Dartmouth-Hitchcock

Paul E. Palumbo, MD

Under the leadership of Dartmouth-Hitchcock's foremost expert on treatments for HIV infections among younger children in the developing world, an international team of clinician/scientists this week revealed further evidence of a need to revise current standards for vaccination.

In the June 21 issue of the New England Journal of Medicine, pediatrician Paul E. Palumbo, MD, and his colleagues cite "extraordinarily strong" evidence reinforcing findings from previous clinical trials comparing an alternative drug regimen with current, conventional practice.

Palumbo, director of the International Pediatric HIV program at Dartmouth-Hitchcock Medical Center (DHMC) and a professor of pediatric medicine at the Geisel School of Medicine at Dartmouth, has been leading clinical trials at nine sites in sub-Saharan Africa and one site in India since 2006. In the most recent trial, with 288 HIV-infected children between ages two years and 36 months, all of the patients received a combination of drugs that included two antiretroviral medications. About half also received the drug nevirapine, a longtime tool for treating 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 percent of the children in the nevirapine group and in 19.3 percent of those in the lopinavir group. Ten children in the nevirapine group died, from a number of causes, compared with three children in the lopinavir group.

"The difference in the risk of death did not reach statistical significance," Palumbo said, "but it was certainly worrisome."

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.