PRNewswire - Thursday, December 16, 1999

"These data suggest a good outcome for children receiving this therapy," said Stephen Spector, MD, Chair of the Executive Committee for the Pediatric AIDS Clinical Trial Group (PACTG), Professor of Pediatrics at the University of California, San Diego, and Chief, Division of Infectious Diseases, and co-author of the study. "The children are currently being followed to assess the long-term benefit of this treatment."

The Centers for Disease Control and Prevention statistics show that 8,461 children have been reported with AIDS in the United States since the beginning of the epidemic, and 1,956 are currently reported living with HIV. "Due to limitations in reporting, we believe that the CDC numbers are low. There are probably approximately 15,000 children and adolescents living with HIV in the United States," said Dr. Spector.

"We are pleased with the results of this study. These data are important for the treatment of children living with HIV and AIDS, and illustrate our commitment to developing new therapies to meet medical needs," said Nicholas L. Teti, President of DuPont Pharmaceuticals Company.

PACTG 382

In this open-label study conducted by the PACTG, all of the children enrolled were treated with Sustiva and Viracept(R) (nelfinavir mesylate), along with two nucleoside reverse transcriptase inhibitors. Based on an intent-to-treat analysis, 75.5 percent of the 57 children studied had plasma HIV RNA levels of less than 400 copies/mL and 63.3 percent had less than 50 copies/mL after 48 weeks of therapy. The median CD4 cell increase over this period was +74 cells. The combination was generally well-tolerated by most children.

"After 48 weeks, the virus was undetectable in more than half of the children," said Stuart Starr, MD, Professor of Pediatrics at the University of Pennsylvania School of Medicine; Chief of Immunologic and Infectious Diseases, Childrens' Hospital of Philadelphia, and chair of the clinical study team. "The results are comparable or superior to other combinations and we think that the once-daily dosing with Sustiva may provide an advantage to children and their families. Compliance is a critical issue in pediatric treatment."

The most common treatment related side effects of at least moderate severity were rash (29.8 percent), diarrhea (17.5 percent), and neutropenia (12.3 percent).

DPC 006

Other data from the landmark DuPont Pharmaceuticals 006 study, which compared Sustiva, a non-nucleoside reverse transcriptase inhibitor, to the protease inhibitor, Crixivan(R) (indinavir), were also published in The New England Journal of Medicine today. The article concludes that the combination of Sustiva/AZT/3TC has greater antiviral activity and is better tolerated than the combination of indinavir/AZT/3TC in HIV-1 infected patients.

Until the introduction of Sustiva, preferred first line therapy for HIV-infected patients was considered to be a combination of one or more protease inhibitors plus two nucleoside analogues. Today, Sustiva is the only non-nucleoside reverse transcriptase inhibitor (NNRTI) listed among the preferred antiretroviral agents to be used in first-line combination treatment regimens for HIV-infected individuals who are naive to antiretroviral treatment.

"Study 006 has come to be widely recognized as a benchmark in HIV and AIDS clinical trials," commented Schlomo Staszewski, M.D., Director of the Outpatient Clinic for HIV-infected Patients and of the Antiretroviral Therapy Research Unit at Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.

After 48 weeks of study, the percentage of 450 patients achieving viral load suppression to below quantifiable levels (less than 400 copies/mL) was significantly higher in the Sustiva plus AZT and 3TC group than the indinavir plus AZT and 3TC group (70 percent vs. 48 percent respectively, using the most rigorous intent-to-treat non-completer equals failure analysis). More patients in the indinavir-containing arm discontinued prior to 48 weeks. The difference in discontinuations as a result of adverse events makes it difficult to assess the relative efficacy of the treatment. Using the observed method of analysis, 98 percent versus 84 percent of patients achieved viral load suppression to below quantifiable levels, respectively.

Similar findings were also observed in a re-analysis of patients with baseline viral loads above 100,000 copies/mL (70 percent of patients on the Sustiva plus NRTIs group versus 42 percent on the indinavir plus NRTIs group). Significant CD4 cell count increases were noted with all combinations.

