Induction/Simplification With Atazanavir + Ritonavir + Abacavir/Lamivudine Fixed-Dose Combination In HIV-1 Infection

This study has been completed.

Sponsor:

Collaborator:

GlaxoSmithKline

Information provided by (Responsible Party):

ViiV Healthcare

ClinicalTrials.gov Identifier:

NCT00440947

First received: February 23, 2007

Last updated: March 15, 2012

Last verified: July 2011

History of Changes

Results First Received: May 19, 2011

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Open Label; Primary Purpose: Treatment
Conditions:	Infection, Human Immunodeficiency Virus I HIV Infection
Interventions:	Drug: Abacavir (ABC)/lamivudine (3TC) + atazanavir (ATV) + ritonavir (/r) Drug: Abacavir (ABC)/lamivudine (3TC) + atazanavir (ATV)

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
Participants (PAR) were recruited at 66 centers in the United States of America and Canada. HIV-RNA, human immunodeficiency virus-ribonucleic acid; ml, milliliters.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
The study had a 36-week Non-randomized Induction Phase, followed by an 84-week Randomized Phase. All PAR completing 84 weeks were eligible to enter an optional 60-week extension phase (EP); some PAR chose not to continue in the EP. PAR whose HIV-RNA wasn't <50 copies/ml before Week 36 weren't allowed to randomize at Week 36 and were withdrawn.

Reporting Groups

	Description
ABC/3TC + ATV/r: Induction Phase	Abacavir (ABC) 600 milligrams (mg)/lamivudine (3TC) 300 mg fixed-dose combination tablet (FDC) once a day (QD) plus atazanavir (ATV) 300 mg QD + ritonavir (/r) 100 mg QD during the first 36 weeks of the study (planned interim analysis)
ABC/3TC + ATV: Randomization Phase	Simplification regimen of the ABC/3TC FDC tablet administered QD for an additional 48 weeks in combination with 400 mg ATV QD
ABC/3TC + ATV/r: Randomization Phase	Continuation of ABC/3TC FDC tablet administered QD for an additional 48 weeks in combination with ATV/r QD
ABC/3TC + ATV: Extension Phase	Simplification regimen of the ABC/3TC FDC tablet administered QD for an additional 60 weeks in combination with ATV QD
ABC/3TC + ATV/r: Extension Phase	Continuation of ABC/3TC FDC tablet administered QD for an additional 60 weeks in combination with ATV/r QD

Participant Flow for 3 periods

Period 1: 36-Week Induction Phase

	ABC/3TC + ATV/r: Induction Phase	ABC/3TC + ATV: Randomization Phase	ABC/3TC + ATV/r: Randomization Phase	ABC/3TC + ATV: Extension Phase	ABC/3TC + ATV/r: Extension Phase
STARTED	515	0	0	0	0
COMPLETED	442 ^[1]	0	0	0	0
NOT COMPLETED	73	0	0	0	0
Adverse Event	16	0	0	0	0
Insufficient Viral Load Response	11	0	0	0	0
Protocol-defined Virologic Failure	5	0	0	0	0
Non-compliance	10	0	0	0	0
Lost to Follow-up	16	0	0	0	0
Withdrawal by Subject	7	0	0	0	0
Kaposi Lesions Requiring Chemotherapy	1	0	0	0	0
Took Exclusionary Medications	1	0	0	0	0
Genotype Had Exclusionary Mutations	1	0	0	0	0
Fleeing Police; Outstanding Warrants	1	0	0	0	0
Incarceration	3	0	0	0	0
Pregnancy	1	0	0	0	0

[1]	23 PAR without confirmed HIV-RNA<50c/mL prior to Wk 36 couldn’t be randomized but weren’t withdrawn.

