Clinical trial NCT00428116: Optimizing Pediatric HIV-1 Treatment, Nairobi, Kenya
Official title: Optimizing Pediatric HIV-1 Treatment, Nairobi, Kenya (0-4.5 Month Randomized Controlled Trial)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: HIV Infections
Keywords: HIV-1
Pediatric
HAART
Treatment Naive
Lead sponsor: University of Washington
Sponsor class: OTHER
Collaborators: name: Fred Hutchinson Cancer Center
name: University of Nairobi
name: National Institutes of Health (NIH)
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2007-01-29
Enrollment: 140
Sex: ALL
Maximum age (years): 54
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Given the high mortality associated with infant HIV-1 and the fact that surrogate markers are poorly predictive of mortality risk,empiric highly active antiretroviral therapy (HAART) initiation is started in infants younger than 12 months. A problem with this approach is that it obligates infants to life-long therapy, which may be associated with cumulative drug toxicity, poor adherence, and treatment failure. Early HAART for prevention of mortality during the first 2 years of life has potential to salvage immune function and alter viral set-point, allowing withdrawal of therapy, perhaps for several years, until subsequent CD4% decline requires it. This untested approach is attractive because it combines the survival benefits of early pediatric HAART therapy with the benefits of antiretroviral deferral.

One hundred and fifty infants who initiated HAART at \<13 months of age will be treated with HAART regimen for 24 months after which those who have immune reconstitution and adequate growth (\~100) will be randomized to continued versus deferred therapy. Clinical outcomes, growth, and toxicity will be compared in these children to determine if interruption is a safe and beneficial strategy. Follow-up in this studies will be closely monitored by an external Data Safety and Monitoring Board (DSMB).

Detailed description: Hypothesis: Deferring antiretroviral therapy in infants who have immune reconstitution and adequate growth following early therapy of primary infection (initiated HAART during primary infection at less than 13 months of age) will not compromise clinical status or growth and may spare antiretroviral toxicity.

Specific Aim/Primary Objective: To compare growth and morbidity in infants (who initiated HAART during primary infection at less than or equal to 13 months of age with subsequently normalized CD4% and growth following 24 months of HAART) randomized to deferred versus continuous therapy and followed for an additional 18 months.

Secondary Aim/Secondary Objective: To determine predictors of non-progression of HIV among the infants, including: age, adherence, HIV-1 specific immune responses, baseline HIV-1 RNA, CD4 percent and immune activation.

Design: Randomized clinical trial involving HIV-1 treatment of infants (\<13 months old) for 24 months, followed by randomization and 18 months follow-up of children randomized to continued versus deferred treatment. This trial is unblinded.

Population: HIV-1 infected infants (\<13 months) newly initiating HAART and HIV-1 infected infants already receiving HAART who initiated HAART at age \<13 months will be enrolled. After 24 months of treatment follow-up, children with CD4% \> 25% and normalized growth will be retained in the study and randomized.

Sample size: 150 infants will be enrolled of which 100 are expected to be eligible for randomization (50 in each arm).

Treatment: All infants will be treated with HAART according to WHO and Kenyan national guidelines. The specific regimens that will be used as a part of this study are:

First line regimen

* AZT/3TC/NVP (zidovudine/lamivudine/nevirapine)
* d4T/3TC/NVP (stavudine/lamivudine/nevirapine)
* AZT/3TC/ABC (zidovudine/lamivudine/abacavir)
* d4T/3TC/ABC (stavudine/lamivudine/abacavir)
* ABC/3TC/NVP (abacavir/lamivudine/nevirapine)

Second line regimen - ddI/ABC/LPV/r (didanosine/abacavir/lopinavir-ritonavir (Kaletra))

For infants with prior exposure to nevirapine as part of PMTCT:

First line regimen

- AZT/3TC/LPV/r (zidovudine/lamivudine/lopinavir-ritonavir (kaletra))

Eligibility criteria: Inclusion Criteria:

A. Infants newly initiating HAART

* Less than 13 months of age
* HIV-1 DNA detection with confirmation (positive on two HIV-1 DNA filter paper tests)
* Caregiver of infant plans to reside in Nairobi for at least 3 years (reported by caregiver)
* Caregiver is able to provide sufficient location information

B. Infants already receiving HAART

* Initiated HAART at \<13 months of age
* Records confirming HIV positive status
* Documentation of CD4% and weight prior to HAART initiation
* Must be on 1st line drug regimen

Eligibility for randomization:

* Completed 24 months of treatment with HAART
* Normalized growth: weight for height z-score (WHZ) \> -0.5; Child's weight must be above the 5th weight-for-age percentile and the weight curve must not be flat or falling (i.e. cross 2 major percentile lines or more over the past 3 months)
* CD4% \> 25
* Children who recently initiated or who require anti-tuberculosis treatment at the time of randomization will be ineligible for randomization.

