Anti-HIV Drugs for Ugandan Patients With HIV and Tuberculosis

Delaying HIV Disease Progression With Punctuated Antiretroviral Therapy in HIV-Associated Tuberculosis

This study is designed to determine whether 6 months of anti-HIV drugs given along with tuberculosis treatment will delay the onset of AIDS in HIV infected African patients.

Study Overview

• Status: Completed
• Conditions: HIV Infections; Tuberculosis
• Intervention / Treatment: Drug: Abacavir; Drug: Lamivudine; Drug: Zidovudine; Drug: Tuberculosis treatment

Detailed Description

Tuberculosis (TB) is a common and serious complication of HIV infection in the developing world, especially in sub-Saharan Africa. Since the emergence of the HIV epidemic in Africa, the incidence rates of TB have risen dramatically, overwhelming national TB control programs across the continent. Over 50% of TB patients presenting to TB clinics in Africa are HIV infected. These patients often present in the early stages of HIV infection.

Recent World Health Organization guidelines on the management of HIV-associated pulmonary TB recommend antiretroviral (ARV) therapy in patients with CD4 cells less than 200 cells/mm3, but not for HIV infected TB patients who present with a high CD4 count. In Uganda, over half of HIV infected patients with active TB present to TB clinics with CD4 counts above 200 cells/mm3, and there is evidence that coinfected patients with a high CD4 count should be treated with ARV therapy. First, mortality in HIV-associated TB is high, even when patients respond to effective anti-tuberculosis therapy. Second, excess mortality associated with TB is most evident when CD4 counts are above 200 cell/mm3. Third, in coinfected patients, TB results in prolonged immune activation, which may enhance viral replication and accelerate the decline of CD4 cells.

This study will evaluate whether short-term ARV therapy of abacavir sulfate, lamivudine, and zidovudine given during treatment of active TB will slow progression of HIV disease in TB patients with CD4 counts of at least 350 cells/mm3. The study will also assess the possible risks (e.g., drug toxicities and resistance) and benefits (e.g., more rapid clearance of mycobacterium tuberculosis and reduced TB relapse) of punctuated ARV therapy.

Participants in this study will be HIV infected TB patients with CD4 counts of at least 350 cells/mm3. All participants will receive treatment for TB. Participants will be randomly assigned to receive 6 months of ARV therapy or to delay ARV therapy until CD4 counts drop below 250 cells/mm3. The participants will be followed for 2 years; CD4 counts will be compared between groups.

This study will also follow a group of HIV infected patients without active TB to quantify the extent to which CD4 cell decline is accelerated with active TB and to determine the extent to which a decline is neutralized in patients who receive punctuated ARV therapy.

• Study Type: Interventional
• Enrollment (Anticipated): 350
• Phase: Phase 3

Contacts and Locations

Study Locations

• Uganda
  • Kampala, Uganda
    • Makerere University Medical School

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 13 years to 60 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of pulmonary TB (AFB smear-positive or culture-positive)
• HIV infected
• CD4 count greater than 350 cells/mm3
• Residence within 20 km of Kampala, Uganda
• Willing to use acceptable forms of contraception during the study and for 6 weeks after stopping study medication
• Parent or guardian willing to provide informed consent, if applicable

Exclusion Criteria:

• Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; Participants will receive 6 months of ARV therapy and treatment for TB	Drug: Abacavir; 300 mg tablet taken orally twice daily; Drug: Lamivudine; 300 mg tablet taken orally daily; Drug: Zidovudine; 300 mg tablet taken orally twice daily; Drug: Tuberculosis treatment; Tuberculosis treatment
Experimental: 2; Participants will not receive ARV therapy until CD4 counts drop below 250 cells/mm3. All participants will receive treatment for TB.	Drug: Abacavir; 300 mg tablet taken orally twice daily; Drug: Lamivudine; 300 mg tablet taken orally daily; Drug: Zidovudine; 300 mg tablet taken orally twice daily; Drug: Tuberculosis treatment; Tuberculosis treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
CD4+ decline (slope)	Throughout study
Time to AIDS	Throughout study

Secondary Outcome Measures

Outcome Measure	Time Frame
Safety	Throughout study
Response to antituberculous therapy	Throughout study
Immune reconstitution	Throughout study
Viral drug resistance	Throughout study

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Makerere University
• Investigators: Principal Investigator: Christopher C. Whalen, MD, Case Western Reserve University; Principal Investigator: Roy Mugerwa, MD, Makerere University

Publications and helpful links

General Publications

• Chamie G, Charlebois ED, Srikantiah P, Walusimbi-Nanteza M, Mugerwa RD, Mayanja H, Okwera A, Whalen CC, Havlir DV. Mycobacterium tuberculosis microbiologic and clinical treatment outcomes in a randomized trial of immediate versus CD4(+)-initiated antiretroviral therapy in HIV-infected adults with a high CD4(+) cell count. Clin Infect Dis. 2010 Aug 1;51(3):359-62. doi: 10.1086/654799.

Study record dates

Study Major Dates

• Study Start: October 1, 2004

Study Registration Dates

• First Submitted: February 20, 2004
• First Submitted That Met QC Criteria: February 20, 2004
• First Posted (Estimate): February 23, 2004

Study Record Updates

• Last Update Posted (Estimate): August 12, 2010
• Last Update Submitted That Met QC Criteria: August 10, 2010
• Last Verified: August 1, 2010

More Information

Terms related to this study

• Keywords: Africa; Antiretroviral Therapy
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; 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; Lamivudine; Zidovudine; Abacavir
• Other Study ID Numbers: 1R01AI051219-01A2 (U.S. NIH Grant/Contract)