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| |  Epivir Study Shows Reduction in HIV Disease Progression or Death RESEARCH TRIANGLE PARK, N.C., July 23, 1996 -- A study to determine the effect of the anti-HIV therapy Epivir(R) (lamivudine; 3TC) on survival, delay in disease progression or both, has been stopped after an interim analysis of the data showed a 54 percent reduction in the rate of HIV disease progression, or death, for HIV patients who had Epivir in their treatment regimen, compared to placebo. The endpoint event (disease progression or death) rate in the regimen containing Epivir was nine percent (80 of 935), while the event rate in the placebo containing arm was seventeen percent (81 of 482). The study was designed to investigate the clinical efficacy of adding Epivir to patients' existing anti-HIV therapy, or adding Epivir to Retrovir(R) (zidovudine; AZT) for patients who were not receiving therapy at study entry. The most common existing therapy among patients recruited into the study was Retrovir alone. Discontinuation of the study nearly eight months early was recommended by an independent Data Safety and Monitoring Board (DSMB) following a scheduled interim analysis of data from the trial. The recommendation was made on the basis of data which exceeded the pre-specified requirements for possible discontinuation due to the superior efficacy of one treatment arm. The trial's coordinating committee endorsed the DSMB recommendation. "Members of the DSMB have reviewed the results of the study and unanimously recommend the discontinuation of the trial to allow all participants access to the Epivir+Retrovir combination," said Professor Ragnar Norrby, Chairman of the study's DSMB. Referred to as the CAESAR trial (an acronym for the countries with investigational sites; Canada, Australia, Europe and South Africa), the study was initiated in March of 1995 and was scheduled to conclude in March of 1997. Patients recruited into the study had CD4 cell counts of 25 to 250/mm3 and were currently receiving one of three "background" treatments -- Retrovir alone, Retrovir+ddI or Retrovir+ddc. Patients were then randomized to one of three regimens: their current HIV therapy plus Epivir; current HIV therapy plus Epivir and an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI); or, current therapy plus placebo. Patients accepted into the study who were not receiving any current therapy were treated with Epivir+Retrovir. The median time on study medication at the time of trial discontinuation was approximately 12 months. At the pre-planned interim review, conducted on July 15, the DSMB evaluated data on 1892 patients. Adding Epivir to current therapy resulted in the 54 percent reduction in risk of disease progression or death as compared to adding placebo. The addition of the investigational NNRTI was not shown to provide any additional benefit to that seen with Epivir. Surrogate marker analyses performed on a subset of patients enrolled in the trial were consistent with the clinical results as patients receiving Epivir had more pronounced increases in CD4 cell counts and reductions in the amount of plasma HIV levels than patients receiving placebo. However, the clinical significance of the effect of Epivir in reducing the amount of virus in the blood is unclear. All three arms were generally well tolerated with five percent of patients receiving current therapy plus placebo, three percent of patients receiving current therapy plus Epivir and the NNRTI, and two percent of patients receiving current therapy plus Epivir withdrawing from the study due to adverse events. Also, the addition of Epivir, or Epivir plus the NNRTI, to the existing treatment regimens resulted in no additional clinical or laboratory side effects over the control arm. "The significant reduction in the risk of disease progression or death seen in these data further reinforce the rationale for Epivir+Retrovir as a cornerstone of treatment for HIV and as a widely used foundation for three-drug HIV regimens," said Richard Kent, M.D., vice president and director of worldwide clinical research for Glaxo Wellcome. Today's news comes on the heels of several presentations of preliminary data two weeks ago in Vancouver, BC, at the XI International Conference on AIDS in which the addition of a third drug to the foundation combination of Epivir+Retrovir resulted in unmeasurable plasma HIV levels in a few dozen patients. These trials reported data from 16 to 48 weeks of treatment and used various viral load detection assays that were sensitive to at least 200 copies of HIV RNA per milliliter. The results reported today also support a meta-analysis presented in Vancouver which suggested that Epivir+Retrovir may have been associated with a delay in disease progression in the four pivotal clinical trials on which the drug's accelerated approval was based. In the four pivotal clinical trials, the combination of Epivir+Retrovir demonstrated superior antiviral activity -- as measured by CD4 cell count increases and decreased plasma HIV levels -- when compared to Retrovir alone, while not significantly increasing the toxicity associated with treatment with Retrovir alone. In addition, data from these pivotal trials suggest a unique resistance interaction for this combination. Data from a small number of patients suggest that Epivir may delay the development of HIV resistance to Retrovir in some patients with no previous treatment history, while possibly reversing resistance to Retrovir in a small number of patients who had received extensive prior therapy with Retrovir. However, strains of HIV resistant to both Epivir and Retrovir have been seen. This resistance information is not yet fully understood and continues to be studied in ongoing trials. Epivir+Retrovir was generally well tolerated in clinical trials, with the most commonly reported side effects including headache (35%), nausea (33%), malaise and fatigue (27%), nasal congestion and runny nose (20%), diarrhea (18%), low white blood cell counts (7.2%) and anemia (2.7%). In addition, pancreatitis was observed in 15 percent of pediatric patients in clinical trials, especially in children with advanced HIV disease who had received prior nucleoside analogue therapy. A separate study, to evaluate the effects of Epivir on delaying disease progression or death in pediatric patients is ongoing in the U.S. That study, with a different design and treatment comparisons, is sponsored by Glaxo Wellcome in collaboration with the AIDS Clinical Trials Group. This is a long-term trial and final results are not expected to be available until 1999. An interim analysis of these data will be performed and reported to an independent DSMB when the trial is fully enrolled, which is expected in early 1997. Glaxo Wellcome is a world leader in developing new treatments for HIV disease and AIDS. In 1987, Retrovir became the first drug to be released by the FDA for use in treating HIV and AIDS. In November of 1995, Epivir was released under the FDA's accelerated approval regulations for use in combination with Retrovir. In addition, Glaxo Wellcome discovered, developed and markets several products for the treatment of HIV-related opportunistic infections. Epivir was discovered by BioChem Pharma of Laval, Quebec, Canada. BioChem Pharma licensed the rights to develop Epivir to Glaxo (now Glaxo Wellcome) in 1990.
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