A Study of Zidovudine in HIV-Infected Patients With Liver Disease

A Clinical Study Examining the Pharmacokinetics and Bioavailability of Azidothymidine (AZT, Zidovudine) in Patients With Human Immunodeficiency Virus (HIV) Infection and Hepatic Disease

To examine the pharmacokinetics (blood levels) and bioavailability of zidovudine (AZT) given to patients with HIV infection and chronic liver disease. The specific aim of the study is to provide data permitting the development of guidelines for use of AZT in patients with mild, moderate, or severe liver disease.

AZT is the only antiviral agent that has been shown to be effective in patients with severe HIV infection. However, AZT is largely eliminated from the body through a biochemical reaction that takes place in the liver, and it is possible that patients with underlying liver disease may have altered AZT pharmacokinetics and may metabolize AZT differently, with the result that they are susceptible to an increased risk of serious drug toxicity. This study will examine the pharmacokinetics, elimination, and metabolism of AZT in patients with liver disease. Guidelines developed from the data will be helpful in managing AZT treatment of these HIV-infected persons and will indicate whether the dose of AZT administered should be adjusted to compensate for any changes in its bioavailability and/or pharmacokinetics.

Study Overview

• Status: Completed
• Conditions: Liver Diseases; HIV Infections
• Intervention / Treatment: Drug: Zidovudine

Detailed Description

AZT is the only antiviral agent that has been shown to be effective in patients with severe HIV infection. However, AZT is largely eliminated from the body through a biochemical reaction that takes place in the liver, and it is possible that patients with underlying liver disease may have altered AZT pharmacokinetics and may metabolize AZT differently, with the result that they are susceptible to an increased risk of serious drug toxicity. This study will examine the pharmacokinetics, elimination, and metabolism of AZT in patients with liver disease. Guidelines developed from the data will be helpful in managing AZT treatment of these HIV-infected persons and will indicate whether the dose of AZT administered should be adjusted to compensate for any changes in its bioavailability and/or pharmacokinetics.

Patients are assessed and stratified according to liver function and severity of liver disease. Patients receive an intravenous (IV) dose of AZT on the first day of the study, followed by an oral dose 24 hours later on the second day of the study. Patients fast for 8 hours prior to each dose and for 2 hours after each dose. Liver function tests are repeated on the first day of the study. In each patient, serial measurements of serum and urine AZT and its metabolite, 3'-azido-3'-deoxy-5'-glucuronylthymidine (GAZT), are monitored after both doses.

• Study Type: Interventional
• Enrollment: 39
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston Med Ctr
    • Worcester, Massachusetts, United States, 01655
      • Univ of Massachusetts Med Ctr
  • North Carolina
    • Chapel Hill, North Carolina, United States, 275997215
      • Univ of North Carolina
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 170330850
      • Milton S Hershey Med Ctr
  • Washington
    • Seattle, Washington, United States, 98105
      • Univ of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

Concurrent Medication:

Allowed after completion of day 2 of study:

• Prior medications may be resumed.

Concurrent Treatment:

Allowed after completion of day 2 of study:

• Cytotoxic chemotherapy or radiation therapy for Kaposi's sarcoma.

The study will be divided into three groups of cooperative patients according to mild, moderate, or severe liver disease. Severity of disease will be assessed within 7 days of entry into the study according to laboratory values. Patients must have normal kidney function. No medications should be taken for 48 hours prior to entering the study. Hemophiliacs are included.

Prior Medication:

Allowed:

• Zidovudine (AZT) if discontinued at least 48 hours prior to study entry.

Exclusion Criteria

Co-existing Condition:

Patients will be excluded from the study if unacceptable toxicity develops or if an illness requiring concurrent treatment develops.

Concurrent Medication:

Excluded within 48 hours of study entry:

• All medications. Medication may be resumed after completion of day 2 of the study.

Concurrent Treatment:

Excluded within 48 hours of study entry:

• All treatments. Treatment may be resumed after completion of day 2 of the study.

Patients will be excluded for the following reasons:

• Presence of active opportunistic infections, with the exception of active or chronic hepatitis B virus or hepatitis D virus infection, or ongoing therapy for an opportunistic infection.
• Thrombocytopenia, with platelets less than 50000 platelets/mm3.
• Neutropenia, with polymorphonuclear leukocytes less than 1000 cells/mm3.
• Renal insufficiency, with creatinine greater than 1.5 mg/dl.
• Acute viral hepatitis within 30 days of the study.
• Patients who are expected to be noncompliant or who are unwilling to sign an informed consent statement.

Prior Medication:

Excluded within 48 hours of study entry:

• All medications. Medication may be resumed after completion of day 2 of the study.

Prior Treatment:

Excluded within 30 days of study entry:

• Cytotoxic chemotherapy or radiation therapy for Kaposi's sarcoma. Treatment may be resumed after completion of day 2 of the study.

Active drug or alcohol abuse.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Masking: None (Open Label)

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Study Chair: Lemon SM

Publications and helpful links

General Publications

• Moore KH, Raasch RH, Brouwer KL, Opheim K, Cheeseman SH, Eyster E, Lemon SM, van der Horst CM. Pharmacokinetics and bioavailability of zidovudine and its glucuronidated metabolite in patients with human immunodeficiency virus infection and hepatic disease (AIDS Clinical Trials Group protocol 062). Antimicrob Agents Chemother. 1995 Dec;39(12):2732-7. doi: 10.1128/AAC.39.12.2732.

Study record dates

Study Major Dates

• Study Completion (Actual): May 1, 1990

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: Acquired Immunodeficiency Syndrome; Zidovudine; Liver Diseases; HIV Seropositivity; Liver; Liver Function Tests; Biological Availability
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Infections; 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
• Other Study ID Numbers: ACTG 062; 11036 (Registry Identifier: DAIDS ES Registry Number)