Editor's Note: The U.S. National Institute of Allergy and Infectious Diseases (NIAID) recently issued a communication to HIV/AIDS care providers regarding interim results from a Phase III, randomized, double-blind comparison of three protease inhibitor (PI)-sparing regimens for the initial treatment of HIV infection. As a courtesy to members of the International Association of Physicians in AIDS Care (IAPAC), IAPAC Monthly is publishing said communication regarding Adult AIDS Clinical Trials Group (AACTG) Study A5095.
A recent review of the [AACTG Study A5095] by [the NIAID] Data and Safety Monitoring Board (DSMB) found that in antiretroviral treatment-naive patients, a combination preparation of three nucleoside analogues, Trizivir, was inferior to two other efavirenz (EFV)-containing treatment regimens being evaluated in the study. The data met pre-specified guidelines for stopping this one arm of the study based on virologic failure. There were no concerns about the toxicity of the study drugs.
Antiretroviral-naive patients randomized to receive a combination of abacavir (ABC), lamivudine (3TC), and zidovudine (ZDV) [otherwise known as ABC/3TC/ZDV or Trizivir] experienced virologic failure earlier and more frequently than patients who were randomized to receive either of the two other treatment regimens being evaluated in the study. The two other treatment regimens are:
A total of 1,147 antiretroviral-naive patients were followed for changes in their viral load and CD4 counts. Virologic failure was defined as having an HIV RNA level in plasma above 200 copies/ml (measured by the Roche Amplicor HIV-1 test) at least four months after starting study treatment.
After an average of 32 weeks on study, a total of 167 study volunteers experienced virologic failure: 21 percent in the group receiving ABC/3TC/ZDV versus 10 percent in the other two groups combined. Virologic failure occurred sooner and more often in those receiving ABC/3TC/ZDV alone, regardless of their initial viral load (whether above or below 100,000 copies/mL). Although data on CD4 counts were not available at the time of the interim analysis, the DSMB felt that they would not reverse the outcome. As a result of these data, the DSMB recommended that the ABC/3TC/ZDV treatment arm be stopped.
Therefore, the study volunteers receiving ABC/3TC/ZDV have been unblinded as to what treatment they were taking, and they have been asked to remain in the study for continued follow-up. These volunteers have been offered several alternatives to the use of ABC/3TC/ZDV alone. GlaxoSmithKline, one of the pharmaceutical companies involved with this study, is also working with [the NIAID Division of AIDS] and the A5095 Study team to provide ABC/3TC/ZDV outside the study for patients who choose this option.
Study volunteers originally given one of the other two drug treatments will continue on the study as planned and will not yet be unblinded. They will, however, be told that they are receiving a combination treatment that contains EFV.
All study volunteers will continue to be followed for approximately two years after the last subject is enrolled -- until approximately September 2004. This follow-up period will allow a comparison of the 3TC/ZDV + EFV and ABC/3TC/ZDV + EFV groups. It also will allow more information to be collected from all three groups about how to use antiretroviral drugs.
Although [NIAID is] confident of these findings, they have not been presented at a scientific meeting, peer reviewed, or published. These results will be submitted to the upcoming International AIDS Society meeting in Paris (July 2003), and further analyses (e.g., CD4 count and adherence data) will be forthcoming. A manuscript is in preparation.
It is important to consider this interim study finding in the context of published results, particularly those from prior studies that investigated either triple nucleoside regimens or EFV-based regimens. The risk of virologic failure is clearly an important factor in selecting an initial antiretroviral regimen.
Other factors such as safety, toxicity, adherence, preservation of future treatment options, access, cost, and other issues also remain important in selecting the optimal first regimen for an individual patient.
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