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

This study has been completed.
Sponsor:
Collaborators:
PENTA Foundation
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00039741
First received: June 7, 2002
Last updated: December 31, 2013
Last verified: December 2013
  Purpose

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.


Condition Intervention Phase
HIV Infections
Drug: NRTIs (ABC, FTC, FTC/TDF, 3TC, 3TC/AZT, d4T, TDF, ddC, AZT)
Drug: NNRTIs (EFV, NVP)
Drug: PIs (AMP, IDV, LPV/r, NFV, SQV, RTV)
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Factorial Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Change in Viral Load Measured in log10 HIV-1 RNA Copies/ml [ Time Frame: Baseline visit and 4 years after Study Entry ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Rate of Grade 3 or Higher Signs, Symptoms, or Laboratory Abnormalities Experienced [ Time Frame: Up to 6 yrs. (average 4.85 yrs.) ] [ Designated as safety issue: Yes ]

    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.


  • Participants With Significant HIV-related Clinical Events, Defined as CDC Category C (AIDS Defining) Diagnoses (Except for Recurrent Bacterial Infections)or Death [ Time Frame: Up to 6 yrs. (average 4.85 yrs.) ] [ Designated as safety issue: No ]
  • Time to Switching to an Alternative Class ART Regimen (Based on Initial Randomized Regimen) [ Time Frame: Up to 6 yrs. (average 4.85 yrs.) ] [ Designated as safety issue: No ]
    25th Percentiles in weeks from randomization to starting an alternative class ART regimen (based on initial randomized regimen)

  • Time to HIV-1 RNA of 400 Copies/ml or Greater During First-line Therapy or Permanent Discontinuation of First-line Therapy [ Time Frame: Up to 6 yrs. (average 4.85 yrs.) ] [ Designated as safety issue: No ]
    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.

  • Time to HIV-1 RNA of 30,000 Copies/ml or Greater During Second-line Therapy or Permanent Discontinuation of Second-line Therapy [ Time Frame: Up to 6 yrs. (average 4.85 yrs.) ] [ Designated as safety issue: No ]
    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

  • Number of Children With an HIV-1 RNA Level Less Than 400 Copies/ml Regardless of Therapy at Week 204 [ Time Frame: Week 204 ] [ Designated as safety issue: No ]
  • Change in CD4% From Randomization to 4 Years [ Time Frame: Randomization to 4 years ] [ Designated as safety issue: No ]
  • Number of Children With HIV-1 RNA Less Than 400 Copies/ml and on Original Randomized Therapy at 24 Weeks [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]

Enrollment: 266
Study Start Date: August 2002
Study Completion Date: March 2010
Primary Completion Date: August 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   up to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00039741

  Show 31 Study Locations
Sponsors and Collaborators
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
  More Information

Additional Information:
Publications:
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00039741     History of Changes
Other Study ID Numbers: P390, PENPACT-1B, 10106, PENTA 9/PACTG 390
Study First Received: June 7, 2002
Results First Received: December 19, 2011
Last Updated: December 31, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Drug Therapy, Combination
HIV Protease Inhibitors
Reverse Transcriptase Inhibitors
Viral Load
Treatment Naive

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on September 22, 2014