Efavirenz or Atazanavir/Ritonavir Given With Emtricitabine/Tenofovir Disoproxil Fumarate or Abacavir/Lamivudine in HIV Infected Treatment-Naive Adults

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:

NCT00118898

First received: July 7, 2005

Last updated: January 4, 2016

Last verified: January 2016

History of Changes

Results First Received: January 8, 2010

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Open Label; Primary Purpose: Treatment
Condition:	HIV Infections
Interventions:	Drug: Abacavir/Lamivudine Drug: Atazanavir Drug: Efavirenz Drug: Emtricitabine/Tenofovir disoproxil fumarate Drug: Ritonavir Drug: Abacavir/Lamivudine placebo Drug: Emtricitabine/Tenofovir disoproxil fumarate placebo

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
Recruited at AIDS Clinical Trials Units in the United States and Puerto Rico. Recruitment occurred between September 21, 2005 (date first subject was randomized) and November 20, 2007 (date last subject was randomized).

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
1864 were randomized. Results reported for 1857 eligible participants; 7 were subsequently found ineligible and excluded from all analyses.

Reporting Groups

	Description
EFV, FTC/TDF, and Placebo ABC/3TC	Participants will receive EFV, FTC/TDF, and placebo for ABC/3TC for at least 96 weeks
EFV, Placebo FTC/TDF, and ABC/3TC	Participants will receive EFV, placebo for FTC/TDF, and ABC/3TC for at least 96 weeks
RTV-boosted ATV, FTC/TDF, and Placebo ABC/3TC	Participants will receive RTV-boosted ATV, FTC/TDF, and placebo for ABC/3TC for at least 96 weeks
RTV-boosted ATV, Placebo FTC/TDF, and ABC/3TC	Participants will receive RTV-boosted ATV, placebo for FTC/TDF, and ABC/3TC for at least 96 weeks

Participant Flow: Overall Study

	EFV, FTC/TDF, and Placebo ABC/3TC	EFV, Placebo FTC/TDF, and ABC/3TC	RTV-boosted ATV, FTC/TDF, and Placebo ABC/3TC	RTV-boosted ATV, Placebo FTC/TDF, and ABC/3TC
STARTED	464	465	465	463
Initiated Treatment	461	461	464	462
COMPLETED	343	324	342	322
NOT COMPLETED	121	141	123	141
Death	6	11	6	8
Lost to Follow-up	26	34	33	33
Withdrawal by Subject	10	5	8	8
Site Closure	33	31	28	37
Severe debilitation	1	4	6	4
Not compliant with requirements	11	13	11	11
Not able to get to clinic	34	43	31	40

Baseline Characteristics

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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.
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Reporting Groups

	Description
EFV, FTC/TDF, and Placebo ABC/3TC	Participants will receive EFV, FTC/TDF, and placebo for ABC/3TC for at least 96 weeks
EFV, Placebo FTC/TDF, and ABC/3TC	Participants will receive EFV, placebo for FTC/TDF, and ABC/3TC for at least 96 weeks
RTV-boosted ATV, FTC/TDF, and Placebo ABC/3TC	Participants will receive RTV-boosted ATV, FTC/TDF, and placebo for ABC/3TC for at least 96 weeks
RTV-boosted ATV, Placebo FTC/TDF, and ABC/3TC	Participants will receive RTV-boosted ATV, placebo for FTC/TDF, and ABC/3TC for at least 96 weeks
Total	Total of all reporting groups

