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

HIV Infections Clinical Trial

— PEARLS  

Official title:

Randomized, Open-Label Evaluation of Efficacy of Once-Daily Protease Inhibitor and Once-Daily Non-Nucleoside Reverse Transcriptase Inhibitor-Containing Therapy Combinations for Initial Treatment of HIV-1 Infected Persons From Resource-Limited Settings (PEARLS) Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00084136
• Other study ID #: ACTG A5175
• Secondary ID: 1U01AI068636PEAR
• Status: Completed
• Phase: Phase 4
• Start date: May 2005
• Est. completion date: May 2010

Study information

• Verified date: September 2018
• Source: AIDS Clinical Trials Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study compared 3 different three-drug combinations in HIV infected individuals starting their first HIV treatment regimens. Participants were recruited from resource-limited areas in Africa, Asia, South America, Haiti, and also from the United States. The study hypothesis was each of the once daily combinations (PI based, or NNRTI based) would not have inferior efficacy compared to the twice daily NNRTI based combination.

Description:

In developed countries, standard effective antiretroviral (ARV) therapy for treatment-naive HIV infected people includes three-drug combinations of two nucleoside reverse transcriptase inhibitors (NRTIs) with either a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). However, direct comparisons of ARV efficacy in persons that more closely reflect the worldwide demographics of HIV-1 infection are needed.

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> Trial participants were recruited in Africa (Malawi, South Africa, Zimbabwe), Asia (India, Thailand), South America (Brazil, Peru), Haiti, and the United States.

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> All participants were randomly assigned to one of three arms, and random allocation was stratified by 2 factors: country, and screening plasma HIV-1 RNA level (< 100,000 copies/mL versus >= 100,000 copies/mL). Participants assigned to the ZDV/3TC+EFV arm received lamivudine/zidovudine twice daily and efavirenz once daily. Participants assigned to the ddI+FTC+ATV arm received emtricitabine, atazanavir, and enteric-coated didanosine once daily. Participants assigned to the TDF/FTC+EFV arm received emtricitabine, tenofovir disoproxil fumarate, and efavirenz once daily.

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> Physical exam and blood collection occurred at entry and at most study visits. Participants experiencing virologic failure were offered a switch to another regimen.

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> On May 23, 2008, the ddI+FTC+ATV 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 this arm had significantly more virologic failure (and therefore was inferior when) compared to the ZDV/3TC+EFV arm . Participants still receiving ddI+FTC+ATV were offered alternative medications, and all participants continued to be followed.

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> On November 3, 2009, the DSMB recommended that the study close to all follow-up on May 31, 2010, before the designed termination (based on 30% of participants meeting the primary outcome) was met. The board observed that the recent accumulation of primary efficacy events (i.e. regimen failures) was very slow. Therefore, if the study were to continue another 1-2 years, the precision gained for treatment comparisons would likely be small.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1571
• Est. completion date: May 2010
• Est. primary completion date: May 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria :

• HIV-1 infected

• CD4 count fewer than 300 cells/mm3

• Viral load test result

• Absolute Neutrophil Count at least 750mm3

• Hemoglobin at least 7.5 g/dL

• Platelet count at least 50,000/mm3

• Calculated creatinine clearance at least 60 mL/min

• A , A, and alkaline phosphatase <= 5 times upper limit of normal

• total bilirubin <= 2.5 times upper limit of normal

• Karnofsky performance score of 70 or higher

• Plans to stay in the area for the duration of the study

• Agrees to use acceptable forms of contraception for the duration of the study

Exclusion Criteria:

• More than 7 days exposure to ARVs (except for single-dose NVP or ZDV for any period for the purpose of pMTCT)

• Acute therapy for serious medical illnesses within 14 days prior to study entry

• Certain abnormal laboratory values

• Radiation therapy or chemotherapy within 45 days prior to study entry.

• Any immunomodulator, HIV vaccine, or other investigational therapy within 30 days prior to study entry.

