When to Start Anti-HIV Drugs in Children Infected With HIV (The PREDICT Study)

An Open Label, Randomized Study to Compare Antiretroviral Therapy (ART) Initiation When CD4 is Between 15% to 24% to ART Initiation When CD4 Falls Below 15% in Children With HIV Infection and Moderate Immune Suppression

The purpose of this study is to determine when HIV infected children should begin taking anti-HIV medications in order to improve both patient quality of life and survival.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Abacavir; Drug: Efavirenz; Drug: Lamivudine; Drug: Lopinavir/Ritonavir; Drug: Nelfinavir; Drug: Nevirapine; Drug: Zidovudine

Detailed Description

The use of highly active antiretroviral therapy (HAART) has resulted in a significant reduction in AIDS-related deaths and complications among adults and adolescents. However, the medical management of HIV infected children remains challenging. Access to HIV treatment is limited and early treatment initiation can cause serious complications. Since there is currently no cure for HIV, a balance between treating the disease and maintaining quality of life must be weighed carefully. An evaluation to determine the appropriate time to initiate HAART is necessary to improve both quality of life and survival for HIV infected children.

This study will last 144 weeks. All participants will have a CD4 percentage (CD4%) between 15% and 24% and will be randomly assigned to either receive immediate or delayed HAART. The HAART regimen will consist of two nucleoside reverse transcriptase inhibitors, zidovudine and lamivudine. In addition, participants will also receive either one non-nucleoside reverse transcriptase inhibitor, nevirapine or efavirenz, or one protease inhibitor, ritonavir-boosted lopinavir or nelfinavir. Abacavir will replace zidovudine or lamivudine if participants experience toxicity to the regimen. Participants in the immediate treatment arm will receive HAART on Day 1 of the study regardless of their CD4%. Participants in the delayed treatment arm will receive HAART if their CD4% falls below 15 or if they develop a CDC Category C illness.

Study visits will occur every 4 weeks for the first 12 weeks and then every 12 weeks until the end of the study. Blood collection, physical exams, and medical and medication history reviews will occur at all visits. Adherence, quality of life, and lipodystrophy assessments will occur every 12 weeks for participants on HAART. Participants will be encouraged to enroll in a related substudy to examine the neurodevelopment of HIV infected children.

• Study Type: Interventional
• Enrollment (Actual): 300
• Phase: Phase 3

Contacts and Locations

Study Locations

• Cambodia
  • Phnom Penh, Cambodia
    • National Pediatric Hosp., Cambodia CIPRA CRS
  • Phnom Penh, Cambodia
    • Social Health Clinic, Cambodia CIPRA CRS
• Thailand
  • Chantaburi, Thailand, 22000
    • Prapokklao Hosp. CIPRA CRS
  • Chiang Mai, Thailand, 50180
    • Nakornping Hosp. CIPRA CRS
  • Chonburi, Thailand, 20110
    • Queen Savang Vadhana Memorial Hosp. CIPRA CRS
  • Khon Kaen, Thailand, 40002
    • Srinagarind Hosp. CIPRA CRS
  • Nonthaburi, Thailand, 11000
    • Bamrasnaradura Institute CIPRA CRS
  • Bangkok
    • Pathumwan, Bangkok, Thailand, 10330
      • Hiv-Nat Cipra Crs
  • Chiang Rai
    • Muang, Chiang Rai, Thailand, 57000
      • Chiang Rai Regional Hosp. CIPRA CRS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 12 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• HIV-1 infected
• Antiretroviral naive, defined as never receiving anti-HIV medications, receiving them for less than 7 days, or only receiving them to prevent mother-to-child transmission (MTCT)
• CD4% between 15 and 24 within 30 days prior to study entry
• CDC pediatric clinical classification A or B
• Parent or guardian willing to provide informed consent and willing to follow all study procedures and requirements

Exclusion Criteria:

• Use of systemic chemotherapy, immunomodulators, HIV vaccines, immune globulin, interleukins, or interferons within 30 days prior to study entry
• Active AIDS-defining illnesses (CDC Category C) within 30 days prior to study entry
• Certain abnormal laboratory values
• Known kidney disease
• Known allergy or sensitivity to study drugs
• Require certain medications
• Pregnancy