Baseline Measures

	EFV, FTC/TDF, and Placebo ABC/3TC	EFV, Placebo FTC/TDF, and ABC/3TC	RTV-boosted ATV, FTC/TDF, and Placebo ABC/3TC	RTV-boosted ATV, Placebo FTC/TDF, and ABC/3TC	Total
Number of Participants [units: participants]	464	465	465	463	1857
Age [units: participants]
<=18 years	2	3	2	3	10
Between 18 and 65 years	461	454	461	458	1834
>=65 years	1	8	2	2	13
Age [units: years] Mean (Standard Deviation)	38.2 (9.6)	38.4 (10.5)	38.9 (10.4)	38.0 (9.8)	38.4 (10.1)
Gender [units: participants]
Female	71	98	78	75	322
Male	393	367	387	388	1535
Race/Ethnicity, Customized ^[1] [units: participants]
White Non-Hispanic	197	174	186	189	746
Black Non-Hispanic	151	164	147	153	615
Hispanic (Regardless of Race)	104	106	111	108	429
Asian, Pacific Islander	5	8	12	7	32
Native American, Alaskan Native	4	5	3	2	14
More than One Race	2	5	5	4	16
Unknown	1	3	1	0	5
Region of Enrollment [units: participants]
United States	451	452	452	450	1805
Puerto Rico	13	13	13	13	52
Baseline HIV-1 RNA ^[2] [units: log10 copies/mL] Mean (Standard Deviation)	4.7 (0.7)	4.7 (0.7)	4.7 (0.7)	4.7 (0.7)	4.7 (0.7)
Screening HIV-1 RNA [units: participants]
<100,000 copies/mL	265	266	265	264	1060
>=100,000 copies/mL	199	199	200	199	797
Baseline CD4+ count ^[3] [units: cells/mm3] Median (Inter-Quartile Range)	233.5 (102.5 to 333.5)	225 (103 to 324)	224 (87.0 to 326.5)	236 (71.5 to 345.5)	229.5 (89.5 to 333.8)

[1]	Race/Ethnicity is collected prior to study entry, participants may opt out of reporting.
[2]	Baseline RNA is calculated as the mean of the log10 pre-entry and entry values
[3]	Baseline CD4 count is the average (mean) of 2 measures taken at pre-entry and entry visits.

Outcome Measures

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1. Primary:

Time From Randomization to Virologic Failure [ Time Frame: Follow-up time was variable,median follow-up was 138 weeks; see 'Amount of study follow-up' outcome for details ]

Show Outcome Measure 1

2. Primary:

Time From Treatment Dispensation to a Grade 3/4 Safety Event [ Time Frame: All follow-up while on initially assigned regimen; the median (25th, 75th percentile) follow-up while on initial regimen was 120 (54, 156) weeks and the range was 0 to 205 weeks. ]

Show Outcome Measure 2

3. Primary:

Time From Treatment Dispensation to Treatment Modification [ Time Frame: Follow-up time was variable,median follow-up was 138 weeks; see 'Amount of study follow-up' outcome for details ]

Show Outcome Measure 3

4. Secondary:

Time From Treatment Dispensation to Regimen Failure (First Occurrence of Virologic Failure or Treatment Modification) [ Time Frame: Follow-up time was variable,median follow-up was 138 weeks; see 'Amount of study follow-up' outcome for details ]

Show Outcome Measure 4

5. Secondary:

The Number of Participants With HIV-1 RNA Levels Less Than 50 Copies/mL [ Time Frame: At Weeks 48 and 96 ]

Show Outcome Measure 5

6. Secondary:

Number of Participants With HIV-1 RNA Levels Less Than 200 Copies/mL [ Time Frame: At Weeks 48 and 96 ]

Show Outcome Measure 6

7. Secondary:

Change in CD4 Count (Cells/mm3) From Baseline [ Time Frame: At Weeks 48 and 96 ]

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8. Secondary:

Number of Participants With Virologic Failure and Emergence of Major Resistance [ Time Frame: Follow-up time was variable,median follow-up was 138 weeks; see 'Amount of study follow-up' outcome for details ]

Show Outcome Measure 8

9. Secondary:

Number of Participants Experiencing Certain Targeted Clinical Events, Including Death, AIDS-defining Illness, and HIV-1 Related Events. [ Time Frame: Follow-up time was variable, median follow-up was 138 weeks; see 'Amount of study follow-up' outcome for details ]

Show Outcome Measure 9

10. Secondary:

Change in Fasting Total Cholesterol Level From Baseline [ Time Frame: At Weeks 48 and 96 ]

Show Outcome Measure 10

11. Secondary:

Change in Fasting High-density Lipoprotein (HDL) Cholesterol Level From Baseline [ Time Frame: At Weeks 48 and 96 ]

Hide Outcome Measure 11

Measure Type	Secondary
Measure Title	Change in Fasting High-density Lipoprotein (HDL) Cholesterol Level From Baseline
Measure Description	Only fasting results are included. The protocol did not require that samples be collected fasting.
Time Frame	At Weeks 48 and 96
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.
Intention to treat: All participants with fasting lipids data were included, complete-case approach.