Period 2: 48-Week Randomization Phase

	ABC/3TC + ATV: Randomization Phase	ABC/3TC + ATV/r: Randomization Phase
STARTED	210	209
COMPLETED	194	185
NOT COMPLETED	16	24
Adverse Event	2	5
Protocol-defined Virologic Failure	1	1
Non-compliance	3	4
Lost to Follow-up	2	8
Protocol Violation	0	1
Withdrawal by Subject	2	4
Pregnancy	0	1
Incarceration	3	0
Trying to Get Pregnant	1	0
Physician Decision	2	0

Period 3: Optional 60-Week Extension Phase

	ABC/3TC + ATV: Extension Phase	ABC/3TC + ATV/r: Extension Phase
STARTED	189	180
COMPLETED	160	154
NOT COMPLETED	29	26
Adverse Event	1	3
Insufficient Viral Load Response	1	1
Protocol-defined Virologic Failure	3	2
Non-compliance	1	1
Lost to Follow-up	9	9
Protocol Violation	1	0
Withdrawal by Subject	4	3
Pregnancy	3	0
Participant Moved	1	1
Sponsor Request	1	1
Sponsor Terminated Site	3	3
Unknown	1	0
Physician Decision	0	1
Participant Remained in Cuba	0	1

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.
No text entered.

Reporting Groups

	Description
ABC/3TC + ATV/r	All participants starting the Induction Phase: ABC 600 mg/3TC 300 mg FDC tablet QD plus ATV 300 mg QD + /r 100 mg QD during the first 36 weeks of the study (planned interim analysis)

Baseline Measures

	ABC/3TC + ATV/r
Number of Participants [units: participants]	515
Age [units: Years] Mean (Standard Deviation)	38.3 (10.03)
Gender [units: Participants]
Female	86
Male	429
Race/Ethnicity, Customized [units: participants]
African American/African Heritage	167
American Indian or Alaskan Native	9
Asian - Central/South Asian Heritage	4
Asian - East Asian Heritage	3
Asian - Japanese Heritage	1
Asian - South East Asian Heritage	3
Native Hawaiian or Other Pacific Islander	1
White - Arabic/North African Heritage	5
White - White/Caucasian/European Heritage	316
Mixed Race	6
Number of participants with the indicated baseline HIV-RNA level ^[1] [units: participants]
HIV-1 RNA <100,000	227
HIV-1 RNA 100,000-<250,000	143
HIV-1 RNA 250,000-<500,000	73
HIV-1 RNA >=500,000	72
Number of participants with the indicated Baseline CD4+ Cell Count ^[2] [units: participants]
CD4+ cells <50	69
CD4+ cells 50-<200	190
CD4+ cells >=200	256
Number of participants with the indicated Center for Disease Control (CDC) Classification ^[3] [units: participants]
Asymptomatic HIV Infection	353
Symptomatic (non-AIDS) condition	97
AIDS	65
Median Baseline CD4+ Cell Count [units: cells per cubic millimeter] Median (Full Range)	199 (19 to 754)
Median Baseline HIV-1 RNA Level [units: log10 copies/ml] Median (Full Range)	5.076 (2.989 to 6.620)

[1]	HIV-1 RNA, Human Immunodeficiency Virus type 1 Ribonucleic acid. HIV-1 viral load was measured as virus copies per milliliter (ml) at baseline.
[2]	A CD4+ cell is a T lymphocyte that carries the CD4 antigen. Immunologic response was assessed by CD4+ counts.
[3]	AIDS, Acquired Immunodeficiency Syndrome CDC classifications are Asymptomatic, Symptomatic, or AIDs.

Outcome Measures

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1. Primary:

Percentage of Participants (PAR) Who Achieved Plasma HIV-1 RNA <50 Copies (c) /Milliliter (ml) at the Week 84 Visit [ Time Frame: Week 84 ]

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2. Secondary:

Mean Age at Baseline of Participants Randomized to Treatment for the 48-Week Randomized Phase [ Time Frame: Baseline of Randomized Phase ]

Show Outcome Measure 2

3. Secondary:

Percentage of Participants Who Achieved Plasma HIV-1 RNA <50 c/ml at the Week 36 Visit [ Time Frame: Week 36 ]

