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

HIV Infections Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00039741
• Other study ID #: P390
• Secondary ID: PENPACT-1B10106P
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: August 2002
• Est. completion date: March 2010

Study information

• Verified date: January 2019
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 266
• Est. completion date: March 2010
• Est. primary completion date: August 2009
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 18 Years

Eligibility

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

Related Conditions & MeSH terms

• HIV Infections

Intervention

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
• NNRTIs (EFV, NVP)
Accepted NNRTIs: efavirenz (EFV), nevirapine (NVP) Prescribed per participant's doctor
• 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

Locations

Country	Name	City	State
Puerto Rico	San Juan City Hosp. PR NICHD CRS	San Juan
Puerto Rico	Univ. of Puerto Rico Ped. HIV/AIDS Research Program CRS	San Juan
United States	Usc La Nichd Crs	Alhambra	California
United States	Jacobi Med. Ctr. Bronx NICHD CRS	Bronx	New York
United States	UNC at Chapel Hill School of Medicine - Dept. of Peds., Div. of Immunology & Infectious Diseases	Chapel Hill	North Carolina
United States	Chicago Children's CRS	Chicago	Illinois
United States	Univ. of Chicago - Dept. of Peds., Div. of Infectious Disease	Chicago	Illinois
United States	South Florida CDTC Ft Lauderdale NICHD CRS	Fort Lauderdale	Florida
United States	Univ. of Florida College of Medicine-Dept of Peds, Div. of Immunology, Infectious Diseases & Allergy	Gainesville	Florida
United States	Connecticut Children's Med. Ctr.	Hartford	Connecticut
United States	Texas Children's Hospital CRS	Houston	Texas
United States	Miller Children's Hosp. Long Beach CA NICHD CRS	Long Beach	California
United States	Children's Hospital of Los Angeles NICHD CRS	Los Angeles	California
United States	UCLA-Los Angeles/Brazil AIDS Consortium (LABAC) CRS	Los Angeles	California
United States	St. Jude/UTHSC CRS	Memphis	Tennessee
United States	Univ. of Miami Ped. Perinatal HIV/AIDS CRS	Miami	Florida
United States	UMDNJ - Robert Wood Johnson Med. School, Div. of Allergy, Immunology & Infectious Diseases	New Brunswick	New Jersey
United States	Tulane Univ. New Orleans NICHD CRS	New Orleans	Louisiana
United States	Columbia IMPAACT CRS	New York	New York
United States	Harlem Hosp. Ctr. NY NICHD CRS	New York	New York
United States	Nyu Ny Nichd Crs	New York	New York
United States	Rutgers - New Jersey Medical School CRS	Newark	New Jersey
United States	Children's Hosp. & Research Ctr. Oakland, Ped. Clinical Research Ctr. & Research Lab.	Oakland	California
United States	Oregon Health & Science Univ. - Dept. of Peds., Div. of Infectious Disease	Portland	Oregon
United States	Washington University Therapeutics (WT) CRS	Saint Louis	Missouri
United States	Seattle Children's Hospital CRS	Seattle	Washington
United States	SUNY Stony Brook NICHD CRS	Stony Brook	New York
United States	SUNY Upstate Med. Univ., Dept. of Peds.	Syracuse	New York
United States	USF - Tampa NICHD CRS	Tampa	Florida
United States	Howard Univ. Washington DC NICHD CRS	Washington	District of Columbia
United States	WNE Maternal Pediatric Adolescent AIDS CRS	Worcester	Massachusetts

Sponsors (3)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), PENTA Foundation

Countries where clinical trial is conducted

United States,  Puerto Rico, 

References & Publications (5)

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. — View 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. Review. — View 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. Review. — View Citation

McKinney RE Jr, Cunningham CK. Newer treatments for HIV in children. Curr Opin Pediatr. 2004 Feb;16(1):76-9. Review. — View 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 antiretrov — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Viral Load Measured in log10 HIV-1 RNA Copies/ml		Baseline visit and 4 years after Study Entry
Secondary	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.)
Secondary	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.)
Secondary	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.)
Secondary	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.)
Secondary	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.)
Secondary	Number of Children With an HIV-1 RNA Level Less Than 400 Copies/ml Regardless of Therapy at Week 204		Week 204
Secondary	Change in CD4% From Randomization to 4 Years		Randomization to 4 years
Secondary	Number of Children With HIV-1 RNA Less Than 400 Copies/ml and on Original Randomized Therapy at 24 Weeks		24 weeks

External Links

•   Click here for more information about ACTG 219C (NCT00006304)
•   Click here for more information on changing regimens
•   Click here for more information on HIV regimen failure
•   Click here for more information on starting anti-HIV medications