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

NCT00084136 | Completed Phase 4 Results DMC

• 5 other identifiers: ACTG A51751U01AI068636PEARLSA5185s5K24AI051966-03
• Study Type: interventional
• Target: 1,571
• Locations: 9 countries
• Sites: 42

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.

Conditions

HIV Infections

Keywords

Treatment Naive; Adherence; Drug Resistance; Treatment Failure

Outcome Measures

Primary Outcomes (2)

• 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).

• 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 Outcomes (16)

• Time to Discontinuation of Initial Antiretroviral (ARV) Therapy (PI Comparison)

  Throughout follow-up until ddI+FTC+ATV arm closed (May 22,2008)

• Time to Immunologic Failure (PI Comparison)

  At or after Week 48 (including only follow-up until ddI+FTV+ATV arm closed - May 22,2008)

• Change in CD4 Count From Screening to Weeks 24, 48, 96 (PI Comparison)

  weeks 24, 48 and 96 (including follow-up until ddI+FTC+ARV arm closed - May 22, 2008)

• Time to First Dose Modification or Grade 3 or 4 Adverse Event (PI Comparison)

  Throughout study follow-up until ddI+FTC+ATV arm closed (May 22, 2008)

• Plasma HIV-1 Viral Load Fewer Than 400 Copies/ml (PI Comparison)

  At Weeks 24 and 48 (including only follow-up until ddI+FTC+ARV arm closed - May 22, 2008)

Study Arms (3)

ZDV/3TC+EFV

EXPERIMENTAL

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

Drug: Efavirenz; Drug: Lamivudine/Zidovudine

ddI+FTC+ATV

EXPERIMENTAL

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

Drug: Atazanavir; Drug: Didanosine (enteric-coated); Drug: Emtricitabine

TDF/FTC+EFV

EXPERIMENTAL

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

Drug: Efavirenz; Drug: Emtricitabine/Tenofovir disoproxil fumarate

Interventions

Atazanavir DRUG

400 mg taken orally daily

Also known as: ATV

ddI+FTC+ATV

Didanosine (enteric-coated) DRUG

400 mg taken orally daily

Also known as: ddI

ddI+FTC+ATV

Efavirenz DRUG

600 mg taken orally daily

Also known as: EFV

TDF/FTC+EFV; ZDV/3TC+EFV

Emtricitabine DRUG

200 mg taken orally daily

Also known as: FTC

ddI+FTC+ATV

Emtricitabine/Tenofovir disoproxil fumarate DRUG

200 mg/300 mg taken orally once daily

Also known as: FTC/TDF

TDF/FTC+EFV

Lamivudine/Zidovudine DRUG

150 mg/300 mg taken orally twice daily

Also known as: 3TC/ZDV

ZDV/3TC+EFV

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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\>

You may not qualify if:

• 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\>

Sponsors & Collaborators

• Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (42)

University of Southern California

Los Angeles, California, 90033-1079, United States

Location

UCLA CARE Center CRS

Los Angeles, California, 90095-1793, United States

Location

Harbor General/UCLA

Torrance, California, 90502-2052, United States

Location

Univ. of Colorado Health Sciences Center, Denver

Denver, Colorado, United States

Location

Univ. of Hawaii at Manoa, Leahi Hosp.

Honolulu, Hawaii, 96816-2396, United States

Location

Northwestern University

Chicago, Illinois, 60611-3015, United States

Location

Rush-Presbyterian/St. Lukes (Chicago)

Chicago, Illinois, 60612-3806, United States

Location

Cook County Hospital Core Center

Chicago, Illinois, 60612, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455-0392, United States

Location

Washington University (St. Louis)

St Louis, Missouri, 63108-2138, United States

Location

HIV Prevention & Treatment CRS

HVTN 722 West 168th Street MSPH Bldg., New York, 10032, United States

Location

Beth Israel Medical Center

New York, New York, 10003, United States

Location

Cornell CRS

New York, New York, 10011, United States

Location

NY Univ. HIV/AIDS CRS

New York, New York, 10016, United States

Location

Community Health Network, Inc.

