Attempt to Make AIDS Therapy Simpler Runs Into a Clinical Trial Roadblock

July 16, 2003

Ed Susman

July 15, 2003 (Paris) — Patients infected with human immunodeficiency virus (HIV) would likely be more compliant with long-term therapy if they didn't have to take complicated multidrug regimens to achieve adequate suppression of the virus in their blood.

While a far cry from the early days of protease inhibitor treatments when handfuls of medications were needed all day long, doctors continue to try to make the drug cocktails easier to follow and easier to consume.

A combination drug made up of three nucleoside reverse transcriptase inhibitors (NRTIs), zidovudine, lamivudine, and abacavir (Trizivir; GlaxoSmithKline) has the simple dosing regimen of one pill in the morning and one a night. A group of researchers decided to study whether the triple-drug therapy could suppress the virus as well as combinations of drugs from two or more classes, such as the frequently prescribed cocktail of two NRTIs and the nonnucleoside reverse transcriptase inhibitor efavirenz.

A large study in which the triple NRTI regimen was compared with two treatments containing efavirenz was stopped abruptly because the Data and Safety Monitoring Board of the overseeing agency, the National Institute of Allergy and Infectious Diseases, found that too many patients in the triple NRTI arm were suffering virologic failure compared with patients in the efavirenz arms.

In presenting the results of the trial that was halted, Roy Gulick, MD, associate professor of medicine at Cornell University's Weill College of Medicine in New York City, explained that the goal of the researchers in the AIDS Clinical Trials Group protocol 5095 was not to show that the triple NRTI treatment was better, just to prove it wasn't inferior. Even so, it didn't turn out that way.

"In treatment-naive patients, the combination of zidovudine, lamivudine, and abacavir is inferior to efavirenz-containing treatment in terms of rates and time to virologic failure," Dr. Gulick said here in his oral presentation at the Second International AIDS Society Conference on HIV Pathogenesis and Treatment.

The researchers enrolled 1,147 patients into the study. When the data were analyzed, the researchers found that 82 patients (21%) who were receiving the triple NRTI regimen had experienced virologic failure. Among the patients in the efavirenz arms of the study, 11% experienced virologic failure. "That difference was highly statistically significant at the P < .001 level," he said. Virologic failure in the study was defined as more than 200 copies of the virus at week 16 or later.

Dr. Gulick reported on results after 32 weeks of study. The two efavirenz arms &#151; one in which efavirenz is combined with the same triple NRTI combination and a second arm that compared efavirenz with zidovudine and lamivudine &#151; were not unblinded. The study is continuing to determine if there is a clinical difference in outcomes among those patients. When the triple NRTI arm of the study was terminated, the patients and their physicians were informed and they were allowed to alter their treatment if they desired or they could remain on the triple NRTI therapy.

In addition to the overall findings, Dr. Gulick said that the efavirenz combinations were superior to the triple NRTI approach both among patients with baseline viral loads greater than 100,000 copies/mL and among patients with baseline viral loads less than 100,000 copies. Those results were also statistically significant, he said. Both regimens result in similar improvements in CD4+ cell counts, with patients recording an average increase of 170 cells.

Even though the trial showed that the efavirenz combination was more durable than the triple NRTI formula, the researchers suggested there was still a role that the triple-drug combination could play. "When you have to make decisions in the clinic, sometimes the ease with which a drug can be taken might be more important," said Sheldon Landesman, MD, chief of infectious diseases at Brookdale Hospital Medical Center in Brooklyn, N ew York. He implied that among individuals who were at high risk for being noncompliant with their therapy, being able to take one pill twice a day might be more important than a higher risk of virologic failure.

"Trizivir is a very useful drug," agreed Christine Katlama, MD, professor of medicine at Hôpital Pitie-Salpetriere in Paris, France. And Princy Kumar, MD, associate professor of medicine at Georgetown University in Washington, D.C., said that despite the trial results, clinicians may still find the triple NRTI combination useful because of "its simplicity, its lack of interaction with other drugs, and its utility for future treatment options."

In a separate presentation, Charles Farthing, MD, medical director of the AIDS Healthcare Foundation in Los Angeles, California, reported on a pilot study using another triple NRTI combination of abacavir, lamivudine, and tenofovir as a once-a-day treatment. He observed that 11 of the 19 patients in the study experienced early virologic failure. "Their data provide further concerns about the potency of triple nucleoside regimens in treating patients with HIV infection," he said.

Second IAS Conference: Abstracts 41, 42, 43. Presented July 15, 2003.

Reviewed by Gary D. Vogin, MD