Immediate Versus Deferred Start of Anti-HIV Therapy in HIV-Infected Adults Being Treated for Tuberculosis

NCT ID: NCT00108862

Last Updated: 2018-10-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 809 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-08-31
• Study Completion Date: 2010-07-31

Brief Summary

The purpose of this study is to determine the best time to begin anti-HIV treatment in individuals who have HIV and tuberculosis (TB).

Study hypothesis: Immediate antiretroviral therapy (ART), initiated after approximately 2 weeks of TB treatment, will reduce the frequency of other AIDS-defining illnesses and death in HIV-infected participants being treated for TB by at least 40% at week 48 when compared to deferred ART, initiated at after 8-12 weeks of TB treatment.

Detailed Description

Tuberculosis (TB) is the most important co-infection in the HIV epidemic; the bi-directional relationship between the two diseases is well established. HIV increases the risk for TB acquisition, reactivation, and reinfection, and reduces survival compared to patients with TB alone. In individuals with HIV, TB infection results in reduced survival, increased risk for opportunistic infections, and elevations in HIV replication. Improving the outcome of HIV-infected individuals who develop TB is of high importance. Initiating antiretroviral therapy (ART) shortly after initiating TB treatment may improve outcomes in individuals co-infected with HIV and TB. However, data to support this suggestion were limited before this study began. This study will determine the most appropriate time to initiate ART in HIV-infected individuals who recently initiated treatment for TB.

This study lasted 48 weeks and comprised two steps. At study entry, participants underwent clinical assessment, drug adherence training, and blood collection. In Step 1, participants were randomly assigned to one of two arms. Participants in Arm A initiated ART after approximately 2 weeks of TB treatment. Participants in Arm B deferred ART until after 8 to 12 weeks of TB treatment. In Step 2, Arm B participants initiated ART; Arm A participants did not enter Step 2. ART consisted of efavirenz (EFV) and emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF); FTC and TDF could be given as individual agents. Drug substitutions could be made for participants who could not tolerate the specified regimen. Blood collection and clinical assessments occurred at weeks 4, 8, 12, 16, 24, 32, 40, and 48.

Conditions

HIV Infection; Tuberculosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Immediate ART

The intervention is the strategy of initiating antiretroviral therapy (ART) after approximately 2 weeks of tuberculosis (TB) treatment.

Group Type: EXPERIMENTAL

Strategy: Immediate ART

Intervention Type: OTHER

The intervention is the strategy of initiating antiretroviral therapy (ART) after approximately 2 weeks of rifampin (RIF)- or other rifamycin-based TB treatment according to in-country national TB treatment guidelines. The study-provided ART is efavirenz (EFV) 600 mg (1 tablet orally), emtricitabine (FTC) 200 mg (1 capsule orally), and tenofovir disoproxil fumarate (TDF) 300 mg (1 tablet orally) daily. Substitutions with other locally available U.S. Food and Drug Administration (FDA)-approved or tentatively approved antiretrovirals that are compatible with TB treatment may be used at the discretion of the site investigator. The TB treatment will be supplied and monitored by the host country TB control program.

Deferred ART

The intervention is the strategy of initiating ART after 8 to 12 weeks of TB treatment.

Group Type: ACTIVE_COMPARATOR

Strategy: Deferred ART

Intervention Type: OTHER

The intervention is the strategy of initiating ART either after 8-12 weeks of RIF- or other rifamycin-based TB treatment according to in-country national TB treatment guidelines. The study-provided ART is EFV 600 mg (1 tablet orally), FTC 200 mg (1 capsule orally), and TDF 300 mg (1 tablet orally) daily. Initiation outside of these windows, on a case by case basis, is permitted at the discretion of the site investigator. Substitutions with other locally available U.S. FDA-approved or tentatively approved antiretrovirals that are compatible with TB treatment may be used at the discretion of the site investigator. The TB treatment will be supplied and monitored by the host country TB control program.

Interventions

Strategy: Immediate ART

The intervention is the strategy of initiating antiretroviral therapy (ART) after approximately 2 weeks of rifampin (RIF)- or other rifamycin-based TB treatment according to in-country national TB treatment guidelines. The study-provided ART is efavirenz (EFV) 600 mg (1 tablet orally), emtricitabine (FTC) 200 mg (1 capsule orally), and tenofovir disoproxil fumarate (TDF) 300 mg (1 tablet orally) daily. Substitutions with other locally available U.S. Food and Drug Administration (FDA)-approved or tentatively approved antiretrovirals that are compatible with TB treatment may be used at the discretion of the site investigator. The TB treatment will be supplied and monitored by the host country TB control program.

Intervention Type: OTHER

Strategy: Deferred ART

The intervention is the strategy of initiating ART either after 8-12 weeks of RIF- or other rifamycin-based TB treatment according to in-country national TB treatment guidelines. The study-provided ART is EFV 600 mg (1 tablet orally), FTC 200 mg (1 capsule orally), and TDF 300 mg (1 tablet orally) daily. Initiation outside of these windows, on a case by case basis, is permitted at the discretion of the site investigator. Substitutions with other locally available U.S. FDA-approved or tentatively approved antiretrovirals that are compatible with TB treatment may be used at the discretion of the site investigator. The TB treatment will be supplied and monitored by the host country TB control program.

