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

NCT ID: NCT00084136

Last Updated: 2018-10-10

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE4

Total Enrollment

1571 participants

Study Classification

INTERVENTIONAL

Study Start Date

2005-05-31

Study Completion Date

2010-05-31

Brief Summary

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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

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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.

Conditions

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HIV Infections

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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ZDV/3TC+EFV

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

Group Type EXPERIMENTAL

Efavirenz

Intervention Type DRUG

600 mg taken orally daily

Lamivudine/Zidovudine

Intervention Type DRUG

150 mg/300 mg taken orally twice daily

ddI+FTC+ATV

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

Group Type EXPERIMENTAL

Atazanavir

Intervention Type DRUG

400 mg taken orally daily

Didanosine (enteric-coated)

Intervention Type DRUG

400 mg taken orally daily

Emtricitabine

Intervention Type DRUG

200 mg taken orally daily

TDF/FTC+EFV

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

Group Type EXPERIMENTAL

Efavirenz

Intervention Type DRUG

600 mg taken orally daily

Emtricitabine/Tenofovir disoproxil fumarate

Intervention Type DRUG

200 mg/300 mg taken orally once daily

Interventions

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Atazanavir

400 mg taken orally daily

Intervention Type DRUG

Didanosine (enteric-coated)

400 mg taken orally daily

Intervention Type DRUG

Efavirenz

600 mg taken orally daily

Intervention Type DRUG

Emtricitabine

200 mg taken orally daily

Intervention Type DRUG

Emtricitabine/Tenofovir disoproxil fumarate

200 mg/300 mg taken orally once daily

Intervention Type DRUG

Lamivudine/Zidovudine

150 mg/300 mg taken orally twice daily

Intervention Type DRUG

Other Intervention Names

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ATV ddI EFV FTC FTC/TDF 3TC/ZDV

Eligibility Criteria

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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\>
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role collaborator

Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections

NETWORK

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Thomas B. Campbell, MD

Role: STUDY_CHAIR

University of Colorado, Denver

Timothy Flanigan, MD

Role: STUDY_CHAIR

The Miriam Hospital

James Hakim, MscClinEpi, FRCP

Role: STUDY_CHAIR

Department of Medicine, University of Zimbabwe

Nagalingeswaran Kumarasamy, MD

Role: STUDY_CHAIR

Centre for AIDS Research and Education

Locations

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University of Southern California

Los Angeles, California, United States

Site Status

UCLA CARE Center CRS

Los Angeles, California, United States

Site Status

Harbor General/UCLA

Torrance, California, United States

Site Status

Univ. of Colorado Health Sciences Center, Denver

Denver, Colorado, United States

Site Status

Univ. of Hawaii at Manoa, Leahi Hosp.

Honolulu, Hawaii, United States

Site Status

Northwestern University

Chicago, Illinois, United States

Site Status

Rush-Presbyterian/St. Lukes (Chicago)

Chicago, Illinois, United States

Site Status

Cook County Hospital Core Center

Chicago, Illinois, United States

Site Status

University of Minnesota

Minneapolis, Minnesota, United States

Site Status

Washington University (St. Louis)

St Louis, Missouri, United States

Site Status

HIV Prevention & Treatment CRS

HVTN 722 West 168th Street MSPH Bldg., New York, United States

Site Status

Beth Israel Medical Center

New York, New York, United States

Site Status

Cornell CRS

New York, New York, United States

Site Status

NY Univ. HIV/AIDS CRS

New York, New York, United States

Site Status

Community Health Network, Inc.

Rochester, New York, United States

Site Status

Univ. of Rochester ACTG CRS

Rochester, New York, United States

Site Status

University of North Carolina

Chapel Hill, North Carolina, United States

Site Status

Wake County Health and Human Services Clinical Research Site

Chapel Hill, North Carolina, United States

Site Status

Duke University Medical Center

Durham, North Carolina, United States

Site Status

University of Cincinnati

Cincinnati, Ohio, United States

Site Status

The Ohio State Univ. AIDS CRS

Columbus, Ohio, United States

Site Status

Hosp. of the Univ. of Pennsylvania CRS

Philadelphia, Pennsylvania, United States

Site Status

Stanley Street Treatment and Resource

Providence, Rhode Island, United States

Site Status

The Miriam Hosp. ACTG CRS

Providence, Rhode Island, United States

Site Status

Vanderbilt Therapeutics CRS

Nashville, Tennessee, United States

Site Status

University of Texas, Southwestern Medical Center

Dallas, Texas, United States

Site Status

University of Texas, Galveston

Galveston, Texas, United States

Site Status

Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS

Manguinhos, Rio de Janeiro, Brazil

Site Status

Hospital Nossa Senhora da Conceicao

Porto Alegre, Rio Grande do Sul, Brazil

Site Status

Les Centres GHESKIO CRS

Bicentenaire, Port-au-Prince, Haiti

Site Status

YRG CARE Medical Ctr., VHS Chennai CRS

Rajiv Gandhi Salai Taramani, Chennai, India

Site Status

NARI Pune CRS

Pune, Maharashtra, India

Site Status

NARI Clinic at NIV CRS

Maharashtra State, Pune, India

Site Status

Dr. Kotnis Dispensary

Pune, , India

Site Status

College of Med. JHU CRS

P.O. Box 1131, Blantyre, Malawi

Site Status

University of North Carolina Lilongwe CRS

Mzimba Road, Lilongwe, Malawi

Site Status

Asociacion Civil Impacta Salud y Educacion - Miraf CRS

Barranco, Lima region, Peru

Site Status

San Miguel CRS

San Miguel, Lima region, Peru

Site Status

Wits HIV CRS

Johannesburg, Gauteng, South Africa

Site Status

Durban Adult HIV CRS

Durban, KwaZulu-Natal, South Africa

Site Status

Chiang Mai Univ. ACTG CRS

P.O. Box 80, Chiang Mai, Thailand

Site Status

UZ-Parirenyatwa CRS

AIDS Research Unit P.O. Box A178, Harare, Zimbabwe

Site Status

Countries

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United States Brazil Haiti India Malawi Peru South Africa Thailand Zimbabwe

References

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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. doi: 10.1097/01.qai.0000243092.40490.26.

Reference Type BACKGROUND
PMID: 16967040 (View on PubMed)

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

Reference Type BACKGROUND
PMID: 15310939 (View on PubMed)

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. doi: 10.1089/apc.2005.19.224.

Reference Type BACKGROUND
PMID: 15857194 (View on PubMed)

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.

Reference Type DERIVED
PMID: 34477118 (View on PubMed)

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.

Reference Type DERIVED
PMID: 25979186 (View on PubMed)

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.

Reference Type DERIVED
PMID: 25681380 (View on PubMed)

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.

Reference Type DERIVED
PMID: 24979445 (View on PubMed)

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.

Reference Type DERIVED
PMID: 22936892 (View on PubMed)

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.

Reference Type DERIVED
PMID: 22585772 (View on PubMed)

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.

Reference Type DERIVED
PMID: 21499794 (View on PubMed)

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.

Reference Type DERIVED
PMID: 20961784 (View on PubMed)

Other Identifiers

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1U01AI068636

Identifier Type: NIH

Identifier Source: secondary_id

View Link

PEARLS

Identifier Type: -

Identifier Source: secondary_id

A5185s

Identifier Type: -

Identifier Source: secondary_id

5K24AI051966-03

Identifier Type: NIH

Identifier Source: secondary_id

View Link

ACTG A5175

Identifier Type: -

Identifier Source: org_study_id

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