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| |  ICAAC: Selective Serotonin Reuptake Inhibitors Do Not Affect Anti-HIV Sustiva (Efavirenz) TORONTO, ON -- September 19, 2000 -- Data presented at the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy suggest that when selective serotonin reuptake inhibitors (SSRIs) are used at the same time patients with HIV infection are receiving DuPont Pharma's Sustiva® (efavirenz), virologic outcome, CD4 cell response and/or safety are not compromised. The findings, from Study DMP 266-006, indicate that the pharmacokinetics of Sustiva, a non-nucleoside reverse transcriptase inhibitor, do not appear to be affected by the concomitant use of SSRIs. Data for the 851 patients treated with Sustiva in the 006 study (n equals 1266) were evaluated and of these patients, the 334 patients treated with Sustiva who had population pharmacokinetic (PK) samples collected after 16-24 weeks were considered. Seventeen patients in this subgroup were receiving SSRIs (Paxil®, paroxetine; Zoloft®, sertraline; and Prozac®, fluoxetine) at entry into the 006 study. The results of the retrospective analysis show that the mean area-under- the-curve (AUC), Cmax and trough levels of Sustiva were consistent with what was observed with patients treated with Sustiva in the absence of these SSRIs in the 006 study. The mean AUC, Cmax and trough concentrations of Sustiva in the group taking SSRIs were 220.5 micromolar/hr, 12.8 micromolar and 7.1 micromolar, respectively. The mean AUC, Cmax and trough concentrations of Sustiva in the group not taking SSRIs were 192.3 micromolar/hr, 11.6 micromolar and 6.0 micromolar, respectively. "Since SSRIs are commonly used in patients with HIV, we investigated the outcome of patients using SSRIs and Sustiva," said Nancy Ruiz, M.D., Senior Medical Director, Worldwide Medical Affairs, DuPont Pharmaceuticals. "The data suggest that patients may use SSRIs without compromising the pharmacokinetics, safety and efficacy of Sustiva." Additional data using the rigorous method of reporting data called intent-to-treat: non-completer=failure analysis show that 82.4 percent (14/17) had viral load less than 50 copies/mL after 48 weeks of treatment. The mean CD4 cell count increase from baseline was 235 cells/mm3 at 48 weeks. Safety data from Study 006 indicate that adverse events greater than or equal to grade 2 were experienced by 59 percent (10/17) of patients in the group taking SSRIs compared to 52 percent (431/834) who were not taking SSRIs. No patients discontinued due to adverse events in the SSRI-containing arm compared to 7 percent (54/834) of patients in the other arm. Three patients in the SSRI-containing arm discontinued for other reasons. The reported grade 2 or higher adverse events in the SSRI-containing arm were rash, dizziness, nausea, fatigue, diarrhea, dyspepsia and hypertriglyceridemia. Study 006 is an open-label, multinational, multicenter study in 1,266 HIV- 1 positive patients. Entry criteria required that patients be naive to prior treatment with PIs, NNRTIs and 3TC. Patients were randomized in an open-label fashion to one of the following treatment groups: Sustiva (600 mg QD)+zidovudine (300 mg BID)+3TC (150 g BID); Sustiva (600 mg QD)+indinavir (1,000 mg q8h); or indinavir (800 mg q8h)+zidovudine (300 mg BID)+3TC (150 mg BID). 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, DuPont Pharma.
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