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Adding a fourth medication to a standard three-drug "cocktail" employed to suppress HIV and prevent AIDS does not improve the effectiveness of treatment, concludes a major multicenter clinical trial led by physician-scientists at NewYork-Presbyterian Hospital/Weill Cornell Medical Center in New York City.

"We saw no differences over three years between the 4- and 3-drug regimens in terms of decreasing HIV levels, increasing the immune system T cells or side effects," says Dr. Roy M. Gulick, director of the HIV Clinical Trials Unit at NewYork-Presbyterian/Weill Cornell and associate professor of medicine at Weill Cornell Medical College.

These findings suggest that current triple-drug therapies continue to perform remarkably well for the large majority of patients," according to Dr. Gulick. "In fact, more than 80 percent of our patients reduced their HIV levels to below detection for the three years of the study."

"For these patients, adding a fourth drug provided no added benefit," he concludes.

The findings, based on a 2001-2005 study of 765 HIV-infected patients, will be published as the lead article in a special HIV/AIDS-themed issue of the Journal of the American Medical Association, timed to coincide with the 16th International AIDS Conference in Toronto, Canada, Aug. 13 to 18.

Dr. Gulick presented the findings at a special JAMA-sponsored AIDS Conference press briefing, on Sunday, August 13.

The study was funded by a grant from the National Institutes of Health as part of the AIDS Clinical Trials Group (ACTG) initiative – a coordinated network of HIV/AIDS researchers working at 33 institutions across the country.

The motivation for the study was simple, Dr. Gulick explains.

"With HIV-suppressing antiretroviral drugs, researchers initially discovered that two drugs together worked better than one, and then that three medicines worked even better than two," he says. "With each additional medication, we saw decreased progression to AIDS and decreased deaths. However, an open question was whether 4 drugs would work better than 3."

A few prior trials have looked at the question of whether using four drugs might trump using three, Dr. Gulick notes. But the results of those trials have been tough to interpret, because adding the fourth drug meant adding an extra medication for patients, with the potential for more inconvenience and side effects.

That meant that differences between the two strategies – in terms of the patients’ ability to keep up with the pills and the occurrence of drug-related side effects – could have confounded the results.

"We got around that problem, however," says Dr. Gulick.

He explains that standard antiretroviral therapy typically includes one pill that contains two nucleoside-type drugs – for example, zidovudine/lamivudine. Patients are then given a second pill containing a non-nucleoside drug, such as efavirenz.

"In our 4-drug regimen, we used a single pill that contained three nucleosides – zidovudine/lamivudine plus abacavir. Patients also took the pill containing the non-nucleoside, efavirenz," Dr. Gulick explains.

"So, whether you got the 3- or 4-drug regimen, you still took the same number of pills per day. That means the 4-drug regimen was no more complicated than standard triple therapy."

All of the patients in the study were "treatment-naïve" at the beginning of the trial, meaning that they had never been placed on HIV-suppressing medications before.

The study population – drawn from all 33 ACTG sites nationwide – was also remarkably diverse.

"In the U.S., the epidemic has been moving to minority populations, and so we built our cohort to reflect that. In fact, more than half of those enrolled were people of color, and 19 percent were women," notes study co-author Dr. Bruce R. Schackman, chief of the Division of Health Policy in the Department of Public Health at Weill Cornell Medical College.

In this randomized, double-blind, placebo-controlled study, the researchers gave half the participants the "standard of care" three-drug combo, while the other half received the four-drug regimen.

Researchers at centers across the U.S. used regular blood tests to track three criteria of treatment effectiveness: time to virologic failure (i.e., rebound in HIV level), changes in levels of immune system T cells, and serious side effects.

"By the end of this 3-year study, we found no significant improvement in any of these measures after adding the fourth drug to the standard three-drug regimen," Dr. Gulick says.

Specifically, 26 percent of participants on the three-drug combo reached virologic failure, compared to 25 percent of those on the four-drug combo. Average time to virologic failure was similar between the two groups.

The number of patients who saw their HIV levels dip to undetectable was also similar, regardless of whether they took three or four drugs: 85 percent of patients taking zidovudine-lamivudine-efavirenz achieved HIV-1 RNA counts at or below 50 copies per milliliter, compared to 88 percent of those who added in the fourth drug, abacavir.

There was also no significant difference between the two treatment arms in terms of increases in immune system T cell counts or in the incidence of side effects, the researchers noted.

Why doesn't adding a fourth drug seem to matter? According to Dr. Gulick, "it seems that our current triple-drug therapies are already so effective that it's just hard to improve on that. In that sense, we're doing incredibly well."

But he noted that not every HIV-infected patient will gain equal benefit from standard three-drug therapies.

"There are many reasons a drug combination can fail, even with three medications. And every doctor has to treat patients on a case-by-case basis," he says. "In fact, some patients with HIV do take a fourth medication. Even five- or six-drug regimens are not unheard of in patients with past treatment experience."

But the new study suggests that, for many, if not all patients, starting HIV treatment with the standard triple-drug regimens is sufficient to help keep AIDS at bay.

"As long as patients are able to take their medications as directed and see their doctor if and when problems emerge, HIV can be suppressed and the immune system strengthened with the three-drug regimen we routinely use today," Dr. Gulick concludes.

Co-authors included Dr. Heather Ribaudo and Christina Lalama, Harvard School of Public Health, Boston; Dr. Cecilia Shikuma, University of Hawaii, Honolulu; Dr. William Meyer III, Quest Diagnostics, Inc., Baltimore; Dr. Edward Acosta, University of Alabama, Birmingham; Dr. Jeffrey Schouten, University of Washington, Seattle; Dr. Kathleen Squires, University of Southern California Medical Center, Los Angeles; Dr. Christopher Pilcher, University of North Carolina, Chapel Hill; Dr. Robert Murphy, Northwestern University, Chicago; Dr. Susan Koletar, Ohio State University, Columbus; Dr. Margit Carlson, University of California, Los Angeles; Dr. Richard Reichman, University of Rochester, N.Y.; Barbara Bastow, Social & Scientific Systems, Inc., Silver Springs, Md.; Dr. Karin Klingman, U.S. National Institute of Allergy and Infectious Diseases, Bethesda, Md; and Dr. Daniel Kuritzkes, Brigham and Women’s Hospital and Harvard Medical School, Boston.