Reporting Groups

	Description
EFV, FTC/TDF, and Placebo ABC/3TC	Participants will receive EFV, FTC/TDF, and placebo for ABC/3TC for at least 96 weeks
EFV, Placebo FTC/TDF, and ABC/3TC	Participants will receive EFV, placebo for FTC/TDF, and ABC/3TC for at least 96 weeks
RTV-boosted ATV, FTC/TDF, and Placebo ABC/3TC	Participants will receive RTV-boosted ATV, FTC/TDF, and placebo for ABC/3TC for at least 96 weeks
RTV-boosted ATV, Placebo FTC/TDF, and ABC/3TC	Participants will receive RTV-boosted ATV, placebo for FTC/TDF, and ABC/3TC for at least 96 weeks

Measured Values

	EFV, FTC/TDF, and Placebo ABC/3TC	EFV, Placebo FTC/TDF, and ABC/3TC	RTV-boosted ATV, FTC/TDF, and Placebo ABC/3TC	RTV-boosted ATV, Placebo FTC/TDF, and ABC/3TC
Number of Participants Analyzed [units: participants]	464	465	465	463
Change in Fasting High-density Lipoprotein (HDL) Cholesterol Level From Baseline [units: mg/dL] Median (Inter-Quartile Range)
Week 48	8 (3 to 15)	10 (4 to 18)	5 (-2 to 10)	8 (1 to 16)
Week 96	9 (2 to 16)	11 (3.5 to 18.5)	4 (-1 to 11)	7 (1 to 15)

No statistical analysis provided for Change in Fasting High-density Lipoprotein (HDL) Cholesterol Level From Baseline

12. Secondary:

Change in Fasting Non-high Density Lipoprotein (Non-HDL) Cholesterol Level From Baseline [ Time Frame: At Weeks 48 and 96 ]

Show Outcome Measure 12

13. Secondary:

Change in Fasting Triglyceride Level From Baseline [ Time Frame: At Weeks 48 and 96 ]

Show Outcome Measure 13

14. Other Pre-specified:

Amount of Study Follow-up [ Time Frame: Follow-up time was variable, median follow-up was 138 weeks ]

Show Outcome Measure 14

15. Other Pre-specified:

Number of Participants With Virologic Failure [ Time Frame: Follow-up time was variable, median follow-up was 138 weeks; see 'Amount of study follow-up' outcome for details ]

Show Outcome Measure 15

16. Other Pre-specified:

Cumulative Probability of Not Experiencing Virologic Failure [ Time Frame: At week 48 and 96 ]

Show Outcome Measure 16

17. Other Pre-specified:

Number of Participants With a Grade 3/4 Safety Event [ Time Frame: Over all study follow-up while on initially assigned treatment, median follow-up was 120 weeks ]

Show Outcome Measure 17

18. Other Pre-specified:

Cumulative Probability of Not Experiencing a Grade 3/4 Safety Event [ Time Frame: At week 48 and 96 ]

Show Outcome Measure 18

19. Other Pre-specified:

Number of Participants With Treatment Modification [ Time Frame: Follow-up time was variable, median follow-up was 138 weeks; see 'Amount of study follow-up' outcome for details ]

Show Outcome Measure 19

20. Other Pre-specified:

Cumulative Probability of Not Experiencing Treatment Modification [ Time Frame: At week 48 and 96 ]

Show Outcome Measure 20

21. Other Pre-specified:

Number of Participants With Regimen Failure [ Time Frame: Follow-up time was variable, median follow-up was 138 weeks; see 'Amount of study follow-up' outcome for details ]

