|
|
Study Finds Twice Daily RESCRIPTOR® Enhances PI Effect, Decreases Viral Load Among HIV Patients Who Fail Indinavir Combination Therapy
[ACTG Study Presented at Second International Workshop on Salvage Therapy for HIV Infection]
May 20, 1999
(TORONTO, CANADA) - Preliminary results of an AIDS Clinical Treatment Group study (ACTG 359) found that RESCRIPTOR® (delavirdine mesylate tablets, DLV), dosed at 600 mg twice a day (BID), in combination with dual protease inhibitor (PI) therapies reduced viral load over a 16-week period among HIV patients who had previously failed treatment with indinavir (IDV) combination therapy and had not received prior treatment with non-nucleoside reverse transcriptase inhibitors (NNRTIs).
The study, presented today at the International Workshop on Salvage Therapy for HIV Infection, compared the effect of adding RESCRIPTOR, adefovir dipivoxil (ADV), and a combination of RESCRIPTOR and ADV to dual PI regimens in order to evaluate impact on viral load. Viral load is an indicator of virus concentration and reproduction rate that is increasingly used as a predictor of disease progression. The study also assessed the safety, toxicity and tolerance of the study treatments.
Patients in the partially blinded, multicenter study, all of whom had failed on IDV combination therapy, were randomized to six treatment arms for comparison. Each patient received the soft gelatin capsule form of saquinavir (SQVsgc) in combination with ritonavir (RTV) or nelfinavir (NFV) plus RESCRIPTOR, ADV or a combination of both RESCRIPTOR and ADV. There was no demonstrable difference in virologic response between using RTV or NFV as the second protease inhibitor. The arms, which included RESCRIPTOR, either alone or in combination with ADV, had statistically significant greater percentages of patients with an HIV RNA of <500 copies/ml at week 16 than those arms which included ADV alone. CD4 count rose in all groups between entry and week 16, and there was no significant difference between treatment arms. RESCRIPTOR is a non-nucleoside reverse transcriptase inhibitor (NNRTI).
"This study shows that adding delavirdine to dual protease inhibitor salvage therapy decreases viral load in about 30 to 40 percent of subjects," according to Roy M. Gulick, M.D., M.P.H., Assistant Professor of Medicine, Weill Medical College of Cornell University and lead investigator. "Finding new approaches for managing patients who have failed PI therapies is critically important. The results of this study will help contribute to ongoing efforts to optimize salvage therapy regimens for these patients."
Research suggests that 10 to 50 percent of patients may experience virologic failure on protease inhibitor-containing regimens within their first year of therapy. This study was designed to determine the safety and virologic benefit of two combination PI regimens (RTV+SQV and NFV+SQV) with the addition of other therapies such as RESCRIPTOR, ADV or both, since optimal salvage therapy after PI failure is uncertain.
Study Design
A total of 277 patients entered ACTG 359, a partially blinded, placebo-controlled study, between September 11, 1997, and October 2, 1998. The patient population included women (17 percent), non-Hispanic blacks (29 percent), Hispanics (19 percent), non-Hispanic whites (49 percent), and patients who used intravenous drugs either before or during the study (12 percent). Patients averaged 40 years of age and had an average CD4 count of 229/mm3 at entry. HIV RNA levels averaged 31,746 copies/ml, and 124 subjects had HIV RNA under 20,000 copies/ml and 153 subjects had HIV RNA of 20,000-200,000 copies/ml. No statistically significant imbalances were observed for any of the baseline measures. Everyone must have been treated for at least six months with IDV. Subjects were randomly assigned to one of six treatment arms:
A: Saquinavir soft gel capsule (SQV; Fortovase®) 400 mg twice daily + ritonavir (RTV; Norvir®) 400 mg twice daily + RESCRIPTOR 600 mg twice daily
B: SQV 400 mg twice daily + RTV 400 mg twice daily + adefovir dipivoxil (ADV) 120 mg once daily
C: SQV 400 mg twice daily + RTV 400 mg twice daily + RESCRIPTOR 600 mg twice daily + ADV 120 mg once daily
D: SQV 800 mg three times daily + nelfinavir (NFV, Viracept®) 750 mg three times daily + RESCRIPTOR 600 mg twice daily
E: SQV 800 mg three times daily + NFV 750 mg three times daily + ADV 120 mg once daily
F: SQV 800 mg three times daily + NFV 750 mg three times daily + RESCRIPTOR 600 mg twice daily + ADV 120 mg once daily
Study Results
Thirty percent of all those enrolled in the study (77 of 254 subjects) had HIV RNA less than 500 copies/ml at 16 weeks. Comparison analysis at week 16 showed:
* Arm D (SQV/NFV/RESCRIPTOR) had the highest response
rate, 46 percent (20 of 43 subjects), followed by
* Arm F (SQV/NFV/RESCRIPTOR/ADV), 36 percent (15 of 42)
* Arm A (SQV/RTV/RESCRIPTOR), 33 percent (14 of 42)
* Arm C (SQV/RTV/RESCRIPTOR/ADV), 31 percent (12 of 39)
* Arm B (SQV/RTV/ADV), 20 percent (9 of 44)
* Arm E (SQV/NFV/ADV), 16 percent (7 of 44).
