HIV/AIDS, HIV Infections
Conditions
Brief summary
The investigators hypothesize that switching to a regimen based on efavirenz will be as effective and safe as remaining on a regimen based on Lopinavir/ritonavir for HIV-infected children. The investigators propose an unblinded randomized clinical trial to evaluate a simplification, protease-inhibitor (PI)-sparing treatment strategy among nevirapine (NVP)-exposed HIV-infected children treated initially with lopinavir/ritonavir (LPV/r). HIV-infected children aged 3-5 years, who have a history of exposure to NVP as part of prevention of mother-to-child HIV transmission (PMTCT), initiated LPV/r-based therapy in the first 36 months of life or who were enrolled on the control arm of Neverest 2 and who are virally suppressed with a viral load \< 50 copies/ml will be included. These children will be randomized to either substitute efavirenz (EFV) for LPV/r or to continue on their LPV/r-based regimen. Eight weeks prior to the primary randomization, eligible children will also be randomized to either remain on stavudine (D4T) or switch to abacavir (ABC). Children will be followed with regular viral load and other clinical tests for 48 weeks after the primary randomization. Children in the experimental arm who have breakthrough viremia (-defined as two subsequent viral loads \> 1000 copies/ml) on the EFV-based regimen will reinitiate the LPV/r regimen. The primary objective is to test whether the durability of viral suppression is equivalent when children are switched to EFV-based therapy. The primary study endpoint is failure to have HIV RNA \< 50 copies/ml and/or confirmed viremia \>1000 copies/ml. Secondary aims include comparison of immune preservation, toxicities, selection of resistance mutations, and adherence across the two arms. Antiretroviral drug concentrations and adherence will be investigated as possible explanations for the success and/or failure of this simplification regimen. The overall goal of the study is to contribute to the evidence base to allow expansion of treatment options for HIV-infected children in low resource settings.
Interventions
DRUGEfavirenz (EFV)
Children are assigned to begin a EFV-based antiretroviral based regimen.
Children are assigned to stay on their current LPV/r-based antiretroviral regimen.
DRUGStavudine (D4T)
Children are assigned to stay on their current antiretroviral regimen which includes D4T.
DRUGAbacavir (ABC)
Children stop taking D4T and switch to ABC.
Sponsors
University of Witwatersrand, South Africa
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Columbia University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* HIV-infected child 3 to 5 years of age at time of screening for this trial if enrolled from outside or any age if enrolled from control arm of Neverest II. * Reliable history or documented exposure to NVP used as part of PMTCT * Initiated antiretroviral therapy with LPV/r at age less than 36 months * Receiving LPV/r-based ART for at least 12 months * At least one viral load measurement less than 50 copies/ml conducted as part of screening for the study * ALT measurement grade I or less (DAIDS Toxicity Tables 2004) (Appendix A). These may be repeated until ALTs normalize if necessary.
Exclusion criteria
* Prior treatment with any NNRTI drug as part of a therapeutic regimen * Substitution of other NRTI drugs (instead of 3TC and D4T which are the standard first line regimen) will be allowed.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Viral Rebound | 48 weeks | Probability of viral rebound defined as \>=1 HIV RNA measurements \>50 copies/ml using survival analysis by 48 weeks post-randomization. |
| Viral Failure | 48 weeks | Probability of viral failure defined as \>= 2 HIV RNA measurements \>1000 copies/ml using survival analysis by 48 weeks post-randomization. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CD4 Cell Percentage at 48 Weeks After Randomization | 48 weeks | CD4 Cell Percentage at 48 Weeks After Randomization |
| Percentage of Participants With Elevated Total Cholesterol, Elevated LDL, Abnormal HDL, or Abnormal Triglycerides at 40 Weeks After Randomization | 40 weeks | Percentage of participants with elevated total cholesterol, elevated LDL, abnormal HDL, or abnormal triglycerides at 40 weeks after randomization |
| Highest Grade ALT After Randomization | through 48 weeks post randomization | Highest grade ALT after randomization. Grading was determined based on the Division of AIDS (2004) Toxicity Tables to grade adverse reactions. Grading scale: 0 (none), 1 (mild), 2 (moderate), 3 (severe), 4 (potentially life-threatening). |
Countries
South Africa
Participant flow
Recruitment details
A total of 300 study participants were recruited between June 2010 and October 2012.