Data on the 1266 patients ultimately randomized to this study were recently presented at the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. Those data demonstrated that the patients (n=422) taking Sustiva plus AZT and 3TC experienced greater duration of response (i.e., longer time to treatment failure) through approximately 2 years of treatment than those patients (n=415) taking combinations with indinavir plus AZT and 3TC. These data were statistically significant (p=0.0001).

"These data led to a shift in the standard of care," said Paul A. Friedman, M.D., President, DuPont Pharmaceuticals Research Laboratories. "We continue to strive to design clinical trials that challenge the current thinking and will keep us ahead of this virus."

The rates of nausea (27 percent); vomiting (15 percent); pain, predominantly flank, (11 percent); and increased bilirubin level (8 percent), were significantly higher in the group given indinavir plus nucleoside reverse transcriptase inhibitors than in the two groups treated with the regimens containing Sustiva. Dizziness (9 percent) and impaired concentration (9 percent) were more frequent in the group given Sustiva plus nucleoside reverse transcriptase inhibitors than in the group with indinavir plus two nucleoside reverse transcriptase inhibitors.

Accelerated Approval and Product Labeling

On September 17, 1998, the FDA granted accelerated approval for Sustiva for the treatment of HIV-1 infection in combination with other antiretroviral agents. This 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, product labeling indicates there are no results evaluating long-term suppression of HIV-RNA with Sustiva. DuPont Pharmaceuticals has submitted an application for traditional approval of Sustiva based on two studies showing long-term (48-week) duration of response. Sustiva has also received full approval in several countries in Europe, and received full approval in Canada on an accelerated basis.

Sustiva product labeling states that the most significant adverse events associated with Sustiva therapy are nervous system symptoms and rash. Nervous system symptoms are reported in 52 percent of patients (e.g., dizziness, insomnia, somnolence, impaired concentration, and abnormal dreaming). These symptoms occur early in treatment and generally resolve within two to four weeks. Rarely, patients experience more serious side effects that may affect mood or the ability to think clearly. The discontinuation rate for nervous system symptoms in clinical trials was 2.6 percent. Patients should be cautioned not to operate hazardous machinery or drive if they experience nervous system symptoms. Skin rash, usually mild-to-moderate, was reported in 27 percent of adults. Rash usually occurs in the first two weeks of therapy and resolves with continued treatment within one month. The incidence of severe rash was less than one percent in adults and the discontinuation rate for any grade rash was 1.7 percent. Adverse events in children were generally similar to those in adults with the exception of a higher incidence (40 percent) and a higher frequency of severe rash (7 percent).

Sustiva product labeling also states that 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 is a worldwide business that focuses on research, development, and delivery of pharmaceuticals to treat unmet medical needs in the fights against HIV, cardiovascular disease, central nervous system disorders, cancer and arthritis-related disorders. DuPont Pharmaceuticals is also a leader in medical imaging.

DuPont is a science company, delivering science-based solutions that make a difference in people's lives in food and nutrition; health care; apparel; home and construction; electronics; and transportation. Founded in 1802, the company operates in 65 countries and has 97,000 employees.

For full Sustiva prescribing information, please visit the company's Website at http://www.sustiva.com or call 1-800-4PHARMA (800-474-2762).

Observed data analysis is a common method of analysis in HIV clinical trials. Only patients with data available at the timepoint of analysis are included. Missing information, regardless of the reason, is not counted. Observed data may also be referred to as on-treatment analysis.

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.

Viracept(R) is a registered trademark of Agouron.

Crixivan(R) is a registered trademark of Merck & Co.

SOURCE DuPont Pharmaceuticals

CONTACT: Sandra James of DuPont Pharmaceuticals, 302-892-1306, sandra.k.james@dupontpharma.com; or Abenaa Hayes of Rowland Company, 212-527-8813, ahayes@rowland.com, for DuPont Pharmaceuticals/
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Always watch for outdated information. This article first appeared in 1999. This material is designed to support, not replace, the relationship that exists between you and your doctor.

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