A Randomized, Double-Blind, Four-Arm Study Comparing Combination Nucleoside, Alternating Nucleoside, and Triple-Drug Therapy for the Treatment of Advanced HIV Disease (CD4 <= 50/mm3)

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.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Nevirapine; Drug: Zidovudine; Drug: Didanosine; Drug: Zalcitabine

Detailed Description

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.

• Study Type: Interventional
• Enrollment: 1292
• Phase: Phase 2

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico, 009365067
    • Univ of Puerto Rico
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Univ of Alabama at Birmingham
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hosp of Los Angeles
    • Los Angeles, California, United States, 900331079
      • Univ of Southern California / LA County USC Med Ctr
    • Pasadena, California, United States, 91105
      • Huntington Memorial Hosp / Children's Hosp of Los Angeles
    • San Diego, California, United States, 921036325
      • Univ of California / San Diego Treatment Ctr
    • San Francisco, California, United States, 941102859
      • San Francisco AIDS Clinic / San Francisco Gen Hosp
    • San Francisco, California, United States, 94115
      • Stanford at Kaiser / Kaiser Permanente Med Ctr
    • San Francisco, California, United States, 941102859
      • San Francisco Gen Hosp
    • San Jose, California, United States, 951282699
      • Santa Clara Valley Med Ctr / AIDS Community Rsch Consortium
    • Stanford, California, United States, 943055107
      • San Mateo AIDS Program / Stanford Univ
    • Stanford, California, United States, 943055107
      • Stanford Univ Med Ctr
    • Sylmar, California, United States, 91342
      • Olive View Med Ctr
    • Torrance, California, United States, 90502
      • Harbor UCLA Med Ctr
  • Colorado
    • Denver, Colorado, United States, 80262
      • Univ of Colorado Health Sciences Ctr
    • Denver, Colorado, United States, 80262
      • Denver Dept of Health and Hosps
    • Denver, Colorado, United States, 80262
      • Mountain States Reg Hemo Ctr / Univ of Colorado
    • Denver, Colorado, United States, 80262
      • Rose Med Ctr
  • Connecticut
    • New Haven, Connecticut, United States, 065102483
      • Yale Univ / New Haven
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown Univ Med Ctr
    • Washington, District of Columbia, United States, 20059
      • Howard Univ
    • Washington, District of Columbia, United States, 20037
      • George Washington Univ / Hershey Med Ctr
    • Washington, District of Columbia, United States, 200072197
      • HIV Ctr - District of Columbia Gen Hosp
    • Washington, District of Columbia, United States, 200072197
      • Whitman - Walker Clinic / Georgetown Univ Med Ctr
  • Florida
    • Miami, Florida, United States, 331361013
      • Univ of Miami School of Medicine
    • Tampa, Florida, United States, 33612
      • Univ of South Florida
  • Hawaii
    • Honolulu, Hawaii, United States, 96816
      • Univ of Hawaii
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern Univ Med School
    • Chicago, Illinois, United States, 60612
      • Rush Presbyterian - Saint Luke's Med Ctr
    • Chicago, Illinois, United States, 60612
      • Cook County Hosp
    • Chicago, Illinois, United States, 60640
      • Louis A Weiss Memorial Hosp
  • Indiana
    • Indianapolis, Indiana, United States, 462025250
      • Indiana Univ Hosp
    • Indianapolis, Indiana, United States, 46202
      • Methodist Hosp of Indiana / Life Care Clinic
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Univ of Louisville / East Tennesee Comprehensive Hem Ctr
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Harvard (Massachusetts Gen Hosp)
    • Boston, Massachusetts, United States, 02118
      • Boston Med Ctr
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess - West Campus
    • Worcester, Massachusetts, United States, 01605
      • Worcester Memorial Hosp / Med Ctr of Cntrl MA-Memorial
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Univ of Minnesota
    • Minneapolis, Minnesota, United States, 55415
      • Hennepin County Med Clinic
    • Saint Paul, Minnesota, United States, 55101
      • St Paul Ramsey Med Ctr
  • Missouri
    • Saint Louis, Missouri, United States, 63112
      • St Louis Regional Hosp / St Louis Regional Med Ctr
  • Nebraska
    • Omaha, Nebraska, United States, 681985130
      • Univ of Nebraska Med Ctr
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth - Hitchcock Med Ctr / Med Ctr Cntrl Massachusetts
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Robert Wood Johnson Med School / Hershey Med Ctr
    • Newark, New Jersey, United States, 071032714
      • Univ of Medicine & Dentistry of New Jersey / Univ Hosp
  • New York
    • Albany, New York, United States, 122083479
      • Albany Med College / Division of HIV Medicine A158
    • Albany, New York, United States, 122083479
      • Adirondack Med Ctr at Saranac Lake
    • Albany, New York, United States, 122083479
      • Mid - Hudson Care Ctr
    • Bronx, New York, United States, 10461
      • Bronx Municipal Hosp Ctr/Jacobi Med Ctr
    • Bronx, New York, United States, 10465
      • Jack Weiler Hosp / Bronx Municipal Hosp
    • Bronx, New York, United States, 10467
      • Montefiore Med Ctr / Bronx Municipal Hosp
    • Bronx, New York, United States, 10468
      • Bronx Veterans Administration / Mount Sinai Hosp