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 1; Immediate treatment; individuals receive HAART on Day 1 of the study	Drug: Abacavir; 8 mg/kg (up to 300 mg/dose) take orally twice daily; Drug: Efavirenz; 200 to 600 mg taken orally once daily; Drug: Lamivudine; 4 mg/kg (up to 150 mg/dose) taken orally twice daily; Drug: Lopinavir/Ritonavir; 230 mg/57.5 mg/m^2 body surface area taken orally twice daily with food; Drug: Nelfinavir; 45-55 mg/kg taken orally twice daily with food; Drug: Nevirapine; 120 mg/m^2 once daily for first 14 days, tehn 200 mg/m^2 (up to 400 mg/day) twice daily; Drug: Zidovudine; 180-240 mg/m^2 every 12 hours (up to 300 mg/dose)
Active Comparator: 2; Delayed treatment; individuals receive HAART if their CD4 percentage falls below 15 percentage OR if they develop a CDC category C illness	Drug: Abacavir; 8 mg/kg (up to 300 mg/dose) take orally twice daily; Drug: Efavirenz; 200 to 600 mg taken orally once daily; Drug: Lamivudine; 4 mg/kg (up to 150 mg/dose) taken orally twice daily; Drug: Lopinavir/Ritonavir; 230 mg/57.5 mg/m^2 body surface area taken orally twice daily with food; Drug: Nelfinavir; 45-55 mg/kg taken orally twice daily with food; Drug: Nevirapine; 120 mg/m^2 once daily for first 14 days, tehn 200 mg/m^2 (up to 400 mg/day) twice daily; Drug: Zidovudine; 180-240 mg/m^2 every 12 hours (up to 300 mg/dose)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
AIDS-free survival	Week 144

Secondary Outcome Measures

Outcome Measure	Time Frame
Direct and indirect cost of treatment per patient	Week 144
Number and duration of hospitalizations	throughout study
Time to and number of Grades 3 or 4 HAART-related toxicity and intolerance	throughout study
Number of HAART regimen changes	throughout study
Number of Grades 1 or 2 infectious episodes	throughout study
Number of courses of antibiotics used	throughout study
Number of HIV-related clinical events	throughout study
Virologic failure, defined as HIV viral load of 1000 copies/ml	Week 24 after HAART initiation
Presence of a resistance mutation in participants with virologic failure	throughout study
Change of growth in Z scores	study entry to Week 144
Change in CD4% and time-weighted average change	study entry and Week 144
CD4 less than 10%	Week 144
Average scores of the child's quality of life over time	Week 144
Percentage adherence to HAART over time by pill count/weighing liquid medication bottles, self report, and questionnaire	throughout study
Presence of iron deficiency anemia	study entry and Weeks 24, 48, 72, 96, 120, and 144
HIV viral sequence	study entry and treatment failure
HIV viral replication capacity	throughout study
Cytotoxic T-cell (CTL) response	throughout study
Percentage of different T-cell subsets	study entry and Weeks 48, 96, and 144

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Comprehensive International Program of Research on AIDS
• Investigators: Study Chair: Kiat Ruxrungtham, MD, MPH, Department of Medicine at Chulalongkorn University, Bangkok, Thailand; Study Chair: Saphonn Vonthanak, MD, PhD, National Center for HIV/AIDS Dermatology and STDs, Phnom Penh, Cambodia