Show Outcome Measure 3

4. Secondary:

Percentage of Participants Who Achieved Plasma HIV-1 RNA <50 c/ml at the Week 84 Visit [ Time Frame: Week 84 ]

Show Outcome Measure 4

5. Secondary:

Percentage of Participants Who Achieved Plasma HIV-1 RNA <50 c/ml at the Week 144 Visit [ Time Frame: Week 144 ]

Show Outcome Measure 5

6. Secondary:

Percentage of Participants Who Achieved Plasma HIV-1 RNA <400 c/ml at the Week 36 Visit [ Time Frame: Week 36 ]

Show Outcome Measure 6

7. Secondary:

Percentage of Participants Who Achieved HIV-1 RNA <400 c/ml at the Week 84 Visit [ Time Frame: Week 84 ]

Show Outcome Measure 7

8. Secondary:

Percentage of Participants Who Achieved HIV-1 RNA <400 c/ml at the Week 144 Visit [ Time Frame: Week 144 ]

Show Outcome Measure 8

9. Secondary:

Number of Participants Who Met the Protocol-defined Virologic Failure (PDVF) Criteria at Week 36 [ Time Frame: Week 36 ]

Show Outcome Measure 9

10. Secondary:

Number of Participants Who Met the PDVF Criteria at Week 84 [ Time Frame: Week 84 ]

Show Outcome Measure 10

11. Secondary:

Number of Participants Who Met the PDVF Criteria at Week 144 [ Time Frame: Week 144 ]

Show Outcome Measure 11

12. Secondary:

Change From Baseline in HIV-1 RNA at Week 36 [ Time Frame: Baseline and Week 36 ]

Show Outcome Measure 12

13. Secondary:

Change From Baseline in HIV-1 RNA at Week 84 [ Time Frame: Baseline and Week 84 ]

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14. Secondary:

Change From Baseline in HIV-1 RNA at Week 144 [ Time Frame: Baseline and Week 144 ]

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15. Secondary:

Change From Baseline in CD4+ Cell Count at Week 36 [ Time Frame: Baseline and Week 36 ]

Show Outcome Measure 15

16. Secondary:

Change From Baseline in CD4+ Cell Count at Week 84 [ Time Frame: Baseline and Week 84 ]

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17. Secondary:

Change From Baseline in CD4+ Cell Count at Week 144 [ Time Frame: Baseline and Week 144 ]

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18. Secondary:

Number of Confirmed Virologic Failure Participants With Treatment-emergent HIV Genotypic Resistance in Reverse Transcriptase and Protease From Baseline Through Week 36 [ Time Frame: Baseline through Week 36 ]

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19. Secondary:

Number of Confirmed Virologic Failure Participants With Treatment-emergent HIV Genotypic Resistance in Reverse Transcriptase and Protease From Randomization at Week 36 Through Week 84 [ Time Frame: Randomization at Week 36 through Week 84 ]

Show Outcome Measure 19

20. Secondary:

Number of Confirmed Virologic Failure Participants With Treatment-emergent HIV Genotypic Resistance in Reverse Transcriptase and Protease From Week 84 Through Week 144 [ Time Frame: Week 84 through Week 144 ]

Show Outcome Measure 20

21. Secondary:

Number of Confirmed Virologic Failure Participants From Baseline Through Week 36 With Treatment-emergent Reductions in Susceptibility to Abacavir, Lamivudine, Atazanavir, or Ritonavir [ Time Frame: Baseline through Week 36 ]

Show Outcome Measure 21

22. Secondary:

Number of Confirmed Virologic Failure Participants From Randomization at Week 36 Through Week 84 With Treatment-emergent Reductions in HIV Susceptibility to Abacavir, Lamivudine, Atazanavir, or Ritonavir [ Time Frame: Randomization at Week 36 through Week 84 ]

