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| ID | Type | Description | Link |
|---|---|---|---|
| R01HD023412 | U.S. NIH Grant/Contract | View source |
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DSMB recommended termination because TI was safe but not durable.
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| Name | Class |
|---|---|
| Fred Hutchinson Cancer Center | OTHER |
| University of Nairobi | OTHER |
| National Institutes of Health (NIH) | NIH |
| Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) |
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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).
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
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))
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Interrupted HAART | No Intervention | After 24 months of treatment with HAART, half the eligible infants will be randomized to interrupted treatment and followed for 18 months. | |
| Continued HAART | Active Comparator | After 24 months of treatment with HAART, half the eligible infants will be randomized to continued treatment with HAART for 18 months. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| HAART | Drug | Combination first line antiretrovirals as previously described. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Growth at 18 Months Post-randomization | Weight and height will be transformed to the weight-for-age Z-score (i.e., WAZ) and height-for-age Z-score (i.e., HAZ) using World Health Organization Child Growth Standards, taking into account the infant's age and gender. | 18 months of post-randomization follow-up |
| Measure | Description | Time Frame |
|---|---|---|
| Morbidity | severe adverse events including death, pneumonia, diarrhea, and other adverse events | 18 months post-randomization |
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Inclusion Criteria:
A. Infants newly initiating HAART
B. Infants already receiving HAART
Eligibility for randomization:
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| Name | Affiliation | Role |
|---|---|---|
| Dalton Wamalwa, MMed, MPH | Department of Paediatrics and Child Health, Kenyatta National Hospital, University of Nairobi | Principal Investigator |
| Grace C John-Stewart, MD, PhD | University of Washington | Principal Investigator |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27177316 | Result | 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. | |
| 27308805 | Result | 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. |
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Of 140 infants enrolled, 37 infants died, 11 were lost, and 7 were withdrawn. Of 75 infants who completed 2 years ART pre-randomization, 33 were ineligible for randomization and 42 were randomized.
Infants were identified from Nairobi City Council clinics, the Kenyatta National Hospital (KNH) wards, and the HIV treatment clinic. Recruitment occurred from 2007-2009.
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| ID | Title | Description |
|---|---|---|
| FG000 | Continued HAART | After 24 months of HAART, infants were continued on HAART. |
| FG001 | Interrupted HAART | After 24 months of treatment with HAART, half the eligible infants will be randomized to interrupted treatment and followed for 18 months. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
following 24 months of HAART
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| ID | Title | Description |
|---|---|---|
| BG000 | Continued HAART | After 24 months of treatment with HAART, half the eligible infants will be randomized to continued treatment with HAART for 18 months. |
| BG001 | Interrupted HAART |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Growth at 18 Months Post-randomization | Weight and height will be transformed to the weight-for-age Z-score (i.e., WAZ) and height-for-age Z-score (i.e., HAZ) using World Health Organization Child Growth Standards, taking into account the infant's age and gender. | Posted | Median | Inter-Quartile Range | z-score | 18 months of post-randomization follow-up |
|
18 months post-randomization
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Continued HAART | After 24 months of treatment with HAART, half the eligible infants will be randomized to continued treatment with HAART for 18 months. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Death | Infections and infestations | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Upper respiratory infection | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Grace John-Stewart | University of Washington | 206 543 4278 | gjohn@uw.edu |
| ID | Term |
|---|---|
| D015658 | HIV Infections |
| ID | Term |
|---|---|
| D000086982 | Blood-Borne Infections |
| D003141 | Communicable Diseases |
| D007239 | Infections |
| D015229 | Sexually Transmitted Diseases, Viral |
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| ID | Term |
|---|---|
| D023241 | Antiretroviral Therapy, Highly Active |
| ID | Term |
|---|---|
| D004359 | Drug Therapy, Combination |
| D004358 | Drug Therapy |
| D013812 | Therapeutics |
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| NIH |
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| 27481854 | Result | 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. |
| 27603293 | Result | 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. |
| 25886564 | Result | 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. |
| 25144793 | Result | 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. |
| 24550373 | Result | 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. |
| 23385950 | Result | 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. |
| 30768490 | Derived | 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. |
| 28095807 | Derived | 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. |
| Lost to Follow-up |
|
After 24 months of treatment with HAART, half the eligible infants will be randomized to interrupted treatment and followed for 18 months.
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Median | Inter-Quartile Range | months |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| CD4% | Median | Inter-Quartile Range | percent |
|
| Log10 HIV RNA level | Median | Inter-Quartile Range | copies/ml |
|
|
|
|
| Secondary | Morbidity | severe adverse events including death, pneumonia, diarrhea, and other adverse events | Posted | Number | participants | 18 months post-randomization |
|
|
|
|
| 2 |
| 21 |
| 21 |
| 21 |
| EG001 | Interrupted HAART | After 24 months of treatment with HAART, half the eligible infants will be randomized to interrupted treatment and followed for 18 months. | 1 | 21 | 21 | 21 |
| Hepatotoxicity | Hepatobiliary disorders | Systematic Assessment |
|
| Cellulitis | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Pneumonia | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| High cholesterol | Metabolism and nutrition disorders | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
|
| Lymphadenopathy | Blood and lymphatic system disorders | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Anemia | Blood and lymphatic system disorders | Systematic Assessment |
|
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| D012749 | Sexually Transmitted Diseases |
| D016180 | Lentivirus Infections |
| D012192 | Retroviridae Infections |
| D012327 | RNA Virus Infections |
| D014777 | Virus Diseases |
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
| D007153 | Immunologic Deficiency Syndromes |
| D007154 | Immune System Diseases |
| Diarrhea |
|
| Death |
|
| Cox regression Anderson Gill |
| 0.60 |
| 2-Sided |
| Superiority or Other |
| Pneumonia | Regression, Cox | 0.60 | 2-Sided | Superiority or Other |
| Diarrhea | Regression, Cox | 0.77 | 2-Sided | Superiority or Other |
| Death | Log Rank | 0.29 | 2-Sided | Superiority or Other |