Made in India, the Ideal `Cocktail’ for AIDS
5 May 2004 (New York Times)
See online : Made in India, the Ideal `Cocktail’ for AIDS
By Donald G. McNeil Jr.
A three-year study of AIDS drugs has identified what the research leaders believe is the ideal triple-therapy cocktail for new patients.
The successful cocktail, known colloquially as "two nukes plus a non-nuke," is the same one that the World Health Organization has been recommending in poor countries since 2002. It is also the same combination that Indian suppliers of generic drugs have been putting in three-in-one pills since 2001.
Another drug cocktail examined in the study,a "three-nuke combination", did so poorly that patients were taken off it. The failed cocktail is the only one made as a three-in-one pill by any Western pharmaceutical company.
The study, its authors said, suggests that patients who have never been on AIDS drugs should be started on a combination of two nucleoside reverse transcriptase inhibitors ("nukes") and a non-nucleoside reverse transcriptase inhibitor ("non-nuke").
Currently, American and European doctors prescribe many different mixes of the 20 drugs approved for fighting AIDS infections, and shift the mixes as patients develop resistance or side effects.
The study of 1,147 patients, published in the April 29 issue of the New England Journal of Medicine, looked for an ideal regimen for new patients that avoided protease inhibitors. Those drugs are effective and often prescribed by Western doctors, but they can damage the liver or shift body fat into unsightly humps.
The study was begun before any drugs in the two newest classes of AIDS drugs, fusion inhibitors and integrase inhibitors, were approved.
AIDS experts said a second conclusion from the study was that the three-in-one pills offered by generic drug makers from India were better for new patients than any of those sold or planned by Western drug companies.
The study "reinforces the point" that the type of cocktail recommended for poor countries by the World Health Organization is right for rich countries as well, said the study’s lead author, Dr. Roy M. Gulick, director of the H.I.V. clinical trials unit at Weill Cornell Medical College in New York City.
The latest guidelines from the National Institutes of Health for American doctors recommend starting new patients either on the same two-nukes-plus-a-non-nuke regimen that the W.H.O. recommends, or a two-nukes-plus-a-protease-inhibitor regimen.
Most of the Weill Cornell study’s 1,147 patients were nonwhite and 19 percent were women, Dr. Gulick said, so the study’s conclusions should be applicable worldwide.
The AIDS expert who led the committee that formulated the W.H.O. guidelines, Dr. Scott Hammer, chief of the division of infectious diseases at Columbia Presbyterian Medical Center, said the W.H.O. made its 2002 recommendation because the combination worked well and the drugs were generally cheap.
Besides their toxicity problems, he said, protease inhibitors were expensive because only companies that held patents on the drugs made them, and some of the medications required refrigeration, which is impossible to guarantee in, for example, rural Africa.
In the new study, the cocktail that worked best was a mix of the "nukes," AZT and lamivudine plus the "non-nuke" efavirenz. After 32 weeks on the cocktail, 89 percent of the patients had almost undetectable levels of virus in their blood.
The cocktail that did less well was a mixture of AZT and lamivudine plus abacavir. After 32 weeks, only 79 percent of the patients had low levels of virus.
That cocktail is sold by GlaxoSmithKline as a three-in-one pill under the name Trizivir.
However, because it is "clearly inferior" at suppressing the virus, it is "no longer recommended for first-line use" said Dr. David Bangsberg, a professor of medicine at the University of California at San Francisco who monitors treatment around the world.
Most of the study was paid for and monitored by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health.
Glaxo provided its drugs and paid part of the analysis costs, said Mary Faye Dark, a Glaxo spokeswoman.
"We aren’t surprised that Trizivir alone didn’t do as well," Ms. Dark said. The decision to take the study’s patients off it was made in February 2003.
But she said the cocktail still worked in many patients and should play a role in AIDS therapy, especially for maintaining patients whose viral loads have first been lowered by other regimens.
Most three-in-one pills now made by Indian generics makers contain AZT, lamivudine and nevirapine.
Nevirapine is in the same "non-nuke" class as efavirenz and a recent study in Lancet, the British medical journal, found them to be equivalent. Nevirapine is a well-established drug, but it causes a serious rash in some patients, so generics makers are moving toward making compounds with efavirenz as well.
The N.I.H. guidelines prefer efavirenz because it causes fewer rashes, but accept nevirapine as a substitute.
Both the "nukes" and "non-nukes" block reverse transcriptase, an enzyme that allows the RNA in an AIDS virus particle to replicate itself inside the DNA of a healthy T cell, a trigger cell for the body’s immune system. Unable to replicate, the virus cannot spread to other T cells and destroy the immune system.