To determine the relative clinical efficacy of zidovudine ( AZT ) plus didanosine (ddI), AZT
plus zalcitabine ( ddC ), AZT alternating monthly with ddI, and AZT/ddI plus nevirapine in
HIV-infected patients with advanced disease.
The rapid emergence of resistant HIV strains has been observed in patients receiving
monotherapy with a nucleoside analog or non-nucleoside reverse transcriptase inhibitor. Use
of combination therapy with two nucleoside drugs or convergent combination therapy with two
nucleosides and a non-nucleoside RT inhibitor may minimize the evolution of these resistant
HIV strains. Since toxicity is a major problem in patients with advanced disease who are
receiving combination nucleoside therapy, alternating the two drugs may provide a way of
retaining several benefits of combination therapy while minimizing the increased toxicity.
Patients are randomized to receive either AZT/ddC, AZT/ddI, AZT alternating monthly with ddI,
or AZT/ddI/nevirapine. Patients are evaluated at week 0 and every 4 weeks thereafter for 2
years. Pharmacologic, virologic, and macroneurologic substudies will be conducted. Patients
who are already enrolled on protocol ACTG 193 will be given the option of continuing on their
originally assigned ACTG 193 therapy for an additional 6 months or undergoing
re-randomization to one of the four treatment arms on ACTG 193A.
Inclusion Criteria
Concurrent Medication:
Required:
- PCP prophylaxis.
Allowed:
- Erythropoietin maintenance.
- G-CSF and GM-CSF.
- Prophylaxis for Mycobacterium avium intracellulare.
- Antifungal prophylaxis or treatment with specific drugs.
- Maintenance therapy for opportunistic infection.
- Over-the-counter medications or alternative therapies such as vitamins and herbs.
- Antibiotics as clinically indicated.
- Steroids for < 21 days for acute problems.
- Antipyretics, analgesics, allergy medication, antidepressants, sleep medications, oral
contraceptives, or other appropriate medications.
Concurrent Treatment:
Allowed:
- Radiation therapy for cutaneous Kaposi's sarcoma.
- Acupuncture.
Patients must have:
- Documented HIV infection.
- CD4 count <= 50 cells/mm3.
- Either no prior nucleoside therapy OR a history of prior nucleoside therapy in the
absence of high-grade intolerance.
- Life expectancy of at least 6 months.
- Consent of parent or guardian if < 18 years of age.
- Normal chest x-ray at baseline or within 6 months prior to study entry in the absence
of new pulmonary or cardiac symptoms (per 12/28/94 amendment).
NOTE:
- Patients who withdrew from protocol ACTG 193 therapy prior to activation of ACTG 193A
are not eligible.
Exclusion Criteria
Co-existing Condition:
Patients with the following symptoms or conditions are excluded:
- Abnormal baseline chest x-ray.
- New pulmonary or cardiac symptoms.
- Psychological or emotional problems sufficient to prevent compliance with study
medication.
Concurrent Medication:
Excluded:
- Systemic chemotherapy for malignancy.
- Acute or induction therapy for opportunistic infection.
- Antiretroviral drugs other than study drugs.
- Biological response modifiers.
- Erythromycin, phenytoin, phenobarbital, warfarin, or coumadin.
Patients with the following prior conditions are excluded:
- History of recurrent grade 3 or greater toxicity to AZT, ddI, or ddC on two or more
occasions.
- Evidence of active pulmonary disease within 6 months prior to study entry.
- History of grade 3 or worse peripheral neuropathy.
- History of acute or chronic pancreatitis.
Prior Medication:
Excluded:
- Prior nevirapine.
Excluded within 7 days prior to study entry:
- Acute therapy for opportunistic infection (maintenance therapy is permitted).
- Acute systemic therapy for a nonopportunistic infection or other medical condition.
- Antiretroviral drugs other than AZT, ddI, or ddC.
- Biological response modifiers.
- d4T therapy.
- Nucleosides other than those used in the study.
- Antibiotics containing clavulanate potassium.
