To validate that the alteration of codon 215 of reverse transcriptase in plasma virus precedes the increase in viral burden as measured in the peripheral blood and the decline in CD4 count that have been observed in association with clinical failure on zidovudine (AZT). To determine whether alternative regimens of antiretroviral agents alter the course of viral burden as measured in the peripheral blood and CD4 changes in patients with HIV infection. To obtain further data on the safety and immunologic and virologic response to AZT/didanosine/nevirapine.
Of the HIV-1 mutations reported to be associated with zidovudine resistance, the mutation at codon 215 of the reverse transcriptase gene is the most commonly occurring and has the greatest impact on susceptibility. When this mutation appears, a change in drugs may prevent further immunologic and virologic deterioration.
Initially, all patients receive AZT alone. After detection of a 215 mutation in plasma RNA, patients are randomized to one of three treatment arms: AZT alone, AZT plus ddI, or AZT/ddI plus nevirapine. Patients are followed every 8 weeks and receive treatment for up to 4 years.
AS PER AMENDMENT 5/9/96: All AZT monotherapy options have been eliminated. Patients will be randomized to either Arm II or Arm III, regardless of their codon 215 status. All patients who were randomized to Arm I following a mutation at codon 215 will be rerandomized to Arm II or Arm III. All patients who were randomized to either Arm II or Arm III following a mutation at codon 215 will remain on their initial randomized assignment.
Minimum age: 13 Years.
- Chemoprophylaxis for Pneumocystis carinii pneumonia.
- Antibiotics, antifungals, and antiviral medications, as clinically indicated.
- Regularly prescribed medication such as antipyretics, analgesics, allergy medications, antidepressants, sleep medications, oral contraceptives, or any other medications deemed appropriate by the primary care provider.
- Limited localized radiation therapy to the skin.
Prior Medication: Required:
- AZT (minimum 300 mg/day) for at least 1 month (uninterrupted) but no more than 2 years immediately prior to study entry.
Patients must have:
- Asymptomatic HIV infection.
- CD4 count 300-600 cells/mm3.
- No plasma/serum PCR for codon 215 mutation at screening.
- Prior AZT monotherapy.
- All Department of Defense (DOD)-eligible patients must be at least 18 years of age. Enrollment of women is encouraged.
AS PER AMENDMENT 04/03/95:
- DOD female patients must have a negative pregnancy test within 48 hours prior to study entry.
Patients with the following symptoms or conditions are excluded:
- Symptomatic grade 2 or worse peripheral neuropathy.
- Unable to swallow capsules and tablets.
- Other medical condition that contraindicates study participation.
- Systemic cytotoxic chemotherapy.
- Biologic response modifiers (such as interferon, ampligen, or PEG-IL2).
- Anti-HIV agents other than study drugs.
- Other investigational agents.
- Foscarnet unless clinically indicated for unresponsive herpes virus infection.
- Chronic antacid or H-2 blocker use.
- Rifampin or rifamycin class agents.
- Antibiotics containing clavulanic acid.
- Radiation therapy other than limited localized therapy to skin.
Patients with the following prior condition are excluded:
- History of pancreatitis.
- Prior therapy with nucleoside or non-nucleoside antiretroviral agents other than AZT.
- Immune modulating therapies (e. g., IFN-alpha, gp160) within 60 days prior to screening.
- Blood transfusion within the preceding 2 weeks.
Illicit drug or alcohol abuse.
