Just a FYI.
http://www.washingtonpost.com/wp-dyn/artic...-2003Dec10.htmlThree Drugs Work Best Against AIDS in Study
But Over 2 Years, Response Rates Fell
By David Brown
Washington Post Staff Writer
Thursday, December 11, 2003; Page A34
One particular combination of three antiretroviral drugs works much better than many others in suppressing the AIDS virus and just as well as some four-drug combinations.
Those are among the conclusions of a study being published today that seeks to cut a clear path through the increasingly dense thicket of choices facing AIDS patients and their physicians.
"It really suggests for the first time that how we combine the drugs makes a big difference. That's an issue that we've been trying to understand better for a while," said Gregory K. Robbins, a physician at Harvard Medical School who helped lead a large team of American and Italian researchers.
But although the studies provide useful guidance, they also highlight the shortcomings of current treatments for HIV. Out of about 1,000 patients, 45 percent tried and abandoned at least one, and often two, drug combinations over the course of two years. The drugs either stopped working, or the patients stopped taking them because of intolerable side effects or for other reasons.
The failure rate -- high but not unprecedented in HIV treatments -- suggests that the size of the challenge facing treatment advocates who hope to bring antiretrovirals to millions of AIDS patients in poor countries over the next two years.
There are now 20 antiretroviral drugs approved in the United States. They fall into three groups -- nucleoside and non-nucleoside reverse transcriptase inhibitors, and protease inhibitors -- always given in combinations of three or more. As a result, the therapeutic strategies doctors can theoretically choose now number in the thousands.
In the new study, one of the largest to compare AIDS treatments, the researchers ran a head-to-head contest among six of the more popular combinations. None of the patients had been on antiretrovirals before. Their HIV infections were about midway through the typical course, based on a standard measure of damage to the immune system. Their average number of CD4 cells was 280, with normal being a count of 600 to 1,200.
The winning combination was AZT (the oldest AIDS drug), lamivudine (also known as 3TC) and efavirenz. The first two are nucleosides, and the third, a non-nucleoside. Although the advent of the first protease inhibitor in 1995 ushered in the era of lifesaving "triple therapy," the combinations containing protease inhibitors did not perform as well.
After 48 months, the AZT-3TC-efavirenz combination was still working and tolerable in about 90 percent of those taking it. For the three other three-drug combinations, the percentages were 60 to 70. Because some people dropped out without explanation, the percentage still on their first combination after two years was somewhat lower for all groups.
When the protease inhibitor nelfinavir was added to the winning three-drug combination, the four drugs were not measurably better than the three alone.
Curiously, although the AZT-3TC-efavirenz combination was clearly the best, combinations containing the nucleosides AZT and 3TC were not always better than regimens containing two other nucleosides. Instead, some drugs perform best in concert with particular other ones.
Combinations that include didanosine (ddI) and stavudine (d4T) together caused more serious side effects than others and should not be used unless absolutely necessary, wrote the authors of the paper, which appears in the New England Journal of Medicine.
HIV treatment guidelines put out by the Department of Health and Human Services were updated in October to reflect the new findings, some of which had been described before publication.
The winning combination of AZT-3TC-efavirenz is one of four recommended by the World Health Organization in its "3 by 5" initiative, which aims to put 3 million AIDS patients in developing countries on antiretroviral therapy by the end of 2005. AZT and 3TC can be taken as a single pill twice a day, and efavirenz as a single pill once a day.
The findings suggest that clinicians implementing "3 by 5" should be prepared to adjust their initial medication choices for many patients, all of whom will be getting treatment for the first time and whose infections will be at least as advanced as those in the study.
However, the American and Italian physicians almost certainly had a lower threshold for declaring a treatment a "failure" than the 3-by-5 clinicians are likely to have. Antiretroviral combinations do not have to completely suppress the virus to greatly benefit a patient.
Even in its imperfect form, antiretroviral therapy "has had an enormous reduction in mortality and morbidity from AIDS, and we need to extend its benefit to people who are going to be dead in two years or so if we don't intervene," said John W. Mellors, a leading AIDS researcher at the University of Pittsburgh.
Robbins, the Harvard researcher, called the winning combination "a good regimen that is easy to take, is well-tolerated and within the grasp of the developing world."
