ST. LOUIS—The use of aggressive antiretroviral therapy has dramatically reduced the perinatal transmission of the human immunodeficiency virus (HIV) in North America and Europe. While a number of questions remain unanswered regarding the processes behind neuronal injury and death in HIV, the value of prophylactic antiretroviral treatment is undisputed.

The risk of perinatal transmission in untreated pregnant women is reported to be 25% to 30%. In a presentation at the 29th Annual Meeting of the Child Neurology Society, Leon Epstein, MD, reported that aggressive therapy can reduce this rate to less than 8%. Dr. Epstein is Professor of Pediatrics at Northwestern University, and Head of the Division of Neurology, Children's Memorial Hospital, in Chicago.

"The prophylaxis for the transmission of HIV goes back to 1994 … it has seriously decreased, by 70%, the perinatal transmission. It was found to be efficacious even in women with advanced disease," he said. "The interesting question that is still under very active investigation is, 'Why isn't it transmitted to the other 70%—why is the placenta such a good barrier?'"

Dr. Epstein reported that animal studies have demonstrated that the virus enters the nervous system early in the infection. However, it is not known whether central nervous system infection in HIV is an ongoing process over a long period of time or whether it begins abruptly during end-stage disease. For this reason, it is unclear whether antiretroviral therapy will be effective in eradicating infection from the central nervous system.

"There is some evidence that circulating monocytes do exist infected with HIV that may repeatedly enter the nervous system, and that if these cells are suppressed, maybe this end stage can be prevented," he said. In a small number of cases, limited infection may occur in astrocytes. While this does not result in increased production of virus, it may impair astrocyte function, resulting in another phase of HIV infection in the nervous system. Dr. Epstein suggested that while therapies now in use may reduce the incidence of acute cases such as those seen in the 1980s and early 1990s, new manifestations of the disease may appear 10 or 15 years from now.

It is known that infected microglia and macrophages produce large numbers of cytokines and other inflammatory mediators, and that microglia release greater numbers of cytokines than do peripheral macrophages. In the developing nervous system, microglia are more potent than in the adult nervous system; therefore it is thought that microglia may play a particularly important role in preventing HIV infection in children.

Dr. Epstein explained that inflammatory mediators produce a cascade of events including excitotoxicity, free radical production, and oxidative stress in neurons. This cascade is instigated by the infected macrophage or microglia, which release toxic products, leading to chronic inflammation, thought to cause neuronal injury. He noted that inflammatory mediators are typically studied in isolation. While this allows researchers to demonstrate the effect of a given mediator, he stressed that in HIV infection these agents do not act in isolation. "In a real-life situation, these things are probably not isolated, and blocking one might just allow another to be active."

In vitro studies have demonstrated that the putative neurotoxins in HIV exert neuronal injury through glutamate receptors. Therefore, it is believed that neurons may be protected from injury by blocking glutamate receptors. However, certain inflammatory mediators can cause death in cell lines that do not have glutamate receptors. This may occur as a result of weak excitotoxicity, resulting in changes in cell membrane excitability.

It was originally believed that an acute phase followed HIV infection, during which an individual could be symptomatic or asymptomatic; this was followed by a latent phase, during which the virus was not present, only to reappear a number of years later, in the final stage of the disease.

However, the use of polymerase chain reactor (PCR) techniques has enabled investigators to quantify the amount of viral message manufactured in the plasma, down to extremely small amounts. This has enabled the detection of virus throughout the course of HIV infection. "The person who is infected makes huge numbers of these viral particles and, curiously enough, clears huge numbers of these virus particles for many months. And then at some point, eventually this virus level rises, and ultimately it will cause disease."

The observation that virus is continually present led to the idea that suppression of ongoing viral replication might be used to prevent the onset of immune deficiency and its complications. "That has been the case—it's been highly effective," he reported.

One question that remains unanswered is that of potential reservoirs for central nervous system infection. While it is easy to measure virus in the plasma, the activity of the virus in the lymph nodes and in the brain cannot be readily studied. "The other tissues, other than the blood, are probably where most of the viral burden is, so you're only measuring … the tip of the iceberg," Dr. Epstein said.

CARE OF HIV-POSITIVE CHILDREN

Care of children with HIV is typically undertaken at specialized centers, and it involves the use of at least one highly active protease inhibitor and two nucleoside analog reverse transcriptase inhibitors. Newer medications on the horizon include an integrase inhibitor and drugs that can block the chemokine receptors CCR5 and CXCR4, which have recently been identified as essential to the process by which the virus infects cells.

"These therapies are very effective, and there's no doubt that when you give this combination of antiretroviral therapy, you can drop the virus plasma level dramatically. You can take somebody with very high amounts of virus in their plasma and drop it down to undetectable levels," Dr. Epstein said.

While these therapies are extremely effective, they are expensive; as a result they are unavailable in poor countries where HIV is epidemic—sub-Saharan Africa, Asia, South America, and parts of the Caribbean. "These are major problems. There's a real mismatch between a decreasing incidence of perinatally transmitted HIV infection in the US and Europe, and a relentless rise in prevalence in most of the developing world where the virus is."

In the absence of antiretroviral therapy in developing countries, Dr. Epstein stressed the importance of education in reducing rates of HIV infection in women. While clearly not a replacement for effective drug therapy, he said education in certain sub-Saharan nations has reduced infection rates in women of childbearing age. "Education is a factor. It's not trivial," he remarked.

Interest in cost-effective vaccines remains high, and Dr. Epstein is relatively optimistic that a vaccine will eventually be developed. Also, as most infection is transmitted not long before and during the perinatal period, it is thought that if drug therapy is introduced one or two weeks prior to birth and continued during the intrapartum period, it may reduce the number of infected children born in developing countries.

NR