Prior Treatment:
Excluded:
- More than 4 units of blood in a 30-day period.
Active alcohol or drug abuse.
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
Stanford at Kaiser / Kaiser Permanente Med Ctr, San Francisco, California 94115, United States
San Francisco Gen Hosp, San Francisco, California 941102859, United States
San Francisco AIDS Clinic / San Francisco Gen Hosp, San Francisco, California 941102859, United States
Stanford Univ Med Ctr, Stanford, California 943055107, United States
Univ of Southern California / LA County USC Med Ctr, Los Angeles, California 900331079, United States
Huntington Memorial Hosp / Children's Hosp of Los Angeles, Pasadena, California 91105, United States
Children's Hosp of Los Angeles, Los Angeles, California 90027, 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
Olive View Med Ctr, Sylmar, California 91342, United States
Mountain States Reg Hemo Ctr / Univ of Colorado, Denver, Colorado 80262, United States
Univ of Colorado Health Sciences Ctr, Denver, Colorado 80262, United States
Denver Dept of Health and Hosps, 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
Georgetown Univ Med Ctr, Washington, District of Columbia 20007, United States
Whitman - Walker Clinic / Georgetown Univ Med Ctr, Washington, District of Columbia 200072197, United States
HIV Ctr - District of Columbia Gen Hosp, Washington, District of Columbia 200072197, 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
Univ of South Florida, Tampa, Florida 33612, United States
Univ of Hawaii, Honolulu, Hawaii 96816, United States
Northwestern Univ Med School, Chicago, Illinois 60611, United States
Rush Presbyterian - Saint Luke's Med Ctr, Chicago, Illinois 60612, United States
Cook County Hosp, Chicago, Illinois 60612, United States
Louis A Weiss Memorial Hosp, Chicago, Illinois 60640, United States
Indiana Univ Hosp, Indianapolis, Indiana 462025250, United States
Methodist Hosp of Indiana / Life Care Clinic, Indianapolis, Indiana 46202, United States
Univ of Louisville / East Tennesee Comprehensive Hem Ctr, Louisville, Kentucky 40202, United States
Harvard (Massachusetts Gen Hosp), Boston, Massachusetts 02114, 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 Paul Ramsey Med Ctr, St. Paul, Minnesota 55101, United States
Hennepin County Med Clinic, Minneapolis, Minnesota 55415, United States
St Louis Regional Hosp / St Louis Regional Med Ctr, St. Louis, Missouri 63112, United States
Univ of Nebraska Med Ctr, Omaha, Nebraska 681985130, United States
Dartmouth - Hitchcock Med Ctr / Med Ctr Cntrl Massachusetts, Lebanon, New Hampshire 03756, United States
Univ of Medicine & Dentistry of New Jersey / Univ Hosp, Newark, New Jersey 071032714, United States
Robert Wood Johnson Med School / Hershey Med Ctr, New Brunswick, New Jersey 08903, United States
Montefiore Drug Treatment Ctr / Bronx Municipal Hosp, Bronx, New York 10461, United States
Montefiore Family Health Ctr / Bronx Municipal Hosp, Bronx, New York 10461, United States
Samaritan Village Inc / 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
Mount Sinai Med Ctr / Hemophilia Treatment Ctr, New York, New York 10029, 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
Montefiore Med Ctr Adolescent AIDS Program, Bronx, New York 10467, United States
SUNY / Health Sciences Ctr at Brooklyn, Brooklyn, New York 112032098, United States
Saint Clare's Hosp and Health Ctr, New York, New York 10019, 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
Univ of North Carolina, Chapel Hill, North Carolina 275997215, United States
Moses H Cone Memorial Hosp, Greensboro, North Carolina 27401, United States
Case Western Reserve Univ, Cleveland, Ohio 44106, United States
