Prospective Evaluation of Anti-retroviral Combinations for Treatment Naive, HIV Infected Persons in Resource-limited Settings (PEARLS)

This study has been completed.

Sponsor:

Collaborator:

National Institute of Allergy and Infectious Diseases (NIAID)

Information provided by:

AIDS Clinical Trials Group

ClinicalTrials.gov Identifier:

NCT00084136

First received: June 7, 2004

Last updated: August 10, 2011

Last verified: August 2011

History of Changes

Results First Received: July 13, 2011

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Efficacy Study; Intervention Model: Parallel Assignment; Masking: Open Label; Primary Purpose: Treatment
Condition:	HIV Infections
Interventions:	Drug: Atazanavir Drug: Didanosine (enteric-coated) Drug: Efavirenz Drug: Emtricitabine Drug: Emtricitabine/Tenofovir disoproxil fumarate Drug: Lamivudine/Zidovudine

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 43 sites from 9 countries: 28 in the US, 4 in India, 2 each in Brazil, Malawi, Peru and South Africa, and 1 each in Haiti, Thailand and Zimbabwe, between May 2005 to August 2007.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
HIV-infected, treatment-naive men and women, at least 18 years of age with CD4+ count <300 cells/mm^3.

Reporting Groups

Description

ZDV/3TC+EFV

ZDV/3TC+EFV participants will receive lamivudine/zidovudine and efavirenz

ddI+FTC+ATV

ddI+FTC+ATV participants will receive emtricitabine, atazanavir, and enteric-coated didanosine >

> On May 23, 2008, Arm B was closed following a planned interim review by the study's independent Data and Safety Monitoring Board (DSMB). The DSMB recommendation was based upon compelling evidence that Arm B had significantly more virologic failure (and therefore was inferior when) compared to Arm A. Participants still receiving Arm B medications were offered alternatives, and all participants continued to be followed.

TDF/FTC+EFV

TDF/FTC+EFV participants will receive emtricitabine/tenofovir disoproxil fumarate and efavirenz

Participant Flow for 2 periods

Period 1: PI Comparison

	ZDV/3TC+EFV	ddI+FTC+ATV
STARTED	519	526
COMPLETED	464 ^[1]	479 ^[1]
NOT COMPLETED	55	47
Death	10	9
Lost to Follow-up	11	8
Withdrawal by Subject	33	30
Clinic site closed	1	0

[1]	Follow-up was until ddI+FTC+ATV arm was closed per DSMB recommendation on May 23, 2008.

Period 2: NRTI Comparison

	ZDV/3TC+EFV	TDF/FTC+EFV
STARTED	519	526
COMPLETED	418 ^[1]	444 ^[1]
NOT COMPLETED	101	82
Death	20	18
Lost to Follow-up	14	12
Withdrawal by Subject	54	38
Clinic site closed	12	14
Not reason above	1	0

[1]	Follow-up though study closeout period (final visit between April 1 and May 31, 2010).

Baseline Characteristics

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Reporting Groups

	Description
ZDV/3TC+EFV	ZDV/3TC+EFV participants will receive lamivudine/zidovudine and efavirenz
ddI+FTC+ATV	ddI+FTC+ATV participants will receive emtricitabine, atazanavir, and enteric-coated didanosine > > On May 23, 2008, Arm B was closed following a planned interim review by the study's independent Data and Safety Monitoring Board (DSMB). The DSMB recommendation was based upon compelling evidence that Arm B had significantly more virologic failure (and therefore was inferior when) compared to Arm A. Participants still receiving Arm B medications were offered alternatives, and all participants continued to be followed.
TDF/FTC+EFV	TDF/FTC+EFV participants will receive emtricitabine/tenofovir disoproxil fumarate and efavirenz
Total	Total of all reporting groups

