In the first study of its kind, researchers report today that so-called triple therapy for HIV-positive individuals can not only reduce blood levels of the virus, but also significantly slows the progression from infection to actual clinical symptoms of AIDS.
In a separate study, scientists also show that the combination of a protease inhibitor with two conventional antiviral drugs, AZT and 3TC, can keep AIDS virus levels low for as long as a year. Some experts had feared that the virus would become resistant to such combinations or that the drugs would lose effect over time.
The two studies in the New England Journal of Medicine provide strong confirmation that triple therapy is the best way to attack AIDS and that its use should be extended to the about two-thirds of America's 900,000 HIV-positive people who are not receiving it, experts said.
"This is the first definitive study documenting the effectiveness of this therapy for such a sustained period," said Dr. John W. Mellors of the Veterans Affairs Pittsburgh Health Care System.
"This is a giant step toward making HIV infection a controllable illness," said Dr. Roy Gulick of the New York University School of Medicine.
In an editorial in the same issue, the New England Journal of Medicine called for mandatory nationwide reporting of the names of HIV-positive individuals to health authorities in an effort to better control spread of the disease. California, New York and 21 other states do not require such reporting.
Now that HIV infection has become more manageable, such reporting would allow health authorities to identify other infected individuals more quickly and begin treatment, journal deputy editor Dr. Robert Steinbrook argued in the editorial.
Early in the AIDS epidemic, the stigma associated with HIV infections was so great that researchers thought privacy issues overwhelmed the need for such notifications. But mandatory reporting has grown much less controversial recently, largely because new treatments have allowed many such individuals to carry on normal lives.
The four protease inhibitors now approved by the Food and Drug Administration have revolutionized the treatment of AIDS over the past two years. The new drugs, which block the activity of an enzyme called protease that is crucial to replication of the virus, are quite potent by themselves in halting proliferation of HIV.
But when combined with two other, more conventional AIDS drugs, they have been shown in a number of studies to reduce the amount of HIV in the bloodstream to levels that are undetectable with existing technology.
Researchers have assumed that lowering virus levels so dramatically would improve the patient's clinical condition, but the new study is the first to document that impact, Gulick said.
In the first study, conducted at 30 sites across the country--including UCLA, UC San Diego and the San Diego VA Medical Center--1,156 patients were given either triple therapy with the protease inhibitor indinavir added to AZT and 3TC or the combination of AZT and 3TC alone.
This study was especially valuable, said Dr. Douglas Richman of the San Diego VA and UC San Diego, because the patients reflected a cross-section of AIDS patients in this country. Twenty-eight percent of the participants were African American, 19% were Hispanic and 17% were female. Most previous studies of triple therapy, he said, have focused primarily on gay white males.
The team found that only 6% of the patients taking the triple therapy developed AIDS-related infections or cancers, compared to 11% of those receiving only the antiviral drugs. Furthermore, only 1.4% of those taking triple therapy died during the average 35 weeks of the study, compared to 3.1% of those receiving AZT and 3TC.
The second study, conducted at New York University, UC San Diego and two other sites, involved 97 patients. All had previously taken AZT, most had taken at least one other anti-AIDS drug as well, but none had previously been given a protease inhibitor.
Their average T-cell count at the beginning of the study was a low 144, so they were clinically defined as already having developed AIDS. T-cells are white blood cells that normally attack viruses, but they are also attacked--and destroyed--by HIV. Their level is a sign of how far the disease has progressed.
Among those patients receiving indinavir, AZT and 3TC, the team reported, 82% showed a drop in blood HIV levels below the limits of detectability and sustained the drop for more than a year. Some have now gone for 16 months, Gulick reported earlier this year.
In comparison, only 43% of those who received indinavir alone were able to maintain such low levels for a year, and none of those who received only AZT and 3TC did so.
The T-cell counts of those who received triple therapy also improved by an average of about 150.
About 3% of the patients in each study dropped out because of side effects from the drugs or an inability to maintain the rigorous dosing schedules. The most serious side effect was the formation of kidney stones in about 4% of patients. Nausea was also a problem.
The therapy was least effective, Mellors said, in those with the most advanced infections, those who had already been treated with 3TC or a protease inhibitor or those who were not able to take the drugs on a regular basis. Researchers believe that failure to adhere to a rigid schedule of taking the drugs can lead to the evolution of drug-resistant strains of the virus, and the studies seemed to support that conclusion.
In June, a federal panel recommended that triple therapy be considered for every patient who is HIV-positive and that it be started early in the course of infection, when it can do the most good. But the high cost of the drugs, $12,000 or more per year, has limited their use. Only about a third of the estimated 650,000 to 900,000 HIV-positive people in the United States are receiving the drugs, according to current estimates.
An AIDS advocacy group noted Wednesday that more than half of the 50 states' AIDS Drug Assistance Programs, which provide the drugs to people who cannot afford them, have imposed new limits to cope with the increased demand for the drugs.
The journal editorial advocated increased funding for such programs and that triple therapy be made more widely available.