Stanford at Kaiser / Kaiser Permanente Med Ctr, San Francisco, California 94115, United States
Stanford Univ Med Ctr, Stanford, California 943055107, United States
UCLA CARE Ctr, Los Angeles, California 90095, United States
Harbor UCLA Med Ctr, Torrance, California 90502, United States
San Mateo AIDS Program / Stanford Univ, Stanford, California 943055107, United States
Santa Clara Valley Med Ctr / AIDS Community Rsch Consortium, San Jose, California 951282699, United States
Univ of Colorado Health Sciences Ctr, Denver, Colorado 80262, United States
Children's Hosp of Washington DC, Washington, District of Columbia 200102916, United States
Georgetown Univ Med Ctr, Washington, District of Columbia 20007, United States
Walter Reed Army Med Ctr, Washington, District of Columbia 20307, United States
George Washington Univ / Hershey Med Ctr, Washington, District of Columbia 20037, United States
Emory Univ Hosp / Pediatrics, Atlanta, Georgia 30306, United States
Emory Hemo Comp Evaluation Clinic / East TN Comp Hemo Ctr, Atlanta, Georgia 303652225, United States
San Juan City Hosp, San Juan 009367344, Puerto Rico
Ramon Ruiz Arnau Univ Hosp / Pediatrics, Bayamon 00956, Puerto Rico
Queens Med Ctr, Honolulu, Hawaii 96816, United States
Univ of Hawaii, Honolulu, Hawaii 96816, United States
Indiana Univ Hosp, Indianapolis, Indiana 462025250, United States
Univ of Iowa Hosp and Clinic, Iowa City, Iowa 52242, 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
Natl Naval Med Ctr, Bethesda, Maryland 208995000, United States
Fitzsimmons Army Med Ctr, Rockville, Maryland 20850, United States
Beth Israel Deaconess Med Ctr, Boston, Massachusetts 02215, United States
Univ of Minnesota, Minneapolis, Minnesota 55455, United States
St Paul Ramsey Med Ctr, St. Paul, Minnesota 55101, United States
Hennepin County Med Clinic, Minneapolis, Minnesota 55415, United States
Univ of Nebraska Med Ctr, Omaha, Nebraska 681985130, 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
Bellevue Hosp / New York Univ Med Ctr, New York, New York 10016, United States
Jack Weiler Hosp / Bronx Municipal Hosp, Bronx, New York 10465, 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
SUNY / Erie County Med Ctr at Buffalo, Buffalo, New York 14215, 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 Med Ctr Adolescent AIDS Program, Bronx, New York 10467, United States
Carolinas Med Ctr, Charlotte, North Carolina 28203, United States
Univ of North Carolina, Chapel Hill, North Carolina 275997215, United States
Wake County Dept of Health, Raleigh, North Carolina 27610, United States
Case Western Reserve Univ, Cleveland, Ohio 44106, United States
Ohio State Univ Hosp Clinic, Columbus, Ohio 432101228, United States
Med College of Ohio, Toledo, Ohio 43699, United States
MetroHealth Med Ctr, Cleveland, Ohio 441091998, United States
Univ of Pennsylvania at Philadelphia, Philadelphia, Pennsylvania 19104, United States
Thomas Jefferson Univ Hosp, Philadelphia, Pennsylvania 191075098, United States
Milton S Hershey Med Ctr, Hershey, Pennsylvania 170330850, United States
Univ of Tennessee / E Tennessee Comprehensive Hemophilia Ctr, Knoxville, Tennessee 37920, United States
Vanderbilt Univ Med Ctr, Nashville, Tennessee 37203, United States
Wilford Hall Med Ctr, Lackland AFB, Texas 782365300, United States
Univ of Texas Galveston, Galveston, Texas 775550435, United States
Brooke Army Med Ctr, San Antonio, Texas 78284, United States
Slade DE, Vavro CL, Stapleton JT, Swack N, StClair MH. A novel mutation at codon 215 of HIV RT. Int Conf AIDS. 1993 Jun 6-11;9(1):239 (abstract no PO-A26-0625)
Mayers D, Merigan T, Gilbert P. T215Y/F mutation associated with zidovudine (ZDV) resistance leads to poor response to ZDV+ddI or ZDV+ddI+NVP: ACTG244/RV79. Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:91 (abstract no 129)
Holodniy M, Katzenstein D, Mole L, Winters M, Merigan T. Human immunodeficiency virus reverse transcriptase codon 215 mutations diminish virologic response to didanosine-zidovudine therapy in subjects with non-syncytium-inducing phenotype. J Infect Dis. 1996 Oct;174(4):854-7.