    • Bronx, New York, United States, 10467
      • Montefiore Med Ctr Adolescent AIDS Program
    • Bronx, New York, United States, 10461
      • Montefiore Drug Treatment Ctr / Bronx Municipal Hosp
    • Bronx, New York, United States, 10461
      • Montefiore Family Health Ctr / Bronx Municipal Hosp
    • Bronx, New York, United States, 10461
      • Samaritan Village Inc / Bronx Municipal Hosp
    • Bronx, New York, United States, 10467
      • North Central Bronx Hosp / Bronx Municipal Hosp
    • Bronx, New York, United States, 10461
      • Comprehensive Health Care Ctr / Bronx Municipal Hosp
    • Brooklyn, New York, United States, 112032098
      • SUNY / Health Sciences Ctr at Brooklyn
    • Buffalo, New York, United States, 14215
      • SUNY / Erie County Med Ctr at Buffalo
    • Elmhurst, New York, United States, 11373
      • City Hosp Ctr at Elmhurst / Mount Sinai Hosp
    • Manhasset, New York, United States, 11030
      • North Shore Univ Hosp
    • New York, New York, United States, 10003
      • Beth Israel Med Ctr
    • New York, New York, United States, 10021
      • Cornell Univ Med Ctr
    • New York, New York, United States, 10016
      • Bellevue Hosp / New York Univ Med Ctr
    • New York, New York, United States, 10021
      • Mem Sloan - Kettering Cancer Ctr
    • New York, New York, United States, 10029
      • Mount Sinai Med Ctr
    • New York, New York, United States, 10037
      • Harlem Hosp Ctr
    • New York, New York, United States, 100323784
      • Columbia Presbyterian Med Ctr
    • New York, New York, United States, 10019
      • Saint Clare's Hosp and Health Ctr
    • New York, New York, United States, 10029
      • Mount Sinai Med Ctr / Hemophilia Treatment Ctr
    • Rochester, New York, United States, 14642
      • Univ of Rochester Medical Center
    • Syracuse, New York, United States, 13210
      • SUNY / State Univ of New York
  • North Carolina
    • Chapel Hill, North Carolina, United States, 275997215
      • Univ of North Carolina
    • Greensboro, North Carolina, United States, 27401
      • Moses H Cone Memorial Hosp
  • Ohio
    • Cincinnati, Ohio, United States, 452670405
      • Univ of Cincinnati
    • Cincinnati, Ohio, United States, 45267
      • Univ of Kentucky Lexington
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve Univ
    • Cleveland, Ohio, United States, 441091998
      • MetroHealth Med Ctr
    • Columbus, Ohio, United States, 432052696
      • Columbus Children's Hosp
    • Toledo, Ohio, United States, 43699
      • Med College of Ohio
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 170330850
      • Milton S Hershey Med Ctr
    • Hershey, Pennsylvania, United States, 170330850
      • Saint Michael's Med Ctr / Milton S Hershey Med Ctr
    • Philadelphia, Pennsylvania, United States, 19104
      • Univ of Pennsylvania at Philadelphia
    • Philadelphia, Pennsylvania, United States, 191075098
      • Thomas Jefferson Univ Hosp
    • Philadelphia, Pennsylvania, United States, 191046073
      • Girard Med Ctr
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Med Univ of South Carolina / UNC
    • West Columbia, South Carolina, United States, 29169
      • Julio Arroyo
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • Univ of Tennessee / E Tennessee Comprehensive Hemophilia Ctr
    • Nashville, Tennessee, United States, 37203
      • Meharry Med College
  • Texas
    • Galveston, Texas, United States, 775550435
      • Univ of Texas Galveston
    • Houston, Texas, United States, 77030
      • Univ Texas Health Science Ctr / Univ Texas Med School
  • Washington
    • Seattle, Washington, United States, 981224304
      • Univ of Washington
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54301
      • Northern Wisconsin Hemophilia Ctr / Saint Vincent's Hosp
    • Wauwatosa, Wisconsin, United States, 532130127
      • Great Lakes Hemophilia Foundation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 13 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Masking: Double

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Bristol-Myers Squibb; Glaxo Wellcome
• Investigators: Study Chair: Henry WK; Study Chair: Kahn JO; Study Chair: Balfour HH

Publications and helpful links

General Publications

• 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)
• 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. doi: 10.1097/00002030-199909100-00011.
• 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. doi: 10.1097/00042560-199812010-00004.
• 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)
• 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)

Study record dates

Study Major Dates

• Study Completion (Actual): September 1, 1996

Study Registration Dates

• First Submitted: November 2, 1999
• First Submitted That Met QC Criteria: August 30, 2001
• First Posted (Estimate): August 31, 2001

Study Record Updates

• Last Update Posted (Actual): November 4, 2021
• Last Update Submitted That Met QC Criteria: October 27, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Drug Therapy, Combination; Nevirapine; Acquired Immunodeficiency Syndrome; Didanosine; Zidovudine; Zalcitabine
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antimetabolites; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Nevirapine; Zidovudine; Didanosine; Zalcitabine
• Other Study ID Numbers: ACTG 193A; 11169 (Registry Identifier: DAIDS ES Registry Number)