PRNewswire - Saturday September 26, 1998

These results were obtained using the standard Amplicor(TM) assay, as well as the non-approved ultrasensitive assay, which is the new goal of therapy according to the IAS-USA guidelines. Efficacy data from this study in the Sustiva package insert are based on reduction in HIV-RNA at 24 weeks using the Amplicor(TM) assay.

These and other Sustiva data were presented at the current 38th Interscience Conference on Antimicrobial Agents and Chemotherapy in San Diego. The FDA recently approved Sustiva, a non-nucleoside reverse transcriptase inhibitor (NNRTI) for treatment of HIV infection when used in combination with other antiretroviral agents. The indication is based on analyses of plasma HIV-RNA levels and CD4 cell counts in controlled studies of up to 24 weeks in duration. At present, there are no results from clinical trials evaluating long-term suppression of HIV-RNA with Sustiva.

"Since the introduction of protease inhibitors, research has suggested that initial HIV treatment combinations should include a protease inhibitor in order to attain a desirable level of potency and efficacy," said Javier Morales-Ramirez, M.D., CEO and President, Clinical Research Puerto Rico, San Juan, Puerto Rico. "Now there's evidence that supports initiating antiretroviral therapy with Sustiva. We can now achieve a high level of efficacy in many patients without using a protease inhibitor."

Study 006, a large-scale, open-label Phase III clinical trial was designed to evaluate Sustiva(TM) (efavirenz) in combination with other commonly used antiretrovirals compared to the standard of care:

Sustiva (600 mg, once daily) in combination with nucleoside analogues AZT (300 mg, twice daily) and 3TC (150 mg, twice daily);

Sustiva (600 mg, once daily) in combination with protease inhibitor indinavir (1000 mg, every eight hours); and,

Indinavir (800 mg, every eight hours) in combination with AZT (300 mg, twice daily) and 3TC (150 mg, twice daily).

After 36 weeks of treatment, the Sustiva/AZT/3TC combination suppressed viral load to below quantifiable levels (BQL, less than 400 copies/mL) in 73% (102/140) of patients as determined by the most rigorous method of reporting data (an analysis referred to as "non-completer = failure'*). The proportion of patients achieving BQL in the Sustiva(TM) (efavirenz)/indinavir arm and the indinavir/AZT/3TC arm by this analysis was 54% (74/136) and 51% (72/140), respectively. The disproportionate number of discontinuations in the control arm makes it difficult to assess the relative efficacy of the treatment regimens in this open-label study.

Patients who entered the study with high viral load (greater than 100,000) copies/mL) also experienced HIV-RNA suppression to BQL. The results of this study are unlike previous studies where high baseline viral load increased the risk of treatment failure. The proportion of patients with high viral load achieving BQL at 36 weeks using the traditional observed data analysis was 97% (29/30), 64% (21/33), and 87% (20/23) for the Sustiva/AZT/3TC, Sustiva/indinavir, and indinavir/AZT/3TC combinations, respectively.

For all patients in Study 006 (450 patients), CD4 cell counts increased by more than 170 cells/mm3 from baseline. Efficacy data beyond 24 weeks and from patients with high viral load at study entry are not described in the Sustiva package insert.

Safety data from Study 006 at 36 weeks are similar to observations reported at 24 weeks. When Sustiva was combined with AZT/3TC, the most commonly reported treatment-related side effects (greater than or equal to) Grade 2 were nausea (11%), rash, maculopapular (10%), dizziness (9%), impaired concentration (8%), fatigue (7%) and headache (7%). Patients on regimens containing Sustiva experienced more nervous system symptoms (55 vs 24%) and had more new-onset rashes (29 vs 16%) than patients on the indinavir/AZT/3TC arm. However, severe rashes were reported in less than one percent of patients receiving Sustiva in this study.

Data Suggest Sustiva Performs Well in Two-drug Combinations with both Viracept(R) (nelfinavir) and Crixivan(R) (indinavir):

Clinical investigators also presented results today from two DuPont Pharmaceuticals studies evaluating the use of Sustiva in a two-drug combination with a protease inhibitor. In both studies, results suggest that Sustiva(R) (efavirenz), when used in combination with either Viracept or Crixivan, reduces HIV-RNA and elevates CD4 cell counts in HIV-1 infected patients.