Univ of Cincinnati, Cincinnati, Ohio 452670405, United States
Columbus Children's Hosp, Columbus, Ohio 432052696, United States
Med College of Ohio, Toledo, Ohio 43699, United States
MetroHealth Med Ctr, Cleveland, Ohio 441091998, United States
Univ of Kentucky Lexington, Cincinnati, Ohio 45267, United States
Univ of Pennsylvania at Philadelphia, Philadelphia, Pennsylvania 19104, United States
Thomas Jefferson Univ Hosp, Philadelphia, Pennsylvania 191075098, United States
Girard Med Ctr, Philadelphia, Pennsylvania 191046073, United States
Milton S Hershey Med Ctr, Hershey, Pennsylvania 170330850, United States
Saint Michael's Med Ctr / Milton S Hershey Med Ctr, Hershey, Pennsylvania 170330850, United States
Julio Arroyo, West Columbia, South Carolina 29169, United States
Med Univ of South Carolina / UNC, Charleston, South Carolina 29425, United States
Univ of Tennessee / E Tennessee Comprehensive Hemophilia Ctr, Knoxville, Tennessee 37920, United States
Meharry Med College, Nashville, Tennessee 37203, United States
Univ Texas Health Science Ctr / Univ Texas Med School, Houston, Texas 77030, United States
Univ of Texas Galveston, Galveston, Texas 775550435, United States
Univ of Washington, Seattle, Washington 981224304, United States
Great Lakes Hemophilia Foundation, Wauwatosa, Wisconsin 532130127, United States
Northern Wisconsin Hemophilia Ctr / Saint Vincent's Hosp, Green Bay, Wisconsin 54301, United States
Henry K, Erice A, Tierney C, Balfour HH Jr, Fischl MA, Kmack A, Liou SH, Kenton A, Hirsch MS, Phair J, Martinez A, Kahn JO. A randomized, controlled, double-blind study comparing the survival benefit of four different reverse transcriptase inhibitor therapies (three-drug, two-drug, and alternating drug) for the treatment of advanced AIDS. AIDS Clinical Trial Group 193A Study Team. J Acquir Immune Defic Syndr Hum Retrovirol. 1998 Dec 1;19(4):339-49.
Price RW, Yiannoutsos C, Zaborski L, Kmack A, Henry K, Tierney C, Clifford D. Neurological substudies of ACTG protocol 193A: quantitative neurological performance measures and treatment outcomes. Conf Retroviruses Opportunistic Infect. 1998 Feb 1-5;5th:176 (abstract no 516)
Robinson P, Cotton D, Curry R, Henry K, Hall D, Myers M. Analysis of nevirapine (NVP) effect on clinical endpoints (CEs) of HIV progression or death in ACTG trial 193A. Conf Retroviruses Opportunistic Infect. 1998 Feb 1-5;5th:210 (abstract no 700)
Henry K, Tierney C, Kahn J, Balfour H, Jiang Q, Kmack A, Fischl M. A randomized, double-blind, placebo-controlled study comparing combination nucleoside and triple therapy for the treatment of advanced HIV disease (CD4 less than or equal to 50/mm(3)). Conf Retroviruses Opportunistic Infect. 1997 Jan 22-26;4th:207 (abstract no LB6)
Coplan P, Nikas A, Saah A, Nessly M, Doll L, Leavitt R, Benson J, Guess H. No association observed between indinavir therapy for HIV/AIDS and myocardial infarction in 4 clinical trials with 2,825 subjects. Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:191 (abstract no 658)
Erice A, Tierney C, Balfour HH Jr, Liou S, Kahn JO, Henry WK. Virologlc effect of therapy with reverse transcriptase inhibitors (RTIs) in patients with AIDS and less than 50 CD4+ T cells per mm(3): a substudy of ACTG 193a. Conf Retroviruses Opportunistic Infect. 1998 Feb 1-5;5th:204 (abstract no 662)
Price RW, Yiannoutsos CT, Clifford DB, Zaborski L, Tselis A, Sidtis JJ, Cohen B, Hall CD, Erice A, Henry K. Neurological outcomes in late HIV infection: adverse impact of neurological impairment on survival and protective effect of antiviral therapy. AIDS Clinical Trial Group and Neurological AIDS Research Consortium study team. AIDS. 1999 Sep 10;13(13):1677-85.
