Anti-HIV Drug Regimens and Treatment-Switching Guidelines in HIV Infected Children

A Phase II/III Randomized, Open-Label Study of Combination Antiretroviral Regimens and Treatment-Switching Strategies in HIV-1-Infected Antiretroviral Naive Children Between 30 Days and 18 Years of Age

Little is known about what treatment combinations are best for HIV infected children. This study examined the long-term effectiveness of different anti-HIV drug combinations in children and strategies for switching treatment if the first treatment does not work. The study enrolled children who had not previously taken anti-HIV medication. Participants in this study were recruited in the United States, South America and Europe.

Some European children may also enroll in a substudy that will observe changes in body fat in children taking anti-HIV medications.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: NRTIs (ABC, FTC, FTC/TDF, 3TC, 3TC/AZT, d4T, TDF, ddC, AZT); Drug: PIs (AMP, IDV, LPV/r, NFV, SQV, RTV); Drug: NNRTIs (EFV, NVP)

Detailed Description

Antiretroviral therapy in children aims to prolong clinical and immunologic health. Currently, there are no data defining a particular highly active antiretroviral therapy (HAART) strategy as the optimal first-line therapy for children. This study evaluated the long-term efficacy of two HAART regimens used as initial therapy: 1) two nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor (PI), and 2) two NRTIs plus a nonnucleoside reverse transcriptase inhibitor (NNRTI). It also evaluated different strategies for switching therapy when the initial regimen fails. The long-term nature of this study should clarify whether early switching of therapy improves immunologic and virologic outcomes, or results in a more rapid exhaustion of treatment options. The study was conducted in the United States and in Europe.

Participants in this study had a CD4 cell count and viral load test during a screening visit. Participants had an entry visit that included blood and urine tests. Participants were then randomly assigned to one of four groups: Groups PI/1K and PI/30K received two NRTIs plus a PI; Groups NNRTI/1K and NNRTI/30K received two NRTIs plus an NNRTI. The medications allowed in the study were: abacavir, didanosine, emtricitabine, emtricitabine/tenofovir disoproxil fumarate, lamivudine, lamivudine/zidovudine, stavudine, tenofovir disoproxil fumarate, zalcitabine, and zidovudine (NRTIs); efavirenz and nevirapine (NNRTIs); efavirenz/emtricitabine/tenofovir disoproxil fumurate (NNRTI/NRTI); and amprenavir,atazanavir, darunavir, fosamprenavir calcium, indinavir, lopinavir/ritonavir, nelfinavir, saquinavir, ritonavir, and tipranavir (PIs). Note: Per the 06/28/05 amendment of this trial, emtricitabine, emtricitabine/tenofovir disoproxil fumarate, and tenofovir dioproxil fumarate were added to the list of medications that could be included in a participant's treatment regimen.

For participants whose initial regimen failed, or who experienced clinical disease progression (indicated by the development of a new CDC Category C diagnosis) or other clinical disease progression at or after Week 24 of first-line therapy, second-line therapy was strongly encouraged. (However, if poor adherence was suspected as a possible reason for an increase in HIV viral load, the site and the clinician were to try to improve patient adherence and obtain additional confirmatory viral load values within a five-week time frame.) In second-line therapy, participants who initially took NRTIs with a PI switched to NRTIs and an NNRTI. Participants who initially took NRTIs and an NNRTI switched to NRTIs and a PI. The timing of the switch was based on the participant's group: Groups PI/1K and NNRTI/1K switched to second-line treatment when viral load was 1,000 copies/ml or greater; Groups PI/30K and NNRTI/30K switched to second-line treatment when viral load was 30,000 copies/ml or greater. Participants who failed second-line therapy discontinued study treatment and were offered the best available therapy at the discretion of the clinician.

Participants had study visits at Weeks 2, 4, 8, 12, 16, 24, and every 12 weeks thereafter until the drug regimen was switched to second-line treatment. Participants then had a re-entry visit and the schedule of visits restarted. Participants were in the study between 4 and 7 years, depending on when they enrolled. All study visits included medical history, a physical exam, and blood collection. Urine collection occurred at most visits. Participants were asked to complete adherence questionnaires and PACTG participants underwent neuropsychological assessments at selected visits.

All participants in this study were encouraged to coenroll in PACTG 219C, Long-Term Effects of HIV Exposure and Infection in Children. Participants in the European portion of the study may be asked to enroll in a substudy to observe the development and progression of lipodystrophy syndrome in children.

