Pediatric Urgent Start of Highly Active Antiretroviral Treatment (HAART) (PUSH)

• ClinicalTrials.gov Identifier: NCT02063880
• Recruitment Status: Completed
• First Posted: February 17, 2014
• Results First Posted: July 25, 2017
• Last Update Posted: May 14, 2018
• Sponsor: University of Washington
• Collaborators: University of Nairobi; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Information provided by (Responsible Party): Grace John-Stewart, University of Washington

Tracking Information

• First Submitted Date: August 21, 2012
• First Posted Date: February 17, 2014
• Results First Submitted Date: May 1, 2017
• Results First Posted Date: July 25, 2017
• Last Update Posted Date: May 14, 2018
• Study Start Date: March 2013
• Actual Primary Completion Date: November 2015 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: May 2, 2017): All-cause Mortality [ Time Frame: 6 months post-HAART initiation ]
• Original Primary Outcome Measures (submitted: February 13, 2014): All-cause mortality [ Time Frame: 6 months post-HAART initiation ]

Current Secondary Outcome Measures (submitted: July 28, 2017)

• Number of Participants With Evidence of Immune Reconstitution and Inflammatory Syndrome (IRIS) [ Time Frame: 6 months post-HAART initiation ]
  Confirmed, possible or likely IRIS based on external independent review
• Number of Participants With Potential Drug Toxicity [ Time Frame: 6 months post-HAART initiation ]
  Participants with adverse events that are deemed to be potentially related to medications.

Original Secondary Outcome Measures (submitted: February 13, 2014)

• IRIS [ Time Frame: 6 months post-HAART initiation ]
• Drug toxicity [ Time Frame: 6 months post-HAART initiation ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Pediatric Urgent Start of Highly Active Antiretroviral Treatment (HAART)
• Official Title: Urgent Versus Post-Stabilization ART in HIV-1 Infected Children With Severe Co-Infections

Brief Summary

Design: Randomized clinical trial involving hospitalized HIV-1 infected children. Children will be randomized to randomized to urgent (<48 hours) versus early antiretroviral therapy (7-14 days). This trial will be unblinded.

Population: Hospitalized HIV-1 infected children who are antiretroviral therapy (ART) naïve ≤ 12 years of age.

Sample size: 360 children will be randomized (180 per arm).

Treatment: All infants will be treated with ART according to World Health Organization (WHO) and Kenyan national guidelines.

Study duration: Enrollment into the study will occur over the course of 36-48 months and each infant will be routinely followed for a maximum of 6 months.

Study site: Kenyan hospitals.

Primary hypothesis:

HIV-1 infected children hospitalized with severe co-infection either may be unsalvageable due to too far advanced immunosuppression/co-infection or may benefit from urgent ART.

Secondary hypotheses:

Urgent ART during an acute infection could potentially result in increased risk of immune reconstitution inflammatory syndrome (IRIS) or drug toxicities/interactions.

Specific aims:

1. To compare the 6 month all-cause mortality rate, incidence of immune reconstitution inflammatory syndrome (IRIS), and incidence of drug toxicity in HIV-1 infected children (≤ 12 years old) presenting to hospital with a serious infection randomized to urgent (<48 hours) versus early ART (7-14 days).
2. To determine co-factors for mortality, IRIS, and drug toxicity. Potential cofactors will include: baseline weight-for-age, height-for-age, weight-for-height (Z-scores), CD4, HIV-1 RNA, type of co-infection, age, rate of viral load and CD4 change following ART, immune activation markers, pathogen and HIV-1 specific immune responses.

Secondary aim: To determine etiologies of IRIS and to compare immune reconstitution to HIV, TB, EBV and CMV following ART overall and in each trial arm.

• Detailed Description: Children will be followed and compared for 6-month mortality.
• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Human Immunodeficiency Virus
• Immune Reconstitution Inflammatory Syndrome

Intervention

• Other: Urgent ART
  Children will be started on HAART <48 hours after enrollment.
  Other Name: HAART regimens recommended by WHO and Kenya MOH.
• Other: Early ART
  Children will be started on ART after stabilization 7-14 days after enrollment.