Primary outcomes:
measure: Growth at 18 Months Post-randomization
timeFrame: 18 months of post-randomization follow-up
Secondary outcomes:
measure: Morbidity
timeFrame: 18 months post-randomization
Other outcomes:
Locations:
Study officials:
affiliation: Department of Paediatrics and Child Health, Kenyatta National Hospital, University of Nairobi
name: Dalton Wamalwa, MMed, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Washington
name: Grace C John-Stewart, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wamalwa D, Benki-Nugent S, Langat A, Tapia K, Ngugi E, Moraa H, Maleche-Obimbo E, Otieno V, Inwani I, Richardson BA, Chohan B, Overbaugh J, John-Stewart GC. Treatment interruption after 2-year antiretroviral treatment initiated during acute/early HIV in infancy. AIDS. 2016 Sep 24;30(15):2303-13. doi: 10.1097/QAD.0000000000001158.
citation: 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.
citation: Sridharan G, Wamalwa D, John-Stewart G, Tapia K, Langat A, Moraa Okinyi H, Adhiambo J, Chebet D, Maleche-Obimbo E, Karr CJ, Benki-Nugent S. High Viremia and Wasting Before Antiretroviral Therapy Are Associated With Pneumonia in Early-Treated HIV-Infected Kenyan Infants. J Pediatric Infect Dis Soc. 2017 Sep 1;6(3):245-252. doi: 10.1093/jpids/piw038.
citation: Asbjornsdottir KH, Hughes JP, Wamalwa D, Langat A, Slyker JA, Okinyi HM, Overbaugh J, Benki-Nugent S, Tapia K, Maleche-Obimbo E, Rowhani-Rahbar A, John-Stewart G. Differences in virologic and immunologic response to antiretroviral therapy among HIV-1-infected infants and children. AIDS. 2016 Nov 28;30(18):2835-2843. doi: 10.1097/QAD.0000000000001244.
citation: Wagner A, Slyker J, Langat A, Inwani I, Adhiambo J, Benki-Nugent S, Tapia K, Njuguna I, Wamalwa D, John-Stewart G. High mortality in HIV-infected children diagnosed in hospital underscores need for faster diagnostic turnaround time in prevention of mother-to-child transmission of HIV (PMTCT) programs. BMC Pediatr. 2015 Feb 15;15:10. doi: 10.1186/s12887-015-0325-8.
citation: Benki-Nugent S, Eshelman C, Wamalwa D, Langat A, Tapia K, Okinyi HM, John-Stewart G. Correlates of age at attainment of developmental milestones in HIV-infected infants receiving early antiretroviral therapy. Pediatr Infect Dis J. 2015 Jan;34(1):55-61. doi: 10.1097/INF.0000000000000526.
citation: Slyker JA, Casper C, Tapia K, Richardson B, Bunts L, Huang ML, Wamalwa D, Benki-Nugent S, John-Stewart G. Accelerated suppression of primary Epstein-Barr virus infection in HIV-infected infants initiating lopinavir/ritonavir-based versus nevirapine-based combination antiretroviral therapy. Clin Infect Dis. 2014 May;58(9):1333-7. doi: 10.1093/cid/ciu088. Epub 2014 Feb 18.
citation: Langat A, Benki-Nugent S, Wamalwa D, Tapia K, Ngugi E, Diener L, Richardson BA, Melvin A, John-Stewart GC. Lipid changes in Kenyan HIV-1-infected infants initiating highly active antiretroviral therapy by 1 year of age. Pediatr Infect Dis J. 2013 Jul;32(7):e298-304. doi: 10.1097/INF.0b013e31828afb2a.
citation: Benki-Nugent SF, Martopullo I, Laboso T, Tamasha N, Wamalwa DC, Tapia K, Langat A, Maleche-Obimbo E, Marra CM, Bangirana P, Boivin MJ, John-Stewart GC. High Plasma Soluble CD163 During Infancy Is a Marker for Neurocognitive Outcomes in Early-Treated HIV-Infected Children. J Acquir Immune Defic Syndr. 2019 May 1;81(1):102-109. doi: 10.1097/QAI.0000000000001979.
citation: Benki-Nugent S, Wamalwa D, Langat A, Tapia K, Adhiambo J, Chebet D, Okinyi HM, John-Stewart G. Comparison of developmental milestone attainment in early treated HIV-infected infants versus HIV-unexposed infants: a prospective cohort study. BMC Pediatr. 2017 Jan 17;17(1):24. doi: 10.1186/s12887-017-0776-1.