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Treatment Options for Protease Inhibitor-exposed Children (NEVEREST-III)

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ClinicalTrials.gov Identifier: NCT01146873
Recruitment Status : Completed
First Posted : June 22, 2010
Results First Posted : May 4, 2016
Last Update Posted : March 13, 2017
Information provided by (Responsible Party):

Study Description
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.

Condition or disease Intervention/treatment Phase
HIV/AIDS HIV Infections Drug: Efavirenz (EFV) Drug: Lopinavir/ritonavir (LPV/r) Drug: Stavudine (D4T) Drug: Abacavir (ABC) Phase 3

Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 300 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Treatment Options for Protease Inhibitor-exposed Children
Study Start Date : July 2010
Primary Completion Date : December 2014
Study Completion Date : December 2014

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS
U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Active Comparator: 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.
Drug: Lopinavir/ritonavir (LPV/r)
Children are assigned to stay on their current LPV/r-based antiretroviral regimen.
Experimental: 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.
Drug: Efavirenz (EFV)
Children are assigned to begin a EFV-based antiretroviral based regimen.
Active Comparator: Group D: Stavudine (D4T)
Children are assigned to remain on their current antiretroviral regimen, which includes D4T. D4T was given at 1 mg/kg twice daily
Drug: Stavudine (D4T)
Children are assigned to stay on their current antiretroviral regimen which includes D4T.
Experimental: Group A: Abacavir (ABC)
Children stop taking D4T and switch to ABC. ABC was given at 8 mg/kg twice daily.
Drug: Abacavir (ABC)
Children stop taking D4T and switch to ABC.

Outcome Measures

Primary Outcome Measures :
  1. Viral Rebound [ Time Frame: 48 weeks ]
    Probability of viral rebound defined as >=1 HIV RNA measurements >50 copies/ml using survival analysis by 48 weeks post-randomization.

  2. Viral Failure [ Time Frame: 48 weeks ]
    Probability of viral failure defined as >= 2 HIV RNA measurements >1000 copies/ml using survival analysis by 48 weeks post-randomization.

Secondary Outcome Measures :
  1. CD4 Cell Percentage at 48 Weeks After Randomization [ Time Frame: 48 weeks ]
    CD4 Cell Percentage at 48 Weeks After Randomization

  2. Percentage of Participants With Elevated Total Cholesterol, Elevated LDL, Abnormal HDL, or Abnormal Triglycerides at 40 Weeks After Randomization [ Time Frame: 40 weeks ]
    Percentage of participants with elevated total cholesterol, elevated LDL, abnormal HDL, or abnormal triglycerides at 40 weeks after randomization

  3. Highest Grade ALT After Randomization [ Time Frame: 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).

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   3 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01146873

South Africa
Rahima Moosa Mother and Child Hospital
Johannesburg, Gauteng, South Africa
Sponsors and Collaborators
Columbia University
University of Witwatersrand, South Africa
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Principal Investigator: Louise Kuhn, PhD Columbia University
More Information

Responsible Party: Louise Kuhn, Professor, Columbia University
ClinicalTrials.gov Identifier: NCT01146873     History of Changes
Other Study ID Numbers: AAAE1145
R01HD061255 ( U.S. NIH Grant/Contract )
First Posted: June 22, 2010    Key Record Dates
Results First Posted: May 4, 2016
Last Update Posted: March 13, 2017
Last Verified: January 2017

Additional relevant MeSH terms:
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Cytochrome P-450 CYP2C9 Inhibitors
Cytochrome P-450 CYP2C19 Inhibitors
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers