ix-year-old June does a little dance, a twirl, and a lively step across the spare, brightly lit kitchen in Brockton, Mass., a tough, working class city about an hour south of Boston. Her mother, Lenora Figueroa, is the epitome of the word bustle as she gets dinner ready for June, her three siblings, and an assortment of cousins draped on the couch and chairs in front of the television in the next room. Thick glasses make the little girl's eyes look huge. It doesn't take much to make her smile. And then, before you know it, you're treated to the spectacle of that smile erupting into a giggle. "She's my little miracle child," says her HIV-infected mother of her HIV-infected daughter. "If she had died, I would have just dissolved."
In the United States, more than 8,000 children have been born with HIV acquired from their infected mothers since the AIDS epidemic began over 20 years ago. In the early years, they were doomed to short, disease-ravaged lives. Many were placed in foster homes. Two developments in the early and mid-1990s turned that situation around. First, antiretroviral therapy for pregnant women cut the chance of mother- to-infant transmission from about 25 percent to less than 5 percent. As a result, the number of infected children dropped dramatically. Second, the combinations of drugs that worked so well to control HIV in infected adults were tried in children--and produced miracles like June Robinson, who was on the verge of dying from pneumocystis carinii pneumonia as a two-month-old baby.
Epidemiologists and biostatisticians at the Harvard School of Public Health aren't miracle workers. But they have been guiding lights for some of the most important studies behind these advances. They played a critical role in the original "076" trial that showed AZT blocked vertical, mother- to-infant transmission. And last fall, Professor Steven Gortmaker was the lead author of a study in the New England Journal of Medicine that showed that combination therapy has led to a 67 percent decrease in the mortality rate among HIV-infected children. "Statisticians are on every study and part of everything that we do. It's not us and them. It's just us," says Sandra Burchett, an AIDS researcher and clinician at Harvard-affiliated Children's Hospital in Boston.
Competing agendas and egos have splintered some aspects of AIDS research, particularly vaccine development. In contrast, comity and cooperation has made for steady progress in prevention and treatment of the disease in children. The Pediatric AIDS Clinical Trials Group is an umbrella organization with about 50 active studies at any one time. Led by Professor Michael Hughes, about 30 statisticians at the School are the biostatistical hub of this group, analyzing trial results and advising clinicians like Burchett about study design and data collection so their findings will withstand statistical scrutiny. Gortmaker, who is in the Department of Health and Social Behavior, has led efforts to measure the social and mental development of HIV-infected children. Now that it's known that the AIDS drugs keep children alive, researchers are starting to look at their long-term consequences, as well as signs that the virus is resisting their effects. "We're in a honeymoon period that isn't over for us yet," says Burchett warily.
Dinner's been scooped into bowls. Children have scattered into bedrooms or found their way back to the television. Lenora Figueroa is still on her feet, still talking a mile a minute. She says she wants June to have an "innocent childhood." She boasts about how her daughter is doing in school as a first-grader: "She is reading, she is writing, she is doing math." But she also acknowledges that things could change--that a miracle could turn into a mirage. "We've got now. I don't know how long she's going to be in my life. But we've got now."
That "now" starts every morning for June with 18 milliliters of AZT and 7 milliliters of a related drug called 3TC. The dosages are the same at night. As far as "drug cocktails" go, hers is pretty simple and doesn't include a protease inhibitor, the class of drugs that many associate with combination therapy for HIV-infected people. The medicines come in liquid form, and her mother uses a large, plastic syringe-like device to measure it out from large bottles. Lenora says her daughter has never given her any trouble taking her medicine; June says she doesn't like them, but "if I don't take them I'm going to get sick and die."
Doctors were pretty optimistic that children would benefit from combination therapy, according to Burchett, but getting children to take the drugs was a problem. Liquid and powder formulations eventually solved the obstacle of numerous and oversized pills, but not the yucky taste. Generous servings of maple syrup, pudding, grape juice, and even Nutella, the chocolate-hazelnut spread, have been a lifesaver in that regard, notes Burchett. Hughes says one of the trickiest issues for the pediatrics trials group has been dosing levels. In cancer trials, the philosophy is to set the lowest possible dose for children because the drugs are so toxic. But in AIDS, starting at a low dose might just "tease" the virus and provoke resistance.
at Children's Hospital in Boston were among the 1,028 subjects in the
pediatric AIDS study published in the Nov. 22, 2001 issue of the New
England Journal of Medicine. Dubbed Protocol 219, it's an ongoing,
forward-looking study of the long-term effects of AIDS drugs. When enrollment
started in 1996, just 7 percent of the children were on combination therapy.
In 1999, when this particular "slice" of the study was over,
it had climbed to 73 percent. The mortality rate went in the opposite
direction. In 1996, it was 5.3 percent. Three years later, after combination
therapy had become common, it had plunged to 0.7 percent.
Hughes says there are some significant hurdles to tracking the growth and development of this cohort of HIV-infected children as they grow into adults. Many of the standard IQ tests that might be used to measure mental development are designed for cross-sectional "snapshots," not following children over time. Moreover, because minimum scores on the tests may be set too high to assess some HIV-infected children, incomplete data poses what statisticians term a "censoring problem." Meanwhile, Gortmaker and his colleagues are hoping they've provided one solution by developing a multi-component General Health Assessment for Children. By collecting information on missed school days, physical function, behavioral problems, pain symptoms, and so on, he believes the index will make it possible to objectively track a child's quality of life over a period of time. A study in the February 2002 issue of the American Journal of Public Health reported that a high percentage of older children born with HIV suffers from behavioral problems and mental illness. Burchett paints a sunnier picture, although she is worried about what's going to happen as this cohort of children becomes teens. "Now they are developing and seem to be pretty much on track. Next, the name of the game is going to be adherence to these complicated regimens."
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