• Study Type: Interventional
• Enrollment (Actual): 266
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico, 00936
    • San Juan City Hosp. PR NICHD CRS
  • San Juan, Puerto Rico, 00935
    • Univ. of Puerto Rico Ped. HIV/AIDS Research Program CRS
• United States
  • California
    • Alhambra, California, United States, 91803
      • Usc La Nichd Crs
    • Long Beach, California, United States, 90806
      • Miller Children's Hosp. Long Beach CA NICHD CRS
    • Los Angeles, California, United States, 90095-1752
      • UCLA-Los Angeles/Brazil AIDS Consortium (LABAC) CRS
    • Los Angeles, California, United States, 90027-6062
      • Children's Hospital of Los Angeles NICHD CRS
    • Oakland, California, United States, 94609
      • Children's Hosp. & Research Ctr. Oakland, Ped. Clinical Research Ctr. & Research Lab.
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Connecticut Children's Med. Ctr.
  • District of Columbia
    • Washington, District of Columbia, United States, 20060
      • Howard Univ. Washington DC NICHD CRS
  • Florida
    • Fort Lauderdale, Florida, United States, 33316
      • South Florida CDTC Ft Lauderdale NICHD CRS
    • Gainesville, Florida, United States, 32610-0296
      • Univ. of Florida College of Medicine-Dept of Peds, Div. of Immunology, Infectious Diseases & Allergy
    • Miami, Florida, United States, 33136
      • Univ. of Miami Ped. Perinatal HIV/AIDS CRS
    • Tampa, Florida, United States, 33606
      • USF - Tampa NICHD CRS
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Chicago Children's CRS
    • Chicago, Illinois, United States, 60637
      • Univ. of Chicago - Dept. of Peds., Div. of Infectious Disease
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane Univ. New Orleans NICHD CRS
  • Massachusetts
    • Worcester, Massachusetts, United States, 01605
      • WNE Maternal Pediatric Adolescent AIDS CRS
  • Missouri
    • Saint Louis, Missouri, United States, 63110-1010
      • Washington University Therapeutics (WT) CRS
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901-1969
      • UMDNJ - Robert Wood Johnson Med. School, Div. of Allergy, Immunology & Infectious Diseases
    • Newark, New Jersey, United States, 07103
      • Rutgers - New Jersey Medical School CRS
  • New York
    • Bronx, New York, United States, 10461
      • Jacobi Med. Ctr. Bronx NICHD CRS
    • New York, New York, United States, 10016
      • Nyu Ny Nichd Crs
    • New York, New York, United States, 10032
      • Columbia IMPAACT CRS
    • New York, New York, United States, 10037
      • Harlem Hosp. Ctr. NY NICHD CRS
    • Stony Brook, New York, United States, 11794-8111
      • SUNY Stony Brook NICHD CRS
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Med. Univ., Dept. of Peds.
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7220
      • UNC at Chapel Hill School of Medicine - Dept. of Peds., Div. of Immunology & Infectious Diseases
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science Univ. - Dept. of Peds., Div. of Infectious Disease
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude/UTHSC CRS
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital CRS
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital CRS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Older than 30 days and younger than 18 years of age (may enroll up to the day before their 18th birthday)
• HIV infected
• Not previously on HAART or received anti-HIV drugs for less than 56 consecutive days after birth to prevent mother-to-infant HIV transmission. Participants who have previously received nevirapine for the prevention of mother-to-infant HIV transmission are not eligible for this study.
• Willing to use acceptable methods of contraception

Exclusion Criteria:

• Grade 3 or 4 clinical or laboratory toxicity. More information on this criterion can be found in the protocol.
• Active opportunistic infection or a serious bacterial infection at the time of study entry
• Pancreas, nervous system, blood, liver, or kidney problems that make it impossible to take study medications
• Taking any medication that cannot be combined with the study medications in first-line therapy
• Received therapy for cancer
• Pregnant or breastfeeding

