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

Phase 4

Completed

Conditions: HIV Infection
Tuberculosis

Registration Number: NCT00108862

Lead Sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 809

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Percent of Participants Who Survived Without AIDS Progression.	Through week 48	As this was a study of the strategy of providing antiretroviral therapy (ART) during the initial treatment of TB versus deferring ART until TB was treated for 8-12 weeks, all eligible participants randomized were followed for 48 weeks, whether they started ART as scheduled, whether they started ART at all, or even if the participant did not have TB and discontinued TB treatment. The percent surviving without a new AIDS-defining illness was calculated using a Kaplan-Meier estimator with an associated standard error.

Secondary Outcome Measures

Name	Time	Method
Time to First New AIDS-defining Illness or Death.	Through week 48	All eligible participants were included in this analysis. Weeks from randomization to first new AIDS-defining illness or death was analyzed using a stratified Cox proportional hazards regression model. The stratification was by screening CD4 cell count: \<50 cells/mm3 versus =\>50 cells/mm3.
Percent of Participants With HIV IRIS.	Through week 48	All eligible participants were included in this analysis. The percent of participants with HIV-associated immune reconstitution inflammatory syndrome (IRIS) was calculated with an associated standard error.
Percent of Participants Reporting a Grade 3 or 4 Adverse Event or Laboratory Abnormality	Through week 48	All eligible participants were included in this analysis. The percent of participants whose highest reported grade of adverse events and laboratory abnormalities was Grade 3 or 4 was calculated with an associated standard error, where Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening/disabling, and Grade 5=death.
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.	Through week 48	TB treatment outcome was assessed in the 800 eligible participants who had confirmed or probable TB at study entry. The sites determined if the TB was resolved. If TB was not resolved, TB treatment outcome status was determined based on whether TB treatment was ongoing at the last study visit; if the participant died while TB treatment was ongoing; or if the participant was lost to follow-up, withdrew consent, or other reason for lacking TB resolution status. Percents were calculated with associated standard errors.
Percent of Participants Whose CD4 Increased by at Least 100 Cells/mm^3 Between Baseline and Week 48.	Through week 48	All eligible participants were included in the analysis. Participants who were lost-to-follow-up (LFU) prior to week 48 or who were alive with a CD4 cell count increase of less than 100 cells/mm\^3 were grouped separately those who died or whose CD4 cell count increased by at least 100 cells/mm\^3. Participants missing CD4 cell counts at week 48 were coded as LFU in this analysis. The percents were calculated with associated standard errors.
Percent of Participants With MTB IRIS.	Through week 48	All eligible participants were included in this analysis. The percent of participants with Mycobacteria tuberculosis (MTB)-associated immune reconstitution inflammatory syndrome (IRIS) was calculated with an associated standard error.
Percent of Participants With Culture-confirmed Tuberculosis (TB) Who Survived Without AIDS Progression.	Through week 48	This analysis was based on 374 participants with culture-confirmed TB at entry. The percent with culture-confirmed TB surviving without a new AIDS-defining illness was calculated using a Kaplan-Meier estimator with an associated standard error.
Percent of Participants Who Interrupted or Discontinued at Least One Tuberculosis (TB) Medication Due to Toxicity.	Through week 48	All eligible participants were included in this analysis. The percent of participants who interrupted at least one TB medication for more than one day due to toxicity or discontinued at least one TB medication due to toxicity was calculated with an associated standard error.
Percent of Participants Whose HIV Viral Load Was Less Than 400 Copies/mL at Week 48.	Through week 48	All eligible participants were included in the analysis. Participants who were lost-to-follow-up (LFU) prior to week 48 or who were alive with a HIV viral load at least 400 copies/mL were grouped separately those those who died or who had HIV viral loads below 400 copies/mL. Participants missing HIV viral loads at week 48 were coded as LFU in this analysis. Percents were calculated with associated standard errors.

Trial Locations

Locations (26): University of Southern California (1201)
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Los Angeles, California, United States
University of California, San Diego, AVRC CRS (701)
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San Diego, California, United States
University of California, San Francisco AIDS CRS (801)
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San Francisco, California, United States
NY Univ. HIV/AIDS CRS (401)
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New York, New York, United States
Molepolole Prevention/Treatment Trials CRS (12702)
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Molepolole, Botswana
Gaborone Prevention/Treatment Trials CRS (12701)
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Gaborone, Botswana
Projecto Praca Onze/Hesfa CRS (30333)
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Rio de Janeiro, Brazil
Les Centres GHESKIO CRS (30022)
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Bicentenaire, Port-au-Prince, Haiti
College of Med. JHU CRS (30301)
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Blantyre, Malawi
Asociacion Civil Impacta Salud y Educacion - Miraf CRS (11301)
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Lima, Peru
Soweto ACTG CRS (12301)
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Johannesburg, South Africa
CAPRISA eThekwini CRS (31422)
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Durban, KwaZulu-Natal, South Africa
Durban Adult HIV CRS (11201)
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Durban, South Africa
Univ. of Witwatersrand CRS (11101)
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Johannesburg, South Africa
Kalingalinga Clinic CRS (12801)
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Lusaka, Zambia
Joint Clinical Research Centre (JCRC) (12401)
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Kampala, Uganda
University of North Carolina Lilongwe CRS (12001)
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Lilongwe, Malawi
UZ-Parirenyatwa CRS (30313)
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Harare, Zimbabwe
Hospital Nossa Senhora da Conceicao CRS (12201)
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Porto Alegre, RS, Brazil
Instituto de Pesquisa Clinica Evandro Chagas (12101)
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Rio de Janeiro, Brazil
Chiang Mai University ACTG CRS (11501)
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Chiang Mai, Thailand
Walter Reed Project - Kenya Med. Research Institute Kericho CRS (12501)
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Kericho, Kenya
Y.R.G Ctr, for AIDS Research and Education (11701)
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Chennai, India
AMPATH at Moi Univ. Teaching Hosp. Eldoret CRS (12601)
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Eldoret, Kenya
National AIDS Research Institute Pune CRS (11601)
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Pune, Maharashtra, India
Investigaciones Medicas en Salud (INMENSA) (11302)
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San Isidro, Lima, Peru