HIV Infections
Conditions
Keywords
HIV-1, Pediatric, HAART, Treatment Naive
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))
Interventions
DRUGHAART
Combination first line antiretrovirals as previously described.
Sponsors
Fred Hutchinson Cancer Center
University of Nairobi
National Institutes of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of Washington
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 54 Months
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Growth at 18 Months Post-randomization | 18 months of post-randomization follow-up | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Morbidity | 18 months post-randomization | severe adverse events including death, pneumonia, diarrhea, and other adverse events |
Participant flow
Recruitment details
Infants were identified from Nairobi City Council clinics, the Kenyatta National Hospital (KNH) wards, and the HIV treatment clinic. Recruitment occurred from 2007-2009.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Continued HAART After 24 months of treatment with HAART, half the eligible infants will be randomized to continued treatment with HAART for 18 months. | 21 |
| Interrupted HAART After 24 months of treatment with HAART, half the eligible infants will be randomized to interrupted treatment and followed for 18 months. | 21 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Interrupted HAART | Total | Continued HAART |
|---|---|---|---|
| Age, Categorical <=18 years | 21 Participants | 42 Participants | 21 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 30.0 months | 30.0 months | 29 months |
| CD4% | 34 percent | 33 percent | 33 percent |
| Log10 HIV RNA level | 2.18 copies/ml | 2.18 copies/ml | 2.18 copies/ml |
| Region of Enrollment Kenya | 21 participants | 42 participants | 21 participants |
| Sex: Female, Male Female | 8 Participants | 23 Participants | 15 Participants |
| Sex: Female, Male Male | 13 Participants | 19 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 21 / 21 | 21 / 21 |
| serious Total, serious adverse events | 2 / 21 | 1 / 21 |
Outcome results
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.
Time frame: 18 months of post-randomization follow-up
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Continued HAART | Growth at 18 Months Post-randomization | WAZ (z-score) | -0.57 z-score |
| Continued HAART | Growth at 18 Months Post-randomization | HAZ (z-score) | -1.04 z-score |
| Interrupted HAART | Growth at 18 Months Post-randomization | WAZ (z-score) | -0.17 z-score |
| Interrupted HAART | Growth at 18 Months Post-randomization | HAZ (z-score) | -0.78 z-score |
Comparison: WAZ-score comparison at 18 monthsp-value: 0.15Wilcoxon (Mann-Whitney)
Comparison: HAZ score at 18 monthsp-value: 0.45Wilcoxon (Mann-Whitney)
Secondary
Morbidity
severe adverse events including death, pneumonia, diarrhea, and other adverse events
Time frame: 18 months post-randomization
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Continued HAART | Morbidity | Death | 1 participants |
| Continued HAART | Morbidity | Pneumonia | 4 participants |
| Continued HAART | Morbidity | Severe adverse events | 2 participants |
| Continued HAART | Morbidity | Diarrhea | 7 participants |
| Interrupted HAART | Morbidity | Severe adverse events | 1 participants |
| Interrupted HAART | Morbidity | Death | 0 participants |
| Interrupted HAART | Morbidity | Diarrhea | 12 participants |
| Interrupted HAART | Morbidity | Pneumonia | 3 participants |
Comparison: SAEsp-value: 0.39log rank or Cox regression
Comparison: Pneumoniap-value: 0.6Cox regression Anderson Gill
Comparison: Pneumoniap-value: 0.6Regression, Cox
Comparison: Diarrheap-value: 0.77Regression, Cox
Comparison: Deathp-value: 0.29Log Rank