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PI/1K; Two NRTIs plus a PI with a regimen change recommended at when viral load reaches 1000 copies/ml or higher	Drug: NRTIs (ABC, FTC, FTC/TDF, 3TC, 3TC/AZT, d4T, TDF, ddC, AZT); Accepted NRTIs: abacavir sulfate (ABC), emtricitabine (FTC), emtricitabine/Tenofovir disoproxil fumarate (FTC/TDF), lamivudine (3TC), lamivudine/zidovudine (3TC/AZT), stavudine (d4T), tenofovir disoproxil fumarate (TDF), zalcitabine (ddC), zidovudine (AZT) Prescribed per participant's doctor; Other Names: 2 NRTIs/PI, change@viral load 1000 copies/ml or higher; 2 NRTIs/PI, change@viral load 30,000 copies/ml or higher; 2 NRTIs/NNRTI, change@viral load 1000 copies/ml or higher; 2 NRTIs/NNRTI, change@viral load 30,000 copies/ml or higher; Drug: PIs (AMP, IDV, LPV/r, NFV, SQV, RTV); Accepted PIs: amprenavir (APV). indinavir sulfate (IDV), lopinavir/ritonavir (LPV/r), nelfinavir mesylate (NFV), saquinavir (SQV), ritonavir (RTV) Prescribed per participant's doctor; Other Names: 2 NRTIs/PI, change@viral load 1000 copies/ml or higher; 2 NRTIs/PI, change@viral load 30,000 copies/ml or higher
Experimental: NNRTI/1K; 2 NRTIs plus an NNRTI with a regimen change recommended when viral load reaches 1,000 copies/ml or higher	Drug: NRTIs (ABC, FTC, FTC/TDF, 3TC, 3TC/AZT, d4T, TDF, ddC, AZT); Accepted NRTIs: abacavir sulfate (ABC), emtricitabine (FTC), emtricitabine/Tenofovir disoproxil fumarate (FTC/TDF), lamivudine (3TC), lamivudine/zidovudine (3TC/AZT), stavudine (d4T), tenofovir disoproxil fumarate (TDF), zalcitabine (ddC), zidovudine (AZT) Prescribed per participant's doctor; Other Names: 2 NRTIs/PI, change@viral load 1000 copies/ml or higher; 2 NRTIs/PI, change@viral load 30,000 copies/ml or higher; 2 NRTIs/NNRTI, change@viral load 1000 copies/ml or higher; 2 NRTIs/NNRTI, change@viral load 30,000 copies/ml or higher; Drug: NNRTIs (EFV, NVP); Accepted NNRTIs: efavirenz (EFV), nevirapine (NVP) Prescribed per participant's doctor; Other Names: 2 NRTIs/NNRTI, change@viral load 1000 copies/ml or higher; 2 NRTIs/NNRTI, change@viral load 30,000 copies/ml or higher
Experimental: PI/30K; 2 NRTIs plus 1 PI with a regimen change recommended when viral load reaches 30,000 copies/ml or higher	Drug: NRTIs (ABC, FTC, FTC/TDF, 3TC, 3TC/AZT, d4T, TDF, ddC, AZT); Accepted NRTIs: abacavir sulfate (ABC), emtricitabine (FTC), emtricitabine/Tenofovir disoproxil fumarate (FTC/TDF), lamivudine (3TC), lamivudine/zidovudine (3TC/AZT), stavudine (d4T), tenofovir disoproxil fumarate (TDF), zalcitabine (ddC), zidovudine (AZT) Prescribed per participant's doctor; Other Names: 2 NRTIs/PI, change@viral load 1000 copies/ml or higher; 2 NRTIs/PI, change@viral load 30,000 copies/ml or higher; 2 NRTIs/NNRTI, change@viral load 1000 copies/ml or higher; 2 NRTIs/NNRTI, change@viral load 30,000 copies/ml or higher; Drug: PIs (AMP, IDV, LPV/r, NFV, SQV, RTV); Accepted PIs: amprenavir (APV). indinavir sulfate (IDV), lopinavir/ritonavir (LPV/r), nelfinavir mesylate (NFV), saquinavir (SQV), ritonavir (RTV) Prescribed per participant's doctor; Other Names: 2 NRTIs/PI, change@viral load 1000 copies/ml or higher; 2 NRTIs/PI, change@viral load 30,000 copies/ml or higher
Experimental: NNRTI/30K; 2 NRTIs plus an NNRTI with a regimen change recommended when viral load reaches 30,000 copies/ml or higher	Drug: NRTIs (ABC, FTC, FTC/TDF, 3TC, 3TC/AZT, d4T, TDF, ddC, AZT); Accepted NRTIs: abacavir sulfate (ABC), emtricitabine (FTC), emtricitabine/Tenofovir disoproxil fumarate (FTC/TDF), lamivudine (3TC), lamivudine/zidovudine (3TC/AZT), stavudine (d4T), tenofovir disoproxil fumarate (TDF), zalcitabine (ddC), zidovudine (AZT) Prescribed per participant's doctor; Other Names: 2 NRTIs/PI, change@viral load 1000 copies/ml or higher; 2 NRTIs/PI, change@viral load 30,000 copies/ml or higher; 2 NRTIs/NNRTI, change@viral load 1000 copies/ml or higher; 2 NRTIs/NNRTI, change@viral load 30,000 copies/ml or higher; Drug: NNRTIs (EFV, NVP); Accepted NNRTIs: efavirenz (EFV), nevirapine (NVP) Prescribed per participant's doctor; Other Names: 2 NRTIs/NNRTI, change@viral load 1000 copies/ml or higher; 2 NRTIs/NNRTI, change@viral load 30,000 copies/ml or higher

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in Viral Load Measured in log10 HIV-1 RNA Copies/ml	Baseline visit and 4 years after Study Entry

