To some extent, pediatric AIDS research has become a victim of its own success. When ACTG 076 proved that treatment of pregnant women with AZT could halve the rate of vertical transmission, some AIDS researchers began eyeing the pediatric research budget hungrily: certainly, they thought, as the number of HIV-infected children drops substantially, scarce research dollars could be reallocated. For their part, advocates for pediatric AIDS note that pediatric AIDS research will remain vital for both scientific and ethical reasons. Many questions remain unanswered, and, while the domestic population of infected children shrinks, the number of children with AIDS world-wide continues to grow at an alarming rate. Recent hearings of the FDA's Antiviral Drugs Advisory Committee have been marked by angry and heart-wrenching protests by AIDS advocates and parents of HIV-infected children, who, despite the media appeal of AIDS babies, see their children being left behind as therapy for adults dramatically improves.
In mid-March, however, Agouron Pharmaceuticals' nelfinavir (Viracept) and Abbott Laboratories' ritonavir (Norvir) became the first HIV protease inhibitors to be approved for use in children. The US Food & Drug Administration (FDA) granted marketing approval to the two companies through regulations that allow approval of infant formulations of marketed drugs based on evidence that the product has a similar pharmacological profile in children, without substantial reason to expect differences in safety or efficacy. In the face of this exciting news, two leading advocates for children with AIDS agreed to discuss the changing face of pediatric AIDS research with TAG's Spencer Cox.
Dr. Arthur J. Ammann, former Director of the Pediatric AIDS Foundation's Ariel Project and currently President of the American Foundation for AIDS Research (AmFAR), said, "I hope that these approvals will change the pediatric standard of care. It has been extraordinarily difficult to view the changes in treatment in the adult population, and then to just watch children progress in their disease without the benefit of protease inhibitors. I hope that these drugs will now be used in conjunction with measurements of viral load to make therapeutic decisions for children, such as when to start therapy, and when to change treatment."
Advocates for children with AIDS have long complained that pharmaceutical companies have delayed development of infant formulations, leaving children to suffer, due to their perception that such formulations are not profitable. Diane Donavan, President of Positively Kids, an advocacy organization which focuses on HIV-infected children, said, "There is a huge lag between the standard of care for HIV-infected children and adults. Most of the drugs available to adults do not have pediatric formulations or are developed two or three years behind adult formulations."
Dr. Ammann added, "If you look back at the first ten antiretroviral therapies approved, historically there has been a two-year lag up until the 3TC approval. That was the first breakthrough. Abbott, for example, said it was moving quickly. But they already had the oral formulation, and blithely delayed submission for a year. Not to give too much credit to Agouron, but here's an example of a drug that was formulated and studied in children prior to approval: within eight months they had an FDA approval for pediatrics. I think this is an example of what shouldbe done with every antiretroviral drug."
Ms. Donavan also noted that this development lag meant that the standard treatment of HIV-infected children was probably sub-optimal: "Current standard of care guidelines still recommend AZT or ddI monotherapy. The National Pediatric HIV Resource Center is currently working on new guidelines, but when they held a meeting in July of 1996, most researchers still wanted to recommend ddI monotherapy as the treatment of choice. Within the past three months, more researchers are agreeing that we need to treat early and aggressively. Once this document is finished and published, the standard of care hopefully will include combination therapy for children with HIV infection."
The recent success in preventing transmission of HIV from mother to child, however, may be only further propagating complacency in government-sponsored pediatric AIDS research. The Levine Commission, which recently completed a review of all AIDS research spending at the National Institutes of Health, recommended substantial reductions in the budget of the Pediatric AIDS Clinical Trials Group (PACTG), on the assumption that the US would simply not have enough children to study. Donavan disagrees. "Adolescents are still the highest risk group for new infection. This falls under pediatric research. In addition, not all women will receive antiretroviral therapy or prenatal care, so we will still have children born with HIV. Another fact to consider is the global picture of HIV."
Dr. Ammann says that we will need a shift in emphasis to what we will do internationally. "In the US, we're looking at probably fewer than 500 HIV-infected infants a year, but world-wide it's more like 5,000 annually. This raises some important questions ethically about how we'll intervene internationally to conduct pediatric AIDS research." Still, he points out, there are reasons to maintain a strong pediatric research effort. Some research questions, he suggests, could optimally be answered in children. "Clearly now, we have a very narrow window to answer certain questions that haven't been answered yet. One of the questions is the effect of combination therapy as early intervention in infants. Here's a setting where you know precisely when the patient was infected, and we can look at the ways antiretroviral therapy affects outcome and long-term viral dynamics. These questions are very important for both children and adults."