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

This study has been completed.

Sponsor:

Collaborator:

National Institute of Allergy and Infectious Diseases (NIAID)

Information provided by (Responsible Party):

AIDS Clinical Trials Group

ClinicalTrials.gov Identifier:

NCT00108862

First received: April 19, 2005

Last updated: July 9, 2012

Last verified: July 2012

History of Changes

Results First Received: September 27, 2011

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Open Label; Primary Purpose: Treatment
Conditions:	HIV Infection Tuberculosis
Interventions:	Other: Strategy: Immediate ART Other: Strategy: Deferred ART

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Study participants were recruited at 26 sites from 13 countries: 4 each from U.S. and South Africa; 3 from Brazil; 2 each from Peru, Botswana, Kenya, Malawi, and India; and 1 each from Haiti, Uganda, Zambia, Zimbabwe, and Thailand, between September 2006 and August 2009.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
HIV-infected persons at least 13 years of age, naive to antiretroviral therapy, who had received 1-14 cumulative days of a rifamycin-based TB regimen within 28 days prior to study entry, and had a CD4 count <250 cells/mm3. Randomization was stratified by screening CD4 (<50 vs =>50). Three participants were deemed ineligible and taken off study.

Reporting Groups

Description

Immediate ART

These participants initiated HIV antiretroviral therapy (ART) within 72 hours of randomization, which took place at most 2 weeks after initiating rifampin (RIF)- or other rifamycin-based TB treatment according to in-country national TB treatment guidelines. The study-provided drugs were efavirenz (EFV) 600 mg (provided to non-U.S. sites only; 1 tablet orally) and emtricitabine (FTC) 200 mg/tenofovir disoproxil fumarate (TDF) 300 mg (1 fixed-dose combination tablet orally) once daily. FTC 200 mg (1 capsule) and TDF 300 mg (1 tablet) could be substituted for the fixed-dose combination tablet and was provided by the study. Participants who could not tolerate EFV could be offered nevirapine (NVP) 200 mg daily for 14 days, then 200 mg twice daily. Substitutions with other locally-available U.S. Food and Drug Administration (FDA)-approved or tentatively approved antiretrovirals (ARVs) that were compatible with TB therapy could be used at the discretion of the site investigator.

Deferred ART

These participants deferred ART until 8 to 12 weeks after initiation of their RIF- or other rifamycin-based TB treatment according to in-country national TB treatment guidelines. The study-provided drugs were EFV 600 mg (provided to non-U.S. sites only; 1 tablet orally) and FTC 200 mg/TDF 300 mg (1 fixed-dose combination tablet orally) once daily. FTC 200 mg (1 capsule) and TDF 300 mg (1 tablet) could be substituted for the fixed-dose combination tablet and was provided by the study. Participants who could not tolerate EFV could be offered NVP 200 mg daily for 14 days, then 200 mg twice daily. Substitutions with other locally-available U.S. FDA-approved or tentatively approved ARVs that were compatible with TB therapy could be used at the discretion of the site investigator.

Participant Flow: Overall Study

	Immediate ART	Deferred ART
STARTED	405	401 ^[1]
COMPLETED	337	339
NOT COMPLETED	68	62
Death	31	37
Withdrawal by Subject	10	6
Lost to Follow-up	27	19

[1]	Three participants who were deemed clinically ineligible and taken off study were omitted.

Baseline Characteristics

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Reporting Groups

	Description
Immediate ART	These participants initiated HIV antiretroviral therapy (ART) within 72 hours of randomization, which took place at most 2 weeks after initiating rifampin (RIF)- or other rifamycin-based TB treatment according to in-country national TB treatment guidelines. The study-provided drugs were efavirenz (EFV) 600 mg (provided to non-U.S. sites only; 1 tablet orally) and emtricitabine (FTC) 200 mg/tenofovir disoproxil fumarate (TDF) 300 mg (1 fixed-dose combination tablet orally) once daily. FTC 200 mg (1 capsule) and TDF 300 mg (1 tablet) could be substituted for the fixed-dose combination tablet and was provided by the study. Participants who could not tolerate EFV could be offered nevirapine (NVP) 200 mg daily for 14 days, then 200 mg twice daily. Substitutions with other locally-available U.S. Food and Drug Administration (FDA)-approved or tentatively approved antiretrovirals (ARVs) that were compatible with TB therapy could be used at the discretion of the site investigator.
Deferred ART	These participants deferred ART until 8 to 12 weeks after initiation of their RIF- or other rifamycin-based TB treatment according to in-country national TB treatment guidelines. The study-provided drugs were EFV 600 mg (provided to non-U.S. sites only; 1 tablet orally) and FTC 200 mg/TDF 300 mg (1 fixed-dose combination tablet orally) once daily. FTC 200 mg (1 capsule) and TDF 300 mg (1 tablet) could be substituted for the fixed-dose combination tablet and was provided by the study. Participants who could not tolerate EFV could be offered NVP 200 mg daily for 14 days, then 200 mg twice daily. Substitutions with other locally-available U.S. FDA-approved or tentatively approved ARVs that were compatible with TB therapy could be used at the discretion of the site investigator.
Total	Total of all reporting groups

