Clinical trial NCT00084136: Prospective Evaluation of Anti-retroviral Combinations for Treatment Naive, HIV Infected Persons in Resource-limited Settings
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV Infections
Keywords: Treatment Naive
Adherence
Drug Resistance
Treatment Failure
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2004-06-08
Enrollment: 1571
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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

\> 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. \>

\>

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

\> 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. \>

\> 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.

Eligibility criteria: 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\>

Primary outcomes:
measure: Time to Treatment Failure (PI Comparison)
timeFrame: 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).
measure: Time to Treatment Failure (NRTI Comparison)
timeFrame: 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 outcomes:
measure: Time to Discontinuation of Initial Antiretroviral (ARV) Therapy (PI Comparison)
timeFrame: Throughout follow-up until ddI+FTC+ATV arm closed (May 22,2008)
measure: Time to Immunologic Failure (PI Comparison)
timeFrame: At or after Week 48 (including only follow-up until ddI+FTV+ATV arm closed - May 22,2008)
measure: Change in CD4 Count From Screening to Weeks 24, 48, 96 (PI Comparison)
timeFrame: weeks 24, 48 and 96 (including follow-up until ddI+FTC+ARV arm closed - May 22, 2008)
measure: Time to First Dose Modification or Grade 3 or 4 Adverse Event (PI Comparison)
timeFrame: Throughout study follow-up until ddI+FTC+ATV arm closed (May 22, 2008)
measure: Plasma HIV-1 Viral Load Fewer Than 400 Copies/ml (PI Comparison)
timeFrame: At Weeks 24 and 48 (including only follow-up until ddI+FTC+ARV arm closed - May 22, 2008)
measure: Time to Loss of Virologic Response by Week 48 (Defined by FDA TLOVR Algorithm - Excluding Study Allowed ARV Substitutions)(PI Comparison)
timeFrame: Week 48 (using follow-up only until closing of ddI+FTV+ATV arm on May 22,2008)
measure: Time to Loss of Virologic Response at Week 48 (Defined by FDA TLOVR Algorithm - Including All ARV Substitutions)(PI Comparison)
timeFrame: Week 48 (using follow-up only until closing of ddI+FTV+ATV arm on May 22,2008)
measure: Time to Discontinuation of Initial Antiretroviral (ARV) Therapy (NRTI Comparison)
timeFrame: Throughout follow-up until study closed (May 31,2010)
measure: Time to Immunologic Failure (NRTI Comparison)
timeFrame: At or after Week 48 (including all follow-up through study closure - May 31,2010)
measure: Change in CD4 Count From Screening to Weeks 24, 48, 96 (NRTI Comparison)
timeFrame: weeks 24, 48 and 96 (including all follow-up through to study closure on May 31, 2010)
measure: Plasma HIV-1 Viral Load Fewer Than 400 Copies/ml (NRTI Comparison)
timeFrame: At Weeks 24 and 48 (including follow-up through to study closure on May 31, 2010)
measure: Time to Loss of Virologic Response at Week 48 (Defined by FDA TLOVR Algorithm - Excluding Study Allowed ARV Substitutions)(NRTI Comparison)
timeFrame: Week 48 (using follow-up through study closure on May 31,2010)
measure: Time to Loss of Virologic Response at Week 96 (Defined by FDA TLOVR Algorithm - Excluding Study Allowed ARV Substitutions)(NRTI Comparison)
timeFrame: Week 96 (using follow-up through to study closure on May 31,2010)
measure: Time to Loss of Virologic Response at Week 48 (Defined by FDA TLOVR Algorithm - Including All ARV Substitutions)(NRTI Comparison)
timeFrame: Week 48 using follow-up through study closure on May 31,2010
measure: Time to Loss of Virologic Response at Week 96 (Defined by FDA TLOVR Algorithm - Including All ARV Substitutions)(NRTI Comparison)
timeFrame: Week 96 using follow-up through study closure on May 31,2010
measure: Time to First Dose Modification or Grade 3 or 4 Adverse Event (NRTI Comparison)
timeFrame: Throughout study follow-up until study closure (May 31, 2010)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS
state: California
city: Torrance
country: United States
facility: Harbor General/UCLA
state: California
city: Denver
country: United States
facility: Univ. of Colorado Health Sciences Center, Denver
state: Colorado
city: Honolulu
country: United States
facility: Univ. of Hawaii at Manoa, Leahi Hosp.
state: Hawaii
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush-Presbyterian/St. Lukes (Chicago)
state: Illinois
city: Chicago
country: United States
facility: Cook County Hospital Core Center
state: Illinois
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University (St. Louis)
state: Missouri
city: HVTN 722 West 168th Street MSPH Bldg.
country: United States
facility: HIV Prevention & Treatment CRS
state: New York
city: New York
country: United States
facility: Beth Israel Medical Center
state: New York
city: New York
country: United States
facility: Cornell CRS
state: New York
city: New York