Show Outcome Measure 21

22. Other Pre-specified:

Cumulative Probability of Not Experiencing Regimen Failure [ Time Frame: At week 48 and 96 ]

Show Outcome Measure 22

Serious Adverse Events

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Other Adverse Events

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Limitations and Caveats

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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
HIV-1 drug resistance testing and HLA-B*5701 testing were not standard of care during enrollment. EFV and RTV-boosted ATV were open-label, and blinded FTC/TDF vs. ABC/3TC were unblinded in the >=100,000 cp/mL screening viral load stratum Feb 2008.

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.

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

Publications:

Anderson PL. Pharmacologic perspectives for once-daily antiretroviral therapy. Ann Pharmacother. 2004 Nov;38(11):1924-34. Epub 2004 Oct 12. Review.

Kress KD. HIV update: emerging clinical evidence and a review of recommendations for the use of highly active antiretroviral therapy. Am J Health Syst Pharm. 2004 Oct 1;61 Suppl 3:S3-14; quiz S15-6. Review. Erratum in: Am J Health Syst Pharm. 2004 Nov 15;61(22):2350.

Robbins GK, De Gruttola V, Shafer RW, Smeaton LM, Snyder SW, Pettinelli C, Dubé MP, Fischl MA, Pollard RB, Delapenha R, Gedeon L, van der Horst C, Murphy RL, Becker MI, D'Aquila RT, Vella S, Merigan TC, Hirsch MS; AIDS Clinical Trials Group 384 Team. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med. 2003 Dec 11;349(24):2293-303.

Shafer RW, Smeaton LM, Robbins GK, De Gruttola V, Snyder SW, D'Aquila RT, Johnson VA, Morse GD, Nokta MA, Martinez AI, Gripshover BM, Kaul P, Haubrich R, Swingle M, McCarty SD, Vella S, Hirsch MS, Merigan TC; AIDS Clinical Trials Group 384 Team. Comparison of four-drug regimens and pairs of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med. 2003 Dec 11;349(24):2304-15.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Longenecker CT, Kitch D, Sax PE, Daar ES, Tierney C, Gupta SK, McComsey GA; AIDS Clinical Trials Group Study A5224s Team. Reductions in Plasma Cystatin C After Initiation of Antiretroviral Therapy Are Associated With Reductions in Inflammation: ACTG A5224s. J Acquir Immune Defic Syndr. 2015 Jun 1;69(2):168-77. doi: 10.1097/QAI.0000000000000557.

Mollan KR, Smurzynski M, Eron JJ, Daar ES, Campbell TB, Sax PE, Gulick RM, Na L, O'Keefe L, Robertson KR, Tierney C. Association between efavirenz as initial therapy for HIV-1 infection and increased risk for suicidal ideation or attempted or completed suicide: an analysis of trial data. Ann Intern Med. 2014 Jul 1;161(1):1-10. doi: 10.7326/M14-0293. Erratum in: Ann Intern Med. 2014 Aug 19;161(4):308.

Sax PE, Zolopa A, Brar I, Elion R, Ortiz R, Post F, Wang H, Callebaut C, Martin H, Fordyce MW, McCallister S. Tenofovir alafenamide vs. tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: a randomized phase 2 study. J Acquir Immune Defic Syndr. 2014 Sep 1;67(1):52-8. doi: 10.1097/QAI.0000000000000225.

Erlandson KM, Kitch D, Tierney C, Sax PE, Daar ES, Melbourne KM, Ha B, McComsey GA. Impact of randomized antiretroviral therapy initiation on glucose metabolism. AIDS. 2014 Jun 19;28(10):1451-61. doi: 10.1097/QAD.0000000000000266.

Erlandson KM, Kitch D, Tierney C, Sax PE, Daar ES, Tebas P, Melbourne K, Ha B, Jahed NC, McComsey GA. Weight and lean body mass change with antiretroviral initiation and impact on bone mineral density. AIDS. 2013 Aug 24;27(13):2069-79. doi: 10.1097/QAD.0b013e328361d25d.

