A Comparison of Three Treatments for Advanced HIV Disease in Patients Who Have Received Nucleoside Therapy in the Past

A Randomized, Double-Blind, Three-Arm Study Comparing Combination to Monthly Alternating Nucleoside Therapy for the Treatment of Advanced HIV Disease (CD4 <= 50/mm3) With a Prior History of Nucleoside Therapy

To compare the efficacy, safety and tolerance, and other clinical and immunologic effects of zidovudine (AZT) plus zalcitabine (dideoxycytidine; ddC), AZT plus didanosine (ddI), and AZT alternating monthly with ddI as measured by differences in survival among HIV-infected persons who have received 6 or more months of nucleoside monotherapy and have a CD4 count greater than or equal to 50 cells/mm3.

Combining two nucleoside drugs has the theoretical advantage of optimal protection against the evolution of resistant strains of HIV. However, one major problem with combination nucleoside therapy in patients with advanced disease is the increased toxicity resulting from such therapy. One approach to minimize toxicity while perhaps retaining some of the benefits of combination therapy is to alternate the two drugs.

Study Overview

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

Detailed Description

Combining two nucleoside drugs has the theoretical advantage of optimal protection against the evolution of resistant strains of HIV. However, one major problem with combination nucleoside therapy in patients with advanced disease is the increased toxicity resulting from such therapy. One approach to minimize toxicity while perhaps retaining some of the benefits of combination therapy is to alternate the two drugs.

Patients are randomized to one of three treatment arms: AZT plus ddI, AZT plus ddC, and AZT alone alternating monthly with ddI. Half of the patients receiving AZT alternating monthly with ddI will start with AZT, while the other half will start with ddI. Treatment continues until death or termination of the study. Patients are followed every 4 weeks. The study will include a subset of patients for whom virologic, pharmacokinetic, and macroneurologic assessments will be made.

• Study Type: Interventional
• Enrollment: 654
• Phase: Phase 2

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico, 00936
    • Puerto Rico-AIDS CRS
• Tanzania
  • Mbeya, Tanzania
    • Mbeya Med. Research Program, Mbeya Referral Hosp. CRS
• United States
  • California
    • Los Angeles, California, United States, 90033
      • USC CRS
    • Palo Alto, California, United States, 94115
      • Stanford CRS
    • San Diego, California, United States, 92103
      • Ucsd, Avrc Crs
    • San Francisco, California, United States
      • Ucsf Aids Crs
    • San Jose, California, United States
      • Santa Clara Valley Med. Ctr.
    • San Mateo, California, United States
      • San Mateo County AIDS Program
    • Torrance, California, United States, 90502
      • Harbor-UCLA Med. Ctr. CRS
  • Colorado
    • Aurora, Colorado, United States
      • University of Colorado Hospital CRS
  • Florida
    • Miami, Florida, United States
      • Univ. of Miami AIDS CRS
  • Hawaii
    • Honolulu, Hawaii, United States, 96816
      • Univ. of Hawaii at Manoa, Leahi Hosp.
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Cook County Hosp. CORE Ctr.
    • Chicago, Illinois, United States, 60612
      • Rush Univ. Med. Ctr. ACTG CRS
    • Chicago, Illinois, United States
      • Northwestern University CRS
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana Univ. School of Medicine, Infectious Disease Research Clinic
    • Indianapolis, Indiana, United States, 46202
      • Methodist Hosp. of Indiana
  • Iowa
    • Iowa City, Iowa, United States
      • Univ. of Iowa Healthcare, Div. of Infectious Diseases
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital ACTG CRS
    • Boston, Massachusetts, United States, 02118
      • Bmc Actg Crs
    • Boston, Massachusetts, United States
      • Beth Israel Deaconess - East Campus A0102 CRS
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota, ACTU
    • Minneapolis, Minnesota, United States, 55415
      • Hennepin County Med. Ctr., Div. of Infectious Diseases
  • Missouri
    • Saint Louis, Missouri, United States
      • Washington U CRS
    • Saint Louis, Missouri, United States
      • St. Louis ConnectCare, Infectious Diseases Clinic
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • Univ. of Nebraska Med. Ctr., Durham Outpatient Ctr.
  • New York
    • New York, New York, United States, 10016
      • NY Univ. HIV/AIDS CRS
    • New York, New York, United States, 10021
      • Cornell University A2201
    • New York, New York, United States, 10003
      • Beth Israel Med. Ctr. (Mt. Sinai)
    • New York, New York, United States, 10021
      • Memorial Sloan-Kettering Cancer Ctr.
    • Rochester, New York, United States, 14642
      • Univ. of Rochester ACTG CRS
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Unc Aids Crs
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • Univ. of Cincinnati CRS
    • Cleveland, Ohio, United States, 44106
      • Case CRS
    • Columbus, Ohio, United States
      • The Ohio State Univ. AIDS CRS
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hosp. of the Univ. of Pennsylvania CRS
  • Washington
    • Seattle, Washington, United States, 98122
      • University of Washington AIDS CRS

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.
• Prophylaxis for MAI or fungal infections.
• Antibiotics.
• Over-the-counter, alternative, or regularly prescribed drugs.
• Steroids, if for < 21 days.

Concurrent Treatment:

Allowed:

• Radiation therapy for cutaneous Kaposi's sarcoma.

Patients must have:

• HIV infection.
• CD4 count <= 50 cells/mm3.
• Prior nucleoside monotherapy for at least 6 months.
• Life expectancy of at least 6 months.

Prior Medication: Required:

• Nucleoside monotherapy for at least 6 months. Active alcohol or drug abuse.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

• Severe peripheral neuropathy.
• Psychological or emotional problems sufficient to prevent study compliance.

Concurrent Medication:

Excluded:

• Systemic chemotherapy for malignancy.
• Acute or induction therapy for opportunistic infection.

Patients with the following prior conditions are excluded:

• History of acute or chronic pancreatitis.
• Grade 3 or greater toxicity to AZT, ddI, or ddC on two or more occasions.

Prior Medication:

Excluded:

• Non-study nucleosides or biologic response modifiers within 7 days prior to study entry.
• Acute therapy for opportunistic process within 14 days prior to study entry.
• Acute systemic therapy for other medical conditions within 14 days prior to study entry.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment

Collaborators and Investigators

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

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)
• 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.
• Fichtenbaum CJ, Powderly WG. Refractory mucosal candidiasis in patients with human immunodeficiency virus infection. Clin Infect Dis. 1998 Mar;26(3):556-65. doi: 10.1086/514571.

Study record dates

Study Major Dates

• Study Completion (Actual): May 1, 1993

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 28, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Drug Therapy, Combination; 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; Zidovudine; Didanosine; Zalcitabine
• Other Study ID Numbers: ACTG 193; 11168 (Registry Identifier: DAIDS ES Registry Number)