Pre-assignment details
Two children discontinued the study prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| Group 1: Lopinavir/Ritonavir (LPV/r) Participants are assigned to remain on their current LPV/r-based antiretroviral regimen. Ritonavir-boosted lopinavir syrup was given twice per day at 230 mg/m\^2 per dose. Children able to swallow tablets were given 1 tablet twice per day (200 mg lopinavir/50 mg ritonavir) if body surface area was less than 0.9m\^2 or 2 tablets twice per day if body surface area was 0.9m\^2 or higher. | 148 |
| Group 2: Efavirenz (EFV) Participants are assigned to switch to an EFV-based antiretroviral regimen. Efavirenz was prescribed once daily in the evening at 200 mg for weights of 10 kg to 13.9 kg (22-30 lb) and 300mg for weights of 14 kg to 24.9 kg (31-55 lb). Efavirenz was available in 50-mg and 200-mg capsules. If children were unable to swallow capsules, caregivers were shown how to open the capsules and dissolve the contents in water. | 150 |
| Total | 298 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Transfer out | 0 | 6 |
Baseline characteristics
| Characteristic | Group 1: Lopinavir/Ritonavir (LPV/r) | Group 2: Efavirenz (EFV) | Total |
|---|---|---|---|
| Age, Continuous | 4.26 years STANDARD_DEVIATION 1 | 4.28 years STANDARD_DEVIATION 0.9 | 4.27 years STANDARD_DEVIATION 0.9 |
| Sex: Female, Male Female | 80 Participants | 78 Participants | 158 Participants |
| Sex: Female, Male Male | 68 Participants | 72 Participants | 140 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 148 | 0 / 150 |
| serious Total, serious adverse events | 0 / 148 | 2 / 150 |
Outcome results
Primary
Viral Failure
Probability of viral failure defined as \>= 2 HIV RNA measurements \>1000 copies/ml using survival analysis by 48 weeks post-randomization.
Time frame: 48 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Group 1: Lopinavir/Ritonavir (LPV/r) | Viral Failure | 0.020 probability of viral failure |
| Group 2: Efavirenz (EFV) | Viral Failure | 0.027 probability of viral failure |
p-value: <0.001Kaplan-Meier methods
Primary
Viral Rebound
Probability of viral rebound defined as \>=1 HIV RNA measurements \>50 copies/ml using survival analysis by 48 weeks post-randomization.
Time frame: 48 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Group 1: Lopinavir/Ritonavir (LPV/r) | Viral Rebound | 0.284 probability of viral rebound |
| Group 2: Efavirenz (EFV) | Viral Rebound | 0.176 probability of viral rebound |
p-value: <0.001Kaplan-Meier methods
Secondary
CD4 Cell Percentage at 48 Weeks After Randomization
CD4 Cell Percentage at 48 Weeks After Randomization
Time frame: 48 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Group 1: Lopinavir/Ritonavir (LPV/r) | CD4 Cell Percentage at 48 Weeks After Randomization | 34.7 percentage of cells |
| Group 2: Efavirenz (EFV) | CD4 Cell Percentage at 48 Weeks After Randomization | 37.5 percentage of cells |
p-value: <0.001t-test, 2 sided
Secondary
Highest Grade ALT After Randomization
Highest grade ALT after randomization. Grading was determined based on the Division of AIDS (2004) Toxicity Tables to grade adverse reactions. Grading scale: 0 (none), 1 (mild), 2 (moderate), 3 (severe), 4 (potentially life-threatening).
