To determine the safety and anti-HIV activity of delavirdine mesylate ( U-90152 ) in
combination with zidovudine ( AZT ) and/or didanosine ( ddI ) versus AZT/ddI combination.
U-90152 has demonstrated anti-HIV activity. Since the combination of this drug with either
AZT or ddI has synergistic inhibitory activity against HIV-1 in vitro, and triple therapy
appears to have greater inhibitory activity against HIV-1 in vitro than dual therapy, the use
of U-90152 in combination with AZT and/or ddI may improve the benefits of these drugs in
persons with HIV disease.
Patients are randomized to receive U-90152/AZT/ddI, U-90152/AZT, U-90152/ddI, or AZT/ddI for
48 weeks.
Inclusion Criteria
Concurrent Medication:
Required:
- PCP prophylaxis for patients with CD4 count <= 200 cells/mm3.
Allowed:
- Topical antifungal agents.
- Oral ketoconazole, fluconazole, and itraconazole for candidiasis or disseminated
fungal infections.
- Isoniazid, ethambutol, pyrazinamide, clofazimine, ciprofloxacin, and clarithromycin
for acute or maintenance therapy for mycobacterial disease (also clarithromycin for
MAC prophylaxis).
- Acute or maintenance therapy for toxoplasmosis.
- Acute or maintenance therapy with acyclovir (no more than 1000 mg/day) for herpes
simplex virus infection.
- rEPO and rG-CSF.
- Antibiotics for bacterial infections (except rifampin and rifabutin).
- Antipyretics, analgesics, nonsteroidal anti-inflammatory agents, antiemetics, and
methadone.
Concurrent Treatment:
Allowed for cutaneous Kaposi's sarcoma:
- Localized radiation therapy.
- Limited intralesional therapy.
Patients must have:
- HIV infection.
- CD4 count 100 - 500 cells/mm3.
- Prior cumulative monotherapy of <= 6 months (may have taken either AZT or ddI, but not
both) OR no prior antiretroviral therapy.
Exclusion Criteria
Co-existing Condition:
Patients with the following symptoms or conditions are excluded:
- Malignancy (other than basal or squamous cell carcinoma of the skin, Stage 1 or 2
cervical intraepithelial neoplasia, or minimal Kaposi's sarcoma).
- Considered to be unlikely to comply with study requirements.
Concurrent Medication:
Excluded:
- Antiretroviral therapies and biologic response modifiers (except for study
medications, rEPO, and rG-CSF).
- Rifampin.
- Rifabutin.
- Terfenadine.
- Astemizole.
- Loratadine.
- Quinidine.
- Digitoxin.
- Systemic corticosteroids for more than 21 consecutive days.
- Foscarnet.
- Systemic cytotoxic chemotherapy for a malignancy.
Patients with the following prior conditions are excluded:
- History of intolerance to AZT at <= 600 mg/day or ddI at <= 400 mg/day or
discontinuation of either drug for toxicity.
- History of intolerance to trifluoperazine or piperazine citrate (per amendment).
- History of pancreatitis.
- History of grade 2 or worse peripheral neuropathy.
- Unexplained temperature >= 38. 5 C on any 7 days within the past 30 days.
- Chronic diarrhea on any 15 days during the past 30 days.
Prior Medication:
Excluded:
- Prior foscarnet as induction or maintenance therapy.
- Prior U-90152.
- Prior ddC or d4T.
- Prior AZT/ddI in combination or taken separately at different times.
- Prior non-nucleoside reverse transcriptase inhibitors (nevirapine, atevirdine, etc.).
- Prior protease inhibitors (although patients from ACTG 282 are eligible).
- HIV-1 vaccine within the past 21 days.
- Acute treatment for a serious infection or for any opportunistic infection within the
past 14 days.
Excluded within the past 30 days:
- Interferon or interleukin.
- Rifampin.
- Rifabutin.
- Terfenadine.
- Astemizole.
- Loratadine.
- Recombinant EPO or G-CSF.
- Hydroxyurea.
- SPV-30.
- Any other investigational drug.
Active drug or alcohol use.