Baseline Measures

	ZDV/3TC+EFV	ddI+FTC+ATV	TDF/FTC+EFV	Total
Number of Participants [units: participants]	519	526	526	1571
Age [units: years] Mean ± Standard Deviation	35 ± 9	35 ± 8	35 ± 9	35 ± 9
Age, Customized [units: participants]
Between 18 and 29 years	141	146	146	433
Between 30 and 39 years	244	221	225	690
Between 40 and 49 years	100	129	116	345
At least 50 years	34	30	39	103
Gender [units: participants]
Female	241	256	242	739
Male	278	270	284	832
Region of Enrollment [units: participants]
Brazil	79	76	76	231
Haiti	35	32	33	100
India	81	86	88	255
Malawi	74	74	73	221
Peru	42	48	44	134
South Africa	70	70	70	210
Thailand	32	33	35	100
United States	70	70	70	210
Zimbabwe	36	37	37	110
CD4 count, Continuous ^[1] [units: cells/mm^3] Mean ± Standard Deviation	163 ± 85	167 ± 83	155 ± 81	162 ± 83
CD4 count, Categorical ^[2] [units: participants]
< 50 cells/mm^3	68	63	69	200
Between 50 and 99 cells/mm^3	70	77	82	229
Between 100 and 199 cells/mm^3	174	161	193	528
Between 200 and 249 cells/mm^3	104	128	107	339
Between 250 and 299 cells/mm^3	103	97	75	275
Plasma HIV-1 RNA, Continuous [units: log10 copies/mL] Median ( Inter-Quartile Range )	5.0 ( 4.6 to 5.4 )	5.1 ( 4.5 to 5.5 )	5.0 ( 4.5 to 5.5 )	5.0 ( 4.6 to 5.5 )
Plasma HIV-1 RNA, Categorical [units: participants]
<= 400 copies/mL	3	6	3	12
Between 400 and 4000 copies/mL	22	19	14	55
Between 4001 and 40,000 copies/mL	103	119	124	346
Between 40,001 and 400,000 copies/mL	311	283	284	878
Between 400,001 and 749,999 copies/mL	45	58	55	158
>= 750,000 copies/mL	35	40	46	121
Missing	0	1	0	1

[1]	Screening value used for study eligibility as no other pre-randomization CD4 cell counts available
[2]	Screening CD4 count used for study eligibility as no other pre-randomization counts available.

Outcome Measures

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1. Primary:

Time to Treatment Failure (PI Comparison) [ Time Frame: Virologic failure starting 14 weeks following randomization; disease progression starting 12 weeks following randomization; and death occurring at any time following randomization. Follow-up until ddI+FTC+ATV arm closed (May 22, 2008). ]

Show Outcome Measure 1

2. Primary:

Time to Treatment Failure (NRTI Comparison) [ Time Frame: Virologic failure starting 14 weeks following randomization; disease progression starting 12 weeks following randomization; and death occurring at any time following randomization. Follow-up through study closure (May 31, 2010). ]

Show Outcome Measure 2

3. Secondary:

Time to Discontinuation of Initial Antiretroviral (ARV) Therapy (PI Comparison) [ Time Frame: Throughout follow-up until ddI+FTC+ATV arm closed (May 22,2008) ]

Show Outcome Measure 3

4. Secondary:

Time to Immunologic Failure (PI Comparison) [ Time Frame: At or after Week 48 (including only follow-up until ddI+FTV+ATV arm closed - May 22,2008) ]

Show Outcome Measure 4

5. Secondary:

Change in CD4 Count From Screening to Weeks 24, 48, 96 (PI Comparison) [ Time Frame: weeks 24, 48 and 96 (including follow-up until ddI+FTC+ARV arm closed - May 22, 2008) ]

Show Outcome Measure 5

6. Secondary:

Time to First Dose Modification or Grade 3 or 4 Adverse Event (PI Comparison) [ Time Frame: Throughout study follow-up until ddI+FTC+ATV arm closed (May 22, 2008) ]

Show Outcome Measure 6

7. Secondary:

Plasma HIV-1 Viral Load Fewer Than 400 Copies/ml (PI Comparison) [ Time Frame: At Weeks 24 and 48 (including only follow-up until ddI+FTC+ARV arm closed - May 22, 2008) ]

Show Outcome Measure 7

8. Secondary:

Time to Loss of Virologic Response by Week 48 (Defined by FDA TLOVR Algorithm - Excluding Study Allowed ARV Substitutions)(PI Comparison) [ Time Frame: Week 48 (using follow-up only until closing of ddI+FTV+ATV arm on May 22,2008) ]