• Current alcohol or drug abuse that, in the opinion of the site investigator, would interfere with study participation

• Inflamed pancreas within 3 years prior to study entry

• Allergy/sensitivity to any of the study drugs or their formulations

• Heart rate less than 40 beats/min

• History of untreated, active second- or third-degree heart block

• Currently detained in jail or for treatment of a psychiatric or physical illness

• Vomiting or inability to swallow medications

• Pregnancy

Related Conditions & MeSH terms

• HIV Infections

Intervention

Drug:
• Atazanavir
400 mg taken orally daily
• Didanosine (enteric-coated)
400 mg taken orally daily
• Efavirenz
600 mg taken orally daily
• Emtricitabine
200 mg taken orally daily
• Emtricitabine/Tenofovir disoproxil fumarate
200 mg/300 mg taken orally once daily
• Lamivudine/Zidovudine
150 mg/300 mg taken orally twice daily

Locations

Country	Name	City	State
Brazil	Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS	Manguinhos	Rio De Janeiro
Brazil	Hospital Nossa Senhora da Conceicao	Porto Alegre	RS
Haiti	Les Centres GHESKIO CRS	Bicentenaire	Port-au-Prince
India	NARI Clinic at NIV CRS	Maharashtra State	Pune
India	Dr. Kotnis Dispensary	Pune
India	NARI Pune CRS	Pune	Maharashtra
India	YRG CARE Medical Ctr., VHS Chennai CRS	Rajiv Gandhi Salai Taramani	Chennai
Malawi	University of North Carolina Lilongwe CRS	Mzimba Road	Lilongwe
Malawi	College of Med. JHU CRS	P.O. Box 1131	Blantyre
Peru	Asociacion Civil Impacta Salud y Educacion - Miraf CRS	Barranco	Lima
Peru	San Miguel CRS	San Miguel	Lima
South Africa	Durban Adult HIV CRS	Durban	KwaZulu Natal
South Africa	Wits HIV CRS	Johannesburg	Gauteng
Thailand	Chiang Mai Univ. ACTG CRS	P.O. Box 80	Chiang Mai
United States	University of North Carolina	Chapel Hill	North Carolina
United States	Wake County Health and Human Services Clinical Research Site	Chapel Hill	North Carolina
United States	Cook County Hospital Core Center	Chicago	Illinois
United States	Northwestern University	Chicago	Illinois
United States	Rush-Presbyterian/St. Lukes (Chicago)	Chicago	Illinois
United States	University of Cincinnati	Cincinnati	Ohio
United States	The Ohio State Univ. AIDS CRS	Columbus	Ohio
United States	University of Texas, Southwestern Medical Center	Dallas	Texas
United States	Univ. of Colorado Health Sciences Center, Denver	Denver	Colorado
United States	Duke University Medical Center	Durham	North Carolina
United States	University of Texas, Galveston	Galveston	Texas
United States	Univ. of Hawaii at Manoa, Leahi Hosp.	Honolulu	Hawaii
United States	HIV Prevention & Treatment CRS	HVTN 722 West 168th Street MSPH Bldg.	New York
United States	UCLA CARE Center CRS	Los Angeles	California
United States	University of Southern California	Los Angeles	California
United States	University of Minnesota	Minneapolis	Minnesota
United States	Vanderbilt Therapeutics CRS	Nashville	Tennessee
United States	Beth Israel Medical Center	New York	New York
United States	Cornell CRS	New York	New York
United States	NY Univ. HIV/AIDS CRS	New York	New York
United States	Hosp. of the Univ. of Pennsylvania CRS	Philadelphia	Pennsylvania
United States	Stanley Street Treatment and Resource	Providence	Rhode Island
United States	The Miriam Hosp. ACTG CRS	Providence	Rhode Island
United States	Community Health Network, Inc.	Rochester	New York
United States	Univ. of Rochester ACTG CRS	Rochester	New York
United States	Washington University (St. Louis)	Saint Louis	Missouri
United States	Harbor General/UCLA	Torrance	California
Zimbabwe	UZ-Parirenyatwa CRS	AIDS Research Unit P.O. Box A178	Harare

Sponsors (2)

