Clinical trial NCT00108862: Immediate Versus Deferred Start of Anti-HIV Therapy in HIV-Infected Adults Being Treated for Tuberculosis
Official title: A Strategy Study of Immediate Versus Deferred Initiation of Antiretroviral Therapy for AIDS Disease-Free Survival in HIV-Infected Persons Treated for Tuberculosis With CD4 Less Than 250 Cells/mm^3
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV Infection
Tuberculosis
Keywords: Treatment Naive
TB
HIV
Antiretroviral Agents
Strategy Study
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2005-04-20
Enrollment: 809
Sex: ALL
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Percent of Participants Who Survived Without AIDS Progression.
timeFrame: Through week 48
Secondary outcomes:
measure: Percent of Participants Reporting a Grade 3 or 4 Adverse Event or Laboratory Abnormality
timeFrame: Through week 48
measure: Time to First New AIDS-defining Illness or Death.
timeFrame: Through week 48
measure: Percent of Participants With Culture-confirmed Tuberculosis (TB) Who Survived Without AIDS Progression.
timeFrame: Through week 48
measure: Percent of Participants Who Interrupted or Discontinued at Least One Tuberculosis (TB) Medication Due to Toxicity.
timeFrame: Through week 48
measure: Percent of Participants With Confirmed or Probable Tuberculosis (TB) Whose TB Resolved, or Who Required TB Treatment Through the End of Follow-up, or Died, or Were Lost to Follow-up.
timeFrame: Through week 48
measure: Percent of Participants Whose CD4 Increased by at Least 100 Cells/mm^3 Between Baseline and Week 48.
timeFrame: Through week 48
measure: Percent of Participants With MTB IRIS.
timeFrame: Through week 48
measure: Percent of Participants With HIV IRIS.
timeFrame: Through week 48
measure: Percent of Participants Whose HIV Viral Load Was Less Than 400 Copies/mL at Week 48.
timeFrame: Through week 48
Other outcomes:
measure: Percent of Participants in the Less Than 50 Cells/mm^3 CD4 Stratum Who Survived Without AIDS Progression.
timeFrame: Through week 48
measure: Percent of Participants in the Greater Than or Equal to 50 Cells/mm^3 CD4 Stratum Who Survived Without AIDS Progression.
timeFrame: Through week 48
Locations:
city: Los Angeles
country: United States
facility: University of Southern California (1201)
state: California
city: San Diego
country: United States
facility: University of California, San Diego, AVRC CRS (701)
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco AIDS CRS (801)
state: California
city: New York
country: United States
facility: NY Univ. HIV/AIDS CRS (401)
state: New York
city: Gaborone
country: Botswana
facility: Gaborone Prevention/Treatment Trials CRS (12701)
city: Molepolole
country: Botswana
facility: Molepolole Prevention/Treatment Trials CRS (12702)
city: Porto Alegre
country: Brazil
facility: Hospital Nossa Senhora da Conceicao CRS (12201)
state: RS
city: Rio de Janeiro
country: Brazil
facility: Instituto de Pesquisa Clinica Evandro Chagas (12101)
city: Rio de Janeiro
country: Brazil
facility: Projecto Praca Onze/Hesfa CRS (30333)
city: Bicentenaire
country: Haiti
facility: Les Centres GHESKIO CRS (30022)
state: Port-au-Prince
city: Pune
country: India
facility: National AIDS Research Institute Pune CRS (11601)
state: Maharashtra
city: Chennai
country: India
facility: Y.R.G Ctr, for AIDS Research and Education (11701)
city: Eldoret
country: Kenya
facility: AMPATH at Moi Univ. Teaching Hosp. Eldoret CRS (12601)
city: Kericho
country: Kenya
facility: Walter Reed Project - Kenya Med. Research Institute Kericho CRS (12501)
city: Blantyre
country: Malawi
facility: College of Med. JHU CRS (30301)
city: Lilongwe
country: Malawi
facility: University of North Carolina Lilongwe CRS (12001)
city: San Isidro
country: Peru
facility: Investigaciones Medicas en Salud (INMENSA) (11302)
state: Lima
city: Lima
country: Peru
facility: Asociacion Civil Impacta Salud y Educacion - Miraf CRS (11301)
city: Durban
country: South Africa
facility: CAPRISA eThekwini CRS (31422)
state: KwaZulu-Natal
city: Durban
country: South Africa
facility: Durban Adult HIV CRS (11201)
city: Johannesburg
country: South Africa
facility: Soweto ACTG CRS (12301)
city: Johannesburg
country: South Africa
facility: Univ. of Witwatersrand CRS (11101)
city: Chiang Mai
country: Thailand
facility: Chiang Mai University ACTG CRS (11501)
city: Kampala
country: Uganda
facility: Joint Clinical Research Centre (JCRC) (12401)
city: Lusaka
country: Zambia
facility: Kalingalinga Clinic CRS (12801)
city: Harare
country: Zimbabwe
facility: UZ-Parirenyatwa CRS (30313)
Study officials:
affiliation: San Francisco General Hospital and University of California, San Francisco
name: Diane Havlir, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.