Diagnosis: Hope
It was tragedy enough that she contracted HIV and then passed the virus on to her two children.
But what grieved the late Elizabeth Glaser, perhaps more than anything, were the days in 1987 and 1988 when she was able to take the medication AZT while her very ill daughter, Ariel, could not.
Ariel succumbed quickly to the disease, dying in 1988 at age 7--three years before AZT was approved for use in children. Glaser, a well-known figure in Hollywood who went on to co-found the Pediatric AIDS Foundation, died in 1994.
Although children are still stragglers in the 14-year-old epidemic, the outlook is beginning to improve.
Last month, the Food and Drug Administration approved two HIV drugs for use in children, both from the family of protease inhibitors that have shown great promise in adults.
Despite that welcomed news for the 4,500 HIV-infected children in the United States, the approval came more than a year after adult patients obtained access to protease inhibitors, which appear to work by lowering the amount of virus in the blood. And children--especially infants and toddlers --remain seriously handicapped in their ability to fight the virus for reasons that are both biological and economic.
“Any time drugs are approved for use in pediatrics, we consider it a significant achievement. Throughout most of this epidemic, we have lagged--often by several years--behind the adult approvals,” says Dr. Paul Church, director of the Children’s AIDS Center at Childrens Hospital Los Angeles.
And that lag continues despite the approvals of nelfinavir by Agouron Pharmaceuticals and ritonavir by Abbott Laboratories. “Many children don’t have access to the new drugs, with the costs involved,” says Susan DeLaurentis, chief executive officer of the Pediatric AIDS Foundation. “It’s still too early for the pediatric community to feel the real hope that we see in the adult community.”
(Nelfinavir costs about $3,000 a year for a 35-pound child; however, Agouron makes the medication free to children who cannot afford it or whose insurance does not cover it. Ritonavir costs $1,000 to $6,000 per year, depending on the size of the child.)
Families of children with HIV remain frustrated that only two protease inhibitors (out of four on the market) are approved for use in children, DeLaurentis says. While doctors can, and often do, prescribe the other protease inhibitors for their pediatric patients, they do so without fully knowing the toxicity, dosage or effectiveness, DeLaurentis says. And drugs that lack FDA approval are usually not covered by insurance or Medicaid.
Moreover, none of the protease inhibitors is approved for use in children younger than 2, a period when, researchers suspect, the right combination of drug therapy might cure the disease.
“Time and time again, we hear families say, ‘I can take this; why can’t my child?’ ” DeLaurentis says. “It has happened all the way through this epidemic. Elizabeth Glaser was taking AZT, but she couldn’t give it to her children.” AZT was the first drug marketed for HIV, in 1987.
It has been only in the past few months that Glaser’s surviving child, Jake, 12, has begun taking a protease inhibitor. He is responding well to the treatment.
For many children, these advances come not a moment too soon.
Daniel Kollado, a New Jersey AIDS activist, was on the verge of giving his own AIDS medications to his 6-year-old son, Aaron. Both father and son have HIV. Kollado’s wife died of complications of AIDS four years ago.
“Last winter, things were not looking good for my son,” Kollado says. “He was failing. It was so sad knowing that I had access to a protease and it was in my cabinet and I couldn’t administer it to my child. At times I thought, well, maybe I could just dose it down and give it to him. But I was still taking a huge chance, and I didn’t feel it was ethical to do that. It’s a horrible position for a parent to be in.”
Kollado was recently able to obtain nelfinavir for Aaron, however, as well as another new medication. The child, he says, is thriving on the “cocktail” of HIV drugs.
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Children have not been a priority in AIDS drug development for two reasons: Far fewer children are infected than adults, and drug development is difficult in children, experts say. Nationally, the number of HIV-infected children is expected to decline as more infected women are identified through voluntary testing during pregnancy and undergo treatment to prevent transmission to the fetus. Worldwide, however, the rate of infection in children is climbing.
Agouron Pharmaceuticals, based in San Diego, was the first drug company to incorporate children into the development of its drug but faced numerous challenges.
“It’s a long-standing ethical principle that you take your first look at a drug in adults because of the risks involved,” says Peter Johnson, the firm’s president and chief executive officer. “Once the risk is determined, then you may be able to begin testing in children.
“Beyond that, there are some fairly tedious technical issues. The development of a formula from the active drug is fairly tricky. For little kids, tablets or capsules are often not practical. We have to look for a powder or liquid amenable for use in children. And that is not a nontrivial task.”
Doctors and parents of HIV-positive children must also grapple with the practical problems of putting children on the new therapies. For example, the protease inhibitors usually come in capsule form, which is very difficult for children to swallow. One favorable aspect of the newly approved drugs is that nelfinavir comes in a powder and ritonavir in a liquid.
If the medicine tastes awful, kids won’t take it, Church says.
“The protease inhibitors are fairly hideous [tasting] when you attempt to mix them in something for a kid. Some simply refuse to take it. If we cannot get medication into the child any other way, we have actually gone as far as having the parents consider a stomach tube. That requires surgery, and there are all sorts of complications possible with that. But the potential benefits are so great that we don’t want to deny children the benefits.”
And making the medicine palatable isn’t the last challenge. Doctors are still in the process of learning how these drugs will work in children.
“The real hurdle is that you are sometimes surprised by the way children metabolize medication. It can be faster or slower than adults,” says Dr. Katherine Luzuriaga, a pediatric AIDS specialist at the University of Massachusetts.
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The marketing of the two protease inhibitors for kids does not mean all the questions are resolved, she says. In petitioning the FDA for approval, “neither of the companies had to present data that said that these drugs were truly efficacious in children and, if they are efficacious, how to best use them. The challenge for us is to figure out how best to use these drugs,” Luzuriaga says.
Doctors are also faced with the problem of wanting to put children on a combination of the drugs even though the medications are being approved in piecemeal fashion.
“We have a group of children who have had all the previous drugs. We know that serial mono therapy [taking only one drug at a time] is not going to work. It may buy time, but it’s doomed to failure,” Church says.
And, the medications will need to remain effective for, perhaps, a child’s lifetime.
“We are potentially talking about taking these drugs for many more years than an adult,” Church says. “We don’t know the effects of these drugs on a developing child, although I suspect it will be minimal.”
But a far different scenario is also envisioned. Some doctors suggest that children, especially infants, might be among the first HIV patients to be cured of the disease if they are immediately started on heavy doses of medications. Researchers are particularly interested in this strategy for infants, although none of the protease inhibitors are approved yet for children younger than 2.
Luzuriaga and UCLA researchers recently completed a study that tested a combination of three medications in newborns. Of six HIV-positive infants, one has shown no trace of the virus in his blood after 20 months of treatment. Another baby tested negative for 16 months before the virus broke through. She is testing negative again after being switched to a different combination.
“That provides some hope that we can a least achieve long-term control of viral replication,” Luzuriaga says. “We think in the youngest age group we have to be very hard-hitting.”
Other studies on medication in both infants and older children are set to begin this month, which may help to resolve some of the major lingering questions. “This next year or two will be very telling,” Luzuriaga says.
“We saw our first child with HIV in 1983. After 14 years of watching this develop, it’s very gratifying to see things start to happen,” Church says. “When I sit down with a family now, I’m much more convinced that we’re talking about a big difference [in life expectancy]. Not just six months.”
