Important note: Information in this article was accurate in 1997. The state of the art may have changed since the publication date.
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* Sustiva is present in patient cerebrospinal fluid.
* Sustiva, when given once daily, does not require a dosing change in combination with the protease inhibitor nelfinavir (Viracept(R), Agouron), nor does the combination necessitate a nelfinavir dosing adjustment.
* Sustiva does not significantly induce the metabolism of antifungal agent fluconazole (Diflucan(R), Pfizer).
* Sustiva in combination with the protease inhibitor indinavir (Crixivan(R), Merck) suppresses HIV-RNA in blood to below quantifiable levels (400 copies/mL) in high percentages of patients.
* Sustiva inhibits wild-type and most single amino acid substitution mutant variants of HIV-1 associated with NNRTI resistance.
* Sustiva appears to be generally well tolerated.
Sustiva will be available through expanded access programs in the United States and Canada, beginning October 1.
Cerebrospinal Fluid Penetration
Analysis of cerebrospinal fluid (CSF) samples in three patients with HIV taking 200 mg of Sustiva(TM) (efavirenz) once daily found measurable levels of Sustiva. Additional studies are underway to confirm and extend these findings.
Pharmacokinetic Interactions
Coadministration of Sustiva (400 mg, once daily) and nelfinavir (Viracept(R), Agouron) (750 mg, every eight hours) resulted in an increase of approximately 15 percent in nelfinavir blood levels. "These data indicate that once-daily efavirenz and nelfinavir at regular doses may be a promising combination, and such clinical trials are underway," said Nancy Ruiz, M.D., F.A.C.P., Medical Director of Virology, DuPont Merck.
In addition, a 400 mg once-daily dose of Sustiva did not affect blood levels of antifungal agent fluconazole (Diflucan(R), Pfizer) (400 or 200 mg, once daily).
Impact on Mutation
In ongoing evaluation, Sustiva has been found to inhibit wild-type and most single amino acid substitution mutant variants of HIV-1 associated with NNRTI resistance. Sustiva retains its activity against nucleoside analog resistant mutants.
Viral Load Suppression
In data reported at 48 weeks, 59 patients receiving combination therapy with Sustiva (200 mg, once daily) and indinavir (Crixivan(R), Merck) (800 or 1,000 mg, every eight hours) achieved a 2.38 log10 average reduction in HIV-RNA levels out of a possible 2.49 log10, and 88 percent of patients achieved HIV-RNA levels below the level of quantification (400 copies/mL). In the Sustiva/indinavir combination arm of the study, patients experienced an average CD4 cell count elevation of 245 cells/mm(3).
In the control arm of the study, 42 patients were given indinavir (Crixivan(R), Merck) alone for 12 weeks (800 or 1,000 mg every eight hours). At that time, Sustiva(TM) (efavirenz) (200 mg once daily, subsequently increased to 600 mg after a minimum of 36 weeks) and d4T (Zerit(R), Bristol-Myers Squibb) (variable dosing) were added, and the indinavir dose was raised for all patients to 1,000 mg every eight hours. After 48 weeks in the study, these patients achieved a 1.89 log10 average reduction in HIV-RNA levels out of a possible 2.42 log10, and 68 percent of them achieved HIV-RNA levels below the level of quantification (400 copies/mL). In this arm, patients experienced an average CD4 cell count elevation of 150 cells/mm(3).
Tolerability
In the 48-week Sustiva and indinavir combination study, Sustiva was generally well tolerated. There was no apparent increase in side effects for treatments containing Sustiva over indinavir alone (only two patients in the indinavir arm of the study and three patients in the Sustiva plus indinavir combination arm of the study discontinued due to adverse clinical events). Reported side effects are lightheadedness, dizziness and feeling "out of sorts." These symptoms are less likely to happen if Sustiva is taken before bedtime and they tend to go away after taking the medication for a few weeks. Other side effects like headache, nausea, diarrhea and mild to moderate rash have occurred when taking Sustiva with other anti-HIV medications.
Expanded Access
An expanded access program was recently announced by The DuPont Merck Pharmaceutical Company to enable more patients to gain access to Sustiva and to continue monitoring its safety. Beginning October 1, Sustiva will be available through this program to people who have CD4 cell counts of 50 cells/mm(3) or less and who are failing therapy or are intolerant to their current treatment regimen. In the program, Sustiva must be used in combination with at least one other commercial or investigational antiretroviral to which a patient has not been previously exposed. DuPont Merck designed the expanded access program with input from representatives of national HIV/AIDS patient advocacy organizations to ensure Sustiva would be readily available to appropriate patients who currently have limited therapeutic options.
Additional Studies
Additional studies are ongoing or planned to investigate the safety and effectiveness of triple combinations of higher doses of Sustiva(TM) (efavirenz) with nucleoside reverse transcriptase inhibitors; combinations of Sustiva with nelfinavir (Viracept(R), Agouron), indinavir (Crixivan(R), Merck) or ritonavir (Norvir(R), Abbott); interactions of Sustiva with other antiretrovirals and drugs to treat opportunistic infections; and, Sustiva in pediatric regimens.
The DuPont Merck Pharmaceutical Company is a worldwide, research-based pharmaceutical company which markets its products under the DuPont Pharma name. Formed in 1991 as a partnership between DuPont and Merck & Co., Inc., DuPont Merck is focused on research, development and delivery of pharmaceuticals to treat unmet medical needs in the fight against HIV, cardiovascular disease, central nervous system disorders, cancer and arthritis-related disorders. The company is also a leader in radiopharmaceuticals.
SOURCE DuPont Merck Pharmaceutical Company
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