Publications and helpful links

General Publications

• Lindsey JC, Malee KM, Brouwers P, Hughes MD; PACTG 219C Study Team. Neurodevelopmental functioning in HIV-infected infants and young children before and after the introduction of protease inhibitor-based highly active antiretroviral therapy. Pediatrics. 2007 Mar;119(3):e681-93. doi: 10.1542/peds.2006-1145. Epub 2007 Feb 12.
• Nikolic-Djokic D, Essajee S, Rigaud M, Kaul A, Chandwani S, Hoover W, Lawrence R, Pollack H, Sitnitskaya Y, Hagmann S, Jean-Philippe P, Chen SH, Radding J, Krasinski K, Borkowsky W. Immunoreconstitution in children receiving highly active antiretroviral therapy depends on the CD4 cell percentage at baseline. J Infect Dis. 2002 Feb 1;185(3):290-8. doi: 10.1086/338567. Epub 2002 Jan 8.
• Puthanakit T, Aurpibul L, Oberdorfer P, Akarathum N, Kanjananit S, Wannarit P, Sirisanthana T, Sirisanthana V. Hospitalization and mortality among HIV-infected children after receiving highly active antiretroviral therapy. Clin Infect Dis. 2007 Feb 15;44(4):599-604. doi: 10.1086/510489. Epub 2007 Jan 9.
• Walker AS, Doerholt K, Sharland M, Gibb DM; Collaborative HIV Paediatric Study (CHIPS) Steering Committee. Response to highly active antiretroviral therapy varies with age: the UK and Ireland Collaborative HIV Paediatric Study. AIDS. 2004 Sep 24;18(14):1915-24. doi: 10.1097/00002030-200409240-00007.
• Paul RH, Cho KS, Belden AC, Mellins CA, Malee KM, Robbins RN, Salminen LE, Kerr SJ, Adhikari B, Garcia-Egan PM, Sophonphan J, Aurpibul L, Thongpibul K, Kosalaraksa P, Kanjanavanit S, Ngampiyaskul C, Wongsawat J, Vonthanak S, Suwanlerk T, Valcour VG, Preston-Campbell RN, Bolzenious JD, Robb ML, Ananworanich J, Puthanakit T; PREDICT Study Group. Machine-learning classification of neurocognitive performance in children with perinatal HIV initiating de novo antiretroviral therapy. AIDS. 2020 Apr 1;34(5):737-748. doi: 10.1097/QAD.0000000000002471.
• Paul R, Apornpong T, Prasitsuebsai W, Puthanakit T, Saphonn V, Aurpibul L, Kosalaraksa P, Kanjanavanit S, Luesomboon W, Ngampiyaskul C, Suwanlerk T, Chettra K, Shearer WT, Valcour V, Ananworanich J, Kerr S. Cognition, Emotional Health, and Immunological Markers in Children With Long-Term Nonprogressive HIV. J Acquir Immune Defic Syndr. 2018 Apr 1;77(4):417-426. doi: 10.1097/QAI.0000000000001619.
• Paul R, Prasitsuebsai W, Jahanshad N, Puthanakit T, Thompson P, Aurpibul L, Hansudewechakul R, Kosalaraksa P, Kanjanavanit S, Ngampiyaskul C, Luesomboon W, Lerdlum S, Pothisri M, Visrutaratna P, Valcour V, Nir TM, Saremi A, Kerr S, Ananworanich J; Pediatric Randomized Early versus Deferred Initiation in Cambodia and Thailand (PREDICT) Study Group. Structural Neuroimaging and Neuropsychologic Signatures in Children With Vertically Acquired HIV. Pediatr Infect Dis J. 2018 Jul;37(7):662-668. doi: 10.1097/INF.0000000000001852.
• Bunupuradah T, Hansudewechakul R, Kosalaraksa P, Ngampiyaskul C, Kanjanavanit S, Wongsawat J, Luesomboon W, Sophonphan J, Puthanakit T, Ruxrungtham K, Shearer WT, Ananworanich J; PREDICT study group. HLA-DRB1454 and predictors of new-onset asthma in HIV-infected Thai children. Clin Immunol. 2015 Mar;157(1):26-9. doi: 10.1016/j.clim.2014.12.006. Epub 2014 Dec 26. No abstract available.
• Intasan J, Bunupuradah T, Vonthanak S, Kosalaraksa P, Hansudewechakul R, Kanjanavanit S, Ngampiyaskul C, Wongsawat J, Luesomboon W, Apornpong T, Kerr S, Ananworanich J, Puthanakit T; PREDICT Study Group. Comparison of adherence monitoring tools and correlation to virologic failure in a pediatric HIV clinical trial. AIDS Patient Care STDS. 2014 Jun;28(6):296-302. doi: 10.1089/apc.2013.0276.
• Puthanakit T, Saphonn V, Ananworanich J, Kosalaraksa P, Hansudewechakul R, Vibol U, Kerr SJ, Kanjanavanit S, Ngampiyaskul C, Wongsawat J, Luesomboon W, Ngo-Giang-Huong N, Chettra K, Cheunyam T, Suwarnlerk T, Ubolyam S, Shearer WT, Paul R, Mofenson LM, Fox L, Law MG, Cooper DA, Phanuphak P, Vun MC, Ruxrungtham K; PREDICT Study Group. Early versus deferred antiretroviral therapy for children older than 1 year infected with HIV (PREDICT): a multicentre, randomised, open-label trial. Lancet Infect Dis. 2012 Dec;12(12):933-41. doi: 10.1016/S1473-3099(12)70242-6. Epub 2012 Oct 9.
• Kosalaraksa P, Bunupuradah T, Vonthanak S, Wiangnon S, Hansudewechakul R, Vibol U, Kanjanavanit S, Ngampiyaskul C, Wongsawat J, Luesomboon W, Lumbiganon P, Sopa B, Apornpong T, Chuenyam T, Cooper DA, Ruxrungtham K, Ananworanich J, Puthanakit T. Prevalence of anemia and underlying iron status in naive antiretroviral therapy HIV-infected children with moderate immune suppression. AIDS Res Hum Retroviruses. 2012 Dec;28(12):1679-86. doi: 10.1089/AID.2011.0373. Epub 2012 Jul 25.
• Bunupuradah T, Ubolyam S, Hansudewechakul R, Kosalaraksa P, Ngampiyaskul C, Kanjanavanit S, Wongsawat J, Luesomboon W, Pinyakorn S, Kerr S, Ananworanich J, Chomtho S, van der Lugt J, Luplertlop N, Ruxrungtham K, Puthanakit T; PREDICT study group. Correlation of selenium and zinc levels to antiretroviral treatment outcomes in Thai HIV-infected children without severe HIV symptoms. Eur J Clin Nutr. 2012 Aug;66(8):900-5. doi: 10.1038/ejcn.2012.57. Epub 2012 Jun 20.
• Kanjanavanit S, Puthanakit T, Vibol U, Kosalaraksa P, Hansudewechakul R, Ngampiyasakul C, Wongsawat J, Luesomboon W, Wongsabut J, Mahanontharit A, Suwanlerk T, Saphonn V, Ananworanich J, Ruxrungtham K; PREDICT study group. High prevalence of lipid abnormalities among antiretroviral-naive HIV-infected Asian children with mild-to-moderate immunosuppression. Antivir Ther. 2011;16(8):1351-5. doi: 10.3851/IMP1897.
• Bunupuradah T, Puthanakit T, Kosalaraksa P, Kerr SJ, Kariminia A, Hansudewechakul R, Kanjanavanit S, Ngampiyaskul C, Wongsawat J, Luesomboon W, Chuenyam T, Vonthanak S, Vun MC, Vibol U, Vannary B, Ruxrungtham K, Ananworanich J; PREDICT Study Group. Poor quality of life among untreated Thai and Cambodian children without severe HIV symptoms. AIDS Care. 2012;24(1):30-8. doi: 10.1080/09540121.2011.592815. Epub 2011 Jul 21.
• Ananworanich J, Apornpong T, Kosalaraksa P, Jaimulwong T, Hansudewechakul R, Pancharoen C, Bunupuradah T, Chandara M, Puthanakit T, Ngampiyasakul C, Wongsawat J, Kanjanavanit S, Luesomboon W, Klangsinsirikul P, Ngo-Giang-Huong N, Kerr SJ, Ubolyam S, Mengthaisong T, Gelman RS, Pattanapanyasat K, Saphonn V, Ruxrungtham K, Shearer WT; PREDICT Study Group. Characteristics of lymphocyte subsets in HIV-infected, long-term nonprogressor, and healthy Asian children through 12 years of age. J Allergy Clin Immunol. 2010 Dec;126(6):1294-301.e10. doi: 10.1016/j.jaci.2010.09.038.
• Wongsawat J, Puthanakit T, Kanjanavanit S, Hansudewechakul R, Ngampiyaskul C, Kerr SJ, Ubolyam S, Suwanlerk T, Kosalaraksa P, Luesomboon W, Ngo-Giang-Huong N, Chandara M, Saphonn V, Ruxrungtham K, Ananworanich J; PREDICT Study Group. CD4 cell count criteria to determine when to initiate antiretroviral therapy in human immunodeficiency virus-infected children. Pediatr Infect Dis J. 2010 Oct;29(10):966-8. doi: 10.1097/INF.0b013e3181e0554c.

