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| |  AIDS2000: Potent Results Seen With Sustiva (Efavirenz) And ABT- 378/Ritonavir Combination TORONTO, ON -- July 17, 2000 -- Data recently presented suggest that DuPont Pharma's Sustiva® (efavirenz), a non-nucleoside reverse transcriptase inhibitor (NNRTI), and the experimental protease inhibitor (PI) ABT- 378/ritonavir (ABT-378/r) are a potent HIV combination treatment when used in protease inhibitor-experienced, NNRTI-naive patients. The data, from the M98- 957 Study Group presented last week at the XIIIth International AIDS Conference in Durban, South Africa, point to the potential use of these agents in combination, with nucleoside reverse transcriptase inhibitors (NRTIs), in the effective treatment of HIV. Intent-to-treat data from this randomized study show that of the 28 patients analyzed after 24 weeks of treatment, 82 percent (23/28) of the patients, treated with 600 mg of Sustiva once-daily and 533/133 mg of ABT- 378/r twice daily plus physician-selected NRTIs, had viral load less than 400 copies/mL. The mean increase in CD4 cell count observed at week 24 was 41 cells/mL. "The preliminary results with this antiretroviral combination are encouraging," said Nathan Clumeck, M.D., Department of Infectious Diseases, Centre Hospitalier Universaire St. Pierre, Brussels. "They indicate the potential potency of this treatment option in a patient population that may not have many therapy choices available to them." M98-957 was a 24-week safety and efficacy evaluation of 57 multiple protease inhibitor-experienced/NNRTI-naive patients. Mean plasma HIV-RNA at baseline was 4.4log10 copies/mL and the mean CD4 cell count was 325 cells/uL. Safety data from this study indicate that the most common adverse events of at least moderate severity were diarrhea and asthenia. Lipid elevations were the most common laboratory abnormality. Four of 57 patients discontinued ABT-378/r due to adverse events at 24 weeks. Additional data presented by Philip Keiser, M.D., Medical Director, Amelia Court HIV/AIDS Clinic, Division of Infectious Diseases, University of Texas Southwestern Medical Center, Dallas, Texas at the XIIIth International AIDS Conference last week indicate that salvage therapy with Sustiva provides the longest viral suppression in NNRTI-naive, protease inhibitor-experienced patients also treated with a protease inhibitor to which the virus was still sensitive (sensitive protease inhibitor). These results, using time-to- treatment failure as the primary endpoint, suggest that Sustiva should be an anchor of salvage therapy in patients with NNRTI-sensitive HIV virus. Well- known and long used as a measurement of a drug's clinical efficacy in oncology, time-to-treatment failure measures the efficacy of a drug regimen as a function of the durability of its action over time. In the time-to-treatment failure analysis, the best outcome was observed in NNRTI-naive patients treated with Sustiva and a sensitive protease inhibitor - 252 days. Time-to-treatment failure in NNRTI-naive patients treated with Sustiva and without a sensitive protease inhibitor was 114 days. In NNRTI-experienced patients treated with Sustiva and with a sensitive protease inhibitor, it was 23 days. In NNRTI-experienced patients treated with Sustiva without a sensitive protease inhibitor it was 38 days. In this study, 67 patients were followed for a median of 156 days and had a median experience of seven prior antiretroviral drugs and three prior protease inhibitors - 57 percent had previous NNRTI experience. Baseline median viral load was 68,752 copies/mL and median baseline CD4 count was 128 cells/mm3. Predictors of failure were previous NNRTI experience, baseline CD4 count less than 128 cells/mm3, baseline viral load greater than 68,000 copies/mL or treatment with less than three sensitive drugs. In January 2000, the U.S. Department of Health and Human Services (DHHS) named Sustiva as the only non-nucleoside reverse transcriptase inhibitor to be "strongly recommended" for use in first-line combination with NRTIs for the treatment of HIV-infected individuals. Sustiva (efavirenz), developed by the DuPont Pharmaceuticals Company, is approved, in capsule formulation, for the treatment of HIV-1 infection, in combination with other antiretroviral agents. This is based on analyses of plasma HIV-RNA levels and CD4 cell counts in controlled studies of up to 24 weeks in duration. Sustiva is unique for its efficacy and simple dosing regimen. Three Sustiva capsules can be taken once a day compared to four to 18 pills per day for a protease inhibitor. Sustiva can be taken on an empty or full stomach; however, a high fat meal may increase the absorption of Sustiva and should be avoided. This flexibility around dosing with meals combined with its efficacy and potency may help patients maintain more normal lives while combating HIV. Clinical trials with Sustiva have demonstrated that the majority of patients, including patients with baseline viral counts in excess of 100,000 units or "copies" per millilitre (copies/mL) had viral loads reduced to below quantifiable levels (less than 400 copies/mL). Sustiva is also present in the cerebrospinal fluid, one of several sanctuaries for the virus that make treatment more difficult. The clinical significance of this presence is unknown. This potency, combined with its efficacy in first-line and salvage therapy, makes Sustiva an important addition to HIV therapy regimens, receiving expedited approval in both Canada and the United States. Sustiva has also proven to be generally well tolerated by adult patients. The most notable side effects associated with Sustiva therapy are nervous system symptoms and rash. In clinical trials, slightly greater than half of the patients, 52 per cent, have reported central nervous system symptoms that may include dizziness, insomnia, somnolence, impaired concentration and abnormal dreaming. However, central nervous system effects were severe enough to cause treatment discontinuation in 2.6 per cent of patients. Rash is usually mild-to-moderate in severity and often resolves itself within one month of continued therapy with Sustiva. Among patients receiving Sustiva, 1.7 per cent discontinued therapy due to rash. In controlled trials, serious psychiatric symptoms observed were severe depression (0.9 percent), suicidal ideation or attempts (0.5 percent), aggressive behavior (0.3 percent), paranoid reactions (0.2 percent) and manic reactions (0.1 percent). These problems were seen at a similar frequency in control groups and tended to occur more often in patients with a history of mental illness, where the frequency of each of these events was approximately one percent. A few suicides have been reported; however, a causal relationship to Sustiva has not been established. Patients with serious psychiatric experiences should contact their physician. Women should not become pregnant while taking Sustiva because birth defects have been seen in animals given efavirenz at levels similar to those given to humans. Patients should be cautioned not to operate hazardous machinery or drive if they experience nervous system symptoms. Sustiva should not be administered concurrently with Hismanal® (astemizole), Prepulsid® (cisapride), Versed® (midazolam), Halcion® (triazolam) or ergot derivatives. Current treatment guidelines recommend against the use of any antiretroviral agent as monotherapy. Therefore, Sustiva must not be used as a single agent to treat HIV or added on as a sole agent to a failing regimen. The choice of new antiretroviral agents to be used in combination with Sustiva should take into consideration the potential for viral cross-resistance. Sustiva therapy should always be initiated in combination with at least one other antiretroviral agent to which the patient has not been previously exposed. Related links: Sustiva, Hismanal, Prepulsid, Versed, Halcion and DuPont Pharma.
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