Human Immunodeficiency Virus, Immune Reconstitution Inflammatory Syndrome
Conditions
Keywords
HIV-1, IRIS
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.
Interventions
OTHERUrgent ART
Children will be started on HAART \<48 hours after enrollment.
OTHEREarly ART
Children will be started on ART after stabilization 7-14 days after enrollment.
Sponsors
University of Nairobi
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 12 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| All-cause Mortality | 6 months post-HAART initiation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Evidence of Immune Reconstitution and Inflammatory Syndrome (IRIS) | 6 months post-HAART initiation | Confirmed, possible or likely IRIS based on external independent review |
| Number of Participants With Potential Drug Toxicity | 6 months post-HAART initiation | Participants with adverse events that are deemed to be potentially related to medications. |
Countries
Kenya
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
Urgent ART: Children will be started on HAART \<48 hours after enrollment. | 90 |
| Early ART Initiation of HAART 7-14 days after enrollment.
Early ART: Children will be started on ART after stabilization 7-14 days after enrollment. | 91 |
| Total | 181 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 21 | 18 |
| Overall Study | Ineligible | 0 | 2 |
| Overall Study | Lost to Follow-up | 7 | 7 |
Baseline characteristics
| Characteristic | Urgent ART | Early ART | Total |
|---|---|---|---|
| Age, Continuous | 2 Years | 1.8 Years | 1.9 Years |
| CD4% | 12.5 % | 17 % | 14.5 % |
| Region of Enrollment Kenya | 90 participants | 91 participants | 181 participants |
| Sex: Female, Male Female | 40 Participants | 41 Participants | 81 Participants |
| Sex: Female, Male Male | 50 Participants | 50 Participants | 100 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 21 / 90 | 18 / 91 |
| other Total, other adverse events | 10 / 90 | 12 / 91 |
| serious Total, serious adverse events | 34 / 90 | 40 / 91 |
Outcome results
Primary
All-cause Mortality
Time frame: 6 months post-HAART initiation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Urgent ART | All-cause Mortality | 21 participants |
| Early ART | All-cause Mortality | 18 participants |
Secondary
Number of Participants With Evidence of Immune Reconstitution and Inflammatory Syndrome (IRIS)
Confirmed, possible or likely IRIS based on external independent review
Time frame: 6 months post-HAART initiation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Urgent ART | Number of Participants With Evidence of Immune Reconstitution and Inflammatory Syndrome (IRIS) | 10 participants |
| Early ART | Number of Participants With Evidence of Immune Reconstitution and Inflammatory Syndrome (IRIS) | 12 participants |
Secondary
Number of Participants With Potential Drug Toxicity
Participants with adverse events that are deemed to be potentially related to medications.
Time frame: 6 months post-HAART initiation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Urgent ART | Number of Participants With Potential Drug Toxicity | 23 participants |
| Early ART | Number of Participants With Potential Drug Toxicity | 15 participants |