Smith KY, Tierney C, Mollan K, Venuto CS, Budhathoki C, Ma Q, Morse GD, Sax P, Katzenstein D, Godfrey C, Fischl M, Daar ES, Collier AC; AIDS Clinical Trials Group 5202 Study Team. Outcomes by sex following treatment initiation with atazanavir plus ritonavir or efavirenz with abacavir/lamivudine or tenofovir/emtricitabine. Clin Infect Dis. 2014 Feb;58(4):555-63. doi: 10.1093/cid/cit747. Epub 2013 Nov 18.

McComsey GA, Daar ES, O'Riordan M, Collier AC, Kosmiski L, Santana JL, Fichtenbaum CJ, Fink H, Sax PE, Libutti DE, Gerschenson M. Changes in fat mitochondrial DNA and function in subjects randomized to abacavir-lamivudine or tenofovir DF-emtricitabine with atazanavir-ritonavir or efavirenz: AIDS Clinical Trials Group study A5224s, substudy of A5202. J Infect Dis. 2013 Feb 15;207(4):604-11. doi: 10.1093/infdis/jis720. Epub 2012 Nov 29.

Mollan K, Daar ES, Sax PE, Balamane M, Collier AC, Fischl MA, Lalama CM, Bosch RJ, Tierney C, Katzenstein D; AIDS Clinical Trials Group Study A5202 Team. HIV-1 amino acid changes among participants with virologic failure: associations with first-line efavirenz or atazanavir plus ritonavir and disease status. J Infect Dis. 2012 Dec 15;206(12):1920-30. doi: 10.1093/infdis/jis613. Epub 2012 Nov 12.

McComsey GA, Kitch D, Sax PE, Tebas P, Tierney C, Jahed NC, Myers L, Melbourne K, Ha B, Daar ES. Peripheral and central fat changes in subjects randomized to abacavir-lamivudine or tenofovir-emtricitabine with atazanavir-ritonavir or efavirenz: ACTG Study A5224s. Clin Infect Dis. 2011 Jul 15;53(2):185-96. doi: 10.1093/cid/cir324.

McComsey GA, Kitch D, Daar ES, Tierney C, Jahed NC, Tebas P, Myers L, Melbourne K, Ha B, Sax PE. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: Aids Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis. 2011 Jun 15;203(12):1791-801. doi: 10.1093/infdis/jir188.

Daar ES, Tierney C, Fischl MA, Sax PE, Mollan K, Budhathoki C, Godfrey C, Jahed NC, Myers L, Katzenstein D, Farajallah A, Rooney JF, Pappa KA, Woodward WC, Patterson K, Bolivar H, Benson CA, Collier AC; AIDS Clinical Trials Group Study A5202 Team. Atazanavir plus ritonavir or efavirenz as part of a 3-drug regimen for initial treatment of HIV-1. Ann Intern Med. 2011 Apr 5;154(7):445-56. doi: 10.7326/0003-4819-154-7-201104050-00316. Epub 2011 Feb 14.

Sax PE, Tierney C, Collier AC, Fischl MA, Mollan K, Peeples L, Godfrey C, Jahed NC, Myers L, Katzenstein D, Farajallah A, Rooney JF, Ha B, Woodward WC, Koletar SL, Johnson VA, Geiseler PJ, Daar ES; AIDS Clinical Trials Group Study A5202 Team. Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. N Engl J Med. 2009 Dec 3;361(23):2230-40. doi: 10.1056/NEJMoa0906768. Epub 2009 Dec 1.

Responsible Party:	AIDS Clinical Trials Group
ClinicalTrials.gov Identifier:	NCT00118898 History of Changes
Other Study ID Numbers:	ACTG A5202 1U01AI068636 ( US NIH Grant/Contract Award Number ) ACTG 5224s ( Other Identifier: Substudy )
Study First Received:	July 7, 2005
Results First Received:	January 8, 2010
Last Updated:	January 4, 2016
Health Authority:	United States: Federal Government

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