Show Outcome Measure 22

23. Secondary:

Number of Confirmed Virologic Failure Participants From Week 84 Through Week 144 With Treatment-emergent Reductions in HIV Susceptibility to Abacavir, Lamivudine, Atazanavir, or Ritonavir [ Time Frame: Week 84 through Week 144 ]

Show Outcome Measure 23

24. Secondary:

Mean Percent Compliance at Week 36 [ Time Frame: Week 36 ]

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Measure Type	Secondary
Measure Title	Mean Percent Compliance at Week 36
Measure Description	Percent compliance is defined as the total number of pills taken divided by the total number of pills prescribed. The total number of pills taken was calculated by subtracting any returned pills from the total number of pills that were dispensed to each participant during this period. Compliance was calculated for each medication in the regimen.
Time Frame	Week 36
Safety Issue	No

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.
ITT-E Population, Induction Phase. Participants with an unknown number of pills returned (including those whose pill bottles were not returned) were not included in this analysis.

Reporting Groups

	Description
ABC/3TC + ATV/r: Induction Phase	Induction Phase: ABC 600 mg/3TC 300 mg FDC tablet QD plus ATV 300 mg QD + /r 100 mg QD during the first 36 weeks of the study (planned interim analysis)

Measured Values

	ABC/3TC + ATV/r: Induction Phase
Number of Participants Analyzed [units: participants]	503
Mean Percent Compliance at Week 36 [units: percent compliance] Mean (Standard Deviation)
Abacavir/Lamivudine	92.2 (13.05)
Ritonavir	92.3 (12.15)
Atazanavir	92.7 (12.50)

No statistical analysis provided for Mean Percent Compliance at Week 36

25. Secondary:

Mean Percent Compliance at Week 84 [ Time Frame: Week 84 ]

Show Outcome Measure 25

26. Secondary:

Mean Percent Compliance at Week 144 [ Time Frame: Week 144 ]

Show Outcome Measure 26

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
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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: GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.

Results Point of Contact:

Name/Title: GSK Response Center
Organization: ViiV Healthcare
phone: 866-435-7343

Publications:

L Ross, E Dejesus, M Potter, A LaMarca, D Murphy, I Melendez-Rivera, D Ward, P Wannamaker, J Uy, L Patel, H Amrine-Madsen, J Horton. Epidemiological and Genotypic Clustering of HIV infection within North America During 2007 International HIV & Hepatitis Drug Resistance Workshop & Curative Strategies, 8-12 June 2010, Dubrovnik, Croatia, Poster 150.

Young B, Squires K, Patel P, Dejesus E, Bellos N, Berger D, Sutherland-Phillips DH, Liao Q, Shaefer M, Wannamaker P. First large, multicenter, open-label study utilizing HLA-B*5701 screening for abacavir hypersensitivity in North America. AIDS. 2008 Aug 20;22(13):1673-5. doi: 10.1097/QAD.0b013e32830719aa.

• L Ross, K Squires, B Young, E DeJesus, N Bellos, D Murphy, A Rachlis, H Zhao, L Patel, L Ross, P Wannamaker, M Shaefer. Genotypic Screening Impact in ARIES [Atazanavir (ATV) + Ritonavir (/r) + Abacavir/Lamivudine (ABC/3TC) for 36 Weeks Followed By Randomization to ATV +ABC/3TC or ATV/r + ABC/3TC for 48 Wks in HIV-infected, ART Naïve Patients] :Low Rates of Virologic Failure. The 19th Annual Canadian Conference on HIV/AIDS Research, 13-16 May 2010, Saskatoon, Canada. Poster P-169.

K Squires, E DeJesus, N Bellos, D Ward, D Murphy, H Zhao, L Patel, L Ross, P Wannamaker, M Shaefer. Sustained Virologic Efficacy of Atazanavir (ATV) Versus Atazanavir/Ritonavir (ATV/r), each in Combination with Abacavir/Lamivudine (ABC/3TC) over 120 Weeks: the ARIES Trial. 48th ICAAC; September 12-15, 2010, Boston, MA. Poster H-204.

