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AIDS Juggernaut Continues Unabated.

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Dec. 28, 1999 (Atlanta) -- On the last day of 1999, HIV will infect 15,000 people worldwide, according to estimates from the Joint United Nations Program on HIV/AIDS. By the first day of 2000, the AIDS pandemic will be spreading even faster.

Of the 16.3 million AIDS deaths since the beginning of the epidemic, 2.6 million occurred in 1999. At year-end, an estimated 33.6 million people worldwide are living with HIV infection. For 95% of these people, potent new anti-HIV drugs are completely unavailable. But 1999 brought bad news even to those fortunate enough to have access to potent anti-HIV drugs known as highly active antiretroviral therapy (HAART): sooner or later, the drugs will fail to contain the AIDS virus.

"There is no greater challenge facing people treating HIV than the management of antiretroviral [anti-HIV] treatment failure," said, John Mellors, MD, University of Pittsburgh. "The time will vary, but eventually immunologic [immune system] failure will occur. Those who believe this will not occur -- the burden of proof is on them."

It once was hoped that HAART would be able to eradicate HIV. A better understanding of the dynamics of HIV infection now shows that the virus is able to lie dormant in various reservoirs such as genital secretions and certain immune cells from which it periodically emerges to reseed itself. Because anti-HIV drugs act only on an active virus, these reservoirs are not affected by HAART.

"HIV eradication is now seen as a rare possibility -- or impossibility," said leading AIDS researcher Michael Saag, MD, of the University of Alabama School of Medicine, in Birmingham. "This has made us rethink everything from the possibility of eradication to when to start therapy."

Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, agreed with this assessment. "Eradication is predicated on no ongoing viral replication -- which we now see isn't going to happen," says Fauci.

Early attempts to flush HIV from its hiding place with chemicals called cytokines show promise but require a great deal more refinement before they lead to approaches in humans. Better immunologic tools also reveal another grim fact about HIV infection: While immune responses to infections that occur due to a suppressed immune system by HIV, or opportunistic infections, improve in patients receiving HAART, immune responses to HIV itself remain depressed.

There have been exciting reports from patients who, for one reason or another, stopped taking HAART at various times. Nearly all such patients had their virus surge back during these drug 'holidays.' However, a few of these individuals have developed potent anti-HIV immune responses that can control (but not eliminate) the virus. Researchers are frantically trying to understand what it is that went right for these few patients, but they warn AIDS patients not to try this dangerous experiment on their own.

By far, the most pressing issue facing physicians whose patients have access to HAART is how best to use currently available agents. About 25% of new U.S. HIV infections already are resistant to at least one AIDS drug -- as well as for those failing earlier treatments. This year also saw the widespread availability of new tests that determine if a person's particular strain of HIV is resistant to certain drugs.

A principal reason for HAART failure is the toxicity of available drugs. A particularly disturbing side effect is the disruption of fat metabolism seen in patients receiving HIV protease inhibitors, leading to deposits of fat in the abdomen, back of the neck, and breasts with loss of muscle and fat in the face and limbs and metabolic events (diabetes, increased bleeding in hemophiliacs, increased cholesterol). These side effects can be managed with varying degrees of success, but a major breakthrough in 1999 was the confirmation of earlier studies showing that Sustiva (efavirenz) can be combined with other non-protease inhibitor HIV drugs for potent and long-lasting anti-HIV effect. This novel HAART combination allows physicians and patients the option of reserving the potent protease inhibitors for later use.

Many new drugs are in the development pipeline. Two highly promising types of new drugs are the fusion inhibitors, which prevent HIV from binding to target cells, and integrase inhibitors, which attack a viral enzyme crucial for HIV replication. Progress reports on both types of drugs -- some of which already are in early clinical trials -- are scheduled for the 7th Conference on Retroviruses and Opportunistic Infections, to be held in January 2000. Reports also are expected on other approaches, including various gene therapies.

The advent of new drugs will mean little to nations too poor to afford HAART. For the poorer nations of the world, it is generally accepted that only a relatively inexpensive and effective HIV vaccine can stop the AIDS juggernaut. Indeed, the keynote lecture at the upcoming Retrovirus conference will be a report on the state of HIV vaccines by Gary Nabel, MD, PhD, the chief of the new AIDS Vaccine Research Center at the National Institutes of Health. Unfortunately, Nabel's 2000 report is unlikely to announce any more progress than did a similar keynote address at the 1999 Conference on Vaccine Research by Margaret I. "Peggy" Johnston, assistant director for AIDS vaccines at the National Institute of Allergy and Infectious Diseases.

"There has been good immunogenicity with some candidate vaccines," Johnston said. "I say good, not excellent. We don't know if good is good enough, and we must turn to efficacy trials to evaluate this."

Johnston noted that one possible vaccine, called AidsVax, is being tested by VaxGen, the manufacturer. "In three years or so we should have information on whether there is any efficacy," she said.

Various other vaccines are being tested, but thus far only 50% to 70% of all vaccine recipients show an anti-HIV response. A novel approach to an HIV vaccine may make current candidates obsolete. This approach, announced in 1999 by Rachel A. LaCasse, Jack H. Nunberg, PhD, and colleagues at the University of Montana, takes advantage of the recently-discovered ability of HIV to hide its most sensitive parts until just before it attacks a target cell. LaCasse and colleagues killed the virus just at this crucial moment, and in animal studies found that this killed virus could lead to the formation of very effective antibodies to fight the disease.

The good news continues for efforts to stop mother-to-child HIV transmission, often called "vertical transmission." The proven ability of AZT to greatly reduce the chances that an infected woman will pass the virus to her infant has, in the U.S. and Western Europe, translated into enormous reductions in method of transmission. "The elimination of perinatal [around the time of birth] HIV transmission may be possible," says CDC researcher Mary Lou Lindegren, MD.

Disturbing evidence suggests that AZT damages mitochondria, the power plant of every cell, in infants exposed to the drug. However, a study published in the Journal of the American Medical Association in early 1999 found no harmful effects from maternal AZT use in children as old as six years. And less toxic drugs such as Viramune (nevirapine) also appear to be capable of reducing HIV transmission from mother to child.

The major question for the year 2000 is the extent to which AZT or other drugs will be made available to women in developing nations. While long-term use of these drugs remains unaffordable, short-term use to prevent perinatal transmission may be possible. Enormous questions remain unresolved: is perinatal prevention enough, or should a mother be treated throughout the breastfeeding period? Also, to what degree should drug companies and the governments of industrialized nations subsidize perinatal prevention in the developing world?

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