Time frame: through 48 weeks post randomization
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1: Lopinavir/Ritonavir (LPV/r) | Highest Grade ALT After Randomization | Grade 1 | 8 number of participants |
| Group 1: Lopinavir/Ritonavir (LPV/r) | Highest Grade ALT After Randomization | Grade 3 | 1 number of participants |
| Group 1: Lopinavir/Ritonavir (LPV/r) | Highest Grade ALT After Randomization | Grade 2 | 0 number of participants |
| Group 1: Lopinavir/Ritonavir (LPV/r) | Highest Grade ALT After Randomization | Grade 4 | 0 number of participants |
| Group 1: Lopinavir/Ritonavir (LPV/r) | Highest Grade ALT After Randomization | Grade 0 | 139 number of participants |
| Group 2: Efavirenz (EFV) | Highest Grade ALT After Randomization | Grade 4 | 1 number of participants |
| Group 2: Efavirenz (EFV) | Highest Grade ALT After Randomization | Grade 0 | 120 number of participants |
| Group 2: Efavirenz (EFV) | Highest Grade ALT After Randomization | Grade 1 | 16 number of participants |
| Group 2: Efavirenz (EFV) | Highest Grade ALT After Randomization | Grade 2 | 10 number of participants |
| Group 2: Efavirenz (EFV) | Highest Grade ALT After Randomization | Grade 3 | 3 number of participants |
p-value: 0.003Chi-squared
Secondary
Percentage of Participants With Elevated Total Cholesterol, Elevated LDL, Abnormal HDL, or Abnormal Triglycerides at 40 Weeks After Randomization
Percentage of participants with elevated total cholesterol, elevated LDL, abnormal HDL, or abnormal triglycerides at 40 weeks after randomization
Time frame: 40 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1: Lopinavir/Ritonavir (LPV/r) | Percentage of Participants With Elevated Total Cholesterol, Elevated LDL, Abnormal HDL, or Abnormal Triglycerides at 40 Weeks After Randomization | Elevated total cholesterol | 24.8 percentage of participants |
| Group 1: Lopinavir/Ritonavir (LPV/r) | Percentage of Participants With Elevated Total Cholesterol, Elevated LDL, Abnormal HDL, or Abnormal Triglycerides at 40 Weeks After Randomization | Abnormal HDL | 4.8 percentage of participants |
| Group 1: Lopinavir/Ritonavir (LPV/r) | Percentage of Participants With Elevated Total Cholesterol, Elevated LDL, Abnormal HDL, or Abnormal Triglycerides at 40 Weeks After Randomization | Elevated LDL | 18.6 percentage of participants |
| Group 1: Lopinavir/Ritonavir (LPV/r) | Percentage of Participants With Elevated Total Cholesterol, Elevated LDL, Abnormal HDL, or Abnormal Triglycerides at 40 Weeks After Randomization | Abnormal triglycerides | 22.8 percentage of participants |
| Group 2: Efavirenz (EFV) | Percentage of Participants With Elevated Total Cholesterol, Elevated LDL, Abnormal HDL, or Abnormal Triglycerides at 40 Weeks After Randomization | Elevated LDL | 9.8 percentage of participants |
| Group 2: Efavirenz (EFV) | Percentage of Participants With Elevated Total Cholesterol, Elevated LDL, Abnormal HDL, or Abnormal Triglycerides at 40 Weeks After Randomization | Elevated total cholesterol | 13.3 percentage of participants |
| Group 2: Efavirenz (EFV) | Percentage of Participants With Elevated Total Cholesterol, Elevated LDL, Abnormal HDL, or Abnormal Triglycerides at 40 Weeks After Randomization | Abnormal triglycerides | 10.5 percentage of participants |
| Group 2: Efavirenz (EFV) | Percentage of Participants With Elevated Total Cholesterol, Elevated LDL, Abnormal HDL, or Abnormal Triglycerides at 40 Weeks After Randomization | Abnormal HDL | 4.2 percentage of participants |