Results at 24 weeks from study 024, an ongoing open-label Phase II clinical trial investigating the use of Sustiva in combination with Viracept, show reduction on HIV-RNA and increases in CD4 cell counts in both treatment- experienced and treatment-naive patients. Using the traditional observed data analysis, 77 percent (17/22) of treatment-naive patients achieved HIV-RNA BQL and 63 percent (15/24) of NRTI-experienced patients achieved HIV-RNA BQL. Patients experienced CD4 cell count increases of 49 cells/mm3 and 87 cells/mm3, respectively.

Results from DuPont Pharmaceuticals Study 003, which investigated the two- drug combination, Sustiva and Crixivan, showed 84 percent (37/44) of patients taking the combination maintained HIV-RNA BQL for 84 weeks using the observed data analysis. Patients experienced a CD4 cell count increase of 306 cells/mm3. No efficacy data from study 024 or Study 003 are described in the Sustiva package insert. At present, there are no results form controlled clinical trials evaluating the long-term suppression of HIV-RNA with Sustiva.

The most commonly reported treatment-related side effects greater than or equal to Grade 2 in the 62 patients in Study 024 include diarrhea (21%), rash, maculopapular (15%), dizziness (6%) and nausea (6%). The most commonly reported new-onset side effects greater than or equal to Grade 2 in the 59 patients in Study 003 include abdominal pain (10%), diarrhea (10%), pain (8%), increased liver enzymes (8%) and hematuria (8%).

Data on the use of Sustiva in children will be presented for the first time on September 27, 1998. The presentation will provide results from an AIDS Clinical trials Group (ACTG) study designed to determine the best dosing of Sustiva in children while also evaluating the efficacy, safety, and tolerability of Sustiva(TM) (efavirenz). The dosing information obtained from this study is the basis of the pediatric dose recommendations in the Sustiva package insert.

Overall, safety data from clinical trials show Sustiva is generally well tolerated. The most significant adverse events associated with Sustiva therapy are nervous system symptoms, which are reported in 52 percent of patients (e.g., dizziness, insomnia, somnolence, impaired concentration, and abnormal dreaming). The discontinuation rate for nervous system symptoms was 2.6 percent. These symptoms occur early in treatment and generally resolve within a few weeks.

Rarely, patients have more serious side effects that may affect mood or ability to think clearly. Skin rash, usually mild-to-moderate, was reported in 27% of patients. The incidence of severe rash was less than 1% and the discontinuation rate for any grade rash was 1.7%. The incidence of rash was higher in children (40%) than in adults and the incidence of severe rash was also higher in children (7%).

Resistant virus emerges rapidly when NNRTIs are administered 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. Sustiva therapy should always be initiated in combination with at least one other antiretroviral agent to which the patient has not been previously exposed.

Women should not become pregnant while taking Sustiva because birth defects have been seen in animals given Sustiva.

DuPont Pharmaceuticals will soon begin including children in its worldwide early access programs. Since these programs began in October 1997, the combined Sustiva early access programs have become one of the largest expanded access programs for treatment of HIV. To date, more than 14,000 individuals worldwide have accessed Sustiva though early access programs. For information about ongoing programs in Canada and Europe, physicians and patients may call 800-998-6854 in Canada, or +44-0-38-842779 in Europe.

DuPont Pharmaceuticals is committed to helping patients seek reimbursement for Sustiva(TM) (efavirenz). The company will offer both reimbursement counseling and a comprehensive patient assistance program to ensure access to the drug for eligible patients. For more information call 800-344-4486.

In June, Sustiva was filed with regulatory authorities in Europe. Submission for approval has also been made to Canadian regulatory authorities.

DuPont Pharmaceuticals, a wholly owned subsidiary of DuPont, is a worldwide, research-based pharmaceutical company that markets its products under the DuPont Pharma name. The company focuses in 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 medical imaging.

Amplicor is a trademark of Roche Laboratories

Viracept is a registered trademark of Agouron.

Crixivan is a registered trademark of Merck & Co.

Non-completer=failure data analysis is a method of reporting data in which missing data is reported as equivalent to failure (i.e., above quantifiable viral load). Only if a patient's viral load measurement is missing or unavailable at one time point in the study, the patient's results are not included in the analysis at that point -- if the patient's viral load was BQL both before and after that point.

SOURCE: DuPont Pharmaceuticals
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