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For Release: June 20, 2012
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Clinical trial led by a Geisel professor reveals a more effective treatment for HIV-infected infants

Paul Palumbo, MD

Hanover, N.H.—The standard treatment for HIV-infected children in the developing world may need to be revised, according to a study led by Paul Palumbo, MD, a professor of medicine and of pediatrics at the Geisel School of Medicine at Dartmouth.

In an article published in the June 21 issue of the New England Journal of Medicine, Palumbo and an international team of researchers revealed the findings of a clinical trial that compared the current standard treatment to an alternative drug regimen. The trial, which was conducted at nine sites in sub-Saharan Africa and one site in India, enrolled 288 HIV-infected children between two and 36 months of age. All of the children were given a combination of drugs that included two antiretroviral medications. About half also received the drug nevirapine, which has long been used to treat HIV in children. The other half received ritonavir-boosted lopinavir (marketed under the brand name Kaletra) instead of nevirapine.

The primary endpoint in the trial had two components: virologic failure or the discontinuation of treatment for any reason, including death or the development of tuberculosis. Virologic failure meant that the treatment failed to induce a tenfold reduction in the level of HIV in a child's blood by 12 to 24 weeks on the regimen or that the virus level remained detectable in the blood at the end of 24 weeks.

At the end of 24 weeks, the treatment had failed in 40.8% of the children in the nevirapine group and in 19.3% of those in the lopinavir group. Ten children in the nevirapine group died, from a number of causes, compared to three children in the lopinavir group. "The difference in the risk of death did not reach statistical significance, but it was certainly worrisome," said Palumbo.

Overall, children in the nevirapine group were about two-and-a-half times more likely to have the treatment fail or to die than were children in the lopinavir group. "No matter how you looked at it--virologic failure, death, or toxicity of the treatment--Kaletra did better than nevirapine," Palumbo said. "The findings were extraordinarily strong."

Palumbo is vice chair of the International Maternal Pediatric Adolescent AIDS Clinical Trial Group (IMPAACT), the organization that designed and carried out the trial. This study was one of two parallel trials comparing nevirapine to lopinavir in young children. The treatment regimen in the other trial was the same, but the children in that cohort had previously been exposed to nevirapine at birth. A common method of trying to prevent the transmission of HIV from mothers to children is to give a single dose of nevirapine to the mother during labor and then a single dose to the child just after birth. That method can prevent the transmission of HIV about half the time, Palumbo noted, but it had failed to prevent transmission in the children enrolled in the study. That trial was stopped early, in the spring of 2009, when the independent data and safety monitoring board concluded that the data showed that lopinavir was clearly superior to nevirapine. The results of that trial were published in the New England Journal of Medicine in 2010, and, in response to the findings, the World Health Organization (WHO) changed its guidelines to recommend treatment with lopinavir rather than nevirapine in infants exposed to nevirapine at birth.

Based on the new findings, Palumbo has already talked to the WHO about potential changes in treatment guidelines for children not previously exposed to nevirapine, but there are a number of complicating factors. Nevirapine is less expensive than lopinavir, it is more tolerant of high temperatures, and it can be given in a single formulation that is combined with the two antiretroviral drugs. Lopinavir is not formulated with the two antiretrovirals, so each drug has to be administered separately. "People in the field really want to be able to use nevirapine, and I fully understand that," Palumbo said. "It has really created a conflict as to what is the next best step. In South Africa, they have already mandated Kaletra for all children under age three, but in many other countries where resources aren't as available they are struggling with this issue."

The researchers are now investigating the reasons that nevirapine did not prove to be as effective as lopinavir and conducting a long-term follow-up study with the children in the trial to track the long-term safety and efficacy of the treatments.

The Geisel School of Medicine at Dartmouth, founded in 1797, strives to improve the lives of the communities we serve through excellence in learning, discovery, and healing. The nation's fourth-oldest medical school, the Geisel School of Medicine has been home to many firsts in medical education, research and practice, including the discovery of the mechanism for how light resets biological clocks, creating the first multispecialty intensive care unit, the first comprehensive examination of U.S. health care cost variations (The Dartmouth Atlas), and the first Center for Health Care Delivery Science, which launched in 2010. As one of America's top medical schools, Dartmouth's Geisel School of Medicine is committed to training new generations of diverse physician leaders who will help solve our most vexing challenges in health care

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