Univ of Puerto Rico, San Juan 009365067, Puerto Rico
Univ of Alabama at Birmingham, Birmingham, Alabama 35294, United States
Univ of California / San Diego Treatment Ctr, San Diego, California 921036325, United States
VA Hosp at San Diego / Pediatrics, San Diego, California 92161, United States
Stanford at Kaiser / Kaiser Permanente Med Ctr, San Francisco, California 94115, United States
San Francisco Gen Hosp, San Francisco, California 941102859, United States
Stanford Univ Med Ctr, Stanford, California 943055107, United States
Summitt Med Ctr / San Francisco Gen Hosp, Oakland, California 94609, United States
Univ of Southern California / LA County USC Med Ctr, Los Angeles, California 900331079, United States
Olive View Med Ctr, Sylmar, California 91342, United States
USC Univ Hosp & Ambulatory Hlth Care Ctr / USC Med Ctr, Los Angeles, California 900334508, United States
Denver Dept of Health and Hosps, Denver, Colorado 80262, United States
Kaiser Permanente Franklin Med Ctr, Denver, Colorado 80262, United States
Rose Med Ctr, Denver, Colorado 80262, United States
Yale Univ / New Haven, New Haven, Connecticut 065102483, United States
Howard Univ, Washington, District of Columbia 20059, United States
George Washington Univ / Hershey Med Ctr, Washington, District of Columbia 20037, United States
Univ of Miami School of Medicine, Miami, Florida 331361013, United States
Queens Med Ctr, Honolulu, Hawaii 96816, United States
Univ of Hawaii, Honolulu, Hawaii 96816, United States
Indiana Univ Hosp, Indianapolis, Indiana 462025250, United States
Methodist Hosp of Indiana / Life Care Clinic, Indianapolis, Indiana 46202, United States
Tulane Univ / Charity Hosp of New Orleans, New Orleans, Louisiana 701122699, United States
Johns Hopkins Hosp, Baltimore, Maryland 21287, United States
State of MD Div of Corrections / Johns Hopkins Univ Hosp, Baltimore, Maryland 212052196, United States
Harvard (Massachusetts Gen Hosp), Boston, Massachusetts 02114, United States
Beth Israel Deaconess Med Ctr, Boston, Massachusetts 02215, United States
Beth Israel Deaconess - West Campus, Boston, Massachusetts 02215, United States
Boston Med Ctr, Boston, Massachusetts 02118, United States
Worcester Memorial Hosp / Med Ctr of Cntrl MA-Memorial, Worcester, Massachusetts 01605, United States
Univ of Minnesota, Minneapolis, Minnesota 55455, United States
St Louis Regional Hosp / St Louis Regional Med Ctr, St. Louis, Missouri 63112, United States
Montefiore Family Health Ctr / Bronx Municipal Hosp, Bronx, New York 10461, United States
SUNY / State Univ of New York, Syracuse, New York 13210, United States
Univ of Rochester Medical Center, Rochester, New York 14642, United States
Mem Sloan - Kettering Cancer Ctr, New York, New York 10021, United States
Bellevue Hosp / New York Univ Med Ctr, New York, New York 10016, United States
Mount Sinai Med Ctr, New York, New York 10029, United States
Jack Weiler Hosp / Bronx Municipal Hosp, Bronx, New York 10465, United States
Cornell Univ Med Ctr, New York, New York 10021, United States
Bronx Municipal Hosp Ctr/Jacobi Med Ctr, Bronx, New York 10461, United States
Montefiore Med Ctr / Bronx Municipal Hosp, Bronx, New York 10467, United States
Bronx Veterans Administration / Mount Sinai Hosp, Bronx, New York 10468, United States
SUNY / Erie County Med Ctr at Buffalo, Buffalo, New York 14215, United States
Beth Israel Med Ctr, New York, New York 10003, United States
City Hosp Ctr at Elmhurst / Mount Sinai Hosp, Elmhurst, New York 11373, United States
SUNY / Health Sciences Ctr at Brooklyn, Brooklyn, New York 112032098, United States
North Shore Univ Hosp, Manhasset, New York 11030, United States
North Central Bronx Hosp / Bronx Municipal Hosp, Bronx, New York 10467, United States
Comprehensive Health Care Ctr / Bronx Municipal Hosp, Bronx, New York 10461, United States
Columbia Presbyterian Med Ctr, New York, New York 100323784, United States
Adirondack Med Ctr at Saranac Lake, Albany, New York 122083479, United States
Mid - Hudson Care Ctr, Albany, New York 122083479, United States
Albany Med College / Division of HIV Medicine A158, Albany, New York 122083479, United States
Harlem Hosp Ctr, New York, New York 10037, United States
Montefiore Adolescent AIDS Prog / Bronx Municipal Hosp, Bronx, New York 10461, United States
Case Western Reserve Univ, Cleveland, Ohio 44106, United States
Univ of Cincinnati, Cincinnati, Ohio 452670405, United States
Ohio State Univ Hosp Clinic, Columbus, Ohio 432101228, United States
Thomas Jefferson Univ Hosp, Philadelphia, Pennsylvania 191075098, United States
Julio Arroyo, West Columbia, South Carolina 29169, United States
Univ of Texas Galveston, Galveston, Texas 775550435, United States
Univ of Washington, Seattle, Washington 981224304, United States
Youngstown Hemophilia Ctr / Great Lakes Hemophilia Fdn, Wauwatosa, Wisconsin 53213, United States
Griffit B, Morse G, Demeter L, Bassett R, Hughes M, Friedland G. Relationship between delavirdine (DLV) plasma levels, HIV RNA responses and DLV resistance during combination therapy with zidovudine (ZDV), and didanosine (ddI). Int Conf AIDS. 1998;12:52 (abstract no 12206)
Freimuth WW, Chuang-Stein CJ, Greenwald CA, Wathen LK, Edge-Padbury BA, Cox SR, Daenzer CL, Wang Y, Carberry PA. Delavirdine (DLV) combined with zidovudine (ZDV) or didanosine (ddI) produces sustained reduction in viral burden and increases in CD4 count in early and advanced HIV-1 infection. Int Conf AIDS. 1996 Jul 7-12;11(1):22 (abstract no MoB295)
Nokta M, Turk P. Partial restoration of HIV specific neutralizing activity (NA) of HIV infected patients receiving antiretrovial therapy: DDI/delaviridine (DLV), AZT/DLV, DDI/AZT or DDI/AZT/DLV. Int Conf AIDS. 1998;12:516 (abstract no 31108)
Friedland GH, Pollard R, Griffith B, Hughes M, Morse G, Bassett R, Freimuth W, Demeter L, Connick E, Nevin T, Hirsch M, Fischl M. Efficacy and safety of delavirdine mesylate with zidovudine and didanosine compared with two-drug combinations of these agents in persons with HIV disease with CD4 counts of 100 to 500 cells/mm3 (ACTG 261). ACTG 261 Team. J Acquir Immune Defic Syndr. 1999 Aug 1;21(4):281-92.
Demeter LM, Meehan PM, Morse G, Gerondelis P, Dexter A, Berrios L, Cox S, Freimuth W, Reichman RC. HIV-1 drug susceptibilities and reverse transcriptase mutations in patients receiving combination therapy with didanosine and delavirdine. J Acquir Immune Defic Syndr Hum Retrovirol. 1997 Feb 1;14(2):136-44.