Baseline Measures

	Immediate ART	Deferred ART	Total
Number of Participants [units: participants]	405	401	806
Age [units: participants]
<=18 years	0	2	2
Between 18 and 65 years	403	398	801
>=65 years	2	1	3
Age [units: years] Median ( Inter-Quartile Range )	34 ( 29 to 40 )	34 ( 29 to 42 )	34 ( 29 to 41 )
Gender [units: participants]
Female	139	166	305
Male	266	235	501
Region of Enrollment [units: participants]
South Africa	109	112	221
Malawi	69	68	137
Brazil	57	56	113
Kenya	36	36	72
Peru	23	25	48
India	26	21	47
Zambia	17	17	34
Zimbabwe	16	17	33
Uganda	15	14	29
Botswana	13	15	28
Haiti	12	8	20
United States	9	10	19
Thailand	3	2	5
TB Diagnosis Level at Entry [units: participants]
Confirmed TB	193	181	374
Probable TB	208	218	426
Not TB	4	2	6
Drug-Resistant TB Status at Entry [units: participants]
Rifampin (RIF) Resistant TB	1	0	1
Isoniazid (INH) Resistant TB	3	5	8
RIF and INH Resistant TB (Multi-Drug Resistant TB)	1	4	5
RIF and INH Sensitive TB	400	392	792
Time to ART Start from Start of TB Medications [units: days] Median ( Inter-Quartile Range )	10 ( 7 to 12 )	70 ( 66 to 75 )	14 ( 10 to 70 )

Outcome Measures

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1. Primary:

Percent of Participants Who Survived Without AIDS Progression. [ Time Frame: Through week 48 ]

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2. Secondary:

Percent of Participants Reporting a Grade 3 or 4 Adverse Event or Laboratory Abnormality [ Time Frame: Through week 48 ]

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3. Secondary:

Time to First New AIDS-defining Illness or Death. [ Time Frame: Through week 48 ]

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4. Secondary:

Percent of Participants With Culture-confirmed Tuberculosis (TB) Who Survived Without AIDS Progression. [ Time Frame: Through week 48 ]

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5. Secondary:

Percent of Participants Who Interrupted or Discontinued at Least One Tuberculosis (TB) Medication Due to Toxicity. [ Time Frame: Through week 48 ]

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6. Secondary:

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. [ Time Frame: Through week 48 ]

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7. Secondary:

Percent of Participants Whose CD4 Increased by at Least 100 Cells/mm^3 Between Baseline and Week 48. [ Time Frame: Through week 48 ]

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8. Secondary:

Percent of Participants With MTB IRIS. [ Time Frame: Through week 48 ]

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9. Secondary:

Percent of Participants With HIV IRIS. [ Time Frame: Through week 48 ]

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10. Secondary:

Percent of Participants Whose HIV Viral Load Was Less Than 400 Copies/mL at Week 48. [ Time Frame: Through week 48 ]

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11. Other Pre-specified:

Percent of Participants in the Less Than 50 Cells/mm^3 CD4 Stratum Who Survived Without AIDS Progression. [ Time Frame: Through week 48 ]

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Measure Type	Other Pre-specified
Measure Title	Percent of Participants in the Less Than 50 Cells/mm^3 CD4 Stratum Who Survived Without AIDS Progression.
Measure Description	Participants were included as described in the Outcome Measure Description for the Primary Outcome, except that only those in the <50 CD4 stratum were analyzed. The percent surviving without a new AIDS-defining illness was calculated using a Kaplan-Meier estimator with an associated standard error.
Time Frame	Through week 48
Safety Issue	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Numbers presented use the intent-to-treat approach (i.e., ignoring changes from randomized treatment strategy).

Reporting Groups

Description

Immediate ART

Deferred ART

Measured Values

	Immediate ART	Deferred ART
Number of Participants Analyzed [units: participants]	144	141
Percent of Participants in the Less Than 50 Cells/mm^3 CD4 Stratum Who Survived Without AIDS Progression. [units: percent of participants] Number ( 95% Confidence Interval )	16 ( 10 to 21 )	27 ( 19 to 39 )

Statistical Analysis 1 for Percent of Participants in the Less Than 50 Cells/mm^3 CD4 Stratum Who Survived Without AIDS Progression.

Groups ^[1]	All groups
Method ^[2]	Z-test, 2-sided
P Value ^[3]	0.02
Mean Difference (Final Values) ^[4]	11
Standard Error of the mean	± 5
95.08% Confidence Interval	( 2 to 21 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The study was not powered for this pre-specified subgroup analysis.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Interim reviews employed group sequential monitoring using an > O'Brien-Fleming use function. At final analysis, the a priori threshold for statistical significance was 0.0492.
[4]	Other relevant estimation information:
	The difference in percents was calculated as the percent failed in the Deferred ART arm minus the percent failed in the Immediate ART arm.

12. Other Pre-specified:

Percent of Participants in the Greater Than or Equal to 50 Cells/mm^3 CD4 Stratum Who Survived Without AIDS Progression. [ Time Frame: Through week 48 ]

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Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: In accordance with the Clinical Trials Agreement between NIAID (DAIDS) and company collaborators, NIAID (DAIDS) provides companies with a copy of any abstract, press release, or manuscript prior to submission for publication with sufficient time for company review and comment. The publication/other disclosure can be delayed up to 30 additional business days for manuscripts and five (5) business days for abstracts, to preserve U.S. or foreign patent or other intellectual property rights.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
None.

Results Point of Contact:

Name/Title: ClinicalTrials.gov Coordinator
Organization: Center for Biostatistics in AIDS Research, Harvard School of Public Health
phone: (617)432-2829
e-mail: CBAR.ClinicalTrials.Gov@sdac.harvard.edu

No publications provided by AIDS Clinical Trials Group

Publications automatically indexed to this study:

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.

Responsible Party:	AIDS Clinical Trials Group
ClinicalTrials.gov Identifier:	NCT00108862 History of Changes
Other Study ID Numbers:	ACTG A5221, 1U01AI068636, ACTG A5221
Study First Received:	April 19, 2005
Results First Received:	September 27, 2011
Last Updated:	July 9, 2012
Health Authority:	United States: Federal Government

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