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

• Direct and indirect cost of treatment per patient [ Time Frame: Week 144 ] [ Designated as safety issue: No ]
• Number and duration of hospitalizations [ Time Frame: throughout study ] [ Designated as safety issue: No ]
• Time to and number of Grades 3 or 4 HAART-related toxicity and intolerance [ Time Frame: throughout study ] [ Designated as safety issue: Yes ]
• Number of HAART regimen changes [ Time Frame: throughout study ] [ Designated as safety issue: No ]
• Number of Grades 1 or 2 infectious episodes [ Time Frame: throughout study ] [ Designated as safety issue: No ]
• Number of courses of antibiotics used [ Time Frame: throughout study ] [ Designated as safety issue: No ]
• Number of HIV-related clinical events [ Time Frame: throughout study ] [ Designated as safety issue: No ]
• Virologic failure, defined as HIV viral load of 1000 copies/ml [ Time Frame: Week 24 after HAART initiation ] [ Designated as safety issue: No ]
• Presence of a resistance mutation in participants with virologic failure [ Time Frame: throughout study ] [ Designated as safety issue: No ]
• Change of growth in Z scores [ Time Frame: study entry to Week 144 ] [ Designated as safety issue: No ]
• Change in CD4% and time-weighted average change [ Time Frame: study entry and Week 144 ] [ Designated as safety issue: No ]
• CD4 less than 10% [ Time Frame: Week 144 ] [ Designated as safety issue: No ]
• Average scores of the child's quality of life over time [ Time Frame: Week 144 ] [ Designated as safety issue: No ]
• Percentage adherence to HAART over time by pill count/weighing liquid medication bottles, self report, and questionnaire [ Time Frame: throughout study ] [ Designated as safety issue: No ]
• Presence of iron deficiency anemia [ Time Frame: study entry and Weeks 24, 48, 72, 96, 120, and 144 ] [ Designated as safety issue: No ]
• HIV viral sequence [ Time Frame: study entry and treatment failure ] [ Designated as safety issue: No ]
• HIV viral replication capacity [ Time Frame: throughout study ] [ Designated as safety issue: No ]
• Cytotoxic T-cell (CTL) response [ Time Frame: throughout study ] [ Designated as safety issue: No ]
• Percentage of different T-cell subsets [ Time Frame: study entry and Weeks 48, 96, and 144 ] [ Designated as safety issue: No ]

• Direct and indirect cost of treatment per patient
• number and duration of hospitalizations
• time to and number of grades 3 or 4 HAART-related toxicity and intolerance
• number of HAART regimen changes
• number of grades 1 or 2 infectious episodes
• number of courses of antibiotics used
• number of HIV-related clinical events
• virologic failure, defined as HIV RNA viral load of 1000 copies/ml or more after 24 weeks of HAART
• presence of a resistance mutation in participants with virologic failure
• change of growth in Z scores from baseline to Week 144
• change in CD4% from baseline to Week 144 and time-weighted average change from baseline over 144 weeks
• CD4 less than 10% at Week 144
• average scores of quality of life over time
• adherence to HAART over time
• presence of iron deficiency anemia
• HIV viral sequence
• HIV viral replication capacity
• CTL response
• percentage of different T cell subsets

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.

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.

• 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: 1
  Immediate treatment; individuals receive HAART on Day 1 of the study
  Interventions:

  • Drug: Abacavir
  • Drug: Efavirenz
  • Drug: Lamivudine
  • Drug: Lopinavir/Ritonavir
  • Drug: Nelfinavir
  • Drug: Nevirapine
  • Drug: Zidovudine
• 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
  Interventions:

  • Drug: Abacavir
  • Drug: Efavirenz
  • Drug: Lamivudine
  • Drug: Lopinavir/Ritonavir
  • Drug: Nelfinavir
  • Drug: Nevirapine
  • Drug: Zidovudine

• 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. 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. 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. 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.
• 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.
• 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. 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.
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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