Helpful Links

• Click here for more information about the HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT)

Study record dates

Study Major Dates

• Study Start: April 1, 2006
• Primary Completion (Actual): September 1, 2011
• Study Completion (Actual): September 1, 2011

Study Registration Dates

• First Submitted: October 4, 2005
• First Submitted That Met QC Criteria: October 4, 2005
• First Posted (Estimate): October 6, 2005

Study Record Updates

• Last Update Posted (Estimate): December 4, 2013
• Last Update Submitted That Met QC Criteria: December 2, 2013
• Last Verified: December 1, 2013

More Information

Terms related to this study

• Keywords: Child; Nevirapine; Lamivudine; Efavirenz; Infant; Zidovudine; Nelfinavir; Treatment Naive; Lopinavir/Ritonavir; Kaletra; Abacavir; 3TC; Treatment Initiation; Preschool Child; AZT; Retrovir; Epivir; NVP; Viramune; EFV; Sustiva; LPV/r; NFV; Viracept; ABC; Ziagen
• 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 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; HIV Protease Inhibitors; Viral Protease Inhibitors; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Nevirapine; Ritonavir; Lopinavir; Lamivudine; Zidovudine; Nelfinavir; Efavirenz; Abacavir
• Other Study ID Numbers: CIPRA TH001; PREDICT (CardioDx); 10409 (DAIDS ES)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No