K Squires, B Young, E DeJesus, N Bellos, D Murphy, D Sutherland-Phillips, H Zhao, L Patel, L Ross, P Wannamaker, M Shaefer. Atazanavir/Ritonavir (ATV/r) + Abacavir/Lamivudine (ABC/3TC) in Antiretroviral (ART)-Naive HIV-1 Infected HLA-B*5701 Negative Subjects Demonstrates Efficacy and Safety: the ARIES Trial. 48th ICAAC; October 25-28, 2008, Washington, DC. Poster H-1250a.

K Squires, B Young, E DeJesus, N Bellos, D Murphy, D Sutherland-Phillips, H Zhao, L Patel, L Ross, P Wannamaker, M Shaefer. Similar Efficacy and Tolerability of Atazanavir (ATV) Compared to ATV/Ritonavir (RTV, r), Each in Combination with Abacavir/Lamivudine (ABC/3TC), after Initial Suppression with ABC/3TC + ATV/r in HIV-1 Infected Patients: 84 Week Results of the ARIES Trial. 5th IAS Conference; Cape Town, South Africa. Abstract WELBB103

Squires KE, Young B, DeJesus E, Bellos N, Murphy D, Sutherland-Phillips DH, Zhao HH, Patel LG, Ross LL, Wannamaker PG, Shaefer MS; ARIES Study Team. Safety and efficacy of a 36-week induction regimen of abacavir/lamivudine and ritonavir-boosted atazanavir in HIV-infected patients. HIV Clin Trials. 2010 Mar-Apr;11(2):69-79. doi: 10.1310/hct1102-69.

Squires KE, Young B, Dejesus E, Bellos N, Murphy D, Zhao HH, Patel LG, Ross LL, Wannamaker PG, Shaefer MS; ARIES study team. Similar efficacy and tolerability of atazanavir compared with atazanavir/ritonavir, each with abacavir/lamivudine after initial suppression with abacavir/lamivudine plus ritonavir-boosted atazanavir in HIV-infected patients. AIDS. 2010 Aug 24;24(13):2019-27. doi: 10.1097/QAD.0b013e32833bee1b.

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

Ross LL, Horton J, Hasan S, Brown JR, Murphy D, DeJesus E, Potter M, LaMarca A, Melendez-Rivera I, Ward D, Uy J, Shaefer MS. HIV-1 transmission patterns in antiretroviral therapy-naïve, HIV-infected North Americans based on phylogenetic analysis by population level and ultra-deep DNA sequencing. PLoS One. 2014 Feb 26;9(2):e89611. doi: 10.1371/journal.pone.0089611. eCollection 2014.

Squires KE, Young B, DeJesus E, Bellos N, Murphy D, Ward D, Zhao HH, Ross LL, Shaefer MS; ARIES Study Team. ARIES 144 week results: durable virologic suppression in HIV-infected patients simplified to unboosted atazanavir/abacavir/lamivudine. HIV Clin Trials. 2012 Sep-Oct;13(5):233-44. doi: 10.1310/hct1305-233.

Young B, Squires KE, Ross LL, Santiago L, Sloan LM, Zhao HH, Wine BC, Pakes GE, Margolis DA, Shaefer MS; Aries EPZ108859 Study Team. Inflammatory biomarker changes and their correlation with Framingham cardiovascular risk and lipid changes in antiretroviral-naive HIV-infected patients treated for 144 weeks with abacavir/lamivudine/atazanavir with or without ritonavir in ARIES. AIDS Res Hum Retroviruses. 2013 Feb;29(2):350-8. doi: 10.1089/AID.2012.0278. Epub 2012 Dec 5.

Responsible Party:	ViiV Healthcare
ClinicalTrials.gov Identifier:	NCT00440947 History of Changes
Other Study ID Numbers:	EPZ108859
Study First Received:	February 23, 2007
Results First Received:	May 19, 2011
Last Updated:	March 15, 2012
Health Authority:	Canada: Health Canada United States: Food and Drug Administration

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