Infants exposed to a Norvir (ritonavir)–inclusive regimen—notably Kaletra (lopinavir/ritonavir)—during pregnancy and immediately after birth may be at an increased risk for adrenal dysfunction, according to a French study published in the July 6 issue of The Journal of the American Medical Association. The researchers also warn of life-threatening adrenal insufficiency in infants born prematurely and exposed to Kaletra and, quite possibly, other Norvir-boosted protease inhibitors.

Kaletra is approved in the United States for infants at least 14 days old, if they are born with HIV. What isn't well understood is Kaletra's safety if used to prevent mother-to-child transmission of the virus during pregnancy or immediately after birth.

In April 2010, one of the centers of the French national screening program for congenital adrenal hyperplasia—a group of inherited disorders of the adrenal glands—examined dried blood spots from two infants exposed to Kaletra during pregnancy and at the time of birth; the researchers identified increases in a hormone produced by the adrenal glands, small triangle-shaped organs that sit on top of the kidneys and regulate the body's stress response.

Knowing that adrenal insufficiency can be serious in newborns—it can lead to life-threatening hormone imbalances—Albane Simon, MD, of the Hopital Necker-Enfants Maiades in Paris and her colleagues conducted a study to assess whether infant exposure to Kaletra was associated with changes in adrenal function, compared with standard Retrovir (zidovudine)–based treatment.

Among mother-child pairs in the Paris area enrolled in the study cohort between December 2004 and September 2008, Simon's group evaluated 50 infants who were born to HIV-positive mothers and who received Kaletra just after birth, along with 108 infants who received standard prophylaxis: Retrovir alone, Retrovir plus Epivir (lamivudine) or Retrovir plus Viramune (nevirapine).

Among the 50 newborns treated with Kaletra, average levels of the adrenal hormone 17-hydroxyprogesterone (17OHP) tended to be higher than those treated with a standard Retrovir-based regimen. In fact, seven Kaletra-exposed infants had abnormally high levels of the adrenal hormone, compared with none of the infants receiving Retrovir-based treatment.

Levels of 17OHP tended to be of greatest statistical significance among infants receiving Kaletra during pregnancy and immediately after birth.

Another hormone, dehydroepiandrosterone sulfate (DHEA-S), was also found to be significantly elevated in infants receiving Kaletra. Consistent with the findings for 17OHP, the DHEA-S values were significantly higher only in infants receiving Kaletra during both pregnancy and at birth.

Simon's group reported that full-term infants treated with Kaletra did not experience any symptoms of adrenal problems, even if they had elevated 17OHP or DHEA-S levels. Her team did note, however, a potential danger in infants born before their due dates. “[Three] premature newborns experienced life-threatening symptoms compatible with adrenal insufficiency, including hyponatremia [abnormally low level of sodium in the blood] and hyperkalemia [higher-than-normal levels of potassium in the blood, associated with kidney failure].” Cardiogenic shock, or damage to the heart, was documented in one case.

The authors note, however, that all symptoms resolved once the Kaletra treatment was completed.

“Our findings of the association between lopinavir-ritonavir and transient adrenal dysfunction in HIV-1 uninfected newborns suggest that lopinavir-ritonavir and more generally ritonavir boosting should be used with caution, if at all, in premature infants,” Simon and her colleagues warn.

“If this drug regimen is administered to full-term infants,” they continue, “it should be used under electrolyte monitoring. 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.”