Show Outcome Measure 8

9. Secondary:

Time to Loss of Virologic Response at Week 48 (Defined by FDA TLOVR Algorithm - Including All ARV Substitutions)(PI Comparison) [ Time Frame: Week 48 (using follow-up only until closing of ddI+FTV+ATV arm on May 22,2008) ]

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Measure Type	Secondary
Measure Title	Time to Loss of Virologic Response at Week 48 (Defined by FDA TLOVR Algorithm - Including All ARV Substitutions)(PI Comparison)
Measure Description	Time from randomization to any of the following events occurring prior to week 48: changed any ARV medication (including permanent discontinuation of all medications); discontinued study follow-up or died; absence of virologic suppression defined as 2 consecutive plasma HIV-1 RNA values < 400 copies/mL; two consecutive plasma HIV-1 RNA values > 400 copies/mL following virologic suppression.
Time Frame	Week 48 (using follow-up only until closing of ddI+FTV+ATV arm on May 22,2008)
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.
No text entered.

Reporting Groups

	Description
ZDV/3TC+EFV	ZDV/3TC+EFV participants will receive lamivudine/zidovudine and efavirenz
ddI+FTC+ATV	ddI+FTC+ATV participants will receive emtricitabine, atazanavir, and enteric-coated didanosine
TDF/FTC+EFV	TDF/FTC+EFV participants will receive emtricitabine/tenofovir disoproxil fumarate and efavirenz

Measured Values

	ZDV/3TC+EFV	ddI+FTC+ATV	TDF/FTC+EFV
Number of Participants Analyzed [units: participants]	519	526	0
Time to Loss of Virologic Response at Week 48 (Defined by FDA TLOVR Algorithm - Including All ARV Substitutions)(PI Comparison) [units: weeks] Number ( 95% Confidence Interval )
5th percentile	0 ( 0 to 0 )	0 ( 0 to 0 )
10th percentile	0 ( 0 to 0 )	0 ( 0 to 0 )
25th percentile	32 ( 16 to 48 )	48 ( 32 to NA ) ^[1]

[1]	Not estimable as the upper limit for survival function at all weeks is above 75%

No statistical analysis provided for Time to Loss of Virologic Response at Week 48 (Defined by FDA TLOVR Algorithm - Including All ARV Substitutions)(PI Comparison)

10. Secondary:

Time to Discontinuation of Initial Antiretroviral (ARV) Therapy (NRTI Comparison) [ Time Frame: Throughout follow-up until study closed (May 31,2010) ]

Show Outcome Measure 10

11. Secondary:

Time to Immunologic Failure (NRTI Comparison) [ Time Frame: At or after Week 48 (including all follow-up through study closure - May 31,2010) ]

Show Outcome Measure 11

12. Secondary:

Change in CD4 Count From Screening to Weeks 24, 48, 96 (NRTI Comparison) [ Time Frame: weeks 24, 48 and 96 (including all follow-up through to study closure on May 31, 2010) ]

Show Outcome Measure 12

13. Secondary:

Plasma HIV-1 Viral Load Fewer Than 400 Copies/ml (NRTI Comparison) [ Time Frame: At Weeks 24 and 48 (including follow-up through to study closure on May 31, 2010) ]

Show Outcome Measure 13

14. Secondary:

Time to Loss of Virologic Response at Week 48 (Defined by FDA TLOVR Algorithm - Excluding Study Allowed ARV Substitutions)(NRTI Comparison) [ Time Frame: Week 48 (using follow-up through study closure on May 31,2010) ]

Show Outcome Measure 14

15. Secondary:

Time to Loss of Virologic Response at Week 96 (Defined by FDA TLOVR Algorithm - Excluding Study Allowed ARV Substitutions)(NRTI Comparison) [ Time Frame: Week 96 (using follow-up through to study closure on May 31,2010) ]

