Treatment With Combinations of Several Antiviral Drugs in Infants and Young Children With HIV Infection

Early Intensive Antiretroviral Combination Therapy in HIV-1 Infected Infants and Children

This trial tests the safety and effectiveness of the early use of combinations of anti-HIV drugs in HIV-infected infants and young children in an effort to block virus growth and preserve normal immune functions.

Various anti-HIV drug combinations need to be tested in order to find the best way to treat infants and children who have been infected with HIV during birth.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Nevirapine; Drug: Lamivudine; Drug: Stavudine; Drug: Zidovudine; Drug: Nelfinavir mesylate; Drug: Abacavir sulfate

Detailed Description

This study examines the antiretroviral activity of ZDV/3TC/NVP in vertically-infected infants and children aged 15 days up to 2 years, and ZDV/3TC/NVP/ABC in vertically-infected infants and children aged 30 days up to 2 years. This study will assess HIV-1 and CD4/CD8 T-cell kinetics, activation, and maturation. It will also test the concept that early (younger than 3 months of age) use of potent, combination antiretroviral therapy will allow the long-term control of viral replication with preservation of normal immune function. [AS PER AMENDMENT 3/11/98: This study will also examine the antiretroviral activity of ZDV/3TC/NVP/NFV in vertically infected infants and children.]

This is a 2-part Phase I/II, open-label trial in HIV-infected infants. Part A assesses the triple combination of ZDV, 3TC, and NVP. Four to eight patients are enrolled in each age cohort (Cohort 1: at least 15 days, no more than 3 months; Cohort 2: over 3 months, no more than 2 years). Part B assesses the quadruple combination of ZDV, 3TC, NVP, and ABC. Eight patients are enrolled in each age cohort (Cohort 3: at least 30 days, no more than 3 months; Cohort 4: over 3 months, no more than 2 years). [AS PER AMENDMENT 3/11/98: This study is now a 3-part Phase I/II trial. Parts A and B are as above. Part C will assess the quadruple regimen of d4T, 3TC, NVP and NFV. Up to 8 patients will be enrolled in each age cohort (Cohort 5: at least 15 days, no more than 3 months; Cohort 6: over 3 months, no more than 2 years). If 3 of 4 patients in either cohort of Part B do not achieve plasma RNA less than 1,000 copies/ml after 16 weeks of quadruple therapy, enrollment of patients to that cohort will stop and enrollment of 8 patients to the corresponding cohort in Part C will begin. For Part C, patients whose RNA level is no more than 1,000 copies/ml at Week 16 will remain on assigned treatment until Week 104. If at any time between Weeks 16 and 104 a patient's RNA level increases to greater than 1,000 copies/ml, plasma RNA will be repeated within 1 week. If both RNA levels are greater than 1,000 copies/ml, the patient will discontinue study treatment and be followed every 12 weeks for 1 year.] [AS PER AMENDMENT 4/14/99: The study has been extended for an additional 96 weeks for children with continued suppression of viral replication (RNA less than 400 copies/ml) at Week 104. If at any time between Week 12 or 16 and Week 200 a patient's RNA level increases to greater than 1,000 copies/ml, plasma RNA will be repeated within 1 week. If both RNA levels are above 1,000 copies/ml, the patient will discontinue treatment for best available therapy and be followed every 12 weeks for 1 year following the discontinuation of study treatment.] [AS PER AMENDMENT 9/16/99: An additional cohort (Cohort 7) of 5 to 10 patients has been added. Cohort 7 includes patients between 15 days and 3 months of age. Cohort 7 patients who experience suppression of viral replication at Week 104 are followed through Week 200.]

• Study Type: Interventional
• Enrollment (Anticipated): 55
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32209
      • Univ. of Florida College of Medicine-Dept of Peds, Div. of Immunology, Infectious Diseases & Allergy
  • Louisiana
    • New Orleans, Louisiana, United States, 701122699
      • Tulane/LSU Maternal/Child CRS
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Univ. of Maryland Med. Ctr., Div. of Ped. Immunology & Rheumatology
    • Baltimore, Maryland, United States, 212874933
      • Johns Hopkins Hosp. & Health System - Dept. of Peds., Div. of Infectious Diseases
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • BMC, Div. of Ped Infectious Diseases
    • Springfield, Massachusetts, United States, 01199
      • Baystate Health, Baystate Med. Ctr.
    • Worcester, Massachusetts, United States, 016550001
      • WNE Maternal Pediatric Adolescent AIDS CRS
  • Michigan
    • Detroit, Michigan, United States
      • Univ. of Mississippi Med. Ctr Children's Hosp.
  • New York
    • New York, New York, United States
      • Nyu Ny Nichd Crs
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 191044318
      • The Children's Hosp. of Philadelphia IMPAACT CRS
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hosp. CRS
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Children's Hosp. of the King's Daughters, Infectious Disease

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 weeks to 2 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

Children may be eligible for this study if they:

• Are 15 days to 2 years old.
• Have consent of parent or legal guardian.
• Are HIV-positive.

