the predominant cytochrome P450 enzyme in the fetal and neonatal liver, necessitated our scientific consideration. Interestingly, during the fetal period, the 16α-hydroxylation of DHEA-S by CYP3A7 is thought to be important in controlling placental estriol synthesis and full-term gestation. − During the neonatal phase, CYP3A7 activity, maximal at birth, starts to decline after the first week of life, progressively switching to the CYP3A4 isoform throughout the first year. − Despite the changes in expression and activity level, CYP3A7 is the major CYP3A isoform in the neonatal liver and is thought to be important in both drug and steroid metabolism processes. ,, Inhibition of CYP3A7 by protease inhibitors has been previously assessed in vitro using testosterone as the probe substrate, and it revealed ritonavir as a potent inhibitor with an IC 50 of 0.6 μM .…”

“…Therefore, inhibition of CYP3A7 by ritonavir-lopinavir or nevirapine could suggest a common mode of action of these drugs hindering DHEA and DHEA-S metabolism in the neonatal liver and leading to an increase in circulating concentrations of these androgenic hormones and their precursors. It is notable that the neonates presenting adrenal hormonal imbalance after receiving the ARV treatment generally returned to normal levels a few days after stopping the treatment. − The early postnatal period is a transitional phase for the adrenal glands undergoing important structural remodeling with rapid involution of the inner fetal zone, the region of the adrenal cortex producing a large quantity of androgens that are essential for fetal development . With the involution of the fetal zone, DHEA-S production by the adrenal is decreased, and the zona glomerulosa and fasciculata are rapidly developing.…”

“…Prevention of mother-to-child human immunodeficiency virus (HIV) transmission during pregnancy, delivery, and breastfeeding by using antiretroviral therapy (ART) has proven to be extremely beneficial in reducing the number of new HIV-1 infections in children. − The antiretroviral (ARV) drug regimens used for pregnant women and neonates include nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), or integrase strand transcriptase inhibitors (INSTIs) with treatment frequency and duration dependent on the risk factors involved. , However, these treatments have their challenges with modulating metabolic pathways in both the mother and the newborn resulting in dyslipidemia, glucose intolerance, and abnormal mitochondrial function or adrenal dysfunction. − The PI ritonavir-boosted lopinavir regimen, also known as Kaletra, is used during pregnancy or as a prophylactic treatment for neonates and has been associated with premature birth and transient adrenal insufficiency in newborns. ,− Previous studies have shown elevated plasma concentrations of adrenal steroid hormones including 17α-hydroxy progesterone (17-OHP), dehydroepiandrosterone (DHEA), and dehydroepiandrosterone 3-sulfate (DHEA-S) in neonates receiving the Kaletra treatment (Figure ). ,, Several hypotheses regarding the mechanism of adrenal hormonal imbalance and the associated life-threatening symptoms observed in newborns subjected to Kaletra therapy have been proposed. One of the excipients of Kaletra is propylene glycol, and while it is not known to effect steroidogenesis, it has been proposed that the alcohol properties of the compound may be responsible for some of the harmful effects including heart, kidney, and breathing complications .…”

“…Inhibition of CYP3A7, therefore, could cause irrevocable harm to the developing fetus. While the involvement of the hepatic CYP3A enzymes in the deleterious side effects of Kaletra has been postulated in previous studies, , to our knowledge no research has been conducted to examine the impact of CYP3A7 inhibition by lopinavir and ritonavir on endogenous DHEA-S metabolism. Given that ritonavir is a potent inhibitor of CYP3A4, it is a reasonable hypothesis that it is highly likely to also inhibit CYP3A7 and interfere with the oxidation of DHEA-S.…”