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Trial Results Show Triple Nucleoside Combination Clearly Inferior To Efavirenz in Treatment-Naive HIV Patients: Presented at IAS-HIV

By Michael Smith and Ed Susman

PARIS, FRANCE -- July 14, 2003 -- Use of the convenient triple nucleoside drug containing zidovudine, lamivudine, and abacavir is clearly inferior to regimens in which the antiretroviral drugs are combined with the non-nucleoside reverse transcriptase inhibitor efavirenz in treatment-naive patients infected with human immunodeficiency virus, Researchers said here July 14^th at the 2^nd International AIDS Society Conference on HIV Pathogenesis and Treatment.

In the AIDS Clinical Trials Group study protocol 5095, researchers attempted to show that treatment with the simple triple nucleoside analogue -- 1 pill twice a day -- was not inferior to combinations containing efavirenz in suppressing virus.

But the study was stopped early upon a recommendation by the National Institute of Allergy and Infectious Diseases' Data and Safety Monitoring Board, because the triple nucleoside arm was proving to be inferior to zidovudine, lamivudine, and efavirenz as well as inferior to the triple nucleoside analogue and efavirenz.

The comparison between the 2 efavirenz arms is continuing, said Dr. Roy Gulick, MD, associate professor of medicine at the Weill College of Medicine, Cornell University, in New York City, United States, who presented the results of ACTG 5095.

"In treatment-naive patients," Dr. Gulick said, "the combination of zidovudine, lamivudine, and abacavir was inferior to efavirenz-containing treatment in terms of rates and time to virologic failure."

The study enrolled 1,147 patients and Dr. Gulick reported on results after a median of 32 weeks of treatment. When the triple nucleoside 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 nucleoside therapy.

When the study was stopped, 21% of patients taking the triple nucleoside regimen had experienced virologic failure compared with 11% of the patients in the pooled efavirenz arms, he reported in an oral session. "That difference was highly statistically significant at the P<0.001 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 also said that the efavirenz combinations were superior to the triple nucleoside regimen among patients who first entered the trial with viral roads greater than 100,000 copies/mL, and it was superior among patients who entered the trial with HIV levels less than 100,000 copies/mL. Those results were also statistically significant, he said.

Treatment was generally well tolerated, he said, and all patients self-reported compliance with the regimen at weeks 4, 12, and 24. There were no reported differences in compliance. However, he said that 22% of patients who experienced virologic failure had wild-type virus at the time of virologic failure, an indication that compliance might have been less than perfect in these patients.

Both regimens resulted in similar improvements in CD4-positive cell counts, with patients recording an average increase of 170 cells, Dr. Gulick said.

Princy Kumar, MD, an associate professor of medicine at Georgetown University, in Washington, DC, United States, said that despite the trial results clinicians still may find the triple combination useful because of "its simplicity, its lack of interaction with other drugs, and its utility for future treatment options."

And Christine Katlama, MD, a professor of medicine at Hôpital Pitié-Salpêtrière, in Paris, France, noted that the combination of nucleoside analogues in 1 pill "makes it a very practical drug."

However, Charles Farthing, MD, medical director of the AIDS Healthcare Foundation, in Los Angeles, California, United States, reported on a pilot study using a once-a-day triple nucleoside drug combination of abacavir, lamivudine, and tenofovir. But 11 of the 19 patients in the study experienced early virologic failure.

"These data provide further concerns about the potency of triple nucleoside regimens in treating patients with HIV infection," he said.

David B. Clifford, MD, of Washington University in St. Louis, Missouri, United States, reported on a substudy, called ACTG 5097, examining efavirenz-associated neurologic symptoms among 300 patients in the 3 arms of the 5095 trial. The "good news," Dr. Clifford said, is that patients in all 3 arms showed an expected improvement in neurologic functioning after the initiation of treatment.

But, he added, the 200 participating patients in the efavirenz arms did show a range of neuropsychological symptoms in the early days of treatment. Most resolved after a few weeks of therapy, he said.

The goal of the study was "to put a simple measure on neuropsychological functioning," he said. To do that, neuropsychological performance was summarized as Z-scores of Digit Symbol Substitution and Trailmaking A and B tests. Additional measures were Pittsburgh Sleep Quality Index (PSQI), Center for Epidemiologic Studies' Depression scale, Spielberger State-Trait Anxiety Inventory, efavirenz serum levels, and a symptom list. Measures were made at baseline and at weeks 1, 4, 12, and 24.

In the first week of treatment, Dr. Clifford said, efavirenz causes symptoms that a neurologist would interpret as a vestibular disorder -- dizziness, a sense that the room is spinning, a feeling of falling -- and a range of others. But by week 4 of treatment, Dr. Clifford said, the symptoms generally resolved without treatment.

In the same way, the sleep quality index revealed significantly more "bad dreams" at week 1, a difference that reached significance at the P=0.038 level. By week 4, the efavirenz arms were essentially the same as the triple nucleoside arm. Indeed, global PSQI scores and reported sleep quality were better. There were no significant differences in changes in depression or anxiety between the treatment arms, Dr. Clifford said.

The ACTG trials were supported in part by Boehringer Ingelheim, Bristol-Myers Squibb and GlaxoSmithKline.


[Study title: A Comparative Study Of 3 Protease Inhibitor-Sparing Antiretroviral Regimens For The Initial Treatment Of HIV Infection. 42. Induction Of Antiretroviral-Naïve HIV-Infected Subjects With Trizivir (TZV) And Sustiva (EFV) For 48 Weeks (Ess40013). 43. Early Virologic Failure In A Pilot Study Evaluating The Efficacy Of Abacavir, Lamivudine And Tenofovir In The Treatment Naive HIV-Infected Patients. Abstracts. 41. ACTG 5095]

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