country: United States
facility: NY Univ. HIV/AIDS CRS
state: New York
city: Rochester
country: United States
facility: Community Health Network, Inc.
state: New York
city: Rochester
country: United States
facility: Univ. of Rochester ACTG CRS
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Chapel Hill
country: United States
facility: Wake County Health and Human Services Clinical Research Site
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Columbus
country: United States
facility: The Ohio State Univ. AIDS CRS
state: Ohio
city: Philadelphia
country: United States
facility: Hosp. of the Univ. of Pennsylvania CRS
state: Pennsylvania
city: Providence
country: United States
facility: Stanley Street Treatment and Resource
state: Rhode Island
city: Providence
country: United States
facility: The Miriam Hosp. ACTG CRS
state: Rhode Island
city: Nashville
country: United States
facility: Vanderbilt Therapeutics CRS
state: Tennessee
city: Dallas
country: United States
facility: University of Texas, Southwestern Medical Center
state: Texas
city: Galveston
country: United States
facility: University of Texas, Galveston
state: Texas
city: Manguinhos
country: Brazil
facility: Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS
state: Rio De Janeiro
city: Porto Alegre
country: Brazil
facility: Hospital Nossa Senhora da Conceicao
state: RS
city: Bicentenaire
country: Haiti
facility: Les Centres GHESKIO CRS
state: Port-au-Prince
city: Rajiv Gandhi Salai Taramani
country: India
facility: YRG CARE Medical Ctr., VHS Chennai CRS
state: Chennai
city: Pune
country: India
facility: NARI Pune CRS
state: Maharashtra
city: Maharashtra State
country: India
facility: NARI Clinic at NIV CRS
state: Pune
city: Pune
country: India
facility: Dr. Kotnis Dispensary
city: P.O. Box 1131
country: Malawi
facility: College of Med. JHU CRS
state: Blantyre
city: Mzimba Road
country: Malawi
facility: University of North Carolina Lilongwe CRS
state: Lilongwe
city: Barranco
country: Peru
facility: Asociacion Civil Impacta Salud y Educacion - Miraf CRS
state: Lima
city: San Miguel
country: Peru
facility: San Miguel CRS
state: Lima
city: Johannesburg
country: South Africa
facility: Wits HIV CRS
state: Gauteng
city: Durban
country: South Africa
facility: Durban Adult HIV CRS
state: KwaZulu Natal
city: P.O. Box 80
country: Thailand
facility: Chiang Mai Univ. ACTG CRS
state: Chiang Mai
city: AIDS Research Unit P.O. Box A178
country: Zimbabwe
facility: UZ-Parirenyatwa CRS
state: Harare
Study officials:
affiliation: University of Colorado, Denver
name: Thomas B. Campbell, MD
role: STUDY_CHAIR
affiliation: The Miriam Hospital
name: Timothy Flanigan, MD
role: STUDY_CHAIR
affiliation: Department of Medicine, University of Zimbabwe
name: James Hakim, MscClinEpi, FRCP
role: STUDY_CHAIR
affiliation: Centre for AIDS Research and Education
name: Nagalingeswaran Kumarasamy, MD
role: STUDY_CHAIR
References:
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citation: Saag MS. Initiation of antiretroviral therapy: implications of recent findings. Top HIV Med. 2004 Jul-Aug;12(3):83-8.
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citation: Gatechompol S, Zheng L, Bao Y, Avihingsanon A, Kerr SJ, Kumarasamy N, Hakim JG, Maldarelli F, Gorelick RJ, Welker JL, Lifson JD, Hosseinipour MC, Eron JJ, Ruxrungtham K. Prevalence and risk of residual viremia after ART in low- and middle-income countries: A cross-sectional study. Medicine (Baltimore). 2021 Sep 3;100(35):e26817. doi: 10.1097/MD.0000000000026817.
citation: Firnhaber C, Smeaton LM, Grinsztejn B, Lalloo U, Faesen S, Samaneka W, Infante R, Rana A, Kumarasamy N, Hakim J, Campbell TB. Differences in antiretroviral safety and efficacy by sex in a multinational randomized clinical trial. HIV Clin Trials. 2015 May-Jun;16(3):89-99. doi: 10.1179/1528433614Z.0000000013. Epub 2015 May 15.
citation: Kantor R, Smeaton L, Vardhanabhuti S, Hudelson SE, Wallis CL, Tripathy S, Morgado MG, Saravanan S, Balakrishnan P, Reitsma M, Hart S, Mellors JW, Halvas E, Grinsztejn B, Hosseinipour MC, Kumwenda J, La Rosa A, Lalloo UG, Lama JR, Rassool M, Santos BR, Supparatpinyo K, Hakim J, Flanigan T, Kumarasamy N, Campbell TB, Eshleman SH; AIDS Clinical Trials Group (ACTG) A5175 Study Team. Pretreatment HIV Drug Resistance and HIV-1 Subtype C Are Independently Associated With Virologic Failure: Results From the Multinational PEARLS (ACTG A5175) Clinical Trial. Clin Infect Dis. 2015 May 15;60(10):1541-9. doi: 10.1093/cid/civ102. Epub 2015 Feb 13.
citation: 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.
citation: 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;9(8):e1001290. doi: 10.1371/journal.pmed.1001290. Epub 2012 Aug 14.
citation: 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. doi: 10.1542/peds.2011-2340. Epub 2012 May 14.
citation: 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. doi: 10.1007/s10461-011-9947-5.
citation: 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. doi: 10.1016/j.ijid.2010.08.002. Epub 2010 Oct 18.