Rochester, New York, 14642-0001, United States

Location

Univ. of Rochester ACTG CRS

Rochester, New York, 14642-0001, United States

Location

University of North Carolina

Chapel Hill, North Carolina, 27514, United States

Location

Wake County Health and Human Services Clinical Research Site

Chapel Hill, North Carolina, 27514, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

University of Cincinnati

Cincinnati, Ohio, 45267-0405, United States

Location

The Ohio State Univ. AIDS CRS

Columbus, Ohio, 43210, United States

Location

Hosp. of the Univ. of Pennsylvania CRS

Philadelphia, Pennsylvania, 19104, United States

Location

Stanley Street Treatment and Resource

Providence, Rhode Island, 02906, United States

Location

The Miriam Hosp. ACTG CRS

Providence, Rhode Island, 02906, United States

Location

Vanderbilt Therapeutics CRS

Nashville, Tennessee, 37204, United States

Location

University of Texas, Southwestern Medical Center

Dallas, Texas, United States

Location

University of Texas, Galveston

Galveston, Texas, 77555-0435, United States

Location

Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS

Manguinhos, Rio de Janeiro, Brazil

Location

Hospital Nossa Senhora da Conceicao

Porto Alegre, Rio Grande do Sul, 91350-200, Brazil

Location

Les Centres GHESKIO CRS

Bicentenaire, Port-au-Prince, HT-6110, Haiti

Location

YRG CARE Medical Ctr., VHS Chennai CRS

Rajiv Gandhi Salai Taramani, Chennai, 600113, India

Location

NARI Pune CRS

Pune, Maharashtra, India

Location

NARI Clinic at NIV CRS

Maharashtra State, Pune, India

Location

Dr. Kotnis Dispensary

Pune, 411026, India

Location

College of Med. JHU CRS

P.O. Box 1131, Blantyre, Malawi

Location

University of North Carolina Lilongwe CRS

Mzimba Road, Lilongwe, Malawi

Location

Asociacion Civil Impacta Salud y Educacion - Miraf CRS

Barranco, Lima region, Peru

Location

San Miguel CRS

San Miguel, Lima region, Peru

Location

Wits HIV CRS

Johannesburg, Gauteng, 2092, South Africa

Location

Durban Adult HIV CRS

Durban, KwaZulu-Natal, 4001, South Africa

Location

Chiang Mai Univ. ACTG CRS

P.O. Box 80, Chiang Mai, 50200, Thailand

Location

UZ-Parirenyatwa CRS

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

Location

Related Publications (11)

• 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.

  PMID: 16967040 BACKGROUND

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

  PMID: 15310939 BACKGROUND

• 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.

  PMID: 15857194 BACKGROUND

• 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.

  PMID: 34477118 DERIVED

• 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.

  PMID: 25979186 DERIVED

• 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.

  PMID: 25681380 DERIVED

• 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.

  PMID: 24979445 DERIVED

• 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.

  PMID: 22936892 DERIVED

• 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.

  PMID: 22585772 DERIVED

• 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.

  PMID: 21499794 DERIVED

• 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.

  PMID: 20961784 DERIVED

MeSH Terms

Conditions

HIV Infections

Interventions

Atazanavir Sulfate; Didanosine; efavirenz; Emtricitabine; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; lamivudine, zidovudine drug combination

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Oligopeptides; Peptides; Amino Acids, Peptides, and Proteins; Inosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Dideoxynucleosides; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Tenofovir; Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Adenine; Drug Combinations; Pharmaceutical Preparations

Results Point of Contact

• Title: ACTG ClinicalTrials.gov Coordinator
• Organization: ACTG Network Coordinating Center, Social and Scientific Systems, Inc.

ACTGCT.Gov@s-3.com

(301) 628-3313

Study Officials

• Thomas B. Campbell, MD

  University of Colorado, Denver

  STUDY CHAIR

• Timothy Flanigan, MD

  The Miriam Hospital

  STUDY CHAIR

• James Hakim, MscClinEpi, FRCP

  Department of Medicine, University of Zimbabwe

  STUDY CHAIR

• Nagalingeswaran Kumarasamy, MD

  Centre for AIDS Research and Education

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 7, 2004
• First Posted: June 8, 2004
• Study Start: May 1, 2005
• Primary Completion: May 1, 2010
• Study Completion: May 1, 2010
• Last Updated: October 10, 2018
• Results First Posted: August 9, 2011

Record last verified: 2018-09

Locations

ZA (2); IN (4); PE (2); BR (2); MA (2); US (27); HA (1); TH (1); ZI (1)