It was spring of 1996 when Beth Bye says she returned from the dead. The Wisconsin woman hadn't actually died, but with her body ravaged in the late stages of AIDS infection, she had run out of options, and death was, indeed, near. AIDS-related dementia and blindness had crept in — signs that her doctor told her meant time was short. She made funeral arrangements and considered moving to a hospice for her remaining days.

Then, as if to say "not so fast," medical science handed her another option. New drugs called protease inhibitors, first approved in 1995, were about to revolutionize the treatment of patients infected with the AIDS virus. These drugs usually are taken with two other drugs called reverse transcriptase inhibitors. The combined drug "cocktail" has helped change AIDS in the last three years from being an automatic death sentence to what is now often a chronic, but manageable, disease.

Within two months of beginning the triple cocktail treatment, also known as highly active antiretroviral therapy (HAART), Bye's viral load — a measure of new AIDS virus produced in the body — dropped to undetectable levels. Her red and white blood cell counts normalized, an important sign that the immune system was starting to work again. Suddenly she could do simple things she had long given up, such as walk the dog for 2 miles. Bye, now 40, was even able to return to her teaching job and currently works 30 hours a week.

"My recovery was like being on death row and getting that last minute pardon from the governor," she says.

This so-called "Lazarus Effect," named for the biblical figure who was raised from the dead, has occurred with many AIDS patients who take the triple therapy. "It returns many who were debilitated and dying to relatively healthy and productive life," says Richard Klein, HIV/AIDS coordinator for the Food and Drug Administration's Office of Special Health Issues.

Many health experts, in fact, credit the powerful HAART therapy with helping the domestic AIDS death rate to drop by 47 percent in 1997, the last year for which figures are available. Other factors have contributed as well, says Anthony Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases. "It is also likely that increased access to care, our growing expertise and experience in caring for HIV-infected people, and the decrease in new HIV infections in the late 1980s due to prevention efforts are partly responsible for the reduction in HIV-related deaths we are seeing today."

In 1997, for the first time since 1990, AIDS fell out of the top 10 causes of death in the United States, dropping from 8th to 14th place, according to the national Centers for Disease Control and Prevention. By 1998, about 16,000 people were still alive who would have died the previous year if AIDS mortality had continued at its former rate. Still, about 40,000 new infections occur yearly.

A 'One-Two Punch'

So far, the combination HAART treatment is the closest thing medical science has to an effective therapy. The key to its success in some patients lies in the drug combination's ability to disrupt HIV at different stages in its replication. Reverse transcriptase inhibitors, which usually make up two drugs in the HAART regimen, restrain an enzyme crucial to an early stage of HIV duplication. Protease inhibitors hold back another enzyme that functions near the end of the HIV replication process. The combination can be prescribed to those newly infected with the virus, as well as AIDS patients

FDA approved the first drug specifically to combat HIV and AIDS in 1987. Commonly known as AZT (zidovudine), it is in the family of reverse transcriptase inhibitors called nucleoside analogs. Others in this class include ddi (didanosine), ddc (zalcitabine), D4T (stavudine), 3TC (lamivudine), and most recently Ziagen (abacavir). In 1997, FDA approved Combivir, a mixture of AZT and 3TC that allows patients to reduce the number of pills needed, which can be upwards of 20 a day for certain drug combinations.

Viramune (nevirapine), the first reverse transcriptase inhibitor in a class called non-nucleoside analogs, was approved in 1996. The following year, FDA approved a related drug, Rescriptor (delavirdine). In 1998, a third drug in this class, Sustiva (efavirenz) was approved.

Protease inhibitors, the last part of the triple cocktail, have only been on the market about three years. FDA approved the first one, Invirase (saquinavir), in late 1995.

Others approved since include Norvir (ritonavir), Crixivan (indinavir), Viracept (nelfinavir), and Agenerase (amprenivir). Viracept was the first of its class to be labeled for use in children and adults. Norvir and Agenerase are now approved for children as well. FDA also has approved Fortovase, a new formulation of saquinavir that comes in a soft gelatin capsule that allows more drug to be absorbed into the body than the earlier version.

Regimen Has Drawbacks

Though the use of protease inhibitors with other AIDS drugs has had a drastic impact on the health of HIV and AIDS patients, there are drawbacks. For example, the HAART treatment is not an AIDS cure, says FDA's Klein. Though HIV, the virus that causes AIDS, may not be detectable in the blood following successful HAART treatment, experts generally feel that the virus is still present, lurking in hiding spots such as the lymph nodes, the brain, testes, and the retina.

"The improved sense of well-being, and the belief that lower viral load means they will not transmit the virus, has translated, in some communities, to a lapse in certain prevention practices," Klein says. He adds that this is dangerous because infected people, even with diminished viral counts, can spread the virus.

Another concern is that the combination therapy, besides being very expensive, requires a much more complicated treatment regimen. "Patients need to stay aware of and adhere to their dosing schedule," says Klein. "If not taken on a strict regimen, protease inhibitors can result in the emergence of HIV strains that are resistant to treatment." Numerous studies also have shown that viral load can rapidly "rebound" to high levels if patients discontinue part or all of the triple therapy regimen.

Tags: HIV and AIDS

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