Intervention Type: OTHER

Other Intervention Names

Early ART

Eligibility Criteria

Inclusion Criteria

• HIV-infected.
• Confirmed or probable TB (more information on the criterion can be found in the protocol).
• Chest x-ray within 30 days prior to study entry.
• Receipt of 1-14 cumulative days of rifampin- or other rifamycin-based TB treatment that was initiated within 28 days prior to study entry.
• CD4 count less than 250 cells/mm^3 within 30 days prior to study entry.
• Willing to use acceptable methods of contraception while on study drugs and for 6 weeks after stopping these drugs.
• Able to swallow oral medications.
• Parent of guardian willing to provide informed consent, if applicable.
• Karnofsky performance score =>20 at time of study entry.

Exclusion Criteria

• ART for longer than 7 cumulative days prior to study entry or treatment for any period of time with one or more antiretrovirals. Participants who have taken ART during pregnancy or for occupational exposure are not excluded.
• Allergy or sensitivity to any of the study drugs or their formulations.
• History of multidrug-resistant TB.
• Receipt of any investigational therapy or chemotherapy within 30 days prior to study entry.
• Certain medications.
• Breastfeeding.

• Minimum Eligible Age: 13 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: collaborator

Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Diane Havlir, MD

Role: STUDY_CHAIR

San Francisco General Hospital and University of California, San Francisco

Locations

University of Southern California (1201)

Los Angeles, California, United States

University of California, San Diego, AVRC CRS (701)

San Diego, California, United States

University of California, San Francisco AIDS CRS (801)

San Francisco, California, United States

NY Univ. HIV/AIDS CRS (401)

New York, New York, United States

Gaborone Prevention/Treatment Trials CRS (12701)

Gaborone, , Botswana

Molepolole Prevention/Treatment Trials CRS (12702)

Molepolole, , Botswana

Hospital Nossa Senhora da Conceicao CRS (12201)

Porto Alegre, Rio Grande do Sul, Brazil

Instituto de Pesquisa Clinica Evandro Chagas (12101)

Rio de Janeiro, , Brazil

Projecto Praca Onze/Hesfa CRS (30333)

Rio de Janeiro, , Brazil

Les Centres GHESKIO CRS (30022)

Bicentenaire, Port-au-Prince, Haiti

National AIDS Research Institute Pune CRS (11601)

Pune, Maharashtra, India

Y.R.G Ctr, for AIDS Research and Education (11701)

Chennai, , India

AMPATH at Moi Univ. Teaching Hosp. Eldoret CRS (12601)

Eldoret, , Kenya

Walter Reed Project - Kenya Med. Research Institute Kericho CRS (12501)

Kericho, , Kenya

College of Med. JHU CRS (30301)

Blantyre, , Malawi

University of North Carolina Lilongwe CRS (12001)

Lilongwe, , Malawi

Investigaciones Medicas en Salud (INMENSA) (11302)

San Isidro, Lima region, Peru

Asociacion Civil Impacta Salud y Educacion - Miraf CRS (11301)

Lima, , Peru

CAPRISA eThekwini CRS (31422)

Durban, KwaZulu-Natal, South Africa

Durban Adult HIV CRS (11201)

Durban, , South Africa

Soweto ACTG CRS (12301)

Johannesburg, , South Africa

Univ. of Witwatersrand CRS (11101)

Johannesburg, , South Africa

Chiang Mai University ACTG CRS (11501)

Chiang Mai, , Thailand

Joint Clinical Research Centre (JCRC) (12401)

Kampala, , Uganda

Kalingalinga Clinic CRS (12801)

Lusaka, , Zambia

UZ-Parirenyatwa CRS (30313)

Harare, , Zimbabwe

Countries

United States; Botswana; Brazil; Haiti; India; Kenya; Malawi; Peru; South Africa; Thailand; Uganda; Zambia; Zimbabwe

References

Crump JA, Wu X, Kendall MA, Ive PD, Kumwenda JJ, Grinsztejn B, Jentsch U, Swindells S. Predictors and outcomes of Mycobacterium tuberculosis bacteremia among patients with HIV and tuberculosis co-infection enrolled in the ACTG A5221 STRIDE study. BMC Infect Dis. 2015 Jan 13;15:12. doi: 10.1186/s12879-014-0735-5.

Reference Type: DERIVED

PMID: 25582793 (View on PubMed)

Havlir DV, Kendall MA, Ive P, Kumwenda J, Swindells S, Qasba SS, Luetkemeyer AF, Hogg E, Rooney JF, Wu X, Hosseinipour MC, Lalloo U, Veloso VG, Some FF, Kumarasamy N, Padayatchi N, Santos BR, Reid S, Hakim J, Mohapi L, Mugyenyi P, Sanchez J, Lama JR, Pape JW, Sanchez A, Asmelash A, Moko E, Sawe F, Andersen J, Sanne I; AIDS Clinical Trials Group Study A5221. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med. 2011 Oct 20;365(16):1482-91. doi: 10.1056/NEJMoa1013607.

Reference Type: DERIVED

PMID: 22010914 (View on PubMed)

Other Identifiers

1U01AI068636

Identifier Type: NIH

Identifier Source: secondary_id

View Link

ACTG A5221

Identifier Type: OTHER

Identifier Source: secondary_id

ACTG A5221

Identifier Type: -

Identifier Source: org_study_id