[Treatment Horizons]

by Chael Needle

While researchers and physicians have tended to agree that treatment should be started in young children with HIV who show symptoms, they have differed about treatment initiation if children are asymptomatic. A recent study, however, suggests that early treatment with HAART in asymptomatic children fosters more positive outcomes than even treatment started just one month later. Led by Dr. Bonnie Maldonado, MD, a pediatric infectious disease expert at Lucile Packard Children’s Hospital and an associate professor of pediatrics at Stanford’s School of Medicine, the study was published in the May 11 issue of JAMA.

As part of a large, California-based surveillance research project started by Dr. Maldonado when she arrived at Stanford in 1988 from a two-year stint at the CDC, where she studied epidemiology, the observational study looked at the rate of progression to AIDS and death in different sets of 205 children with Category C disease (as the CDC calls it) during three significant treatment periods from 1988 to 2001. The study sought to follow “the natural history of children with HIV disease—treatment trends, survival rates, progression of HIV disease, what was making things better or making things worse over time,” says Dr. Maldonado, whose team culled data from all the major treatment centers around the state.

The impetus of this particular study in part was energized by trying to understand a “sudden peak” in progression to AIDS-related death in infants with HIV. “In children who have been infected with HIV in utero, about one-third  will get very sick and die very rapidly, within the first three to four years of life. In the other two-thirds, the progression of symptoms and deaths really are much more prolonged,” says Maldonado.

The researchers looked at children during their first three years of life in order to focus on the early, rapid progression puzzle piece. The three different treatment periods compared were: 1988–1991, a period of no treatments, “except perhaps clinical trials treatment and AZT;” 1992–1995, characterized by some antiretroviral treatment and the onset of treatment to prevent mother-to-child transmission; and 1996–2001, a period that saw consistent treatment with combination HAART therapy, and specifically protease inhibitor-containing regimens. “Over those three periods, the children did better and better [in terms of progression to AIDS symptoms and/or death]. They were not only identified as infected earlier, but they got better treatment over time.”

The study produced two significant findings, the first of which shows that the youngest children, born in 1996 or later, did much better than the other children. Upon analysis, Dr. Maldonado and her team attributed this success to receiving triple therapy—and receiving it very early. “Of all the children who received triple therapy, no matter when they were born, none of those children developed AIDS and none of them died by three years of age. That’s compared to fifty and sixty-seven percent of the other two groups [who died of AIDS]. Triple therapy can prevent this early progression—and we’ve never been able to show that before today.”  The second significant finding shows that even monotherapy or dual therapy, started in the first two months of life, meant the “children were less likely to develop AIDS and die compared to children who started their treatment a month later.”

The study brings up lots of other questions, says Dr. Maldonado, who points out that, because early, rapid progression only affects one-third of children, they don’t know whether all children should receive triple therapy early or only a particular subset of children. Also, the long-term effects of triple therapy on children remain unknown: “Nobody over ten has had triple therapy since they were young, so we don’t really know what the long-term effects of HAART therapy are going to be on children. Is it going to breed more viral resistance, cause life-threatening toxicities, or will it be debilitating? Will children on HAART therapy fail to respond [to it later on] if they started so young?”

Dr. Maldonado says that the next step is to conduct clinical trials “where children can be randomized to receive different types of treatment, early or delayed, and see if that difference in treatment times has an impact on the children’s development of AIDS and death. If there is a difference, which markers predict which children should be getting early therapy?”

Dr. Maldonado, who works in Zimbabwe through a Stanford partnership with the University of Zimbabwe and the Municipal Health Department in a city outside of the capital, argues that lessons learned from studies like this one need also to be applied to treatment of HIV/AIDS in developing countries where “certainly we’re going to start seeing [sudden peaks in progression] in children outside the United States, in Africa and Asia, for instance.”

Chael Needle wrote about megestrol acetate NanoCrystal Dispersion technology as a possible treatment for body wasting for the May issue.

June 2005