Treatment Options for Protease Inhibitor-exposed Children (NEVEREST-III)
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
HIV/AIDS HIV Infections |
Drug: Efavirenz Drug: Lopinavir/ritonavir (LPV/r) Drug: D4T Drug: Abacavir (ABC) |
Phase 3 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Factorial Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Treatment Options for Protease Inhibitor-exposed Children |
- Maintenance of viral suppression [ Time Frame: through 24 and 48 weeks post randomization ] [ Designated as safety issue: No ]HIV RNA quantity < 50 copies/ml
- Confirmed viral rebound [ Time Frame: through 24 weeks and 48 weeks post randomization ] [ Designated as safety issue: Yes ]HIV RNA > 1000 copies/ml twice
- Magnitude of CD4 response, hospital admissions, new stage II or greater clinical conditions [ Time Frame: through 48 weeks ] [ Designated as safety issue: No ]
- ALT elevations, HDL, LDL, CRP, fat distribution [ Time Frame: through 48 weeks ] [ Designated as safety issue: No ]
Drug related toxicities, Including fat distribution and metabolic parameters
Including when co-treated for tuberculosis
- child Adherence to medication [ Time Frame: through 48 weeks ] [ Designated as safety issue: No ]assessed by pharmacy reconciliation of medications brought back
| Estimated Enrollment: | 400 |
| Study Start Date: | June 2010 |
| Estimated Study Completion Date: | December 2014 |
| Estimated Primary Completion Date: | December 2014 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Active Comparator: Group 1: Lopinavir/ritonavir (LPV/r)
Participants are assigned to remain on their current LPV/r-based antiretroviral regimen
|
Drug: Lopinavir/ritonavir (LPV/r)
Children are assigned to stay on their current LPV/r-based antiretroviral regimen.Dosing of medication will follow standard guidelines based on body surface area calculations or on body weight depending on drug, and will be in accordance with the South African Treatment guidelines.
Other Names:
|
|
Experimental: Group 2: Efavirenz (EFV)
Participants are assigned to switch to an EFV-based antiretroviral regimen
|
Drug: Efavirenz
Children are assigned to begin a EFV-based antiretroviral based regimen. Dosing of medication will follow standard guidelines based on body surface area calculations or on body weight depending on drug, and will be in accordance with the South African Treatment guidelines.
Other Names:
|
|
Active Comparator: Group D: D4T
Children are assigned to remain on their current antiretroviral regimen, which includes D4T
|
Drug: D4T
Children are assigned to stay on their current antiretroviral regimen which includes D4T. Dosing of medication will follow standard guidelines based on body surface area calculations or on body weight depending on drug, and will be in accordance with the South African Treatment guidelines.
Other Names:
|
|
Experimental: Group A: Abacavir (ABC)
Children stop taking D4T and switch to ABC.
|
Drug: Abacavir (ABC)
Children stop taking D4T and switch to an abacavir. Dosing of medication will follow standard guidelines based on body surface area calculations or on body weight depending on drug, and will be in accordance with the South African Treatment guidelines.
Other Names:
|
Eligibility| Ages Eligible for Study: | 3 Years and older |
| Genders Eligible for Study: | Both |
| Accepts 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.
Contacts and Locations| South Africa | |
| Rahima Moosa Mother and Child Hospital | |
| Johannesburg, Gauteng, South Africa | |
| Principal Investigator: | Louise Kuhn, PhD | Columbia University |
More Information
No publications provided
| Responsible Party: | Louise Kuhn, Professor, Columbia University |
| ClinicalTrials.gov Identifier: | NCT01146873 History of Changes |
| Other Study ID Numbers: | AAAE1145 |
| Study First Received: | June 8, 2010 |
| Last Updated: | November 18, 2012 |
| Health Authority: | United States: Institutional Review Board United States: Federal Government South Africa: Human Research Ethics Committee South Africa: Medicines Control Council |
Additional relevant MeSH terms:
|
HIV Infections Acquired Immunodeficiency Syndrome Lentivirus Infections Retroviridae Infections RNA Virus Infections Virus Diseases Sexually Transmitted Diseases, Viral Sexually Transmitted Diseases Immunologic Deficiency Syndromes Immune System Diseases Slow Virus Diseases Protease Inhibitors Ritonavir Lopinavir Stavudine |
Efavirenz Abacavir Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Pharmacologic Actions Antimetabolites Reverse Transcriptase Inhibitors Nucleic Acid Synthesis Inhibitors Anti-Retroviral Agents Antiviral Agents Anti-Infective Agents Therapeutic Uses Anti-HIV Agents HIV Protease Inhibitors |
ClinicalTrials.gov processed this record on March 03, 2013