Study Arms

• Experimental: Urgent ART

  Initiation of highly active antiretroviral therapy (HAART) within 48 hours of enrollment.

  Antiretroviral therapy will include regimens recommended by the Kenyan Ministry of Health.

  Intervention: Other: Urgent ART
• Active Comparator: Early ART
  Initiation of HAART 7-14 days after enrollment.
  Intervention: Other: Early ART

Publications *

• Njuguna IN, Cranmer LM, Wagner AD, LaCourse SM, Mugo C, Benki-Nugent S, Richardson BA, Stern J, Maleche-Obimbo E, Wamalwa DC, John-Stewart G. Brief Report: Cofactors of Mortality Among Hospitalized HIV-Infected Children Initiating Antiretroviral Therapy in Kenya. J Acquir Immune Defic Syndr. 2019 Jun 1;81(2):138-144. doi: 10.1097/QAI.0000000000002012.
• LaCourse SM, Cranmer LM, Njuguna IN, Gatimu J, Stern J, Maleche-Obimbo E, Walson JL, Wamalwa D, John-Stewart GC, Pavlinac PB. Urine Tuberculosis Lipoarabinomannan Predicts Mortality in Hospitalized Human Immunodeficiency Virus-Infected Children. Clin Infect Dis. 2018 May 17;66(11):1798-1801. doi: 10.1093/cid/ciy011.
• Njuguna IN, Cranmer LM, Otieno VO, Mugo C, Okinyi HM, Benki-Nugent S, Richardson B, Stern J, Maleche-Obimbo E, Wamalwa DC, John-Stewart GC. Urgent versus post-stabilisation antiretroviral treatment in hospitalised HIV-infected children in Kenya (PUSH): a randomised controlled trial. Lancet HIV. 2018 Jan;5(1):e12-e22. doi: 10.1016/S2352-3018(17)30167-4. Epub 2017 Nov 14.
• Wagner AD, Njuguna IN, Andere RA, Cranmer LM, Okinyi HM, Benki-Nugent S, Chohan BH, Maleche-Obimbo E, Wamalwa DC, John-Stewart GC. Infant/child rapid serology tests fail to reliably assess HIV exposure among sick hospitalized infants. AIDS. 2017 Jul 17;31(11):F1-F7. doi: 10.1097/QAD.0000000000001562.
• Njuguna IN, Wagner AD, Cranmer LM, Otieno VO, Onyango JA, Chebet DJ, Okinyi HM, Benki-Nugent S, Maleche-Obimbo E, Slyker JA, John-Stewart GC, Wamalwa DC. Hospitalized Children Reveal Health Systems Gaps in the Mother-Child HIV Care Cascade in Kenya. AIDS Patient Care STDS. 2016 Mar;30(3):119-24. doi: 10.1089/apc.2015.0239.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 2, 2017): 183
• Original Estimated Enrollment (submitted: February 13, 2014): 360
• Actual Study Completion Date: November 2015
• Actual Primary Completion Date: November 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Aged ≤ 12 years old (reported)
• HIV-1 positive (for example, two rapid HIV-1 antibody tests for children >18 months and not breastfeeding, or one HIV-1 DNA/RNA test for children ≤18 months or who are breastfeeding)
• Not currently receiving antiretroviral therapy (history of pMTCT does not affect eligibility)
• Eligible to receive ART, according to current WHO guidelines
• Caregiver plans to reside in study catchment area for at least 6 months (reported)
• Caregiver provides sufficient locator information

Exclusion Criteria:

• Suspected meningitis, any other central nervous system infection, or encephalitis

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 12 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Kenya

Administrative Information

• NCT Number: NCT02063880
• Other Study ID Numbers: STUDY00001052; 2R01HD023412-21 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: after primary and secondary outcomes are published

• Current Responsible Party: Grace John-Stewart, University of Washington
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Washington
• Original Study Sponsor: Same as current

Collaborators

• University of Nairobi
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Principal Investigator: Grace John Stewart, MD, PhD; University of Washington

• PRS Account: University of Washington
• Verification Date: April 2018