Show Outcome Measure 15

16. Secondary:

Time to Loss of Virologic Response at Week 48 (Defined by FDA TLOVR Algorithm - Including All ARV Substitutions)(NRTI Comparison) [ Time Frame: Week 48 using follow-up through study closure on May 31,2010 ]

Show Outcome Measure 16

17. Secondary:

Time to Loss of Virologic Response at Week 96 (Defined by FDA TLOVR Algorithm - Including All ARV Substitutions)(NRTI Comparison) [ Time Frame: Week 96 using follow-up through study closure on May 31,2010 ]

Show Outcome Measure 17

18. Secondary:

Time to First Dose Modification or Grade 3 or 4 Adverse Event (NRTI Comparison) [ Time Frame: Throughout study follow-up until study closure (May 31, 2010) ]

Show Outcome Measure 18

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 Trial 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 for 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
No text entered.

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:

Bartlett JA, Johnson J, Herrera G, Sosa N, Rodriguez A, Liao Q, Griffith S, Irlbeck D, Shaefer MS; for the Clinically Significant Long-term Antiretroviral Sequential Sequencing Study (CLASS) Team. Long-Term Results of Initial Therapy With Abacavir and Lamivudine Combined With Efavirenz, Amprenavir/Ritonavir, or Stavudine. J Acquir Immune Defic Syndr. 2006 Sep 7; [Epub ahead of print]

Saag MS. Initiation of antiretroviral therapy: implications of recent findings. Top HIV Med. 2004 Jul-Aug;12(3):83-8. Review.

Tapper ML, Daar ES, Piliero PJ, Smith K, Steinhart C. Strategies for initiating combination antiretroviral therapy. AIDS Patient Care STDS. 2005 Apr;19(4):224-38. Review.

Publications automatically indexed to this study:

Campbell TB, Smeaton LM, Kumarasamy N, Flanigan T, Klingman KL, Firnhaber C, Grinsztejn B, Hosseinipour MC, Kumwenda J, Lalloo U, Riviere C, Sanchez J, Melo M, Supparatpinyo K, Tripathy S, Martinez AI, Nair A, Walawander A, Moran L, Chen Y, Snowden W, Rooney JF, Uy J, Schooley RT, De Gruttola V, Hakim JG; PEARLS study team of the ACTG. Efficacy and safety of three antiretroviral regimens for initial treatment of HIV-1: a randomized clinical trial in diverse multinational settings. PLoS Med. 2012 Aug;9(8):e1001290. Epub 2012 Aug 14.

Nielsen-Saines K, Komarow L, Cu-Uvin S, Jourdain G, Klingman KL, Shapiro DE, Mofenson L, Moran L, Campbell TB, Hitti J, Fiscus S, Currier J; ACTG 5190/PACTG 1054 Study Team. Infant outcomes after maternal antiretroviral exposure in resource-limited settings. Pediatrics. 2012 Jun;129(6):e1525-32. Epub 2012 May 14.

Safren SA, Hendriksen ES, Smeaton L, Celentano DD, Hosseinipour MC, Barnett R, Guanira J, Flanigan T, Kumarasamy N, Klingman K, Campbell T. Quality of life among individuals with HIV starting antiretroviral therapy in diverse resource-limited areas of the world. AIDS Behav. 2012 Feb;16(2):266-77.

Firnhaber C, Smeaton L, Saukila N, Flanigan T, Gangakhedkar R, Kumwenda J, La Rosa A, Kumarasamy N, De Gruttola V, Hakim JG, Campbell TB. Comparisons of anemia, thrombocytopenia, and neutropenia at initiation of HIV antiretroviral therapy in Africa, Asia, and the Americas. Int J Infect Dis. 2010 Dec;14(12):e1088-92. Epub 2010 Oct 18.

Responsible Party:	Daniel R. Kuritzkes, M.D., Social & Scientific Systems, Inc.
ClinicalTrials.gov Identifier:	NCT00084136 History of Changes
Other Study ID Numbers:	ACTG A5175, 1U01AI068636, PEARLS, A5185s, 5-K24-AI051966-03
Study First Received:	June 7, 2004
Results First Received:	July 13, 2011
Last Updated:	August 10, 2011
Health Authority:	United States: Federal Government

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