Made in India, the Ideal `Cocktail' for AIDS

By DONALD G. McNEIL Jr. New York Times. Published: May 4, 2004

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.

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