Exclusion Criteria

Children will not be eligible for this study if they:

• Have certain infections which require treatment during the study.
• Have received certain medications.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Antiretroviral activity of ZDV/3TC/NVP	Throughout study
Durability of viral suppression	Throughout study
Immune competence and HIV-1 specific immune respones with prolonged viral suppression beyond 104 weeks	Throughout study
Antiretroviral activity of ZDV/3TC/NVP/1592U89 regimen	Throughout study
Antiretroviral activity of d4T/3TC/NVP/NFV regimen	Throughout study
Tolerance and pharmacokinetic profile of NFV	Throughout study

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Study Chair: Katherine Luzuriaga

Publications and helpful links

General Publications

• Luzuriaga K, McManus M, Britto P, Wu HL, Lindsey J, Sullivan JL. Viral kinetics and control of replication following potent early combination antiretroviral therapy of vertical HIV-1 infection. HIV Pathog Treat Conf. 1998 Mar 13-19;52 (abstract no 2024)
• Capparelli E, Sullivan J, Mofenson L, Smith B, Graham B, Britto P, Becker M, Luzuriaga K. Pharmacokinetics (PK) of nelfinavir and its metabolite (M8) in HIV-infected infants following BID or TID administration. 8th Conf Retro and Opportun Infect. 2001 Feb 4-8 (abstract no 729)
• Luzuriaga K, Wu H, McManus M, Britto P, Borkowsky W, Burchett S, Smith B, Mofenson L, Sullivan JL. Dynamics of human immunodeficiency virus type 1 replication in vertically infected infants. J Virol. 1999 Jan;73(1):362-7. doi: 10.1128/JVI.73.1.362-367.1999.
• Luzuriaga K, Mcmanus M, Britto P, Wu H, Lindsey J, Smith B, Mofenson L, Sullivan JL. Early combination antiretroviral therapy of vertical HIV-1 infection: viral kinetics and control of viral replication. Conf Retroviruses Opportunistic Infect. 1998 Feb 1-5;5th:225 (abstract no LB12)
• Capparelli EV, Sullivan JL, Mofenson L, Smith E, Graham B, Britto P, Becker MI, Holland D, Connor JD, Luzuriaga K; Pediatric ACTG 356 Investigators. Pharmacokinetics of nelfinavir in human immunodeficiency virus-infected infants. Pediatr Infect Dis J. 2001 Aug;20(8):746-51. doi: 10.1097/00006454-200108000-00006.
• Luzuriaga K, McManus M, Mofenson L, Britto P, Graham B, Sullivan JL; PACTG 356 Investigators. A trial of three antiretroviral regimens in HIV-1-infected children. N Engl J Med. 2004 Jun 10;350(24):2471-80. doi: 10.1056/NEJMoa032706.
• McManus M, Henderson J, Gautam A, Brody R, Weiss ER, Persaud D, Mick E, Luzuriaga K; PACTG 356 Investigators. Quantitative Human Immunodeficiency Virus (HIV)-1 Antibodies Correlate With Plasma HIV-1 RNA and Cell-associated DNA Levels in Children on Antiretroviral Therapy. Clin Infect Dis. 2019 May 2;68(10):1725-1732. doi: 10.1093/cid/ciy753.

Study record dates

Study Major Dates

• Study Completion (Actual): January 1, 2005

Study Registration Dates

• First Submitted: November 2, 1999
• First Submitted That Met QC Criteria: August 30, 2001
• First Posted (Estimate): August 31, 2001

Study Record Updates

• Last Update Posted (Actual): November 4, 2021
• Last Update Submitted That Met QC Criteria: October 27, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Drug Therapy, Combination; Nevirapine; Reverse Transcriptase Inhibitors; Anti-HIV Agents; HIV-1; Stavudine; Lamivudine; RNA, Viral; Viral Load; CD4 Lymphocyte Count; Zidovudine; HIV Protease Inhibitors; Nelfinavir; Virus Replication
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; HIV Infections; Infections; Acquired Immunodeficiency Syndrome; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antimetabolites; Protease Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; HIV Protease Inhibitors; Viral Protease Inhibitors; Nevirapine; Lamivudine; Zidovudine; Stavudine; Nelfinavir; Abacavir
• Other Study ID Numbers: ACTG 356; 10605 (Other Identifier: CTEP); PACTG 356