When the PIs RTV and NFV were compared (everyone on Arms A, B, and C compared to everyone on Arms D, E, and F), the reduction in HIV RNA levels was about the same. When RESCRIPTOR (Arms A and D) was compared to ADV (Arms B and E), HIV RNA levels were lower in subjects who were treated with RESCRIPTOR. HIV RNA levels were about the same in subjects treated with RESCRIPTOR alone (Arms A and D) and both RESCRIPTOR and ADV (Arms C and F).
A total of 48 subjects (17 percent) had serious side effects, and a total of 102 subjects (37 percent) had Grade 3 and 4 changes in blood tests likely due to the toxic effects of these antiretroviral drugs. When all six treatment arms were compared, there were slightly fewer side effects and blood test changes in subjects treated with ADV than with RESCRIPTOR. Diarrhea, nausea and ache/pain/discomfort were the most frequently reported signs and symptoms across all treatment groups. There was no significant difference for signs and symptoms Grade 2 or higher among treatment arms.
An earlier analysis of the ACTG 359 study data that looked at the pharmacokinetic activity of these combination therapies found that when RESCRIPTOR was used instead of ADV it increased the area under the curve (AUC) values of each of the PIs by at least 50 percent. The results also indicate that ADV appears to decrease the concentrations of RESCRIPTOR in the blood by 50 percent. However, this apparent interaction between RESCRIPTOR and ADV must be confirmed in larger pharmacokinetic studies.
Longer-term follow-up data for these study subjects are being collected and analyzed. Additional analyses of subject adherence, HIV resistance and pharmacokinetics (drug levels) and the relationship to the anti-HIV effect of these regimens are in progress.
AIDS Clinical Trials Group
The AIDS Clinical Trials Group is the largest HIV trials organization in the world and has played a key role in providing important data for HIV/AIDS treatment and prevention strategies. The ACTG is composed of, and directed by, leading clinical scientists in HIV/AIDS therapeutic research.
RESCRIPTOR
RESCRIPTOR, an NNRTI marketed by Pharmacia & Upjohn, received accelerated approval in the US on April 7, 1997. It is also marketed in Brazil, Mexico, Argentina, Peru, Australia and Canada, and marketing authorization applications have been submitted in the European Union and Switzerland.
RESCRIPTOR tablets are indicated for the treatment of HIV-1 infection in combination with appropriate antiretroviral agents when therapy is warranted. The indication is based on surrogate market changes in clinical studies. Clinical benefit has not been demonstrated with RESCRIPTOR based on survival or incidence of AIDS- defining clinical events.
RESCRIPTOR has been shown to be generally well tolerated. The most commonly reported side effect attributable to RESCRIPTOR was a skin rash that occurred in 18 percent of patients. In most cases, the rash disappeared within three to 14 days without a dosage reduction or interruption of treatment (4.3 percent of patients in clinical trials discontinued due to rash).
The recommended dose for RESCRIPTOR is 400 mg, taken three times daily with or without food. RESCRIPTOR should always be administered in combination with appropriate antiretroviral therapy. The tablets are 100 mg each and are dispersible in water to make consumption easier, while 200mg and 300mg tablets are under development.
Pharmacia & Upjohn is a global, innovation-driven pharmaceutical and health care company. Pharmacia & Upjohn's products, services and employees demonstrate its commitment to improve wellness and quality of life for people around the world.
| Media Contacts:
Karen Carolonza Pharmacia & Upjohn 908-306-4763 |
Louise Leavitt Fleishman-Hillard 212-453-2441 |
| Pharmacia & Upjohn Patient Product Services
Hotline:
1-888-691-6813 Pharmacia & Upjohn Physician/Pharmacist Hotline: 1-800-253-8600 ext. 3-8244 |
|
Go to the NNRTI Menu
Go to the Treatments for HIV/AIDS Menu
Go to the HIVpositive.us Main Menu
39