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Grade 3 or Higher Signs, Symptoms, or Laboratory Abnormalities Experienced	Adverse events were graded according to the following guidelines: PACTG: "The Manual for Expedited Reporting of Adverse Events to DAIDS" (DAIDS EAE Manual) dated May 6, 2004. PENTA: International Conference for Harmonization (ICH) requirements and the EU Clinical Trials Directive 2001/20/EC (20). A rating of Grade 3 is severe and Grade 4 is life-threatening. The rate of serious (Grade 3 or above)events is reported as the number of events per 100 child/years.	Up to 6 yrs. (average 4.85 yrs.)
Participants With Significant HIV-related Clinical Events, Defined as CDC Category C (AIDS Defining) Diagnoses (Except for Recurrent Bacterial Infections)or Death		Up to 6 yrs. (average 4.85 yrs.)
Time to Switching to an Alternative Class ART Regimen (Based on Initial Randomized Regimen)	25th Percentiles in weeks from randomization to starting an alternative class ART regimen (based on initial randomized regimen)	Up to 6 yrs. (average 4.85 yrs.)
Time to HIV-1 RNA of 400 Copies/ml or Greater During First-line Therapy or Permanent Discontinuation of First-line Therapy	25th Percentiles in weeks from randomization HIV-1 RNA of 400 copies/ml or greater during first-line therapy or permanent discontinuation of first-line therapy.	Up to 6 yrs. (average 4.85 yrs.)
Time to HIV-1 RNA of 30,000 Copies/ml or Greater During Second-line Therapy or Permanent Discontinuation of Second-line Therapy	25th Percentiles in weeks from randomization to HIV-1 RNA of 30,000 copies/ml or greater during second-line therapy or permanent discontinuation of second-line therapy	Up to 6 yrs. (average 4.85 yrs.)
Number of Children With an HIV-1 RNA Level Less Than 400 Copies/ml Regardless of Therapy at Week 204		Week 204
Change in CD4% From Randomization to 4 Years		Randomization to 4 years
Number of Children With HIV-1 RNA Less Than 400 Copies/ml and on Original Randomized Therapy at 24 Weeks		24 weeks

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); PENTA Foundation
• Investigators: Study Chair: Ross E. McKinney, Jr., MD, Duke University; Study Chair: Ann J. Melvin, MD, Division of Infectious Diseases, Children's Hospital and Medical Center, Seattle, WA

Publications and helpful links

General Publications

• Hoody DW, Fletcher CV. Pharmacology considerations for antiretroviral therapy in human immunodeficiency virus (HIV)-infected children. Semin Pediatr Infect Dis. 2003 Oct;14(4):286-94. doi: 10.1053/j.spid.2003.09.004.
• Brogly S, Williams P, Seage GR 3rd, Oleske JM, Van Dyke R, McIntosh K; PACTG 219C Team. Antiretroviral treatment in pediatric HIV infection in the United States: from clinical trials to clinical practice. JAMA. 2005 May 11;293(18):2213-20. doi: 10.1001/jama.293.18.2213.
• McKinney RE Jr, Cunningham CK. Newer treatments for HIV in children. Curr Opin Pediatr. 2004 Feb;16(1):76-9. doi: 10.1097/00008480-200402000-00014.
• Havens PL. Principles of antiretroviral treatment of children and adolescents with human immunodeficiency virus infection. Semin Pediatr Infect Dis. 2003 Oct;14(4):269-85. doi: 10.1053/j.spid.2003.09.005.
• PENPACT-1 (PENTA 9/PACTG 390) Study Team; Babiker A, Castro nee Green H, Compagnucci A, Fiscus S, Giaquinto C, Gibb DM, Harper L, Harrison L, Hughes M, McKinney R, Melvin A, Mofenson L, Saidi Y, Smith ME, Tudor-Williams G, Walker AS. First-line antiretroviral therapy with a protease inhibitor versus non-nucleoside reverse transcriptase inhibitor and switch at higher versus low viral load in HIV-infected children: an open-label, randomised phase 2/3 trial. Lancet Infect Dis. 2011 Apr;11(4):273-83. doi: 10.1016/S1473-3099(10)70313-3. Epub 2011 Jan 31.

Helpful Links

• Click here for more information about ACTG 219C (NCT00006304)

Study record dates

Study Major Dates

• Study Start: August 1, 2002
• Primary Completion (Actual): August 1, 2009
• Study Completion (Actual): March 1, 2010

Study Registration Dates

• First Submitted: June 7, 2002
• First Submitted That Met QC Criteria: June 10, 2002
• First Posted (Estimate): June 11, 2002

Study Record Updates

• Last Update Posted (Actual): November 5, 2021
• Last Update Submitted That Met QC Criteria: November 3, 2021
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: Drug Therapy, Combination; Reverse Transcriptase Inhibitors; Viral Load; HIV Protease Inhibitors; Treatment Naive
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections
• Other Study ID Numbers: P390; 10106 (Other Identifier: CTEP); PENPACT-1B; PENTA 9/PACTG 390