Friday, July 15, 2011

In HIV-1-uninfected newborns of HIV-infected mothers, treatment with the protease inhibitor lopinavir-ritonavir may lead to adrenal dysfunction

Lopinavir-ritonavir may alter adrenal function in neonates
Reuters Health • The Doctor's Channel Daily Newscast

NEW YORK (Reuters Health) –

In HIV-1-uninfected newborns of HIV-infected mothers, treatment with the protease inhibitor lopinavir-ritonavir may lead to adrenal dysfunction, including life-threatening adrenal insufficiency in premature infants, report researchers in the July 6 issue of the Journal of the American Medical Association.

The findings suggest that “lopinavir-ritonavir and more generally ritonavir boosting should be used with caution, if at all, in premature infants, and if this drug regimen is administered to full-term infants, it should be used under electrolyte monitoring,” Dr. Albane Simon, of the Hopital Necker-Enfants Malades, Assistance Publique-Hopitaux de Paris and colleagues write. “Whether more prolonged exposure of HIV-1-infected or uninfected infants via breast milk is associated with endocrine disruption should be carefully investigated, and the apparent risk associated with prenatal ritonavir exposure also merits further evaluation,” they add. Lopinavir-ritonavir is licensed in the United States for HIV-infected newborns older than 14 days and in Europe for children older than 2 years. However, published data on its use in newborns are “scarce and limited to a few pharmacokinetic studies,” the researchers note in their paper. An April 2010 report from France noted a transient increase in 17-hydroxyprogesterone (17OHP) in 2 children treated at birth with lopinavir-ritonavir. 17OHP is a steroid hormone produced mainly by the adrenal glands.

This prompted Dr. Simon's team to assess whether immediate postnatal exposure to lopinavir-ritonavir is associated with changes in adrenal function compared with standard prophylactic treatment with zidovudine.

Among 50 HIV-1 uninfected neonates who received lopinavir-ritonavir just after birth for at least 3 days and a median of 30 days, 7 (14%) had abnormally elevated 17OHP levels ( > 16.5 ng/mL for term infants or > 23.1 ng/mL for preterm infants) on days 1 to 6. By contrast, none of 108 control children who received standard prophylaxis with zidovudine alone (n = 100), zidovudine plus lamivudine (n = 6) or zidovudine plus nevirapine (n = 2) had elevated 17OHP levels.

The median 17OHP concentration for term newborns treated with lopinavir-ritonavir was 9.9 ng/mL versus 3.7 ng/mL for term control infants (P < 0.001). 17OHP was assayed as part of the French national screening program for congenital adrenal hyperplasia (CAH). The investigators point out that “despite reportedly weak transplacental transfer of lopinavir and ritonavir,” 17OHP levels were highest among infants exposed during pregnancy and postnatally. Dr. Simon's team also had median values for DHEA-S, the circulating form of a steroid produced primarily by the adrenal cortex.

These values were also higher with lopinavir-ritonavir exposure (9,242 ng/mL for term infants versus 484 ng/mL for term control infants; P < 0.001). Levels of 17OHP and DHEA-S showed a strong positive correlation (P = 0.001).

According to the investigators, “All term newborns treated with lopinavir-ritonavir were asymptomatic, although 3 premature newborns experienced life-threatening symptoms compatible with adrenal insufficiency, including hyponatremia and hyperkalemia with, in 1 case, cardiogenic shock. All symptoms resolved following completion of the lopinavir-ritonavir treatment.” “Although these findings cannot establish a causal relationship, further studies are needed to test the hypothesis of whether lopinavir-ritonavir may act as an inhibitor of adrenal steroid synthesis in fetuses and newborns,” the investigators write.

JAMA 2011;306:70-78.

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