Clinical trial NCT00039741: Anti-HIV Drug Regimens and Treatment-Switching Guidelines in HIV Infected Children
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: HIV Infections
Keywords: Drug Therapy, Combination
HIV Protease Inhibitors
Reverse Transcriptase Inhibitors
Viral Load
Treatment Naive
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: PENTA Foundation
First posted: 2002-06-11
Enrollment: 266
Sex: ALL
Minimum age (years): 30
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: 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.

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 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

Primary outcomes:
measure: Change in Viral Load Measured in log10 HIV-1 RNA Copies/ml
timeFrame: Baseline visit and 4 years after Study Entry
Secondary outcomes:
measure: Rate of Grade 3 or Higher Signs, Symptoms, or Laboratory Abnormalities Experienced
timeFrame: Up to 6 yrs. (average 4.85 yrs.)
measure: Participants With Significant HIV-related Clinical Events, Defined as CDC Category C (AIDS Defining) Diagnoses (Except for Recurrent Bacterial Infections)or Death
timeFrame: Up to 6 yrs. (average 4.85 yrs.)
measure: Time to Switching to an Alternative Class ART Regimen (Based on Initial Randomized Regimen)
timeFrame: Up to 6 yrs. (average 4.85 yrs.)
measure: Time to HIV-1 RNA of 400 Copies/ml or Greater During First-line Therapy or Permanent Discontinuation of First-line Therapy
timeFrame: Up to 6 yrs. (average 4.85 yrs.)
measure: Time to HIV-1 RNA of 30,000 Copies/ml or Greater During Second-line Therapy or Permanent Discontinuation of Second-line Therapy
timeFrame: Up to 6 yrs. (average 4.85 yrs.)
measure: Number of Children With an HIV-1 RNA Level Less Than 400 Copies/ml Regardless of Therapy at Week 204
timeFrame: Week 204
measure: Change in CD4% From Randomization to 4 Years
timeFrame: Randomization to 4 years
measure: Number of Children With HIV-1 RNA Less Than 400 Copies/ml and on Original Randomized Therapy at 24 Weeks
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Alhambra
country: United States
facility: Usc La Nichd Crs
state: California
city: Long Beach
country: United States
facility: Miller Children's Hosp. Long Beach CA NICHD CRS
state: California
city: Los Angeles
country: United States
facility: Children's Hospital of Los Angeles NICHD CRS
state: California
city: Los Angeles
country: United States
facility: UCLA-Los Angeles/Brazil AIDS Consortium (LABAC) CRS
state: California
city: Oakland
country: United States
facility: Children's Hosp. & Research Ctr. Oakland, Ped. Clinical Research Ctr. & Research Lab.
state: California
city: Hartford
country: United States
facility: Connecticut Children's Med. Ctr.
state: Connecticut
city: Washington
country: United States
facility: Howard Univ. Washington DC NICHD CRS
state: District of Columbia
city: Fort Lauderdale
country: United States
facility: South Florida CDTC Ft Lauderdale NICHD CRS
state: Florida
city: Gainesville
country: United States
facility: Univ. of Florida College of Medicine-Dept of Peds, Div. of Immunology, Infectious Diseases & Allergy
state: Florida
city: Miami
country: United States
facility: Univ. of Miami Ped. Perinatal HIV/AIDS CRS
state: Florida
city: Tampa
country: United States
facility: USF - Tampa NICHD CRS
state: Florida
city: Chicago
country: United States
facility: Chicago Children's CRS
state: Illinois
city: Chicago
country: United States
facility: Univ. of Chicago - Dept. of Peds., Div. of Infectious Disease
state: Illinois
city: New Orleans
country: United States
facility: Tulane Univ. New Orleans NICHD CRS
state: Louisiana
city: Worcester
country: United States
facility: WNE Maternal Pediatric Adolescent AIDS CRS
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University Therapeutics (WT) CRS
state: Missouri
city: New Brunswick
country: United States
facility: UMDNJ - Robert Wood Johnson Med. School, Div. of Allergy, Immunology & Infectious Diseases
state: New Jersey
city: Newark
country: United States
facility: Rutgers - New Jersey Medical School CRS
state: New Jersey
city: Bronx
country: United States
facility: Jacobi Med. Ctr. Bronx NICHD CRS
state: New York
city: New York
country: United States
facility: Nyu Ny Nichd Crs
state: New York
city: New York
country: United States
facility: Columbia IMPAACT CRS
state: New York
city: New York
country: United States
facility: Harlem Hosp. Ctr. NY NICHD CRS
state: New York
city: Stony Brook
country: United States
facility: SUNY Stony Brook NICHD CRS
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Med. Univ., Dept. of Peds.
state: New York
city: Chapel Hill
country: United States
facility: UNC at Chapel Hill School of Medicine - Dept. of Peds., Div. of Immunology & Infectious Diseases
state: North Carolina
city: Portland
country: United States
facility: Oregon Health & Science Univ. - Dept. of Peds., Div. of Infectious Disease
state: Oregon
city: Memphis
country: United States
facility: St. Jude/UTHSC CRS
state: Tennessee
city: Houston
country: United States
facility: Texas Children's Hospital CRS
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Hospital CRS
state: Washington
city: San Juan
country: Puerto Rico
facility: Univ. of Puerto Rico Ped. HIV/AIDS Research Program CRS
city: San Juan
country: Puerto Rico
facility: San Juan City Hosp. PR NICHD CRS
Study officials:
affiliation: Duke University
name: Ross E. McKinney, Jr., MD
role: STUDY_CHAIR
affiliation: Division of Infectious Diseases, Children's Hospital and Medical Center, Seattle, WA
name: Ann J. Melvin, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.