Lead Sponsor	Collaborator
AIDS Clinical Trials Group	National Institute of Allergy and Infectious Diseases (NIAID)

Countries where clinical trial is conducted

United States,  Zimbabwe,  Brazil,  Haiti,  India,  Malawi,  Peru,  South Africa,  Thailand, 

References & Publications (3)

Bartlett JA, Johnson J, Herrera G, Sosa N, Rodriguez A, Liao Q, Griffith S, Irlbeck D, Shaefer MS; 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 Nov 1;43(3):284-92. — View Citation

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

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to Treatment Failure (PI Comparison)	Time from randomization to the earliest of: scheduled week of first plasma sample meeting virologic failure (two consecutive plasma HIV-1 RNA values 1,000 copies/mL or higher, regardless of whether ARV medications being taken at the time); scheduled week of first AIDS defining diagnosis (WHO Stage 4 (2005), plus microsporidiosis, cyclospora gastroenteritis and Chaga's disease), not attributed to Immune Reconstitution Inflammatory Syndrome (reviewed by chairs); date of death (due to any cause). Plasma drawn every 8 weeks (except confirmation samples could be drawn earlier).	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).
Primary	Time to Treatment Failure (NRTI Comparison)	Time from randomization to the earliest of: scheduled week of first plasma sample meeting virologic failure (two consecutive plasma HIV-1 RNA values 1,000 copies/mL or higher, regardless of whether ARV medications being taken at the time); scheduled week of first AIDS defining diagnosis (WHO Stage 4 (2005) plus microsporidiosis, cyclospora gastroenteritis and Chaga's disease), not attributed to Immune Reconstitution Inflammatory Syndrome (reviewed by chairs); date of death (due to any cause). Plasma drawn every 8 weeks (except confirmation samples could be drawn earlier).	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).
Secondary	Time to Discontinuation of Initial Antiretroviral (ARV) Therapy (PI Comparison)	Time is measured from date of treatment initiation to earliest of the following: date of last participant contact (premature discontinuation of study follow-up); date all ARV medications were held (if all medications held for at least 8 weeks, for any reason); date that any ARV medication was changed (excluding the following single ARV substitutions: stavudine or tenofovir for zidovudine, nevirapine for efavirenz, or didanosine for tenofovir).	Throughout follow-up until ddI+FTC+ATV arm closed (May 22,2008)
Secondary	Time to Immunologic Failure (PI Comparison)	Time from randomization to the first scheduled study visit (week 48 or later) with a CD4+ cell count fewer than 100 cells/mm3.	At or after Week 48 (including only follow-up until ddI+FTV+ATV arm closed - May 22,2008)
Secondary	Change in CD4 Count From Screening to Weeks 24, 48, 96 (PI Comparison)	Available pre-randomization CD4 cell counts were limited to the single CD4 cell count used for study eligibility (and therefore must have been fewer than 300 cells/mm3).	weeks 24, 48 and 96 (including follow-up until ddI+FTC+ARV arm closed - May 22, 2008)
Secondary	Time to First Dose Modification or Grade 3 or 4 Adverse Event (PI Comparison)	Time from treatment dispensation to the first occurring of the following: week of first ARV medication change; week of first grade 3 or higher sign/symptom or laboratory abnormality (total bilirubin was excluded) that was at least one grade higher than baseline. Grading used the Division of AIDS (DAIDS) 2004 Severity of Adverse Events Tables.	Throughout study follow-up until ddI+FTC+ATV arm closed (May 22, 2008)
Secondary	Plasma HIV-1 Viral Load Fewer Than 400 Copies/ml (PI Comparison)	Number of participants with plasma HIV-1 Viral load fewer than 400 copies/mL at study visit weeks 24 and 48. Closest observed result between 20 and up to 28 weeks (for week 24), and between 44 and up to 52 (for week 48) used if multiple results available. Missing values excluded, and both study treatment status and history ignored.	At Weeks 24 and 48 (including only follow-up until ddI+FTC+ARV arm closed - May 22, 2008)
Secondary	Time to Loss of Virologic Response by Week 48 (Defined by FDA TLOVR Algorithm - Excluding Study Allowed ARV Substitutions)(PI Comparison)	Time from randomization to any of the following events occurring prior to week 48: discontinued ARV regimen (see time to discontinuation of initial ARV therapy above); 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.	Week 48 (using follow-up only until closing of ddI+FTV+ATV arm on May 22,2008)
Secondary	Time to Loss of Virologic Response at Week 48 (Defined by FDA TLOVR Algorithm - Including All ARV Substitutions)(PI Comparison)	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.	Week 48 (using follow-up only until closing of ddI+FTV+ATV arm on May 22,2008)
Secondary	Time to Discontinuation of Initial Antiretroviral (ARV) Therapy (NRTI Comparison)	Time is measured from date of treatment initiation to earliest of the following: date of last participant contact (premature discontinuation of study follow-up); date all ARV medications were held (if all medications held for at least 8 weeks, for any reason); date that any ARV medication was changed (excluding the following single ARV substitutions: stavudine or tenofovir for zidovudine, nevirapine for efavirenz, or didanosine for tenofovir).	Throughout follow-up until study closed (May 31,2010)
Secondary	Time to Immunologic Failure (NRTI Comparison)	Time from randomization to the first scheduled study visit (week 48 or later) with a CD4+ cell count fewer than 100 cells/mm3.	At or after Week 48 (including all follow-up through study closure - May 31,2010)
Secondary	Change in CD4 Count From Screening to Weeks 24, 48, 96 (NRTI Comparison)	Available pre-randomization CD4 cell counts were limited to the single CD4 cell count used for study eligibility (and therefore must have been fewer than 300 cells/mm3).	weeks 24, 48 and 96 (including all follow-up through to study closure on May 31, 2010)
Secondary	Plasma HIV-1 Viral Load Fewer Than 400 Copies/ml (NRTI Comparison)	Number of participants with plasma HIV-1 Viral load fewer than 400 copies/mL at study visit weeks 24 and 48. Closest observed result between 20 and up to 28 weeks (for week 24), and between 44 and up to 52 (for week 48) used if multiple results available. Missing values excluded, and both study treatment status and history ignored.	At Weeks 24 and 48 (including follow-up through to study closure on May 31, 2010)
Secondary	Time to Loss of Virologic Response at Week 48 (Defined by FDA TLOVR Algorithm - Excluding Study Allowed ARV Substitutions)(NRTI Comparison)	Time from randomization to any of the following events occurring prior to week 48: discontinued ARV regimen (see time to discontinuation of initial ARV therapy above); 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.	Week 48 (using follow-up through study closure on May 31,2010)
Secondary	Time to Loss of Virologic Response at Week 96 (Defined by FDA TLOVR Algorithm - Excluding Study Allowed ARV Substitutions)(NRTI Comparison)	Time from randomization to any of the following events occurring prior to week 96: discontinued ARV regimen (see time to discontinuation of initial ARV therapy above); 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.	Week 96 (using follow-up through to study closure on May 31,2010)
Secondary	Time to Loss of Virologic Response at Week 48 (Defined by FDA TLOVR Algorithm - Including All ARV Substitutions)(NRTI Comparison)	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.	Week 48 using follow-up through study closure on May 31,2010
Secondary	Time to Loss of Virologic Response at Week 96 (Defined by FDA TLOVR Algorithm - Including All ARV Substitutions)(NRTI Comparison)	Time to any of the following events occurring prior to week 96: 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.	Week 96 using follow-up through study closure on May 31,2010
Secondary	Time to First Dose Modification or Grade 3 or 4 Adverse Event (NRTI Comparison)	Time from treatment dispensation to the first occurring of the following: week of first ARV medication change; week of first grade 3 or higher sign/symptom or laboratory abnormality (total bilirubin was excluded) that was at least one grade higher than baseline. Grading used the Division of AIDS (DAIDS) 2004 Severity of Adverse Events Tables.	Throughout study follow-up until study closure (May 31, 2010)